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Objective: Patients with primary adrenal insufficiency (PAI) are thought to be particularly vulnerable to COVID-19; however, little is known about its true impact on this group. We assessed morbidity and health promotion attitudes during the pandemic amongst a large cohort of patients with PAI.

Design: Cross-sectional, single-centre study.

Methods: In May 2020, COVID-19 advice on social distancing and sick-day rules was distributed to all patients with PAI registered with a large secondary/tertiary care centre. A semi-structured questionnaire was used to survey patients in early 2021.

Results: Of 207 contacted patients, 162 responded (82/111 with Addison’s disease, AD; 80/96 with congenital adrenal hyperplasia, CAH). Patients with AD were older than those with CAH (median age 51 vs. 39 years; p<0.001) and had more comorbidities (Charlson comorbidity index ≥2 47.6% vs. 10.0%; p<0.001). By the time of the survey, 47 patients (29.0%) had been diagnosed with COVID-19, the second commonest cause of sick-day dosing during the study and the leading trigger of adrenal crises (4/18 cases). Patients with CAH had a higher risk of COVID-19 compared to AD (adjusted odds ratio 2.53 [95% CI 1.07-6.16], p=0.036), were less inclined to have the COVID-19 vaccine (80.0% vs. 96.3%; p=0.001), and were less likely to have undergone hydrocortisone self-injection training (80.0% vs. 91.5%; p=0.044) or wear medical alert jewellery (36.3% vs. 64.6%; p=0.001).

Conclusions: COVID-19 was a principal trigger for adrenal crises and sick-day dosing in patients with PAI. Despite a higher risk of COVID-19, patients with CAH showed less engagement with self-protective attitudes.

Skeletal muscle is the main metabolic tissue responsible for glucose homeostasis in the body. It is surrounded by the extracellular matrix (ECM) consisting of three layers: epimysium, perimysium, and endomysium. ECM plays an important role in the muscle, as it provides integrity and scaffolding cells. The observed disturbances in this structure are related to the abnormal remodeling of the ECM (through an increase in the concentration of its components). ECM rearrangement may impair insulin action by increasing the physical barrier to insulin transport and reducing insulin transport into muscle cells as well as by directly inhibiting insulin action through integrin signaling. Thus, improper ECM remodeling may contribute to the development of insulin resistance (IR) and related comorbidities. In turn, IR-associated conditions may further aggravate disturbances of ECM in skeletal muscle. This review describes the major components of the ECM that are necessary for its proper function. Particular attention was also paid to receptors (integrins) involved in the signaling of metabolic pathways. Finally, changes in ECM components in the context of clinical and animal studies are discussed. This article will help the reader to systematize knowledge related to the ECM and to better understand the relationship between ECM remodeling and IR, and its role in the pathogenesis of T2DM. The information in this article presents the concept of the role of ECM and its remodeling in the pathogenesis of IR, which may contribute to developing new therapeutic solutions.

Investigating sex chromosome trisomies (SCTs) may help in understanding neurodevelopmental pathways underlying the risk for neurobehavioral problems and psychopathology. Knowledge about the neurobehavioral phenotype is needed to improve clinical care and early intervention for children with SCT. This is especially relevant considering the increasing number of early diagnosed children with the recent introduction of noninvasive prenatal screening. The TRIXY Early Childhood Study is a longitudinal study designed to identify early neurodevelopmental risks in children with SCT, aged 1–7 years. This review summarizes the results from the TRIXY Early Childhood Study, focusing on early behavioral symptoms in areas of autism spectrum disorder, attention-deficit hyperactivity disorder, and communication disorders, and underlying neurocognitive mechanisms in domains of language, emotion regulation, executive functioning, and social cognition. Behavioral symptoms were assessed through structured behavior observation and parental questionnaires. Neurocognition was measured using performance tests, eyetracking, and psychophysiological measures of arousal. In total, 209 children aged 1–7 years were included: 107 children with SCT (33 XXX, 50 XXY, and 24 XYY) and 102 age-matched population controls. Study outcomes showed early behavioral symptoms in young children with SCT, and neurocognitive vulnerabilities, already from an early age onward. Neurobehavioral and neurocognitive difficulties tended to become more pronounced with increasing age and were rather robust, independent of specific karyotype, pre/postnatal diagnosis, or ascertainment strategy. A more longitudinal perspective on neurodevelopmental ‘at-risk’ pathways is warranted, also including studies assessing the effectiveness of targeted early interventions. Neurocognitive markers that signal differences in neurodevelopment may prove to be helpful in this. Focusing on early development of language, social cognition, emotion regulation, and executive functioning may help in uncovering early essential mechanisms of (later) neurobehavioral outcome, allowing for more targeted support and early intervention.

Background: Heart failure (HF) is a complex and multifactorial syndrome caused by impaired heart function. The high morbidity and mortality of HF cause a heavy burden of illness worldwide. Non-thyroidal illness syndrome (NTIS) refers to aberrant serum thyroid parameters in patients without past thyroid disease. Observational studies have indicated that NTIS is associated with a higher risk of all-cause mortality in HF. This meta-analysis aimed to investigate the association between NTIS and HF prognosis.

Methods: Medline, Embase, Web of Science, and the Cochrane database were searched for any studies reporting an association between NTIS and HF prognosis from inception to July 1st 2022. A meta-analysis was then performed. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS). The heterogeneity of the results was assessed with I2 and Cochran's Q statistics. Sensitivity analysis and publication bias analysis were also conducted.

Results: A total of 626 studies were retrieved, and 18 studies were finally included in the meta-analysis. The results showed that NTIS in HF patients was significantly associated with an increased risk of all-cause mortality and major cardiovascular events (MACE), but not with in-hospital mortality. The stability of the data was validated by the sensitivity analysis. There was no indication of a publication bias in the pooled results for all-cause mortality and MACE.

Conclusions: This meta-analysis showed that NTIS was associated with a worse outcome in HF patients. However, the association between NTIS and in-hospital mortality of HF patients requires further investigation.

Low bone mass is common in men with Klinefelter syndrome (KS), with a prevalence of 6-15% of osteoporosis and of 25-48% of osteopenia. Reduced bone mass has been described since adolescence and it might be related to both reduced bone formation and higher bone resorption. Although reduced testosterone levels are clearly involved in the pathogenesis, this relation is not always evident. Importantly, fracture risk is increased independently from bone mineral density (BMD) and testosterone levels. Here we discuss the pathogenesis of osteoporosis in patients with KS, with a particular focus on the role of testosterone and testis function. In fact, other hormonal mechanisms, such as global Leydig cell dysfunction, causing reduced Insulin-like factor 3 (INSL3) and 25-OH vitamin D levels, and high FSH and estradiol levels, might be involved. Furthermore, genetic aspects related to the supernumerary X chromosome might be involved, as well as androgen receptor expression and function. Notably, body composition, skeletal mass and strength, and age at diagnosis are other important aspects. Although Dual-Energy X-ray Absorptiometry (DXA) is recommended in the clinical workflow for patients with KS to measure BMD, recent evidence suggests that alterations in the microarchitecture of the bones and vertebral fractures might be present even in subjects with normal BMD. Therefore, analysis of trabecular bone score (TBS), high resolution peripheral quantitative CT and vertebral morphometry seem promising tools to better estimate the fracture risk of patents with KS. This review also summarizes the evidence on the best available treatments for osteoporosis in men with KS, with or without hypogonadism.

Congenital adrenal hyperplasia (CAH) is a recessive condition that affects the adrenal glands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids, adult patients with CAH often experience impaired gonadal function. In pubertal boys and in men with CAH, circulating testosterone is produced by the adrenal glands as well as the testicular, steroidogenic cells. In this European two-center study, we evaluated the function of Leydig and Sertoli cells in 61 boys and men with CAH, primarily due to 21-hydroxylase deficiency. Despite conventional hormone replacement therapy, our results indicated a significant reduction in serum concentrations of both Leydig cell-derived hormones (i.e., insulin-like factor 3 [INSL3] and testosterone) and Sertoli cell-derived hormones (i.e., inhibin B and anti-Müllerian hormone) in adult males with CAH. Serum concentrations of INSL3 were particularly reduced in those with testicular adrenal rest tumors. To our knowledge, this is the first study to evaluate circulating INSL3 as a candidate biomarker to monitor Leydig cell function in patients with CAH.