A Case of Metastatic Atypical Neuroendocrine Tumor with ALK Translocation and Diffuse Brain Metastases.

A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well-validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non-small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine-needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies. In this article, we present a case of a 52-year-old never-smoking male who presented with widely metastatic atypical neuroendocrine tumor to the bones and the brain. Molecular genotyping using DNA harvested from a bone metastasis was unsuccessful due to limited material. Subsequent ctDNA analysis revealed an ALK translocation. The clinical significance of the mutation in this particular cancer type and therapeutic strategies are discussed.Key pointsTo our knowledge, this index case represents the first reported ALK translocation identified in an atypical carcinoid tumor.Liquid biopsy such as circulating tumor DNA is a feasible alternative platform for identifying sensitizing genomic alterations.Second-generation ALK inhibitors represent a new paradigm for treating ALK-positive patients with brain metastases

Age effects and the influence of varying proportions of terrestrial and marine dietary protein on the stable nitrogen-isotope compositions of pig bone collagen and soft tissues from a controlled feeding experiment

In this study, femoral collagen, rib collagen, femoral muscle, loin muscle and liver samples from sows, piglets and pigs raised in a controlled feeding study are analysed for their nitrogen-isotope compositions. The objectives of this research are to investigate the relationship between tissue and dietary δ15N values across age categories under controlled feeding and housing conditions, and to assess tissue 15N-enrichment relative to diet when pigs of different ages are consuming terrestrial, marine, or mixed terrestrial-marine dietary protein. There is a strong linear relationship between all tissue δ15N values and the amount of marine protein consumed, but the δ15N values do not become consistently elevated for all individuals consuming the same diet until at least 25% of the dietary protein source is marine-derived. Adolescent pigs also had consistently lower δ15N values than either piglets or sows consuming the same diet for collagen and muscle, which is most likely caused by the differences in growth rate among the age categories. Further, for some tissues and animals, a linear relationship between the amount of marine protein consumed and the Δ15NTissue – Whole Diet offset was also observed. We suggest that this variability results from both age-associated growth rates and differential incorporation of amino acids from terrestrial and marine dietary protein into rapidly growing tissue

Advancing professionalization in human simulation: perspectives of SP educators from around the world on the Association of SP Educators Standards of Best Practice

Introduction Between 2013 and 2017, the Association of SP Educators (ASPE), a global organization of educators dedicated to the work of human simulation, developed Standards of Best Practice (SOBP) for working with human role players in simulation. These individuals are known by diverse terms, including simulated or standardized patients or participants (SPs). This study had two aims: (1) to understand the ways in which the ASPE SOBP are relevant to the practices of SP educators around the world, and (2) to identify improvements to the ASPE SOBP from a global perspective. Methods This qualitative study was undertaken between January 2020 and July 2022. Subjects consented to audio-recorded interviews. A collaborative, inductive coding approach was adopted, followed by thematic analysis, aligned with the methods described by Braun and Clarke. Themes were further updated following reflexive conversations amongst the investigators at meetings over the course of several months and were aligned with the study aims. Results Twelve SP educators from six continents participated. Four primary themes were identified (each with multiple subthemes): influencing SP educator practices; advancing professionalization; identifying challenges to implementation; and bridging gaps in the ASPE SOBP. Discussion A diverse group of SP educators from around the world identified the ASPE SOBP in general as relevant and applicable to their practice. The standards provided both guidance and flexibility for working with SPs in a safe, effective and quality-based way. At the same time there were challenges noted and recommendations made that can help to inform future iterations of the standards

Multi-person sex among a sample of adolescent female urban health clinic patients

Adolescent sexual activity involving three or more people is an emerging public health concern. The goal of this exploratory, cross-sectional study was to describe the prevalence, correlates, and context of multiple-person sex among a sample of adolescent females seeking health care from an urban clinic. Because sex involving multiple people may either be consensual (i.e., “three-ways” or “group sex”) or forced (i.e., “gang rape”), we use the term “multi-person sex” (MPS) to encompass these experiences. Subjects were 328 females, ages 14–20 years old, who utilized a Boston-area community- or school-based health clinic between April and December of 2006, and completed an anonymous survey using computer-assisted self-interview software. Overall, 7.3% reported ever having had a MPS experience. Of these, 52% reported ever being pressured to engage in MPS and 43% reported ever being threatened or forced. Condom nonuse by at least one male participant in the most recent MPS was reported by 45%. Controlling for potential demographic confounders, MPS was associated with cigarette smoking (adjusted prevalence ratio [APR], 3.83; 95% confidence interval [CI], 1.56–9.44), sexual initiation prior to age 15 (APR, 2.50; 95% CI, 1.04–5.98), ever being diagnosed with an STI (APR, 2.55; 95% CI, 1.08–6.03), dating violence victimization (APR, 4.43; 95% CI, 1.68–11.69), childhood sexual abuse victimization (APR, 4.30; 95% CI, 1.83–10.07) and past-month pornography exposure (APR, 4.79; 95% CI, 1.91–11.98). Additional study of the perpetration and prevention of adolescent MPS is urgently needed

Oral serum-derived bovine immunoglobulin improves duodenal immune reconstitution and absorption function in patients with HIV enteropathy.

ObjectivesTo examine the impact of serum-derived bovine immunoglobulin, an oral medical food known to neutralize bacterial antigen and reduce intestinal inflammation, on restoration of mucosal immunity and gastrointestinal function in individuals with HIV enteropathy.DesignOpen-label trial with intensive 8-week phase of bovine serum immunoglobulin (SBI) 2.5 g twice daily with a 4-week washout period and an optional 9-month extension study.MethodsHIV enteropathy was defined as chronic gastrointestinal symptoms including frequent loose or watery stools despite no identifiable, reversible cause. Upper endoscopy for tissue immunofluorescent antibody assay and disaccharide gut permeability/absorption studies were performed before and after 8 weeks of SBI to test mucosal immunity and gastrointestinal function. Blood was collected for markers of microbial translocation, inflammation, and collagen kinetics. A validated gastrointestinal questionnaire assessed changes in symptoms.ResultsAll eight participants experienced profound improvement in symptoms with reduced bowel movements/day (P = 0.008) and improvements in stool consistency (P = 0.008). Gut permeability was normal before and after the intervention, but D-xylose absorption increased in seven of eight participants. Mucosal CD4 lymphocyte densities increased by a median of 139.5 cells/mm2 from 213 to 322 cells/mm2 (P = 0.016). Intestinal-fatty acid binding protein (I-FABP), a marker of enterocyte damage, initially rose in seven of eight participants after 8 weeks (P = 0.039), and then fell below baseline in four of five who continued receiving SBI (P = 0.12). Baseline serum I-FABP levels were negatively correlated with subsequent rise in mucosal CD4 lymphocyte densities (r = -0.74, P = 0.046).ConclusionSBI significantly increases intestinal mucosal CD4 lymphocyte counts, improves duodenal function, and showed evidence of promoting intestinal repair in the setting of HIV enteropathy

The prevention of lower urinary tract symptoms (PLUS) research consortium: A transdisciplinary approach toward promoting bladder health and preventing lower urinary tract symptoms in women across the life course

Lower urinary tract symptoms (LUTS) are highly prevalent in women, and are expected to impose a growing burden to individuals and society as the population ages. The predominance of research related to LUTS has focused on underlying pathology, disease mechanisms, or the efficacy of treatments for women with LUTS. Although this research has been vital for helping to reduce or ameliorate LUTS conditions, it has done little to prevent the onset of LUTS. Health promotion and prevention require an expansion of scientific inquiry beyond the traditional paradigm of studying disease mechanisms and treatment to the creation of an evidence base to support recommendations for bladder health promotion and, in turn, prevention of LUTS. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) introduced the concept of prevention as an important priority for women's urologic research as a prelude to supporting the formation of the Prevention of Lower Urinary Tract Symptoms (PLUS) research consortium. In this article, we introduce the PLUS research consortium to the scientific community; share the innovative paradigms by which the consortium operates; and describe its unique research mission: to identify factors that promote bladder health across the life course and prevent the onset of LUTS in girls and women

Dietary Methionine Restriction Regulates Liver Protein Synthesis and Gene Expression Independently of Eukaryotic Initiation Factor 2 Phosphorylation in Mice

Background: The phosphorylation of eukaryotic initiation factor 2 (p-eIF2) during dietary amino acid insufficiency reduces protein synthesis and alters gene expression via the integrated stress response (ISR).Objective: We explored whether a Met-restricted (MR) diet activates the ISR to reduce body fat and regulate protein balance.Methods: Male and female mice aged 3-6 mo with either whole-body deletion of general control nonderepressible 2 (Gcn2) or liver-specific deletion of protein kinase R-like endoplasmic reticulum kinase (Perk) alongside wild-type or floxed control mice were fed an obesogenic diet sufficient in Met (0.86%) or an MR (0.12% Met) diet for ≤5 wk. Ala enrichment with deuterium was measured to calculate protein synthesis rates. The guanine nucleotide exchange factor activity of eIF2B was measured alongside p-eIF2 and hepatic mRNA expression levels at 2 d and 5 wk. Metabolic phenotyping was conducted at 4 wk, and body composition was measured throughout. Results were evaluated with the use of ANOVA (P < 0.05).Results: Feeding an MR diet for 2 d did not increase hepatic p-eIF2 or reduce eIF2B activity in wild-type or Gcn2-/- mice, yet many genes transcriptionally regulated by the ISR were altered in both strains in the same direction and amplitude. Feeding an MR diet for 5 wk increased p-eIF2 and reduced eIF2B activity in wild-type but not Gcn2-/- mice, yet ISR-regulated genes altered in both strains similarly. Furthermore, the MR diet reduced mixed and cytosolic but not mitochondrial protein synthesis in both the liver and skeletal muscle regardless of Gcn2 status. Despite the similarities between strains, the MR diet did not increase energy expenditure or reduce body fat in Gcn2-/- mice. Finally, feeding the MR diet to mice with Perk deleted in the liver increased hepatic p-eIF2 and altered body composition similar to floxed controls.Conclusions: Hepatic activation of the ISR resulting from an MR diet does not require p-eIF2. Gcn2 status influences body fat loss but not protein balance when Met is restricted

De novoframeshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies

BACKGROUND: Currently, diagnosis of affected individuals with rare genetic disorders can be lengthy and costly, resulting in a diagnostic odyssey and in many patients a definitive molecular diagnosis is never achieved despite extensive clinical investigation. The recent advent and use of genomic medicine has resulted in a paradigm shift in the clinical molecular genetics of rare diseases and has provided insight into the causes of numerous rare genetic conditions. In particular, whole exome and genome sequencing of families has been particularly useful in discovering de novo germline mutations as the cause of both rare diseases and complex disorders. CASE PRESENTATION: We present a six year old, nonverbal African American female with microcephaly, autism, global developmental delay, and metopic craniosynostosis. Exome sequencing of the patient and her two parents revealed a heterozygous two base pair de novo deletion, c.1897_1898delCA, p.Gln633ValfsX13 in ASXL3, predicted to result in a frameshift at codon 633 with substitution of a valine for a glutamine and introduction of a premature stop codon. CONCLUSIONS: We provide additional evidence that, truncating and frameshifting mutations in the ASXL3 gene are the cause of a newly recognized disorder characterized by severe global developmental delay, short stature, microcephaly, and craniofacial anomalies. Furthermore, we expand the knowledge about disease causing mutations and the genotype-phenotype relationships in ASXL3 and provide evidence that rare, nonsynonymous, damaging mutations are not associated with developmental delay or microcephaly

Why are drug-related deaths among women increasing in Scotland? A mixed-methods analysis of possible explanations

Drug-related deaths have increased significantly in Scotland in recent years, with a much greater percentage increase in deaths among women than among men. We undertook a mixed-methods project to identify explanations for this trend, comprising three parallel methodological strands: (i) an analysis of available routine data, including drug treatment data, death registrations, and surveys of people using needle exchanges; (ii) thematic analysis of interviews and focus groups with professional stakeholders and (iii) secondary analysis of interviews with women who use drugs. Results indicated that the observed trend is likely to reflect multiple, interacting causes. Potential contributors identified were: ageing; changing patterns of substance use; increasing prevalence of physical and mental health co-morbidities; changing relationships and parenting roles; changes to treatment services and wider health and social care provision; unintended consequences or poor implementation of recovery-oriented practice; and changes in the social security system. Policy responses to rising drug-related death rates require a gender-informed approach, recognising the commonalities and differences between men and women who use drugs; the diversity of experiences within each gender; and the intersections between gender and other forms of inequality, such as poverty