The historical progression of positron emission tomography research in neuroendocrinology.

The rapid and continual development of a number of radiopharmaceuticals targeting different receptor, enzyme and small molecule systems has fostered Positron Emission Tomography (PET) imaging of endocrine system actions in vivo in the human brain for several decades. PET radioligands have been developed to measure changes that are regulated by hormone action (e.g., glucose metabolism, cerebral blood flow, dopamine receptors) and actions within endocrine organs or glands such as steroids (e.g., glucocorticoids receptors), hormones (e.g., estrogen, insulin), and enzymes (e.g., aromatase). This systematic review is targeted to the neuroendocrinology community that may be interested in learning about positron emission tomography (PET) imaging for use in their research. Covering neuroendocrine PET research over the past half century, researchers and clinicians will be able to answer the question of where future research may benefit from the strengths of PET imaging.

Endocrine-disrupting chemicals: Mainstream recognition of health effects and implications for the practicing internist.

Rapidly advancing evidence documents that a broad array of synthetic chemicals found ubiquitously in the environment contribute to disease and disability across the lifespan. Although the early literature focused on early life exposures, endocrine-disrupting chemicals (EDCs) are now understood to contribute substantially to chronic disease in adulthood, especially metabolic, cardiovascular, and reproductive consequences as well as endocrine cancers. The contribution to mortality is substantial, with over 90,000 deaths annually and at least $39 billion/year in lost economic productivity in the United States (US) due to exposure to certain phthalates that are used as plasticizers in food packaging. Importantly, exposures are disproportionately high in low-income and minoritized populations, driving disparities in these conditions. Though non-Hispanic Blacks and Mexican Americans comprise 12.6% and 13.5% of the US population, they bear 16.5% and 14.6% of the disease burden due to EDCs, respectively. Many of these exposures can be modified through safe and simple behavioral changes supported by proactive government action to both limit known hazardous exposures and to proactively screen new industrial chemicals prior to their use. Routine healthcare maintenance should include guidance to reduce EDC exposures, and a recent report by the Institute of Medicine suggests that testing be conducted, particularly in populations heavily exposed to perfluoroalkyl substances-chemicals used in nonstick coatings as well as oil- and water-resistant clothing.

Corticosterone exposure is associated with long-term changes in DNA methylation, physiology and breeding decisions in a wild bird.

When facing challenges, vertebrates activate a hormonal stress response that can dramatically alter behaviour and physiology. Although this response can be costly, conceptual models suggest that it can also recalibrate the stress response system, priming more effective responses to future challenges. Little is known about whether this process occurs in wild animals, particularly in adulthood, and if so, how information about prior experience with stressors is encoded. One potential mechanism is hormonally mediated changes in DNA methylation. We simulated the spikes in corticosterone that accompany a stress response using non-invasive dosing in tree swallows (Tachycineta bicolor) and monitored the phenotypic effects 1 year later. In a subset of individuals, we characterized DNA methylation using reduced representation bisulfite sequencing shortly after treatment and a year later. The year after treatment, experimental females had stronger negative feedback and initiated breeding earlier-traits that are associated with stress resilience and reproductive performance in our population-and higher baseline corticosterone. We also found that natural variation in corticosterone predicted patterns of DNA methylation. Finally, corticosterone treatment influenced methylation on short (1-2 weeks) and long (1 year) time scales; however, these changes did not have clear links to functional regulation of the stress response. Taken together, our results are consistent with corticosterone-induced priming of future stress resilience and support DNA methylation as a potential mechanism, but more work is needed to demonstrate functional consequences. Uncovering the mechanisms linking experience with the response to future challenges has implications for understanding the drivers of stress resilience.

Endocrine, cardiac and neuropsychological aspects of adult congenital adrenal hyperplasia.

OBJECTIVE: To investigate the metabolic, cardiovascular, and neuropsychological phenotype, quality of life (QoL), and hormonal regulation in individuals with congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired synthesis of cortisol in the adrenal cortex and, if untreated compensatory hyperandrogenism. CAH is associated with an increased cardiovascular and metabolic morbidity, possibly due to overtreatment with glucocorticoids, leading to weight gain, insulin resistance, and metabolic syndrome. DESIGN, PARTICIPANTS, MEASUREMENTS: Thirty-seven individuals with CAH and 33 age- and sex-matched controls were evaluated at a single centre at Aarhus University Hospital with echocardiography, electrocardiogram, 24-h blood pressure, biochemistry, anthropometrics, and autism spectrum, anxiety, depression, personality, cognitive failures, and QoL were assessed using questionnaires. RESULTS: CAH individuals had lower height than controls (170.5 vs. 182.9 cm in males and 160.2 vs. 170.1 cm in females, p < 0.01). Compared with female controls, females with CAH had higher haemoglobin (8.8 vs. 8.2 mmol/L, p = 0.003) and BMI (29.7 vs. 25.5 kg/m2, p = 0.006), reduced insulin sensitivity (HOMA-IR): 2.7 vs. 1.9, p = 0.018), prolonged E-wave deceleration time (193 vs. 174 cm, p = 0.015), and E/é ratios (5.4 vs. 4.5, p = 0.017), and lower self-reported QoL. Males with CAH had more cognitive complaints (p = 0.034) and higher autistic scores (19.9 vs. 14.9; p = 0.068) compared with male controls. More individuals with CAH than controls reported writing problems. CONCLUSION: A sex-specific comorbidity profile is evident in CAH, with females presenting with decreased metabolic and overall self-reported health, whereas males with CAH presented with increased cognitive complaints and autistic traits.

Pituitary deficiencies related to optic nerve hypoplasia and visual acuity.

OBJECTIVE: Optic nerve hypoplasia (ONH), the congenital underdevelopment of the optic nerve, is an increasing cause of visual impairment and is associated with pituitary dysfunction. Past studies have focused on the relationship between ONH, pituitary deficiencies, and brain imaging. However, recent studies have demonstrated the true risk for hypopituitarism lies with the presence or absence of ONH, irrespective of midline brain findings. This study reviewed the relationship between the health of the optic nerve (visual acuity) and pituitary gland (number and age of development of pituitary deficiencies) as a way to stratify risk, regardless of imaging findings. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective chart review of 197 patients seen at a single center from 2013 to 2022. Visual assessment was defined by distance acuity, and the presence of nystagmus or afferent pupillary defect. Pituitary deficiencies were diagnosed per Endocrine Society guidelines. RESULTS: In children with bilateral ONH (bONH), profound visual impairment was associated with more pituitary deficiencies between 0 and 15 years of age. The odds of having any pituitary deficiency were 4.9 times higher (95% confidence interval [95% CI]: 2.4-10.1) for patients with bONH versus unilateral ONH (uONH). Central hypothyroidism was the most common first presenting pituitary deficiency followed by growth hormone across all patients. CONCLUSION: This study shows a significant association between severity of visual impairment and increased probability of pituitary deficiencies in children with bONH versus uONH. Children with ONH require urgent endocrine evaluation due to risk of pituitary deficiencies, but risk stratification may also be based on severity of visual impairment.

Creating a SNOMED CT reference set for common endocrine disorders based on routine clinic correspondence.

BACKGROUND: Routine clinical coding of clinical outcomes in outpatient consultations still lags behind the coding of episodes of inpatient care. Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) offers an opportunity for standardised coding of key clinical information. Identifying the most commonly required SNOMED terms and grouping these into a reference set will aid future adoption in routine clinical care. OBJECTIVE: To create a common endocrinology reference set to standardise the coding for outcomes of outpatient endocrine consultations, using a semi-automated extraction of information from existing clinical correspondence. METHODS: Retrospective review of data from an adult tertiary outpatient endocrine clinic between 2018 and 2019. A total of 1870 patients from postcodes within two regional areas of NHS Grampian (Aberdeen City and Aberdeenshire) attended the clinic. Following consultation, an automated script extracted each problem statement which was manually coded using the 'disorder' concepts from SNOMED CT (UK edition). RESULTS: The review identified 298 relevant endocrine diagnoses, 99 findings and 142 procedures. There were a total of 88 (29.5%) commonly seen endocrine conditions (e.g., Graves' disease, anterior hypopituitarism and Addison's disease) and 210 (70.5%) less commonly seen endocrine conditions. Subsequently, consultant endocrinologists completed a survey regarding the common endocrine conditions; 28 conditions have 100% agreement, 25 have 90%-99% agreement, 31 have 50%-89% agreement and 4 have less than 59% agreement (which were excluded). CONCLUSION: Automated text parsing of structured endocrine correspondence allowed the creation of a SNOMED CT reference set for common endocrine disorders. This will facilitate funding and planning of service provision in endocrinology by allowing more accurate characterisation of the patient cohorts needing specialist endocrine care.

A high-volume study on the impact of diabetes mellitus on clinical outcomes after surgical and percutaneous cardiac interventions.

BACKGROUND: Type I and type II diabetes mellitus (DM) patients have a higher prevalence of cardiovascular diseases, as well as a higher mortality risk of cardiovascular diseases and interventions. This study provides an update on the impact of DM on clinical outcomes, including mortality, complications and reinterventions, using data on percutaneous and surgical cardiac interventions in the Netherlands. METHODS: This is a retrospective, nearby nationwide study using real-world observational data registered by the Netherlands Heart Registration (NHR) between 2015 and 2020. Patients treated for combined or isolated coronary artery disease (CAD) and aortic valve disease (AVD) were studied. Bivariate analyses and multivariate logistic regression models were used to evaluate the association between DM and clinical outcomes both unadjusted and adjusted for baseline characteristics. RESULTS: 241,360 patients underwent the following interventions; percutaneous coronary intervention(N = 177,556), coronary artery bypass grafting(N = 39,069), transcatheter aortic valve implantation(N = 11,819), aortic valve replacement(N = 8,028) and combined CABG and AVR(N = 4,888). The incidence of DM type I and II was 21.1%, 26.7%, 17.8%, 27.6% and 27% respectively. For all procedures, there are statistically significant differences between patients living with and without diabetes, adjusted for baseline characteristics, at the expense of patients with diabetes for 30-days mortality after PCI (OR = 1.68; p <.001); 120-days mortality after CABG (OR = 1.35; p <.001), AVR (OR = 1.5; p <.03) and CABG + AVR (OR = 1.42; p =.02); and 1-year mortality after CABG (OR = 1.43; p <.001), TAVI (OR = 1.21; p =.01) and PCI (OR = 1.68; p <.001). CONCLUSION: Patients with DM remain to have unfavourable outcomes compared to nondiabetic patients which calls for a critical reappraisal of existing care pathways aimed at diabetic patients within the cardiovascular field.

The intrafollicular concentrations of biologically active cortisol in women rise abruptly shortly before ovulation and follicular rupture.

STUDY QUESTION: What is the temporal activity and the concentration in follicular fluid (FF) of the anti-inflammatory steroid cortisol during the ovulatory process in humans? SUMMARY ANSWER: Intrafollicular concentrations of cortisol become massively upregulated close to ovulation concomitant with an exceptionally high biological activity securing a timely and efficient termination of inflammatory processes. WHAT IS KNOWN ALREADY: Ovulation has been described as a local, controlled inflammatory process resulting in the degeneration of the follicle wall which facilitate oocyte extrusion. Ovulation also affects the glucocorticoid metabolism of granulosa cells (GCs) and although de novo synthesis of cortisol only occurs in the adrenal cortex, the mid-cycle surge has been shown to induce a change from high expression of HSD11B2, inactivating cortisol to cortisone, to high expression of HSD11B1 which reversibly catalyses cortisol production from cortisone. Furthermore, high concentrations of progesterone and 17OH-progesterone within follicles may cause dislodging of cortisol from cortisol binding protein (CBP) thereby activating the biological activity of cortisol. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 50 women undergoing fertility treatment according to a standard antagonist protocol at a university hospital-affiliated fertility clinic in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women donated FF and GCs from one follicle for research purpose aspirated at one of four time points during the process of final maturation of follicles: T = 0 h, T = 12 h, T = 17 h, T = 32 h. A second sample was collected at oocyte pick up at T = 36 h. The concentration of cortisol and cortisone together with a range of sex steroids was measured by LC-MS/MS in FF collected at the five time points mentioned above. Whole genome microarray data, validated by q-PCR analysis, was used to evaluate gene expression of CYP11B1, CYP21A2, HSD11B1, HSD11B2, and NR3C1 in GCs at the same time points. MAIN RESULTS AND THE ROLE OF CHANCE: The concentration of cortisol was significantly increased from a few nM at 0 h to around 100-140 nM (P ≤ 0.0001) at 32-36 h, whilst cortisone was almost constant from 0 to 17 h at a concentration of between 90 and 100 nM being significantly reduced to 25-40 nM (P ≤ 0.0001) at 32-36 h. This was paralleled by a 690-fold upregulation of HSD11B1 from 0 to 12 h increasing to a more than 20.000-fold change at 36 h. HSD11B2 was quickly downregulated 15- to 20-fold after ovulation induction. Concentrations of progesterone and 17OH-progesterone increased during the ovulatory process to high levels which in essence displaces cortisol from its binding protein CBP due to similar binding affinities. Furthermore, a significant decrease in 11-deoxycortisol expression was seen, but CYP11B1 expression was below detection limit in GCs. LIMITATIONS, REASONS FOR CAUTION: The study included women undergoing ovarian stimulation and results may differ from the natural cycle. More observations at each specific time point may have strengthened the conclusions. Furthermore, we have not been able to measure the actual active biological concentration of cortisol. WIDER IMPLICATIONS OF THE FINDINGS: For the first time, this study collectively evaluated the temporal pattern of cortisol and cortisone concentrations during human ovulation, rendering a physiological framework for understanding potential dysregulations in the inflammatory reaction of ovulation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the University Hospital of Copenhagen, Rigshospitalet, and Novo Nordisk Foundation grant number NNF21OC00700556. Interreg V ÔKS through ReproUnion (www.reprounion.eu); Region Zealand Research Foundation. The funders had no role in study design, collection of data, analyses, writing of the article, or the decision to submit it for publication. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Predicting Infertility: How Genetic Variants in Oocyte Spindle Genes Affect Egg Quality.

Successful reproduction relies on the union of a single chromosomally normal egg and sperm. Chromosomally normal eggs develop from precursor cells, called oocytes, that have undergone accurate chromosome segregation. The process of chromosome segregation is governed by the oocyte spindle, a unique cytoskeletal machine that splits chromatin content of the meiotically dividing oocyte. The oocyte spindle develops and functions in an idiosyncratic process, which is vulnerable to genetic variation in spindle-associated proteins. Human genetic variants in several spindle-associated proteins are associated with poor clinical fertility outcomes, suggesting that heritable etiologies for oocyte dysfunction leading to infertility exist and that the spindle is a crux for female fertility. This chapter examines the mammalian oocyte spindle through the lens of human genetic variation, covering the genes TUBB8, TACC3, CEP120, AURKA, AURKC, AURKB, BUB1B, and CDC20. Specifically, it explores how patient-identified variants perturb spindle development and function, and it links these molecular changes in the oocyte to their cognate clinical consequences, such as oocyte maturation arrest, elevated egg aneuploidy, primary ovarian insufficiency, and recurrent pregnancy loss. This discussion demonstrates that small genetic errors in oocyte meiosis can result in remarkably far-ranging embryonic consequences, and thus reveals the importance of the oocyte's fine machinery in sustaining life.

Obesity, diabetes and risk of bone fragility: How BMAT behavior is affected by metabolic disturbances and its influence on bone health.

PURPOSE: Osteoporosis is a metabolic bone disease characterized by decreased bone strength and mass, which predisposes patients to fractures and is associated with high morbidity and mortality. Like osteoporosis, obesity and diabetes are systemic metabolic diseases associated with modifiable risk factors and lifestyle, and their prevalence is increasing. They are related to decreased quality of life, functional loss and increased mortality, generating high costs for health systems and representing a worldwide public health problem. Growing evidence reinforces the role of bone marrow adipose tissue (BMAT) as an influential factor in the bone microenvironment and systemic metabolism. Given the impact of obesity and diabetes on metabolism and their possible effect on the bone microenvironment, changes in BMAT behavior may explain the risk of developing osteoporosis in the presence of these comorbidities. METHODS: This study reviewed the scientific literature on the behavior of BMAT in pathological metabolic conditions, such as obesity and diabetes, and its potential involvement in the pathogenesis of bone fragility. RESULTS: Published data strongly suggest a relationship between increased BMAT adiposity and the risk of bone fragility in the context of obesity and diabetes. CONCLUSION: By secreting a broad range of factors, BMAT modulates the bone microenvironment and metabolism, ultimately affecting skeletal health. A better understanding of the relationship between BMAT expansion and metabolic disturbances observed in diabetic and obese patients will help to identify regulatory pathways and new targets for the treatment of bone-related diseases, with BMAT as a potential therapeutic target.

Feasibility of caregiver diabetes distress screening in routine clinical care of youth with type 1 diabetes.

AIMS: Caregiver diabetes distress (DD) consists of feeling overwhelmed, sad, and/or concerned; one-third of parents of youth with type 1 diabetes (T1D) report severe distress up to 4 years after T1D diagnosis. PAID-PR (Problem Areas in Diabetes Survey-Parent Revised) assesses DD primarily in research settings; however, less is known about its clinical utility. We aimed to identify the feasibility of implementing PAID-PR screening at a diverse, academic US paediatric diabetes center during routine clinic follow-up visits through quality improvement methodologies. METHODS: The PAID-PR was intended to be offered in English to caregivers at all paediatric T1D appointments, by the front desk during appointment check-in, or through REDCap prior to telehealth appointments or at local sites to all eligible caregivers. Adult psychosocial resources were provided to all, regardless of score. Forms were scored after appointments; scores ≥80 were referred to Diabetes Psychology providers for follow-up. RESULTS: A total of 391 caregivers completed the PAID-PR, though only half of eligible caregivers received it in person. Response rates were highest in person (90%), compared to REDCap (25%). In total, 27% (n = 107) scored ≥56 (DD). Of those with DD, 21% (n = 23) scored ≥80 and were referred to psychology. Demographics are reported in Table 1. PAID-PR score was positively correlated to A1c (p = 0.038) and inversely to child age (p = 0.014). CONCLUSION: Clinic caregiver DD screening was implemented with higher response rates in person; however, expanding in-person screening to all eligible caregivers is necessary. Furthermore, since the PAID-PR was in English, some caregivers with DD were likely missed. Future directions include screening in additional languages.

Basal plasma oxytocin & fecal cortisol concentrations are highly heritable and associated with individual differences in behavior & cognition in dog puppies.

Oxytocin and cortisol are hormones that can influence cognition and behavior, but the relationships between endogenous concentrations and individual differences in cognitive and behavioral phenotypes remain poorly understood. Across mammals, oxytocin has important roles in diverse social behaviors, and in dogs, it has been implicated in human-oriented behaviors such as social gaze and point-following. Cortisol, an end-product of the hypothalamic-pituitary-adrenal (HPA) axis, is often studied in relation to temperament and emotional reactivity, but it is also known to modulate executive functions. In this study, we measured basal fecal cortisol (n = 247) and plasma oxytocin (n = 249) in dog puppies from a pedigreed population (Canine Companions ®). We collected cognitive and behavioral data from these subjects (n = 247), including measures of human-oriented social cognition, memory, inhibitory control, perceptual discriminations, and temperament. Oxytocin concentrations were estimated to be very highly heritable (h2 = 0.90-0.99) and cortisol concentrations were estimated to be moderately-highly heritable (h2 = 0.43-0.47). Bayesian mixed models controlling for relatedness revealed that oxytocin concentrations were positively associated with spatial working memory and displayed a negative quadratic relationship with behavioral laterality, but no credible associations were seen for social measures. Cortisol concentrations exhibited a negative linear relationship with performance on an inhibitory control task and a negative quadratic relationship with bold behavioral reactions to a novel object. Collectively, our results suggest that individual differences in oxytocin and cortisol concentrations are under strong genetic control in dogs and are associated with phenotypic variation in aspects of temperament, behavioral laterality, and executive function.

Defining the brain control of physiological stability.

The last few decades have seen major advances in neurobiology and uncovered novel genetic and cellular substrates involved in the control of physiological set points. In this Review, I discuss the limitations in the definition of homeostatic set points established by Walter B Canon and highlight evidence that two other physiological systems, namely rheostasis and allostasis provide distinct inputs to independently modify set-point levels. Using data collected over the past decade, the hypothalamic and genetic basis of regulated changes in set-point values by rheostatic mechanisms are described. Then, the role of higher-order brain regions, such as hippocampal circuits, for experience-dependent, allostatic induced changes in set-points are outlined. I propose that these systems provide a hierarchical organization of physiological stability that exists to maintain set-point values. The hierarchical organization of physiology has direct implications for basic and medical research, and clinical practice.

How new communication behaviors evolve: Androgens as modifiers of neuromotor structure and function in foot-flagging frogs.

How diverse animal communication signals have arisen is a question that has fascinated many. Xenopus frogs have been a model system used for three decades to reveal insights into the neuroendocrine mechanisms and evolution of vocal diversity. Due to the ease of studying central nervous system control of the laryngeal muscles in vitro, Xenopus has helped us understand how variation in vocal communication signals between sexes and between species is produced at the molecular, cellular, and systems levels. Yet, it is becoming easier to make similar advances in non-model organisms. In this paper, we summarize our research on a group of frog species that have evolved a novel hind limb signal known as 'foot flagging.' We have previously shown that foot flagging is androgen dependent and that the evolution of foot flagging in multiple unrelated species is accompanied by the evolution of higher androgen hormone sensitivity in the leg muscles. Here, we present new preliminary data that compare patterns of androgen receptor expression and neuronal cell density in the lumbar spinal cord - the neuromotor system that controls the hind limb - between foot-flagging and non-foot-flagging frog species. We then relate our work to prior findings in Xenopus, highlighting which patterns of hormone sensitivity and neuroanatomical structure are shared between the neuromotor systems underlying Xenopus vocalizations and foot-flagging frogs' limb movement and which appear to be species-specific. Overall, we aim to illustrate the power of drawing inspiration from experiments in model organisms, in which the mechanistic details have been worked out, and then applying these ideas to a non-model species to reveal new details, further complexities, and fresh hypotheses.

An interdisciplinary integrated specialized one-stop outpatient clinic for idiopathic intracranial hypertension-a comprehensive assessment of clinical outcome.

BACKGROUND AND PURPOSE: Management of idiopathic intracranial hypertension (IIH) is complex requiring multiple specialized disciplines. In practice, this creates considerable organizational and communicational challenges for healthcare professionals and patients. Thus, an interdisciplinary integrated outpatient clinic for IIH (comprising neurology, neuroophthalmology, neuroradiology, neurosurgery and endocrinology) was established with central coordination and a one-stop concept. Here, the aim was to evaluate the effects of this one-stop concept on objective clinical outcome. METHODS: In a retrospective cohort study, the one-stop era with integrated care (IC) (1 July 2021 to 31 December 2022) was compared to a reference group receiving standard care (SC) (1 July 2018 to 31 December 2019) regarding visual impairment/worsening and headache improvement/freedom 6 months after diagnosis. Multivariate binary logistic regression models were used to adjust for confounders. RESULTS: Baseline characteristics of the IC group (n = 85) and SC group (n = 81) were comparable (female 90.6% vs. 90.1%; mean age 33.6 vs. 32.8 years; median body mass index 31.8 vs. 33.0; median cerebrospinal fluid opening pressure 32 vs. 34 cmH2O; at diagnosis, visual impairment was present in 71.8% vs. 69.1% and chronic headache in 55.3% vs. 56.8% in IC vs. SC). IC was associated with a higher likelihood of achieving both headache improvement (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.52-4.33, p < 0.001) and headache freedom (OR 1.75, 95% CI 1.11-3.09, p = 0.031). Regarding the risk of visual impairment and visual worsening IC was superior numerically but not statistically significantly (OR 0.87, 95% CI 0.69-1.16, p = 0.231, and OR 0.67, 95% CI 0.41-1.25, p = 0.354). CONCLUSIONS: Interdisciplinary integrated care of IIH is favourably associated with headache outcomes and potentially also visual outcomes.

Longitudinal assessment of Leydig cell function in male survivors of childhood cancer.

BACKGROUND: As the number and longevity of childhood cancer survivors increases, assessing treatment-associated late effects remains crucial. We longitudinally examined the incidence of and associated risk factors for Leydig cell dysfunction (LCD) and Leydig cell failure (LCF) in men treated for pediatric cancers at our institution. PROCEDURE: We performed a retrospective longitudinal cohort study of adult male survivors treated for various childhood cancers who are at risk for LCD. The outcomes of interest were serum testosterone and luteinizing hormone (LH) levels during childhood and adulthood. Risk factors assessed included treatment with stem cell transplant, total body irradiation (TBI), and exposure to alkylating agents. RESULTS: Out of 118 eligible subjects, 7.6% had LCF and 14.4% had LCD. Median age at last testosterone level was 20 years. Subjects with sufficient testosterone levels in adulthood (N = 105) remained sufficient for a mean of 11.1 years following completion of cancer treatment. We found significant associations between LCF and treatment with TBI (p < .003) and between LCF in adulthood and testosterone insufficiency in childhood (p < .001). No statistically significant association was found between LCF and cyclophosphamide equivalent dose greater than 20 g/m2 (p = .2). LCF/LCD occurred in a small number of nonirradiated patients treated with the highest doses of alkylators. CONCLUSIONS: Incidence of LCF and LCD are low in male survivors of childhood cancer. Longitudinally, there is an association between childhood testosterone insufficiency and LCF in adulthood. Alkylating agents and stem cell transplant without TBI were not associated with LCF in our study.

Evaluation of five multisteroid LC‒MS/MS methods used for routine clinical analysis: comparable performance was obtained for nine analytes.

OBJECTIVES: A mass spectrometry (LC‒MS/MS)-based interlaboratory comparison study was performed for nine steroid analytes with five participating laboratories. The sample set contained 40 pooled samples of human serum generated from preanalyzed leftovers. To obtain a well-balanced distribution across reference intervals of each steroid, the leftovers first underwent a targeted mixing step. METHODS: All participants measured a sample set once using their own multianalyte protocols and calibrators. Four participants used in-house developed measurement platforms, including IVD-CE certified calibrators, which were used by three participants; the 5th lab used the whole LC‒MS kit from an IVD manufacturer. All labs reported results for 17-hydroxyprogesterone, androstenedione, cortisol, and testosterone, and four labs reported results for 11-deoxycortisol, corticosterone, cortisone, dehydroepiandrosterone sulfate (DHEAS), and progesterone. RESULTS: Good or acceptable overall comparability was found in Bland‒Altman and Passing‒Bablok analyses. Mean bias against the overall mean remained less than ±10 % except for DHEAS, androstenedione, and progesterone at one site and for cortisol and corticosterone at two sites (max. -18.9 % for androstenedione). The main analytical problems unraveled by this study included a bias not previously identified in proficiency testing, operator errors, non-supported matrix types and higher inaccuracy and imprecision at lower ends of measuring intervals. CONCLUSIONS: This study shows that intermethod comparison is essential for monitoring the validity of an assay and should serve as an example of how external quality assessment could work in addition to organized proficiency testing schemes.

Review of Subcutaneous Insulin Regimens in the Management of Diabetic Ketoacidosis in Adults and Pediatrics.

OBJECTIVE: Summarize the studies evaluating the use of subcutaneous (SQ) insulin in the management of diabetic ketoacidosis (DKA) in adults and pediatrics. DATA SOURCES: A PubMed literature search was conducted for articles published between 2000 and the end of May 2024 which contained the following terms in their title: (1) subcutaneous, glargine, or basal and (2) ketoa*. STUDY SELECTION AND DATA EXTRACTION: Review articles, guidelines, meta-analysis, commentaries, studies not related to the acute management of DKA, studies evaluating continuous SQ insulin, animal studies, if the time to DKA resolution was not clearly defined, and studies where basal insulin was administered greater than 6 hours after the insulin infusion was started were excluded. DATA SYNTHESIS: The electronic search identified 58 articles. Following the initial screening 38 articles were excluded and 3 were added after bibliography review. Of the 23 articles assessed for eligibility, 7 were excluded. Sixteen articles were included. Five studies compared SQ rapid/short-acting insulin and intravenous (IV) insulin infusions in adults, 4 compared SQ rapid/short-acting insulin and IV insulin infusions in pediatrics, 4 evaluated IV insulin infusions with or without SQ basal insulin in adults, and 3 evaluated IV insulin infusions with or without SQ basal insulin in pediatrics. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: In comparison with IV insulin infusions, rapid/short-acting SQ insulin regimens were associated with reduced ICU admission rates, hospital length of stay, and hospitalization costs. IV insulin infusion regimens that included a single SQ basal insulin dose upon therapy initiation were associated with reduced concurrent IV insulin infusion durations. CONCLUSION: Studies reviewed suggest that SQ insulin regimens may be as effective and safe as IV insulin infusions in the management of DKA and are associated with the conservation of resources. Providers may refer to this review when establishing or modifying their DKA management protocols.

A Review of the Safety and Efficacy of Bexagliflozin for the Management of Type 2 Diabetes.

OBJECTIVE: To review the pharmacology of bexagliflozin in addition to its safety and efficacy from available clinical trials used for its approval, as well as available clinical evidence to date. DATA SOURCES: A search of the National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov) and PubMed database was performed from inception through June 1, 2023. STUDY SELECTION AND DATA EXTRACTION QUANTIFICATION: The following study designs were included: meta-analyses, systematic review, clinical trial, or observational study design. Abstracts and drug monographs were also reviewed. Narrative or scoping reviews were excluded. Only articles in the English language and those evaluating the pharmacology, pharmacokinetics, safety, or efficacy of bexaglifozin in humans were included. DATA SYNTHESIS: Bexagliflozin reduces hemoglobin A1c ~0.5% with similar reductions in systolic blood pressure and body weight to other SGLT2 inhibitors. No cardiovascular outcomes trial is published, nor ongoing at this time. Adverse effects are similar to other SGLT2 inhibitors (genital mycotic and urinary tract infections, increased urination) including a warning for lower extremity amputation similar to canagliflozin. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Although no cost-effectiveness data are available, statements from the manufacturer suggest a competitive price point. Given limited trial data, lower cost, if chosen, may create a temporary niche for bexagliflozin pending generic availability of other SGLT2 inhibitors. However, given lack of cardiovascular and renal outcome data, empagliflozin, dapagliflozin, or canagliflozin may be preferred. CONCLUSION: Bexagliflozin appears safe and effective as monotherapy and add-on pharmacological therapy for the treatment of T2D.

The effect of dehydration, hyperchloremia and volume of fluid resuscitation on acute kidney injury in children admitted to hospital with diabetic ketoacidosis.

BACKGROUND: Acute kidney injury (AKI) is a recognized comorbidity in pediatric diabetic ketoacidosis (DKA), although the exact etiology is unclear. The unique physiology of DKA makes dehydration assessments challenging, and these patients potentially receive excessive amounts of intravenous fluids (IVF). We hypothesized that dehydration is over-estimated in pediatric DKA, leading to over-administration of IVF and hyperchloremia that worsens AKI. METHODS: Retrospective cohort of all DKA inpatients at a tertiary pediatric hospital from 2014 to 2019. A total of 145 children were included; reasons for exclusion were pre-existing kidney disease or incomplete medical records. AKI was determined by change in creatinine during admission, and comparison to a calculated baseline value. Linear regression multivariable analysis was used to identify factors associated with AKI. True dehydration was calculated from patients' change in weight, as previously validated. Fluid over-resuscitation was defined as total fluids given above the true dehydration. RESULTS: A total of 19% of patients met KDIGO serum creatinine criteria for AKI on admission. Only 2% had AKI on hospital discharge. True dehydration and high serum urea levels were associated with high serum creatinine levels on admission (p = 0.042; p < 0.001, respectively). Fluid over-resuscitation and hyperchloremia were associated with delayed kidney recovery (p < 0.001). Severity of initial AKI was associated with cerebral edema (p = 0.018). CONCLUSIONS: Dehydration was associated with initial AKI in children with DKA. Persistent AKI and delay to recovery was associated with hyperchloremia and over-resuscitation with IVF, potentially modifiable clinical variables for earlier AKI recovery and reduction in long-term morbidity. This highlights the need to re-address fluid protocols in pediatric DKA.