Citations

AbstractBackgroundDiagnosing gastroesophageal reflux disease (GERD) can be challenging given varying symptom presentations, and complex multifactorial pathophysiology. The gold standard for GERD diagnosis is esophageal acid exposure time (AET) measured by pH‐metry. A variety of additional diagnostic tools are available. The goal of this consensus was to assess the individual merits of GERD diagnostic tools based on current evidence, and provide consensus recommendations following discussion and voting by experts.MethodsThis consensus was developed by 15 experts from nine countries, based on a systematic search of the literature, using GRADE (grading of recommendations, assessment, development and evaluation) methodology to assess the quality and strength of the evidence, and provide recommendations regarding the diagnostic utility of different GERD diagnosis tools, using AET as the reference standard.Key ResultsA proton pump inhibitor (PPI) trial is appropriate for patients with heartburn and no alarm symptoms, but nor for patients with regurgitation, chest pain, or extraesophageal presentations. Severe erosive esophagitis and abnormal reflux monitoring off PPI are clearly indicative of GERD. Esophagram, esophageal biopsies, laryngoscopy, and pharyngeal pH monitoring are not recommended to diagnose GERD. Patients with PPI‐refractory symptoms and normal endoscopy require reflux monitoring by pH or pH‐impedance to confirm or exclude GERD, and identify treatment failure mechanisms. GERD confounders need to be considered in some patients, pH‐impedance can identify supragrastric belching, impedance‐manometry can diagnose rumination.ConclusionsErosive esophagitis on endoscopy and abnormal pH or pH‐impedance monitoring are the most appropriate methods to establish a diagnosis of GERD. Other tools may add useful complementary information.

Abstract Sweet's syndrome (SS) is a neutrophilic dermatosis characterised by the acute onset of erythematous papules or plaques and a constellation of symptoms including fever, leucocytosis, and histopathology demonstrating nodular, pustular, or diffuse infiltrate of neutrophils with marked papillary oedema. SS can be a manifestation of inflammatory bowel disease and often coincides with periods of disease flares. Only a few cases of SS associated with ulcerative colitis are reported in the literature, and no cases have involved pulmonary manifestations in the paediatric population. We present a case of a 14-year-old girl presenting with new onset ulcerative colitis requiring emergent colectomy with subsequent development of pulmonary SS. Treatment consisted of intravenous and oral corticosteroids and dapsone. SS should be considered in the differential diagnosis of prolonged fever with cutaneous involvement and systemic symptoms. Special consideration should be given to paediatric patients with extracutaneous manifestations, particularly pulmonary involvement.

Abstract Cerebrospinal fluid (CSF) is a clear, transparent fluid derived from blood plasma that protects the brain and spinal cord against mechanical shock, provides buoyancy, clears metabolic waste and transports extracellular components to remote sites in the brain. Given its contact with the brain and the spinal cord, CSF is the most informative biofluid for studies of the central nervous system (CNS). In addition to other components, CSF contains extracellular vesicles (EVs) that carry bioactive cargoes (e.g., lipids, nucleic acids, proteins), and that can have biological functions within and beyond the CNS. Thus, CSF EVs likely serve as both mediators of and contributors to communication in the CNS. Accordingly, their potential as biomarkers for CNS diseases has stimulated much excitement for and attention to CSF EV research. However, studies on CSF EVs present unique challenges relative to EV studies in other biofluids, including the invasive nature of CSF collection, limited CSF volumes and the low numbers of EVs in CSF as compared to plasma. Here, the objectives of the International Society for Extracellular Vesicles CSF Task Force are to promote the reproducibility of CSF EV studies by providing current reporting and best practices, and recommendations and reporting guidelines, for CSF EV studies. To accomplish this, we created and distributed a world‐wide survey to ISEV members to assess methods considered ‘best practices’ for CSF EVs, then performed a detailed literature review for CSF EV publications that was used to curate methods and resources. Based on responses to the survey and curated information from publications, the CSF Task Force herein provides recommendations and reporting guidelines to promote the reproducibility of CSF EV studies in seven domains: (i) CSF Collection, Processing, and Storage; (ii) CSF EV Separation/Concentration; (iii) CSF EV Size and Number Measurements; (iv) CSF EV Protein Studies; (v) CSF EV RNA Studies; (vi) CSF EV Omics Studies and (vii) CSF EV Functional Studies.

AbstractBackgroundMicroglia, the resident brain immune cells, play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA‐155 (miR‐155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer’s disease (AD) pathogenesis remains unclear.MethodsWe used RNAseq and immunohistochemistry (n = 6‐8 per sex per group) to investigate the gene expression profile and AD pathology. We further utilized single‐cell RNAseq (n = 5 per group) to identify microglial clusters. Whole‐tissue proteomics (n = 4) was applied to detect the protein changes in brain milieu. Moreover, we used spontaneous alternation and forced alternation tests to evaluate the cognition (n = 33‐36).ResultWe report that microglial deletion of miR‐155 induces a pre‐MGnD activation state via interferon‐g (IFNg) signaling and blocking IFNg signaling attenuates MGnD induction and microglial phagocytosis. Single‐cell RNAseq analysis of microglia from AD mouse model identifies Stat1 and Clec2d as pre‐MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque‐associated synaptic degradation, and improves cognition.ConclusionOur study demonstrates a novel miR‐155‐mediated regulatory mechanism of MGnD and the beneficial role of IFNg‐responsive pre‐MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR‐155 and IFNg as potential therapeutic targets for AD.

AbstractBackgroundAPOE ε4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD).MethodGeneration of CX3CR1‐CREERT2 mice crossed to APOE‐KI(E3 and E4)fl/fl: APP/PS1 and APOE‐KI(E3 and E4)fl/fl: P301S mice. Microglia and astrocytes were isolated and sequenced using either bulk RNA‐seq (MGnD‐Paradigm) or single‐cell RNA‐seq. Crosstalk between cells was determined using the NichenetR database and validated using 1) recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) adoptive transfer of microglia, from APOE3‐KI, APOE4‐KI, and APOE4‐cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes. Validation in the brain of AD donors carrying the APOE e3/3 and e3/4 alleles.ResultHere we show, in mice and in humans, a negative role of microglial APOE4 in the induction of MGnD response to neurodegeneration. Deletion of microglial APOE4 restores MGnD phenotype, associated with neuroprotection in P301S tau transgenic mice, and decreases pathology in APP/PS1 mice. MGnD‐astrocyte crosstalk associated with b‐amyloid (Ab) plaque encapsulation and clearance is mediated via Lgals3 signaling following microglial APOE4 deletion. In the brain of AD donors carrying the APOE ε4 allele, we found a sex‐dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, as compared to APOE ε3/3 carriers. Mechanistically, APOE4‐mediated induction of ITGB8‐TGFb signaling impairs MGnD response via upregulation of TGFb‐mediated microglial homeostatic checkpoints, including INPP5D. Microglial deletion of Inpp5d restores MGnD‐astrocyte crosstalk and facilitates plaque clearance in APP/PS1 mice. Genetic and pharmacological blocking of ITGB8‐TGFb signaling enhanced MGnD response associated with increased plaque clearance in AD mice.ConclusionWe identify the microglial APOE4‐ITGB8‐TGFb pathway as a negative regulator of microglia‐astrocyte response to AD pathology, and restoring MGnD phenotype via blocking ITGB8‐TGFb signaling may provide new molecular targets to modulate and restore functional microglia in AD.

Abstract Introduction Obesity is a global health crisis that has been growing over the past few decades. The economic burden associated with obesity is substantial as it is associated with multiple disabling chronic diseases, such as cardiovascular disease, certain cancers, osteoarthritis, chronic pain, and mental illness. Obesity is known to be a risk factor for sexual dysfunction in men, but this association is less well understood in women. Aims To provide a narrative review of the available literature on the relationship between overweight/obesity and female sexual dysfunction, elaborate on the possible mechanisms explaining this association, and discuss the effects of weight loss on sexual function in those with obesity. Methods A search of the medical literature was carried out in PubMed and Medline, focusing on original research and systematic reviews of original research on obesity and sexual function in women. Results The relationship between obesity and female sexual function is not consistent across studies. While women with obesity are more likely to have worse sexual function and avoid sexual activity, many studies have failed to identify these associations. Lifestyle changes resulting in weight loss lead to better sexual function, and bariatric surgery has been shown to improve sexual function in the first couple of years following the procedure; yet, the long-term effects of weight loss and bariatric surgery are still uncertain. Conclusions The evidence on the relationship between obesity and female sexual function is mixed. Nevertheless, weight loss has been shown to improve sexual function in women with obesity. The impact of weight loss medications and the long-term effect of bariatric surgery on female sexual function require further study.

Introduction: Warfarin is a commonly prescribed anticoagulant for treating atrial fibrillation, mechanical valves, and venous thromboembolism. Warfarin dose management remains challenging due to dosing variability between patients and warfarin’s narrow therapeutic window. Time in therapeutic range (TTR) is critical to warfarin’s safety and efficacy, but TTR typically remains low (40-50%) in community practices. Specialized anticoagulation clinics and protocolized approaches can increase TTR but have great administrative burdens and health care costs. Aim: To develop standardized optimal warfarin dose decision support using a machine learning model based on time series anticoagulation data and patient demographic characteristics Methods: The dataset included 12,497 warfarin patients monitored in the anticoagulation tracker of electronic medical records across the Mayo Clinic Enterprise. The dataset contained time series anticoagulation data (warfarin dose, INR, INR target range) and patient demographic characteristics. We implemented an offline deep reinforcement learning model (DRL) to predict the cumulative warfarin dose for the days until the next INR test based on a patient’s historical anticoagulation data. Prior approaches utilized traditional supervised learning methods such as regression or Long Short Term Memory (LSTM) neural networks to approximate a function mimicking the behavior of the training data. On the other hand, DRL learned an optimal dosing policy through continuous interaction and feedback from the training data. The key advantage of DRL is the model can learn to behave differently (and potentially better) for suboptimal clinical states in the data such as overdosing or underdosing. To evaluate the DRL model we compared the predicted warfarin doses with the physician-prescribed doses Results: DRL model’s prediction accuracy was 96.96%, outperforming our implementation of a baseline LSTM model with a prediction accuracy of 70.58%. Further evaluation of the DRL model indicated that the model correctly adjusted the warfarin dose at time steps when patients had out-of-range INRs. Conclusions: Offline deep reinforcement learning demonstrates potential in supporting warfarin dose management to maximize TTR.

Abstract Bone pain is a well-known quality-of-life detriment for individuals with prostate cancer and is associated with survival. This study expands previous work into racial differences in multiple patient-reported dimensions of pain and the association between baseline and longitudinal pain and mortality. This is a prospective cohort study of individuals with newly diagnosed advanced prostate cancer enrolled in the International Registry for Men with Advanced Prostate Cancer (IRONMAN) from 2017 to 2023 at U.S. sites. Differences in four pain scores at study enrollment by race were investigated. Cox proportional hazards models and joint longitudinal survival models were fit for each of the scale scores to estimate HRs and 95% confidence intervals (CI) for the association with all-cause mortality. The cohort included 879 individuals (20% self-identifying as Black) enrolled at 38 U.S. sites. Black participants had worse pain at baseline compared with White participants, most notably a higher average pain rating (mean 3.1 vs. 2.2 on a 10-point scale). For each pain scale, higher pain was associated with higher mortality after adjusting for measures of disease burden, particularly for severe bone pain compared with no pain (HR, 2.47; 95% CI: 1.44–4.22). The association between pain and all-cause mortality was stronger for participants with castration-resistant prostate cancer compared with those with metastatic hormone-sensitive prostate cancer and was similar among Black and White participants. Overall, Black participants reported worse pain than White participants, and more severe pain was associated with higher mortality independent of clinical covariates for all pain scales. Significance: Black participants with advanced prostate cancer reported worse pain than White participants, and more pain was associated with worse survival. More holistic clinical assessments of pain in this population are needed to determine the factors upon which to intervene to improve quality of life and survivorship, particularly for Black individuals.

PURPOSE There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. METHODS We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. RESULTS Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2–enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. CONCLUSION This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.