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Background Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that the metabolic stress induced by a KD combined with metformin would enhance radiation’s efficacy. We sought to assess the tolerability and feasibility of this approach. Methods A single-institution phase I clinical trial. Radiotherapy was either 60 or 35 Gy over 6 or 2 weeks, for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a Modified Atkins Diet (ModAD) supplemented with medium chain triglycerides (MCT). There were three cohorts: Dietary intervention alone, and dietary intervention combined with low-dose or high-dose metformin; all patients received radiotherapy. Factors associated with blood ketone levels were investigated using a mixed-model analysis. Results A total of 13 patients were accrued, median age 61 years, of whom six had newly diagnosed and seven with recurrent disease. All completed radiation therapy; five patients stopped the metabolic intervention early. Metformin 850 mg three-times daily was poorly tolerated. There were no serious adverse events. Ketone levels were associated with dietary factors (ketogenic ratio, p < 0.001), use of metformin (p = 0. 02) and low insulin levels (p = 0.002). Median progression free survival was ten and four months for newly diagnosed and recurrent disease, respectively. Conclusions The intervention was well tolerated. Higher serum ketone levels were associated with both dietary intake and metformin use. The recommended phase II dose is eight weeks of a ModAD combined with 850 mg metformin twice daily.

Background: Impaired bone health is a recognized complication of type 1 diabetes. This study evaluated the effects of low-carbohydrate (LC) and Mediterranean (MED) diets on bone turnover markers in adolescents and young adults. Methods: In a 24-week randomized controlled trial, 40 individuals aged 12–21 years, with type 1 diabetes, were assigned to an LC or MED intervention (20 participants per group). C-terminal telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at baseline and 24 weeks. Results: The groups had similar baselines. At 24 weeks, the between-group difference in delta glucose time in range was not statistically significant; median daily carbohydrate intake was 86 g (68–95) in LC and 130 g (102–173) in MED (p < 0.001). Comparing LC to MED, the median BMI z-score was lower (−0.1 [−0.3 to −0.1] vs. 0.0 [−0.1 to −0.1], p = 0.10), and calcium (p = 0.035) and magnesium intakes (p = 0.030) were lower. These associations did not remain statistically significant after false-discovery-rate correction. The median-adjusted alkaline phosphatase level decreased significantly in the LC group (p = 0.009). The median CTX changed following LC from 395 pg/mL (232–591) to 423 pg/mL (289–591) (p = 0.278); and following MED, from 357 pg/mL (244–782) to 296 pg/mL (227–661) (p = 0.245). P1NP changed in LC from 95 ng/mL (68–112) to 88 ng/mL (62–97) (p = 0.056) and in MED from 76 ng/mL (54–198) to 71 ng/mL (55–122) (p = 0.594). Conclusions: Exploratory analyses of bone turnover markers showed insignificant differences following LC and MED diets.

Brain injury following congenital heart surgery is associated with long-term neurodevelopmental deficits. Early identification of such injury may guide timely neuroprotective interventions. The calcium-binding protein S100B has been established in retrospective studies to be associated with poor neurological outcomes after surgery. These findings suggest that S100B may serve as a biomarker of central nervous system injury. Our study prospectively investigates the predictive value of S100B as a marker for new neurological deficits (NND) in infants undergoing cardiac surgery. In a prospective cohort of 130 infants undergoing congenital heart surgery, S100B was sampled before (  = 0, S100B1) and six hours after surgery (  = 6, S100B2). Neurological function was assessed using the Pediatric Stroke Outcome Measure (PSOM) before surgery and at discharge. A PSOM increase of ≥ 1 point was defined as a positive NND result. S100B levels were normalized by age (z-scores), and ROC analysis was used to evaluate predictive performance and determine the optimal diagnostic cut-off value. The S100B2 z-score showed the highest predictive value for NND with 93% sensitivity (28/30), 85% specificity (85/100), a negative predictive value of 0.98 (85/87), a positive predictive value of 0.65 (28/43), and a likelihood odds ratio of 79.3. A threshold of two standard deviations provided the best diagnostic accuracy. In multivariate analysis, the S100B2 z-score remained the strongest independent NND predictor. Age-normalized S100B levels measured 6 h post-surgery can serve as a marker to identify or exclude early brain injury leading to NND, supporting their use in post-surgical clinical decision-making.

Background This study investigated whether high physical activity affects ovarian reserve in normo-ovulatory, reproductive-age women. Methods This prospective, observational study compared 31 professional female athletes, with 31 women who did not engage in physical activity. It was conducted 2017–2020 in a tertiary medical center. Normo-ovulatory, professional athletes, ages 20–35 years were recruited from The Wingate Institute—the Israeli National Institute for Sport Excellence. They had high International Physical Activity Questionnaire (IPAQ) scores. Non-physically active women, matched by age and body mass index, were recruited from hospital staff. Women were evaluated for ovarian reserve markers on day 2–5 of the menstrual cycle, including follicular stimulating hormone, antral follicle count, anti-Mullerian hormone and Inhibin B. Results The average age of the high physical activity group was 29.9 ± 4.2 years and the nonactive group 31.6 ± 4.2 years ( p  = 0.062). Body mass index of both groups were similar (22.5 ± 5.0 vs. 21.4 ± 2.5, respectively; p  = 0.1). No differences were observed with respect to follicle stimulating hormone ( p  = 0.12) and anti-Mullerian hormone ( p  = 0.16). A trend towards higher total antral follicle count in the high physical activity group vs. the non-active group (34.5 ± 12.9 vs. 28.1 ± 15.2, p  = 0.08) and lower Inhibin B (68.1 ± 36.8 vs. 89.4 ± 46.1, p  = 0.05). Menarche age correlated with anti-Mullerian hormone (r = 0.387, p  = 0.003), as did total antral follicle count (r = 0.368, p  = 0.004). IPAQ scores and basal follicle stimulating hormone levels were negatively correlated (r = − 0.292, p  = 0.005). Conclusions Athletic, normo-ovulatory women have ovarian reserves that are at least as good as those of the general population. As this is the first study examining this issue, it could cautiously reassure women engaged in high physical activity regarding ovarian reserve.

Risk management in health care systems applies to all hospital employees and directors as they deal with human life and emergency routines. There is a constant need to decrease risk and increase patient safety in the hospital environment. The purpose of this article is to review the laboratory testing procedures for parathyroid hormone and adrenocorticotropic hormone (which are characterized by short half-lives) and to track failure modes and risks, and offer solutions to prevent them. During a routine quality improvement review at the Endocrine Laboratory in Tel Hashomer Hospital, we discovered these tests are frequently repeated unnecessarily due to multiple failures. The repetition of the tests inconveniences patients and leads to extra work for the laboratory and logistics personnel as well as the nurses and doctors who have to perform many tasks with limited resources. A team of eight staff members accompanied by the Head of the Endocrine Laboratory formed the team for analysis. The failure mode and effects analysis model (FMEA) was used to analyze the laboratory testing procedure and was designed to simplify the process steps and indicate and rank possible failures. A total of 23 failure modes were found within the process, 19 of which were ranked by level of severity. The FMEA model prioritizes failures by their risk priority number (RPN). For example, the most serious failure was the delay after the samples were collected from the department (RPN =226.1). This model helped us to visualize the process in a simple way. After analyzing the information, solutions were proposed to prevent failures, and a method to completely avoid the top four problems was also developed.

Klotho is an aging-modulating protein expressed mainly in the kidneys and choroid plexus, which can also be shed, released into the circulation and act as a hormone. Klotho deficient mice are smaller compared to their wild-type counterparts and their somatotropes show marked atrophy and reduced number of secretory granules. Recent data also indicated an association between klotho levels and growth hormone (GH) levels in acromegaly. We aimed to study the association between klotho levels and GH deficiency (GHD) in children with growth impairment. Prospective study comprising 99 children and adolescents (aged 9.0 ± 3.7 years, 49 male) undergoing GH stimulation tests for short stature (height-SDS = -2.1 ± 0.6). Klotho serum levels were measured using an α-klotho ELISA kit. Klotho levels were significantly lower (p<0.001) among children with organic GHD (n = 11, 727 ± 273 pg/ml) compared to both GH sufficient participants (n = 59, 1497 ± 754 pg/ml) and those with idiopathic GHD (n = 29, 1645 ± 778 pg/ml). The difference between GHS children and children with idiopathic GHD was not significant. Klotho levels positively correlated with IGF-1- standard deviation scores (SDS) (R = 0.45, p<0.001), but were not associated with gender, pubertal status, age or anthropometric measurements. We have shown, for the first time, an association between low serum klotho levels and organic GHD. If validated by additional studies, serum klotho may serve as novel biomarker of organic GHD.

During pregnancy, fetal glucose production is suppressed, with rapid activation immediately postpartum. Fatty acid–binding protein 4 (FABP4) was recently demonstrated as a regulator of hepatic glucose production and systemic metabolism in animal models. Here, we studied the role of FABP4 in regulating neonatal glucose hemostasis. Serum samples were collected from pregnant women with normoglycemia or gestational diabetes at term, from the umbilical circulation, and from the newborns within 6 hours of life. The level of FABP4 was higher in the fetal versus maternal circulation, with a further rise in neonates after birth of approximately 3-fold. Neonatal FABP4 inversely correlated with blood glucose, with an approximately 10-fold increase of FABP4 in hypoglycemic neonates. When studied in mice, blood glucose of 12-hour-old WT, Fabp4 –/+ , and Fabp4 –/– littermate mice was 59 ± 13 mg/dL, 50 ± 11 mg/dL, and 43 ± 11 mg/dL, respectively. Similar to our observations in humans, FABP4 levels in WT mouse neonates were approximately 8-fold higher compared with those in adult mice. RNA sequencing of the neonatal liver suggested altered expression of multiple glucagon-regulated pathways in Fabp4 –/– mice. Indeed, Fabp4 –/– liver glycogen was inappropriately intact, despite a marked hypoglycemia, with rapid restoration of normoglycemia upon injection of recombinant FABP4. Our data suggest an important biological role for the adipokine FABP4 in the orchestrated regulation of postnatal glucose metabolism.

The human endocrine system orchestrates critical physiological processes, yet a systematic quantitative synthesis of clinically relevant circulating hormones has been lacking. Here, we present a comprehensive, integrative analysis of circulating human hormones, leveraging clinically validated reference intervals across major endocrine subsystems. We use clinically validated reference intervals that we further validate using published datasets. Our analysis reveals that the total mass of circulating hormones is approximately 40 ± 2 mg. We find that this mass in healthy young adults is dominated by Adiponectin and DHEAS, which constitute over 90% of both total hormone weight and copy number. We show there are on the order of a million hormone molecules per cell in the human body. Females have about half the number of circulating hormone molecules compared to males. Across 56 hormones with curated affinity data, free (receptor-available) concentration correlates with receptor binding affinity, with class-specific scaling. Bioavailability mechanisms segregate by chemical class, consistent with chemical structure constraining available buffering strategies. Together, these data provide a quantitative reference for the human endocrine system and highlight relationships linking receptor affinity, bioavailability, and chemical class.

Purpose To assesse circulating levels of Anti-Müllerian hormone (AMH) as a predictor of oocyte number and their potential to mature in vitro in both normo-ovulatory (NO) women and in women with Polycystic Ovary Syndrome (PCOS) undergoing in vitro maturation (IVM) treatments. Methods We prospectively studied NO women and women diagnosed with PCOS, (age range 21–39 years) underwent IVM treatments at our center. Serum AMH levels were quantified before each cycle and correlated to oocytes number, maturation and fertilization during in vitro maturation. Results 104 NO and 30 PCOS IVM cycles were followed with retrieval of a total of 672 and 491 oocytes, respectively. In NO women, the serum AMH level positively correlated with the number of oocytes retrieved, ( R  = 0.6; P <0.0001) the number of M2 oocytes at 24 and 48 h ( R  = 0.4; P <0.01; R  = 0.26 p  < 0.007, respectively) and with the total number of M2 oocytes ( R  = 0.47; P  < 0.0001). In the PCOS group, the serum AMH level positively correlated only with the number of oocytes retrieved ( R  = 0.43; P <0.03). Receiver operating characteristic (ROC) analyses showed that a cutoff AMH level of 1.56 (ng/ml) could identify patients with 5 or more oocytes at OPU with a sensitivity of 83 % and a specificity of 75 %. An AMH level of 1.63 (ng/ml) was the threshold for 5 or more matured oocytes (sensitivity = 81 %, specificity = 53 %). Conclusions Serum AMH may be used as a marker to identify candidates for IVM treatment in both NO and PCOS women.

Key messageMenstruation of adolescent girls might be influenced by Covid-19 mRNA vaccine, however, the ovarian reserve estimated by AMH is not compromised.BackgroundRecent studies have suggested that the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine causes menstrual abnormalities which led to concerns regarding its influence on the reproductive system. This study aims to investigate the influence of the SARS-CoV-2 mRNA vaccine on gynecologic well-being and future fertility of adolescent girls.MethodsThis is a prospective cohort study conducted at a university affiliated medical center between June and July 2021. Adolescent girls aged 12–16 years who were vaccinated by two Pfizer-BioNTech Covid-19 vaccines (21 days apart) were included in the study. All participants completed a computerized questionnaire regarding their general medical and gynecological background at recruitment and 3 months later. Blood samples were collected for AMH levels before and 3 months following the first mRNA vaccineResultsThe study group consisted of 35 girls, and of them, follow-up was completed by questionnaire and AMH sampling in 35 (90%) and 22 (56%) girls, respectively. Among the 22/35 girls who reported regular menstruation before vaccination, seven (31.8%) experienced irregularities post-vaccination. Four of the eight pre-menarche girls included in the study reported on menarche on follow-up. Median AMH levels were 3.09 (IQR 1.96–4.82) μg/L and 2.96 (2.21–4.73) μg/L at baseline and after 3 months, respectively (p = 0.07). After controlling for age, BMI and presentation of side effects, no association was demonstrated to the change in AMH levels (AMH2-AMH1).ConclusionsAlthough menstruation of adolescent girls might be influenced by Covid-19 mRNA vaccine, it seems that the ovarian reserve estimated by AMH is not compromised.Clinical trial registrationNational Institutes of Health (NCT04748172).