USFDA gives tentative nod for Lupin diabetes drug Sitagliptin

Mumbai: Global pharma major Lupin Limited has announced
that it has received tentative approval from the United States Food and Drug Administration (U.S. FDA)
for its Abbreviated New Drug Application (ANDA), Sitagliptin Tablets USP, 25 mg, 50 mg, and 100 mg
to market a generic equivalent of Januvia Tablets, 25 mg, 50 mg, and 100 mg, of Merck Sharp and
Dohme Corp.

This product will be manufactured at Lupin’s Pithampur facility in India.


Sitagliptin Tablets USP, 25 mg, 50 mg, and 100 mg are indicated as an adjunct to diet and exercise to
improve glycemic control in patients with type 2 diabetes mellitus.

Sitagliptin Tablets (RLD Januvia) had estimated annual sales of USD 5789.3 million in the U.S. (IQVIA
MAT October 2023). 

Read also: Include Ankle Brachial Index test to exclude peripheral artery disease: CDSCO Panel Tells Lupin on Denosumab PK/PD study

Medical Dialogues team had earlier reported that the Company had received tentative approval from the USFDA for its Abbreviated New Drug Application for Dapagliflozin Tablets, 5 mg, and 10 mg to market a generic equivalent of Farxiga Tablets, 5 mg, and 10 mg of AstraZeneca AB.

Read also: Lupin Dapagliflozin Tablets gets tentative USFDA okay

Lupin is an innovation-led transnational pharmaceutical company headquartered in Mumbai, India. The
Company develops and commercializes a wide range of branded and generic formulations, biotechnology
products, and APIs in over 100 markets in the U.S., India, South Africa, and across the Asia Pacific (APAC), Latin
America (LATAM), Europe, and Middle East regions.
The Company specializes in the cardiovascular, anti-diabetic, and respiratory segments and has
a significant presence in the anti-infective, gastro-intestinal (GI), central nervous system (CNS), and women’s
health areas. The company
invested 7.9% of its revenue in research and development in FY23.
Lupin has 15 manufacturing sites, 7 research centers.

Read also: Lupin Diagnostics unveils Regional Reference Laboratory in Chennai

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New gene therapy promising for reducing seizures in children with focal cortical dysplasia

UK: A recent study, published in Brain, sought to find an alternative to surgery for children with focal cortical dysplasia.

UCL researchers developed a new gene therapy to cure a devastating form of childhood epilepsy, which the study shows can significantly reduce seizures in mice.

Focal cortical dysplasia is caused by areas of the brain that have developed abnormally and is among the most common causes of drug-resistant epilepsy in children. It frequently occurs in the frontal lobes, which are important for planning and decision-making. Epilepsy in focal cortical dysplasia is associated with comorbidities, including learning disabilities.

Although surgery to remove the affected brain malformation is effective, its use is severely limited by the risk of permanent neurological deficit and does not always result in seizure freedom.

Consequently, researchers at the UCL Queen Square Institute of Neurology evaluated a gene therapy based on the overexpression of a potassium channel which regulates neuronal excitability in a mouse model of focal cortical dysplasia in the frontal lobe.

Potassium channels control the movement of potassium ions in and out of cells. When there is an overexpression of a potassium channel, it means that there is greater regulation, resulting in the decrease of the activity of cells and, in turn, stopping seizures.

Co-corresponding author, Professor Gabriele Lignani (UCL Queen Square Institute of Neurology), said: “It is very exciting to see that this new gene therapy could potentially be used as an effective alternative to surgery in patients with focal cortical dysplasia.”

Gene therapies have previously been shown to work in another form of epilepsy where seizures arise in the temporal lobes, but have not been tested in focal cortical dysplasia.

In this case, the researchers introduced an engineered potassium channel gene called EKC into the affected frontal lobe of the epileptic mice. For added safety, they used a virus that is unable to replicate in order to carry the potassium channel gene.

Before giving the treatment, researchers monitored the mice’s brain activity for 15 days. They then injected either the virus carrying the EKC gene or a control virus into the affected brain area. The team then monitored the mice’s brain activity for another 15 days.

The researchers found that the gene therapy reduced seizures by an average of 87% when compared with the control group, without affecting the mouse’s memory or behaviour.

Lead author Dr Vincent Magloire (UCL Queen Square Institute of Neurology) said: “Following the successful study in mice, we believe the treatment is suitable for clinical translation, and, taking into account the size of the unmet need, it could be deployed to thousands of children who are currently severely affected by uncontrolled seizures.”

Co-corresponding author, Professor Dimitri Kullmann (UCL Queen Square Institute of Neurology) added: “Plans for a first in human clinical trial are underway and are planned in the next five years.”

Reference:

Amanda Almacellas-Barbanoj, Robert T. Graham, Jenna Carpenter, Marco Leite, Justin Hoke, Felisia Hardjo, James Scott-Solache, Christos Chimonides, : Anti-seizure Gene Therapy for Focal Cortical Dysplasia, https://doi.org/10.1093/brain/awad387.

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Post-meal insulin surge not a villain, says new research

Researchers at Sinai Health have unearthed vital information about the relationship between insulin levels after eating and long-term heart and metabolic health. The research upends the notion that insulin surge following food intake is a bad thing.

On the contrary-it could be an indicator of good health to come.

Led by Dr. Ravi Retnakaran, Clinician-Scientist at the Lunenfeld-Tanenbaum Research Institute, part of Sinai Health, the study set out to explore how insulin levels after meals impact cardiometabolic health. While past research has yielded conflicting results, suggesting both harmful and beneficial effects, this new study aimed to provide a clearer picture over an extended period of time.

The team reported their findings in the online journal eClinicalMedicine, published by the Lancet group.

Normally, insulin levels rise after eating to help manage blood sugar. However, the concern is whether a rapid increase in insulin after a meal could spell bad health. Some believe the insulin surge, especially after eating carbs, promotes weight gain and contributes to insulin resistance. This occurs when the body’s cells don’t respond well to insulin, making it harder to control blood sugar levels and increasing the risk of type 2 diabetes.

“The suggestion has been made by some people that those insulin peaks have deleterious effects by promoting weight gain,” said Dr. Retnakaran, who is also Endocrinologist at the Leadership Sinai Centre for Diabetes at Mount Sinai Hospital where he holds the Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration. He is also a Professor at the University of Toronto’s Temerty Faculty of Medicine.

“Sometimes I see patients in the clinic who have adopted this notion, maybe from the internet or what they’re reading, that they can’t have their insulin level go too high,” he said.

The science is just not conclusive enough to support this notion. Most studies on this topic were either conducted over a short period of time or were based on insulin measurements in isolation that are inadequate and can be misleading, said Dr. Retnakaran.

His team sought to address this problem by looking at cardiometabolic implications of insulin response over the long term, and in a way that accounts for baseline blood sugar levels. The latter point is key because each person has an individual insulin response that varies depending on how much sugar is in the blood.

The study followed new mothers because the insulin resistance that occurs during pregnancy makes it possible to determine their future risk of type 2 diabetes. 306 participants were recruited during pregnancy, between 2003 and 2014, and underwent comprehensive cardiometabolic testing, including glucose challenge tests, at one, three, and five years after giving birth. The glucose challenge test measures glucose and insulin levels at varying time points after a person has had a sugary drink containing 75 grams of glucose and following a period of fasting.

While commonly used in medical practice, the interpretation of insulin levels from the test can be misleading if one does not account for baseline blood sugar. “It’s not just about insulin levels; it’s about understanding them in relation to glucose,” Dr. Retnakaran said, pointing out that this is where many past interpretations fell short. A better measurement is the corrected insulin response (CIR) that accounts for baseline blood glucose levels, and which is slowly gaining prominence in the field, he said.

The study revealed some surprising trends. As the corrected insulin response increased, there was a noticeable worsening in waist circumference, HDL (good cholesterol) levels, inflammation, and insulin resistance, if one did not consider accompanying factors. However, these seemingly negative trends were accompanied by better beta-cell function. Beta cells produce insulin, and their ability to do so is closely associated with diabetes risk – the better the beta cell function, the lower the risk.

“Our findings do not support the carbohydrate-insulin model of obesity,” said Dr. Retnakaran. “We observed that a robust post-challenge insulin secretory response-once adjusted for glucose levels-is only associated with the beneficial metabolic effects”.

“Not only does a robust post-challenge insulin secretory response not indicate adverse cardiometabolic health, but rather it predicts favorable metabolic function in the years to come.”

There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal. But it’s not that simple

In the long run, higher corrected insulin response levels were linked with better beta-cell function and lower glucose levels, without correlating with BMI, waist size, lipids, inflammation, or insulin sensitivity or resistance. Most importantly, women who had the highest CIR had a significantly reduced risk of developing pre-diabetes or diabetes in the future.

“This research challenges the notion that high post-meal insulin levels are inherently bad and is an important step forward in our understanding of the complex roles insulin plays in regulation of metabolism,” said Anne-Claude Gingras, Director of LTRI and Vice-President of Research at Sinai Health.

Dr. Retnakaran hopes their findings will reshape how medical professionals and the public view insulin’s role in metabolism and weight management.

“There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal. But it’s not that simple,” he said.

Reference:

Ravi Retnakaran, Jiajie Pu, Anthony J. Hanley, Philip W. Connelly, Mathew Sermer, Bernard Zinman, Future cardiometabolic implications of insulin hypersecretion in response to oral glucose: a prospective cohort study, DOI:https://doi.org/10.1016/j.eclinm.2023.102363.

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Mannose supplementation reduces ageing-induced changes in urinary tract that increase susceptibility to UTIs: Study

USA: A recent study revealed that mannose supplementation can reduce the severity of aging-associated decline in urinary tract functionality, suggesting that this common, over-the-counter supplement could improve the age-associated dysfunction and help reduce urinary tract infections (UTIs).

“Mannose supplementation could counter age-associated urothelial dysfunction in addition to limiting recurring UTIs,” the resarchers wrote in their study published in Developmental Cell. 

Aging poses a number of challenges to the body’s well-being, one of the most important being an increased susceptibility to multiple diseases, including UTIs. The connection between aging and more prevalent UTIs is not well understood, but now researchers at Baylor College of Medicine have found an explanation.

The researchers show that compared to the younger counterpart, the aging urinary tract in animal models changes how it functions at the cellular level in ways that seem to favor the establishment and recurrence of UTIs. Furthermore, the researchers also found that the sugar D-mannose reduces the severity of aging-associated decline in urinary tract functionality, suggesting that this common, over-the-counter supplement could improve this age-associated dysfunction and help reduce UTIs.

“We began this study by comparing the functions of naturally aging cells in mouse bladders with those of younger animals, in the absence of a bacterial infection. Specifically, we studied urothelial cells, the cells that line the inside of the bladder where urine is stored,” said corresponding author Dr. Indira Mysorekar, professor of medicine – infectious diseases and E.L. Wagner, M.D., Chair of Internal Medicine at Baylor.

The researchers investigated a process called autophagy that all cells naturally use to clean up old or defective cellular materials by digesting and recycling them in structures called lysosomes. “We found that the recycling process naturally slows down as urothelial cells age,” said Mysorekar, a professor in the Huffington Center on Aging. “Older cells accumulate larger lysosomes that are less effective at degrading cellular materials, which leads to their toxic accumulation inside the cell.”

Aged urothelial cells also accumulate more damaging reactive oxygen species (ROS) than younger tissues. “ROS are molecules that can harm tissues, and the redox response that normally neutralizes ROS in younger cells is dampened in aging urothelial cells,” said co-first author Dr. Arnold M. Salazar, senior staff scientist in the Mysorekar lab. “Consequently, an inflammatory process builds up, leading to cell death. Dead urothelial cells leave their location, exfoliating the bladder and disrupting its integrity, which further exacerbates age-related dysfunction.”

Importantly, they also discovered that treating aged mice with D-Mannose, a natural sugar, restores autophagy and mitigates ROS and urothelial cell shedding, suggesting that mannose supplementation could counter age-associated human urothelial dysfunction.

Mysorekar, Salazar and their colleagues then compared bacterial UTIs in older animals versus younger animals. “We found that aged mice have more bacterial reservoirs in the urinary tract and are more prone to spontaneous recurrent UTI than younger mice, suggesting that the age-related dysfunction of the tissue could explain the higher recurrence of UTIs observed in older age,” Salazar said.

“Collectively, our results demonstrate that normal aging affects bladder physiology, with aging alone increasing baseline cellular stress and susceptibility to infection,” said Mysorekar, also a professor of molecular virology and microbiology. “We suggest that mannose supplementation could counter age-associated urothelial dysfunction in addition to limiting recurring UTIs.”

Reference:

Chetanchandra S. Joshi, Arnold M. Salazar, Caihong Wang, Marianne M. Ligon, Rayvanth R. Chappidi, Bisiayo E. Fashemi, Paul A. Felder, Amy Mora, Sandra L. Grimm, Cristian Coarfa, Indira U. Mysorekar, D-Mannose reduces cellular senescence and NLRP3/GasderminD/IL-1β-driven pyroptotic uroepithelial cell shedding in the murine bladder, Developmental Cell, 2023, https://doi.org/10.1016/j.devcel.2023.11.017.

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Insulin resistance associated with cardiovascular pathology that contributes to HF

USA: A recent study published in the Journal of Cardiology has revealed an association of insulin resistance with subclinical myocardial dysfunction and reduced functional capacity in patients with heart failure with preserved ejection fraction (HFpEF).

The findings may inform treatment strategies focused on using tools for estimating insulin resistance and selecting insulin-sensitizing drugs which may improve exercise capacity and cardiac function.

In heart failure with preserved ejection fraction insulin resistance and obesity are prevalent and are associated with adverse cardiovascular (CV) outcomes. Insulin resistance measurement is difficult outside of research settings, and there is no information on its correlation to parameters of myocardial dysfunction and functional status.

To fill this knowledge gap, Allison G. Hays, University School of Medicine, Baltimore, MD, USA, and colleagues aimed to assess the role of estimated glucose disposal rate (eGDR), an easily calculated metric using commonly available clinical variables that reflects insulin resistance, in a well-characterized cohort of HFpEF patients.

They tested the hypothesis that increased insulin resistance (measured by reduced eGDR) is associated with abnormalities in cardiac function and structure in patients with HFpEF.

The study included 92 HFpEF patients with New York Heart Association class II to IV symptoms. The mean age of the participants was 65 years, 64 % were women, and 95 % had hypertension. Mean (SD) BMI was 39 (9.6) kg/m2, glycated haemoglobin 6.7 (1.6) %, and eGDR 3.3 (2.6) mg × kg−1 min−1. They underwent 2D echocardiography, clinical assessment, and a 6-minute walk (6 MW) test. Insulin resistance was defined by the estimated glucose disposal rate. Lower eGDR indicates increased insulin resistance (unfavourable).

Myocardial function and structure were assessed by average E/e’ ratio, left ventricular (LV) mass, left atrial volume, right ventricular systolic pressure, LV longitudinal strain (LVLS), LV ejection fraction, and tricuspid annular plane systolic excursion. Association were evaluated between eGDR and adverse myocardial function in unadjusted and multivariable-adjusted analyses using analysis of variance testing and multivariable linear regression.

The study led to the following findings:

  • Increased insulin resistance was associated with worse LVLS in a graded fashion [mean −13.8 %, −14.4 %, −17.5 % for first, second, and third eGDR tertiles, respectively]. This association persisted after multivariable adjustment.
  • There was also a significant association between worse insulin resistance and decreased 6 MW distance on univariate analysis, but not on multivariable-adjusted analysis.

“In a well-characterized cohort of HFpEF patients, our findings showed a significant relationship between eGDR and LVLS, suggesting that insulin resistance is associated with CV pathology that contributes to HFpEF pathophysiology, independent of common covariates implicated in HFpEF,” the researchers wrote.

Reference:

Gudenkauf, B., Shaya, G., Mukherjee, M., Michos, E. D., Madrazo, J., Mathews, L., Shah, S. J., Sharma, K., & Hays, A. G. (2024). Insulin resistance is associated with subclinical myocardial dysfunction and reduced functional capacity in heart failure with preserved ejection fraction. Journal of Cardiology, 83(2), 100-104. https://doi.org/10.1016/j.jjcc.2023.06.008

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AIIMS Announces Schedule For Fee Payment, Release Of Admit Card For Professional UG Exams, details

Delhi: All India Institute of Medical Sciences (AIIMS) has announced the schedule of payment of examination fee and release of admit cards for professional examinations of undergraduate December 2023 to January 2024.

Online registration for submission of the examination fee will be opened on 16.12.2023. The registration closing date is 24.12.2023.

Undergraduate students who are likely to appear for above mentioned examinations are advised to visit the website of AIIMS under the Student Tab to go to the desired course, Click on the Professional Exams Registration link, fill out the Examination Form, and make payment for Examination Fees through Debit/Credit Card/Net Banking only. The fees to be paid will be populated automatically depending on the course.

Also Read:AIIMS Announces Reporting Schedule For NEET SS Allotted Candidates Of 1st Round For January 2024 Session

Admit Card –

Only those eligible candidates who have paid their Examination Fees as per the above-mentioned schedule will be able to download their Admit Card w.e.f. 18.12.2023 onwards by visiting the website of AIIMS under the Student Tab for the desired course. Click on the Admit Card link, Enter Enrolment Number and Date of Birth to download the admit card.

All India Institute of Medical Sciences, New Delhi, is a globally acclaimed public medical research university and hospital based in New Delhi, India. The institute is governed by the AIIMS Act 1956 and operates autonomously under the Ministry of Health and Family Welfare.

Objectives of AIIMS –

1. To develop a pattern of teaching in undergraduate and postgraduate medical education in all its branches so as to demonstrate the high standard of medical education to all medical colleges and other allied institutions in India.

2. To bring together in one place educational facilities of the highest order for the training of the personnel in all important branches of the health activity.

3. To attain self-sufficiency in postgraduate medical education.

To view the notice, click on the link below –

https://medicaldialogues.in/pdf_upload/notice-fee-admit-card-january-2024-website-227964.pdf

Also Read:71 seats available for INI SS January 2024 at JIPMER: Know eligibility criteria, seat matrix, fee, all admission details here

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Oral Acitretin and TAC Effective in treatment of Oral Lichen Planus: JAMA

Symptomatic Oral Lichen Planus (OLP) has been a formidable challenge to treat, but a recent clinical trial revealed a positive outcome. The study from Postgraduate Institute of Medical Education and Research in Chandigarh, compared the efficacy of a combination therapy of oral acitretin with topical triamcinolone acetonide (TAC) and 0.1%—with TAC monotherapy in patients with symptomatic OLP. The findings of the study were published in Journal of American Medical Association.

This investigator-initiated trial involved 64 patients aged 18 and older with symptomatic OLP, employing a placebo-controlled, investigator- and patient-blinded randomized design. The patients were randomized into a group receiving a combination of oral acitretin and TAC, and the other group receiving TAC combined with a placebo. The treatment was for 28 weeks with an additional 8 weeks of treatment-free follow-up.

Results showed a statistically significant advantage for the combination therapy. In the intention-to-treat analysis, a higher number of patients in the treatment group achieved a 75% or higher reduction in Oral Disease Severity Score (ODSS) compared to the placebo group at both 28 weeks and 36 weeks.

The combination therapy demonstrated a superior performance in the reduction of relapses during the posttreatment follow-up. The low relapse rates further solidified the effectiveness of the dual approach, offering a ray of hope for patients suffering with symptomatic OLP.

This trial opened new doors for managing OLP, indicating that a combination of oral acitretin and TAC might be a potent therapeutic strategy than TAC monotherapy. The medical community anticipates the treatment landscape for symptomatic OLP by improving the quality of life for many individuals affected by this challenging condition.

Source:

Vinay, K., Kumar, S., Dev, A., Cazzaniga, S., Borradori, L., Thakur, V., & Dogra, S. (2023). Oral Acitretin Plus Topical Triamcinolone vs Topical Triamcinolone Monotherapy in Patients With Symptomatic Oral Lichen Planus. In JAMA Dermatology. American Medical Association (AMA). https://doi.org/10.1001/jamadermatol.2023.4889

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Seaweed supplementation improves glycemic control and diabetes management

A recent study published in the Journal of Nutrients found compelling evidence that support the potential of seaweed supplementation in the management of diabetes. Diabetes pose a pervasive health threat and the need for effective prevention and management strategies paramount, this study looked into the impact of seaweed consumption on various facets of blood glucose control.

Diabetes demands innovative approaches to prevention and management. To recognize the efficacy of dietary interventions like the Mediterranean diet and calorie restriction coupled with exercise-induced weight reduction, researchers turned their attention to the potential benefits of seaweed. With its rich content of polyphenols and fucoidan, seaweed has been associated with blood glucose regulation, improved intestinal health, and enhanced lipid profiles.

This exhaustive analysis conducted with the help of databases including PubMed, RISS, Google Scholar, ScienceDirect, and the Cochrane Library. 23 studies were included in this comprehensive meta-analysis.

The results of the study were;

Postprandial blood glucose, glycated hemoglobin (HbA1c), and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) levels demonstrated substantial improvements in the group supplemented with seaweed compared to the control group.

Fasting blood glucose and insulin levels did not exhibit significant associations with seaweed consumption.

Seaweed supplementation taken particularly at higher doses (1000 mg or more) proved more beneficial than lower doses. Specific seaweed varieties that include Laminaria digitata, Undaria pinnatifida, Acophyllum nodosum, and Fucus vesiculosus, were identified as particularly effective in improving blood glucose levels.

This research suggests that seaweed supplementation could be a promising strategy to reduce the postprandial blood glucose, HbA1c, and HOMA-IR levels and offers a tangible avenue for improved blood glucose management and a potential decrease in the risk of type 2 diabetes.

Source:

Kim, Y. R., Park, M. J., Park, S. Y., & Kim, J. Y. (2023). Brown Seaweed Consumption as a Promising Strategy for Blood Glucose Management: A Comprehensive Meta-Analysis. Nutrients, 15(23). https://doi.org/10.3390/nu15234987

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Increased risk of suicidal ideation and suicide around menstrual cycles, finds study

USA: In the first longitudinal study of how suicidal thoughts and related symptoms fluctuate across the menstrual cycle, University of Illinois Chicago (UIC) researchers identified when some female patients are at the highest risk, offering new guidance for clinicians about when to focus interventions with suicidal patients.

The study, published in the American Journal of Psychiatry, revealed that female patients with a history of suicidality experience an increased risk of suicidal ideation or suicidal planning in the days surrounding menstruation, according to a new study by researchers at the University of Illinois Chicago.

“As clinicians, we feel responsible for keeping our patients safe from a suicide attempt, but we often don’t have much information about when we need to be most concerned about their safety,” said Tory Eisenlohr-Moul, associate professor of psychiatry at UIC and senior author of the paper. “This study establishes that the menstrual cycle can affect many people who have suicidal thoughts, which makes it one of the only predictable recurring risk factors that has been identified for detecting when a suicide attempt might occur.”

The American Journal of Psychiatry study, which is co-led by postdoctoral researcher Jaclyn Ross and MD/PhD student Jordan Barone, followed 119 patients who completed a daily survey to track suicidal thoughts and other mental health symptoms over at least one menstrual cycle. The design allowed the researchers to collect detailed data on changes in patients’ mental health over the course of their cycle. Previous research did not have this sort of tracking and only worked to estimate the timing of a person’s menstrual cycle status with a single timepoint after a suicide attempt.

Those past studies observed a pattern where suicide attempts increased in the days just before or after the onset of menses-the “perimenstrual” phase. The new UIC study replicated this pattern, finding that suicidal ideation was more severe and suicidal planning was more likely to occur during this point in the cycle compared to other phases.

The daily data also allowed the researchers to delve deeper into differences between individuals in how the cycle affects symptoms and suicidality.

“Previously, there haven’t been good predictors for why or when Person A is likely to make a suicide attempt versus when Person B is going to make an attempt,” Barone said. “Not everyone is hormone sensitive to the cycle in the same way, and we were able to statistically show the value of including individual differences in our models.”

Most patients in the study reported significant elevation of psychiatric symptoms such as depression, anxiety and hopelessness in the premenstrual and early menstrual phases, while others reported emotional changes at different times of their cycle. Individuals also varied in the specific psychiatric symptoms that appeared alongside suicidal thoughts.

“People differed in which emotional symptoms were most correlated with suicidality for them,” Eisenlohr-Moul said. “Just because the cycle makes somebody irritable or have mood swings or feel anxious, it doesn’t necessarily mean that that’s going to have the same effect on creating suicidality for each person.”

That observation fits with the broader research focus of Eisenlohr-Moul’s group, the CLEAR lab. The laboratory also studies premenstrual dysphoric disorder, a condition associated with an increased risk of suicidal thoughts and behaviors. Observational studies and clinical trials led by Eisenlohr-Moul have found that PMDD may result from some people’s heightened sensitivity to the reproductive hormones estrogen and progesterone — and stabilizing those hormones may lessen symptoms.

Similar dynamics of hormone sensitivity may be at play in the influence of the menstrual cycle upon suicidal thoughts in people without PMDD, the authors said. But more research is needed to determine how these factors affect each other in individual patients, and how that information could best be used clinically to prevent suicide attempts.

One idea is for patients to keep track of their mental health symptoms over the course of their cycle — as subjects did in the current study — to enable their clinicians to make personalized recommendations about their care.

“We’re excited to use the best methods out there to try to create individual prediction models for each person, so that we’re not putting people into a box,” Eisenlohr-Moul said. “We want to really figure out: does the cycle matter for this person, and then exactly how does it matter and how we can best intervene based on that information.”

Reference:

Jaclyn M. Ross, Jordan C. Barone, Hafsah Tauseef, Katja M. Schmalenberger, Anisha Nagpal, Natania A. Crane, Tory A. Eisenlohr-Moul, Predicting Acute Changes in Suicidal Ideation and Planning: A Longitudinal Study of Symptom Mediators and the Role of the Menstrual Cycle in Female Psychiatric Outpatients With Suicidality, https://doi.org/10.1176/appi.ajp.20230303.

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Serial amnioinfusions improve survival in neonates without kidneys; long-term management remains a concern: JAMA

USA: In neonates with bilateral renal agenesis, prenatal serial amnioinfusions can mitigate neonatal lethal pulmonary hypoplasia, but infants face substantial morbidity independent of lung function, according to the RAFT trial.

In the nonrandomized clinical trial, published in the Journal of the American Medical Association (JAMA), 82% of live-born infants survived to 14 days of life or longer and placement of dialysis access, but there was a reduction in longer-term neonatal survival. Serial amnioinfusions were not associated with severe maternal complications.

A higher number of amnioinfusions, higher birth weight, and gestational age greater than 32 weeks were all factors associated with survival to 14 days. There was no occurrence of serious maternal complications, although delivery before 37 weeks gestation was universal and 61% had preterm prelabour rupture of membranes.

Bilateral renal agenesis is the most severe congenital anomaly of the fetal urinary tract. Fetal anuria leads to a lack of amniotic fluid, which depressurizes the airways, impairing pulmonary development and resulting in lethal pulmonary hypoplasia. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival. Therefore, Jena L. Miller, Johns Hopkins University, Baltimore, Maryland, and colleagues aimed to assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks gestation to mitigate lethal pulmonary hypoplasia.

The nonrandomized trial was conducted from 2018 to 2022 at 9 US fetal therapy centres. Centres had to have a maternal-fetal medicine doctor who had performed amnioinfusion procedures for anhydramnios or oligohydramnios at least 15 times before.

Outcomes are reported for 21 pairs of mother-fetus with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies.

The intervention involved ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks gestation to maintain normal amniotic fluid levels. An additional three mothers elected against the infusions and entered an expectant management group providing observational data before and after delivery. All of the expectant management fetuses died.

The primary endpoint was postnatal infant survival to 14 days of life or longer with dialysis access placement.

The researchers reported the following findings:

  • The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal mortality and morbidity beyond the primary endpoint despite the demonstration of the efficacy of the intervention.
  • There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days.
  • All participants were delivered before 37 weeks’ gestation. The primary outcome was achieved in 14 of 17 live-born infants.
  • Factors associated with survival to the primary outcome included a higher number of amnioinfusions, higher birth weight, and gestational age greater than 32 weeks.
  • Only 6 (35%) of the 17 neonates born alive survived hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life.

“The findings indicate that serial amnioinfusions mitigated lethal pulmonary hypoplasia but were linked with preterm delivery,” the researchers wrote. “The lower survival to discharge rate underscores the additional mortality burden independent of lung function.”

“There is a need for additional long-term data to fully characterize the outcomes in surviving neonates and assess the mortality and morbidity burden,” they concluded.

Reference:

Miller JL, Baschat AA, Rosner M, et al. Neonatal Survival After Serial Amnioinfusions for Bilateral Renal Agenesis: The Renal Anhydramnios Fetal Therapy Trial. JAMA. 2023;330(21):2096–2105.

doi:10.1001/jama.2023.21153

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