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Background: Myocarditis is an inflammatory heart disease caused by viral infections that can lead to heart failure, and occurs more often in men than women. Since animal studies have shown that myocarditis is influenced by sex hormones, we hypothesized that endocrine disruptors, which interfere with natural hormones, may play a role in the progression of the disease. The human population is exposed to the endocrine disruptor bisphenol A (BPA) from plastics, such as water bottles and plastic food containers. Methods: Male and female adult BALB/c mice were housed in plastic versus glass caging, or exposed to BPA in drinking water versus control water. Myocarditis was induced with coxsackievirus B3 on day 0, and the endpoints were assessed on day 10 post infection. Results: We found that male BALB/c mice that were exposed to plastic caging had increased myocarditis due to complement activation and elevated numbers of macrophages and neutrophils, whereas females had elevated mast cell activation and fibrosis. Conclusions: These findings show that housing mice in traditional plastic caging increases viral myocarditis in males and females, but using sex-specific immune mechanisms.

Objectives: Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry. Design: Retrospective study. Setting: Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry. Patients: Children (< 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021. Interventions: None. Measurements and Main Results: The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25–14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index (n = 817) was 19.4 kg/m2 (16–25.8 kg/m2), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU (n = 379) and hospital (n = 857) stay were 3.9 days (2–7.7 d) and 4 days (1.9–7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased. Conclusions: In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults.

Abstract Context Identification of modifiable risk factors, including genetic and acquired disorders of lipid and lipoprotein metabolism, is increasingly recognized as an opportunity to prevent premature cardiovascular disease (CVD) in at-risk youth. Pediatric endocrinologists are at the forefront of this emerging public health concern and can be instrumental in beginning early interventions to prevent premature CVD-related events during adulthood. Aim In this article, we use informative case presentations to provide practical approaches to the management of pediatric dyslipidemia. Cases We present 3 scenarios that are commonly encountered in clinical practice: isolated elevation of low-density lipoprotein cholesterol (LDL-C), combined dyslipidemia, and severe hypertriglyceridemia. Treatment with statin is indicated when the LDL-C is ≥190 mg/dL (4.9 mmol/L) in children ≥10 years of age. For LDL-C levels between 130 and 189 mg/dL (3.4-4.89 mmol/L) despite dietary and lifestyle changes, the presence of additional risk factors and comorbid conditions would favor statin therapy. In the case of combined dyslipidemia, the primary treatment target is LDL-C ≤130 mg/dL (3.4 mmol/L) and the secondary target non-high-density lipoprotein cholesterol &lt;145 mg/dL (3.7 mmol/L). If the triglyceride is ≥400 mg/dL (4.5 mmol/L), prescription omega-3 fatty acids and fibrates are considered. In the case of triglyceride &gt;1000 mg/dL (11.3 mmol/L), dietary fat restriction remains the cornerstone of therapy, even though the landscape of medications is changing. Conclusion Gene variants, acquired conditions, or both are responsible for dyslipidemia during childhood. Extreme elevations of triglycerides can lead to pancreatitis. Early identification and management of dyslipidemia and cardiovascular risk factors is extremely important.

Background: Longitudinal, but not cross-sectional, cognitive testing is one option proposed to define transitional cognitive decline for individuals on the Alzheimer’s disease continuum. Objective: Compare diagnostic accuracy of cross-sectional subtle objective cognitive impairment (sOBJ) and longitudinal objective decline (ΔOBJ) over 30 months for identifying 1) cognitively unimpaired participants with preclinical Alzheimer’s disease defined by elevated brain amyloid and tau (A+T+) and 2) incident mild cognitive impairment (MCI) based on Cogstate One Card Learning (OCL) accuracy performance. Methods: Mayo Clinic Study of Aging cognitively unimpaired participants aged 50 + with amyloid and tau PET scans (n = 311) comprised the biomarker-defined sample. A case-control sample of participants aged 65 + remaining cognitively unimpaired for at least 30 months included 64 who subsequently developed MCI (incident MCI cases) and 184 controls, risk-set matched by age, sex, education, and visit number. sOBJ was assessed by OCL z-scores. ΔOBJ was assessed using within subjects’ standard deviation and annualized change from linear regression or linear mixed effects (LME) models. Concordance measures Area Under the ROC Curve (AUC) or C-statistic and odds ratios (OR) from conditional logistic regression models were derived. sOBJ and ΔOBJ were modeled jointly to compare methods. Results: sOBJ and ΔOBJ-LME methods differentiated A+T+ from A-T- (AUC = 0.64, 0.69) and controls from incident MCI (C-statistic = 0.59, 0.69) better than chance; other ΔOBJ methods did not. ΔOBJ-LME improved prediction of future MCI over baseline sOBJ (p = 0.003) but not over 30-month sOBJ (p = 0.09). Conclusion: Longitudinal decline did not offer substantial benefit over cross-sectional assessment in detecting preclinical Alzheimer’s disease or incident MCI.

Objective: We aimed to investigate prospective associations between milk bioactives related to metabolic health (glucose, insulin, leptin, C reactive protein [CRP], and interleukin 6 [IL-6]) and incident formula initiation at 3 and 6 months postpartum. Design: This study included 363 mother–infant dyads who were fully breastfed at 1 month and participated in the prospective Mothers and Infants Linked for Healthy Growth study from pregnancy to 6 months postpartum. Associations between milk glucose, leptin, insulin, CRP, and IL-6 at 1 and 3 months and incident formula feeding (FF) at 3 and 6 months, respectively, were tested using multiple logistic regression, adjusting for numerous potential confounders such as maternal age and prepregnancy body mass index. Results: At 3 months postpartum, 1-month glucose (odds ratio [OR] 0.45 [95% confidence interval (CI): 0.27–0.75], p ≤ 0.01) and smaller decreases in glucose from 1 to 3 months (OR 0.51 [95% CI: 0.28–0.92], p = 0.03) were associated with lower odds of FF, whereas 1-month leptin (OR 2.30 [95% CI: 1.30–4.07], p < 0.01) and larger increase in insulin (OR 1.86 [95% CI: 1.23–2.81], p < 0.01) and leptin (OR 2.17 [95% CI: 1.29–3.68], p < 0.01) from 1 to 3 months were associated with increased odds of FF. At 6 months, insulin increases (OR 2.08 [95% CI: 1.03–4.17], p = 0.04) were associated with higher odds of FF. Conclusions: In a cohort of women with established lactation, 1-month milk glucose, insulin, and leptin predicted initiation of FF at 3 months. Early milk composition may provide a window into mammary gland function, allowing identification of women at risk of not meeting their breastfeeding goals.

Abstract Background Grade 3 gastroenteropancreatic neuroendocrine neoplasms (G3 GEPNENs) are often aggressive, and the optimal treatment is unclear for this subgroup of neuroendocrine neoplasms (NENs). Temozolomide (TEM)-based regimens have been increasingly used to treat grade 1–2 NENs, but their efficacy in G3 NENs remains undetermined. We aimed to assess the clinical efficacy of TEM-containing regimens in advanced grade 3 GEPNENs. Materials and Methods A multicenter retrospective review (2008–2018) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen was undertaken within a North American partnership to pool data. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports. Results One hundred and thirty patients in six high-volume NEN centers were included (median age 55, 64% male, 18% functional, 67% pancreatic NEN). Forty-nine percent were well-differentiated, 35% poorly differentiated, and 15% unknown based on local pathology reports. The regimen used was capecitabine and temozolomide (CAPTEM) in 92% and TEM alone in 8%. Radiological response by local assessment was seen in 36% of patients. Median TTF was 3.6 months and median overall survival (OS) 19.2 months. Six percent of patients required discontinuation of therapy due to adverse events. TTF was longer in first-line treatment (7.8 months vs. 2.9 months; hazard ratio, 1.62; 95% confidence interval, 1.11–2.36; p = .015) and in patients with pancreatic NENs (panNENs) compared with gastrointestinal NENs (5.8 months vs 1.8 months; p = .04). The overall response rate was higher in the first-line setting (51% vs 29%; p = .02) and in panNEN (41% vs 23%; p = .04). Conclusion This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NEN centers as a partnership. Thirty-six percent of patients showed some degree of radiographic response, and treatment was generally well tolerated, although the median duration of response was short. Response rates and time to treatment failure were superior in the first-line setting. CAPTEM should be considered a viable treatment option in this setting. Further randomized trials are warranted. Implications for Practice Neuroendocrine neoplasms (NENs) are heterogeneous, and optimal treatment for aggressive grade 3 (G3) NENs remains undetermined. The capecitabine and temozolomide (CAPTEM) regimen has been used in low-grade pancreas NENs but there are few data for its safety and efficacy in the G3 setting. This article reports on the efficacy of temozolomide-containing regimens, particularly CAPTEM, in management of G3 NENs. The good tolerance and response rate show that CAPTEM should be considered a viable regimen in treatment of G3 NENs pending confirmatory prospective studies.

Background: It is standard of care and an accreditation requirement to screen for and address distress and psychosocial needs in patients with cancer. This study assessed the availability of mental health (MH) and chemical dependency (CD) services at US cancer centers. Methods: The 2017–2018 American Hospital Association (AHA) survey, Area Health Resource File, and Centers for Medicare & Medicaid Services Hospital Compare databases were used to assess availability of services and associations with hospital-level and health services area (HSA)–level characteristics. Results: Of 1,144 cancer centers surveyed, 85.4% offered MH services and 45.5% offered CD services; only 44.1% provided both. Factors associated with increased adjusted odds of offering MH services were teaching status (odds ratio [OR], 1.76; 95% CI, 1.18–2.62), being a member of a hospital system (OR, 2.00; 95% CI, 1.31–3.07), and having more beds (OR, 1.04 per 10-bed increase; 95% CI, 1.02–1.05). Higher population estimate (OR, 0.98; 95% CI, 0.97–0.99), higher percentage uninsured (OR, 0.90; 95% CI, 0.86–0.95), and higher Mental Health Professional Shortage Area level in the HSA (OR, 0.99; 95% CI, 0.98–1.00) were associated with decreased odds of offering MH services. Government-run (OR, 2.85; 95% CI, 1.30–6.22) and nonprofit centers (OR, 3.48; 95% CI, 1.78–6.79) showed increased odds of offering CD services compared with for-profit centers. Those that were members of hospital systems (OR, 1.61; 95% CI, 1.14–2.29) and had more beds (OR, 1.02; 95% CI, 1.01–1.03) also showed increased odds of offering these services. A higher percentage of uninsured patients in the HSA (OR, 0.92; 95% CI, 0.88–0.97) was associated with decreased odds of offering CD services. Conclusions: Patients’ ability to pay, membership in a hospital system, and organization size may be drivers of decisions to co-locate services within cancer centers. Larger organizations may be better able to financially support offering these services despite poor reimbursement rates. Innovations in specialty payment models highlight opportunities to drive transformation in delivering MH and CD services for high-need patients with cancer.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

The human adenovirus phylogenetic tree is split across seven species (A–G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-existing immunity detected across screened populations. However, many aspects of the basic virology of species D—such as their cellular tropism, receptor usage, and in vivo biodistribution profile—remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)—a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications.