Plasma Cell Mucositis: A Clinical Conundrum.

Plasma cell mucositis (PCM) is an unusual disorder most evident in the accessible mucosa and usually reported in the upper aerodigestive tract, although it is named according to its specific anatomical site of involvement such as plasma cell cheilitis, plasma cell gingivitis, plasma cell vulvitis, and Zoon's balanitis. PCM reflects a dense polyclonal rather than a monoclonal plasma cell proliferation of unclear and unknown etiology. This perplexing disorder tends to be treated by avoiding possible triggers and intralesional and/or systemic steroids. In this work, we provide a review and update on PCM, which often represents a clinical conundrum.

Liver-specific Mettl14 deletion induces nuclear heterotypia and dysregulates RNA export machinery.

Modification of RNA with N6-methyladenosine (m6A) has gained attention in recent years as a general mechanism of gene regulation. In the liver, m6A, along with its associated machinery, has been studied as a potential biomarker of disease and cancer, with impacts on metabolism, cell cycle regulation, and pro-cancer state signaling. However these observational data have yet to be causally examined in vivo. For example, neither perturbation of the key m6A writers Mettl3 and Mettl14, nor the m6A readers Ythdf1 and Ythdf2 have been thoroughly mechanistically characterized in vivo as they have been in vitro. To understand the functions of these machineries, we developed mouse models and found that deleting Mettl14 led to progressive liver injury characterized by nuclear heterotypia, with changes in mRNA splicing, processing and export leading to increases in mRNA surveillance and recycling.

A nucleosome switch primes Hepatitis B Virus infection.

Chronic hepatitis B virus (HBV) infection is an incurable global health threat responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, Smc5/6. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. Establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA drives X transcription. We corroborated these findings in cells and further showed that the chromatin destabilizing molecule CBL137 inhibits X transcription and HBV infection in hepatocytes. Our results shed light on a long-standing paradox and represent a potential new therapeutic avenue for the treatment of chronic HBV infection.

Assessing the impact of jail-initiated medication for opioid use disorder: A multisite analysis of the SOMATICS collaborative.

The objective of this study was to estimate the associations of jail-initiated medication for opioid use disorder (MOUD) and patient navigation (PN) with opioid use disorder (OUD) at 6 months post-release. Three randomized trials (combined N = 330) were combined to assess whether MOUD (extended-release naltrexone or interim methadone) initiated prior to release from jail with or without PN would reduce the likelihood of a DSM-5 diagnosis of OUD 6 months post-release relative to enhanced treatment-as-usual (ETAU). Across the three studies, assignment to MOUD compared to ETAU was not associated with an OUD diagnosis at 6 months post-release (69% vs. 75%, respectively, OR = 0.67, 95% CI: 0.42 to 1.20). Similarly, PN compared to MOUD without PN was not associated with an OUD diagnosis (63% vs 77%, respectively, OR = 0.61, 95% CI: 0.27 to 1.53). Results underscore the need to further optimize the effectiveness of MOUD for patients initiating treatment in jail, beginning with an emphasis on post-release treatment adherence.

Space radiation damage rescued by inhibition of key spaceflight associated miRNAs.

Our previous research revealed a key microRNA signature that is associated with spaceflight that can be used as a biomarker and to develop countermeasure treatments to mitigate the damage caused by space radiation. Here, we expand on this work to determine the biological factors rescued by the countermeasure treatment. We performed RNA-sequencing and transcriptomic analysis on 3D microvessel cell cultures exposed to simulated deep space radiation (0.5 Gy of Galactic Cosmic Radiation) with and without the antagonists to three microRNAs: miR-16-5p, miR-125b-5p, and let-7a-5p (i.e., antagomirs). Significant reduction of inflammation and DNA double strand breaks (DSBs) activity and rescue of mitochondria functions are observed after antagomir treatment. Using data from astronaut participants in the NASA Twin Study, Inspiration4, and JAXA missions, we reveal the genes and pathways implicated in the action of these antagomirs are altered in humans. Our findings indicate a countermeasure strategy that can potentially be utilized by astronauts in spaceflight missions to mitigate space radiation damage.

Extramammary Paget Disease. Part I. Epidemiology, Pathogenesis, Clinical Features, and Diagnosis.

Extramammary Paget disease (EMPD) is a rare skin cancer of apocrine-rich skin that mimics common inflammatory and infectious dermatoses, leading to delays in diagnosis and increased patient morbidity. Better clinical recognition of this entity, multidisciplinary patient assessment, and deeper understanding of the underlying pathophysiology are essential to improve patient care and disease outcomes. It is important to distinguish primary intraepithelial/micro-invasive EMPD from invasive EMPD or cases with adenocarcinoma arising within EMPD. This 2-part continuing medical education series provides a complete picture of EMPD. Part 1 of this continuing medical education series reviews the epidemiology, oncogenesis, clinical and histopathologic presentation, workup, and prognosis of this rare cancer.

ß1 integrins regulate cellular behavior and cardiomyocyte organization during ventricular wall formation.

AIMS: The mechanisms regulating the cellular behavior and cardiomyocyte organization during ventricular wall morphogenesis are poorly understood. Cardiomyocytes are surrounded by extracellular matrix (ECM) and interact with ECM via integrins. This study aims to determine whether and how ß1 integrins regulate cardiomyocyte behavior and organization during ventricular wall morphogenesis in the mouse. METHODS AND RESULTS: We applied mRNA deep sequencing and immunostaining to determine the expression repertoires of α/ß integrins and their ligands in the embryonic heart. Integrin ß1 subunit (ß1) and some of its ECM ligands are asymmetrically distributed and enriched in the luminal side of cardiomyocytes, and fibronectin surrounds cardiomyocytes, creating a network for them. Itgb1, which encodes the ß1, was deleted via Nkx2.5Cre/+ to generate myocardial-specific Itgb1 knockout (B1KO) mice. B1KO hearts display an absence of a trabecular zone but a thicker compact zone. The levels of hyaluronic acid and versican, essential for trabecular initiation, were not significantly different between control and B1KO. Instead, fibronectin, a ligand of ß1, was absent in the myocardium of B1KO hearts. Furthermore, B1KO cardiomyocytes display a random cellular orientation and fail to undergo perpendicular cell division, be organized properly, and establish the proper tissue architecture to form trabeculae. Mosaic clonal lineage tracing showed that Itgb1 regulates cardiomyocyte transmural migration and proliferation autonomously. CONCLUSIONS: ß1 is asymmetrically localized in the cardiomyocytes, and some of its ECM ligands are enriched along the luminal side of the myocardium, and fibronectin surrounds cardiomyocytes. ß1 integrins are required for cardiomyocytes to attach to the ECM network. This engagement provides structural support for cardiomyocytes to maintain shape, undergo perpendicular division, and establish cellular organization. Deletion of Itgb1 leads to loss of ß1 and fibronectin and prevents cardiomyocytes from engaging the ECM network, resulting in failure to establish tissue architecture to form trabeculae.

Hospital admissions among patients with Comorbid Substance Use disorders: a secondary analysis of predictors from the NavSTAR Trial.

BACKGROUND: Individuals with substance use disorders (SUDs) frequently use acute hospital services. The Navigation Services to Avoid Rehospitalization (NavSTAR) trial found that a patient navigation intervention for hospitalized patients with comorbid SUDs reduced subsequent inpatient admissions compared to treatment-as-usual (TAU). METHODS: This secondary analysis extends previous findings from the NavSTAR trial by examining whether selected patient characteristics independently predicted hospital service utilization and moderated the effect of the NavSTAR intervention. Participants were 400 medical/surgical hospital patients with comorbid SUDs. We analyzed 30- and 90-day inpatient readmissions (one or more readmissions) and cumulative incidence of inpatient admissions through 12 months using multivariable logistic and negative binomial regression, respectively. RESULTS: Consistent with primary findings and controlling for patient factors, NavSTAR participants were less likely than TAU participants to be readmitted within 30 (P = 0.001) and 90 (P = 0.03) days and had fewer total readmissions over 12 months (P = 0.008). Hospitalization in the previous year (P < 0.001) was associated with cumulative readmissions over 12 months, whereas Medicaid insurance (P = 0.03) and index diagnoses of infection (P = 0.001) and injuries, poisonings, or procedural complications (P = 0.004) were associated with fewer readmissions. None of the selected covariates moderated the effect of the NavSTAR intervention. CONCLUSIONS: Previous findings showed that patient navigation could reduce repeat hospital admissions among patients with comorbid SUDs. Several patient factors were independently associated with readmission. Future research should investigate risk factors for hospital readmission among patients with comorbid SUDs to optimize interventions. TRIAL REGISTRATION: NIH ClinicalTrials.gov NCT02599818, Registered November 9, 2015 https://classic. CLINICALTRIALS: gov/ct2/show/NCT02599818 .

From endometrium to fingernail bed: histological evaluation of a rare cutaneous metastasis.

In the dermatological spectrum of oncologic manifestations, cutaneous metastases from endometrial carcinoma stand as a rarity, given the tumour's predilection for neighbouring uterine regions. We present an exceptional case of a patient in her mid-50s, whereby an endometrial carcinoma, defying conventional pathways, manifested on the skin and nail of her distal fourth finger, an unusual site for cutaneous metastases, with a specific histology of the primary cancer.

Netherton syndrome-A therapeutic challenge in childhood.

Key Clinical Message: High-dose intravenous immunoglobulin exhibits great potential in the treatment of Netherton syndrome. Abstract: Netherton syndrome (NS) is a rare autosomal recessive genodermatosis (OMIM #256500) characterized by superficial scaling, atopic manifestations, and multisystemic complications. It is caused by loss-of-function mutations in the SPINK5 gene, which encode a key kallikrein protease inhibitor. There are two subtypes of the syndrome that differ in clinical presentation and immune profile: ichthyosiform erythroderma and ichthyosis linearis circumflexa. NS is a multisystemic disease with numerous extracutaneous manifestations. Current therapy for patients with NS is mainly supportive, as there is no curative or specific treatment, especially for children with NS, but targeted therapies are being developed. We describe an 8-year-old boy with genetically proven NS treated with intravenous immunoglobulin for recurrent skin and systemic infections from infancy, growth retardation, and associated erythroderma. Under this therapy, his skin status, infectious exacerbations, and quality of life all improved. Knowledge of the cytokine-mediated pathogenesis of NS and the development of new biologic drugs open new possibilities for NS patients. However, the different therapeutic options have been applied in a limited number of cases, and variable responses have been shown. Randomized controlled trials with a sufficient number of patients stratified and treated according to their specific immune profile and clinical phenotype are needed to evaluate the safety and efficacy of treatment options for patients with NS.

Commercial Tobacco Endgame Goals: Early experiences from six countries.

INTRODUCTION: Tobacco use is a major threat to health globally. A number of countries have adopted 'endgame goals' to minimise smoking prevalence. The INSPIRED project aims to describe and compare the experiences of the first six countries to adopt an endgame goal. METHODS: Data were collected on the initial experiences of endgame goals in Canada, Finland, Ireland, New Zealand (Aotearoa), Scotland, and Sweden up to 2018. Information was collated on the nature of the endgame goals, associated interventions and strategies, potential enablers and barriers, and perceived advantages and disadvantages. RESULTS: The INSPIRED countries had relatively low smoking prevalences and moderate to strong smokefree policies. Their endgame goals aimed for smoking prevalences of 5% or less. Target dates ranged from 2025 to 2035. Except for New Zealand (Aotearoa), all countries had an action plan to support their goal by 2018. However, none of the plans incorporated specific endgame measures. Lack of progress in reducing inequities was a key concern, despite the consideration of equity in all of the country's goals and/or action plans. Experience with endgame goals was generally positive, however participants thought additional interventions would be required to equitably meet their endgame goal. CONCLUSIONS: There was variation in the nature and approach to endgame goals. This suggests that countries should consider adopting endgame goals and strategies to suit their social, cultural, and political contexts. The experiences of the INSPIRED countries suggest that further and more significant interventions will be required for the timely and equitable achievement of endgame goals. IMPLICATIONS: By 2018, six countries (Canada, Finland, Ireland, New Zealand (Aotearoa), Scotland, and Sweden) had introduced government-endorsed 'endgame goals', to rapidly reduce smoking prevalence to very low levels by a specified date. The nature and implementation of endgame goals was variable. Early experiences with the goals were generally positive, but progress in reducing smoking prevalence was insufficient, particularly for priority groups. This finding suggests more significant interventions ('endgame interventions') and measures to reduce inequities need to be implemented to achieve endgame goals. Variation in the nature and experience of endgame goals demonstrates the importance of designing endgame strategies that suit distinct social, cultural, and political contexts.

Women and Treatment for Opioid Use Disorder: Contributors to Treatment Success From the Perspectives of Women in Recovery, Women With Past Attempts in Drug Treatment, and Health and Criminal Justice Professionals.

Introduction: The disproportionate incidence of opioid use disorder (OUD) and the alarming increases in opioid-related overdose deaths among women highlight a clear need for the expansion of effective harm reduction and treatment practices. Research supports medications for opioid use disorders (MOUD) as an effective intervention; however, with low rates of utilization of such, there is a need to identify factors that facilitate MOUD treatment uptake and retention for women. Thus, the current study examines contributors to treatment success through the triangulation of perspectives from affected women as well as health and criminal justice professionals. Methods: Interviews (N = 42) were conducted from May to July 2022 with women in recovery who previously used or currently use MOUD (N = 10), women who currently use opioids who terminated a MOUD program previously (N = 10), SUD treatment professionals (N = 12), and criminal justice professionals who work with women who use opioids (N = 10). Interviews for all participants centered around their backgrounds, perceived barriers and facilitators to MOUD treatment, and issues specific to women in treatment for substance use disorder. We used a thematic qualitative data analysis process to analyze transcripts. Results: Participants highlighted contributors to treatment success from 3 domains: (1) internal processes (including promoting self-efficacy and setting realistic goals), (2) access to resources (including material resources, such as food and shelter, educational resources and social support), and (3) treatment structure (such as treatment type and protocol). Conclusion: Internal processes, access to resources, and treatment structure contribute to MOUD treatment success for women with OUD. Structured support where experiences are shared, and realistic goals are set, may promote feelings of acceptance and empowerment, thereby bolstering chances of treatment success. Additionally, the court system can promote evidence-based and trauma-informed substance use treatment and provide accessible educational resources related to substance use to extend these benefits to more women.

Herpes zoster infection in pregnancy: features and consequences.

Herpes (varicella) zoster (HZ) infection occurs in 4 people per 1000 in the general US population (irrespective of prior varicella infection and vaccination status) each year and has been the subject of scientific inquiry for decades. The consequences of infection are myriad and may depend on the dermatome of involvement as well as host factors such as age, comorbidities, prior treatment or immunization, and immunologic status. Pregnancy is associated with an altered immune and hormonal status in the mother. While maternal HZ infection during pregnancy is not uncommon, the implications for both mother and child are not well established, although multiple studies of perinatal maternal HZ infection suggest no intrauterine transmission to the fetus. We review the current literature on herpes zoster infection in pregnancy, including epidemiology, diagnosis, potential immunologic sequelae, and strategies for prevention and treatment.

Patient and provider medication preferences affect treatment outcomes among adolescents and young adults with opioid use disorder.

BACKGROUND: The opioid epidemic in the United States has not spared youth or young adults, as evidenced by a six-fold increase in opioid use disorder (OUD) diagnoses in the last two decades. Given this dramatic rise, a call for greater uptake and accessibility of medications for opioid use disorder (MOUDs) among youth and young adults has ensued, resulting in an increasing number of MOUD treatment pathways for this vulnerable population. METHODS: This secondary data analysis seeks to characterize patient and provider preferences for MOUD treatment pathways, and test for associations between baseline MOUD treatment preferences and opioid use and treatment adherence outcomes. Participants included 288 youth and young adults (age 15-21 years), recruited from a residential treatment program in Maryland. The study assessed patient preferences at baseline (n = 253) and provider preferences at patient treatment discharge (n = 224). Mixed-effects negative binomial regression models were conducted for opioid use outcomes, and logistic regressions were conducted for treatment adherence outcomes. RESULTS: Results indicate that congruence of treatment with patients' (Incidence Rate Ratio [IRR] = 0.65) and providers' (IRR = 0.66) preferences was significantly associated with reduced self-reported days of opioid use in the past 90 days, but only for patients receiving extended-release naltrexone (XR-NTX). Results also indicated that patients were less likely to switch medication treatment pathways (e.g., from XR-NTX to buprenorphine, or vice versa) during follow-up if they received their preferred treatment at baseline, a finding which held true for both XR-NTX (Odds Ratio [OR] = 0.32) and buprenorphine (OR = 0.22). CONCLUSIONS: Receipt of MOUD congruent with patient and provider preferences was associated with reduced opioid use and greater treatment adherence in this sample of youth and young adults with OUD.

Association of ever use of e-cigarettes with health and lifestyle variables among young adults: a Canadian health measure survey study.

Research suggests that vaping raises oxidative stress levels and has been implicated in poor mental health. The objective of this study is to assess cross-sectional associations between quality of life (QOL) indicators and e-cigarette (EC) use in young Canadian adults. We used data from the 2016-2017 Canadian Health Measures Survey. We compared physical activity (daily steps), physiological measurements (high-density lipoprotein for cholesterol level), self-perceived life stress, mental health, and QOL between ever-use EC users and non-users. Multivariable binary or ordinal logistic regressions were used to calculate odds ratios (OR) with 95% confidence intervals (CI). Analyses included 905 participants (15-30 years) with 115 (12.7%) reporting EC use and 790 non-users. After adjusting for confounders, compared to non-users, EC users had significantly higher odds of being physically active (OR = 2.19, 95%CI: 1.14-4.20) but also with self-reported extreme life stress (OR = 2.68, 95%CI: 1.45-4.92). Albeit statistically non-significant, EC users also had higher odds of poorer QOL (OR = 1.12, 95%CI: 0.64-1.95). No statistically significant interactions between EC use, cigarette smoking, cannabis consumption and health outcomes were observed. CONCLUSION: Our study found that EC use was independently and significantly associated with increased odds of life stress and an indication of poorer QOL. Ongoing surveillance on young EC users is important to measure the long-term impact of vaping on their physical, mental health and quality of life to target for interventions. WHAT IS KNOWN: • E-cigarette use has been associated with high-risk behaviours and adverse mental health outcomes, such as depression and anxiety. WHAT IS NEW: • E-cigarette users had significantly higher odds of being physically active and higher amounts of life stress.