Multi-locus imprinting disturbance (MLID): interim joint statement for clinical and molecular diagnosis.

BACKGROUND: Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need. METHODS: A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations. RESULTS: In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID. CONCLUSIONS: MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3-5 years to evaluate the research advancements and update this guidance as needed.

Racial and Ethnic Variations in Resilience Factors Among Sexual and Gender Minority Midlife and Older Adults.

BACKGROUND AND OBJECTIVES: This study explores resilience factors among sexual and gender minority (SGM) midlife and older adults, identifying historical/environmental, psychological, social, and behavioral predictors, and examining variations across racial/ethnic subgroups. By adopting a resilience-focused perspective, this research contributes to understanding strengths in the SGM community in the context of aging. RESEARCH DESIGN AND METHODS: Using weighted survey data from Aging with Pride: National Health, Aging, and Sexuality/Gender Study, this research investigates distinct risk and protective factors associated with resilience among SGM midlife and older adults. Subgroup variations were assessed using regression models. Factors moderated by race/ethnicity were integrated into final interaction models. RESULTS: Hispanic and Black individuals showed significantly higher resilience than non-Hispanic Whites. Lifetime victimization and day-to-day discrimination were negatively associated with resilience. Positive associations were found for higher income, identity affirmation, larger network size, greater social participation, increased physical activity, and sufficient food intake. Interaction models revealed nuanced patterns by subgroups; education negatively impacted resilience among Black individuals, while income positively influenced Hispanic individuals' resilience. The Other racial/ethnic group demonstrated unique associations between optimal sleep and resilience. DISCUSSION AND IMPLICATIONS: This study shifts from a deficit-based to a resilience-focused approach among SGM midlife and older adults, revealing key strengths within diverse subgroups. Results underscore the significance of recognizing racial/ethnic differences in factors promoting resilience and posing risks for SGM midlife and older adults. Tailoring interventions to address the intersectional needs of SGM aging populations is essential for enhancing their abilities to bounce back from adverse events.

Bifunctional Ligands: Evaluating the Role of Acidic Protons in the Secondary Coordination Sphere.

To evaluate bifunctional ligand reactivity involving NH acidic sites in the secondary coordination sphere of metal complexes, complexes where the proton has been substituted with a methyl group (NMe) are often investigated. An alternative strategy would involve substitution of the NH group for an O. This contribution considers and compares the merits of these approaches; the synthesis and characterization of cationic square planar Rh carbonyl complexes bearing diprotic bispyrazole pyridine ligand L1, and the bis-methylated pyrazole pyridine ligand L1Me are described. The syntheses and characterization of the novel monoprotic pyrazole isoxazole pyridine ligand L2 and aprotic bisisoxazole pyridine ligand L3, and their corresponding Rh carbonyl complexes are also described. The different CO stretching frequencies of all four Rh-complexes suggest that substitutions of NH with NMe, as well as O, lead to significant electronic differences, and these differences are further demonstrated to lead to different ligand addition/substitution reactivities of the four isoelectronic Rh-complexes. Overall, the results suggest that the electronic differences arising due to NH substitutions can be significant and must be accounted for prior to invoking the participation of the proton.

Artemisinin-resistant malaria in Africa demands urgent action.

Investment in community health workers is essential.

Gender Trends in Authorship of Gastroenterology Randomized Controlled Trial Literature.

INTRODUCTION: We describe female authorship trends in gastroenterology (GI) randomized controlled trial literature as a novel focus on gender bias in academic GI. METHODS: Using a systematic PubMed search, we extracted GI randomized controlled trial reports published from 2011 to 2022. We describe time trends in proportions of females among first and last authors overall and within GI subspecialties and high-impact journals. RESULTS: The proportion of females increased from 25.4% to 36.8% and from 14.3% to 24.8% among first and last authors, respectively. Smaller increases in female authorship occurred in most subgroups, although there were proportionately fewer females among authors in high-impact journals and advanced therapeutic endoscopy publications. DISCUSSION: Over the past decade, female authorship in GI RCT reports has increased. However, female representation, particularly among senior authors and in high-impact journals, remains significantly lower. Despite recent improvements, female still constitutes a minority of the authors of original GI RCTs.

Use of population pharmacokinetic-pharmacodynamic modelling to inform antimalarial dose optimization in infants.

Infants bear a significant malaria burden but are usually excluded from participating in early dose optimization studies that inform dosing regimens of antimalarial therapy. Unlike older children, infants' exclusion from early-phase trials has resulted in limited evidence to guide accurate dosing of antimalarial treatment for uncomplicated malaria or malaria-preventive treatment in this vulnerable population. Subsequently, doses used in infants are often extrapolated from older children or adults, with the potential for under- or overdosing. Population pharmacokinetic-pharmacodynamic (PK-PD) modelling, a quantitative methodology that applies mathematical and statistical techniques, can aid the design of clinical studies in infants that collect sparse pharmacokinetic data as well as support the analysis of such data to derive optimized antimalarial dosing in this complex and at-risk yet understudied subpopulation. In this review, we reflect on what PK-PD modelling can do in programmatic settings of most malaria-endemic areas and how it can be used to inform antimalarial dose optimization for preventive and curative treatment of uncomplicated malaria in infants. We outline key developmental physiological changes that affect drug exposure in early life, the challenges of conducting dose optimization studies in infants, and examples of how PK-PD modelling has previously informed antimalarial dose optimization in this subgroup. Additionally, we discuss the limitations and gaps of PK-PD modelling when used for dose optimization in infants. To utilize modelling well, there is a need to generate useful, sparse, PK and PD data in this subpopulation to inform antimalarial optimal dosing in infancy.

Modulation of intracellular calcium activity in interstitial cells of Cajal by inhibitory neural pathways within the internal anal sphincter.

The internal anal sphincter (IAS) functions to maintain continence. Previous studies utilizing mice with cell-specific expression of GCaMP6f revealed two distinct subtypes of intramuscular interstitial cells of Cajal (ICC-IM) with differing Ca2+ activities in the IAS. The current study further examined Ca2+ activity in ICC-IM and its modulation by inhibitory neurotransmission. The spatiotemporal properties of Ca2+ transients in Type II ICC-IM mimicked those of smooth muscle cells (SMCs) indicating their joint participation in the "SIP" syncytium. Electrical field stimulation (EFS; atropine present) abolished localized and whole-cell Ca2+ transients in Type I and II ICC-IM. The purinergic antagonist MRS2500 did not abolish EFS responses in either cell type whereas the NOS inhibitor L-NNA abolished responses in Type I but not Type II ICC-IM. Combined antagonists abolished EFS responses in Type II ICC-IM. In both ICC-IM subtypes, the ability of EFS to inhibit Ca2+ release was abolished by L-NNA, but not MRS2500 suggesting that the nitrergic pathway directly inhibits ICC-IM by blocking Ca2+ release from intracellular stores. Since IRAG1 is expressed in ICC-IM it is possible that it participates in the inhibition of Ca2+ release by nitric oxide. PDGFRᵯC+ cells but not ICC-IM expressed P2Y1R and SK3 suggesting that the purinergic pathway indirectly blocks whole-cell Ca2+ transients in Type II ICC-IM via PDGFRᵯC+ cells. This study provides the first direct evidence for functional coupling between inhibitory motor neurons and ICC-IM subtypes in the IAS with contractile inhibition ultimately dependent upon electrical coupling between SMCs, ICC and PDGFRᵯC+ cells via the SIP syncytium.

State-of-the-art imaging for children with central lymphatic disorders.

Lymphatic imaging plays a crucial role in novel lymphatic interventions, offering valuable insights into central lymphatic drainage. Lymphatic system abnormalities may appear in various pediatric disorders, and accurate imaging is crucial for effective diagnosis and tailored therapeutic interventions. Traditional imaging modalities have offered valuable insights, but the demand for non-invasive, high-resolution techniques has fueled the development of innovative lymphatic imaging methods. In this review, we explore the state of the art in lymphatic imaging specifically within the context of pediatric surgery.

Perspectives of patients, parents, and health care providers on facilitators of and barriers to the transition from pediatric to adult care in inflammatory bowel disease: a qualitative descriptive study.

Background: The typical transition from pediatric to adult care in patients with inflammatory bowel disease occurs with an increase in health care utilization and a decrease in adherence to medications and scheduled appointments. An effective transition could reduce negative impacts but requires identifying opportunities to improve this process. This study aims to describe barriers and facilitators of transition according to patients, parents, and health care providers. Methods: This study used a qualitative description approach. The lead author conducted semi-structured interviews with 17 patients, 13 parents, and 15 providers recruited from Western Canada. Latent content analysis identified themes in interview transcripts. Results: The theme of preparedness emerged across all groups as a transition facilitator. Other facilitators that emerged included patient characteristics, supportive parents, home environment, and supportive adult care team. Themes of barriers that emerged included patient factors, "hovering parents" and family factors, navigating a new health care system, and travel distance. Conclusions: This study describes facilitators and barriers according to each stakeholder involved in the transition process. Future studies should focus on designing and evaluating interventions aimed at promoting facilitators and addressing identified barriers in patients preparing to transition from pediatric to adult care.

Mental Health Experiences of Adolescents and Young Adults with Inflammatory Bowel Disease During Transition to Adult Care: A Qualitative Descriptive Study.

OBJECTIVE: To explore the mental health experiences of adolescents and young adults (AYA) with inflammatory bowel disease (IBD) enrolled in a randomized controlled trial evaluating the impact of a multimodal transition intervention. STUDY DESIGN: Virtual semistructured interviews were held with 21 AYA aged 16 through 18 years with IBD. Guided by qualitative description, interviews were digitally recorded, transcribed verbatim, and analyzed using an inductive approach to reflexive thematic analysis. RESULTS: Three themes were generated from the data: (1) a continuum of integration between IBD and personal identity in adolescence and young adulthood; (2) manifestations of the mind-gut connection among AYA with IBD; and (3) hopes and priorities for addressing mental health in IBD care. CONCLUSIONS: AYA with IBD endorsed the criticality of incorporating mental health discussions into routine care during the transition to adult care, given the co-occurrence of psychosocial stressors throughout this period. A series of factors promoting and hindering the integration of IBD into one's identity were identified and could be explored in clinical encounters.

How we do it: Cardiac implantable devices are not a contraindication to MRI: time for a paradigm shift.

Magnetic resonance imaging (MRI) is now an indispensable diagnostic tool in medicine due to its outstanding contrast resolution and absence of radiation exposure, enabling detailed tissue characterization and three-dimensional anatomical representation. This is especially important when evaluating individuals with congenital heart disease (CHD) who frequently require cardiac implantable electrical devices (CIEDs). While MRI safety issues have previously limited its use in patients with CIEDs, new advances have called these limitations into question. However, difficulties persist in the pediatric population due to the continued lack of specific safety data both related to imaging young children and the specific CIED devices they often require. This paper discusses MRI safety considerations related to imaging patients with CIEDs, investigates pediatric-specific problems, and describes thorough methods for safe MRI access, highlighting the significance of specialized institutional guidelines.

Transgender older adults' prior military service: Mental health differences by gender identification.

Despite a proportionally higher likelihood of serving, the role of prior military service in the mental health of transgender individuals is understudied. Research on the impact of military service on mental health tends to be proximal. We examined the distal relationship between prior military service, identity stigma, and mental health among transgender older adults, drawing comparisons between transgender men and women. We conducted a series of weighted multivariate linear models to predict the relationships between prior military service, identity stigma, perceived stress, and depression among 183 transgender women and men aged 51-87 (M = 60.11, SD = 0.668) using 2014 data from the National Health, Aging, and Sexuality/Gender Study. Prior military service was negatively associated with depression and perceived stress; identity stigma was positively associated with both. Prior military service and lower depression and perceived stress were significant for transgender men, but not women. Identity stigma was significant with depression and perceived stress among transgender women, but not transgender men. Our preliminary findings suggest that prior military service may serve as a protective factor for mental health among transgender men, but not transgender women. We need to better understand how military experience interacts with other characteristics, such as differing gender identities influences the mental health of transgender service members. Further research is needed to inform underlying mechanisms whereby military service differentially impacts mental health by gender identity so all active-duty personnel can share in the many benefits that accrue from military service, including protective effects on mental health in later life. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Letting go of control: A qualitative descriptive study exploring parents' perspectives on their child's transition from pediatric to adult care for inflammatory bowel disease.

Parents of young adults with chronic disease are important stakeholders in their child's transition from pediatric to adult care. There remains a gap in characterizing the parent experience during transition. This study describes the experiences of 13 mothers of young adults with inflammatory bowel disease during their child's transition. Most parents expressed fear and sadness about their child transitioning. Themes relating to involvement in their child's adult care included: direct involvement (sub-themes: disease management; logistics of care); and indirect involvement. Reasons for involvement included themes of parent's feelings and child's circumstances. Themes of involvement were discussed in terms of previous research on parenting of children with chronic disease. We suggest that future efforts focus on improving empathy and understanding toward parents of transitioning children and providing resources on how they can best support their child during transition and transfer to adult care.

Insertion of Molecular Oxygen into a Gold(III)-Hydride Bond.

The use of molecular oxygen as an oxidant in chemical synthesis has significant environmental and economic benefits, and it is widely used as such in large-scale industrial processes. However, its adoption in highly selective homogeneous catalytic transformations, particularly to produce oxygenated organics, has been hindered by our limited understanding of the mechanisms by which O2 reacts with transition metals. Of particular relevance are the mechanisms of the reactions of oxygen with late transition metal hydrides as these metal centers are better poised to release oxygenated products. Homogeneous catalysis with gold complexes has markedly increased, and herein we report the synthesis and full characterization of a rare AuIII-H, supported by a diphosphine pincer ligand (tBuPCP = 2,6-bis(di-tert-butylphosphinomethyl)benzene). [(tBuPCP)AuIII-H]+ was found to cleanly react with molecular oxygen to yield a stable AuIII-OOH complex that was also fully characterized. Extensive kinetic studies on the reaction via variable temperature NMR spectroscopy have been completed, and the results are consistent with an autoaccelerating radical chain mechanism. The observed kinetic behavior exhibits similarities to that of previously reported PdII-H and PtIV-H reactions with O2 but is not fully consistent with any known O2 insertion mechanism. As such, this study contributes to the nascent fundamental understanding of the mechanisms of aerobic oxidation of late metal hydrides.

Health, Economic, and Social Disparities among Lesbian, Gay, Bisexual, and Sexually Diverse Adults: Results from a Population-Based Study.

We investigated health, economic, and social disparities among lesbian, gay, bisexual, and sexually diverse adults, 18 years and older. Analyzing 2011-2019 Washington State Behavioral Risk Factor Surveillance System (N = 109,527), we estimated and compared the prevalence rates of background characteristics, economic and social indicators, health outcomes, chronic conditions, health care access, health behaviors, and preventive care by gender and sexual identity. Sexual minority adults reported heightened risks of poor general health, physical and mental health, disability, subjective cognitive decline, and financial barriers to health care, compared with their straight counterparts. Economic disparities and disability were evident for lesbians and both bisexual adult women and men. We found higher rates of smoking and excessive drinking among lesbians and bisexual women, and higher rates of smoking and living alone among gay men. Sexually diverse adults experience disparities in health care access. This study is one of the first to identify disparities among sexually diverse populations, in addition to lesbian, gay, and bisexual adults. More research is required to understand the mechanisms of disparities within these groups to address their distinct intervention needs.

Resident Synovial Macrophages in Synovial Fluid: Implications for Immunoregulation in Infectious and Inflammatory Arthritis.

Objectives: Resident synovial macrophages (RSM) provide immune sequestration of the joint space and are likely involved in initiation and perpetuation of the joint-specific immune response. We sought to identify RSM in synovial fluid (SF) and demonstrate migratory ability, in additional to functional changes that may perpetuate a chronic inflammatory response within joint spaces. Methods: We recruited human patients presenting with undifferentiated arthritis in multiple clinical settings. We used flow cytometry to identify mononuclear cells in peripheral blood and SF. We used a novel transwell migration assay with human ex-vivo synovium obtained intra-operatively to validate flow cytometry findings. We used single cell RNA-sequencing (scRNA-seq) to further identify macrophage/monocyte subsets. ELISA was used to evaluate the bone-resorption potential of SF. Results: We were able to identify a rare population of CD14dim, OPG+, ZO-1+ cells consistent with RSM in SF via flow cytometry. These cells were relatively enriched in the SF during infectious processes, but absolutely decreased compared to healthy controls. Similar putative RSM were identified using ex vivo migration assays when MCP-1 and LPS were used as migratory stimulus. scRNA-seq revealed a population consistent with RSM transcriptionally related to CD56+ cytotoxic dendritic cells and IDO+ M2 macrophages. Conclusion: We identified a rare cell population consistent with RSM, indicating these cells are likely migratory and able to initiate or coordinate both acute (septic) or chronic (autoimmune or inflammatory) arthritis. RSM analysis via scRNA-seq indicated these cells are M2 skewed, capable of antigen presentation, and have consistent functions in both septic and inflammatory arthritis.

Incidence and Prevalence of Primary Sclerosing Cholangitis: A Meta-analysis of Population-based Studies.

BACKGROUND: Primary sclerosing cholangitis is a chronic liver disease associated with significant morbidity, mortality, and healthcare utilization. We conducted a systematic review and meta-analysis of population-based studies of the incidence and prevalence of primary sclerosing cholangitis. METHODS: Medline and Embase were systematically searched to identify population-based studies of a defined geographic area and reported the incidence or prevalence of primary sclerosing cholangitis in the general population. Meta-analyses, using random-effects, were performed to calculate overall and country-specific incidence (per 100 000 persons/year) and prevalence rates (per 100 000 persons) with 95% confidence intervals. RESULTS: The 14 studies on incidence and the 12 for prevalence originated from North America, Asia, Europe, and Oceania. Incidence and prevalence rates of primary sclerosing cholangitis were 0.87 (95% confidence interval, 0.59-1.29) and 13.53 (95% confidence interval, 10.20-17.94) per 100 000 persons, respectively. CONCLUSIONS: Both the prevalence and incidence of primary sclerosing cholangitis is low in the general population. Future studies on the incidence and prevalence of primary sclerosing cholangitis in the general population should be directed at Asia, Africa, and Latin America to allow for a more robust assessment of the global epidemiology of primary sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic liver disease with complications such as cirrhosis, cancer, and death. This study summarizes the incidence (0.87 per 100 000) and prevalence (13.53 per 100 000) of PSC and highlight needs in research to study the epidemiology of PSC.