Search

Background & Aims Patient symptom reporting often does not correlate with the pathophysiological markers of esophageal disease, including eosinophilic esophagitis (EoE). Esophageal hypervigilance and symptom-specific anxiety are emerging as important considerations in understanding symptom reporting. As such, we aimed to conduct the first study of these constructs in EoE. Methods A retrospective review of an EoE patient registry was conducted and included eosinophils per high power field (from esophagogastroduodenoscopy biopsy: proximal, distal), endoscopic reference score, distal distensibility plateau (functional luminal imaging probe), Brief Esophageal Dysphagia Questionnaire, Visual Dysphagia Question of EoE Activity Index, Northwestern Esophageal Quality of Life scale, and the Esophageal Hypervigilance and Anxiety Scale. Correlational and regression analyses evaluated relationships of hypervigilance and anxiety with Brief Esophageal Dysphagia Questionnaire, Visual Dysphagia Question of EoE Activity Index, and Northwestern Esophageal Quality of Life scale when controlling for histology and endoscopic severity. Results One hundred and three patients had complete data, 69.9% were male, and the mean (SD) age was 40.66 (13.85) years. Forty-one percent had elevated dysphagia and 46% had elevated hypervigilance and anxiety. Esophageal symptom–specific anxiety emerged as the most important predictor of Brief Esophageal Dysphagia Questionnaire severity (44.8% of the variance), Visual Dysphagia Question of EoE Activity Index severity (26%), and poor health-related quality of life (HRQoL) (55.3%). Hypervigilance was also important, but to a lesser extent. Pathophysiological variables did not significantly predict symptoms or HRQoL. Recent food impaction can predict symptom-specific anxiety and proton pump inhibitor use can reduce hypervigilance. Conclusions Hypervigilance and symptom-specific anxiety are important for our understanding of self-reported patient outcomes in EoE. These processes outweigh endoscopic and histologic markers of EoE disease activity across dysphagia, difficulty eating, and HRQoL. Clinicians should assess hypervigilance and anxiety, especially in patients with refractory symptoms and poor HRQoL.

The Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS) collaborators are a group of more than 70 gastroenterologists, pathologists, allergists, researchers, dietitians, psychologists, and methodologists who convened in a series of in-person and virtual meetings between 2018 and 2020 with the aim of developing a core outcome set (COS) for use in therapeutic studies of pharmacologic and dietary therapies for the treatment of eosinophilic esophagitis (EoE). Given heterogeneity in reported outcomes and uncertainties regarding the most appropriate end points for use in both randomized controlled trials (RCTs) and observational studies involving EoE patients, the EoE experts launched the COREOS exercise in 2018 to standardize outcome definitions using methods established by the Core Outcome Measures in Effectiveness Trials (COMET) initiative.1,2 The COS was developed using a multiphase approach, which is summarized in Figure 1. In the first phase, systematic reviews of the literature and patient engagement surveys were conducted to identify candidate outcomes that have been previously measured and are important to patients with EoE. Next, this information was used to build a framework of different outcome domains, and working groups for each domain were assembled to review the literature for relevant end points.3–6 The relative importance of these domains was categorized in a Delphi survey as core, important, and research agenda domains, and discussed in a moderated in-person meeting on May 17, 2019 at Digestive Disease Week (San Diego, CA). In phase 3, a comprehensive list of outcome measures within each of the core domains was evaluated by the COREOS collaborators in a 2-round Delphi survey and, finally, outcomes were ratified in a virtual meeting on December 8, 2020. In this meeting summary, we highlight the major points of discussion that occurred during the development of the EoE COS.

Background and objectives Women’s ability to negotiate condom use helps prevent sexually transmissible infections (STIs) and unintended pregnancies. The aim of this study was to assess the relationship between substance use, risk perception and the certainty of using condoms in several hypothetical situations. Methods This is a secondary analysis from the Australian Contraceptive ChOice pRoject (ACCORd) cluster randomised controlled trial. Descriptive statistics and logistic regression were used for the analysis. Results At baseline, contraceptive questions were answered by 698 women attending 57 general practices in Melbourne, Australia. Condom use was reported by 47%. Of those using condoms as the sole form of contraception (n = 137), 20% used them inconsistently. Dual protection was used by 58% of women (188/325). Condoms and the pill were more frequently used than condoms and longer-acting contraceptives. Women were less likely to be confident negotiating condom use when using substances. Discussion Substance use and the concurrent use of other forms of contraception impact use of condoms. Even when condoms are the sole form of contraception with willing partners, use is inconsistent, leaving women at risk of pregnancy and STI.

Background Patients with chronic illness are at increased risk for traumatic stress because of medical trauma. Initial studies of posttraumatic stress (PTS) in patients with inflammatory bowel disease (IBD) have found that approximately one-third of patients may experience significant PTS symptoms including flashbacks, nightmares, hypervigilance, disrupted sleep, and low mood. We aim to better characterize PTS in IBD and its relationship with patient outcomes in a large cohort of patients with IBD. Methods Adult patients registered with the Crohn’s & Colitis Foundation/University of North Carolina IBD Partners database were invited to complete a supplementary survey between February and July 2020. The Post Traumatic Stress Disorder Checklist-5th edition was administered as a supplemental survey. Additional data from IBD Partners included disease severity, surgery and hospital history, demographics, and health care utilization. Results A total of 797 patients participated (452 with Crohn disease, 345 with ulcerative colitis). No impacts on response patterns because of the COVID-19 pandemic were found. Although 5.6% of the sample reported an existing PTS diagnosis because of IBD experiences, 9.6% of participants met the full IBD-related PTS diagnostic criteria per the Post Traumatic Stress Disorder Checklist-5th edition. Female patients, younger patients, those with less educational attainment, non-White patients, and Hispanic patients reported higher levels of PTS symptoms. Patients with higher PTS symptoms were more likely to have been hospitalized, have had surgery, have more severe symptoms, and not be in remission. Increased PTS was also associated with increased anxiety, depression, pain interference, fatigue, and health care utilization. Conclusions The present findings support prior research that approximately one-quarter to one-third of patients with IBD report significant symptoms of PTS directly from their disease experiences, and certain demographic groups are at higher risk. In addition, PTS is associated with several IBD outcomes. Patients with higher PTS symptoms are less likely to be in remission and may utilize more outpatient gastrointestinal services. Intervention trials to mitigate PTS symptoms in patients with IBD are warranted.

Spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a type of arthrogryposis multiplex congenita (AMC), is characterized by congenital joint contractures, prenatal fractures of long bones, and respiratory distress and results from biallelic variants in ASCC1. Here, we describe an infant with severe, diffuse hypotonia, congenital contractures, and pulmonary hypoplasia characteristic of SMABF2, with the unique features of cleft palate, small spleen, transverse liver, and pulmonary thromboemboli with chondroid appearance. This infant also had impaired coagulation with diffuse petechiae and ecchymoses which has only been reported in one other infant with AMC. Using trio whole genome sequencing, our proband was identified to have biallelic variants in ASCC1. Using deep next generation sequencing of parental cDNA, we characterized alteration of splicing encoded by the novel, maternally inherited ASCC1 variant (c.297-8 T > G) which provides a mechanism for functional pathogenicity. The paternally inherited ASCC1 variant is a rare nonsense variant (c.466C > T; p.Arg156*) that has been previously identified in one other infant with AMC. This report extends the phenotypic characteristics of ASCC1-associated AMC (SMABF2) and describes a novel intronic variant that partially disrupts RNA splicing.

Psychogastroenterology is the specialty treatment of patients living with chronic illnesses that affect the digestive tract using evidence-based methods, the most often being cognitive behavioral therapy tailored to the digestive illness and gut-directed hypnotherapy. While patients with all digestive conditions are referred for services, the most common are irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Clinical interventions target disease processes, including visceral hypersensitivity and autonomic nervous system arousal, while leveraging resilience and coping strategies to enhance patient self-management of their disease. Opportunities exist for psychologists both in integrated gastroenterology clinics and in private practice settings. The protocols and clinical process of working with the patient are described in detail.

PURPOSE OF REVIEW: Social media use by patients with inflammatory bowel disease (IBD) and their respective providers continues to increase, promoting disease awareness and scholarship. In this review article, we summarize the current literature regarding social media use and IBD, discuss both the patient and physician perspective, and provide guidance to avoid commonly encountered pitfalls. RECENT FINDINGS: Patients and providers commonly rely on social media to share medical information, advocate for improved IBD care, and to network and collaborate on common research interests. This shift from more traditional formats of education and networking continues to grow exponentially, and even more rapidly so during the COVID-19 pandemic. SUMMARY: Social media use in the IBD community will continue to grow and lead to further innovation. Providers should be aware of social media as a valuable tool for their patients and themselves.

BackgroundVeterans report relatively high rates of intimate partner violence (IPV) due to high trauma exposure. Alcohol use disorder (AUD), which is more prevalent among veterans, is a risk factor for IPV use and recidivism following IPV intervention. Using data from a prior randomized control trial of a trauma-informed IPV intervention, we examined the moderating effect of AUD on treatment outcomes among veterans.MethodsParticipants were 61 male veterans (M age = 37.18, SD = 13.23; 82% White; 18% met criteria for AUD) who participated in the Strength at Home (SAH) IPV intervention. Generalized mixed modelling was used to examine the effects of AUD and treatment attendance on posttreatment reductions in IPV.ResultsA significant three-way interaction between time, AUD, and session attendance was observed with respect to reductions in psychological IPV. Specifically, psychological IPV decreased significantly over time, but to a lesser extent among individuals with AUD, regardless of treatment attendance.DiscussionResults indicate that participants with AUD receive less benefit from treatment with regard to coercive and controlling abusive behaviors. Findings speak to the need for adapting IPV intervention in order to address problematic alcohol use and related externalizing psychopathology.

BACKGROUND: Direct-acting antivirals (DAAs) are expected to improve outcomes for patients with hepatitis C virus (HCV) infection after liver transplantation (LT). We aim to evaluate trends in post-LT outcomes with availability of DAAs. METHODS: We retrospectively evaluated US adults transplanted from January 1, 2002, to March 31, 2018, using the United Network for Organ Sharing Registry, stratified by pre-DAA (January 1, 2002– to December 31, 2013) vs. post-DAA (January 1, 2014–, to March 31, 2018) eras. Adjusted multivariate Cox regression analyses and competing risk models evaluated likelihood of graft failure, death, and retransplantation (re-LT). RESULTS: Among 97,147 patients, 30.2% had HCV infection and 19.4% had hepatocellular carcinoma (HCC). Of all patients, 31.9% experienced graft failure, 27.1% died after LT, and 4.7% underwent re-LT. The post-DAA era experienced lower likelihood of graft failure (hazard ratio [HR] = 0.69, p

Infection is a rare occurrence after revision anterior cruciate ligament reconstruction (rACLR). Because of the low rates of infection, it has been difficult to identify risk factors for infection in this patient population. The purpose of this study was to report the rate of infection following rACLR and assess whether infection is associated with patient- and surgeon- dependent risk factors. We reviewed two large prospective cohorts to identify patients with postoperative infections following rACLR. Age, sex, body mass index (BMI), smoking status, history of diabetes, and graft choice were recorded for each patient. The association of these factors with postoperative infection following rACLR was assessed. There were 1423 rACLR cases in the combined cohort, with 9 (0.6%) reporting post-operative infections. Allografts had a higher risk of infection than autografts (odds ratio=6.8; 95% CI: 0.9-54.5; p=0.045). Diabetes (odds ratio=28.6; 95% CI: 5.5-149.9; p=0.004) was a risk factor for infection. Patient age, sex, BMI and smoking status were not associated with risk of infection after rACLR. STATEMENT OF CLINICAL SIGNIFICANCE: While there is a low rate of infection following rACLR, use of allograft and comorbidity with diabetes are associated with a higher risk of infection following this surgery.

Background: Drugs used for Parkinson's disease (PD) are mainly responsible for only relieving major symptoms, but may present several side effects that are typical of such pharmacological treatment. Methods: This study aimed to use in silico methods for drug designing inhibitors of the PD therapeutic target, monoamine oxidase B (MAO-B). Thus, 20 MAO-B inhibitors from the BindingDB database were selected followed by a calculation of their descriptors at DFT B3LYP/6-31G** level of theory. Results: Statistical analysis considering a Pearson correlation matrix led to the selection of electrophilicity index as a descriptor related to the biological activity of inhibitors. Furthermore, based on the prediction of suitable ADME/Tox properties, the molecule CID 54583085 was selected as a template to carry out structural modifications to obtain 3 analogues, whereas molecules B and C showed significant improvement in mutagenicity and carcinogenicity, in relation to the template. Conclusion: Thus, it is concluded that the proposed modifications led us to satisfactory results, since there was an improvement in the toxicological properties of molecules, however, further studies must be carried out to evaluate their biological activities as possible MAO-B inhibitors for PD treatment.

Objective: Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied. Methods: A prospective time-delayed crossover design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS. Results: Thirty-four individuals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%]; Wild–Seber, p < 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%]; Wild–Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate-GS group (log-rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8–89.3%) in

Objective The study sought to evaluate a novel electronic health record (EHR) add-on application for chronic disease management that uses an integrated display to decrease user cognitive load, improve efficiency, and support clinical decision making. Materials and Methods We designed a chronic disease management application using the technology framework known as SMART on FHIR (Substitutable Medical Applications and Reusable Technologies on Fast Healthcare Interoperability Resources). We used mixed methods to obtain user feedback on a prototype to support ambulatory providers managing chronic obstructive pulmonary disease. Each participant managed 2 patient scenarios using the regular EHR with and without access to our prototype in block-randomized order. The primary outcome was the percentage of expert-recommended ideal care tasks completed. Timing, keyboard and mouse use, and participant surveys were also collected. User experiences were captured using a retrospective think-aloud interview analyzed by concept coding. Results With our prototype, the 13 participants completed more recommended care (81% vs 48%; P Discussion Participants completed more recommended care by taking more time when using our prototype. Interviews identified a tension between using the inefficient but familiar EHR vs learning to use our novel prototype. Concept coding of user feedback generated actionable insights. Conclusions Mixed methods can support the design and evaluation of SMART on FHIR EHR add-on applications by enhancing understanding of the user experience.

Objective: Mice genetically deficient in endothelial nitric oxide synthase (Nos3 −/− ) have fasting hyperinsulinemia and hepatic insulin resistance, indicating the importance of Nos3 (nitric oxide synthase) in maintaining metabolic homeostasis. Although the current paradigm holds that these metabolic effects are derived specifically from the expression of Nos3 in the endothelium, it has been established that bone marrow–derived cells also express Nos3. The aim of this study was to investigate whether bone marrow–derived cell Nos3 is important in maintaining metabolic homeostasis. Approach and Results: To test the hypothesis that bone marrow–derived cell Nos3 contributes to metabolic homeostasis, we generated chimeric male mice deficient or competent for Nos3 expression in circulating blood cells. These mice were placed on a low-fat diet for 5 weeks, a time period which is known to induce hepatic insulin resistance in global Nos3-deficient mice but not in wild-type C57Bl/6 mice. Surprisingly, we found that the absence of Nos3 in the bone marrow–derived component is associated with hepatic insulin resistance and that restoration of Nos3 in the bone marrow–derived component in global Nos3-deficient mice is sufficient to restore hepatic insulin sensitivity. Furthermore, we found that overexpression of Nos3 in bone marrow–derived component in wild-type mice attenuates the development of hepatic insulin resistance during high-fat feeding. Finally, compared with wild-type macrophages, the loss of macrophage Nos3 is associated with increased inflammatory responses to lipopolysaccharides and reduced anti-inflammatory responses to IL-4, a macrophage phenotype associated with the development of hepatic and systemic insulin resistance. Conclusions: These results would suggest that the metabolic and hepatic consequences of high-fat feeding are mediated by loss of Nos3/nitric oxide actions in bone marrow–derived cells, not in endothelial cells.

Objectives: To examine metabolic monitoring rates in commercially insured children and adolescents treated with a second-generation antipsychotic (SGA) during calendar years (CYs) 2016 and 2017. Methods: In this retrospective study, data were collected from a large national commercial health plan for the period covering January 1, 2016 to December 31, 2017. Commercially insured children and adolescents, aged 8-19 years with ≥2 SGA prescription claims during the CY, were identified for the CY2016 and CY2017 cohorts. The primary outcome of interest was the percentage of subjects with any glucose or lipid metabolism parameter monitoring. Other calculated metabolic testing rates included glucose, hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), other cholesterol (including triglycerides), and combined glucose and lipid metabolism testing (≥1 test for blood glucose or HbA1c and ≥1 test for LDL-C or other cholesterol). Results: In CY2016 and CY2017, 1502 and 1239 subjects, respectively, were identified for this study. The most common psychiatric diagnoses in CY2016 and CY2017 were major depressive disorder (57.1%, 56.5%, respectively), anxiety disorders (42.9%, 47.5%), attention-deficit/hyperactivity disorder (41.6%, 45.8%), and bipolar disorder (24.1%, 25.9%). The rate of any metabolic testing was 53.5% in CY2016 and 51.3% in CY2017. Glucose testing (50.3%, 46.9%, respectively) was most common in both CYs, followed by LDL-C testing (31.2%, 28.5%). Rates of combined glucose and lipid metabolism testing were 30.7% in CY2016 and 26.9% in CY2017. Conclusions: Given the known potential for adverse cardiometabolic effects, rates of metabolic monitoring associated with SGA use in children and adolescents urgently need to be improved. There is a critical need for understanding barriers to routine monitoring, particularly of lipids, and developing interventions to enhance metabolic monitoring.

BACKGROUND & AIMS: Esophageal hypervigilance and anxiety are emerging as important drivers of dysphagia symptoms and reduced quality of life across esophageal diagnoses. The esophageal hypervigilance and anxiety scale (EHAS) is a validated measure of these cognitive-affective processes. However, its length may preclude it from use in clinical practice. We aimed to create a short form version of the EHAS using established psychometric practices. METHODS: A retrospective review of a registry of patients who visited a university-based esophageal motility clinic for diagnostic testing was conducted. Patients were included if they completed the 15-item EHAS and questionnaires assessing dysphagia severity and health-related quality of life (HRQOL) at the time of motility testing. Principle components factor analysis identified items for possible removal. Tests for reliability and concurrent validity were performed on the full EHAS and short-form version (EHAS-7). RESULTS: 3,976 adult patients with confirmed esophageal disease were included: 30% with achalasia or EGJOO, 13% with EoE, 13% with GERD, 39% normal motility. Eight items were removed from the scale based on a factor loading of > 0.70, resulting in a single scale 7-item EHAS-7 scored from 0 to 28. The EHAS-7 demonstrated excellent internal consistency (α = 0.91) and split-half reliability (0.88) as was found in the full EHAS in the current study and prior validation. Concurrent validity existed between the EHAS-7 and measures of dysphagia (r = 0.33) and HRQOL (r = -0.73, both P < .001). CONCLUSIONS: The EHAS-7 is a 7-item scale to assess esophageal hypervigilance and symptom-specific anxiety that performs as well as the original 15-item version. Shorter questionnaires allow for implementation in clinical practice. The EHAS-7 is a useful tool for clinicians to quickly assess how hypervigilance and anxiety may be contributing to their patients' clinical presentations. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:20 issue:2 pages:E64-E73 ispartof: location:United States status: published

Purpose: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease. Methods: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts. Results: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile–onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile–onset and late-onset phenotypes. Conclusion: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile–onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.

ObjectiveTo determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes.MethodsHere we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher.ResultsLMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms.ConclusionThese findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.

Mutations in the gene encoding cardiac myosin-binding protein-C (MyBPC), a thick filament assembly protein that stabilizes sarcomeric structure and regulates cardiac function, are a common cause for the development of hypertrophic cardiomyopathy. About 10% of carriers of the Δ25bp variant of MYBPC3, which is common in individuals from South Asia, are also carriers of the D389V variant on the same allele. Compared with noncarriers and those with MYBPC3Δ25bp alone, indicators for the development of hypertrophic cardiomyopathy occur with increased frequency in MYBPC3Δ25bp/D389V carriers. Residue D389 lies in the IgI-like C2 domain that is part of the N-terminal region of MyBPC. To probe the effects of mutation D389V on structure, thermostability, and protein–protein interactions, we produced and characterized wild-type and mutant constructs corresponding to the isolated 10 kDa C2 domain and a 52 kDa N-terminal fragment that includes subdomains C0 to C2. Our results show marked reductions in the melting temperatures of D389V mutant constructs. Interactions of construct C0–C2 D389V with the cardiac isoforms of myosin-2 and actin remain unchanged. Molecular dynamics simulations reveal changes in the stiffness and conformer dynamics of domain C2 caused by mutation D389V. Our results suggest a pathomechanism for the development of HCM based on the toxic buildup of misfolded protein in young MYBPC3Δ25bp/D389V carriers that is supplanted and enhanced by C-zone haploinsufficiency at older ages.

The need to evacuate an ICU or operating theatre complex during a fire or other emergency is a rare event but one potentially fraught with difficulty: Not only is there a risk that patients may come to harm but also that staff may be injured and unable to work. Designing newly-built or refurbished ICUs and operating theatre suites is an opportunity to incorporate mandatory fire safety features and improve the management and outcomes of such emergencies: These include well-marked manual fire call points and oxygen shut off valves (area valve service units); the ability to isolate individual zones; multiple clear exit routes; small bays or side rooms; preference for ground floor ICU location and interconnecting routes with operating theatres; separate clinical and non-clinical areas. ICUs and operating theatre suites should have a bespoke emergency evacuation plan and route map that is readily available. Staff should receive practical fire and evacuation training in their clinical area of work on induction and annually as part of mandatory training, including 'walk-through practice' or simulation training and location of manual fire call points and fire extinguishers, evacuation routes and location and operation of area valve service units. The staff member in charge of each shift should be able to select and operate fire extinguishers and lead an evacuation. Following an emergency evacuation, a network-wide response should be activated, including retrieval and transport of patients to other ICUs if needed. A full investigation should take place and ongoing support and follow-up of staff provided.

Objectives To assess and improve the assistive role of a deep, densely connected convolutional neural network (CNN) to hematopathologists in differentiating histologic images of Burkitt lymphoma (BL) from diffuse large B-cell lymphoma (DLBCL). Methods A total of 10,818 images from BL (n = 34) and DLBCL (n = 36) cases were used to either train or apply different CNNs. Networks differed by number of training images and pixels of images, absence of color, pixel and staining augmentation, and depth of the network, among other parameters. Results Cases classified correctly were 17 of 18 (94%), nine with 100% of images correct by the best performing network showing a receiver operating characteristic curve analysis area under the curve 0.92 for both DLBCL and BL. The best performing CNN used all available training images, two random subcrops per image of 448 × 448 pixels, random H&E staining image augmentation, random horizontal flipping of images, random alteration of contrast, reduction on validation error plateau of 15 epochs, block size of six, batch size of 32, and depth of 22. Other networks and decreasing training images had poorer performance. Conclusions CNNs are promising augmented human intelligence tools for differentiating a subset of BL and DLBCL cases.

PurposeSpinal muscular atrophy (SMA), caused by loss of the SMN1 gene, is a leading cause of early childhood death. Due to the near identical sequences of SMN1 and SMN2, analysis of this region is challenging. Population-wide SMA screening to quantify the SMN1 copy number (CN) is recommended by the American College of Medical Genetics.MethodsWe developed a method that accurately identifies the CN of SMN1 and SMN2 using genome sequencing (GS) data by analyzing read depth and eight informative reference genome differences between SMN1/2.ResultsWe characterized SMN1/2 in 12,747 genomes, identified 1568 samples with SMN1 gains or losses and 6615 samples with SMN2 gains or losses and calculated a pan-ethnic carrier frequency of 2%, consistent with previous studies. Additionally, 99.8% of our SMN1 and 99.7% of SMN2 CN calls agreed with orthogonal methods, with a recall of 100% for SMA and 97.8% for carriers, and a precision of 100% for both SMA and carriers.ConclusionThis SMN copy number caller can be used to identify both carrier and affected status of SMA, enabling SMA testing to be offered as a comprehensive test in neonatal care and an accurate carrier screening tool in GS sequencing projects.

OBJECTIVES Symptoms are inconsistently associated with esophageal motor findings on high-resolution manometry (HRM). We aimed to evaluate predictors of dysphagia severity, including esophageal hypervigilance and visceral anxiety, among patients evaluated with HRM. METHODS Adult patients undergoing HRM at 4 academic medical centers (United States and France) were prospectively evaluated. HRM was completed and analyzed per the Chicago Classification v3.0. Validated symptom scores, including the Brief Esophageal Dysphagia Questionnaire and Esophageal Hypervigilance and Anxiety Scale, were completed at the time of HRM. RESULTS Two hundred thirty-six patients, aged 18-85 (mean 53) years, 65% female, were included. Approximately 59 (25%) patients had a major motor disorder on HRM: 19 achalasia, 24 esophagogastric junction outflow obstruction, 12 absent contractility, and 4 jackhammer. Approximately 177 (75%) patients did not have a major motor disorder: 71 ineffective esophageal motility and 106 normal motility. Having a major motor disorder was a significant predictor of dysphagia severity (Radj = 0.049, P < 0.001), but the Esophageal Hypervigilance and Anxiety Scale score carried a predictive relationship of Brief Esophageal Dysphagia Questionnaire that was 2-fold higher than having a major motor disorder: Radj = 0.118 (P < 0.001). This finding remained when evaluated by the major motor disorder group. HRM metrics were nonsignificant. DISCUSSION In a prospective, international multicenter study, we found that esophageal hypervigilance and visceral anxiety were the strongest predictors of dysphagia severity among patients evaluated with HRM. Thus, an assessment of esophageal hypervigilance and visceral anxiety is important to incorporate when evaluating symptom severity in clinical practice and research studies.

Eosinophilic esophagitis (EoE) is a rapidly emerging chronic disease with limited treatments. Impacting both children and adults, EoE and its treatments have the potential to significantly reduce psychological functioning, including increasing anxiety and depression. In this paper, we provide a scoping review of the scientific literature on anxiety and depression in both pediatric and adult patients. We aim to document the current state of research, identify knowledge gaps, recognize unique challenges that EoE patients may face as they relate to psychosocial function, and offer suggestions for future research directions. Based on the current review, both adult and pediatric patients with EoE are at risk for anxiety and depression symptoms, both due to the disease process and the prevailing dietary treatments. Significant gaps exist in the current understanding of anxiety and depression in EoE, providing ample opportunity for future studies to address this important issue.

Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

Understanding factors associated with intimate partner violence (IPV) treatment attendance is of particular importance given high rates of attrition from IPV counseling programs. Individuals who drop out from IPV counseling remain at an increased risk for recidivism. Although numerous studies have examined correlates of IPV treatment completion in civilian samples, no study to date has examined IPV treatment attendance in veterans. Thus, we sought to examine demographic, military, and diagnostic correlates of IPV session attendance in Veterans seeking IPV treatment. The current study examined data from 135 veterans presenting to IPV treatment within the Veteran Affairs (VA) healthcare system. Analyses were conducted from data collected as part of a randomized controlled trial evaluating the efficacy of a 12-session trauma-informed IPV intervention with veterans, Strength at Home. Results indicated that age, courtinvolvement, treatment condition, and substance use disorder were unique predictors of IPV session attendance above and beyond other demographic, military, and diagnostic predictors. Substance use disorder emerged as the most robust predictor of session attendance. These findings suggest that similar to civilian studies, routine assessment of substance use is indicated in IPV programs delivered within the VA healthcare system and that coordinated care between substance abuse and IPV treatment is needed. Our findings also suggest the need for additional efforts to enhance treatment initiation and retention among younger veterans.

Purpose Current diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, genome sequencing (GS) can detect all genomic pathogenic variant types on a single platform. Here we evaluate copy-number variant (CNV) calling as part of a clinically accredited GS test. Methods We performed analytical validation of CNV calling on 17 reference samples, compared the sensitivity of GS-based variants with those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis of GS-based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases. Results We found that CNV calls from GS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed, all of which were confirmed by an orthogonal approach. The pipeline also enabled discovery of a uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of select CNVs enabled breakpoint level resolution of genomic rearrangements and phasing of de novo CNVs. Conclusion Robust identification of CNVs by GS is possible within a clinical testing environment.

GOAL The goal of this study was to evaluate disparities in hospital outcomes among inflammatory bowel disease (IBD) related hospitalizations in the United States with a focus on ethnicity-specific disparities. BACKGROUND IBD-related hospitalizations contribute to significant morbidity and health care economic burden. METHODS IBD-related hospitalizations (identified with ICD-9) among US adults were evaluated using 2007 to 2013 Nationwide Inpatient Sample. In-hospital mortality between groups was evaluated using χ and multivariate logistic regression models, stratified by Crohn's disease (CD) and ulcerative colitis (UC). Inflation-adjusted total hospitalization charges were evaluated using Student t test and multivariate linear regression. RESULTS Among 224,500 IBD-related hospitalizations (77.8% CD, 22.2% UC), overall in-hospital mortality was low (0.99% CD, 0.78% UC). Although Hispanic UC patients had a trend towards higher odds of in-hospital mortality compared with non-Hispanic whites (OR, 1.54; 95% CI, 0.95-2.51; P=0.08), no ethnicity-specific disparities were observed in CD. From 2007 to 2013, mean inflation-adjusted hospitalization charges increased from $29,632 to $41,484, P

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) outcomes among Asians may differ by the Asian ethnic subgroup. We aim to evaluate the impact of the Asian ethnic subgroup on HCC tumor stage, treatment received, and overall survival among US adults. METHODS: Using the 2004–2012 Surveillance, Epidemiology, and End Results U.S. cancer registry, we retrospectively evaluated disparities in HCC tumor stage at diagnosis, HCC treatment received, and overall survival among Asian adults, stratified by Asian ethnic subgroups. Multivariate regression models evaluated the independent impact of Asian ethnic subgroups on the HCC tumor stage at diagnosis, treatment received, and overall long-term survival. RESULTS: Among 8160 Asians with HCC, Southeast Asian (SEA) patients accounted for 26% of all HCC, followed by Chinese (CH) (22%), and Filipinos (FP) (14.0%) patients. Japanese (JP) patients were significantly older than those of the other subgroups (mean 71.1, SD 10.8, P < 0.01). When evaluating HCC stage, FP patients were less likely to have localized HCC and less likely to have HCC within the Milan criteria than CH HCC patients. When evaluating HCC treatment, pacific islanders (PI), FP and SEA patients were significantly less likely to any receive HCC treatment than CH patients. Overall five-year HCC survival was highest among CH HCC patients (33.1%) and lowest among FP (19.9%) and JP patients (22.0%). CONCLUSION: Among Asians with HCC in the US, significant disparities among Asian ethnic subgroups exist. More advanced disease was seen among FP patients, less HCC treatment was seen among FP and SEA patients, and significantly higher mortality was seen among FP, SEA, and JP patients with HCC.

Background and aims Dietary treatments are growing in popularity as interventions for chronic digestive conditions. Patients with irritable bowel syndrome (IBS) often change their eating behaviors to mitigate symptoms. This can occur under the direction of their physician, a dietitian, or be self-directed. Poorly implemented and monitored diet treatments occur frequently with considerable risks for negative consequences. We aim to review the literature related to dietary treatments and risks associated with nutritional deficiencies and disordered eating. Methods Searches were conducted from June to December 2020 on PubMed, MEDLINE, EMBASE, DARE and the Cochrane Database of Systematic Reviews using relevant keywords based on the Patient, Intervention, Comparator and Outcome (PICO) format. Studies included both adult and pediatric populations. Results are synthesized into a narrative review. Results While dietary approaches are efficacious in many research studies, their translation to clinical practice has been less clear. Patients with IBS are at risk for nutritional deficiencies, disordered eating, increased anxiety, and decreases in quality of life in both adult and pediatric groups. Conclusions Physicians prescribing dietary treatment for IBS should be aware of nutritional and psychological risks and implement mitigation measures. These include using a combination of brief, validated questionnaires and clinical history, and collaboration with registered dietitians and/or psychologists. Recommendations for clinical decisions are provided.

Post-traumatic stress symptoms (PTSS) in response to medical trauma are understudied in inflammatory bowel disease (IBD). Two studies identify surgery, hospitalizations, and disease severity as risk factors. We aimed to document IBD-related patient experiences and how these relate to PTSS via a qualitative study. Adult patients with confirmed IBD recruited from two gastroenterology clinics underwent a semi-structured interview with a psychologist and completed the Post Traumatic Stress Disorder Symptom Scale for DSM5 (PSSI-5). Interviews were analyzed using an interpretive phenomenological approach. Themes and subthemes with representative quotations were documented based on thematic saturation. 16 participants, five met PSSI-5 criteria for PTSD. Five themes emerged: disease uncertainty, information exchange/quality, medical procedures, surgery, and coping. Patients with IBD may experience medical PTSS from several sources. Information, communication, and trust in clinicians is vital but may be sub-optimal. Both adaptive and maladaptive coping strategies are used to mitigate PTSS.

Venezuelan equine encephalitis virus (VEEV) is a reemerging alphavirus that can cause encephalitis resulting in severe human morbidity and mortality. Using a high-throughput cell-based screen, we identified a quinolinone compound that protected against VEEV-induced cytopathic effects. Analysis of viral replication in cells identified several quinolinone compounds with potent inhibitory activity against vaccine and virulent strains of VEEV. These quinolinones also displayed inhibitory activity against additional alphaviruses, such as Mayaro virus and Ross River virus, although the potency was greatly reduced. Time-of-addition studies indicated that these compounds inhibit the early-to-mid stage of viral replication. Deep sequencing and reverse genetics studies identified two unique resistance mutations in the nsP2 gene (Y102S/C; stalk domain) that conferred VEEV resistance on this chemical series. Moreover, introduction of a K102Y mutation into the nsP2 gene enhanced the sensitivity of chikungunya virus (CHIKV) to this chemical series. Computational modeling of CHIKV and VEEV nsP2 identified a highly probable docking alignment for the quinolinone compounds that require a tyrosine residue at position 102 within the helicase stalk domain. These studies identified a class of compounds with antiviral activity against VEEV and other alphaviruses and provide further evidence that therapeutics targeting nsP2 may be useful against alphavirus infection.

Introduction Grading dysphagia is crucial for clinical management of patients. The Eckardt score (ES) is the most commonly used for this purpose. We aimed to compare the ES with the recently developed Brief Esophageal Dysphagia Questionnaire (BEDQ) in terms of their correlation and discriminative capacity for clinical and manometric findings and evaluate the effect of gastroesophageal reflux symptoms on both. Methods Symptomatic patients referred for high-resolution manometry (HRM) were prospectively recruited from seven centers in Spain and Latin America. Clinical data and several scores (ES, BEDQ, GERDQ) were collected and contrasted to HRM findings. Standard statistical analysis was performed. Key Results 426 patients were recruited, 31.2% and 41.5% being referred exclusively for dysphagia and GERD symptoms, respectively. Both BEDQ and ES were independently associated with achalasia. Only BEDQ was independently associated with being referred for dysphagia and with relevant HRM findings. ROC curve analysis for achalasia diagnosis showed AUC of 0.809 for BEDQ and 0.765 for ES, with the main difference being higher BEDQ sensitivity (80.0% vs 70.8% for ES). GERDQ independently predicted ES but not BEDQ. In the absence of dysphagia (BEDQ = 0), GERD symptoms significantly determine ES. Conclusions and Inferences Our study suggests both the BEDQ and ES can complementarily describe symptomatic burden in achalasia. BEDQ has several advantages over the ES in the dysphagia evaluation, basically due to its higher sensitivity for manometric diagnosis and independence of GERD symptoms. ES should be used as an achalasia-specific metric, while BEDQ is a better symptom-generic evaluating tool.

Background A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study. Methods Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case. Results Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia. Conclusions We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.

Background & Aims Dietary modification is common in patients with digestive diseases to improve symptoms; however, food avoidance can become problematic. Avoidant Restrictive Food Intake Disorder (ARFID) is characterized as failure to meet one’s nutritional needs owing to sensory hypersensitivity, lack of interest in eating, or fear of aversive consequences from eating, and is associated with negative medical and psychosocial outcomes. This study characterizes ARFID behaviors in adults with achalasia, celiac sprue, eosinophilic esophagitis, and inflammatory bowel disease. Methods In this cross-sectional study, 289 adults aged 18 and older completed self-report measures evaluating use of dietary treatment, ARFID symptoms, and psychosocial outcomes. Primary analyses investigated the occurrence of ARFID in patients with achalasia, celiac, eosinophilic esophagitis, and inflammatory bowel disease. Secondary analyses explored the associations between ARFID symptoms and clinical and psychosocial outcomes. Results More than half (53.7%) of the total sample met the diagnostic criteria for ARFID based on the Nine-Item ARFID Screen (NIAS), with 78.4% of patients with achalasia meeting criteria. Patients on a physician-directed diet showed greater fear of gastrointestinal symptoms (P = .025), less interest in food (P = .046), and a higher total NIAS score (P = .045). For patients using dietary therapy, those who had met with a dietitian reported higher NIAS scores (P = .039). Food avoidance/restriction was associated with increased anxiety and depression, and diminished health-related quality of life. Conclusions It is likely that ARFID rates, as measured by the NIAS, are inflated in these 4 patient groups. These findings highlight the need for updated assessments of ARFID in patients with complex digestive diseases.

Summary Background In about half of all patients with a suspected monogenic disease, genomic investigations fail to identify the diagnosis. A contributing factor is the difficulty with repetitive regions of the genome, such as those generated by segmental duplications. The ATAD3 locus is one such region in which recessive deletions and dominant duplications have recently been reported to cause lethal perinatal mitochondrial diseases characterized by pontocerebellar hypoplasia or cardiomyopathy, respectively. Methods Whole-exome, whole-genome, and long-read DNA sequencing techniques combined with studies of RNA and quantitative proteomics were used to investigate 17 subjects from 16 unrelated families with suspected mitochondrial disease. Findings We report 6 different de novo duplications in the ATAD3 gene locus causing a distinctive presentation, including lethal perinatal cardiomyopathy, persistent hyperlactacidemia, and frequently, corneal clouding or cataracts and encephalopathy. The recurrent 68-kb ATAD3 duplications are identifiable from genome and exome sequencing but usually missed by microarrays. The ATAD3 duplications result in the formation of identical chimeric ATAD3A/ATAD3C proteins, altered ATAD3 complexes, and a striking reduction in mitochondrial oxidative phosphorylation complex I and its activity in heart tissue. Conclusions ATAD3 duplications appear to act in a dominant-negative manner and the de novo inheritance infers a low recurrence risk for families, unlike most pediatric mitochondrial diseases. More than 350 genes underlie mitochondrial diseases. In our experience, the ATAD3 locus is now one of the five most common causes of nuclear-encoded pediatric mitochondrial disease, but the repetitive nature of the locus means ATAD3 diagnoses may be frequently missed by current genomic strategies. Funding Australian NHMRC, US Department of Defense, US National Institutes of Health, Japanese AMED and JSPS agencies, Australian Genomics Health Alliance, and Australian Mito Foundation.

Tuberculosis (TB) is a serious infectious disease of chronic evolution caused by Mycobacterium tuberculosis (MTB). In general, TB control depends on many factors, among which a fast and accurate diagnosis is essential, which in turn makes it possible to carry out a complete treatment involving the proper administration of medications by patients with active disease, that is, to prevent the transmission and evolution of this disease. Despite efforts to TB control, only in 2018, about 1.5 million people died for causes attributed to TB. This likely is due to the appearance of multidrug-resistant strains to known drugs, as well as individuals with HIV/AIDS who are more susceptible to TB. Thus, in this perspective, it is fundamentally important to develop new therapeutic options for the treatment of TB. Hence, this chapter aims to identify new therapeutic alternatives available in the scientific literature based on the use of functional nanoscale materials as strategies to control the increase in bacterial resistance to drugs commonly used in the treatment of TB.

BACKGROUND: End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments. OBJECTIVE: We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE. METHODS: Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists. RESULTS: The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life. CONCLUSIONS: This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:149 issue:2 pages:659-670 ispartof: location:United States status: published

Understanding how exogenous microbes stably colonize the animal gut is essential to reveal mechanisms of action and tailor effective probiotic treatments. Bifidobacterium species are naturally enriched in the gastrointestinal tract of breast-fed infants. Human milk oligosaccharides (HMOs) are associated with this enrichment. However, direct mechanistic proof of the importance of HMOs in this colonization is lacking given milk contains additional factors that impact the gut microbiota. This study examined mice supplemented with the HMO 2ʹfucosyllactose (2ʹFL) together with a 2ʹFL-consuming strain, Bifidobacterium pseudocatenulatum MP80. 2ʹFL supplementation creates a niche for high levels of B.p. MP80 persistence, similar to Bifidobacterium levels seen in breast-fed infants. This synergism impacted gut microbiota composition, activated anti-inflammatory pathways and protected against chemically-induced colitis. These results demonstrate that bacterial-milk glycan interactions alone drive enrichment of beneficial Bifidobacterium and provide a model for tunable colonization thus facilitating insight into mechanisms of health promotion by bifidobacteriain neonates.

BACKGROUND: There is a need to identify factors outside of abnormal reflux that contribute to gastroesophageal reflux disease (GERD). Esophageal hypervigilance is a psychological process impacting symptom experience in esophageal disease. However, little is known about the presence of hypervigilance in GERD phenotypes, especially in those with abnormal acid exposure or symptom index scores. The primary aim was to assess differences in self-reported esophageal hypervigilance across different GERD presentations. The secondary aim was to evaluate esophageal hypervigilance as a predictor of symptom severity. METHODS: We conducted retrospective data analyses on a cohort of adult patients with reflux symptoms that underwent 96-hour wireless pH monitoring from 9/2015 to 9/2017. Patients were stratified into groups based on the number of days they exhibited positive acid exposure time (AET; 0 days, 1-2 days, 3+ days), and symptom index scores (SI; 0 days, 1-day, 2+ days). Esophageal hypervigilance and anxiety, and symptom frequency and severity were assessed between groups. KEY RESULTS: A total of 123 AET cases and 116 SI cases were included for analysis. Esophageal hypervigilance and anxiety scores did not significantly differ based on the number of days of positive AET (p = 0.311) or SI (p = 0.118). Symptom severity and perceived symptom frequency differed between groups. Hypervigilance significantly predicted symptom severity, when controlling for symptom-specific anxiety. CONCLUSIONS: Esophageal hypervigilance is persistent across patients with reflux, irrespective of acid burden and symptom index, and significantly predicts symptom severity. Hypervigilance should be considered as an independent factor contributing to esophageal symptom perception. ispartof: NEUROGASTROENTEROLOGY AND MOTILITY vol:33 issue:8 ispartof: location:England status: published

A variety of endocrine disrupting chemicals (EDCs), including some known to be obesogenic, can be found in household wastewater. Many are only partially treated by wastewater treatment and drinking water purification systems and can enter municipal drinking water supplies. We evaluated drinking water consumption habits in a cohort of obese pediatric patients to determine the percentage that might avoid exposure to EDCs from drinking municipal tap water. Obese (BMI ≥ 95(th) percentile) children presenting to an obesity clinic serving a largely poor and rural population were studied. Self-reported race/ethnicity, insurance status and details concerning type and volume of water consumed were obtained from their medical records. Most homes were supplied with municipal, rather than private well water (90.6% vs. 9.4%, respectively). A majority (76.4%) of patients with municipal water as their water supply only drank bottled water. “Taste” and “Health Concerns” were the most commonly endorsed reasons for eschewing tap water. Bottled water consumption among low socioeconomic status patients may reduce their risk for exposure to EDCs in municipal tap water. Further studies are needed to confirm the generalizability of this observation.

A brief esophageal dysphagia questionnaire (BEDQ) was recently developed in English to evaluate frequency and intensity of dysphagia. Our aim was to validate this questionnaire in French in a cohort of patients referred for esophageal manometry. Patients referred for esophageal high resolution manometry were offered to fill out different questionnaires including Eckart score, GERDQ score and BEDQ. BEDQ was translated in French by two French native speakers and experts in esophageal motility. Patients were grouped according to the indications of esophageal high resolution manometry (dysphagia, GERD, others). The total BEDQ score was calculated and compared between groups. The validation method used the assessment of internal consistency with Cronbach’s alpha and reliability with Guttman split-half reliability. BEDQ questionnaire was completed by 608 patients (44% males, mean age 54 years). The total score had an excellent internal consistency (Cronbach’s alpha = 0.90) and reliability (Guttman statistic = 0.92). The correlation was good with Eckardt score (r = 0.65, p

AIM: To study caregiver reports of children’s experience of physical harm and exposure to family violence due to others’ drinking in nine societies, assess the relationship of harm with household drinking pattern and evaluate whether gender and education of caregiver affect these relationships. METHOD: Using data on adult caregivers from the GENAHTO (Gender and Alcohol’s Harm to Others) project, child alcohol-related injuries and exposure of children to alcohol-related violence (CAIV) rates are estimated by country and pooled using meta-analysis and stratified by gender of the caregiver. Households with and without heavy or harmful drinker(s) (HHD) are compared assessing the interaction of caregiver gender on the relationship between reporting HHD and CAIV, adjusting for caregiver education and age. Additionally, the relationship between caregiver education and CAIV is analysed with meta-regression. RESULTS: The prevalence of CAIV varied across societies, with an overall pooled mean of 4% reported by caregivers. HHD was a consistent correlate of CAIV in all countries. Men and women in the sample reported similar levels of CAIV overall, but the relationship between HHD and CAIV was greater for women than for men, especially if the HHD was the most harmful drinker. Education was not significantly associated with CAIV. CONCLUSION: One in 25 caregivers with children report physical or family violence harms to children because of others’ drinking. The adjusted odds of harm are significantly greater (more than four-fold) in households with a heavy or harmful drinker, with men most likely to be defined as this drinker in the household.

BackgroundUnsafe abortion is an important public health problem in Ghana, making significant contributions to the morbidity and mortality of reproductive-aged women. Although mostly used in explaining mortality associated with perinatal care, recent calls for research on induced abortion in Africa suggest that the Three Delays Model could be used to enhance understanding of women’s experiences and access to induced abortion care.MethodsWe conducted 47 face-to-face interviews with women who had experienced unsafe abortions, with formal abortion providers (abortion providers in hospitals) and with informal and non-legal abortion providers (pharmacy workers and herb sellers). Study participants were recruited from selected hospitals, community pharmacies and markets within the Ashanti region of Ghana. We drew on phenomenology to analyse the data.FindingsThe first delay (in seeking care) occurred because of women’s poor knowledge of pregnancy, the influence of religion, and as a result of women underestimating the seriousness of abortion complications. Factors including cost, provider attitudes, stigma, and the proximity of pharmacies to women’s homes delayed their access to safe abortion and resulted in their experience of the second delay (in reaching a healthcare facility). The third delay (in receiving appropriate care) was a result of hospitals’ non-prioritisation of abortion complications and a shortage of equipment, resulting in long hospital waiting times before treatment.ConclusionThis study has shown the value of the Three Delays Model in illustrating women’s experiences of unsafe abortions and ways of preventing the first, second and third delays in their access to care.

Bacillus anthracis spores that are re-aerosolized from surface deposits after initial contamination present significant health risks for personnel involved in decontamination. To model repeated exposure to low dose B. anthracis spores, three groups of seven rabbits were challenged with multiple low-doses of B. anthracis spores 5 days a week for 3 weeks. Mortality, body temperature, heart and respiration rates, hematology, C-reactive protein, bacteremia, and serum protective antigen were monitored for 21 days post-exposure after the last of multiple doses. All rabbits exposed to a mean daily dose of 2.91 &times, 102 colony forming units (CFU) survived and showed minimal physiological changes attributable to exposure. One of seven rabbits receiving a mean daily dose of 1.22 &times, 103 CFU died and four of seven receiving a mean daily dose of 1.17 &times, 104 CFU died. The LD50 was calculated to be 8.1 &times, 103 CFU of accumulated dose. Rabbits that succumbed to the higher dose exhibited bacteremia and increases above baseline in heart rate, respiration rate, and body temperature. Two rabbits in the mean daily dose group of 1.17 &times, 104 CFU exhibited clinical signs of inhalation anthrax yet survived. This study provides a description of lethality, pathophysiology, and pathology in a controlled multiple low-dose inhalation exposure study of B. anthracis in the rabbit model. The data suggest that the accumulated dose is important in survival outcome and that a subset of rabbits may show clinical signs of disease but fully recover without therapeutic intervention

Background Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain. Methods We present 17 new cases and reviewed 106 reported cases of neurodegeneration with brain iron accumulation type 5. Detailed information related to developmental history and key time to event measures was collected. Results Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole-exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. Although most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age. Conclusions WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.

Background There are difficulties in clinical assessment of patients' health, and there is a need for evaluating instruments that measures self-rated health over time and that are based on the patient's own experiences of their health situation. Aim To describe the trajectory of self-rated health given in a retrospective health-line and its correspondence with the ratings of health given at six different time points during 2 years following a first breast cancer surgery. Designs and methods An explorative prospective cohort study presented according to the STROBE guideline. At six time points, 459 women (26-63 years) completed assessments of self-rated health during 2 years following a first breast cancer surgery. Subsequently, the women retrospectively rated health month by month over the two years by means of a health-line. The women were included consecutively in 2007-2009, last data collection was performed in 2012. Statistical analyses were used to compare the health-line with previous ratings. Results Most women (74-88%) rated their health as good, very good or excellent at all six time points. Health-line ratings were somewhat lower than the ratings made at the actual time-point; however, the illustrated trajectories back in time followed the same patterns as the women had reported during the two years. The lowest ratings of self-rated health were reported at four months after surgery. The retrospective illustrations varied greatly, and poorer health was reported by women undergoing chemotherapy, with lower education and who reported more life events. Conclusions Even if the retrospective ratings by the health-line were somewhat lower than the ratings at the actual time-point, the health-line captures the health trajectory. The individual graphic illustration by means of a health-line may serve as a basis for assessment and support patient health narratives. The findings indicate that life event, lower education and chemotherapy influence concurrent and retrospective self-assessment of health.