Benzodiazepine use during pregnancy is associated with an increased risk for miscarriage, according to new research published in JAMA Psychiatry. Health care professionals should carefully consider the risk-benefit ratio when considering benzodiazepine treatment for pregnant individuals.
Although benzodiazepines can cross the placental barrier and may potentially impact fetal development, they are still used to treat psychiatric and sleep disorders in pregnancy. Studying the effect of benzodiazepines on pregnancy outcomes is challenging as pregnant women are often precluded from randomized clinical trials and confounding factors can bias results in observational studies. The current study aimed to quantify the risk for miscarriage associated with benzodiazepine use during pregnancy, using a case-time-control design that accounts for confounders.
This nationwide, population-based study was conducted in Taiwan using pregnancy data from the National Health Insurance (NHI) database from 2002 to 2019 and the National Birth Certificate Application (BCA) database from 2004 to 2018. Researchers employed a case-time-control design to investigate the association between benzodiazepine use during pregnancy and the risk for miscarriage, comprising 2 analyses: a case-crossover analysis and an exposure time-trend control crossover analysis. The researchers used a conditional logistic model to estimate the odds ratios (ORs) of miscarriage.
Overall, the study included 3,067,122 pregnancies among 1,957,601 women (mean age=30.61; SD, 5.91). Of those pregnancies, 136,134 (4.4%) resulted in miscarriage. The researchers then matched the case group of individuals who experienced miscarriage with controls (based on age, psychiatric medical conditions, lifestyle factors, chronic comorbidities, medication use, and health care utilization), resulting in 134,864 pairs of pregnant women.
Prescribing benzodiazepines should only be considered following a comprehensive evaluation of the potential benefits and risks for both the mother and the child.
Among the cases cohort, 1502 pregnant women were exposed to benzodiazepines during the risk period only (1 to 28 days before miscarriage), and 2806 were exposed during the reference period only (181 to 208 days before the last menstrual period). Case-time-control ORs confirmed that exposure to benzodiazepines was associated with an increased risk for miscarriage (OR, 1.69; 95% CI, 1.52-1.87). Further, subgroup analyses revealed a dose-response association between benzodiazepine exposure and miscarriage, with the OR increasing from 1.61 (95% CI, 1.43-1.82) for low-dose exposure to 1.86 (95% CI, 1.53-2.25) for high-dose exposure.
This nationwide case-time-control study revealed that benzodiazepine use during pregnancy was associated with an approximately 70% increased risk for miscarriage, even after accounting for measurable confounders. Study authors concluded, “Prescribing benzodiazepines should only be considered following a comprehensive evaluation of the potential benefits and risks for both the mother and the child.”
The primary limitation of the study is the potential bias resulting from the use of birth certificate-based and claims-based databases for pregnancy and benzodiazepine exposure measures.
An e-consult program for oncologists and allergy specialists had a mean turnaround time of 19.7 hours.
Nine out of 10 oncologists surveyed were very satisfied with this turnaround time.
Oncologists were satisfied with an electronic system for consulting with allergists about hypersensitivity reactions during chemotherapy, according to a study published in The Journal of Allergy and Clinical Immunology: In Practice.
However, specialists need to become more familiar with the system, Aleena Banerji, MD, allergist and immunologist, and Kimberly G. Blumenthal, MD, MSC, quality and safety officer, both in the division of rheumatology, allergy and immunology, department of medicine, Massachusetts General Hospital, and colleagues wrote.
About half of the chemotherapy hypersensitivity cases that prompted e-consults with allergy specialists did not require formal allergy consultations. Image: Adobe Stock
“Chemotherapy hypersensitivity reactions have an incidence rate ranging from 10% to 15% for carboplatin but increases to more than 20% to 30% after seven cycles of treatment,” Banerji and Blumenthal told Healio in a joint statement.
“Incidence rates of hypersensitivity reactions to paclitaxel and docetaxel are approximately 10% and occur most often during the first or second treatment,” they continued.
Hypersensitivity reactions can range from a mild skin rash or hives to severe, life-threatening anaphylaxis, the authors said.
“Symptoms can appear within minutes of starting the chemotherapy infusion, which can be very scary to patients,” Banerji and Blumenthal said.
Milder reactions can be treated with antihistamines, but when the reaction is severe, trained staff need to be knowledgeable about managing anaphylaxis, they continued.
“Additionally, when a hypersensitivity reaction occurs to first-line treatment, a different second-line agent may be used, which can be associated with worse clinical outcomes for the patient,” Banerji and Blumenthal said.
The system’s success
Clinicians can use electronic consultations (e-consults) when they have questions for other clinicians about care for specific patients in outpatient treatment. These asynchronous communications rely on information available in the electronic health record.
Massachusetts General Hospital supports more than 20,000 e-consults each year across multiple specialties, the authors said, with an expected turnaround for each e-consult of 72 hours.
“The allergy/immunology group has been involved in the care of hundreds of patients with chemotherapy hypersensitivity reactions, but communication about care was frequently by text, phone or email,” Banerji and Blumenthal said.
“These communications were not subsequently documented in the patient’s chart and led to a lack of understanding of the care plan by the whole team, delays in patient care and suboptimal coordination of care,” they said.
The hospital instituted the e-consult program specific to hypersensitivity reactions (HSRs) during chemotherapy in October 2020 to reduce time to allergist recommendations and to improve formal documentation in the EHR.
Between October 2020 and August 2021, hospital personnel completed 165 e-consults specifically about chemotherapy HSRs. The mean turnaround time for these e-consults was 19.7 hours (standard deviation, 24.7 hours).
Each one of these e-consults included clear recommendations using the standard smart phrase in the EHR documentation, the researchers said, and 87 (53%) patients did not need a formal allergy consultation after the e-consult was completed.
The researchers distributed surveys to 47 oncologists before and after the e-consult program was launched. Fourteen (30%) responded to the pre-launch survey, 14 (30%) responded to the post-launch survey and 10 (21%) responded to both.
Seven of the 10 (70%) oncologists who answered both surveys said they primarily used email or texts to contact allergists for guidance when a patient had an HSR due to chemotherapy. The other three used the Epic system to request consultations.
Also, nine of the 10 oncologists who responded to both surveys were very satisfied with their methods for obtaining guidance from allergists in the pre-launch survey, and the 10th was somewhat satisfied.
All 10 of these oncologists also said that contacting an allergist was easy and that they spent less than 15 minutes coordinating allergy care for chemotherapy HSRs. Eight (80%) said they were very satisfied with allergy team response times.
According to the post-launch survey, four of the 10 (40%) continued to use email to contact allergists, and three of them only used email, but all 10 also said that they were very satisfied with their consultation methodology.
Further, 70% of the referring oncologists said that the e-consult’s reply speed was better after the program was launched in the post-launch survey, compared with 40% in the pre-launch survey, although the program did not have any impact on the time that oncologists spent coordinating care with the allergy team.
Nine (90%) of 10 oncologists additionally said that they were very satisfied with the time it took to receive a response from the allergy team once the program was launched, and six (60%) said the program was slightly or significantly better than the previous model for collaboration.
The oncologists unanimously said that the information in the e-consult was helpful for patient care as well.
In the free responses to a survey question about how the e-consults could be improved, two oncologists said they preferred to maintain other options for communication, and one expressed confusion about when a chemotherapy HSR e-consult should be ordered instead of a formal in-person consultation.
Looking ahead
E-consults save costs and improve efficiency in care by preventing the need for formal allergy consult visits, the researchers said, with an average turnaround of less than a day compared with more than 3 months in waiting time for outpatient clinic visits.
The less frequent use of texts and emails for consulting with allergy staff also is an improvement, the researchers continued, because the EHR does not document these communications. Also, texts and emails may lead to safety issues by not complying with health privacy laws and because of their absence in the EHR.
The researchers additionally said they expected more of the oncologists to use the e-consult program because of how it improves patient care. They also expressed surprise that the oncologists spent the same amount of time coordinating care, which they attributed to an existing culture of efficient patient care for HSRs.
“We were surprised about the lack of global understanding around an e-consult program, as our institution has vast experience with using e-consults,” Banerji and Blumenthal said. “Additionally, the lack of universal acceptance around using e-consults with clear benefit to patient care suggests we need to provide better education around e-consults.”
Based on these findings, the researchers called e-consults specific to chemotherapy a useful tool for consultations to improve patient care and EHR documentation, but overall success will depend on specialists who are familiar with the program.
Banerji and Blumenthal said the authors are now developing ways to educate their medical colleagues about the use of e-consults with an understanding of how they lead to improvements in patient care.
“Additionally, our goal is to evaluate the benefits and challenges of using e-consults in a larger number of chemotherapy hypersensitivity reactions,” they said
For certain types of chemotherapy such as platinum drugs and taxanes, immediate hypersensitivity reactions are fairly common. The longer a patient is receiving these drugs, the higher the chance is of experiencing one. For patients who are on these drugs for more than 12 cycles, the chance is almost 50% that they will have a reaction at some point.
There also is a chemotherapy for head and neck cancer (cetuximab) that is a little more likely to cause an immediate reaction in the parts of the country (the Southeastern U.S., mostly) where alpha-gal allergy is present.
Other types of chemotherapy do have hypersensitivity reactions, but they are not as common. They are more like other drugs in their reaction rates. Depending on the drug, you get different profiles of reactions that are possible to experience. This paper appears to mostly focus on the immediate types of reactions based on their description.
Oncologists in our system at Vanderbilt will usually reach out to their allergist colleagues via a consult request in our EHR after a reaction. But typically, they will also reach out personally via phone, EHR messages or HIPAA compliant messaging. The initiation of provider-to-provider communication is important when you are managing an event that might limit a patient’s ability to receive first-line therapy for cancer.
E-consultations can improve care in these cases. Currently, we do not have a formal system promoting e-consultations, but it definitely is something that we do for our oncologists when they or their patients need us to. It is like using the EHR to have a back-and-forth conversation.
I personally think that the most efficient way to go about it, for us, has been to have the oncologist reach out with a referral, let us know what they observed during the reaction, and then we facilitate the patient getting seen by me or a colleague within a week, so we don’t slow down their chemotherapy treatments.
We (the allergists) will then have a telehealth or in-person consultation with the patient to discuss the reaction and the management options. Then we go back to their treating oncologist with recommendations, at which point we all try again using a modified plan under careful observation (sometimes in the hospital setting) and see how it goes. Sometimes we will use chemotherapy skin testing to identify a culprit allergen, but oftentimes it is not necessary since the history is enough to let us know what to do.
So, the system described in this study is similar to my experience. I think we are all trying to tackle this problem of making sure that our vulnerable cancer patients don’t fall through the cracks and miss out on their key chemotherapy treatments even if they have reactions to them. We want to make things safe and keep the quality of what we are doing up to the highest level.
It is important for the public to be aware that there are protocols that can make it possible even for a patient who has had an immediate reaction or allergy (anaphylaxis type) to chemotherapy to tolerate it safely. We use specialized, slow infusion protocols called desensitization protocols to deliver the drugs without setting off their reactions.
It is more work for everyone to treat a patient who has become allergic to their chemotherapy, but it is work that is worth doing to make sure they don’t miss out on the best drugs for their cancer. I have patients that I suspect are still alive today because they did not have to miss out on the drug that was actually working against their tumors.
Finally, I think these authors did a great job in trying to figure out how to facilitate good communication at their institution. When you are dealing with an allergic reaction, 80% to 90% of good medical care going forward comes down to communication amongst the treating team and the patient, in my experience.
Cosby A. Stone Jr., MD, MPH
Assistant Professor in Allergy/Immunology, VUMC Drug Allergy Research, Vanderbilt University Medical Center
More than 13% of users of quetiapine and haloperidol developed severe QT prolongation.
Severe QT prolongation was linked to ventricular arrhythmia and, in quetiapine users, sudden cardiac death.
The antipsychotic drugs quetiapine and haloperidol were associated with severe QT prolongation, ventricular arrhythmias and sudden cardiac death, researchers reported in HeartRhythm.
“The use of the antipsychotics quetiapine and haloperidol to treat mental disorders is widespread,” Shang-Hung Chang, MD, PhD, of the cardiovascular division, department of internal medicine, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan, said in a press release. “In an effort to enhance patient safety and optimize the management of individuals receiving these medications, we have investigated the incidences, risk factors and clinical outcomes of severe QT prolongation to provide valuable insights for health care professionals, patients and caregivers.”
More than 13% of users of quetiapine and haloperidol developed severe QT prolongation.
Using electronic health records from a multicenter health care hospital system in Taiwan, the researchers analyzed data from 8,832 patients administered quetiapine (mean age, 69 years; 59% men) and 2,341 administered haloperidol (mean age, 66 years; 65% men). The outcomes of interest were incidence of severe QT prolongation, defined as a posttreatment corrected QT (QTc) interval exceeding 500 milliseconds or an increase in QTc interval of more than 60 milliseconds compared with baseline, risk factors for severe QT prolongation and clinical outcomes associated with severe QT prolongation.
Severe QT prolongation
The mean increase in QTc was 18.3 milliseconds in quetiapine users and 18.9 milliseconds in haloperidol users, with 13% of the quetiapine group and 14.2% of the haloperidol group developing severe QT prolongation, according to the researchers.
In both groups, risk factors for developing severe QT prolongation included age older than 65 years (P < .001 in quetiapine group; P = .033 in haloperidol group), hypokalemia (P < .001 in quetiapine group; P = .002 in haloperidol group), hypocalcemia (P < .001 in quetiapine group; P = .008 in haloperidol group) and hypomagnesemia (P = .004 in quetiapine group; P = .04 in haloperidol group), the researchers found.
In the quetiapine group, those who developed severe QT prolongation had greater incidence of ventricular arrhythmias (3.8% vs. 1.1%; P < .001) and sudden cardiac death (2.3% vs. 0.8%; P < .001) than those who did not, but there was no difference by severe QT prolongation status in syncope and seizure, Chang and colleagues wrote.
In the haloperidol group, those who developed severe QT prolongation had greater incidence of ventricular arrhythmias (3.3% vs. 1.6%; P = .039), but there was no difference by severe QT prolongation status in sudden cardiac death (P = .414), syncope and seizure, according to the researchers.
‘Be aware of the potential risks’
“Clinicians should be aware of the potential risks associated with quetiapine use, particularly the risk of severe QT prolongation and its associated outcomes, including ventricular arrhythmias and sudden cardiac death,” Chung-Li Wang, MD, of the cardiovascular division, department of internal medicine, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan, said in the release.
In a related editorial, Clifford TeBay, BBSc (Hons), from the Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia, and Jamie I. Vandenberg, PhD, MBBS, FHRS, from the School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales in Sydney, wrote about a limitation of the study: “The age group studied was relatively old and likely included only small numbers of patients in their late teens/twenties, which is when schizophrenia is often first diagnosed and antipsychotic drug commenced. So, we cannot necessarily extrapolate the findings from the present study to this younger cohort that may have fewer comorbidities. Nevertheless, this study represents an important step forward into real-world monitoring of severe QT prolongation.”
“It would be prudent to undertake an ECG before and after commencement of an antipsychotic drug,” Vandenberg said in the release. “If it is an option, one could stop a drug causing QT prolongation and try a different antipsychotic. But if this is not practical, one should pay particular attention to reducing other risk factors, such as prescription of other drugs that may exacerbate QT prolongation, and be vigilant for hypokalemia.”
Researchers have discovered a potential stroke recovery therapy that can restore brain function in mice after a stroke. This therapy, involving inhibitors of the metabotropic glutamate receptor mGluR5, has shown to improve sensorimotor functions even when administered days after a stroke. The study suggests that combined with rehabilitation training, this treatment could offer a new approach to stroke recovery. However, further research, including human trials, is necessary.
Researchers have successfully revived brain function in mice affected by stroke through the use of small molecules, which could potentially be developed into a stroke recovery therapy.
“Communication between nerve cells in large parts of the brain changes after a stroke and we show that it can be partially restored with the treatment,” says Tadeusz Wieloch, senior professor of neurobiology at Lund University in Sweden.
“Concomitantly, the rodents regain lost somatosensory functions, something that around 60 percent of all stroke patients experience today. The most remarkable result is that the treatment began several days after a stroke,” Wieloch continues.
Understanding Stroke and Current Treatment Limitations
In an ischemic stroke, lack of blood flow to the brain causes damage, which rapidly leads to nerve cell loss that affects large parts of the vast network of nerve cells in the brain. This may lead to loss of function such as paralysis, sensorimotor impairment, and vision and speech difficulties, but also to pain and depression.
There are currently no approved drugs that improve or restore the functions after a stroke, apart from clot-dissolving treatment in the acute phase (within 4.5 hours of the stroke). Some spontaneous improvements occur, but many stroke patients suffer chronic loss of function. For example, about 60 percent of stroke sufferers, experience lost somatosensory functions such as touch and position sense.
Promising Results from a Recent Study
An international study published recently in the journal Brain and led by a research team from Lund University in collaboration with University of Rome La Sapeinza and Washington University at St. Louis, shows promising results in mice and rats that were treated with a class of substances that inhibit the metabotropic glutamate receptor (mGluR5), a receptor that regulates communication in the brain’s nerve cell network.
“Rodents treated with the GluR5 inhibitor regained their somatosensory functions,” says Tadeusz Wieloch, who led the study published in BRAIN.
Treatment Timing and Effects
Two days after the stroke, i.e. when the damage had developed and function impairment was most prominent, the researchers started treating the rodents that exhibited the greatest impaired function.
“A temporary treatment effect was seen after just 30 minutes, but treatment for several weeks is needed to achieve a permanent recovery effect. Some function improvement was observed even when the treatment started 10 days after a stroke,” says Tadeusz Wieloch.
Importantly, sensorimotor functions improved, even though the extent of the brain damage was not diminished. This, explains Tadeusz Wieloch, is due to the intricate network of nerve cells in the brain, known as the connectome, i.e. how various areas of the brain are connected and communicate with each other to form the basis for various brain functions.
“Impaired function after a stroke is due to cell loss, but also because of reduced activity in large parts of the connectome in the undamaged brain. The receptor mGluR5 is apparently an important factor in the reduced activity in the connectome, which is prevented by the inhibitor which therefore restores the lost brain function,” says Tadeusz Wieloch.
Enhanced Recovery with Combined Approaches
The results also showed that sensorimotor function was further improved if treatment with the mGluR5 inhibitor was combined with somatosensory training by housing several rodents in cages enriched with toys, chains, grids, and plastic tubes.
The researchers hope that in the future their results could lead to a clinical treatment that could be initiated a few days after an ischemic stroke.
“Combined with rehabilitation training, it could eventually be a new promising treatment. However, more studies are needed. The study was conducted on mice and rats, and of course, needs to be repeated in humans. This should be possible since several mGluR5 inhibitors have been studied in humans for the treatment of neurological diseases other than stroke, and shown to be tolerated by humans,” says Tadeusz Wieloch.
Nearly 20% of pediatric brain tumors occur in the pituitary region, and more than two-thirds of pituitary region tumors were present in girls, according to study findings published in Pituitary.
“Although pituitary tumors have been extensively studied in the adult population, there has been a lack of data specific to the pediatric population, despite — as we found — pituitary region tumors not being wholly uncommon in pediatric patients,” Luz Castellanos, MD, a pediatric endocrinology fellow at Massachusetts General Hospital, told Healio. “Pituitary region tumors comprise a significant proportion of pediatric brain tumors, particularly in adolescent girls, and should be considered in the differential for pediatric patients with symptoms of hypothalamic-pituitary axis dysfunction.”
Castellanos and colleagues analyzed data from the National Cancer Database of pediatric patients aged 21 years and younger who presented with a pituitary region tumor from 2004 to 2017. A microscopic diagnosis or biopsy and/or a surgical procedure were used for pathological confirmation. Children were placed into the infant/toddler age group if diagnosed at younger than 2 years, early childhood if diagnosed at 2 to 5 years, middle childhood for diagnoses at 6 to 11 years, early adolescence if diagnosed at 12 to 18 years and late adolescence for diagnoses at 19 to 21 years.
Pituitary tumors more common in girls
Researchers compared the prevalence of pituitary region tumors in children with data from adult patients between 2010 and 2017. A greater proportion of children in the study presented with a pituitary region tumor compared with adults (19.7% vs. 12.4%; P < .001). Although there was very little difference in the prevalence of pituitary region tumors in adult men vs. women, a larger proportion of girls had pituitary region tumors compared with boys in the pediatric group (27.2% vs. 12.2%; P < .001).
“We were not entirely surprised to see that young females were more likely to present with pituitary adenomas, given that this finding has been previously observed in institutional series and cancer registry data,” Castellanos said. “This female predominance is partly attributed to females exhibiting more obvious symptoms of hypothalamic-pituitary axis dysfunction than males do.”
Age at diagnosis
Of 7,653 children in the study data presenting with a pituitary tumor, 46.9% were diagnosed in early adolescence, 34.8% in late adolescence, 13.3% in middle childhood, 4.1% in early childhood and 0.9% as infants or toddlers, with 68.2% of cases occurring in girls, the researchers wrote. Most tumors were identified as pituitary adenoma (77.9%), followed by craniopharyngiomas (18.1%) and germ cell tumors (1.6%). The prevalence of pituitary adenomas increased during puberty for girls, with 88.8% of pituitary tumors in early adolescent girls and 95.2% in late adolescent girls identified as pituitary adenoma.
When broken down by ethnicity, Asian and Pacific Islander children presented with a pituitary tumor at a mean age of 13.9 years, more than 1 year younger than white, Black and Hispanic adolescents. Those in the Asian/Pacific Islander cohort also had the highest proportion of children with germ cell tumors at 10.2%. The white, Black and Hispanic groups had a germ cell tumor prevalence of 3.1% or less.
Of the total study cohort, 5.5% did not have insurance. Those without insurance presented at a mean age of 17.9 years, 2.3 years older than those with private insurance, 3.66 years older than patients with Medicaid and 2.19 years older than those with other government insurance (P < .001 for all). Patients were more likely to have surgery if they had private insurance (adjusted OR = 1.93; 95% CI, 1.47-2.52; P < .001), Medicaid (aOR= 1.51; 95% CI, 1.14-2; P = .004) or other government insurance (aOR = 1.99; 95% CI, 1.35-2.94; P = .001).
“When seeing a female adolescent patient with headaches, vision changes and hormonal abnormalities, it is important to include pituitary adenoma in the differential and workup,” Castellanos said. “In Asian/Pacific Islander children with pituitary masses, in particular, germ cell tumors should be considered. Uninsured pediatric patients that have pituitary tumors are less likely to be diagnosed earlier in their disease course.”
Bryan Iorgulescu, MD, FCAP, an instructor in the department of pathology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute, told Healio that the findings are the first step to better understand the challenges pediatric patients with pituitary tumors have regarding access to care.
“Building on our findings, certainly more health services research is needed to understand the specific socioeconomic and care setting barriers that pediatric patients with pituitary tumors face in their access to timely and standard-of-care management; as well as how these barriers affect their outcomes,” Iorgulescu said.
Perspective
Pediatric pituitary tumors, an overall rare entity, are often identified when children undergo imaging studies of the hypothalamic-pituitary axis for a suspected endocrine disorder. Castellanos and colleagues provide important additional insight into the etiology and distribution of these tumors. Consistent with prior studies, they identify a higher frequency of pituitary adenomas among older compared to younger children, as well as a female predominance. It is important to note that compared to adults, non-functioning adenomas are not common in the pediatric age range. The most common functional adenomas in pediatrics are associated with hypersecretion of prolactin (female predominance, typically seen in adolescence), ACTH (male predominance prior to puberty, typically seen in adolescence), and growth hormone (male predominance). When identified, an association with possible genetic syndromes, including multiple endocrine neoplasia (MEN1), neurofibromatosis, McCune Albright Syndrome, and others, should be sought in the appropriate clinical context.
The increasing use of neuroimaging for evaluation of headaches, neurologic findings or neurocognitive delays leads to an increasing incidence of pituitary incidentalomas, defined by the endocrine society as “a previously unsuspected pituitary lesion that is discovered on an imaging study performed for an unrelated reason.” These incidentalomas, which can include pars intermedia cysts, pituitary microadenomas or pituitary hypertrophy, similarly have a female predominance and predilection for adolescence compared to younger ages. Microadenomas may be noted in up to 20% of children with diagnosed growth hormone deficiency or precocious puberty, where their causality is debatable in light of their frequent spontaneous resolution on subsequent imaging. Among adolescent girls, it is important to recognize that a physiologic increase in pituitary size and a change in imaging characteristics are normal and must be differentiated from adenomas to the degree possible.
Pituitary tumors, particularly adenomas, pose a clinical conundrum in which clinicians and families must weigh the risks of invasive diagnostic or surgical procedures against the value of tissue diagnosis. The association between germ cell tumors and Asian/Pacific Islander populations in this study and others, as well as both germline and somatic genetic testing, provide valuable insight toward the most appropriate course of action for diagnosis and care.
The FDA has granted rare pediatric disease designation to an alpha-kinase 1 inhibitor to treat patients with , or ROSAH, syndrome.
According to a press release from developer Drug Farm, DF-003 is currently being evaluated in a phase 1 clinical trial assessing safety and pharmacokinetics in healthy volunteers.
The FDA has granted rare pediatric disease designation for a therapeutic intended to treat ROSAH syndrome. Image: Adobe Stock
The rare pediatric disease designation is granted by the FDA for a serious or life-threatening condition that affects fewer than 200,000 people in the United States and primarily affects those aged younger than 18 years.
“Pediatric patients living with ROSAH syndrome face a significant unmet need, with limited options to treat vision loss,” Jeysen Yogaratnam, chief medical officer, Drug Farm, stated in the release. “Obtaining rare pediatric disease designation recognizes the serious and debilitating complications of this rare disease and upholds our goal to provide DF-003 as the first targeted drug for potential treatment in patients afflicted with ROSAH syndrome.”
Most people suffer adversity in childhood that undermines their ability to maintain healthy thoughts, feelings, and behaviors.
Every day, we are exposed to things such as pollution that can increase our risk of illness. Many people take on additional risks—due to tobacco smoke, fast food, or alcohol, for example.
The reason that ACEs contribute to so many diseases is that they are associated with many things that trigger other causes of disease. Think of ACEs as a “cause of causes.”
The psychological effects of ACEs may be more obvious and can include fearful expectations, a conviction that one is unworthy of love or protection, unregulated anger or shame, and discombobulating memories of bad events.
It greatly increases the risk of depression, anxiety disorders, post-traumatic stress disorder, and addictions. The one in three adults who experienced childhood sexual or physical abuse or witnessed interpersonal violence at home have at least twice the incidence of these disorders compared to others.
Finally, the burden of illness isn’t distributed fairly. Maintaining health is more challenging for those who are disadvantaged by poverty, lack of education, language barriers, discrimination, and living with the continuing systemic harms of colonization and multi-generational trauma.
Childhood trauma has a complex relationship with these social determinants of health. On one hand, ACEs aren’t unique to marginalized groups and can occur across all strata of society. On the other hand, the risk of experiencing ACEs may be greater in some groups and the consequences of ACEs may multiply as social forces interact.
Events that occur in childhood may contribute to cascading health risks over one’s lifetime. There are so many paths to illness interacting with one another over decades and compromising health in so many ways, that it should be no surprise that childhood adversity is a profound public health problem.
It’s time that we, as a society, recognize ACEs as the malignant force that they are. Those affected need to be treated with compassion and also with awareness of the long-lasting effects of early adversity on health. Research that helps us understand the lifelong impact of ACEs could help guide prevention of chronic illnesses and mental health issues in the many people who experience adversity during childhood.
A new study finds that adults who experienced high, sustained levels of stress as children were more likely to have health indicators.
Consistent high stress, whether real or perceived, during childhood may contribute to an increased risk of diabetes and poor heart health, a new study reports.
The study, published in the Journal of the American Heart Association, reveals that when people experience stress as young children, they are more likely to be obese and are at greater risk of experiencing metabolic issues, which include diabetes and cardiovascular disease.
The findings are a stark call to action to reduce childhood stress, especially as the rates of depression and anxiety in children have increased over time, according to the U.S. Centers for Disease and Control Prevention (CDC), and as cardiometabolic diseases, which include cardiovascular disease and diabetes, are the leading cause of death in the United States.
To determine the link between childhood stress and cardiometabolic risk, the research team followed 276 participants enrolled in the Southern California Children’s Health Study. The 18-year study began in 2003 and included 154 men and 122 women. Nearly two-thirds (62 percent) of participants were white, about 47 percent were Hispanic, 5.4 percent were Asian, and less than 2 percent were black. Just under half of the participants had parents with cardiometabolic history.
The research team found that adults who experienced high, sustained levels of stress as children were more likely to have health indicators. Specifically, the findings indicate positive associations between perceived stress in childhood and obesity in adulthood. The research team based obesity on body mass index (BMI), body fat, and albumin/globulin ratio, which measures the total protein levels in the blood. Women who experienced stress as children were more likely to be obese as adults than men.
Additionally, perceived stress is likely to influence blood pressure, the study found. Participants who experienced increased levels of perceived stress had higher diastolic blood pressure readings than individuals with lower levels of perceived stress.
How Perceived Stress Leads to Increased Cardiometabolic Risk
According to the study, the link between perceived stress and cardiometabolic risk has two possible explanations. First, individuals under more stress are likely to engage in behaviors that compromise their health, such as eating high-calorie, high-fat diets while not exercising.
“These behavioral risk factors may, in turn, lead to an increased risk of cardiometabolic diseases,” the research team wrote.
The second way perceived stress could lead to cardiometabolic risk is predicated on the theory that stress creates inflammation in the body. Stress hormones like catecholamines and corticosteroids activate the immune system. Excessive, persistent inflammation can stress the cardiovascular system, causing endothelial harm or hardening the arteries.
Need for Healthy Coping Mechanisms More Important Than Ever
The researchers noted their findings “suggest that promoting healthy coping strategies for stress management early in life … may facilitate the prevention of cardiometabolic diseases.”
Childhood stress can occur anytime a child has to adapt or change. Stress can sometimes be caused by positive changes, like when starting a new activity, but most of the time, it is linked to negative changes, like the death of a family member or an illness. Small amounts of stress can be good, but excessive stress can affect how a child thinks, acts, and feels.
Everyday stressors for children include:
Worrying about school.
Managing responsibilities, like school, work, or extracurricular activities.
Peer interactions and bullying.
Self-esteem issues.
Moving, changing schools, or coping with housing issues.
Experiencing puberty.
Watching parents get divorced or separated.
Money problems at home.
Living in an unsafe place.
These stressors can lead to adverse childhood experiences, also known as ACEs. ACEs are potentially traumatic events that occur in childhood that can have a lasting impact on a child, according to the CDC. About 64 percent of U.S. adults reported experiencing at least one type of ACE before the age of 18, and nearly 1 in 6 reported experiencing four or more ACEs.
Our immune system works in concert with an ecosystem of microbes living inside of us.
Researchers from the University of Sydney have said that the results of a pre-clinical study conducted by the university have enhanced understanding of diet’s effect on immunity and gut health.
The Sydney University study found that high-protein diets can trigger an immune response by altering the composition and activity of the gut microbiota—a collection of microorganisms that live in the gut.
Associate Prof. Laurence Macia from the Charles Perkins Centre and Faculty of Medicine and Health at Sydney University said in a news release that the team focused on the relationship between gut microbiota and immunity.
“The focus of our work is on how the gut microbiota–the trillions of bacteria that inhabit the gut–affects the immune system,” Macia said.
“Our ultimate aim is to understand how we can manipulate the bacteria to optimize health, and we know that one of the easiest ways to change the microbiota is to change the diet.”
Traditionally, scientists have focused on the role of dietary fibre when investigating the maintenance of a healthy gut.
In an email to The Epoch Times, Macia said this was because dietary fibres are not digestible by humans and, therefore, whilst intact, reach the colon, which has the highest quantity of bacteria.
“Dietary fibres are thus the main source of energy for the bacteria, while other diet components are used by the host,” Macia said.
Macia said that altering the amount of dietary fibre in a person’s diet dramatically impacts gut health; it is easier to investigate.
Does A Carnivore Diet Encourage Immune Responses
This study explored the effect of 10 different diets, each of which had a different makeup of macronutrients —proteins, fats, and carbohydrates—on mice using sophisticated modelling.
The researchers found that when mice were fed a high-protein diet, their production of bacterial extracellular vesicles— carriers of complex cargo that contains bacterial information such as DNA and proteins— increased.
“We identified that high protein increased the production of some metabolites, which may be due to the direct utilization of proteins by the bacteria,” said Macia.
The increase in bacterial extracellular vesicles was interpreted as an attack by the body, which triggered a sequence of events where immune cells travelled into the gut wall.
“Here we found protein had a huge impact on the gut microbiota, and it was not so much about the type of bacteria that were there, but the type of activity,” said Macia.
“In essence, we discovered a new way of communication between the gut bacteria and the host which was mediated by protein.”
Macia noted that as the results have yet to be validated in humans, the researchers are yet to find out if the immune response observed in the trial is either good or bad for humans.
Lead author and post-doctoral researcher Jian Tan said that researchers are aware that an increase in the gut antibodies —proteins that neutralize foreign germs in the body— generates a stronger level of protection against pathogens, such as salmonella. However, there is also evidence to show that an activated immune system could increase the risk of developing inflammatory bowel disease—a collection of conditions where some or all of the digestive tract is chronically inflamed.
A point the researchers noted is currently observable from modern-day diets since in the Western world, rates of gastrointestinal infections have lowered, while rates of chronic diseases have increased.
Unique Modelling System That Made The Discovery Possible
The study used a geometric framework designed by the Academic Director of the Charles Perkins Centre, Prof. Stephen Simpson, and Prof. David Raubenheimer in 2016, which is useful in the face of modern diets where there is an overabundance of food and overindulgence of food containing specific blends of nutrients.
Other frameworks observe the effect that individual components of a diet have on the body rather than looking into the effect that different diets, involving multiple components with varying blends of nutrients, have on a person.
“Our framework throws down the gauntlet to the whole field of human nutrition,” said Simpson in a Sydney University news release.
“It shows that the prevailing focus on single nutrients is not able to help us understand complex chronic diseases and that an approach based on nutrient balance can help solve the problem.”
Simpson said that using the “nutritional geometry” framework allows researchers to observe patterns that would have otherwise been missed. The framework permits food, diets, meals and dietary patterns to be plotted together based on nutrient consumption, assisting researchers in detecting patterns in the links between diets, health and disease.
“Nutritional geometry’ considers how mixtures of nutrients and other dietary components influence health and disease, rather than focusing on any one nutrient in isolation.”
“Conventional thinking which demonizes fat, carbohydrate or sugar in isolation as causes of the obesity crisis—dubbed the single nutrient approach—has now run its course.”
“This is the first time this model has been applied in immunology, and it could only have happened here at the Charles Perkins Centre. We are excited about what could come next,” Assoc. Prof. Macia said.
Numerous special compounds in bovine colostrum are capable of strengthening the immune system and helping the gut lining heal.
The popularity of bovine colostrum for improving gut and immune health is growing, as more research accumulates showing its far-reaching benefits.
Paola Brown had vibrant health growing up but that changed as an adult. Chronic urinary tract infections led to 15 or more rounds of antibiotics, each one leaving her more and more sick.
She had developed autoimmune issues, one of which was celiac disease, an immune reaction to eating gluten that had damaged the lining of her small intestine and led to uncomfortable symptoms and nutrient malabsorption. Various foods caused miserable disease flare ups; she was worried her nursing children weren’t getting adequate nutrients.
Like many people in her position, Ms. Brown became an expert on her own health—particularly gut health. She wanted to heal the root cause so she could eat a less restrictive diet without gastrointestinal (GI) pain. She began researching food sources that can heal the mucosal lining of the intestinal wall and quickly filled a notebook full of information.
One entry was colostrum—the pre-milk food made by all lactating mammals that helps build a newborn’s immune system. Ms. Brown was intrigued by whether bovine colostrum with its peptides, growth factors, and antibodies could give her body what it needed to heal.
Gut barrier dysfunction, particularly the breakdown of the mucosal lining, is a common problem in gluten-related disorders and is suspected in many other diseases. However, the precise mechanism is still being investigated.
“When I took the colostrum, I was trying to target specific things. But that’s really not the way true health works,” Ms. Brown said. “True health is where you take something that your body needs, and then your body decides and addresses what needs to be addressed.
“I found that I craved this colostrum like nothing I’ve ever craved before. The craving was so profound, I decided I was going to follow my body.”
One thing she learned was that taking antibiotics for the occasional infection like a UTI would only set back her health even more. Now a fierce advocate for homeopathy and curriculum specialist, Ms. Brown learned alternative ways to address infections so she could experience the full benefit of her gut improvements.
She has taken colostrum daily for more than seven years an no longer has to avoid any specific foods.
‘Immune Boosting’ Products Flood Market
Two researchers who studied cow’s milk but eventually honed in on colostrum told The Epoch Times that interest has grown since the start of the COVID-19 pandemic when more people became concerned about immune health.
“Everybody’s looking for an extra edge in staying healthy,” said Steven Frese, assistant professor in nutrition at the University of Nevada. “The pandemic was the beginning of the interest, which shot way up. Companies jumped in and started marketing it.”
In the United States, colostrum is often sold as a dietary supplement, said Mr. Frese, who earned his doctorate at the University of Nebraska and specializes in the human gut microbiome. That means commercially purchased colostrum can’t be sold with claims that it prevents, treats or mitigates disease.
“A lot of the terms you get are ‘immune boosting’ or ‘supports a healthy gut.’ They sound like important things we need, but they’re also hard to define. It’s a way to signal there’s an immune effect without having to nail down a certain function,” he said.
But that doesn’t mean colostrum doesn’t boast some impressive qualities.
Promoting a Healthy GI Tract
Newer studies are pointing to how colostrum can play a role in building gut immunity, protecting the body from infection through the gut, and reducing gut symptoms.
eradicating infections caused by pathogenic bacteria such as Escherichia coli, Helicobacter pylori, and the superbug Clostridioides difficile (C. diff.).
reducing diarrhea and vomiting.
decreasing deadly sepsis infections.
improving nutrient absorption and gut function.
reducing gut damage caused by chemotherapy and non-steroidal anti-inflammatory drugs (NSAIDS).
reducing inflammatory markers.
While not quite as impressive as human milk for newborns, a 2016 study in Applied and Environmental Microbiology showed how bovine colostrum can help improve the intestinal microflora to increase Bifidobacterium species—the formative bacteria for immunity.
This makes it an attractive alternative or supplement to synthetic infant formula products for a more healthy gut seeding, according to Alexis Warchalowski, chief marketing officer of ARMRA Colostrum.
“It’s even safe for children. You can put it in baby formula, a child’s yogurt,” Ms. Warchalowski told The Epoch Times. “It’s really for all stages of life. How much and how often you take really depends on your state of health. It’s really, really powerful.”
Additionally, colostrum contains cytokines that turn the immune system on and off, as well as growth factors that play a role in protecting the body against gastric mucosal damage and inflammation, according to Sercan Karav, associate professor at Canakkale Onsekiz Mart University in Turkey.
“Colostrum is very important, but also it is important for specific groups,” Mr. Karav told The Epoch Times. He said various components of the colostrum are helpful for the GI tract, while others are useful for boosting a compromised immune system. Athletes use it for the growth factors that are normally banned by the World Anti-Doping Agency—unless they are sourced in colostrum. Cosmetic companies are also interested in its anti-aging components.
The reason you are using colostrum is especially important when it comes to picking out the right product. Many manufacturers sterilize it in such a way that destroys immunoglobulins, which die when exposed to high heat but are important for colostrum’s immune repair functions, Mr. Karav said.
Immune-Boosting Components
Along with lactoferrin and antimicrobial factors, immunoglobulins in bovine colostrum are beneficial for building and repairing the human immune system, he said. Lactoferrin has been called the “miracle molecule” and is a glycoprotein that has antiviral and antibacterial properties, as well as being an antioxidant.
The vast antimicrobial properties of colostrum can help create a powerful immune defense by preventing harmful microorganisms from proliferating and causing a pathogenic infection.
“People know that if you feed your infants with colostrum, they will be stronger. This has been known for centuries,” Mr. Karav said. “It is the only superfood in nature that covers everything. It gives everything to the newborn, everything in terms of nutrition, in terms of the growth factors, and the immunological factors. There is no other food that has those characteristics.”
Perhaps the biggest boost to immune health comes from the immunoglobulins G (IgG), A (IgA), and M (IgM)—also called antibodies—found in high concentrations in bovine colostrum. They don’t pass the placental barrier in cows, so calves receive all their antibodies from colostrum.
These antibodies are building blocks to immunity, giving the host the ability to recognize the antigens of bacteria, viruses, and toxins in order to destroy them. “The immunoglobulins levels in bovine colostrum are about 100 times higher than those found in mature milk,” according to the NFS article.
Because bovine colostrum is vital to the immune system of calves—they’ll die without it—ethical considerations abound. Mr. Karav said modern milking technology makes it possible to increase production, and research has teased out the minimum amount necessary for calves.
He consults with farms that want to employ the technology so they can sell colostrum for human consumption in the safest way for their herd and consumers. Without some sort of sterilization, there’s a risk of introducing pathogens from the cows to humans. Techniques vary from low heat pasteurization to freeze drying, as well as ultraviolet light that’s being explored more recently.
While colostrum is a single ingredient, its complexities change its properties so that it’s not uniform. Factors that might impact quality include collection, manufacturing, and the state of the donor cow. The market is saturated with a number of colostrum products that come in the form of capsules, powders, and liquid.
What’s in Your Colostrum?
Of utmost importance is the percentage of IgG in a product. That’s because at its first milking, cows’ colostrum output contains up to 30 percent IgG. That number drops off at each milking until it gets down to 2 percent. At 2 percent, it’s no longer colostrum but milk. Colostrum collection is also limited to the first three days postpartum.
IgG is the best indicator of the quality of colostrum, Mr. Karav said. If a product claims to have 30 percent, it’s unlikely accurate, he said.
“If a company is forthright, you can ask what their IgG percentage is,” Ms. Brown said.
Other considerations when taking colostrum are that each batch naturally varies. Its composition depends on factors such as the breed of cow, how it was fed, its health status, the time of year it gave birth, the types of vaccines the cows had, and how many hours postpartum the colostrum was collected.
Ms. Brown said the colostrum she takes is sourced from various herds in order to make the product more diverse with a variety of antibodies. “I think it really is important to talk about high-quality colostrum. A lot of products labeled colostrum are really powdered milk,” she said.
Colostrum is composed of carbohydrates, proteins (from the immunoglobulins), lipids, minerals, vitamins (A, E, D, K and B complex), amino acids, cytokines, growth factors, and enzymes.
“The most interesting and surprising thing to me is it has telomerase enzyme,” Mr. Karav said. “People love this enzyme because it’s associated with aging,” he said, noting its popularity in cosmetics.
Telomeres are found on the ends of DNA strands and help prevent chromosomes from degenerating during cell division. As cells divide, the telomere structure shortens—a natural part of the cellular aging process. Telomerase can restore missing parts of shortened telomere chains, according to Mr. Karav.
Abundant Research
Ms. Warchalowski said there is vast research on the potency of colostrum—more than 5,000 studies according to the company.
Among those ARMRA touts is one from 2007 showing that colostrum was “at least three times more effective than vaccination to prevent flu and is very cost-effective.” The study, published in Clinical and Applied Thrombosis/Hemostasis, looked at both healthy subjects as well as high-risk cardiovascular patients.
The founder of ARMRA, Dr. Sarah Rahal, is a double board-certified pediatric neurologist who nearly died from a catastrophic health event that ultimately led to the removal of part of her colon and small intestine.
Ms. Warchalowski said Dr. Rahal wanted to make a colostrum product that would preserve as many beneficial properties as possible and help others who needed help with immunity and gut barrier protection.
“What colostrum does is it actually seals up that lining again…it actually strengthens all four layers of your gut wall so invaders are no longer penetrating that internal barrier. What happens is as a result you have incredible gut health. Your cells can now regenerate stronger and faster than they have before,” she said. “Because your body essentially starts to heal itself, all these other amazing things start to happen within your body.”
A fortified gut, Ms. Warchalowski said, may free the body to work on other processes because it’s not working so hard to fight off antigens. The company often hears surprising testimonies about hair regrowth, less gray hair, and improved cognition.
Ms. Brown noted that colostrum isn’t a miracle cure, and changes in the body don’t always occur rapidly. She began with very small doses straight from a local farmer’s cow. Eventually she found a powered supplement. It was months before she noticed changes. With persistence and patience, Ms. Brown said she’s living a completely different life today.
“My husband and I went out of town for our 20th anniversary, and we went to some really fun German-inspired restaurants. I ate whatever I wanted indiscriminately, and I had no problems,” she said. “How do I explain this? Colostrum gave my body what it needed for my body to heal my gut.”
The potential of colostrum is incredible, but Mr. Frese emphasized that it’s a zero-sum game. Robotics allow for it to be collected, yet there will always be limitations.
“If you’re farming like folks did 100 years ago, the answer of how much can be taken is pretty much zero,” he said. “If the farming system is designed better, it will allow you to take some of that colostrum without hurting the cow in the short-term or the long-term. But there’s only so much colostrum that’s made.”
ARYAN'S BLOG 
