OverviewWhats a migraine? What does it feel like?

A migraine is more than a bad headache. Its a neurologic disease with a series of symptoms that might include debilitating pain on one side of your head that you may describe as pulsing or throbbing. Menstrual migraines, also known as hormone headaches, happen right before or during a womans period (up to two days before through three days during) and may get worse with movement, light, smells, or sound. Your symptoms may last for a few hours, but theyll likely last days.

Its estimated that 70% of people who experience migraines are women. Of these women, 60% to 70% report a connection between their menstruation (periods) and their migraine attacks. Women experience migraine attacks three times more frequently than men.

A menstrual migraine is one of several types of migraine headaches. Examples of other migraines include migraine with aura, migraine without aura and chronic migraine.

Hormones are often called your bodys chemical messengers. Theyre in your organs, tissues and bloodstream and theyre made by the endocrine glands. Examples of endocrine glands include your thyroid gland, adrenal glands and pituitary gland. If you have too little of a certain hormone, or too much, that can throw your entire system off balance.

Estrogen and progesterone are the two main sex hormones in women. Estrogen causes female physical features, sets off puberty and aids with reproduction. It also affects your cholesterol, controls your menstrual cycle, protects bone health and affects your heart, skin, bones, brain and other tissues. Its mostly produced by your ovaries.

Your levels of estrogen change. Theyre at the highest amount in the middle of your cycle and the lowest amount when youre on your period. When youre in menopause, they drop very low.

Headaches in women, especially migraines, are related to changes in the levels of estrogen. Levels of estrogen drop immediately before the start of your menstrual flow (menses).

Premenstrual migraines regularly occur during or after the time when the female hormones, estrogen and progesterone, drop to their lowest levels.

Migraine attacks usually improve during pregnancy. However, some women have reported that their migraines started during the first trimester of pregnancy, and then went away.

Menstrual migraines are triggered by a drop in estrogen. Other migraines may be triggered by stress, missing a meal, caffeine, or many other reasons.

About 12% of Americans experience migraines. The majority are women, at least 60% of those women have observed a correlation between their menstrual cycle and their migraines. In other words, theyve noticed that they get a migraine right before or during their period.

Menstrual migraines can start up to three days before your period.

While migraines can start when youre a child, menstrual migraines dont until your periods begin. Women who have periods are the ones who get menstrual migraines.

Changes in estrogen levels, which happen right before your period begins.

In addition to a drop in estrogen, birth control pills and hormone replacement therapy for menopause can change the frequency or severity of migraines. If you notice your migraine headache getting worse after starting one of these medications, it may be worthwhile to ask your healthcare provider for a medication that contains a lower dose of estrogen, or ask for a change from an interrupted dosing regimen to a continuous one.

The symptoms of a menstrual migraine are the same as the symptoms for other types of migraines:

Your healthcare provider will want to establish a history of your migraine-related symptoms, likely asking you to:

Your healthcare provider may also order blood tests and imaging tests (such as a CT scan or MRI) to make sure there are no other causes for your headache. An electroencephalogram (EEG) may be ordered to rule out seizures.

Its helpful to both you and your healthcare provider if you keep a migraine journal. Take note of what symptoms you get, how long your symptoms last, and what makes your menstrual migraine better or worse. You and your healthcare provider may be able to use that information to help you heal, and possibly prevent or anticipate your migraine.

A menstrual migraine is usually treated with nonsteroidal anti-inflammatory medications (NSAIDs). The NSAIDs most often used for menstrual migraine include:

Treatment with the NSAID should begin two to three days before your period starts, and continue through your menstrual flow. Because the medication is taken for a short time only, the risk of gastrointestinal side effects is limited.

Triptans selective serotonin receptor agonists are medicines used for acute migraines. They stop your menstrual migraine after it begins. In the United States there are seven triptan medications approved for use:

Other medications that might be prescribed include:

These drugs should also be started two to three days before your period starts. Continue taking them throughout your menstrual flow.

Because fluid retention (retaining water) often occurs at the same time as your menses, diuretics have been used to prevent menstrual migraines. Some healthcare providers may recommend that you follow a low-salt diet immediately before the start of your menses.

Leuprolide (Lupron) is a medication that affects your hormone levels. Its used only when all other treatment methods have been tried and havent worked.

Talk with your healthcare provider and pharmacist about the side effects of each medication prescribed. The most common side effects of medications prescribed to fight migraines include:

Ask your primary healthcare provider to refer you to a headache specialist.

If you need to continue estrogen supplements after menopause, you should start on the lowest dose of these agents, on an uninterrupted basis. Instead of seven days off the drug, you may be told to take it every day. By maintaining a steady dose of estrogen, the headaches may be prevented. An estrogen patch (such as Estraderm) may be effective in stabilizing the levels of estrogen.

Because most medications taken for migraines can affect your baby, you should avoid them. However, your healthcare provider may give you permission to take a mild pain reliever like acetaminophen. Talk to your healthcare provider before you take any medicine.

Do your best to figure out what makes your hormone headaches better or worse. For example, if light causes pain and you feel overheated, stay in a cool, dark room. Additional tips include:

Your healthcare provider may prescribe preventative medications that you take daily, then increase the dose when youre near your period. Possibilities include:

No type of migraine causes brain damage.

You may have menstrual migraines until youre in menopause.

Schedule a visit with your healthcare provider if:

Call 911 or go immediately to an Emergency Room if:

A note from Cleveland Clinic

A migraine is more than a bad headache. Not only can menstrual migraines get severe, but women have reported that they can be even worse than a migraine that occurs when theyre not on their period. Talk to your healthcare provider about your symptoms. There are preventative measures and treatment options. A menstrual migraine might not be something you just have to live with every month.

Read more from the original source:
Menstrual Migraines (Hormone Headaches) - Cleveland Clinic

Recommendation and review posted by Bethany Smith

OverviewWhat is acromegaly?

Acromegaly (pronounced a-krow-meh-guh-lee) is a rare but serious medical condition that happens when you have high levels of growth hormone (GH) in your body. Your pituitary gland normally produces GH, but tumors on your pituitary or in other parts of your body produce excess GH in acromegaly.

Your pituitary gland is a small, pea-sized endocrine gland located at the base of your brain below your hypothalamus. Your pituitary gland releases eight important hormones, including GH.

Growth hormone, also known as human growth hormone (hGH) and somatotropin, is a natural hormone that acts on many parts of the body to promote growth in children. Once the growth plates (epiphyses) in your bones have fused, GH no longer increases height, but your body still needs GH. After youve finished growing, GH helps to maintain normal bone, cartilage and organ structure and metabolism, including helping to keep your blood glucose (sugar) levels within a healthy range.

If you have too much GH in your body as an adult, it can result in irregularly-shaped bones, increased organ size, elevated blood sugar levels (hyperglycemia) and other symptoms.

Acromegaly and gigantism are both conditions that result from excess growth hormone (GH). The difference is in who the conditions affect adults develop acromegaly, whereas children develop gigantism.

In children, gigantism occurs when they experience excess GH before the growth plates in their bones fuse (before the end of puberty). This causes them to grow very tall. Gigantism is more rare than acromegaly. Some healthcare providers refer to gigantism as pediatric acromegaly.

Once your growth plates have fused, excess GH causes acromegaly. In this case, you dont grow in height, but the excess GH affects your bones shape and your organ size as well as other health factors.

Acromegaly can develop at any age after puberty, but healthcare providers most often diagnose it during the fourth and fifth decades of life (middle age).

Acromegaly is rare. Approximately 3 to 14 of every 100,000 people have been diagnosed with acromegaly.

In adults, acromegaly (excess growth hormone) causes bones, cartilage, body organs and other tissues to increase in size. Characteristic changes in appearance include larger hands, feet, ears, lips and nose and a more prominent jaw and forehead.

Growth hormone (GH) signals your liver to produce another hormone called insulin-like growth factor 1 (IGF-1). IGF-1 is the hormone that actually causes your bones and body tissue to grow and also affects how your body processes blood glucose (sugar) and lipids (fats). High levels of GH result in high levels of IFG-1, which can lead to Type 2 diabetes, high blood pressure (hypertension) and heart disease.

The most common cause of acromegaly is a tumor in your pituitary gland called a pituitary adenoma that causes your pituitary gland to release excess growth hormone (GH).

Pituitary adenomas (tumors) are almost always benign (noncancerous). Most adenomas that cause acromegaly grow slowly, and you may not notice symptoms of excess GH for many years.

Depending on its size and location, the adenoma may press against other pituitary tissue and affect other hormones your pituitary gland makes. If the adenoma is large, it may also press against nearby parts of your brain, causing headaches and vision problems.

In adults, acromegaly affects your bodys bones and tissues and causes them to grow in irregular ways.

Adults with acromegaly may experience the following symptoms:

Other symptoms include:

Acromegaly symptoms often start slowly and may be difficult to notice at first. Some people only notice their hands have grown in size when rings they regularly wear feel tight or their shoe size changes, especially the width.

If youre experiencing these symptoms, its important to talk to your healthcare provider.

Symptoms of acromegaly often show up very slowly over many years. This makes it hard to diagnose.

Your healthcare provider may recommend you see an endocrinologist, a healthcare provider who specializes in hormone-related conditions. They'll make a diagnosis based on your medical history, a thorough clinical evaluation and specialized tests like blood tests and imaging tests.

If youve been diagnosed with acromegaly, your provider may order additional tests to see if the condition has affected other parts of your body. These tests may include:

There are several treatment options for acromegaly. Your healthcare provider will consider your symptoms and circumstances before offering treatment options that are right for you.

The most common treatments for acromegaly are surgery, medication and radiation therapy.

In many cases, surgery greatly improves acromegaly symptoms or corrects the condition entirely. Surgeons most often use a type of surgery called transsphenoidal surgery, which involves going through your nose and sphenoid sinus, a hollow space in your skull behind the nasal passages and below your brain, to perform surgery.

The specifics of the surgery will depend on the size and location of the tumor. The goal of surgery is to remove all of a tumor that is causing excess growth hormone production. If your surgeon removes enough of the tumor, you may not need further treatment. If your surgeon can remove only a part of a tumor, you may need medication or radiation therapy to manage your symptoms and reduce the production of growth hormone.

Your healthcare provider may prescribe one medication or a combination of medications. Medications work in different ways to normalize your bodys growth hormone levels and improve your symptoms. In some cases, a person may take medication until the tumor has shrunk. This can allow a surgeon to then safely remove it. Other people may need to take medication long-term to effectively manage growth hormone levels and symptoms.

Acromegaly is curable in some situations but not all. The cure rate for surgical removal of a pituitary tumor thats causing acromegaly is about 85% for small tumors and 40% to 50% percent for large tumors.

Medication cant cure acromegaly but offers long-term, safe treatment.

Unfortunately, theres nothing you can do to prevent acromegaly. Scientists arent sure what causes pituitary tumors that cause acromegaly to develop, though they think certain genetic factors may play a role.

The prognosis (outlook) for acromegaly depends on how severe it is and how effectively therapies treat the symptoms. Many people with acromegaly see a significant improvement in symptoms after treatment.

If its not treated, acromegaly can significantly change your appearance and the shape of your bones. These symptoms can greatly affect your self-image and quality of life. Support groups help some people cope with the challenges they face because of acromegaly.

Health complications of acromegaly such as heart disease or Type 2 diabetes can also decrease quality of life and even shorten your lifespan. Because of this, its important to contact your healthcare provider if youre experiencing symptoms and to adhere to your treatment plan if youve been diagnosed.

If left untreated, acromegaly can cause the following complications:

Life expectancy for someone with acromegaly depends on the severity of the condition and if they have other health conditions, usually due to untreated acromegaly.

If your growth hormone levels arent properly managed and you have other conditions like heart disease and Type 2 diabetes, your life expectancy may reduce by approximately 10 years.

If you have acromegaly thats properly treated and have normal growth hormone and insulin-like growth factor 1 (IGF-1) levels, youll likely have a normal life expectancy.

If youre experiencing symptoms of acromegaly, its important to talk to your healthcare provider.

If youve been diagnosed with acromegaly, youll need to see your provider regularly to make sure your treatment is working well.

A note from Cleveland Clinic

Acromegaly is a rare but serious condition. The good news is that its treatable with surgery, medication and/or radiation therapy. If youve noticed an increase in size in your hands, feet and/or facial features, its important to talk to your healthcare provider. They can order some simple tests to see if your growth hormone levels are the cause of your symptoms.

See original here:
Acromegaly: What It Is, Causes, Symptoms & Treatment - Cleveland Clinic

Recommendation and review posted by Bethany Smith

It is sometimes called frozen shoulder, even menopause shoulder.

Doctors say the condition, known as adhesive capsulitis, causes stiffness and pain in the shoulder joint. Little is definitively known about the cause.

The ailment more commonly occurs in women over the age of 40. Having diabetes, thyroid disease, heart disease, or Parkinsons disease can also put you at higher risk.

In a new study, researchers decided to hone in on the demographic most affected by adhesive capsulitis menopausal women.

The Duke University team conducted the first known study evaluating whether hormone therapy might reduce the risk of adhesive capsulitis in menopausal women.

The team evaluated medical records from a single institution for nearly 2,000 menopausal women ages 45 to 60. In the group, 152 of the women were receiving hormone replacement therapy (HRT).

While acknowledging the small sample size, the researchers concluded that those not receiving hormone replacement therapy had 99% greater odds of adhesive capsulitis compared to those receiving HRT.

The findings are being presented this week at the North American Menopause Society annual meeting in Atlanta, Georgia. The results have not been published yet in a peer-reviewed journal.

Dr. Anne Cunanan Ford, NCMP, an associate professor of obstetrics and gynecology at the Duke University Medical Center in North Carolina, is the studys lead author.

Our study draws attention to estrogens potential benefit apart from the FDA (Food and Drug Administration) approved indications vasomotor symptoms, bone protection, and vulvovaginal atrophy, she told Healthline.

We know that estrogen plays an important role in the musculoskeletal system, stimulating new bone formation, promoting muscle growth and repair, maintaining connective tissue integrity, and reducing inflammation Ford explained.

If borne out by future prospective studies, the use of systemic hormone therapy may be protective in minimizing adhesive capsulitis she added. Its a condition that causes significant pain, reduction in range of motion, and decreased quality of life in peri and post-menopausal women.

Experts who spoke to Healthline agreed that there needs to be more research.

This pilot study provides preliminary data that will guide future studies further investigating a potential link between menopause and hormone therapy use or non-use, and risk of adhesive capsulitis, said Dr. Stephanie Faubion, the director of the Mayo Clinics Center for Womens Health in Minnesota and Medical Director of the North American Menopause Society.

No conclusions can be made based on these data, she told Healthline.

Its a small study so something like this has to be looked at in bigger numbers, added Dr. G. Thomas Ruiz, the lead OB-GYN at MemorialCare Orange Coast Medical Center in California.

I think its an interesting study in that we know that estrogen receptors are found throughout a womans body, he told Healthline. So its not surprising that there would also be an interaction between joint function ligaments and tendons with estrogen.

So the menopausal state in the absence of estrogen is probably going to change he added. We know with bone, for example, in the absence of estrogen, women will start to lose calcium at a more rapid rate. That puts them at risk of osteoporosis and osteopenia, at an increased risk for hip fractures. So looking at this study I dont necessarily find it too surprising but its also too small a number to make a definitive statement.

Going forward, Ford said: Our data is preliminary and due to the small sample size, this association did not reach statistical significance. Larger prospective studies are needed to evaluate and confirm our findings.

Would hormone therapy work to treat adhesive capsulitis?

We have no idea. There is no data. Hormone therapy does appear to be associated with less joint pain. But the mechanism behind this effect is unknown Faubion said.

Hormone therapy is effective for management of hot flashes, night sweats, sleep disturbance associated with menopause, prevention of osteoporosis, fractures and the treatment of genitourinary syndrome of menopause she explained. It also appears to help with depressive symptoms in the menopause transition.

The benefits of hormone therapy typically outweigh the risks for symptomatic women who are under the age of 60 and within 10 years of the onset of menopause, she added.

Still, many women have questions about the safety of hormone treatment because of previous studies linking some forms of hormone treatment to an increased breast cancer risk.

The American Cancer Society states that estrogen-only HRT is not linked to a higher risk of breast cancer. The Womens Health Initiative studies also found no increase in breast cancer risk in women using systemic estrogen-only HRT.

But organization officials note that in women who have a uterus, using systemic estrogen-only HRT has been shown to increase the risk of endometrial cancer.

Other studies have found a link between systemic estrogen-only HRT and a higher risk of ovarian cancer.

Ruiz says theres an increase in the use of bioidentical hormones that replicate those your body produces and methods of delivering the hormones that bypass the liver.

Keep in mind the medications that were used Premarin and Provera were taken orally and metabolized through the liver, he said. Physiologically that causes a lot of activity in the breast tissue.

Bioidentical hormones are more like your ovaries made thats the definition he added. Then the estrogen can even be given in cream or patch thats absorbed directly So these medications are not metabolized in the liver to make them active.

Ruiz says hormone replacement doses are much lower now and that perhaps new studies need to be done.

Read more from the original source:
Hormone Therapy and Shoulder Pain During Menopause - Healthline

Recommendation and review posted by Bethany Smith

October is recognized as Breast Cancer Awareness Month. During this time, health care systems and organizations aim to provide education, resources, support and prevention information regarding the disease.

The American Cancer Society (ACS), offers these statistics about breast cancer:

Early detection is important because there are more treatment options available and a better chance of survival when breast cancer is caught early, said Charissa Williams, APN, a ThedaCare Hematology & Oncology Specialist. Studies show theres a more than 90% survival rate, if the tumor is caught early.

Regular self-breast exams are one way to detect a cancerous tumor. A breast cancer screening is another way. Mammograms can spot tiny tumors, making it more likely to catch the disease at an earlier stage.

For most women, screening mammography is a safe and effective way to detect breast cancer early, Williams added.

Medical organizations vary on the best age to start screening mammograms (some say as early as age 40) and how often to repeat them. The Centers for Disease Control and Prevention (CDC) has a comparative chart, Breast Cancer Screening Guidelines for Women, to better sort out the timing and frequency of mammogram screening based on your particular situation.

It is important to discuss your individual screening guidelines with your primary care provider, said Williams. For example, those who have a strong family history or certain genetic mutations (BRCA1 or BRCA2) often have earlier screening guidelines than the general population.

Women might also help minimize their chances of developing the disease by modifying their lifestyle. However, Williams notes there are some risks factors that cannot be changed: your age, family history, genetics, race, and being a woman.

There are several modifiable factors that can increase your breast cancer risk, including obesity, poor diet, lack of physical activity, alcohol and tobacco use, and certain types of hormone replacement therapy, she said.

To reduce your risk of breast cancer, Williams suggests you form these habits:

There are more than 3.8 million breast cancer survivors in the United States.

For more information on breast cancer prevention tips, screenings and treatments, visit thedacare.org/breast-cancer.

About ThedaCare

For more than 110 years, ThedaCare has been committed to improving the health and well-being of the communities it serves in Northeast and Central Wisconsin. The organization delivers care to more than 600,000 residents in 17 counties and employs approximately 7,000 health care professionals. ThedaCare has 180 points of care, including eight hospitals. As an organization committed to being a leader in Population Health, team members are dedicated to empowering people to live their unique, best lives. ThedaCare also partners with communities to understand needs, finding solutions together, and encouraging health awareness and action. ThedaCare is the first in Wisconsin to be a Mayo Clinic Care Network Member, giving specialists the ability to consult with Mayo Clinic experts on a patients care. ThedaCare is a not-for-profit health system with a level II trauma center, comprehensive cancer treatment, stroke and cardiac programs, as well as primary care.

For more information, visit thedacare.org or follow ThedaCare on social media. Members of the media should call Cassandra Wallace, Public and Media Relations Consultant at 920.442.0328 or the ThedaCare Regional Medical Center-Neenah switchboard at 920.729.3100and ask for the marketing person on call.

Related

Read the original here:
Helping Reduce Your Risk of Breast Cancer ThedaCare - ThedaCare

Recommendation and review posted by Bethany Smith

CARBONDALE (WSIL) -- A reproductive health clinic that will also provide abortion serves has opened in Carbondale.

TheCHOICES: Memphis Center for Reproductive Health announced they would open a clinic in southern Illinois after learning the Supreme Court would overrule Roe v. Wade. Tennessee has now banned abortion services.

The CHOICES clinic is located on Giant City Road and is now accepting appointments for medication abortions. They started seeing their first patients Tuesday.

The clinic will be the southernmost abortion clinic for most people across the southeast, according to a release.

Eventually, the clinic will also offer gender-affirming hormone therapy, procedural abortions, birth control, sexual wellness and more.

The Memphis location is still open, they just will no longer provide abortion services. They will still provide reproductive and sexual health care.

More coverage:

Read the original:
CHOICES Reproductive Health clinic now open in Carbondale - WSIL TV

Recommendation and review posted by Bethany Smith

Its not all bad news for the province, however, as it received the fewest reports of stock-outs by public healthcare users. Photo: Reuters

NEWS

Every three months, Vuyo* has to travel for about four hours from Matatiele in the Eastern Cape to Durban in KwaZulu-Natal to get her antiretroviral (ARV) treatment.

She has been featured in the second edition of the Eastern Cape State of Health report by Ritshidze, a community-led monitoring system developed by organisations representing people living with HIV.

The organisations include the Treatment Action Campaign, the National Association of People Living with HIV, the Positive Action Campaign, the Positive Womens Network, and the SA Network of Religious Leaders Living with and affected by HIV/Aids.

The Ritshidze data, which was launched on Thursday, reveal improvements at Eastern Cape clinics, but patients still complained about poor treatment at healthcare facilities, which saw them missing their appointments and even stopping their clinic visits.

READ: Intimate partner violence impedes ARV treatment adherence among adolescents - study

Vuyo tested positive for HIV two years ago and was getting her treatment from Matatiele Community Clinic.

On this day, I was in pain and decided to go to the clinic. I told the nurse my problem and she started shouting that I was being careless with my life for not using a condom. She called other nurses and they started talking about me as if I was not there. That day was so embarrassing, and I was hating myself so much. I even thought of dying, and thats when I decided to quit the clinic, she said.

For some time after that incident, Vuyo defaulted on her medication because, when she went to other clinics, she was referred back to Matatiele.

She said:

I then decided to go and get my medication in Durban, as my sister works there. It is working better for me like that, and they give me medication for three months. I dont have problems with the medication and I dont default.

No privacy

Ritshidze data show that 55% of the people interviewed thought that clinic staff were always friendly and professional in the Eastern Cape. This is down from 63% last year.

This poor treatment is off-putting enough for people to miss appointments or even stop going to the clinic altogether. Some report being terrified at what awaits them, read the report.

Some people complained that clinic staff members disclose the status of patients living with HIV in waiting areas.

There were also reports of two or more patients consulted with or counselled in the same room, and people living with HIV separated from other chronic patients.

According to the report for key populations, clinic visits can be traumatic, and staff can be unfriendly and even openly hostile.

Many people we spoke to had given up on healthcare altogether, including 47% of gay and bisexual people, and men who have sex with men; 41% of people who use drugs; 39% of sex workers; and 47% of transgender people.

Despite commitments by Pepfar [The US Presidents Emergency Plan for Aids Relief] and the national health department to roll out a robust key population sensitisation toolkit as part of standard in-service training for all facility staff, disrespect, ill-treatment and dehumanisation of key populations remain a widespread challenge that should be urgently fixed, with consequences for clinic staff who commit privacy violations.

READ: Study finds SA street sex workers have a high chance of being infected with HIV

The report states that, for those key populations still getting healthcare, most go to public healthcare facilities, yet specific services remain extremely limited.

Lubricants were only available in 41% of sites during this reporting period. While, notably, PrEP [pre-exposure prophylaxis] was reported as available at all 45 facilities monitored, the number of facilities that reported offering PrEP to key populations was far lower. Drug dependence and overdose treatments are not available at our clinics, neither is hormone therapy, yet 36% of people who use drugs wanted access to methadone and 35% wanted access to naloxone, and 29% of transgender people wanted access to hormone treatments at their facilities, reads the report.

Slight improvement

Its not all bad news for the province, however, as it received the fewest reports of stock-outs by public healthcare users in the current reporting period, with only 7% of patients who had left, or knew someone who had left, a facility without the medication they needed.

The report said:

Of the sites that reported a stock-out, 15% were forced to send people away empty-handed. The issues outlined in the second edition of the state of health report identify reasons people do not want to go to the clinic to access HIV and tuberculosis prevention and treatment services, and why some people interrupt treatment or disengage from care altogether.

According to the report, understaffed clinics meant that healthcare workers were overburdened, which led to longer waiting times, limited time to attend to public healthcare users and bad attitudes.

These factors directly and negatively impact people living with HIV from starting and staying on treatment. By June next year, the Eastern Cape health department should fill 70% of vacancies in the province, including the 322 vacancies reported at Ritshidze sites, and fill the remaining 30% by the end of the 2023/24 financial year.

The provincial health department should produce annual reports on the number of healthcare workers employed in each district and the number of people and size of areas covered by these healthcare workers. These reports should also include year-on-year comparisons (from at least 2020) of the number of filled posts in all districts and the cost of these posts to the government, the report recommends.

*Not her real name

Read more here:
HIV patients abused and humiliated - News24

Recommendation and review posted by Bethany Smith

Diabetes is characterized by insufficient production of insulin due to the loss or dysfunction of pancreatic beta cells.

A new study published in Cell Metabolism shows that a protein called beta cell expansion factor A (BefA) secreted by gut bacteria could induce the replication of insulin-producing beta cells in neonatal mice.

Understanding the mechanisms underlying the actions of BefA protein could help develop therapies to stimulate beta cell proliferation in individuals with diabetes.

The study also provides a potential explanation of how the gut microbiome could play a role in the development of diabetes.

Study author Dr. Karen Guillemin, a professor at the University of Oregon in Eugene, told Medical News Today:

[Our findings imply] that the activities of gut bacteria in young animals including possibly humans can shape the development of the pancreas in early life. This is important because early life corresponding to about the first 2 years of life in a human is when insulin-producing beta cells are most proliferative, after which they become more quiescent. If this population of beta cells does not proliferate enough during early life, it means that the individual with a small beta cell pool is more vulnerable to developing type 1 diabetes if beta cells are depleted by autoimmune attack.

Dr. Martin Blaser, a professor in the Departments of Medicine and Pathology and Laboratory Medicine at Rutgers University, NJ, commented that this study is exciting because it represents a novel way that we might be able to regrow beta cells in situations with injury like type 1 diabetes.

This is a great example of how basic research on the microbiome of zebrafish can lead to new approaches to treating important human diseases, he added.

Individuals with type 1 diabetes are unable to regulate blood sugar levels due to the loss of insulin-producing beta cells in the pancreas. The loss of beta cells in type 1 diabetes is caused by an autoimmune response against these cells.

In contrast, in type 2 diabetes the body is initially able to produce insulin but the cells in the body do not respond to insulin. In response to the consequent increase in blood glucose levels, beta cells produce more insulin to compensate for the resistance of cells to the hormone. This leads to the exhaustion of beta cells and their dysfunction, resulting in lower insulin levels.

The replication rate of beta cells is high immediately after birth but rapidly declines thereafter. Thus, therapies that stimulate the replication or regeneration of beta cells in adults could help treat diabetes.

The studys authors had previously identified such a protein, called BefA, secreted by gut microbes that could stimulate the proliferation of beta cells in zebrafish.

Moreover, the authors had also identified a version of the BefA protein synthesized by gut bacteria in humans that could stimulate the proliferation of beta cells in zebrafish. In other words, the BefA proteins secreted by gut microbes in humans and zebrafish share a similar structure and function.

In the present study, the researchers further examined the mechanism through which BefA could facilitate the proliferation of pancreatic beta cells in young mice and zebrafish.

Previous studies have shown that the gut microbiome could potentially play a role in the development of diabetes. In their previous work, the study authors had shown that germ-free zebrafish larvae, which show a complete absence of gut microbes, show lower levels of pancreatic beta cell proliferation during development.

In addition, exposure to BefA prevented this decline in beta cell proliferation in germ-free zebrafish larvae.

In the current study, the researchers examined whether the BefA protein performed a similar function in mice. Specifically, they examined the impact of BefA in germ-free and specific pathogen-free (SPF) mice.

SPF mice are reared so that they are not exposed to disease-causing microorganisms that may interfere with the goals of the study.

Similar to germ-free zebrafish larvae, germ-free neonatal mice and SPF mice treated with antibodies at birth showed lower levels of beta cells than untreated SPF.

Notably, the BefA protein was able to rescue beta cell development in germ-free and antibody-treated SPF neonatal mice. Moreover, mice treated with BefA also showed lower blood glucose levels than untreated animals.

The researchers then examined whether the BefA protein could directly interact with beta cells to stimulate their expansion instead of exerting these effects by interacting with other tissues. They cultured pancreatic tissue dissected from germ-free zebrafish larvae and mice pups in the laboratory and exposed the cells to the BefA protein.

The researchers found that the BefA protein was able to directly interact with and stimulate the proliferation of pancreatic beta cells.

In subsequent studies using zebrafish larvae, the researchers examined how BefA protein synthesized by gut microbes could reach the beta cells in the pancreas. The BefA protein could be transmitted to the pancreas via the bloodstream or the hepatopancreatic duct, which connects the pancreas to the gut.

Using zebrafish models with a compromised hepatopancreatic duct or lacking blood vessels, the researchers found that pancreatic beta cell proliferation was reduced in both models.

These results show that BefA protein produced by intestinal microbiota could indeed travel from the intestine via the hepatopancreatic duct or blood vessels to reach the pancreas.

To better understand the function of the BefA protein, the researchers examined the structure of the protein. They found that BefA proteins derived from the bacterial species Klebsiella aerogenes in the human gut, and Aeromonas veronii in zebrafish showed considerable structural differences but shared an identical domain or region of the protein called SYLF.

The researchers found that the SYLF domain could rescue the loss of pancreatic beta cells in germ-free zebrafish larvae. These results suggest that this region could underlie the ability of the BefA protein to induce the proliferation of pancreatic cells.

Evidence from previous studies examining other proteins containing the SYLF domain from a wide range of organisms suggested that the ability of the BefA protein to stimulate beta cell proliferation may be mediated by its interaction with lipid membranes that surround cells.

Consistent with this, the researchers found that the BefA protein was able to permeabilize or disrupt synthetic membranes as well as membranes surrounding the cells of bacteria.

The secretion of BefA protein by certain gut bacteria could damage the cell membrane of other gut bacteria and confer a competitive advantage over these microbes. Moreover, this ability to disrupt cell membranes could also potentially explain the BefA proteins ability to enhance beta cell proliferation.

To test this hypothesis, the researchers exposed cultured pancreatic beta cells to a mutated form of BefA protein with a reduced ability to permeabilize membranes. The mutated BefA protein had a reduced ability to induce the proliferation of cultured pancreatic beta cells from neonatal mice.

These results suggest that the membrane permeabilizing activity of BefA was responsible for mediating its effects on beta cell proliferation. Proteins such as BefA may be secreted by gut microbes to gain a competitive advantage over other bacteria, but could also confer incidental benefits to the human host by facilitating normal pancreatic development.

However, Dr. Guillemin noted: We dont know yet whether BefA can stimulate proliferation of beta cells in older animals, in animals that have experienced beta cell autoimmune attack, or in people, but these are questions we are currently pursuing. We also dont know yet how membrane permeabilization stimulates beta cells to proliferate, but we are also pursuing this question.

In addition to the BefA protein synthesized by a subset of gut microbes, other proteins produced by human cells also possess membrane permeabilizing properties. This includes antimicrobial proteins that form pores in the membrane of bacterial cells and protect the body from harmful bacteria.

The researchers found that the Reg3 protein, a member of the antimicrobial protein family, was also able to increase the proliferation of mice and zebrafish pancreatic cells.

Proteins such as BefA that are produced during microbial competition are known to activate antimicrobial proteins. The study authors think that proteins secreted by gut microbes such as BefA and the antimicrobial proteins that are produced in response to these proteins could play an important role in the development of pancreatic beta cells.

These findings could facilitate the development of strategies for the prevention or treatment of diabetes. The diversification of the microbial communities in the gut occurs at the same time as the proliferation of beta cells after birth.

A lack of microbial diversity during early childhood, especially lower levels of microbes that secrete proteins such as BefA, could thus increase the risk of type 1 diabetes.

Dr. Guillemin explained:

There are several potential future therapeutic applications of our findings. One area is in prevention. It may be possible to perform microbiome profiling combined with other genetic and environmental data analysis to predict whether infants are at high risk for developing type 1 diabetes and if they may benefit from prophylactic administration of BefA-producing gut bacteria or BefA protein formulations to stimulate the development of their beta cell population in the first 2 years of life, which is when beta cells are most proliferative and when the lifelong pool of beta cells is established.

The second area is in the treatment of [type 1 diabetes], she added. It is possible that BefA will prove useful for stimulating the proliferation of beta cells in older individuals and in pancreases following the autoimmune destruction of beta cells, which is the process that causes [type 1 diabetes].

Even if BefA itself is not able to stimulate beta cell proliferation in these circumstances, our studies of the BefA mechanism may uncover new strategies to stimulate beta cell proliferation through membrane manipulations, said Dr. Guillemin.

Read the rest here:
Diabetes and the gut: How a bacterial protein may impact insulin - Medical News Today

Recommendation and review posted by Bethany Smith

During a Targeted Oncology case-based roundtable event, Jennifer M. Matro, MD, discussed the data supporting systemic therapies for treatment of early-stage HER2-positive breast cancer including trastuzumab and pertuzumab.

Targeted OncologyTM: What are the recommended approaches to treating early-stage HER2-positive breast cancer?

MATRO: [What I will discuss] is by no means meant to be a dogmatic approach, but more an adaptive algorithm for early-stage HER2-positive breast cancer. There are patients for whom neoadjuvant treatment is appropriate and patients for whom adjuvant treatment would be appropriate. Starting in the neoadjuvant population, which is now most of our patients: Generally, these are patients who have either positive lymph nodes or T2 tumors, and IV chemotherapy along with dual HER2-targeted therapies [is] appropriate.

After their up-front chemotherapy, they go to surgery. If they have a pCR, like our patient did here, then they proceed to HER2-directed therapy to complete 1 year. [When looking at] trastuzumab plus or minus pertuzumab there is some thought, extrapolating from the APHINITY trial [NCT01358877], that for patients who presented initially with a node-negative diseasemaybe they were T2N0and had a pCR, that you do not necessarily need the pertuzumab; but for patients who are node positive at presentation, include the pertuzumab.1,2

For patients who did not have a pCR, based on the KATHERINE trial [NCT01772472], we have the adjuvant T-DM1 [trastuzumab emtansine (Kadcyla)] for 14 cycles.3 Patients who do not have preoperative therapy and have surgery first are going to be patients who are mostly earlier stage with imaging, T1N0, or if there is a question of the extent of disease.

[In the patient in this case] there are 6 cm of nonmass enhancement and biopsy of the nonmass enhancement shows DCIS. It is unclear what the extent of disease is, and you go ahead with surgery first. If the patient comes out of surgery with negative lymph nodes and smaller tumors, then paclitaxel/trastuzumab for 12 weeks is recommended, as it has been shown in the APT trial [NCT00542451] and a subsequent larger study that the outcomes for those patients are excellent.4

For patients who have larger node-negative cancers, maybe 2 or 3 cm, or are younger and you are worried more about their risk, TCH [docetaxel, carboplatin, and trastuzumab] would also be appropriate. For node-positive patients, we are going to include the dual HER2 therapy. Neratinib [Nerlynx] in the ExteNET trial [NCT00878709] was shown to provide some benefit, particularly for patients with hormone receptorpositive disease and multiple positive lymph nodes.5 That is also part of the consideration in the algorithm for higher-risk patients.

I want to highlight that the trastuzumab biosimilars can be used interchangeably with the brand-name Herceptin, and the subcutaneous formulations of trastuzumab and trastuzumab/pertuzumab can also be used in place of the IV formulations.

Can you discuss APHINITY?

APHINITY is the study that led to the use of dual HER2 therapy in the adjuvant setting.1 The patients, who already had surgery, were randomized to chemotherapy with trastuzumab plus pertuzumab or placebo. The primary end point was invasive-diseasefree survival. They did not restrict the type of chemotherapy; it could be anthracycline or nonanthracycline based. Patients who had hormone-positive disease also got endocrine therapy.

[In the] updated analyses, with invasive-diseasefree survival by subgroup, in the intention-to-treat population, there was just under 3% improvement with the use of pertuzumab. It did not seem to matter whether they were hormone positive or hormone negative, but where the difference was really seen was in the patients who were node positive. The patients who were node positive were driving the benefit seen, and patients who were node negative did not see [much] difference with the addition of pertuzumab. So far, we do not have any overall survival benefit, but it is early and we are waiting for those results.

What is the role of the subcutaneous formulation of trastuzumab and pertuzumab?

The combination of trastuzumab, pertuzumab, and hyaluronidase [Phesgo] for subcutaneous injection has an FDA-approved indication for both early-stage and metastatic disease.6 It can be used in the neoadjuvant or adjuvant setting in combination with chemotherapy, and in the metastatic setting in combination with taxane therapy, predominantly in the first line. I believe it is preconcentrated. I know with the loading dose it is a slightly higher volumeI think it is 15 mL as opposed to 10 mLbut it is [like] a fixed dose.

The FeDeriCa study [NCT03493854] showed that the pharmacokinetics are essentially the same between the subcutaneous formulation and the IV formulation.7 In other studies that have used combination trastuzumab and pertuzumab in those settings, the thought is that the fixed-dose combination can be used for those indications as well.

FeDeriCa was a phase 3 study that was looking primarily at the pharmacokinetics. Patients who were getting preoperative chemotherapy, which was predominantly anthracycline based, were randomly assigned to IV formulation or subcutaneous formulation, and then they had surgery, and then afterward they were continued either on the IV formulation or the subcutaneous formulation. The primary end point was noninferiority of the cycle 7 trough concentration of the pertuzumab, with the fixed dose compared with the IV formulation.

One of the advantages of doing neoadjuvant studies is that we have an immediate end point of response rate. The rate of pCR was the same for both [Figure7]. It was well tolerated; no major differences in risks associated with the IV vs the subcutaneous formulation. A few more patients had a little bit of irritation at the injection site vs infusion reactions.

If you want to discontinue pertuzumab in a low-risk patient as adjuvant therapy, do you have to change back to IV?

There is a trastuzumab-[plus hyaluronidase] subcutaneous injection. The brand name is Hylecta. So, it is the same idea: If you can get access to Phesgo or the dual HER2 injection, you should be able to get access to the trastuzumab-based injection. The trastuzumab-based injection also has extensive pharmacokinetics studies showing that it is similar in efficacy to IV trastuzumab.8,9

Can you discuss the difference in timing between IV and subcutaneous administration?

With standard IV, in the first loading dose, the pertuzumab is supposed to be given over [30 to 60] minutes, and the trastuzumab is given over 30 to 90 minutes, and you have this observation period in between [of 30 to 60 minutes]. It can take hours.

Once you are on and tolerating the trastuzumab and pertuzumab IV, they can be given over 30 minutes each. There is a much shorter observation window, but nonetheless it is going to be at least 1 hour, potentially up to 2 hours. Whereas with the fixed-dose subcutaneous administration, the injection itself takes a couple of minutes. You watch them for another 15 to 30 minutes, so the total time is generally 20 to 40 minutes, so it takes at least half the time. This opens chair time for other patients who need IV infusions, and saves patients from having an IV placed, and it allows them to potentially get their port removed earlier. Generally, it can provide benefits to patients and providers. One thing that remains to be seen is whether this is something that eventually could be given at home.

I was working in Philadelphia at the beginning of the [COVID-19] pandemic, and the University of Pennsylvania at that time took most of the patients who were on leuprolide [Lupron] for ovarian suppression and transitioned them to home nursing. All of those patients were getting injections at home with their leuprolide. They did not have to come in. If you have skilled nursing in the community, is this something that patients may even be able to get at their home or their office? I think that is something that has potential for opening that up as an option, which would be even better for patients.

What is known about which option patients prefer?

We see, based on the PHranceSCa study [NCT03674112], that patients do prefer the subcutaneous formulation.10 PHranceSCa looked at patient preference. Patients who had completed their chemotherapy and surgery and were going to be completing a year of HER2-directed therapy were randomized. Half of the patients got the IV formulation, half got subcutaneous administration for the first 3 cycles, and then they crossed over and switched to whichever one they had not received before, and then they were allowed to choose which one they wanted to finish the rest of the year of HER2 therapy with. The primary objective was patient preference.

What we saw was that 85% of patients preferred the subcutaneous formulation over the IV and 87% chose to use that subcutaneous formulation to finish their treatment after experiencing it. The main reasons were less time in clinic and administration being more comfortable.

REFERENCES

1. Piccart M, Procter M, Fumagalli D, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY trial: 6 years follow-up. J Clin Oncol. 2021;39(13):1448-1457. doi:10.1200/JCO.20.01204

2. von Minckwitz G, Procter M, de Azambuja E, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131. Published correction in N Engl J Med. 2017;377(7):702

3. von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017

4. Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015;372(2):134-141. doi:10.1056/NEJMoa1406281

5. Chan A, Delaloge S, Holmes FA, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-377. doi:10.1016/S1470-2045(15)00551-3

6. Phesgo. Prescribing information. Genentech; 2020. Accessed May 5, 2022. https:// bit.ly/3RFnCsv

7. Tan AR, Im SA, Mattar A, et al; FeDeriCa study group. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021;22(1):85-97. Published correction in Lancet Oncol. 2021;22(2):e42

8. Pivot X, Verma S, Fallowfield L, et al. Efficacy and safety of subcutaneous trastuzumab and intravenous trastuzumab as part of adjuvant therapy for HER2-positive early breast cancer: Final analysis of the randomised, two-cohort PrefHer study. Eur J Cancer. 2017;86:82-90. doi:10.1016/j.ejca.2017.08.019

9. Jackisch C, Stroyakovskiy D, Pivot X, et al. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019;5(5):e190339. doi:10.1001/ jamaoncol.2019.0339

10. OShaughnessy J, Sousa S, Cruz J, et al; PHranceSCa study group. Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): a randomised, open-label phase II study. Eur J Cancer. 2021;152:223-232. doi:10.1016/j.ejca.2021.03.047

Originally posted here:
Recommended Approaches to Treatment for Early-Stage HER2+ Breast Cancer - Targeted Oncology

Recommendation and review posted by Bethany Smith

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In your head, you always imagine the revolution when it starts. It'll start with tanks and gunfire with chaos and soldiers in the street. You'll know when it comes, but it never does. Instead, the really big changes to American life, the profound ones that affect all of us forever, those changes almost always begin quietly with gentle pleas for tolerance. We'd like to do things a little differently, they tell you. We'd like to make a change to some custom or belief that people have been attached to for the last few thousand years, but don't be alarmed. It's not a big deal. You don't even need to participate. All we ask is that you let us live the way we want to live.

That's always the pitch and of course, you always agree to it. Why wouldn't you? Who could say no to that? Some guy down the street wants to wear a dress? OK, fine, have a party. It doesn't affect you. You don't have to wear a dress, so go ahead. Live and let live, but it turns out that's never actually the deal. The guy down the street wears his dress, but after a while, that's not enough for him. He's still angry and for some reason, he's angry with you. And that doesn't make sense because you're the person who had no problem with him wearing a dress in the first place. What did you do wrong?

Well, the problem is you're not wearing a dress and neither are your kids. Your normal-person clothes, the ones you've always worn, are suddenly immoral. You've got to change immediately.

Now, wait a second, you say, that's not what we agreed to. You do your thing and I'll do mine. Remember? They don't remember. They don't care. That's not how it works. You don't get to do your thing anymore. The dress guy's in charge now. Everybody's got to do his thing, the dress thing or face punishment. That's how it goes. "Be tolerant" becomes "show some respect" which evolves very quickly into "bow down before us and lick our feet or else will hurt you." That's the final stage. That's where we are now.

For example, a Democratic lawmaker in Virginia called Elizabeth Guzman is introducing a bill that will charge parents with a felony, strip them of their employment and imprison them if they don't wholeheartedly endorse their minor children's sex changes. So, your 12-year-old daughter says she wants a mastectomy. If you object to that in any way, if you raise questions, Elizabeth Guzman will send you to jail for real. Here's a local news report.:

GOP DEMANDS INVESTIGATION INTO SCHOOLS THAT PARTICIPATED IN GOOGLE'S 'DISCRIMINATORY' FELLOWSHIP PROGRAM

REPORTER: Her bill would expand the state's definition of child abuse and neglect to include parents who do not affirm their child's gender identity or sexual orientation.

ELIZABETH GUZMAN: There is an investigation also in place that is not only, you know, from a social worker, but there's also a police investigation before we make that decision that there is going to be a CPS charge.

REPORTER: What could the penalties be if the investigation concludes and it's concluded that a parent is not affirming of their LGBTQ child? What could the consequences be?

ELIZABETH GUZMAN: Well, we first have to have an investigation. You know, it could be a felony. It could be a misdemeanor, but we know a CPS charge could harm, you know, your employment, could harm your education.

DEMS UNDER FIRE AFTER TIES TO LAWMAKER WHO WANTS TO CRIMINALIZE PARENTS WHO DONT AFFIRM LGBT KIDS EXPOSED

Who is this Elizabeth Guzman? Well, Elizabeth Guzman came to this country not so long ago from Peru as a single mother. Now, rather than wait a while, maybe spend a few generations here before telling you how to raise your children in America, she's decided to get right to it and completely change child-rearing in this country in a way that would never be tolerated for a second in the country from which she comes. Try that in the Andes, honey, and see how that works. Yeah.

But in this country, according to Elizabeth Guzman, you have to affirm your child's sex change or else you're going to prison and the state will raise your kids.

Now you got to think maybe they've wanted this for a while. What would this mean? Well, it would mean fewer intact families. It would mean people like Elizabeth Guzman make the decisions, the meaningful decisions within your house. It means less resistance from you. It means more powerful them. What it doesn't mean is that Elizabeth Guzman will be protecting your kids. She doesn't even claim this law will protect your kids. Instead, she acknowledges the whole point is to "educate parents." Right.

Like the COVID vaccine, this is a pretty easy way to figure out who's on which side. Are you for this? OK, you're on our team. You're willing to surrender control of your own children to Elizabeth Guzman, who, again, just got here. But if you're not for it, then we know you're not on our team. We know who you are. We can silence you. We can punish you because you refuse to be educated.

So, it's a signaling mechanism and you know that because the ideology that underlies it, gender ideology, is completely incoherent. It doesn't make any sense at all. It is not rooted in science. It's a form of religion that's so crazy it dares you to say something about it. What? You can't even say that. If you do, they know you're on the other side.

And it's not just lunatics and ideologues like Elizabeth Guzman from Peru. It's doctors, it's medical professionals.

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Here's a video from Boston Children's Hospital, one of the most famous hospitals in the world, which like many hospitals in the United States at this point under the Joe Biden administration cut the breasts off of minor girls for no medically justifiable reason. Watch a practicing psychologist, now attending psychologist, at Boston Children's Hospital explain how early children can become trans.

DR KERRY MCGREGOR, BOSTON CHILDRENS HOSPITAL: So, most of the patients that we have in the clinic actually know their gender, usually around the age of puberty, but a good portion of children do know as early as seemingly from the womb, and they will usually express their gender identity as very young children, some as soon as they can talk. They might say phrases such as "I'm a girl" or "I'm a boy" or "I'm going to be a woman" or I'm going to be a mom." Kids know very, very early. So, in the Gems Clinic, we see a variety of young children all the way down to ages two and three and usually up to the ages of 9.

That's Kerry McGregor. She's a psychologist. She works at Harvard. I wonder how many children Kerry McGregor has. Has she raised a lot of kids? Has she watched kids carefully? Does she know anything about kids? Because she's telling you if you're a little kid says, "Oh I may be on the other sex," that means your kid is the other sex. Well, that's insane, because almost 100% of kids at one point or another, at a certain point in development, say things like, "I think I'm a boy. I think I'm a girl" and you smile indulgently, "Get back to me in 15 years."

But no, says Kerry McGregor, in the womb you can know.

WORLD MENTAL HEALTH DAY: 'IT'S OK TO ASK FOR SUPPORT OR HELP'

Think about what they're telling you. They're telling you that developing child in the womb is just a part of the mother. Therefore, you can abort that child at any time. It's like an appendectomy, but at the same time, that same cluster of cells, that fetus, can also be woke and ascribe to left liberal gender ideology and you need to honor that.

No sane person could believe any of this voluntarily. It doesn't even make sense on its face. Again, it's a religion and if you resist it, they resort immediately to force. No questions allowed. Again, this is science and the essence of science is relentless questioning about what you think you know is true. That is the scientific method. That's science itself, but it's no longer allowed.

The American Medical Association, which hasutterly beclowned itself, along with the American Academy of Pediatrics and the Children's Hospital Association, just sent a letter to the attorney general of the United States demanding that the Biden administration, and we're quoting, "take swift action to investigate and prosecute high profile users on social media" who have engaged in "disinformation."

You hate to always invoke the German government of 80 years ago, but what else is that? That's totalitarian. They're saying if you disagree with what we're doing, people with guns should come and take you away. Now you'd think someone in the media would point out, "Wow, you know, we can't have that in the United States where people are free to believe what they want and to talk about it in public and to ask questions." In fact, they should be encouraged to, but the media don't say anything like that. They're joining with the Children's Hospital Association, the AMA, to call for more censorship at gun point. Watch.

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MEDHI HASAN:Obviously the question becomes then when misinformation, disinformation is being spread, when hate and threats are being spread, where are the social media companies? What's YouTube doing? What's Twitter doing? And of course, then you have the reaction to that "Oh, this is big tech silencing people." It always becomes a debate about free speech, doesn't it?

BRANDY ZADROZNY: Yeah, it does. You know, last week, Twitter suspended Libs of TikTok specifically for the policy against the promotion of threats, violence and harassment. So, great job, right? But it's been seven days and Libs of TikTok is back now and they're tweeting right this very minute. This is violence, this is harassment. It's clear what these accounts are doing.

It's so funny. Back to the point at the open, when the revolution comes, there won't be tanks and soldiers won't be stormtroopers in all uniforms and symbols. It'll be some unmarried 30-year-old woman talking in a singsong voice inflection at the end. Right. Right. Special glasses or complex glasses that don't actually improve her vision. She'll have all kinds of pointless humanities degrees and she'll be on cable news and say its violence. What she's really saying is "shut up and obey or will hurt you." She's delivering the same message any stormtrooper delivers, but she's doing it in a singsong way. This is disinformation.

Call us literal, but this is the opposite of disinformation, isn't disinformation. This is literally what they're seeing. Boston Children's Hospitals, which we showed you on tape, is telling you what they're doing. They perform double mastectomies on miners for no medical reason whatsoever. That's insane. It ought to be a crime. In a civilized country it would be and they know that because when they were caught, they tried to erase the evidence and they're not alone.

PARENTS STAND UP TO 'CULT' LOUDOUN COUNTY SCHOOL BOARD OVER TRANSGENDER STUDENT POLICY

UCSF, U.W. Health in Wisconsin, Golisano Children's Hospital in New York, Vanderbilt Health, Children's Minnesota, all of these hospitals have deleted the evidence of their gender-affirming procedures, their grotesque mutilation of children after they were publicized. Their own words were publicized online. No one's twisting it. People are just putting up their words and not all the videos have been deleted.

Planned Parenthood is big into this now because it's lucrative. Here's Planned Parenthood in 2021 telling children that so-called puberty blockers are harmless. Oh, right. That's a lie and by the way, there's no such thing as a puberty blocker. These drugs are hormone agonists and they're FDA approved for things like cancer treatment. You get prostate cancer and they lower your testosterone, for example, to prevent the cancer from growing quickly. They are not approved for so-called "puberty blocking." They're unapproved and the long-term effects are not known, but it's pretty obvious they're grim, but Planned Parenthood won't tell you that. Here's their video.

PLANNED PARENTHOOD VIDEO: You're transgender or non-binary. You may find that your puberty experiences don't line up with your gender identity or how you see yourself. That feeling can be uncomfortable, scary and stressful. If that sounds like you, know that you're not alone. There are medicines you can take to delay puberty for a while. They're called puberty blockers, and they work like a stop sign by halting the hormones, testosterone and estrogen that cause puberty changes like facial hair growth and periods. Puberty blockers are safe and can give you more time to figure out what feels right for you, your body and your gender identity.

Everything about that is dark and horrifying and there should be an uprising against that. That's aimed at your childrennot at adults who can make rational decisionsbut children who are people too young to drive or drink alcohol or smoke cigarettes or serve in the military or vote, people who are not (we have agreed as a group) capable of making rational adult decisions and that's aimed at them. It's propaganda aimed at them and it's a lie. Puberty blockers are safe. They are absolutely not safe. You can't delay puberty without damaging severely the bodies of young children. The FDA just identified several "clinically serious cases" of side effects after these drugs were recklessly administered to children by lunatic ideologues.

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FILE- In this June 4, 2019, file photo, a Planned Parenthood clinic is photographed in St. Louis. (AP Photo/Jeff Roberson, File) (AP Photo/Jeff Roberson, File)

The FDA found a "plausible association" between the use of puberty blockers and something called intracranial hypertension. Do you want that for your 13-year-old?

According to the Mayo Clinic, that condition can cause brain swelling, double vision, severe headaches, permanent vision loss. In other words, brain damage. Brain damage! Oh, great. OK.

On top of that, the European Journal of Endocrinology, among many other publications, has found that so-called puberty blockers often cause, "decreased bone density, which is associated with a high risk of osteoporosis" and there are other permanent side effects as well. We don't even know the scope of them because this has never been tested longitudinally ever, but the effects are very obvious and if you poke around on the internet for about 4 minutes, you will see them. One teenage girl just uploaded a video showing the effects of five years of puberty blockers on her. Watch this.

VIDEO: When I talk about being too far gone, I don't really know what else to call it, this is what I mean. This is how deep my voice is. It's gotten deeper over time and it's settled. This is what I mean by hair loss and it just keeps getting worse. It keeps thinning. It keeps receding backwards. You know and I'm not exactly sure that's coming back. Those are the main things when I talk about being androgenized to a point of no return. This is what happens when you give a women testosterone for five years. This is what happens.

Yeah. That's what happens. That and a lot of other things. That's what they're telling you is "gender-affirming." No, it's mutilation. It's grotesque. It's destroying people's lives, children's lives. We made a documentary on this for "Tucker Carlson Originals." We spoke to a lot of people who had endured similar torture.

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HELENA: The testosterone kind of had this effect on me, where with every step that I took, it would feel good for a short amount of time, but then eventually it's like those same feelings come back up.

WALT: There's the initial euphoria that you go through. I changed my gender and everything's going to be wonderful.

KATHY: It was euphoric. I was like, the feeling I had when I started living as a man was I was free. I was finally who I should have been all along.

TUCKER NARRATION: But that euphoria was short-lived.

KATHY: My mental health just got worse. My ability to socialize just got worse. I felt so disconnected from myself. I started using, like drugs and alcohol as a crutch, and I was just a total disaster and the effects of the testosterone on my mental health specifically just made everything 10 million times worse.

WALT: I had bought into the lie and almost took my life.

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It's just awful and every person who is participating in this in their moments of clarity knows that ten years from now, there will be thousands of vocal victims of this moment of true craziness and hysteria that has gripped our country. People's lives are being destroyed right before us. Most adults are too cowardly to say a word about it and the Democratic Party is actively doing all it can to promote this to protect hospitals that are mutilating and destroying the lives of children.

in the state of California Always a bellwether a legislator called ScottWienerhas just sponsored legislation to make California a so-called sanctuary state for kids who want to mutilate their own bodies to castrate themselves. Scott Wiener, really? Is he a good father? Would you trust this guy within 500 yards of a child? Probably not.

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Democrat Gov. Gavin Newsom of California (Tom Williams/CQ-Roll Call, Inc via Getty Images)

Gavin Newsom just signed the bill, of course. So, what's the point here? It's not to protect children. It's not protecting them. Any parent will tell you if you want to protect children, you tell them, take a deep breath and reach adulthood and then make rational decisions about how to live their lives.

You would definitely not let them make a decision, an irreversible decision like this, for themselves. You're their parent. That's the whole point. But the Democratic Party doesn't like parents. The Democratic Party is replacing parents with itself. We're in charge now. It's the most recognizable possible move for any totalitarian movement. Break up the family. Replace parents with politicians. The state is in charge. The party is in charge, obviously, and it's happening all over the country.

Tucker Carlson currently serves as the host of FOX News Channels (FNC) Tucker Carlson Tonight (weekdays 8PM/ET). He joined the network in 2009 as a contributor.

Excerpt from:
TUCKER CARLSON: The Democratic Party is replacing parents with itself - Fox News

Recommendation and review posted by Bethany Smith

Disclaimer: This story contains details of miscarriage which may be upsetting for some.

March 21st, 2022 was the best day of our lives. We adopted our middle daughter and our family was complete. But what got us there? Its easy to see all the highs of adoption, but few know all that goes into getting to that point.

Our story starts back in 2012, when Jared and I (Taylor) met at a softball game. Jared and I went to the same small high school in rural Indiana but did not know each other well as Jared was a few years older than me. After high school, I went to a softball game with a friend to watch her boyfriend play. I was then introduced to Jared and we became friends.

We started dating in the beginning of 2013, and we were engaged just before Christmas that year. We bought a house in May, adopted a couple dogs, and married July 26, 2014.

It was a quick engagement but we were both so confident in our decision and commitment to one another. Early on in our relationship we knew we wanted to have kids. We always envisioned having three or four kids and had always tossed around the idea of foster care and adoption, but were really enjoying just being married.

Two years after getting married, I found out I was pregnant! We were so excited and couldnt wait to begin our lives as parents. I had a relatively easy pregnancy and our daughter, Claire Kristine, was born December 6th, 2016. She was a perfect 9-pound baby, and we ooohed and ahhed over her for days. We quickly settled into our roles as parents and tried our best every day to raise Claire with love and kindness.

The sleepless nights were rough and the exhaustion was catching up with us, but nothing could wipe that new parent glow off our faces. Around Claires first birthday, we bought some land in our hometown and decided to build a home so we could raise Claire (and our future children we were dreaming of having) in the same small-town we grew up in.

We dreamt of farm animals, land to run on, unobstructed sunsets, and perfectly clear starry nights. We lived with my parents during the (longer than expected) building process and were beyond grateful for that opportunity, but were anxious to get back into our own house. We closed on our newly built home on Valentines Day 2019!

At this point in time, Claire was two years old and we had started getting the dreaded questions: Are you going to have more kids? Claire needs a brother or sister! Is she going to be an only child forever? We knew we wanted more kids and now that we were finally in our new house, we felt comfortable adding to our family.

After months of negative pregnancy tests, we were referred to a fertility clinic just to check on everything. The questions from well-meaning people started to hurt and I started to feel like there was something wrong with me. Maybe we would just have one child.

Lots of tests and blood work was done and I had a procedure scheduled. A week before the procedure I found out I was pregnant! I told Jared right away and we were beyond thrilled. I giddily called the fertility clinic and they asked me to come in so they could draw labs and check hormone levels. A couple days later I confidently walked into the clinic to have my blood drawn and was told my due date, June 14th 2020.

Not long after that, the bleeding started and my hormone levels dropped. I was having a very early miscarriage. My world shattered. What? A miscarriage? How is this fair? Didnt that baby know how loved they already were? Did God know how much we wanted this? We were doing everything right; this shouldnt be happening. But it was. Our very wanted child was gone and I was broken.

Thankfully, we were still working with the fertility clinic, had wonderfully supportive family and friends, and clung to our faith. All together they were helping us navigate how to move forward. I remember listening to the song Even If by MercyMe on repeat day after day, just trying to remind myself it would all be okay.

Several doctors appointments and trips to Chicago later, I was told my fallopian tubes were blocked and it was very unlikely I would have more children naturally. The doctor recommended IVF. The state of Indiana does not require health insurance companies to cover fertility treatment, so very few do. The cost, as so many families know, is extreme and it wasnt something we were ready to look into yet. After much prayer and discussion, we decided foster care was the right path for us.

Foster care wasnt a new subject for us. I grew up with an aunt and uncle who fostered children and ended up adopting 2 boys. I have cousins adopted from other countries. We had friends who fostered and we had talked about becoming foster parents in the past. Both of our families are extremely supportive and we knew we would have endless help on this journey.

Shortly after our miscarriage, we contacted our local DCS agency and started the literal mountain of paperwork. The paperwork is long and intense. The questions get personal and it took months to finish.

After we submitted our paperwork, a caseworker came over and studied our home. You talk about fire plans, how to properly store cleaning supplies, and they look into every part of your home and life. We took classes, were re-certified in CPR, had forms filled out and physicals done by our doctors, and asked for references to fill out forms for DCS. Once all of that was said and done, we each sat down separately with our caseworker and had a five-hour interview. Yes, you read that correctly, five hours.

In this interview they dove into our childhood, our past, our traumas, and the highs and lows of our life. They asked hypothetical questions, and attempted to learn every part of our life. Though it seemed daunting and excessive, I understand it now. If my child had to be placed in a strangers home (even if the reason for removal was my own doing) I would want to know they were staying with a family who could appropriately love and care for them.

I remember during one point of my interview, the very nice lady who was interviewing me asked why we wanted to foster and what we were hoping to gain from becoming foster parents. I explained our past fertility issues, the miscarriage, our desire to grow our family, and wanting to share the love we had to give with other children, even if it would only be for a short period of time.

The woman looked at me, gently placed her hand on mine, and said, I need you to know, you will get your heart broken. Not might, will. In this journey, your heart will shatter into a million pieces, things wont always go how you think they will, and your heart will break. Please reach out for help and get support to help you through those inevitable times. She wasnt saying that to scare me but rather to prepare me, and I often thought back to her words during our foster care time.

We became officially licensed foster parents in March of 2020, right at the beginning of the Covid-19 pandemic. Life went on and we didnt receive any phone calls for placements. We had specified we wanted to only foster children younger than our daughter for the time being; we felt that would be best for our family. DCS was more than happy to accommodate our wishes, but did let us know we might not get a call right away.

One month after becoming licensed, I found out I was pregnant again! Joy and fear filled our souls as we anxiously fumbled through the first trimester. Our fear began to subside as bloodwork showed rising hormone levels and we got to see our sweet babe on the ultrasound.

June 14th, 2021 came and it was a hard day. It was our miscarried babys due date and although I was pregnant again, I longed to have that baby in my arms. It was a Sunday and after church Claire and I went to watch Jareds weekly softball game. The game had barely started and my phone rang it was DCS.

I answered and they explained to me they were looking for a placement for a three-day old baby girl. Without even talking to Jared, I said yes. DCS told me to head to the hospital with a car seat for the baby and to have Jared go to the house to meet the social worker and go over everything for the placement. I pulled Jared out of the game and excitedly told him what was happening. He was completely on board and we all headed home to prepare.

As soon as I got home, I grabbed the infant car seat, gave Claire and Jared a hug and a kiss, then headed for the hospital while they stayed behind to wait for the social worker and prepare things for the baby. Upon arrival at the hospital, I was put in a room and told to wait.

A few minutes went by and the nurse wheeled in this tiny, precious 6-pound baby girl. I held her, rocked her, and told her how much I loved her while the nurse went over all the basic discharge information. During this process it hit me: I am in the hospital, holding a newborn baby, on my miscarried babys due date.

God knew what I needed and He provided, like He always does. After lots of paperwork, I carefully drove home and introduced Jared to our foster daughter and Claire to her foster sister, Addisyn.

Addie was such an easy baby and the love we felt for her was no different than the love we felt for our biological child. Our family fell in love with her just as quickly and they were all so helpful as we adjusted to life with a newborn again. Addie had visits with her biological mother on a regular basis as well as several court hearings. It was hard to get used to the ever-changing schedule of visits, court, and caseworkers stopping by but we managed.

Time was flying by and Addie was growing so quickly. Before we knew it, summer turned to fall and Thanksgiving was approaching. During various court hearings and conversations with our caseworker, talks of adoption began to happen. We tried not to get our hopes up, but we couldnt help it. The thought of adopting Addie made our hearts soar. We carried on and were so excited for the holiday season with Addie and the upcoming due date of our baby.

The day before Thanksgiving 2020, Claire and I were in the kitchen baking pies while Addie napped when my phone rang. It was our case worker telling me they needed a home for Addies older brother immediately. We were the only option and he would be at our house in a few hours.

We couldnt turn down a child in need of a home but we were in no way prepared for a 2-year-old boy! I frantically called my husband, my parents, family members, and a few friends, and cried to them as I tried to figure out what to do. (Eight-month pregnant Taylor was very overwhelmed at this point).

Jared came home from work, rearranged Addies room, and put together the extra bed we had in our basement. My dad went to the store to purchase a mattress and bedding. My mom and sister helped me pick up the house and get everything ready. My aunt and grandparents dropped off diapers, clothes, sippy cups, and toys (because this girl mom didnt have anything for a little boy!).

My boss and her husband dropped off more diapers, clothes, and shoes in a variety of sizes. My two best friends came over and made dinner, folded laundry, and reassured me everything would be okay. Our friends and family rallied together and made so much happen in such a short period of time. Ill never be able to appropriately express my gratitude toward them.

The sweetest little boy came to our home that night, scared and confused, but thanks to our amazing people, we had everything we needed to help make him feel comfortable and loved. The next few weeks were an absolute whirlwind. We often werent sure what was happening from one day to the next; we were just trying our best to make the world a little calmer for our kids.

We moved on with the busy holiday season, making it special for everyone in our home. We went Christmas shopping, cut down our Christmas tree, sent out Christmas cards, looked at the lights, and tried to soak up the magic of the holiday season.

A couple weeks into December, shortly after Claires 4th birthday, our caseworker called to tell us Addie and her brothers grandparents were going to be taking both kids. Our hearts sank, we couldnt speak. We knew these children might not be permanent members of our home, but that didnt ease the heartache.

We packed up all of the childrens belongings the best we could and spent every last second showering them with love. Addies brother left first as he already had a relationship with his grandparents. Addies grandparents graciously let us have a few extra days with her.

Over those days we finished packing up Addies whole life into Rubbermaid totes, taking her to see family and friends so they could say goodbye, and soaking up every last second with this perfect 6-month-old baby girl. We were fortunate enough to be able to meet Addies grandparents and actually drop her off at their house. While it didnt make saying goodbye any easier, it was nice to get to know the people who would be caring for her. They even agreed to exchange phone numbers so they could text us pictures and updates.

Claire, Jared, and I all gave Addie one last hug and kiss, as we sobbed getting back into the minivan we had purchased that summer to fit all of the kids. The heartbreak DCS warned us about was happening and it was awful.

Jared and I tried to get back to normal as quickly as possible in order to make things easier for Claire. She had been through a lot over the last six months and we didnt want her to be any more sad or confused than she already was.

The three of us enjoyed a nice Christmas, prepared for the arrival of our second biological baby, and thought about Addie every single day. We were able to stay in touch with her grandparents on a semi-regular basis but we missed her like no other.

We decided to be listed as on hold with DCS as we grieved our last placement, and to give us time to adjust when our baby arrived. January 15, 2022, I gave birth to another beautiful baby girl, Piper Kate. She was the sweetest baby and she healed our hearts.

Claire was loving being a big sister again, but often asked if we would always get to keep this baby. Jared and I reassured her Piper was here to stay, forever. We carried on as a family of four, getting into a routine, and enjoying every moment (except maybe not the ones when Piper was screaming nonstop).

In April, when Piper was four months old, Addies grandparents reached out to us. They asked if we would be willing to take Addie back into our home and family. Due to some unforeseen circumstances, they felt it was best if we raised her, but they would still like to be a part of her life. We said we would absolutely love to foster her again and they would 100% be involved as grandparents.

We talked to and arranged everything with DCS, and a few weeks later Addie moved back in. Our home was so full of joy! Life was hard but so incredibly full. It took time and a lot of support from our family and friends. We slowly settled into our roles as parents of three girls.

In the following months we had lots of court dates, caseworker visits, and Addie had visits with her biological family just like before but things were a bit different this time. Addies permanency plan was changed to adoption. We were cautiously hopeful.

That winter our caseworker advised us to hire an attorney and start getting paperwork ready to adopt Addisyn. We found an amazing attorney to represent us and she began drawing up everything we would need for adoption.

During this time we began to develop a relationship with Addies birth mom. I sent her pictures and updates periodically and she mailed us letters to give to Addie when she is older. She expressed her gratitude to us for caring for sweet Addie and we did our best to express our gratitude to her for blessing us with such an amazing little girl, though theres no way to every thank her for that beautiful gift.

March 21st, 2022, we gathered in a courtroom to officially make Addisyn our daughter. The room was filled with people we love: parents, grandparents, siblings, friends, caseworkers, and even Addies biological grandparents. We hired a photographer to capture every moment of this special day so we would never forget.

We promised to love, care for, and provide for Addisyn, just as we would Claire and Piper, for her entire life. There were tears, smiles, fist bumps, and cheers because Addisyn was officially an Emmons! Addisyn Kay Jean Emmons, forever.

Our days are chaotic but full of love. Claire is 5, Addie is 2, and Piper is 1.5. They wear Jared and I out every single day, but we wouldnt have it any other way. Never in our wildest dreams did we think we would have daughters just seven months apart in age, but God had other plans for our family!

Our foster care license is temporarily suspended so we can focus on our three young children and not losing our sanity. Im not sure what the future looks like for us as foster parents, but we love to help any way we can. There is a great need for loving people in the foster care system and even if you cant foster, you can still help. Adopt, foster, donate, or volunteer. Everybody can do something to make the world a little brighter for our future.

This article was submitted to Love What Matters by Taylor Emmons of Rolling Prairie, IN. You can follow her on Instagram. Join the Love What Matters family and subscribe to our newsletter.

Read more stories like this:

They chose us. Theyre coming in two hours!: Couple shares unexpected sibling adoption from foster care

We got a call for an 8-month-old boy. There were no details. If were going to do it, we might as well just do it!: Woman details journey becoming foster parents

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'You will get your heart broken. Not might, will.': Foster mom shares heartwarming adoption after infertility, heartbreak - Love What Matters

Recommendation and review posted by Bethany Smith

Orphan: First Kill, directed by William Brent Bell (The Boy, Brahms: The Boy II), was released in 2022 and is a prequel to the 2009 flick, Orphan. Like its predecessor, First Kill follows the exploits of the murderous Leena (Isabelle Fuhrman), a 31-year-old woman with a hormonal disorder called hypopituitarism that gives her the appearance of a 10-year-old child. Leena uses this to her advantage, scheming her way into different families who have a first date with their Maker once the gloves (or in this case, the teeth) come off and Leena reveals her true intentions. While the story is loosely based on a case in real life, the campy set-up suggests a film that doesnt take itself too seriously and audiences shouldnt either. Note: I will be discussing spoilers from Orphan and Orphan: Kill, so consider this your official spoiler warning.

Isabelle Fuhrman as Esther in Orphan: First Kill from Paramount Players, eOne, and Dark Castle Entertainment. Photo Credit: Steve Ackerman/Paramount Pictures

Orphan: First Kill has the benefit of leaning into all the campy elements in the first film, which had to play them off as slightly more serious and presented Leena as a straightforward villain. I think the first film is well-made, definitely thrilling, and pretty shocking with some of the material it presents, and not just with Leenas twist. However, First Kill is where the fun begins and it centers the attention directly on Leena rather than the family shes infiltrating.

First Kill opens with Lena staging her escape from the Saarne Institute by seducing one of the guards and killing the institutes art therapist Anna. Because audiences are already familiar with the twist, First Kill wastes no time in presenting Leena as a homicidal, but calculated maniac. Leena researches missing American children with whom she bears a resemblance, choosing to pass herself off as Esther.

Within no time and hardly any investigation later, Esther is the in the states with her family the Albrights: mother Tricia (Julia Stiles), father Allen (Rossif Sutherland), and their son Gunnar (Matthew Finlan). Julia Stiles steals the spotlight as the matriarch of the Albright clan, and while Vera Farmigas character in Orphan was beaten down and broken by tragedy, Stiles Tricia is the opposite: calculated, cruel, manipulative, and straight-up evil.

You see, the twist of First Kill is that Julia was responsible for killing her own daughter Esther and staging her kidnapping to protect the reputation of her equally as awful son Gunnar. Leenas arrival as Esther presents Julia with an unexpected opportunity, to save her marriage with her unaware husband and position her family back to the top of the social ladder. Julia wastes no time in letting Leena know shes on to her, suddenly forcing the audience to take Leenas side as she faces off against someone whos just as manipulative and cruel.

First Kill takes the psychological elements present in Orphan and turns them on their head for a ridiculous slasher film that allows itself to have fun with its premise. Sure the film might have some plot holes and other elements worth critiquing, but at the end of the day, its an entertaining outing with Esther, who I would love to see in more films. A certain suspension of disbelief is required when tuning in to films like Orphan: First Kill.

Sometimes its okay to have fun with a movie and relax the expectation that each new film will break the mold or be the next huge thing. To be honest, I was grinning the entire movie because its just what I like in a horror flick, unapologetic fun, and off-the-rails insanity.

Orphan: First Kill is currently streaming on Paramount+.

Do you think Orphan: First Kill deserves a spot on your October watch list? Tell us why or why not in the comments section.

View original post here:
31 days of horror movies: Orphan: First Kill is a reminder to have fun with movies - 1428 Elm

Recommendation and review posted by Bethany Smith

The fourth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO "blue book"), published in 2016, contains significant revisions. These revisions were performed after consideration by a large international group of pathologists with special expertise in this area. A subgroup of these persons met at the WHO Consensus Conference in Zurich, Switzerland, in 2015 to finalize the revisions. This review summarizes the most significant differences between the newly published classification and the prior version for renal, penile, and testicular tumours. Newly recognized epithelial renal tumours are hereditary leiomyomatosis and renal cell carcinoma (RCC) syndrome-associated RCC, succinate dehydrogenase-deficient RCC, tubulocystic RCC, acquired cystic disease-associated RCC, and clear cell papillary RCC. The WHO/International Society of Urological Pathology renal tumour grading system was recommended, and the definition of renal papillary adenoma was modified. The new WHO classification of penile squamous cell carcinomas is based on the presence of human papillomavirus and defines histologic subtypes accordingly. Germ cell neoplasia in situ (GCNIS) of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours, and testicular germ cell tumours are now separated into two fundamentally different groups: those derived from GCNIS and those unrelated to GCNIS. Spermatocytic seminoma has been designated as a spermatocytic tumour and placed within the group of non-GCNIS-related tumours in the 2016 WHO classification.

Patient summary: The 2016 World Health Organization (WHO) classification contains new renal tumour entities. The classification of penile squamous cell carcinomas is based on the presence of human papillomavirus. Germ cell neoplasia in situ of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours.

Keywords: Male genital organs; Urogenital tract; WHO classification.

See more here:
The 2016 WHO Classification of Tumours of the Urinary System and Male ...

Recommendation and review posted by Bethany Smith

Most species of squirrels -- rodents that inhabit various regions across the globe -- can be grouped as tree or ground squirrels. Information about each groups behaviors and physical traits provides insight needed to determine whether the squirrel of that group is male or female. The sex of a squirrel is difficult to determine if attempting to go by obvious physical characteristics, because male and female squirrels are usually of the same size, shape and color.

Both male and female squirrels are communal, interacting with other squirrels within their immediate living area. However, the nesting habits of male and female tree squirrels differ. Males can be observed nesting together during winter months. It is uncommon for some female tree squirrels, such as fox squirrels, to nest together. An adult squirrel observed interacting with a litter is likely to be the mother of the litter. Male squirrels of any kind do not participate in the rearing process.

Female ground squirrels emerge from hibernation later than their male counterparts. For this reason, ground squirrels observed the soonest after a hibernation period are more likely to be male. Juvenile ground squirrel males exhibit much more movement, exploration and boldness compared to juvenile females. In accordance with this increased movement and exploration, all male juvenile ground squirrels leave the area in which they are born by the time they are one year old. Female ground squirrels stay near the burrows they were born in and form communes with other related females.

The squirrel mating ritual involves a single male or multiple males chasing a female. The males also compete with each other by chasing each other. The most dominant male is the one who typically mates with the female first. The female will sometimes mate with additional suitors afterwards. For some species of tree squirrels, the mating window is so short that the female only remains in estrus, the period of time when pregnancy is possible, for a few hours.

Certain telltale traits of male and female squirrels emerge during the mating season. The scrotum of male squirrels becomes visible because it enlarges and descends. During non-mating periods, the testes are withdrawn into the body. The nipples of adult female squirrels become more prominent during the mating season. The location of the genitals differs between male and female squirrels. The male reproductive organs are located closer to the navel, while the females' are located closer to the anus.

To prevent injury to themselves or the rodents, people should avoid attempting to handle wild squirrels. Feeding squirrels with human food or even a squirrel feeder is discouraged for several reasons. These reasons include accidentally providing food for invasive species, diminishing squirrels' protective fear of humans or providing unhealthy food to the squirrels.

See the article here:
How to Tell If a Squirrel Is Male or Female | Sciencing

Recommendation and review posted by Bethany Smith

Since the dawn of civilization, people have searched for the secret to long life. Famously, Gianni Pes, Michel Poulain and Dan Buettner proposed that diet drives a persons longevity. Other researchers have favored a genetics based explanation for longevity. Recently, a study published in Science found that a mouses genes determine its lifespan, and that there are human orthologs, or analogous genes. The study also found that female and male mice have different genes controlling their lifespans, which is interesting considering that female mice have longer lifespans. The study firmly lands on the side of those who have argued that genes directly determine lifespan. This means that reducing the risk of disease alone is not enough to increase longevity.

While the idea of aging is universal, in scientific terms, it does not have a precise measure. Much as Socrates asked us to investigate the real meaning of widely discussed concepts, scientists have had to work out ways to measure aging, and, this implies, asking what aging really is. Broadly, as the authors of the study note, it is a progressive decline in physical, mental and reproductive capacities, in which a person accumulates morbidities and the risk of dying increases. However, it is not known what the exact interplay is between genes, sex and environment, in determing lifespan.

Researchers have measured aging through a number of traits, such as lifespan, and age-related disease onset. Researchers believe that if they can figure out what the genetic and nongenetic drivers of longevity are, they can develop treatments to improve not just quality of life, but longevity.

A team of scientists led by Robert Williams, looked at the determinants of longevity in 3276 UM-HET3 mice, a type of, or genetically diverse mice that the National Institute on Agings (NIA) Interventions Testing Program (ITP) had been studying. The NIAs TIP had collected this data in 2003, when they were trying to see if dietary interventions would affect the longevity of mice. The mice were raised in closely controlled, homogeneous conditions, and the program collected tissue from them, so they could isolate the impact of genes on the lifespan of mice. The diversity of mice was a result of the need to mirror the diversity in the human genepool. Typically, mice do tend to inbreed, and this warps studies on longevity.

The NIAs TIP did not study the genetic drivers of longevity, and that is the point at which Robert WIlliams and his team began their study. The team were charged with figuring out whether the genetic drivers of longevity are related to sex and age, and whether the nongenetic drivers, such as litter size, or having a good diet from early in life, was important to longevity. In studying these drivers, they were able to classify the changes in liver gene expression of mice in the same genetic cross, according to whether they were driven by age or genotype. The last step in the study was to bring those results together with the orthogonal or itnesecting datasets, to undertake quantitative trait locus mapping, associating phenotypes with genotypes. This would allow the team to figure out which genes are associated with increased longevity.

The team was able to determine genetic loci important for longevity. Sevel of these loci were found in female mice, but, at first, no genetic loci linked specifically to longevity in male mice, were found. When the scientists removed the data for male mice who died at the beginning of the study, they then found genetic loci associated specifically with longevity in male mice. They also found that the factors such as body weight and litter size also impact longevity. For instance, mice with larger body weights and who grew up in smaller litters, died earlier. Consequently, genes linked to body weight and litter size could arguably be linked to longevity. Longevity could be indirectly impacted by the effect of these genes on those factors. However, it is important to note that not all longevity genes are correlated with those factors, opening up the door to the possibility that there are other genes influencing longevity.

The goal of this study was to say something meaningful about longevity in humans, so the study then went to human genome biobanks, and the researchers found sequences that mirrored those in mice. In addition, there was a similar relationship between early development and longevity. They then looked at genes in worms, to see if a similar relationship existed, and if broader conclusions could be drawn about the association of these genes and longevity. Ultimately, they concluded that genes are the primary determinants of longevity.

Go here to see the original:
The Genetic Drivers Of Longevity In Mice, Humans And Worms - Science 2.0

Recommendation and review posted by Bethany Smith

When youre trying to conceive or dealing with fertility issues, it may be tempting to reach for one of the many supplements marketed to boost male fertility. However, research on the safety and efficacy of these supplements is limited.

Since supplements arent regulated by the U.S. Food and Drug Administration (FDA) the way medications are, it can be challenging to know if a supplement contains what it says it does, and what effect it will have on the body, explains Philip Cheng, M.D., a male infertility doctor and urologist with Reproductive Medicine Associates of New Jersey. In order to get the nutrients you need to support healthy sperm production, he recommends focusing on a healthy diet.

Research suggests the following supplements may improve sperm quality, especially if you arent getting enough of the nutrients they provide through your dietbut remember, its always a good idea to check with your physician before adding new supplements to your regimen to avoid interactions with any medications you are taking.

Research notes Coenzyme Q10, also known as ubiquinol, is one of the most studied and promising supplements for improving male fertility. Coenzyme Q10 is an antioxidant naturally produced in your body and stored in your mitochondria (the energy factories in your cells). Its antioxidant properties may help protect sperm from damaging free radicals.

One review found that men who supplemented with CoQ10 experienced significant increases in sperm concentration and sperm motility compared to those who took a placebo.

Russell Hayden, M.D., a Harvard-trained urologist with a sub-specialty in male infertility and microsurgery, recommends 300 milligrams to 400 milligrams of a generic coenzyme Q10 supplement daily to his male infertility patients.

When it comes to supplements for male fertility, DHA omega-3 fatty acid supplementation appears to have some of the strongest data supporting its use, says Lauren Manaker, a registered dietitian and author of Fueling Male Fertility.

Fatty acids like docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are important components of sperm cell membranes, and omega-3 fatty acid intake directly correlates to sperm qualityso the more you consume, you may have higher quality of sperm.

A recent review on the effects of the omega-3 fatty acids EPA and DHA on male infertility found that men who took omega-3 treatments had significantly increased sperm motility compared with men who took a placebo.

If your intake of omega-3s from foods like fatty fish, walnuts, chia and flax seeds is low, you might benefit from taking a supplement.

Women who are trying to conceive are routinely advised to take a prenatal vitamin, but mens prenatals are starting to become popular as well, notes licensed dietitian Becca Romero, a functional nutritionist specializing in fertility. She recommends mens prenatal multivitamins WeNatal For Him and Needed to her patients.

WeNatal For Him is a prenatal supplement for men that is formulated to support overall sperm health. It contains a range of vitamins and minerals along with other ingredients and antioxidants that are marketed to boost male fertility, like maca, CoQ10 and acetyl L-carnitine.

Needed Mens Multi is recommended for men before conceiving and in the years that follow. It contains a wide range of vitamins and minerals, as well as an organic antioxidant blend of foods like grape, cranberry, pomegranate, blueberry, apple, mangosteen, bilberry, chokeberry and goji berry.

A male prenatal multivitamin can fill any nutrition gaps in your diet and help you avoid deficiencies that could impact your sperm quality. When choosing a mens prenatal supplement, steer clear of formulations that contain unstudied ingredients or excessive amounts of vitamins and minerals.

Read the rest here:
A Guide To The Best Fertility Supplements And Vitamins For Men - Forbes

Recommendation and review posted by Bethany Smith

House of the Dragon fans were left scratching their heads last week when the children of a Targaryen and Velaryon union had dark hair.

Viewers saw how the children of Princess Rhaenyra Targaryen (Emma D'Arcy) and Laenor Velaryon (John Macmillan) were fair skinned, brunette ladsthe complete antithesis of their platinum haired parents.

Laenor also happens to be black, adding further mystery to the children's appearance.

House of the Dragon quickly explains the anomaly, revealing the boys were the result of Rhaenyra's affair with Ser Harwin Strong.

In George R. R. Martin's book upon which House of the Dragon and its predecessor Game of Thrones are based, the Targaryens are described as having silver-gold hair with purple eyes that was so distinct it almost looked white thanks to their Valyrian heritage.

Even knowing the boys' true lineage, their brunette coloring still does not entirely explain why their mother's half-siblingsAegon II (Ty Tennant), Helaena (Evie Allen) and Aemond (Leo Ashton)sport the trademark Targaryen blondeness.

They are also the products of a mixed-race union, that of King Viserys Targaryen (Paddy Considine) and Alicent Hightower (Olivia Cooke), a very brunette queen.

In fact, another famous Targaryen from the original Game of Thrones series, Jon Snow (Kit Harrington), was well known for his luscious locks of dark curly hair.

Born as Aegon Targaryen, Snow was the son of Lyanna Stark and Rhaegar Targaryen, a fact only revealed towards the final episodes of the HBO series.

Plenty of fans have theorized over the years as to why some of the most important Targaryens are not blonde at all.

Using 'real world' genetics they analyzed how it would be possible for some mixed race Targaryens are born fair-haired while others do not.

The fans used genome knowledge of dominant and recessive genes to make their conclusions. A dominant gene "refers to the relationship between two versions of a gene," according to the National Genome Research Institute.

Individuals receive two versions of each gene from each of their parents and if the genes differ, the dominant gene will present in their offspring, whether it be in hair color, susceptibility to disease, or other markers.

Fans concluded the Targaryen genes were recessive, but when it came to children of a Targaryen male and non-Valyrian mother their first would be born with darker features, while subsequent offspring were blonde.

"Targaryen males somehow transfer Targaryen traits to their wives and lovers, so second child of the couple inherits Targaryen traits from both mother and father and has Valyrian look. Targaryen genes are somehow "infectious," wrote one fan on a Game of Thornes forum.

This theory works well to explain Snow's dark hair, but is not conclusive because the law of recessive and dominant genes do not seem to be applied consistently across Westeros.

Game of Thrones blogger, Lady Knits A Lot, pointed out that in the original books, three of the five children of Ned and Catelyn Stark were born with the "'Tully look' of red hair and blue eyes, and both of these traits are recessive traits."

"[But] Ned's parents, grandparents and damn near the entire North are described as dark haired and grey eyed," they added.

"So maybe recessive traits are a furphy that we should ignore in Westeros?"

This point was reinforced by Robert Oliver, co-host of The Longest Night podcast dedicated to talking all things Game of Thrones and House of the Dragon.

Oliver told Newsweek the inconsistencies across the shows come down to the fact that how these characters look is key to a plot point.

Rhaenyra's children prove she had an affair, and Jon's very dark hair helped hide the fact he was a Targaryen until the final season.

"It's just storytelling, it needs to be done to move a plot forward," he told Newsweek.

In the case of the House of the Dragon, Rhaenyra's children portrayed as brunette are critical to the conflict which is about to ensue within the dynasty.

"For the purposes of the show, I think what it's doing is it's helpful for Alicent who is trying to implore and impress upon everybody that surrounds her that Rhynaera is not worthy and her children aren't worthy," she said.

"And that it's her children [Alicent's] who should rule after Viserys."

Oliver's assertion comes after Martin himself admitted things don't always add up in the books or series, because it's a fictional world.

"What the fans have to keep in mind... but we're making this s**t up," he told the History of Westeros YouTube channel.

See original here:
Why Not All 'House of the Dragon' Mixed Race Targaryens Are Blonde - Newsweek

Recommendation and review posted by Bethany Smith

Like a few other plant species, cannabis plants can be male or female and sometimes hermaphrodite. For growers of these dioecious plants, its crucial to determine their gender on time.

To the untrained eye, these plant genders have no obvious differences. However, expert growers can identify some early tell-tale signs of the plants gender.

Thus, contrary to popular belief, you can tell a plants gender even before its flowering. After a while of growing cannabis plants, it becomes easier to tell which of your plants are male and female.

Even after four weeks of germination, while plants are still in a vegetative phase, some signs could help you identify the gender of your cannabis plants. The difference between both genders is apparent in the appearance of their pre-flowers, just 3 to 6 weeks after germination.

The gender of a cannabis plant would determine its potency. Female cannabis plants grow highly resinous buds that are rich in cannabinoids such as delta-9 THC. On the other hand, male cannabis plants have low levels of THC.Some of the delta-9 THC products include delta-9 gummies, vapes and tablets.

For this reason, many growers focus on growing only female plants. Growers would prefer the entire crop to be female cannabis to prevent seed production due to male and female plant fertilization.

Plants that have been fertilized have a lower cannabinoid content than unfertilized female plants. With fertilized female buds, youll find more seeds in the crop and fewer THC-rich buds.

The seedless female plant, Sinsemilla, is loved by many for its high THC content and for the duration of time it keeps producing buds.

Some growers use feminized seeds to ensure that every one of their plants is female. If you plant regular cannabis seeds, your harvest will likely be equal parts male and female.

An important identifier of the male cannabis plant is that it does not produce buds. Instead of buds, the sex organ of these male marijuana plants produces pollen sacs. These pollen sacs are responsible for fertilizing the female buds to produce seeds.

Growers do all to avoid having seedy female buds, as these buds produce poor-quality cannabis. This cannabis is not potent and has low levels of cannabinoids. Growers are wary of this situation.

Thus, they always remove the male and hermaphrodite cannabis plants from the crop. If you do this early enough, you can protect your female buds and reap a bountiful harvest.

During a cannabis first sign of flowering stage, you can identify a female plant by its buds. The plants teardrop-shaped buds begin to produce white hairy strands called stigma.

These stigmas protrude from the buds of a female plant, forming a part of the female reproductive organ (pistil). The pistils are located at the plants node, which is the point where the branches grow out of the plants stalks.

These wispy white hairs appear four to six weeks after germinating a cannabis plant. Over time, the white hairs begin to get darker.

Depending on several factors, the female plants pistils and stigma can grow at the top or lower regions of the marijuana plant. However, it is more common to see them growing at the top part of the plant, close to the light source.

The sex organs of the male and female cannabis plants differ significantly. You can identify that a cannabis plant is male as early as four weeks after germinating. This is unlike the female plant that often gets to six weeks before revealing its sex.

Unlike female plants, male cannabis plants produce pollen sacs. These sacs are situated at the points between the nodes and the plants stalk. At first, these sacs appear to look like female buds.

However, they do not have the white hairs that female sacs are known to produce. Also, the male pre-flowers often resemble the shape of a spade, unlike young female buds that have a teardrop shape.

Besides these, there are other morphological features that each plant produces that can help you easily identify their gender. One of these identifiers is the length of the plant. More often than not, male plants tend to grow taller than female marijuana plants.

Also, the stalks of the male marijuana plant would be much thicker to provide support for the plants weight. Generally, a female plant would look shorter and bushier than a male plant.

These attributes are, however, not a conclusive way to identify gender. Some conditions could cause your plant not to appear how it should. The surest way to identify your plants gender remains by the appearance of buds or pollen sacs.

Certain conditions can cause a cannabis plant to become hermaphrodite. Such a plant would have both male and female reproductive organs. Deficiencies in nutrients, disease and other stressful conditions can often lead to a plant forming both sex organs.

The first way to identify a hermaphrodite plant is when it grows both male pollen sacs and female buds. Another sign is when anthers begin to grow among the plants buds. An anther has a yellowish color and is shaped like a banana.

These anthers are capable of fertilizing the female plant as soon as they start forming. Thus, its important to look out for any appearance of anthers in your female crop and trim them off to protect your female plants.

Inspecting your female plants to ensure they do not have male sacs is crucial, as this could lead to self-pollination. Its essential to do this, as even just one hermaphrodite plant can pollinate your entire crop of plants and reduce the quality of your yield.

Even to expert growers, it is impossible to tell the gender of a seed by simply looking at it. The only way to tell its gender is to plant it and wait some weeks for it to mature. The growth of buds or sacs will help you easily identify your male and female plants.

However, some seeds called feminized seeds are bred to grow only female plants. You can even grow some of the top rated CBD strains or weed strains to sell them and earn profit. Thus, if you acquire feminized cannabis seeds from a reputable vendor, you are certain to grow female plants.

Note, however, that it is possible for a small percentage of feminized seeds to sprout hermaphrodite plants. This might be a result of less-than-ideal growing conditions and genetics.

All in all, always ensure to check your female crops frequently to ensure that none are becoming hermaphrodites. If you purchase feminized seeds, also ensure to check your crop to ensure that your vendor mistakenly added no male seeds to the feminized seeds.

Chemical leaf testing has become a popular means of identifying the gender of a cannabis plant. Its become a popular alternative to visual inspection, as the plants can take up to six weeks to reveal their gender.

A chemical test can be carried out on the plants leaves to determine its gender just a few days after germinating.

This chemical test involves the use of DNA and can identify other features of the plant, like its cannabinoid content. Chemical tests have become the go-to choice for expert growers who wish to identify their plants gender early.

To reduce the likelihood of producing hermaphrodite plants, avoid any stress and triggers when the plant is flowering.

To ensure optimal growing conditions, you should observe perfect hygiene and use a balanced nutrient solution to water the plants.

Some growers will retain their male plants for genetic pool diversity. Inbreeding plants and self-pollination can increase the future probability of hermaphrodite plants.

Thus, some growers might keep male plants for that purpose. However, it would be best if you did not keep the male plants close to the female or handle the female plant after contacting pollen grains.

These male plants also produce some terpenes that are great for pest control. Unlike female flowers, male flowers could also contain limited amounts of cannabinoids like CBD and THC and can be used to make hashish.

If you are a hobbyist or expert cannabis grower, you already know that female plants are the most desirable. They produce high-quality cannabis rich in cannabinoids like THC. Thus, its necessary to find out the gender of your plants on time.

Wispy white hairs on the nodes of your plant signify a female cannabis plant, while pollen sacs signify a male plant. However, since these signs can take up to six weeks to show, you might want to consider chemical leaf testing.

All in all, ensure to check your crop often to identify male or hermaphrodite plants and cut them off.

Multiplex Content Recommendation - 1

Read more:
Early Signs Of Male Plant And Female Plant-How To Identify The Difference? - The Island Now

Recommendation and review posted by Bethany Smith

Identification of the CYCD and CDK gene families in Populus tomentosa

To identify CYCD and CDK genes in P. tomentosa, hidden Markov models (HMMs) and Blastp were used to query the whole genome. After the elimination of redundant sequences and examination of domains, we finally identified 43 CYCD and 27 CDK family members (Table S1). A phylogenetic tree was constructed with 24 CYCD and 18 CDK in Populus trichocarpa (PtrCYCD and PtrCDK) to classify and name the successfully identified members12 (Fig.1). Results showed that 47 PotomCYCDs were divided into six subclasses, of which 12, 4, 10, 6, 9 and 2 members belonged to D1, D2/4, D3, D5, D6 and D7 subclasses, respectively. A total of 27 PotomCDKs were divided into seven subclasses, which belonged to 2 members of the CDKA subclass, 1 member of the CDKB subclass, 5 members of the CDKC subclass, 4 members of the CDKD subclass, 4 members of the CDKE subclass, 2 members of the CDKF subclass, and 9 members of the CDKG subclass. The identified members of the P. tomentosa gene family were named in accordance with the gene family members of P. trichocarpa. Considering that P. tomentosa is an allodiploid, a was added to the name of the gene searched from subgenome A (PtA), and b was added to the name of the gene searched from subgenome D (PtD). In phylogenetic tree analysis, most of genes had their alleles with close relationships. However, we found PotomCYCD6;3a was closer to the orthologs gene PtrCYCD6;3 rather than its allele PotomCYCD6;3b. This phenomenon was also found between PotomCYCD3;5, PotomCYCD5;1, PotomCYCD7;1, PotomCDKA;1, PotomCDKE;1 and PotomCDKF;1 and there corresponding orthologs, which revealed that these alleles differentiated during the evolutionary process. An interesting finding was that a small number genes PotomCYCD6;2b, PotomCDKG;2a, PotomCDKC;2a, PotomCDKC3;b, PotomCDKC4;b and PotomCDKB1;1a were lack of their alleles. We speculated that it was the chromosomal variation and transposon insertion that resulted in the loss of these alleles. All these evidences indicated that PotomCYCDs and PotomCDKs were both conserved and differentiated.

Phylogenetic tree analysis of D-type cyclin (CYCD) and cyclin-dependent kinases (CDK) gene family in P. tomentosa and P. trichocarpa. A PotomCYCA gene from P. tomentosa genome was selected as an outgroup gene. (a) Phylogenetic tree analysis of 43 PotomCYCDs and 22 PtrCYCDs. All CYCDs were classified into six distinct groups on the basis of the subfamily of P. trichocarpa CYCDs (from D1 to D7) and were distinguished by different colours. (b) Phylogenetic tree analysis of 27 PotomCDKs and 18 PtrCDKs. All CDKs were classified into seven distinct groups on the basis of the subfamily of P. trichocarpa CDKs (from CDKA to CDKG) and were distinguished by different colours.

To analyse the sequence differences of alleles from different subgenome, we analysed the protein sequence identity of all members of the two gene families. Results showed that in the PotomCYCD gene family, PotomCYCD1;3a and PotomCYCD1;3b (99.0%) had the highest sequence similarity, and PotomCYCD1;2a and PotomCYCD1;2b (80.6%) had the lowest sequence similarity (Table S2). In the PotomCDK gene family, the highest sequence similarity was PotomCDKE;2a and PotomCDKE;2b (99.5%), and the lowest sequence similarity was PotomCDKA;1a and PotomCDKA;1b (82.4%, Table S3). At the same time, we also investigated the basic characteristics of the two family members, such as their AA length, isoelectric point (PI), molecular weight (MW), and subcellular localization (Table S4). Results showed that the AA length of PotomCYCD gene family varied from 256 to 408 AA. The largest protein was PotomCYCD2;1b (45.24kDa), and the smallest protein was PotomCYCD6;2b (29.51kDa). The PI of most CYCD proteins varied around 57. Subcellular localisation prediction results indicated that all PotomCYCD proteins were located in the nucleus. The difference was that the basic characteristics of different subclasses of proteins in the PotomCDK gene family varied remarkably, but the characteristics of different members of the same subclass were relatively similar. The CDKG subclass (except PotomCDKG;2a) had the largest protein (78.6589.63kDa), and the CDKA and CDKB subclasses had the smallest protein (33.7936.53kDa). Although PotomCDKG;2a is only 117aa in length, it contains part of the conserved domains required by CDK, and it is speculated that it might not be functional due to its short length or mutated during evolution. The protein PIs of different CDK subclasses different but were very similar in the same subclass. Subcellular localisation prediction results showed that all PotomCDK proteins were located in the nucleus and that PotomCDKA;1b might also be located in the cytoplasm. PotomCDKG;4b might also be located in the cell membrane and cytoplasm. PotomCDKG;5a might also be located in the cell membrane.

Gene structural diversity and conserved motif divergence are possible mechanisms for the evolution of multigene families43. To further study the gene and protein structure of the CYCD and CDK gene family, we analysed the number and distribution of exons. The results of gene structure analysis showed that the structures of PotomCYCD genes were similar and that the number of exons varied from 4 to 7. The number of exons in the D3 subclass was 4, and the number of exons in other subclasses except PotomCYCD2;1b and PotomCYCD2;2a was 5 or 6 (Fig.2a). The results of the gene structure analysis of PotomCDK genes showed that the number of exons in CDK ranged from 1 to 13. The gene structure amongst members of the same subclass was relatively conserved. For example, none of the four members of CDKE were introns. Amongst the nine members of CDKG, eight members consisted of 1 long exon and 5/6 short exons. A high number of exons were found in CDKA and CDKC, whereas only 3 exons were observed in the CDKF subclass (Fig.2c).

Gene structure and conserved motif compositions of PotomCYCDs and PotomCDKs. (a) Exon/intron structures of PotomCYCDs. (b) Architecture of conserved protein motifs of PotomCYCDs. (c) Exon/intron structures of PotomCDKs. Yellow boxes and black lines indicate exons and introns, respectively, at each CYCD and CDK gene. (d) Architectures of conserved protein motifs of PotomCDKs. These coloured boxes indicate distinct motifs and their corresponding positions in each CYCD and CDK protein sequence. The detailed characteristics of each motif are shown in Table S5.

To elucidate the distribution of the motifs in CYCD and CDK proteins and their function, ten types of motifs and their distributions of CYCDs and CDKs were predicted using the MEME program (Fig.2). Our results indicated that CYCDs contained similar motif types. However, some differences existed amongst different subclasses. Motifs 15 were contained in all subclasses. Motif 6 was unique to D1 and D2/4 subclasses. Motifs 7 and 8 were contained in most subclasses except D5 and D7. Motif 9 was only D7 subclass Class missing. Motif 10 was included in most subclasses except D1 and D2/4 (Fig.2b). In the CDK gene family, motif 1, 2 and 68 were included in all subclasses. Motif 3 was included in most subclasses except CDKA and CDKB. Motif 4 was not found in CDKA subclasses. Motif 5 was not found in CDKF. Motif 9 was only found in CDKE and CDKG subclasses. Motif 10 was unique to CDKG (Fig.2d). Some interesting findings appeared in some alleles. The PotomCYCD5;1a has one more exon than its allele PotomCYCD5;1b and motif 3 presented in the former but not the latter. PotomCYCD6;2b without allele was lack of motif 7 when comparing to other PotomCYCD6. PotomCDKB1;1a, the only one member in PotomCDKB, had almost the same motifs but an extra motif 4 than the PotomCDKA;1. PotomCDKC;4b was lack of the motif 3 and motif 5 when comparing to other PotomCDKC. These findings revealed that some special alleles might have different gene structures and conserved motifs leading to different functions.

At the same time, we analysed the domains and conserved motifs of CYCDs. LxCxE is a key motif for CYCD binding to RBR33. The PEST sequence, a region full of P(Pro), E(Glu), S(Ser) and T(Thr), might result in itself degradation and were often found in D-type cyclins32,33,34. Results showed that all PotomCYCD proteins had Cyclin_N and Cyclin_C domains. No LxCxE motif was observed in the CYCD6 subclass, and the LxCxE motif existed in other subclass proteins. Most CYCD proteins had the PEST motif, but the position of the PEST motif was not fixed (Fig. S1). Multiple sequence alignment with P. trichocarpa CDK gene family proteins showed that their conserved domains were highly consistent with their orthologous proteins in P. trichocarpa (File S1). Amongst them, CDKA had PSTAIRE, CDKB had PPTALRE or PPTTLRE, CDKC had PITAIRE, CDKE had SPTAIRE, and CDKG had PLTSLRE9. However, PotomCDKC;3b and PotomCDKC;4b were not observed with this characteristic motif.

Specific cis-element motifs can be recognised by transcription factors and participate in gene expression regulation. To further study the potential regulatory mechanisms of PotomCYCDs and PotomCDKs in a diversified biological process, particularly in plant hormones and specific expression, 2.0kb upstream sequences from the translation start sites of CYCD and CDK genes were submitted to the PlantCARE database to detect cis-elements. Results showed that the types and numbers of various cis-acting elements of genes in PotomCYCDs and PotomCDKs were similar, thereby implying their functional relatedness. Multiple hormone-responsive elements, such as ABA responsive (DRE1, ABRE, ABRE2, ABRE3a, ABRE4, TCA-element), auxin and/or salicylic acid activation (as-1), auxin responsive (TGA-element), ethylene responsive (ERE), gibberellin responsive (GARE-motif, P-box, TATC-box) and MeJA responsive (CGTCA-motif, TGACG-motif) elements, were found in cis-acting elements in two gene families. Cis-acting element prediction results showed that the two gene families had similar responses to hormones and had the most responsive elements responsive to ABA followed by ethylene responsive. The numbers and positions of various hormone responsive elements on the promoters of each gene are shown in the Fig. S2S3. In the CYCD gene family, the numbers of ABA responsive and ethylene responsive elements in the D7 subclass with only 2 members were 13 and 10, respectively, but no gibberellin responsive and auxin responsive elements were found in the D7 subclass, which might suggest that the D7 The subclass predominantly responded to ABA and ethylene. The number of MeJA responsive elements in the D5 subclass with 6 members was 18, which was the largest amongst all subclasses. This result might suggest that the D5 subclass predominantly responded to MeJA. In the D6 subclass with only 9 members, 16 Gibberellin responsive elements were found, accounting for the largest proportion and suggesting that the D6 subclass predominantly responded to gibberellin. The auxin responsive element was found in all D1D5 subclasses but not in D6 and D7 subclasses (Fig. S2). In the CDK gene family, the number of ABA and ethylene responsive elements in CDKD subclasses with only 4 members was as high as 20 and 17, but gibberellin responsive and auxin responsive elements were not found in CDKD subclasses, which might imply that CDKD subclasses responded to ABA and ethylene. The numbers of MeJA responsive, gibberellin responsive and auxin responsive elements accounted for 8, 3 and 2, respectively, in CDKF subclasses with only 2 members and had the largest proportion. Auxin responsive element was not found in CDKA, CDKB and CDKD subclasses (Fig. S3).

A number of specific expression elements was also found in cis-acting elements in the two gene families, and the proportions of specific expression elements in the two gene family members were also similar. Pollen specific activation elements were the most numerous, with 49 and 41 in CYCD and CDK families, respectively. In addition, two families also included some different cis-acting elements, such as the seed specific regulation element (RY-element) that only existed in the CDK gene family and the cell cycle regulation element (MSA- like) that only existed in the CYCD gene family (Fig. S2S3).

On the basis of the information from the P. tomentosa genomic database, we determined the chromosomal distributions of CYCD and CDK genes (Table S4). Results suggested that CYCD genes were distributed on 26 chromosomes, whereas CDK genes were mapped onto 21 chromosomes (Fig.3). Although 35 chromosomes contained CYCD or CDK genes, the overall distribution was mostly nonuniform. Chromosomes 2A, 2D, 14A and 14D all contained three CYCD genes, whereas only one CYCD gene was distributed on chromosome 4A. Chromosomes 12A and 12D both contained 3 members of CDK genes, whereas chromosome 1A contained only one CDK gene. Interestingly, chromosomes 16D, 17A and 17D did not contain any CYCD or CDK gene.

Circos figure for chromosome distribution with synteny links. Grey and colourful lines represent synteny blocks and duplicated CYCD and CDK gene pairs, respectively, in P. tomentosa. The gene ids in red font are members of the PotomCYCD gene family, and the gene ids in blue font are members of the PotomCDK gene family.

We constructed a synteny analysis between CYCD and CDK genes in P. tomentosa (Table S6). The synteny blocks and the duplicated CYCD and CDK gene pairs were showen by the grey and colourful lines (Fig.3). All CYCD genes and 24 of 27 CDK genes were identified as collinear genes involving WGD or segmental duplication, whereas 2 CDK genes (i.e. PotomCDKC;4b and PotomCDKG;2a) were considered as dispersed genes, and 1 CDK gene (i.e. PotomCDKB1;1a) was considered as a singleton gene (Table S6). Remarkably, some CYCD and CDK genes were associated with at least five syntenic gene pairs, which implied that these genes might be involved in some critical roles during the evolutionary process. Interestingly, tandem duplication events were not found between CYCD and CDK genes in P. tomentosa. Evidence suggested that WGD or segmental duplication led the expansion of CYCD and CDK genes in P. tomentosa.

To further explore the evolutionary relationships of the CYCD and CDK gene families, we performed syntenic analyses amongst Arabidopsis, P. trichocarpa and P. tomentosa (Table S7). Between Arabidopsis and P. trichocarpa, 7 CYCD and 11 CDK gene pairs were found. A total of 81 CYCD and 38 CDK gene pairs were identified between P. trichocarpa and P. tomentosa (Fig.4). We found that 4 of 7 CYCD gene pairs and 9 of 11 CDK gene pairs between Arabidopsis and P. trichocarpa, respectively, were distributed on chromosome 1 and 4 in Arabidopsis. In P. trichocarpa, CYCD gene pairs were predominantly distributed on chromosomes 1, 2, 7, 9, 14 and 19, whereas CDK gene pairs were predominantly located on chromosomes 1, 3, 8, 10 and 12. The situations of CYCD and CDK gene pair distributions on chromosomes in P. tomentosa were similar to P. trichocarpa. Between P. trichocarpa and P. tomentosa, although abundant gene pairs were identified, 1 CYCD (i.e. PotomCYCD6;3b) and 2 CDK (i.e. PotomCDKC;4b and PotomCDKG;2a) genes did not find any syntenic gene.

Synteny of CYCD and CDK genes in Arabidopsis, P. trichocarpa and P. tomentosa. Red and blue lines represent duplicated CYCD and CDK gene pairs, respectively.

To investigate the possible roles of the PotomCYCDs and PotomCDKs, the expression levels of 43 CYCD and 27 CDK genes were determined by transcriptome results in three various tissues, i.e. leaf, stem and root41. Our results indicated that CYCD and CDK genes showed similar expression profiles in different tissues. Most genes were expressed in all three tissues, and alleles from different subgenomes had similar or even the same expression pattern (Figs. S4S5). In CYCD and CDK gene families, most genes showed this expression trend, with the highest expression in stems, followed by roots and leaves. In the CYCD gene family, most D3 subclass gene expression levels conformed to this trend. However, CYCD3;1a, CYCD3;2a and CYCD3;2b gene expression levels were highest in roots, and the expression of CYCD3;2b in leaves was highest amongst all genes. In terms of the overall expression levels of genes in different subclasses, D3 subclass genes had the highest expression, followed by the D1 and D2 subclasses, whereas the D7 subclass was not expressed in all tissues. In the CDK gene family, the expression trends of CDKA and CDKB subclass genes were the same as those mentioned before. The genes of other subclasses are also highly expressed in leaves and roots, such as CDKC;1a/b and CDKG;1a/b had the highest expression in leaves and CDKC;2a/b and CDKG;4a/b had the highest expression in roots. In terms of the overall expression levels of genes in different subclasses, the CDKA subclass had the highest gene expression followed by the CDKG subclass. These results suggested that CYCD and CDK genes had similar expression patterns, implying their functional relevance, and the overall expression level of CYCD genes was lower than that of CDK genes. These results might also indicate that alleles with the same function as in an allodiploid species co-regulated the growth and development of the organism.

In order to analyze the interaction between different CYCD and CDK proteins, the STRING website was used to predict the interaction between different CYCD subclasses and CDK proteins. First, all PotomCYCD and PotomCDK genes were compared with the Arabidopsis database of the STRING website. The comparison results and annotation information are shown in Table S8. The interaction between different subclasses of CYCD and CDK was predicted and the line thickness indicates the strength of data support (Fig.5). Results showed that CDKA (CDC2) was at the core of the interaction relationship. The protein interaction prediction results showed that the D1 subclass could interact with CDKA, CDKD1;1 and CDKE;1 and had the strongest interaction with CDKA. The D2/4 subclass only could have a strong interaction with CDKA. In the D3 subclass, the proteins CYCD3;1 and CYCD3;3 were obtained from the alignment and could interact with CDC2 and CDKE;1, and the interaction with CDKA was stronger. The D5 subclass could interact with CDKA, CDKB1;2, CDKD1;1, CDKD1;3, CDKE;1 and CAK1AT (CDKF). The D6 subclass could interact with CDKA, CDKB1;2, CDKD1;1 and CDKD1;3 has an interaction relationship. The D7 subclass only had a weak interaction relationship with CDKA (Fig.5). These results suggested that different subclasses of CYCD proteins might differ in gene sequence and protein properties and in their interaction with CDKs.

Prediction of the interaction between different subfamilies of PotomCYCDs and PotomCDKs gene family proteins by using the STRING website. (a) Interaction between D1 subfamily and CDKs. (b) Interaction between D2/4 subfamily and CDKs. (c) Interaction between D3 subfamily and CDKs. (d) Interaction between D5 subclass and CDKs. (e) Interaction between D6 subfamily and CDKs. (f) Interaction between D7 subfamily and CDKs. Line thickness indicates the strength of data support.

Previous in vitro yeast two-hybrid (Y2H) experiments and molecular docking experiments showed that PtoCYCD3;3 protein interacts with 12 PtoCDK proteins, of which the strongest interaction is PtoCDKE;212. To verify the reliability of the in vitro Y2H results, in vivo validation in plants was performed using the Bimolecular Fluorescent Complimentary (BIFC) assay. The 12 PtoCDKs screened by Y2H and PtoCYCD3;3 were fused to the N- and C-termini of YFP to construct fusion vectors (YFPNPtoCDKs and YFPCPtoCYCD3;3), and transient infection mediated by Agrobacterium in two fusion proteins were co-expressed in the lower epidermal cells of tobacco. If the two proteins interacted, the two fragments of the fluorescent protein will be close to each other in space, complementary to each other and reconstructed into an active and complete fluorescent protein molecule, thereby generating fluorescence. At the same time, GUS was fused to the N-terminus of YFP (YFPNGUS) and co-expressed with YFPCPtoCYCD3;3 as a negative control. The 12 PtoCDKs (PtoCDKA;1, PtoCDKB1;1, PtoCDKB1;2, PtoCDKB2;1, PtoCDKB2;2, PtoCDKC;2, PtoCDKD;1, PtoCDKD;2, PtoCDKE;2, PtoCDKF;1, PtoCDKG;3 and PtoCDKG;4) and PtoCYCD3;3, showed fluorescence in the nuclei of tobacco epidermal cells (Fig.6). The results indicated that PtoCYCD3;3 also interacted with these 12 PtoCDKs proteins in plants.

BiFC validation in tobacco epidermis. PtoCYCD3;3 connects pSPYCE(MR) vector and PtoCDKs connects pSPYNE(R)173 vector. After co-expression in tobacco leaf epidermal cells, the fluorescence signal was observed under a laser confocal microscope. YFPC-PtoCYCD3;3+YFPN-GUS were used as negative control.YFP: yellow fluorescent signal; NLS-mCherry: nuclear signal localisation label; Bright field: brightfield vision; Merge: superposition of fluorescence signals, bar=50m.

Our previous research found that transgenic PtoCYCD2;1 and transgenic PtoCYCD3;3 poplars have completely opposite phenotypes. Transgenic PtoCYCD2;1 plants have reduced plant height, curled leaves and thin stems42, whereas transgenic PtoCYCD3;3 poplar plants have increased height, curled leaves, thickened stem and branched in advance12. Cloned PtoCYCD2;1 and PtoCYCD3;3 genes were combined with the CYCD gene families of P. tomentosa and P. trichocarpa to construct a phylogenetic tree. Results showed that PtoCYCD2;1 and PtoCYCD3;3 belonged to the D2 and D3 subclasses, respectively, and closely related to the PotomCYCD gene (Fig. S6).

In order to find out the interaction between PtoCYCD2;1 and PtoCDKs, in vitro Y2H and in vivo BIFC experiments were used to detect the interaction. Y2H vectors (pGBKT7PtoCYCD2;1 and pGADT7PtoCDKs) were constructed and co-transformed into yeast AH109 competent cells, and the successfully identified positive yeast strains were spread on different AA-deficient media for Y2H experiment. As a competitive inhibitor of HIS3, 3-AT can inhibit the expression of HIS3 to a certain extent by adding this substance to the culture medium. The growth rates on SD-Trp-Leu-His+10/20mM 3-AT and SD-Trp-Leu-His-Ade culture media were observed to detect the interaction strength between PtoCYCD2;1 and different PtoCDKs proteins. During the 6day observation period, PtoCDKD;3, PtoCDKF;1 and PtoCDKG;5 could grow on SD-Trp-Leu, SD-Trp-Leu-His+10/20mM 3-AT and SD-Trp-Leu-His-Ade culture media, suggesting the strongest interaction. PtoCDKA;1, PtoCDKB1;1, PtoCDKB2;1, PtoCDKB2;2, PtoCDKD;2, PtoCDKE;1, PtoCDKE;2 and PtoCDKG;1 could grow on SD-Trp-Leu, SD-Trp-Leu-His+10/20mM 3-AT culture media, suggesting a strong interaction. PtoCDKC;1, PtoCDKD;1, PtoCDKG;3 and PtoCDKG;4 could only grow on SD-Trp-Leu culture medium, but not on SD-Trp-Leu-His+10/20mM 3-AT and SD-Trp-Leu-His-Ade culture media, indicating that no direct interaction between these proteins (Fig.7). The growths on the SD-Trp-Leu-His+10/20mM 3-AT and SD-Trp-Leu-His-Ade culture media for 3 and 6days were photographed and observed, and the interaction strength of the PtoCDKs gene family members with PtoCYCD2;1 was observed to have the following relationships: PtoCDKD;3=PtoCDKF;1=PtoCDKG;5>PtoCDKA;1>PtoCDKG;1>PtoCDKE;2>PtoCDKE;1>PtoCDKB2;1>PtoCDKB2;2>PtoCDKD;2>PtoCDKB1;1.

Proteinprotein interactions of PtoCYCD2;1 with PtoCDKs. Yeast cells were co-transformed with pGBKT7 and pGADT7 constructs carrying the corresponding genes and grown on SD-Trp-Leu, SD-Leu-Trp-His+10mM 3-AT, SD-Leu-Trp-His+20mM 3-AT, SD-Leu-Trp-His-Ade. AD+BD, AD+BD-PtoCYCD2;1 and AD-PtoCDKs+BD, were used as negative control. Day represents the number of days of growth on the corresponding medium. The triangle represents dilution in a 0.1-fold gradient (1,0.1 and 0.01).

To verify the interaction between PtoCYCD2;1 and PtoCDKD;3, PtoCDKF;1, PtoCDKG;5 and the fastest-growing PtoCDKA;1 on SD-Trp-Leu-His+10/20mM 3-AT culture medium in plants, we successfully constructed BIFC vectors (YFPNPtoCDKs and YFPCPtoCYCD2;1), which were transiently expressed in the lower epidermis of tobacco through Agrobacterium-mediated transient infection. Results showed that only PtoCDKA;1 and PtoCYCD2;1 showed fluorescence in the nuclei of tobacco cells and that PtoCDKD;3, PtoCDKF;1, PtoCDKG;5 and PtoCYCD2;1 co-expressed no fluorescence signal (Fig.8). These results indicated that PtoCYCD2;1 only interacted with PtoCDKA;1 in plants.

BiFC validation in tobacco epidermis. PtoCYCD2;1 connect pSPYCE(MR) vector and PtoCDKs connect pSPYNE(R)173 vector. After co-expression in tobacco leaf epidermal cells, the fluorescence signal was observed under laser confocal microscopy. YFP: yellow fluorescent signal; NLS-mCherry: nuclear signal localisation label; Bright field: bright field vision; Merge: superposition of fluorescence signals. Scale bars forYFPC-PtoCYCD2;1+YFPN-PtoCDKD;3, 50m; for others, 25m.

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Study on the interaction preference between CYCD subclass and CDK family members at the poplar genome level | Scientific Reports - Nature.com

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Researchers performed a nationwide cohort study of the use of calcium-channel blockers and adenosine modulators and risk of hospitalization in bipolar disorder.

CASE VIGNETTE

Mr Amir is a 48-year-old male from the Balkans with a 17-year history of bipolar I disorder with psychotic features. He was last hospitalized for affective symptoms at age 35. He has chronic insomnia, low energy, impaired concentration, and suspiciousness. He also has episodic irritability and anger. He has been on a stable psychotropic regimen of quetiapine 100 mg in the morning and 400 mg at bedtime, and valproic acid 750 mg daily. Mr Amir was diagnosed with comorbid hypertension after multiple elevated readings at his outpatient psychiatry visits. He does not have a primary care physician, so his psychiatrist started him on amlodipine, which was titrated to 10 mg daily. His blood pressure control subsequently improved, without any change in his psychiatric symptoms.

Inadequate response and treatment resistance remain issues in bipolar disorder.1 One approach to identifying novel treatments is drug repurposing, whereby a drug approved for 1 disease is investigated for its potential for a new indication. Previous reviews include the adenosine modulator allopurinol2 and calcium-channel blockers (CCBs)3 for potential repurposing in bipolar disorder, although evidence for the latter has been inconclusive. Allopurinol and dipyridamole are adenosine modulators that may have potential in the treatment of bipolar disorder and other severe mental illnesses.4 Allopurinol is a xanthine oxidase inhibitor used to treat gout and hyperuricemia.4 Dipyridamole is an antithrombotic and vasodilator that inhibits adenosine reuptake.5

The Current Study

Lintunen and colleagues6 investigated the risk of psychiatric hospitalization associated with CCBs (dihydropyridines, verapamil, diltiazem) and adenosine modulators (allopurinol, dipyridamole) in a nationwide Finnish cohort of individuals with bipolar disorder. They identified individuals diagnosed with bipolar disorder between 1987 and 2018 from inpatient, specialized outpatient, sickness absence, and disability pension registers. Follow-up started on January 1, 1996, or at the date of diagnosis, and ended at death, diagnosis of schizophrenia, or on December 31, 2018 (whichever occurred first).

The primary exposures were use of CCBs and adenosine modulators. Thiazide diuretics were used as a negative control. Information on medication use was obtained from the Prescription Register and modeled with PRE2DUP method, which predicts periods of use and non-use.7 The primary outcome was hospitalization due to affective symptoms, based on the Hospital Discharge register. Secondary outcomes were hospitalization due to manic or depressive symptoms or any psychiatric hospitalization. The risk of non-psychiatric hospitalization was also analyzed to consider potential adverse somatic effects of CCBs or adenosine modulators.

Data were analyzed using within-individual models, where individuals act as their own control, based on periods of exposure and non-exposure, using stratified Cox regression. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated for hospitalization-based outcomes comparing periods when the individual was using versus no using the medication. Models were adjusted for use of antipsychotics, mood stabilizers, benzodiazepines and Z-drugs, antidepressants, temporal order of treatments, and time since cohort entry.

The study cohort included 60,045 individuals, with a median follow-up of 8.4 years. Approximately 9056 individuals (15%) used primary dihydropyridines (91%). The most commonly used dihydropyridine was amlodipine (64%). Approximately 2967 individuals (5%) used adenosine modulators (57% allopurinol and 43% dipyridamole). Thiazides were used by 1286 individuals (2%).

Use of CCBs was associated with a decreased risk of hospitalization due to affective symptoms (aHR=0.83, 95% CI 0.78-0.88). The beneficial effect was associated with diltiazem and dihydropyridines, but not verapamil. Results were similar for hospitalization due to depressive symptoms or any reason. However, verapamil and dihydropyridinesbut not diltiazemwere associated with decreased risk of hospitalization due to mania.

Use of adenosine modulators was associated with a decreased risk of hospitalization due to affective symptoms (aHR=0.87, 95% CI 0.79-0.96). Effects were similar for both allopurinol and dipyridamole. Results were similar for any psychiatric hospitalization. Allopurinol, but not dipyridamole, was associated with a decreased risk of hospitalization due to depressive symptoms. There was no association between adenosine modulators and hospitalization due to manic symptoms. Allopurinol was associated with an increased risk of non-psychiatric hospitalization (aHR=1.10, 95% CI 1.03-1.17). The decrease in risk of hospitalization with these medications was greater in individuals under versus over 40 years of age.

Study Conclusions

The authors found that CCBs and adenosine modulators were associated with a decreased risk of hospitalization due to affective symptoms in individuals with bipolar disorder. Study strengths include the large nationwide cohort, long follow-up period, and use of within-individual models, which control for time-invariant factors (eg, genetics). Study limitations include the absence of ratings of symptom severity, the fact that the authors did not adjust for psychosocial treatments, and the potential for selection bias in observational studies.

The Bottom Line

Findings support potential roles for calcium, the purinergic system, and adenosine modulators in the pathophysiology of bipolar disorder. CCBs and adenosine modulators warrant further study in these individuals.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Gitlin M. Treatment-resistant bipolar disorder.Mol Psychiatry. 2006;11(3):227-240.

2. Bartoli F, Cavaleri D, Bachi B, et al. Repurposed drugs as adjunctive treatments for mania and bipolar depression: a meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials.J Psychiatr Res. 2021;143:230-238.

3. Cipriani A, Saunders K, Attenburrow MJ, et al. A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.Mol Psychiatry. 2016;21(10):1324-1332.

4. Hirota T, Kishi T. Adenosine hypothesis in schizophrenia and bipolar disorder: a systematic review and meta-analysis of randomized controlled trial of adjuvant purinergic modulators.Schizophr Res. 2013;149(1-3):88-95.

5. Gamboa A, Abraham R, Diedrich A, et al. Role of adenosine and nitric oxide on the mechanisms of action of dipyridamole.Stroke. 2005;36(10):2170-2175.

6. Lintunen J, Lhteenvuo M, Tanskanen A, et al. Allopurinol, dipyridamole and calcium channel blockers in the treatment of bipolar disorder - a nationwide cohort study.J Affect Disord. 2022;313:43-48.

7. Taipale H, Tanskanen A, Koponen M, et al. Agreement between PRE2DUP register data modeling method and comprehensive drug use interview among older persons.Clin Epidemiol. 2016;8:363-371.

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Calcium-Channel Blocker and Adenosine Modulator Use and Risk of Hospitalization in Bipolar Disorder - Psychiatric Times

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'Israel is advanced in research related to aquaculture and has the capacity to create adequate innovation'

Ahead of a groundbreaking international conference organized by Israels Agriculture and Rural Development Ministry on Marine Aquaculture and Food Technology, i24NEWS had the honor of visiting companies leading in innovation.

Specializing in marine and desert agriculture, the companies have developed solutions to alleviate global food insecurity at a time when certain animal species are threatened with extinction.

Given the rate of population growth, global warming, climate change, rising sea levels, and diminishing fertile areas for agricultural crops, a significant part of the futures food must come from the sea and the desert.

With this in mind, the conference to be held in the southern Israeli resort town of Eilat from October 18 to 20 will bring together agriculture ministers scientists, and major entrepreneurs from Israel, Bahrain, Malta, Morocco, and Jordan.

"We are all aware of the problem of food insecurity and that is why we are trying to provide more protein in our diets, Michal Levy, scientist and senior deputy director general of Israels Agriculture Ministry, told i24NEWS.

Climate change and its influence on agriculture and new forms of food are subjects that we must be concerned about today. We know that Israel is very advanced in research related to aquaculture, and has the capacity to create fish and develop adequate innovations, she said.

The current government is emphasizing programs for students focusing on aquaculture in the Eilat region, which has many advantages in terms of seaweed and fish farming. Additionally, it is encouraging the creation of infrastructure in order to improve the ecosystem of Eilat as well as the rest of Israel to then export such knowledge abroad.

At the Faculty of Agriculture, Food and Environment in Rehovot of central Israel, the team of Dr. Lior David an expert in animal sciences is carrying out advanced studies in fish production to increase sustainability.

In fish, David is studying the genetics of resistance to infectious diseases and sex determination. Knowledge from their basic research is then used to select genetically improved strains of fish to solve problems that hinder fish farming.

"We want to control the male-female ratio by producing more females to produce more births, through hormone injection methods, David explained.

Aquaculture has become the main source of protein production from fish, but the appearance of diseases 20 years ago, in Europe and Israel, which now affect the whole world, complicates the process.

At the Faculty, researchers are particularly working to develop a vaccine that could be injected into fish to reduce the spread of disease. They also inject specific genes into fish eggs to control reproduction and increase the quantity of fish, as well as for cultured fish meat which makes it possible to create real meat by growing animal cells directly from fish.

Spirulina to replace meat?

i24NEWS traveled to the village of Tel Mond near Netanya in central Israel where Simpliigood is located, the first company in the world to exploit a large-scale biomass production technology of spirulina, algae with high nutritional quality.

Through a multidisciplinary approach involving biology, engineering, chemistry, and computer science, Simpliigood is creating the most efficient natural food source on earth Spirulina, one of the most nutritional and plant-based sources of protein on the planet.

About 74 percent of Simpliigoods spirulina is made from crude protein, which provides 18 of the 20 amino acids needed for the body to function properly. It contains three times more protein than meat and helps fight anemia.

"Our company started about ten years ago with the aim of taking spirulina from a luxurious dietary supplement to a staple in our diet; then we started to market it, Bach Baruch CTO at Simpliigood, told i24NEWS.

We are trying to produce yogurts, cheese, ice cream, fish, and even meat from spirulina thanks to solar energy, salt, and water essential to cultivate it.

Spirulina can also replace gluten, create textures, or serve as an emulsifier, but its main purpose is to make diets healthier and richer.

"We harvest fresh spirulina with natural methods without antibiotics or hormones. We can also add flavor and customize colors to make it look like the real thing, Bach said.

At Simpliigood, it is grown in two micro-farms with state-of-the-art technology in 50-degree freshwater ponds to maintain an ideal growth environment.

The company offers a sustainable, affordable, and clean, minimally-processed food alternative with immense value.

Vertical greenhouses: Growing out of season

Producing strawberries in winter? This is one of the missions given to the startup Vertical Field, created in 2006 near the central Israeli city of Raanana.

Using state-of-the-art technology, it meets the needs of the growing population by growing produce in any indoor or outdoor urban space.

The company designed integrated vertical platforms and quickly achieved international success with more than 500 projects worldwide. We are the future in agriculture because we can grow produce out of season, said Gilad Marek, chief agronomist at Vertical Field.

They thus circumvent the disadvantages linked to the climate without entering into competition with farmers. On the contrary, Marek assured that "they work together."

"We use 90 percent water, no pesticides or chemicals, to grow herbs such as basil, lettuce, mint, parsley, coriander, and eventually we hope to produce strawberries, mushrooms, or even cherry tomatoes, Ronen Redel, VP of Business Development at Vertical Field, told i24NEWS.

"We wanted to set up a method that is as close as possible to nature. This technology has several advantages, based on air control, irrigation, and lighting that allow plants to be given the conditions and nutrients they need to grow in 21 days.

Farmers can also supply themselves daily from the container.

Vertical Field developed pilot projects in Australia, Vienna, and the United States, as well as in Ukraine and Russia before the war broke out.

"We can also play with day and night lighting to promote growth, and easily monitor the development of each of the plants. By isolating them from the environment, the plants are thus protected from the parasites and dust responsible for their deterioration, Marek emphasized.

Will Israel's sustainability know-how succeed on the world stage?

Original post:
Israel, A Pioneer In Agriculture Of The Future - I24NEWS - i24NEWS

Recommendation and review posted by Bethany Smith

The Irish Limousin Cattle Societys 50th Anniversary Extravaganza took place in Carrick-on-Shannon last weekend, beginning on Friday (September 30) and drawing to a close on Sunday (October 2).

There was plenty of excitement over the weekend, with the commercial show, pedigree show, heifer sale and Mega Moo raffle being some of the highlights.

A number of sponsors form the agricultural sector contributed to the event including Agriland Media Group, which sponsored a class in the commercial show ring.

The event not only drew crowds from the four corners of Ireland, it witnessed a large delegation from both the UK, Europe and in particular France the home of the Limousin breed.

Prior to the show day, the society offered 100 tickets at a price of 100 each for the Mega Moo draw, the winner of which was Donal Moloney, who selected Eoghan Breslins heifer as his first choice.

The owner of the chosen heifer, Breslin, received a prize of 10,000 from the society, while Moloney walked away from the event with a commercial Limousin heifer for 100.Donal Moloney with his chosen Mega Moo heifer and pictured with owner Eoghan Breslin

Topping the Pre-Inspected Elite Heifer Sale was Co. Cavan breeder Eddie Lynch with his Ernevalley Sweetheart ET which sold for 11,000.

Sample prices from the Elite Heifer Sale:

In the pedigree show classes, the judges on the day were Rikke Benoit from France and Chris Penny from the UK.

The Senior Male Champion went to Killcastle Pierson, owned by Alan and Paul Kelly. This March 2019-born Ampertaine Commander son was out of Killcastle Izzy Monique ET.Killcastle Pierson owned by Alan and Paul Kelly

The Intermediate Male, Overall Male and Overall Limousin Reserve Champion title went to Carrickmore Schumacher ET, owned by the Connell Brothers. This impressive bull is out of Baileys Iceprincess and sired by Sympa.

Carrickmore Schumacher ET was sold privately in the yard for 30,000.Carrickmore Schumacher ET owned by the Connell Brothers

It will be another weekend to remember for William Smiths Milbrook Limousin Herd based in Oldcastle, Co. Meath.

It was Milbrook Nikkiespice ET, a daughter of the famous Milbrook Gingerspice, who was tapped out as Overall Limousin Champion of the Show after earlier being crowned Senior Female Champion and Overall Female Champion.

It was a clean sweep for the Milbrook Limousin Herd in the Overall Female Championship as the reserve champion was also awarded to William Smith for his April 2021-born heifer, Milbrook Senorita ET.

This heifer is a Wilodge Tonka-sired heifer out of Milbrook Enya. She was also crowned Intermediate Female Champion on the day.Milbrook Senorita ET owned by William Smith

The Reserve Champion in the Senior Female Championship was again awarded to William Smith and the Milbrook Herd for Milbrook Nenya ET, a Wilodge Vantastic-sired cow out of Milbrook Enya.Milbrook Nenya ET owned by William Smith

In the Junior Female Championship, it was Co. Cavan man Eddie Lynch with his heifer, Ernevalley Sweetheart ET, who took home the champion sash. This December 2021-born heifer was sired by Nenuphar out of Ernevalley Nadine ET.Ernevalley Sweetheart ET owned by Eddie Lynch

Reserve Champion went to Thomas OShea with his heifer Templequain Selena. She was first in the twelfth class and was sired by Whinfellpark Lomu and out of Templequain Mabelle.Templequain Selena owned by Thomas OShea

With the pedigree males, Castlebrock Trafford ET, a March 2022-born bull bred by Gerard Davis, was awarded Reserve Overall Male Champion.

Trafford was sired by Mereside Godolphin and out of Lomond Lexie. He was earlier tapped out as Junior Male Champion.Castlebrock Trafford ET, Gerard Davis

James OGrady, with his June 2020-born bull Meenross Ring Leader ET, was awarded the Reserve Senior Male Champion sash. This bull was sired by Hatcliff Dancer out of the dam Castleview Felicity.Meenross Ring Leader ET owned by James OGrady

The Connell Brothers took the top spot in the Intermediate Championship, but Darragh OMeara secured reserve champion with his bull Hurricane Scat Man ET who was sired by Ampertaine Foreman and out of Hurricane Lady Hawk ET.Hurricane Scat Man ET owned by Darragh OMeara

The Junior Male Champion was awarded to Gerard Davis, but Padraic Golden took the reserve title with his November 2021-born bull, Clew Bay Smokey.

This bull was sired by Plumtree Fantastic and out of the dam Clew Bay Laoise.Clew Bay Smokey owned by Padraic Golden

The Milbrook Herd finished the day in style by winning the Best Pair of Limousins by the same breeder, while it was A and P Kelly who won Best Group of Three by the same breeder.

The society thanked all who made the event a huge success and gave a particular mention to the council, breeders, organising committee and all who helped out over the weekend.

A special word of thanks was also mentioned to the title sponsors FBD Insurance, and the partner sponsors ABP, Univet, Progressive Genetics and Munster Bovine, as well as all class sponsors on the day.

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Results: Limousin society's 50th anniversary show and sale - Agriland

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Drug resistance and population structure of Plasmodium falciparum and Plasmodium vivax in the Peruvian Amazon | Scientific Reports - Nature.com

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Hair supplements seem like the golden ticket to great hair: all you have to do is pop a pill, sit back, and wait for glossy, thicker hair to reveal itself, right? The reality is a little more complex. When supplements do work, they take time to work, and not all supplements are created equal. Supplements arent regulated by the Food and Drug Administration, which means its difficult to tell which brands are using the highest quality ingredients and which rely on a lot of inexpensive fillers that may sound impressive, but arent going to target your hair follicles in any meaningful way. Unfortunately, a supplements price tag doesnt always tell an accurate story, either.

So, how much should you expect from a hair supplement and what are its limitations? Do supplements actually help hair growth? We asked an expert.

First and foremost, no one treatment will work for all people. Its important to consider the reason why you are shedding hair before finding a solution that works for you (and thats something that should ideally be determined with the help of a board-certified dermatologist).

Hairsupplementsshould be customized to the cause ofhairloss, says Dr. Yoram Harth, board certified dermatologist and medical director ofMDhair. Women with postpartum or stress-relatedhairloss should get a different kind ofsupplementthan women after 40 with post-menopausal or genetic-relatedhairloss. Well-chosensupplementscan help provide the first group with the micronutrients essential forhairregrowth. The second group should look forsupplementsthat include,in addition to essentialvitaminsand minerals, DHT blockers that counteract the effect of dehrdotestoren on thehairfollicles, and plant-like ashwagandhaand reishi and maitake mushrooms can helphairregrowth by reducing inflammation and stress.

There are no miracles in a bottle. And many supplement brands try to skate by adding less-than-effective filler ingredients to their formulas. Knowing the limitations of certain supplements can help temper your expectations and save you money.

Unfortunately, some overhypedhairsupplementscan do more damage than good, says Dr. Harth. Examples are sugary gummysupplementsthat maintain high amounts of biotin. Biotin is a good ingredient, but there is evidence that using it as a single ingredient significantly affectshairregrowth. The high amount of sugar in most of these gummies can hurthairregrowth and its other health disadvantages.

In people with pregnancy, stress, or nutrition related, the most effective ingredients to look for arevitaminsand minerals, according to Dr. Harth. Good addition in these cases in collagen peptide, preferably sourced from wild-caught fish. People with genetically relatedhairloss need to look forsupplementsthat contain natural DHT-blockers combined with thesevitaminsin minerals.

Ready for a shock? Despite how often we hear about the benefits of biotin, it is one of the most hyped hair growth ingredients. Biotin is a good ingredient, but there is evidence that using it as a single ingredient significantly affectshairregrowth, Dr. Harth says. In very high amounts, it can also cause acne breakouts.

The common causes forhairloss in women are genetics, postpartum (pregnancy), crash diets, wrong hairstyling, autoimmune diseases, and hormonal imbalances Dr. Harth says.

The bestsupplementsto help regrowhairare the ones that target the root cause of yourhairloss, Dr. Harth says. Here are some ingredients that Dr. Harth says can aid in hair growth for a number of different hair shedding culprits.

The best naturalsupplementsfor genetic, age, and hormonal-relatedhairloss are plants that can reduce the effect of male hormones, mainly dihydrotestosterone (DHT), on thehairfollicles, Dr. Harth says.

Examples of those plants are:

Saw palmetto is a plant extract believed to block the effects of male hormones on thehairfollicle and reduce excessivehairshedding. These ingredients can be found in topical scalp serums and oralhairsupplements.

Ginseng: A few types of ginseng are believed to help withhairgrowth. For optimal results, look forhairsupplementsplants-based serum that contains the Panax Ginseng Root.

Pygeum Bark Extract: Rich in phytosterols that block the effect of DHT onhairfollicles to enhancehairgrowth.

Broccoli Powder contains antioxidants that reduce free radical damage to the scalp. Bvitaminsin broccoli extract help reduce stress, contributing tohairloss.

The best naturalsupplementsfor Postpartumhairloss will need to replenish thevitamins, minerals, and micronutrients that were depleted during pregnancy, Dr. Harth says and these samesupplementsshould also be safe for breastfeeding women.

Examples of ingredients needed:

Iron helps boost circulation and carries oxygen to the roots of thehair, which allows thehairto grow faster and longer. An iron deficiency can lead tohairloss.

VitaminsC, D, E Having the right amount of thesevitaminsis required for a healthy scalp and regrowth of healthier, thicker newhair.

Vitamin B12 and Folic Acid Helphairfollicles regenerate and heal faster to produce new healthierhair.

Iodine, Magnesium, Zinc, Selenium, Manganese, and Chromium Having the right amount of these minerals is required for a healthy scalp and regrowth of healthier, thicker newhair.

Calcium An essential mineral that helps reducehairbreakage, dry scalp, and brittle nails.

Vitamin K2 By stimulating blood flow to the scalp, it enhances healthyhairregrowth.

Combiningvitamins, minerals, and adaptogens can reduce this type ofhairloss, Dr. Harth says. Examples of natural adaptogens are the Maitake and Reishi Mushrooms. Potent adaptogens, immunomodulatory, and inhibitors of 5-reductase, these mushroom extracts support a healthy scalp and regrowth of newhair.

Hair supplements can be extremely helpful but only if they are targeting your hair loss concern and contain effective ingredients for your personal needs. Before you start any new supplement, check with your doctor. Get a thorough exam to determine the cause of your hair loss and be patient it can take time to experience the benefits of a quality supplement.

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Do Supplements Help Hair Growth? We Asked An Expert - SheFinds

Recommendation and review posted by Bethany Smith

Around 264,000 women are diagnosed with breast cancer every year. Its one of the most common types of cancer in American women.

Heres what you need to know to protect your breast health.

Your body is growing new cells all the time. Usually, these cells die off when you dont need them any longer. Cancer is a group of abnormal cells that mutate and grow out of control when your body doesnt need them. They usually form a lump or mass.

Breast cancer describes any cancer that begins in the breast. It can affect both women and men, although it is rare in men. Out of every 100 breast cancers diagnosed, there is around one case found in a man.

The breast is made of lobules (milk glands), ducts, fat, tissue, lymph nodes and blood vessels. Cancer can start anywhere in the cells of the breast but is most likely to start in the lobules and ducts.

Experts dont know exactly what causes breast cancer, but they have identified some risk factors that make you more likely to get it.

Some risk factors are things you cant change, including:

Breast cancer usually isnt painful. If youre experiencing breast pain or discomfort, its more likely your menstrual cycle is the cause.

If your breast pain is severe or lasts longer than a few weeks, see your health care provider. Breast pain is rarely the main symptom of breast cancer, but it could still happen. Your provider will help you identify the cause of your breast pain and how to treat it.

In early stages, breast cancer can be too small to cause symptoms. This is what makes breast cancer screenings so important. Catching breast cancer early means its more treatable and less likely to have spread to other parts of the body.

As breast cancer grows, it can cause changes in your breasts such as:

If you notice any changes in your breasts, see your health care provider right away.

Find a Sanford Health provider.

There are steps you can take to help prevent breast cancer:

Having children also helps reduce your risk of getting breast cancer, especially if you have children before the age of 30.

The best way to protect your breast health is through regular screenings. Sanford Health recommends getting a mammogram every year starting at age 40. These screenings are important for catching breast cancer early when its most treatable.

Depending on your risk factors, you may need to get screened earlier than age 40. Talk to your doctor to learn when you should start screenings based on your personal risk.

Medical review by Michael Bouton, MD, a breast surgeon at the Sanford Medical Center in Fargo, North Dakota; Andrea Kaster, MD, a family medicine physician in the Edith Sanford Breast Center Fargo in Fargo, North Dakota; and Christina Tello-Skjerseth, MD, a radiologist at the Sanford Clinic in Bismarck, North Dakota.

Posted In Cancer, Cancer Screenings, Women's

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Breast cancer: What you need to know - Sanford Health News

Recommendation and review posted by Bethany Smith

Clinical guidelines greatly influence how doctors care for their patients. By providing recommendations on how to diagnose and treat particular situations, guidelines can help standardize the care patients receive. For instance, when a patient is suffering from an infection, a physician can consult the relevant guidelines to confirm that antibiotics are the appropriate treatment. Regulators, insurance payers and lawyers can also use guidelines to manage a doctors performance, or as evidence in malpractice cases. Often, guidelines compel doctors to provide care in specific ways.

We are physicians who share a common frustration with guidelines based on weak or no evidence. We wanted to create a new approach to medical guidelines built around the humility of uncertainty, in which care recommendations are only made when data is available to support the care. In the absence of such data, guidelines could instead present the pros and cons of various care options.

We got together an international team of physicians and pharmacists to create a guideline on creating guidelines. We call this new type of guideline a WikiGuideline, not affiliated with Wikipedia but similarly opening collaboration to all people. The idea was to enable any qualified practitioner to have a voice in guideline construction, rather than limiting authorship to academics who are politically active in specialty societies in wealthy countries.

The clinical guidelines movement first began to gain steam in the 1960s. Guideline committees, usually composed of subspecialty experts from academic medical centers, would base care criteria on randomized clinical trials, considered the gold standard of empirical evidence.

Unfortunately, many committees have since started providing answers to clinical questions even without data from high-quality clinical trials. Instead, they have based recommendations primarily on anecdotal experiences or low-quality data.

Medical guidelines made with insufficient data can lead to patient harm.

For example, guidelines once instructed doctors to prescribe hormone replacement therapy to all post-menopausal women to prevent breast cancer. However, a subsequent large randomized controlled trial showed that giving hormone replacement therapy actually increased the risk of breast cancer. While guidelines have since been updated to narrow down who would benefit from hormone replacement therapy, prior practices have likely resulted in breast cancer for many patients.

Other poorly made guidelines have also seen similar results.

A guideline that instructed doctors to use higher doses of an antibiotic called vancomycin for bacterial infections was later shown to not be more effective and also increase the risk of kidney failure. Likewise, a guideline that promoted aggressive, rapid administration of antibiotics to patients who may have pneumonia was found to not improve outcomes and cause side effects for patients who did not actually end up diagnosed with pneumonia.

Another guideline promoted the use of medications called beta blockers for certain types of surgeries before researchers learned that they increased the risk of heart attacks during and after the procedures. Similarly, a guideline promoting the use of intensive insulin therapy in the ICU was later shown to cause blood sugar levels to drop to dangerously low levels.

To create a new form of medical guideline that takes the strength of available evidence for a particular practice into account, we gathered 60 other physicians and pharmacists from eight countries on Twitter to draft the first WikiGuideline. Bone infections were voted as the conditions most in need of new guidelines.

We all voted on seven questions about bone infection diagnosis and management to include in the guideline, then broke into teams to generate answers. Each volunteer searched the medical literature and drafted answers to a clinical question based on the data. These answers were repeatedly revised in open dialogue with the group.

These efforts ultimately generated a document with more than 500 references and provided clarity to how providers currently manage bone infections. Of the seven questions we posed, only two had sufficient high-quality data to make a clear recommendation on how providers should treat bone infection. The remaining five questions were answered with reviews that provided pros and cons of various care options.

The recommendations WikiGuidelines arrived at differ from current bone infection guidelines by professional group for medical specialists. For example, WikiGuidelines makes a clear recommendation to use oral antibiotics for bone infections based on numerous randomized controlled trials. Current standard guidelines, however, recommend giving intravenous antibiotics, despite the evidence that giving treatment orally is not only just as effective as giving it intravenously, but is also safer and results in fewer side effects.

Providers benefit from careful review of a clinical case. When there isnt enough data to make a clear recommendation, laying out what data is available can help inform their clinical judgment.

We believe that more inclusive guideline committees that open participation to qualified practitioners instead of just those within specialty societies could help make for better medical guidelines. The WikiGuidelines Group now has over 110 members from over 14 countries, many of which are lower- and lower-middle-income countries. We are currently working on a guideline for managing heart valve infections.

It is our hope that future guidelines can avoid the errors of the past by incorporating the humility of uncertainty into the process, acknowledging when the evidence is unclear and only issuing clear recommendations when high quality data can support them.

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Medical guidelines that embrace the humility of uncertainty could help doctors choose treatments with more research evidence behind them -...

Recommendation and review posted by Bethany Smith