Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology.

Aging is a major risk factor for neurodegenerative diseases, and coronavirus disease 2019 (COVID-19) is linked to severe neurological manifestations. Senescent cells contribute to brain aging, but the impact of virus-induced senescence on neuropathologies is unknown. Here we show that senescent cells accumulate in aged human brain organoids and that senolytics reduce age-related inflammation and rejuvenate transcriptomic aging clocks. In postmortem brains of patients with severe COVID-19 we observed increased senescent cell accumulation compared with age-matched controls. Exposure of human brain organoids to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced cellular senescence, and transcriptomic analysis revealed a unique SARS-CoV-2 inflammatory signature. Senolytic treatment of infected brain organoids blocked viral replication and prevented senescence in distinct neuronal populations. In human-ACE2-overexpressing mice, senolytics improved COVID-19 clinical outcomes, promoted dopaminergic neuron survival and alleviated viral and proinflammatory gene expression. Collectively our results demonstrate an important role for cellular senescence in driving brain aging and SARS-CoV-2-induced neuropathology, and a therapeutic benefit of senolytic treatments.

Pneumococcal Vaccination Recommendation and Completion Rates Among Patients With Inflammatory Bowel Disease and Barriers to Vaccination.

BACKGROUND: Guidelines for inflammatory bowel disease (IBD) patients receiving immunosuppression encouraged both the pneumococcal polysaccharide vaccine (PPSV23) and the pneumococcal conjugate vaccine (PCV13). We aimed to evaluate which pneumococcal vaccines are recommended and administered, and to understand provider and IBD patient knowledge regarding pneumococcal vaccinations. METHODS: We performed a retrospective, cross-sectional analysis of 357 adult IBD patients on immunosuppression in our health care system. Patient demographics and clinical characteristics were collected. The primary outcome was rate of documented vaccinations recommended by providers; the secondary outcome was rate of receipt of the vaccines. We identified factors associated with receipt of any pneumococcal vaccine through multivariable logistic regression. We also performed provider and IBD patient surveys to understand provider and patient knowledge regarding pneumococcal vaccines. We used χ 2 and Fisher exact tests to assess survey responses. RESULTS: Fifty seven percent of IBD patients had any pneumococcal vaccination recommended and 35% had recommendations for both PPSV23 and PCV13. Forty percent received any pneumococcal vaccine and 18% received both vaccines. In multivariable analyses, increasing age (adjusted odds ratio: 1.03, 95% CI: 1.01-1.05) was associated with receipt of any pneumococcal vaccine, after adjusting for gender, race, insurance, disease activity, and time seen in our gastroenterology clinics. In the survey study, on average, 59% of providers correctly answered questions regarding pneumococcal vaccination indications. CONCLUSION: In our health care system, while recommendation for any pneumococcal vaccination was >50%, receipt of both PPSV23 and PCV13 was low. Simplified vaccine regimens (ie, PCV20) will likely improve vaccination rates.

A Prospective Study to Examine Responsiveness and Minimally Important Differences (MIDs) for the CLEFT-Q Scales Following Three Cleft-Specific Operations.

The aim of this study was to examine internal responsiveness and estimate minimally important differences (MIDs) for CLEFT-Q scales.In this prospective cohort study, participants completed the CLEFT-Q appearance and health-related quality of life (HRQL) scales before and six months after cleft-related surgery.Seven cleft centres in Canada, USA and UK participated.Patients were ages 8-29 years with CL/P.Patients underwent rhinoplasty, orthognathic or cleft lip scar revision surgery.Internal responsiveness was examined using Cohen's d effect sizes (ESs) based on the following interpretation: 0.20-0.49 small, 0.50-0.79 moderate and ≥ 0.80 large. MIDs were estimated using two distribution-based approaches.Participants had a rhinoplasty (n = 31), orthognathic (n = 21) or cleft lip scar revision (n = 18) surgery. Most participants were males (56%) and aged 8-11 years (41%). Following rhinoplasty, ESs were larger for the nose (0.92, p = 0.001) and nostrils (0.94, p < 0.001) scales than for the face scale (0.51, p = 0.003). MIDs ranged between 6.2-10.4. For orthognathic surgery, larger ES was observed for the jaws scale (1.80, p < 0.001) compared with the teeth (1.16, p < 0.001), face (1.15, p = 0.001) and lips (0.94, p < 0.001) scales. MIDs ranged between 5.9-14.4. In the cleft lip scar revision sample, the largest ES was observed for the nose scale (0.76, p = 0.03), followed by lips (0.58, p = 0.009) and cleft lip scar (0.50, p = 0.043) scales. MIDs ranged between 6.4-12.3.CLEFT-Q detected change in key outcomes for three cleft-specific surgeries, providing evidence of its responsiveness. Estimated MIDs will aid in interpreting this PROM.

Diversity, equity, and inclusion in gastroenterology and hepatology: a survey of where we stand.

BACKGROUND & AIMS: In the setting of increasing attention to representation in medicine, we aimed to assess current perspectives of racial and ethnic workforce diversity and health care disparities among gastroenterology (GI) and hepatology professionals in the United States. METHODS: We developed and administered a 33-item electronic cross-sectional survey to members of 5 national GI and hepatology societies. Survey items were organized into thematic modules and solicited perspectives on racial and ethnic workforce diversity, health care disparities in GI and hepatology, and potential interventions to enhance workforce diversity and improve health equity. RESULTS: Of the 1219 survey participants, 62.3% were male, 48.7% were non-Hispanic White, and 19.9% were from backgrounds underrepresented in medicine. The most frequently reported barriers to increasing racial and ethnic diversity in GI and hepatology were insufficient representation of underrepresented racial and ethnic minority groups in the education and training pipeline (n = 431 [35.4%]), in professional leadership (n = 340 [27.9%]), and among practicing GI and hepatology professionals (n = 324 [26.6%]). Suggested interventions were to increase career mentorship opportunities (n = 545 [44.7%]), medical student opportunities (n = 520 [42.7%]), and program and professional society leadership roles for underrepresented racial and ethnic minority groups (n = 473 [38.8%]). CONCLUSIONS: Our survey explored imperative and timely perspectives on racial and ethnic representation and health equity among professionals in GI and hepatology. The findings should inform future interventions to address workforce diversity and establish priorities toward improving health equity, ultimately serving as a springboard for professional societies, academic institutions, and other organizations that aim to increase diversity, equity, and inclusion in our field.

Diversity, Equity, and Inclusion in Gastroenterology and Hepatology: A Survey of Where We Stand.

BACKGROUND & AIMS: In the setting of increasing attention to representation in medicine, we aimed to assess current perspectives of racial and ethnic workforce diversity and health care disparities among gastroenterology (GI) and hepatology professionals in the United States. METHODS: We developed and administered a 33-item electronic cross-sectional survey to members of 5 national GI and hepatology societies. Survey items were organized into thematic modules and solicited perspectives on racial and ethnic workforce diversity, health care disparities in GI and hepatology, and potential interventions to enhance workforce diversity and improve health equity. RESULTS: Of the 1219 survey participants, 62.3% were male, 48.7% were non-Hispanic White, and 19.9% were from backgrounds underrepresented in medicine. The most frequently reported barriers to increasing racial and ethnic diversity in GI and hepatology were insufficient representation of underrepresented racial and ethnic minority groups in the education and training pipeline (n = 431 [35.4%]), in professional leadership (n = 340 [27.9%]), and among practicing GI and hepatology professionals (n = 324 [26.6%]). Suggested interventions were to increase career mentorship opportunities (n = 545 [44.7%]), medical student opportunities (n = 520 [42.7%]), and program and professional society leadership roles for underrepresented racial and ethnic minority groups (n = 473 [38.8%]). CONCLUSIONS: Our survey explored imperative and timely perspectives on racial and ethnic representation and health equity among professionals in GI and hepatology. The findings should inform future interventions to address workforce diversity and establish priorities toward improving health equity, ultimately serving as a springboard for professional societies, academic institutions, and other organizations that aim to increase diversity, equity, and inclusion in our field.

Diversity, equity, and inclusion in gastroenterology and hepatology: A survey of where we stand.

BACKGROUND AND AIMS: In the setting of increasing attention to representation in medicine, we aimed to assess current perspectives of racial and ethnic workforce diversity and health care disparities among gastroenterology (GI) and hepatology professionals in the United States. APPROACH AND RESULTS: We developed and administered a 33-item electronic cross-sectional survey to members of five national GI and hepatology societies. Survey items were organized into thematic modules and solicited perspectives on racial and ethnic workforce diversity, health care disparities in GI and hepatology, and potential interventions to enhance workforce diversity and improve health equity. Of the 1219 survey participants, 62.3% were male, 48.7% were non-Hispanic White, and 19.9% were from backgrounds underrepresented in medicine. The most frequently reported barriers to increasing racial and ethnic diversity in GI and hepatology were insufficient representation of underrepresented racial and ethnic minority groups in the education and training pipeline (n = 431 [35.4%]), in professional leadership (n = 340 [27.9%]), and among practicing GI and hepatology professionals (n = 324 [26.6%]). Suggested interventions were to increase career mentorship opportunities (n = 545 [44.7%]), medical student opportunities (n = 520 [42.7%]), and program and professional society leadership roles for underrepresented racial and ethnic minority groups (n = 473 [38.8%]). CONCLUSIONS: Our survey explored imperative and timely perspectives on racial and ethnic representation and health equity among professionals in GI and hepatology. The findings should inform future interventions to address workforce diversity and establish priorities toward improving health equity, ultimately serving as a springboard for professional societies, academic institutions, and other organizations that aim to increase diversity, equity, and inclusion in our field.

Diversity, Equity, and Inclusion in Gastroenterology and Hepatology: A Survey of Where We Stand.

INTRODUCTION: In the setting of increasing attention to representation in medicine, we aimed to assess current perspectives of racial and ethnic workforce diversity and health care disparities among gastroenterology (GI) and hepatology professionals in the United States. METHODS: We developed and administered a 33-item electronic cross-sectional survey to members of 5 national GI and hepatology societies. Survey items were organized into thematic modules and solicited perspectives on racial and ethnic workforce diversity, health care disparities in GI and hepatology, and potential interventions to enhance workforce diversity and improve health equity. RESULTS: Of the 1,219 survey participants, 62.3% were male, 48.7% were non-Hispanic White, and 19.9% were from backgrounds underrepresented in medicine. The most frequently reported barriers to increasing racial and ethnic diversity in GI and hepatology were insufficient representation of underrepresented racial and ethnic minority groups in the education and training pipeline (n = 431 [35.4%]), in professional leadership (n = 340 [27.9%]), and among practicing GI and hepatology professionals (n = 324 [26.6%]). Suggested interventions were to increase career mentorship opportunities (n = 545 [44.7%]), medical student opportunities (n = 520 [42.7%]), and program and professional society leadership roles for underrepresented racial and ethnic minority groups (n = 473 [38.8%]). DISCUSSION: Our survey explored imperative and timely perspectives on racial and ethnic representation and health equity among professionals in GI and hepatology. The findings should inform future interventions to address workforce diversity and establish priorities toward improving health equity, ultimately serving as a springboard for professional societies, academic institutions, and other organizations that aim to increase diversity, equity, and inclusion in our field.

The global incidence of bullous pemphigoid: a systematic review and meta-analysis.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering disorder that mainly affects older people. Although the disease is associated with considerable morbidity and mortality, the burden of disease worldwide is unclear. OBJECTIVES: The study aim is to pool the global incidence of BP and determine whether this varies according to geographic area, age group, setting and study quality. METHODS: Ovid MEDLINE, Ovid Embase and grey literature were systematically searched on 7 April 2020. Two reviewers independently screened, extracted data and appraised each study's quality using the Joanna Briggs Institute critical appraisal tool. Two domains, indicative of selection and survey bias, were used to identify high-quality studies. The cumulative incidence was standardized to 1 year and pooled in a random-effects meta-analysis. Subgroup and sensitivity analyses were conducted. RESULTS: Twenty-seven studies were identified, of which 23 provided cumulative incidence and four provided incidence rates. The cumulative incidence of BP was 8·2 [95% confidence interval (CI) 4·8-13.7] per million people whereas the incidence rate was 34·2 (95% CI 19·2-60·7) per million person-years. Of the continents that contributed more than one study, the cumulative incidence was 10·3 (95% CI 5·8-18·2) and 5·6 (95% CI 3·5-9·0) per million people in Europe and Asia, respectively. The incidence was highest in studies including adults only (n = 2), in population-based studies (n = 9) and in more recent years. The cumulative incidence was higher (13·3 per million people, 95% CI 6·0-29·5) when restricting the analysis to higher-quality studies (n = 11). High heterogeneity (I2 > 82%) was observed across all pooled estimates. CONCLUSIONS: The incidence of BP varies globally, is generally low but appears to be increasing over time. The burden of disease is likely to be underestimated.

Inhibition of the cGAS-STING pathway ameliorates the premature senescence hallmarks of Ataxia-Telangiectasia brain organoids.

Ataxia-telangiectasia (A-T) is a genetic disorder caused by the lack of functional ATM kinase. A-T is characterized by chronic inflammation, neurodegeneration and premature ageing features that are associated with increased genome instability, nuclear shape alterations, micronuclei accumulation, neuronal defects and premature entry into cellular senescence. The causal relationship between the detrimental inflammatory signature and the neurological deficiencies of A-T remains elusive. Here, we utilize human pluripotent stem cell-derived cortical brain organoids to study A-T neuropathology. Mechanistically, we show that the cGAS-STING pathway is required for the recognition of micronuclei and induction of a senescence-associated secretory phenotype (SASP) in A-T olfactory neurosphere-derived cells and brain organoids. We further demonstrate that cGAS and STING inhibition effectively suppresses self-DNA-triggered SASP expression in A-T brain organoids, inhibits astrocyte senescence and neurodegeneration, and ameliorates A-T brain organoid neuropathology. Our study thus reveals that increased cGAS and STING activity is an important contributor to chronic inflammation and premature senescence in the central nervous system of A-T and constitutes a novel therapeutic target for treating neuropathology in A-T patients.

Toxic epidermal necrolysis-like lupus.

Toxic epidermal necrosis (TEN)-like lupus is a rare condition characterized by epidermal loss and mucosal ulceration occurring in patients with acute severe flares of systemic lupus erythematosus. The clinical picture may mimic drug-induced Stevens-Johnson syndrome/TEN; however, the absence of a suitable culprit drug, and the context of acute lupus point to the correct diagnosis. In a case series of three patients, further discriminating features included a slower onset of epidermal loss, more limited mucosal ulceration and a lack of ocular involvement when compared with drug-induced TEN. Histology may show similar features, including basal layer vacuolation, apoptosis and full-thickness epidermal necrosis. Patients with TEN-like lupus may have additional features of lupus, and a lupus band on direct immunofluorescence. It is important to identify this condition correctly, so that these patients can be appropriately managed with early input from Rheumatologists and prompt treatment with high-dose combined immunosuppressant therapy.

Using electronic health records to inform trial feasibility in a rare autoimmune blistering skin disease in England.

BACKGROUND: Trials of novel agents are required to improve the care of patients with rare diseases, but trial feasibility may be uncertain due to concerns over insufficient patient numbers. We aimed to determine the size of the pool of potential participants in England 2015-2017 for trials in the autoimmune blistering skin disease bullous pemphigoid. METHODS: The size of the pool of potential participants was estimated using routinely collected healthcare data from linked primary care (Clinical Practice Research Datalink; CPRD) and secondary care (Hospital Episode Statistics; HES) databases. Thirteen consultant dermatologists were surveyed to determine the likelihood that a patient would be eligible for a trial based on the presence of cautions or contra-indications to prednisolone use. These criteria were applied to determine how they influenced the potential pool of participants. RESULTS: Extrapolated to the population of England, we would expect approximately 10,800 (point estimate 10,747; 95% CI 7191 to 17,239) new cases of bullous pemphigoid to be identified in a three-year period. For a future trial involving oral prednisolone (standard care), the application of cautions to its use as exclusion criteria would result in approximately 365 potential participants unlikely to be recruited, a further 5332 could be recruited with caution, and 5104 in whom recruitment is still possible. 11-17% of potential participants may have pre-existing dementia and require an alternative consent process. CONCLUSIONS: Routinely collected electronic health records can be used to inform the feasibility of clinical trials in rare diseases, such as whether recruitment is feasible nationally and how long recruitment might take to meet recruitment targets. Future trials of bullous pemphigoid in England may use the data presented to inform trial design, including eligibility criteria and consent processes for enrolling people with dementia.

Incidence, prevalence and mortality of bullous pemphigoid in England 1998-2017: a population-based cohort study.

BACKGROUND: A rising incidence and high mortality were found for bullous pemphigoid (BP) over a decade ago in the UK. Updated estimates of its epidemiology are required to understand the healthcare needs of an ageing population. OBJECTIVES: To determine the incidence, prevalence and mortality rates of BP in England from 1998 to 2017. METHODS: We conducted a cohort study of longitudinal electronic health records using the Clinical Practice Research Datalink and linked Hospital Episode Statistics. Incidence was calculated per 100 000 person-years and annual point prevalence per 100 000 people. Multivariate analysis was used to determine incidence rate ratios by sociodemographic factors. Mortality was examined in an age-, sex- and practice-matched cohort, using linked Office of National Statistics death records. Hazard ratios (HRs) were stratified by matched set. RESULTS: The incidence was 7·63 [95% confidence interval (CI) 7·35-7·93] per 100 000 person-years and rose with increasing age, particularly for elderly men. The annual increase in incidence was 0·9% (95% CI 0·2-1·7). The prevalence almost doubled over the observation period, reaching 47·99 (95% CI 43·09-53·46) per 100 000 people and 141·24 (95% CI 125·55-158·87) per 100 000 people over the age of 60 years. The risk of all-cause mortality was highest in the 2 years after diagnosis (HR 2·96; 95% CI 2·68-3·26) and remained raised thereafter (HR 1·54; 95% CI 1·36-1·74). CONCLUSIONS: We report a modest increase in the incidence rate of BP, but show that the burden of disease in the elderly population is considerable. Mortality is high, particularly in the first 2 years after diagnosis.

What's new in atopic eczema? An analysis of systematic reviews published in 2018. Part 1: prevention and topical therapies.

This review is part of a series of annual updates that summarize the evidence base for atopic eczema (AE). The aim is to provide a succinct guide for clinicians on the key findings from 14 systematic reviews on the prevention and topical treatment of AE published or indexed in 2018. Various supplements, including long-chain polyunsaturated fatty acids, vitamin D and the probiotic Lactobacillus rhamnosus GG, given prenatally and postnatally, have not been shown to prevent AE in infants, although mixed strains of probiotics may decrease the risk of AE if given to the mother during pregnancy and to the infant for the first 6 months of life. In the postnatal period, there is no evidence that hydrolysed formula, compared with cow's milk formula (CMF), reduces the risk of AE in partially breastfed infants. However, weak evidence suggests that a specific partially hydrolysed whey formula decreases the risk of AE compared with CMF. No specific skin practices can be recommended to reduce the eczema risk in healthy term babies. There is weak evidence of a low risk of reversible hypothalamic-pituitary-adrenal axis suppression following 2-4 weeks of treatment with low-potency topical steroids, and conflicting evidence as to whether bleach bathing affects skin flora or AE severity. A single study demonstrated that the topical Janus kinase inhibitor tofacitinib at 2% significantly reduces the Eczema Area and Severity Index compared with vehicle. Topical naltrexone cream 1% improves pruritus (measured using a visual analogue scale) by 30% more than placebo. There is weak evidence that topical alternative therapies, including antioxidants, micronutrients and some herbal medicines, may improve AE.

Endoscopic Retrieval of Ingested Bags Following a Multidisciplinary Approach.

Foreign body ingestion encompasses a broad variety of ingested objects, clinical presentations, and treatment approaches, with a wide spectrum of severity and urgency. Herein, we describe the case of a 29-year-old man presenting with abdominal pain following the ingestion of empty plastic bags. Monitoring with serial imaging demonstrated the bags in the stomach 18 hours post-ingestion. Given this finding and worsening pain, a multidisciplinary decision was made to pursue endoscopic retrieval. This case uniquely demonstrates the benefit of rapid multidisciplinary meetings in an emergency room setting leading to the successful removal of ingested bags from the gastric body. While the phenomenon of "body stuffing," or hasty ingestion of bagged drugs to evade law enforcement has become common, there are few reports of endoscopic removal for such cases or those involving empty bag ingestion. This case highlights the importance of repeat abdominal imaging and early endoscopic intervention for foreign objects such as bags as they may be difficult to visualize on imaging, making it unreliable to track their progress. Dynamic imaging should be obtained, with computed tomography (CT) being the gold standard. This report represents the first case of empty bag ingestion, highlighting tenets of timely multidisciplinary management and considerations in endoscopic retrieval as a minimally invasive technique when a patient presents in the emergency department following bag ingestion.

What's new in atopic eczema? An analysis of systematic reviews published in 2018. Part 2: systemic therapies.

This review forms part of an annual update series on atopic eczema (AE), where systematic reviews (SRs) are gathered and appraised to provide a summary of key recent research findings. The focus of this article is systemic therapies used in AE, while a review on prevention and topical therapies is provided in Part 1. In total, 17 SRs on various systemic treatments used in AE were first published or indexed in 2018. There is a lack of evidence to support vitamin D supplementation, montelukast and naltrexone in AE treatment. The adverse effects of systemic corticosteroids are the main barrier to their use, and there is also a lack of data to determine the optimal delivery and duration of treatment with them. Of other immunosuppressants, ciclosporin has the most robust evidence of efficacy. Biologic therapies in AE treatment are being increasingly investigated, and to date, the greatest quantity of data and evidence of efficacy relates to dupilumab. The most commonly reported adverse effects are injection-site reactions and conjunctivitis. Other biologics showing some evidence of efficacy include nemolizumab, lebrikizumab and tralokinumab, although further data are needed. There are currently insufficient data on oral small molecules, including Janus kinase inhibitors, in the treatment of AE. A Cochrane review on probiotics showed no significant benefit, and SRs and meta-analyses on complementary and alternative medicines, including probiotics, in paediatric AE demonstrated significant heterogeneity, thereby limiting their interpretation. This summary of recent SRs provides up-to-date evidence for clinicians on systemic therapies in AE.

Pancreatic Heterotopia Found in the Gastric Antrum Mistaken for Malignancy.

Pancreatic heterotopia is a rare and often incidental finding in clinical practice. The term refers to pancreatic tissue distinct from the normal pancreas and with its own ductal and vascular supply. Usually asymptomatic, ectopic tissue is still prone to infection and may cause clinical complications when mistaken for malignancy or abscess. We describe a 32-year-old woman who presented with epigastric discomfort, initially thought to be a gastric outlet mass concerning for gastric malignancy vs an intraabdominal infection. She was eventually found to have an umbilicated submucosal lesion in the gastric antrum consistent with pancreatic heterotopia. Given the young age and sex of the patient, the differential diagnosis remained broad, underscoring the high risk of mismanagement of pancreatic heterotopia secondary to infrequency of this condition as a presenting diagnosis.