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Patients with inflammatory bowel disease (IBD) on immune-modifying therapies may have a lower vaccine response to certain vaccines. The aim of our study was to evaluate humoral immunogenicity of mRNA coronavirus disease 2019 (COVID-19) vaccines among patients with IBD and healthy controls (HCs).We performed a prospective study to evaluate humoral immunogenicity among patients with IBD and HCs after completion of mRNA COVID-19 vaccines.One hundred twenty-two patients with IBD and 60 HCs were enrolled. All HCs and 97% of patients with IBD developed antibodies. Antibody concentrations were lower in patients with IBD compared with those in HCs (median 31 vs 118 μg/mL; P0.001). Those who received the mRNA-1273 (Moderna) COVID-19 (median 38; interquartile range [IQR] 24-75 vs μg/mL) had higher antibody concentrations compared with those who received the Pfizer-BNT vaccine series (median 22; IQR 11-42 μg/mL; P0.001). Patients on immune-modifying therapy (median 26; IQR 13-50 μg/mL) had lower antibody concentrations compared with those who were on no treatment, aminosalicylates, or vedolizumab (median 59; IQR 31-75 μg/mL; P = 0.003).Almost all patients with IBD in our study mounted an antibody response. Future studies are needed in evaluating sustained humoral immunity and the impact of booster dosing in patients with IBD.

Background Little is known about the incidence of clinical events and treatment patterns among older adults with dementia-related psychosis. Given that dementia-related psychosis comprises various dementia types, this study describes the incidence of clinical events and treatment patterns by dementia type after patients with dementia are diagnosed with psychosis. Methods Adults aged ≥ 65 years with dementia and newly diagnosed with psychosis were identified in US Medicare claims during 2013–2018. Baseline characteristics were evaluated at the time of the psychosis diagnosis. After the initial psychosis diagnosis, incidence rates (IRs) of clinical events (e.g., falls/fractures, infections, healthcare utilization), mortality, and patterns of antipsychotic treatment were described for each dementia type (Alzheimer’s disease [AD], Parkinson’s disease dementia [PDD], dementia with Lewy bodies [DLB], frontotemporal dementia [FTD], vascular dementia [VD], and unspecified dementia). Daily mean cumulative counts were estimated to describe the incidence of recurrent events over time. Mortality was described using Kaplan–Meier survival curves. Results We identified 484,520 patients with dementia-related psychosis: mean age, 84 years (standard deviation, 7.8); female, 66%. At the time of psychosis diagnosis, the most prevalent type of dementia was unspecified dementia (56%), followed by AD (31%), VD (12%), PDD (10%), DLB (3%), and FTD ( Conclusions Patients with dementia-related psychosis had a high burden of comorbidities, frailty, emergency department visits, infections, and death. Specifically, after DRP diagnosis, patients with DLB and VD had the highest burden of clinical events of interest.

LY2775240 is a highly selective, potent and orally‐administered inhibitor of phosphodiesterase 4 (PDE4), and is being investigated as a treatment option for inflammatory disorders, such as psoriasis. LY2775240 was investigated in rodent and rhesus monkey nonclinical models. Treatment with LY2775240 led to significant reductions in TNFα production, a marker of PDE4 engagement upon immune activation, in both nonclinical models. In the first part of a 2‐part first‐in‐human randomized study, a wide dose range of LY2775240 was safely evaluated and found to be well‐tolerated with common adverse events (AEs) of nausea, diarrhea, and headache. No serious AEs were reported. The pharmacokinetic profile of LY2775240 was well‐characterized, with a half‐life that can support once‐a‐day dosing. An ex vivo pharmacodynamic (PD) assay demonstrated dose‐dependent PDE4 target engagement as assessed by reduction in TNFα production. A 20 mg dose of LY2775240 led to near‐maximal TNFα inhibition in this PD assay in the first part of the study and was selected for comparison with the clinical dose of apremilast (30 mg) in the crossover, second part of this study. The 20 mg dose of LY2775240 demonstrated sustained maximal (50%–80%) inhibition of TNFα over all timepoints over the 24‐h duration. The comparator apremilast achieved peak inhibition of ~ 50% at only 4 h postdose with a return to about 10% inhibition within 12 h of dosing. In summary, the nonclinical data and safety, tolerability, and PK/PD data in healthy subjects supports further investigation of LY2775240 in inflammatory indications. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Phosphodiesterase 4 (PDE4) inhibitors, such as apremilast, are currently approved to treat autoimmune disorders, such as psoriasis. LY2775240 is an oral PDE4 inhibitor being developed for treatment of a variety of inflammatory disorders. The degree of enzymatic inhibition achieved by PDE4 inhibitors clinically is poorly understood. WHAT QUESTION DID THIS STUDY ADDRESS? This study investigated single ascending doses of LY2775240, a highly selective oral PDE4 inhibitor, in healthy subjects. LY2775240 was well‐tolerated over the dose range evaluated, and pharmacokinetic/pharmacodynamic (PD) profiles were well‐characterized. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study evaluated different doses of LY2775240 and subsequently compared a selected LY2775240 dose with the clinical dose of apremilast with an ex vivo assay. This information builds a connection between target engagement and clinical efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This is the first report of an ex vivo PD assay that has been systematically implemented in a PDE4 inhibitor Phase 1 study. Early investigation of exposure‐response relationships versus a comparator can support evaluation of clinically meaningful doses of investigational agents.

Background: Children with cancer often experience decreased quality of life (QOL) throughout the illness trajectory. The purpose of this study was to explore the associations of demographic characteristics with QOL in children with advanced cancer. Methods: This secondary analysis was part of a larger randomized clinical trial that evaluated the efficacy of a legacy intervention for children (7–17 years) with relapsed/refractory cancer and their primary parent caregivers. Assessments included child self-reports on the Pediatric Quality of Life Inventory (PedsQL) Cancer Module. Researchers used descriptive and linear regression statistical methods. Results: Children ( n = 128) averaged 10.9 years (SD = 3.0). The majority were female ( n = 68, 53%), white ( n = 107, 84%), had a hematologic malignancy ( n = 67, 52%), with family incomes of $50,000 or less ( n = 81, 63.3%). Statistically significant positive associations of both age and income level with PedsQL scores were observed ( p .05). The strongest correlations for age were with the procedural anxiety ( beta = 0.42), treatment anxiety ( beta = 0.26), and total ( beta = 0.28) scores (all p

OBJECTIVE. Pathologic extranodal extension (ENE) is an important adverse feature for human papillomavirus (HPV)–negative head and neck squamous cell carcinoma (HNSCC), but the prognostic significance of microscopic ENE (ENE(mi)) and role of adjuvant concurrent chemoradiation (CRT) for ENE(mi) remain unclear. This study evaluates (1) the prognostic significance of ENE(mi) in HPV-negative HNSCC and (2) whether adjuvant CRT is associated with improved overall survival (OS) for these patients. STUDY DESIGN. Retrospective cohort study. SETTING. Commission on Cancer (CoC)–accredited facilities. METHODS. This retrospective cohort study included patients in the National Cancer Database from 2009 to 2015 with pathologic node-positive (pN+) HPV-negative HNSCC with either pathologic ENE(mi) or no ENE who had undergone margin-negative surgery. The association of ENE(mi) with OS was evaluated using Cox proportional hazard analyses. Analyses were repeated in patients with ENE(mi) receiving adjuvant therapy to evaluate the association of adjuvant CRT with OS. RESULTS. We included 5483 patients with pN+ HPV-negative HNSCC, of whom 24% had ENE(mi). On multivariable analysis, ENE(mi) was associated with decreased OS relative to no ENE (adjusted hazard ratio [aHR], 1.43; 95% CI, 1.28-1.59). Among patients with ENE(mi) who received ≥60 Gy of adjuvant radiation therapy (RT) (n = 617), adjuvant CRT was not associated with improved OS relative to RT (aHR, 0.91; 95% CI, 0.66-1.27). CONCLUSION. For patients with HPV-negative HNSCC, pN+ with ENE(mi) is associated with worse OS than pN+ without ENE. However, for patients with ENE(mi), concurrent CRT is not associated with improved OS relative to RT. The optimal adjuvant paradigm for ENE(mi) requires additional investigation.

Background: This study evaluated whether the apolipoprotein ɛ4 (APOE4) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer’s disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects. Objective: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ɛ4 allele. Methods: Forty-nine cognitively healthy subjects aged 30–89 years old with the APOE4 allele (n = 12) and without (n = 37) were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli. Results: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p = 0.040) and the level of unpleasantness associated with each (p = 0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level. Conclusion: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted.

Introduction The purpose of this study was to demonstrate the feasibility of a phototherapy kiosk (PK) to engage community adults in health promotion and to stimulate production of circulating 25-hydroxyvitamin (OH)D as effectively as a vitamin D3 oral supplement (OS). Although optimal production of vitamin D comes from sun exposure, ultraviolet B radiation with a wavelength of 290 to 320 nm penetrates exposed skin and may produce vitamin D3 using a PK. Materials and Methods A prospective study was conducted with adults randomized to either six PK treatments or D3 OS for 10 weeks. Serum 25(OH)D was drawn at baseline, 10 weeks, and 14 weeks. Primary outcome was serum 25(OH)D level. Mann–Whitney test was used to assess continuous data and Chi squared test for pairwise comparisons of categorical data. Significance was set at P Results With 18% attrition, final sample size was 88; OS, n = 45, PK, n = 43. Sample was mostly female (60%), median age 35 years, with no differences observed between groups for age, race/ethnicity, marital status, military affiliation, or season of enrollment. Median daily intake of calcium and vitamin D was well below the recommended daily allowance for each nutrient, and group. Baseline median serum 25(OH)D levels were similar. By 10 weeks, PK median level was 30 ng/mL (interquartile range [IQR] 25.8-37.0) and OS was 26 ng/mL (IQR 21.5-30.5), P = .02. The difference in 25(OH)D levels persisted at 14 weeks; the PK group returned to baseline, 27 ng/mL (IQR 22.0-32.5), and OS group declined to 21 ng/mL (IQR 17.0-30.0), P = .02. Conclusion Programmed ultraviolet B phototherapy appears to be an efficacious alternative to oral vitamin D supplementation with consistent use.

Background There is currently no gold standard instrument for assessing pain in severely cognitively impaired adults who are unable to provide self-report. Aims To determine interrater reliability of the PACSLAC and PAINAD in assessing pain behaviors in patients with the same pain stimulus, determine the consistency of the reliable changes between and within the instruments and assess nurse preference for either instrument. Design A single-group, within-subjects repeated-measures design was implemented. Setting The study took place in a small suburban hospital. Participants/Subjects Pain levels were observed at 24, 48, and 72 hours postsurgery using two instruments: Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC) and Pain Assessment in Advanced Dementia Scale (PAINAD). These instruments were selected because they are among the most commonly recommended tools for clinical use. Interrater reliability was analyzed along with reliable changes in pain for each period, and the study concluded with the nurse raters completing a preference survey. Methods A convenience sample of 30 patients was used with a diagnosis of severe dementia rendering the patient unable to reliably express pain, 60+ years of age, recovering from hip fracture surgery. Results Greater interrater reliability was found for the PACSLAC, with reliable change potentially affected by the type and level of pain medication. The nurses’ preference for the tool was split. Conclusions The results of this study indicate that the PACSLAC may be the more reliable tool over the PAINAD; however, rater training and familiarity with the tool is critical.

Purpose Lymphedema associated with head and neck cancer (HNC) therapy causes adverse clinical outcomes. Standard treatment includes professionally administered complete decongestive therapy (CDT). Cost and availability of trained therapists are known barriers to therapy. Advanced pneumatic compression devices (APCD) may address these issues. A randomized, wait-list controlled trial was undertaken to evaluate an APCD in post-treatment HNC patients with lymphedema. Material and methods Eligible patients had completed treatment for HNC, were disease free, and had lymphedema at enrollment. Participants were randomized to wait-list lymphedema self-management (standard of care) or lymphedema self-management plus the use of the APCD bid. Safety (CTCAE V4.0) and feasibility were primary endpoints; secondary endpoints included efficacy measure by objective examination and patient reported outcomes (symptoms, quality of life, function), adherence barriers, and satisfaction. Assessments were conducted at baseline and weeks 4 and 8. Results Forty-nine patients were enrolled (wait-list n = 25; intervention n = 24). In total, forty-three patients completed the study. No device-related Serious Adverse Events were reported. Most patients used the APCD once per day, instead of the prescribed twice per day, citing time related factors as barriers to use. APCD use was associated with significant improvement in perceived ability to control lymphedema (p = 0.003) and visible external swelling (front view p p = 0.004, left p = 0.005), as well as less reported pain. Conclusion This trial supports the safety and feasibility of the APCD for the treatment of secondary lymphedema in head and neck cancer patients. In addition, preliminary data supports efficacy.

We sought to determine the costs of genetic testing and compliance with published guidelines and clinical best practices at our institution. A cost analysis was performed comparing the costs of ordered tests to the cost of the recommended testing. This was an approved quality improvement project at a tertiary teaching hospital in California. We identified charts associated with the genetic testing billing codes for common genetic tests through our contracted laboratory (cystic fibrosis genotyping, Breast cancer susceptibility gene (BRCA 1&2), Methylenetetrahydrofolate reductase (MTHFR), factor V Leiden (FVL), prothrombin gene pathogenic variant, alpha-thalassemia, hemochromatosis, and cell-free fetal DNA). Charts were reviewed retrospectively by a licensed, certified genetic counselor to assess the compliance with published clinical practice guidelines identified on GeneReviews and the American College of Obstetricians and Gynecologists (ACOG). Tests were classified as: appropriate, misordered/not indicated, misordered/false reassurance, and misordered/inadequate. We performed a cost analysis for the recommended test changes. We reviewed 114 charts over a three-month period. Forty-four (38.6%) of the tests were misordered based on published clinical practice guidelines: 24 (21%) were misordered/not indicated, 8 (7%) were misordered/false reassurance, and 12 (10.5%) were misordered/inadequate. Costs of ordered testing ($75,177) were compared to recommended testing after review ($54,265), with a total cost savings of $20,912. In clinical practice, over one-third of genetic tests reviewed were misordered. As these tests are a small fraction of all genetic tests at our institution, future studies should broaden the scope of testing evaluated to understand the magnitude of this problem and potential cost savings. Genetic counselor review and involvement in genetic test ordering can decrease inappropriate healthcare expenditures and improve patient care.

Aim To examine work environment differences between hospital certified nurse practitioners (CNPs) and certified registered nurse anaesthetists (CRNAs). Background Nurse work environments impact patient and nurse outcomes. How differing advanced practice nurse (APRN) roles influence work environments is unknown. Methods Multi-level cross-sectional survey design. APRNs (n = 490) completed the APRN Organizational Climate Questionnaire and Psychological Ownership Questionnaire. Nurse executives (N = 24) reported on Scope of Practice and Institutional Voice. Descriptive, t test, chi-square and linear and mixed-effects regression statistical analyses were employed. Results CNPs reported better organisational climate and job ownership than CRNAs. The largest effects involved relationships with physicians, control over practice and independent practice. Among CNPs, a significant positive relationship was observed between relations with physicians and work engagement. In CRNAs, a similar positive relationship between physician relations and work engagement was only observed for those working in higher scope of practice settings, not for those working in more restrictive settings. Conclusions Significant differences exist in the perceived work environments between CNPs and CRNAs that may be related to differences in job design and historical relations with physician colleagues. Implications for nursing management Efforts to improve APRN work environments in hospital settings should consider differing CRNA and CNP perspectives.

Recent advances in the treatment of inflammatory bowel disease (IBD) include the use of immune modifiers and monoclonal antibodies, such as tumor necrosis factor (TNF) alpha inhibitors, anti-integrin agents, janus kinase inhibitors, and interleukin-12/23 inhibitors. These agents achieve higher rates of clinical remission and mucosal healing than conventional therapy. However, these therapies increase the risk of infections, including some vaccine-preventable diseases. Infections are one of the most common adverse event of immunosuppressive therapy. Thus, providers should optimize immunization strategies to reduce the risk of vaccine-preventable infections in patients with IBD. There are several newly licensed vaccines recommended for adults by the US Advisory Committee on Immunization Practices. This review will focus on how gastroenterology providers can implement the adult immunization schedule approved by ACIP for patients with IBD.

Previously we reported that site-specific modification of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) A3C analog with polyethylene glycol (PEG) dramatically improved the pharmacokinetic properties of the protein in rats. However, we could not evaluate the hematological properties of the PEG-A3C protein in rats because human GM-CSF is inactive in rodents. To study the biological effects of PEGylated GM-CSF analogs in rodents we created a homologous site-specific PEGylated murine (mu) GM-CSF (T3C) protein. muGM-CSF and the T3C protein were expressed in Escherichia coli and purified by column chromatography. The purified T3C protein was covalently modified with a linear 20 kDa- or a branched 40 kDa-maleimide-PEG, and the monoPEGylated proteins purified by column chromatography. muGM-CSF, T3C and the two PEG-T3C proteins had comparable in vitro biological activities, as measured by stimulation of proliferation of the murine FDC-P1 cell line. The PEG-T3C proteins had 10- to 25-fold longer circulating half-lives than muGM-CSF and stimulated greater and longer lasting increases in neutrophils and white blood cells than muGM-CSF following a single intravenous or subcutaneous administration to rats. Treatment of rats made neutropenic with cyclophosphamide with the PEG-T3C proteins shortened the time for recovery of neutrophils to normal levels from 9 or 10 days to 5 or 6 days, whereas muGM-CSF showed no benefit versus vehicle solution. Acceleration of neutrophil recovery in cyclophosphamide-treated rats required a minimum of three PEG-T3C treatments over five days. The PEG-T3C proteins should prove useful for evaluating the potential therapeutic benefits of GM-CSF and long-acting GM-CSF proteins in rodent disease models.

The pervasive, damaging nature of posttraumatic stress disorder (PTSD) presents enormous clinical challenges. Understanding the relationship between patients' perceptions of PTSD symptoms and resilient coping strategies may prompt investigation of clinical interventions that improve adaptive, resilient coping skills. In this study, we examined whether changes in resilient coping were related to changes over time in the PTSD symptoms of intrusion and avoidance. A secondary analysis was conducted using longitudinal data from the community-based Washington State Twin Registry. Participants completed the four-item Brief Resilient Coping Scale (BRCS) and the Avoidance and Intrusion subscales of the Impact of Events Scale (IES) at two points in time that were at least 2 years apart. To limit analyses to participants reporting PTSD symptoms at baseline, an initial value of at least 1.0 on either Avoidance (n = 1,337) or Intrusion (n = 1,206) was required for inclusion in the sample. Using linear regression, we assessed associations of change in BRCS with a change in IES scores, controlling for the respective initial scores on each measure. Controlling for initial BRCS and IES-Intrusion values, we observed a small, statistically significant association between change in BRCS and change in IES-Intrusion scores (b* = -0.07; p = .003). There was no statistically significant association between change in BRCS and change in IES-Avoidance (b*

Objectives Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1–3 inhibitor, as a second or third-line treatment. Materials and Methods We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon’s two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients. Results 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes. Conclusions The FGFR 1–3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.

The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology.To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-β (Aβ) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status.This cohort study includes analysis from 2 independent cross-sectional cohort studies: the discovery cohort of the Plasma Test for Amyloidosis Risk Screening (PARIS) study, a prospective add-on to the Imaging Dementia-Evidence for Amyloid Scanning study, including 249 patients from 2018 to 2019, and MissionAD, a dataset of 437 biobanked patient samples obtained at screenings during 2016 to 2019. Data were analyzed from May to November 2020.Amyloid detected in blood and by positron emission tomography (PET) imaging.The main outcome was the diagnostic performance of plasma Aβ42:40 ratio, together with apoE proteotype and age, for identifying amyloid PET status, assessed by accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC).All 686 participants (mean [SD] age 73.2 [6.3] years; 368 [53.6%] men; 378 participants [55.1%] with amyloid PET findings) had symptoms of mild cognitive impairment or mild dementia. The AUC of plasma Aβ42:40 ratio for PARIS was 0.79 (95% CI, 0.73-0.85) and 0.86 (95% CI, 0.82-0.89) for MissionAD. Ratio cutoffs for Aβ42:40 based on the Youden index were similar between cohorts (PARIS: 0.089; MissionAD: 0.092). A logistic regression model (LRM) incorporating Aβ42:40 ratio, apoE proteotype, and age improved diagnostic performance within each cohort (PARIS: AUC, 0.86 [95% CI, 0.81-0.91]; MissionAD: AUC, 0.89 [95% CI, 0.86-0.92]), and overall accuracy was 78% (95% CI, 72%-83%) for PARIS and 83% (95% CI, 79%-86%) for MissionAD. The model developed on the prospectively collected samples from PARIS performed well on the MissionAD samples (AUC, 0.88 [95% CI, 0.84-0.91]; accuracy, 78% [95% CI, 74%-82%]). Training the LRM on combined cohorts yielded an AUC of 0.88 (95% CI, 0.85-0.91) and accuracy of 81% (95% CI, 78%-84%). The output of this LRM is the Amyloid Probability Score (APS). For clinical use, 2 APS cutoff values were established yielding 3 categories, with low, intermediate, and high likelihood of brain amyloid plaque pathology.These findings suggest that this blood biomarker test could allow for distinguishing individuals with brain amyloid-positive PET findings from individuals with amyloid-negative PET findings and serve as an aid for Alzheimer disease diagnosis.

Neonatal nutritional supplements are widely used to improve growth and development but may increase risk of later metabolic disease, and effects may differ by sex. We assessed effects of supplements on later development and metabolism. We searched databases and clinical trials registers up to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter cognitive impairment in toddlers (13 trials, n = 1410; adjusted relative risk (aRR) 0.88 [95% CI 0.68, 1.13]; p = 0.31) or older ages, nor alter metabolic risk beyond 3 years (5 trials, n = 438; aRR 0.94 [0.76, 1.17]; p = 0.59). However, supplementation reduced motor impairment in toddlers (13 trials, n = 1406; aRR 0.76 [0.60, 0.97]; p = 0.03), and improved motor scores overall (13 trials, n = 1406; adjusted mean difference 1.57 [0.14, 2.99]; p = 0.03) and in girls not boys (p = 0.03 for interaction). Supplementation lowered triglyceride concentrations but did not affect other metabolic outcomes (high-density and low-density lipoproteins, cholesterol, fasting glucose, blood pressure, body mass index). Macronutrient supplementation for infants born small may not alter later cognitive function or metabolic risk, but may improve early motor function, especially for girls.

Altered intestinal microbial composition promotes intestinal barrier dysfunction and triggers the initiation and recurrence of inflammatory bowel disease (IBD). Current treatments for IBD are focused on control of inflammation rather than on maintaining intestinal epithelial barrier function. Here, we show that the internalization of Gram-negative bacterial outer membrane vesicles (OMVs) in human intestinal epithelial cells promotes recruitment of caspase-5 and PIKfyve to early endosomal membranes via sorting nexin 10 (SNX10), resulting in LPS release from OMVs into the cytosol. Caspase-5 activated by cytosolic LPS leads to Lyn phosphorylation, which in turn promotes nuclear translocalization of Snail/Slug, downregulation of E-cadherin expression, and intestinal barrier dysfunction. SNX10 deletion or treatment with DC-SX029, a novel SNX10 inhibitor, rescues OMV-induced intestinal barrier dysfunction and ameliorates colitis in mice by blocking cytosolic LPS release, caspase-5 activation, and downstream signaling. Our results show that targeting SNX10 may be a new therapeutic approach for restoring intestinal epithelial barrier function and promising strategy for IBD treatment.

Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in PRPF31, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between CNOT3 polymorphism, MSR1 repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized PRPF31 and CNOT3 expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C&gt, T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy MSR1 repeat in the PRPF31 promoter, while 3/5 NPCs carried a 4-copy MSR1 repeat. The CNOT3 rs4806718 genotype did not correlate with disease penetrance. PRFP31 expression declined with age in adult cadaveric retina. PRPF31 and CNOT3 expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy MSR1 repeat, but not with CNOT3 polymorphisms.

INTRODUCTION: Checkpoint inhibitors have improved outcomes in metastatic melanoma, with 4-year overall survival (OS) of 46% for anti-PD-1 alone or 53% in combination with anti-CTLA-4. However, the median progression free survival is 6.9 and 11.5 months, respectively. Many who progress have gone on to alternative treatments, including surgery, yet the outcome of patients selected for surgery after checkpoint blockade remains unclear. METHODS: Patients who were treated with checkpoint blockade from 2003 to 2017, followed by metastasectomy, were identified from a prospectively maintained institutional melanoma database. Response to immunotherapy was assessed at the time of surgery. Patients were categorized as having responding, isolated progressing, or multiple progressing lesions. RESULTS: Of the 237 total patients identified, 208 (88%) had stage IV disease and 29 (12%) had unresectable stage III disease at the start of immunotherapy. Median OS following first resection was 21 months. Median follow-up among survivors was 23 months. Complete resection at the first operation (n=87, 37%), was associated with improved survival compared with patients with incomplete resection (n=150, 63%) (median OS not reached (NR) versus 10.8 months, respectively; 95% CI: 7.3,14.8; p

Background Numerous nursing and physician studies have reported the effects of workload, environment, and life circumstances contributing to burnout. Effects may include job dissatisfaction, poor quality of life, and associated negative patient outcomes. Although assessing clinician burnout to determine effective interventions has become a topic of great importance, there are minimal studies specific to advanced practice registered nurses (APRNs). Purpose This single-center study was conducted to assess the prevalence and impact of APRN burnout and to recommend targeted interventions toward improvement of overall health and well-being. Methods A cross-sectional, mixed methods design was used. The voluntary, anonymous survey examined perceptions of wellness, inclusion, social support, personal coping mechanisms, and status of burnout. Results The 78-question survey was sent to 1,014 APRNs (94%) and PAs (6%), with a 43.6% response rate (n = 433); 76.4% were nurse practitioners. Participants were identified as currently experiencing burnout, formerly burned out, or never having experienced burnout. Profiles were developed, and similarities and differences between each group were compared. Of 433 respondents, 40.4% (n = 175) reported having never experienced burnout, 33.3% (n = 144) reported they had formerly experienced burnout, and 26.3% (n = 114) reported they were currently experiencing burnout. Implications for practice The results of the study identified that some APRNs report experiencing burnout at different times in their careers. Recommendations by participants to mitigate burnout included self-care, organizational promotion of health and well-being, career development, and leadership support. This study is one of the first to report on burnout among APRNs and potential interventions to build resilience; however, additional research is warranted.

Pancreatic cancer is the fourth leading cause of cancer-related death in the USA. Early detection of pancreatic cancer may help improve patient survival. It has been hypothesized that acute idiopathic or chronic pancreatitis is associated with an increased risk of pancreatic cancer; however, these conditions may also represent an early manifestation of pancreatic cancer, rather than just being risk factors. Endoscopic ultrasound (EUS) is a sensitive diagnostic modality for the detection of small, early-stage pancreatic tumors. The aim of this study was to evaluate the diagnostic yield of EUS for pancreatic cancer in patients with acute idiopathic or chronic pancreatitis when cross-sectional imaging (CT and/or MRI) was negative for a mass lesion in the pancreas. This study was an IRB-approved retrospective chart review conducted for the period of August 2005 to September 2018. Any patient presenting with acute idiopathic or chronic pancreatitis with a CT and/or MRI imaging negative for a pancreatic mass lesion that underwent an EUS during the study period was selected for inclusion. A retrospective review was performed to evaluate the outcomes of patients who had pancreatic cancer diagnosed from an EUS–FNA (fine needle aspiration) sample. Data were collected on patient demographics and clinical characteristics, inclusive of specific post-diagnosis treatment course. An “event rate” was calculated and is defined as the number of positive pancreatic cancer diagnoses on EUS–FNA from all patients presenting with acute idiopathic or chronic pancreatitis who underwent an EUS examination following a CT and/or MRI study negative for pancreatic mass lesion. A total of 565 patients met inclusion criteria, with 30 cases of confirmed pancreatic cancer diagnosed with EUS–FNA from this group. The event rate for EUS diagnosis of pancreatic cancer was 5.3%. The majority of patients (52.0%) diagnosed with cancer were stages I–II. Endoscopic ultrasound should be a routine part of the diagnostic algorithm when evaluating a patient with acute idiopathic or chronic pancreatitis of unclear etiology, particularly when cross-sectional imaging is negative for a mass lesion and clinical suspicion is high for neoplasia. Further prospective studies are needed to evaluate the role of EUS in this setting.

Background: Sex differences in pain have been shown to exist in older adults with normal cognition and people with Alzheimer’s disease. It is unknown if sex differences in pain in older adults exist in a range of communicative older adults with varying cognitive ability from no impairment to moderately severe cognitive impairment. Objective: This study proposes to compare the association between psychophysical responses to experimental thermal pain between males and females to determine if sex differences in pain exist across the cognitive spectrum. Methods: We conducted a secondary analysis of data from an age- and sex-matched between-groups cross-sectional study examining the psychophysical response to contact heat in people with and without dementia. Results: Median age of males (n = 38) and females (n = 38) was 73 (range: 68–87) with similar distributions of Mini-Mental State Examination (MMSE) scores (range: 11–30). Findings revealed inverse statistically significant associations with the threshold temperature of warmth (females: r = –0.41, p = 0.010; males: r = –0.33, p = 0.044). There was an apparent divergent pattern of MMSE associations with unpleasantness ratings between the groups. At the moderate pain threshold, that difference became statistically significant (p = 0.033). Females demonstrated a positive association of MMSE with unpleasantness (r = 0.30, p = 0.072), while males demonstrated an inverse association at that respective threshold (r = –0.20, p = 0.221). Conclusions: Between-group findings suggest that patterns of responses to thermal stimulus intensity may differ between males and females with worsening cognition with females reporting significantly less unpleasantness with the percept of moderate pain and males reporting significantly higher unpleasantness with moderate pain perception.

Purpose This study sought to identify the articulator-specific mechanisms that underlie reduced and enhanced acoustic vowel contrast in talkers with dysarthria due to Parkinson's disease (PD). Method Seventeen talkers with mild–moderate dysarthria due to PD and 17 controls completed a sentence repetition task using typical, slow, loud, and clear speech. Tongue and jaw articulatory movements were recorded using 3D electromagnetic articulography. Independent tongue displacements, jaw displacements, and acoustic vowel contrast were calculated for the diphthong /aɪ/ embedded in the word kite. Results During typical speech, independent tongue displacement, but not jaw displacement, contributed significantly to the intertalker variance in acoustic vowel contrast. Loudness-related acoustic vowel contrast gains were predominantly jaw driven in controls but driven by the tongue and jaw in talkers with PD. Further, in both groups, clarity-related acoustic vowel contrast gains were predominantly jaw driven. Finally, in both groups, rate-related acoustic vowel contrast gains were predominantly tongue driven; however, the jaw also contributed. These jaw contributions were greater in the PD group than in the control group. Conclusions Findings suggest that a tongue-specific articulatory impairment underlies acoustic vowel contrast deterioration in talkers with PD, at least during the early stages of speech decline. Findings further suggest that slow speech engages the impaired tongue more than loud and clear speech in talkers with PD. However, slow speech was also associated with an abnormally strong jaw response in these talkers, which suggests that a compensatory articulatory behavior may also be elicited.

Numerous factors impact patient recovery following an acute myocardial infarction (AMI). Negative emotional outcomes, such as learned helplessness, are predictors of mortality following AMI, though little is known about these relationships. The purpose of this study was to examine the relationships between social support and self-efficacy with learned helplessness in individuals post-AMI. Using a descriptive cross-sectional design, subjects with a diagnosed AMI within 12 months were recruited. Standardized instruments were used to evaluate social support and self-efficacy and their impact on learned helplessness. A statistically significant, direct relationship was found between social support and self-efficacy, and learned helplessness, suggesting that individuals with better social support and self-efficacy experience less learned helplessness within the first year following an AMI. In developing post-AMI treatment plans, health care staff need to consider encouraging a patient's supportive social network and self-efficacy as meaningful interventions against negative emotional outcomes.

Background and Purpose— Mobile Stroke Units (MSUs) provide innovative prehospital stroke care but their 24/7 operation has not been studied. Our study investigates 24/7 MSU diurnal variations related to transport frequency, patient characteristics, and stroke treatments. Methods— We compared transportation frequency, demographics, thrombolytic and mechanical thrombectomy administration, and treatment metrics across 8-hour shifts (morning, evening, and nocturnal) from our 24/7 MSU in Northwest Ohio prospective database. Results— One hundred ninety-five patients were transported by the MSU. Most transports occurred during the morning shift (52.3%) followed by evening shift (35.8%) and nocturnal shift (11.9%; P trend Conclusions— Morning and evening shifts account for the majority of our MSU transports (88.1%) and therapeutic interventions. Understanding temporal variations in a resource-intensive MSU is critical to its worldwide implementation.

Background and Objectives Caregivers need to understand their health status and the disabilities of the care recipient to engage in effective health management. Infographics tailored with personal health data are a promising approach to facilitating comprehension, particularly for individuals with low health literacy/limited English proficiency. Such approaches may be especially important for dementia caregivers given the high care burden. Research Design and Methods Guided by the Health Belief Model and the Data-Frame Theory of Sensemaking, we conducted iterative participatory design sessions with Hispanic family caregivers (N = 16) of persons with dementia. We created multiple prototype infographic designs to display scores on validated instruments of topics such as caregiving burden, overall health, and psychological distress. We retained and refined designs participants judged to be easily comprehensible. Analysis focused on identifying the graphical elements that contributed to the comprehensibility of designs and on evaluating participants’ reactions to the designs. Results Successful infographics used intuitive scaling consistent with caregivers’ perspective of dementia as inevitable decline. Participants reacted to infographics by describing the self-management actions they would take to address the health issue at hand. Discussion and Implications Tailored infographics supported caregivers’ comprehension of their health status and served as cues to engaging in self-management. As such, they should be presented in the context of informational support that can facilitate selection of appropriate next steps. This can mitigate the potential mental and physical health consequences of caregiving and enable caregivers to continue to care for their relatives with dementia with less damage to their own well-being.

Exercise and meditation improve health and well-being, potentially through decreasing systemic inflammation. In this study, healthy adults (N = 413) were randomized to 8 weeks of training in aerobic exercise, matched mindfulness-based stress reduction, or wait-list control. Three inflammation-related biomarkers (C-reactive protein, interleukin-6, and interferon-gamma-inducible protein-10) were assessed preintervention, directly postintervention, and 17 weeks later. Within-group analyses found that exercise participants had decreased serum interferon-gamma-inducible protein-10 postintervention and 17 weeks later, whereas C-reactive protein was lower in mindfulness-based stress-reduction participants 17 weeks postintervention only. Self-reported physical activity or amount of meditation practice did not predict biomarker changes. This study suggests that (a) training in aerobic exercise can lower interferon-gamma-inducible protein-10, a chemokine associated with interferon activity and illness, and (b) training in mindfulness meditation may have a delayed effect on C-reactive protein, an important inflammatory biomarker. The findings highlight the likelihood of multiple, distinct pathways underlying the health-promoting effects of these lifestyle interventions.

Objective: To present a case of laryngeal lymphoma in a pediatric patient and perform a literature review of this rare entity. Patient: A 13-year-old male presented with a rapidly enlarging right neck mass. Work-up of the neck mass included a computed tomography scan of the neck with contrast and revealed a 2.5 cm right level II neck mass and an asymmetric lobulated soft tissue mass in the right pyriform sinus. Intervention: The patient underwent excisional biopsy of the right supraglottic mass. Once his diagnosis was confirmed, he was treated with a standard lymphoma protocol. Results: Intraoperative frozen analysis revealed a small blue cell tumor. Final pathology demonstrated diffuse large B-cell lymphoma of the germinal center B-cell subtype (GC-DLBCL). The patient underwent treatment with primary chemotherapy 12 days after his original procedure with cyclophosphamide, doxorubicin, vincristine, and prednisone. Conclusion: Laryngeal lymphoma remains extremely rare in the pediatric population. With appropriate treatment, the 5-year disease-free survival remains excellent for germinal center diffuse large B-cell lymphoma.

Currently, the ability to predict or monitor the efficacy of HLA antibody-removal therapies is deficient. We previously reported that titration studies are a consistent and accurate means of assessing antibody strength. To test whether titration studies can also predict which patients are better candidates for desensitization, we studied 38 patients from 3 centers (29 receiving plasmapheresis/low-dose intravenous immunoglobulin [IVIg]; 9 patients receiving high-dose IVIg). For patients undergoing plasmapheresis/low-dose IVIg, antibody titer reduction correlated with number of treatment cycles for both class I and II antibodies but only up to approximately 4 cycles. Reduction in titer slowed with additional cycles, suggesting a limit to the efficacy of this approach. Furthermore, initial titer (predesensitization) can guide the selection of candidates for successful antibody-removal treatment. In our experience, patients with antibodies at an initial titer >1:512 could not be reduced to the goal of a negative lymphocyte crossmatch, corresponding to a 1:16 titer, despite a significant increase in the number of treatment cycles. Change in mean fluorescence intensity (MFI) value did not correlate with success of treatment if initial MFI values were >10 000, likely due to single antigen bead saturation. Overall, we present a potential prognostic tool to predict candidacy and a monitoring tool to assess efficacy of desensitization treatment.

Due to their role in controlling translation, microRNAs emerged as novel therapeutic targets to modulate post-stroke outcomes. We previously reported that miR-21 is the most abundantly induced microRNA in the brain of rodents subjected to preconditioning-induced cerebral ischemic tolerance. We currently show that intracerebral administration of miR-21 mimic decreased the infarct volume and promoted better motor function recovery in adult male and female C57BL/6 mice subjected to transient middle cerebral artery occlusion. The miR-21 mimic treatment is also efficacious in aged mice of both sexes subjected to focal ischemia. Mechanistically, miR-21 mimic treatment decreased the post-ischemic levels of several pro-apoptotic and pro-inflammatory RNAs, which might be responsible for the observed neuroprotection. We further observed post-ischemic neuroprotection in adult mice administered with miR-21 mimic intravenously. Overall, the results of this study implicate miR-21 as a promising candidate for therapeutic translation after stroke.

Objective Weight stigma is prevalent across the world. However, little is known about whether and how the harmful health consequences of weight stigma may vary across countries. The current study examined the association between experiences of weight stigma and multiple eating and exercise-related indicators among a large, multinational sample of adults. Methods Adults enrolled in an international weight management program residing in Australia, Canada, France, Germany, the United Kingdom, and the United States completed identical Web-based surveys in the dominant language for their country. Participants (N = 13,996) reported on their personal experiences of weight stigma and health, including eating behaviors, attitudes toward exercise, and perceived stress. Results More than half of all participants in each country reported experiencing weight stigma. Participants who had experienced weight stigma reported engaging in more eating to cope, gym avoidance, and self-monitoring behaviors, as well as higher levels of stress and reduced eating self-efficacy. These associations were documented over and above sociodemographic characteristics and BMI and did not vary across countries. Conclusions Study findings document uniform health-related correlates of weight stigma within a multinational context and underscore the need for global initiatives to curtail weight stigma in order to support population health.

Alveolar soft part sarcoma (ASPS) is a rare malignant neoplasm that tends to occur in the deep soft tissues of both adults and children. ASPS has a progressive clinical course that is unfortunately characterised by late metastases and an overall poor prognosis. Although the tumour has been reported in a wide range of anatomic sites, few cases of primary laryngeal ASPS are reported in the literature. Here, we report the case of a 24-year-old man with no significant medical history who presented with progressive mild dysphonia and hoarseness. Imaging studies revealed a well-circumscribed, partially cystic submucosal mass with involvement of the right vocal fold and other local structures, and the patient was referred for surgical excision. Morphological and immunohistochemical examination of the excised lesion revealed ASPS. The findings of this case are compared with those of seven additional cases of primary laryngeal ASPS, which were found following literature review.

Background/Objectives Considerable evidence from U.S. studies suggests that weight stigma is consequential for patient-provider interactions and healthcare for people with high body weight. Despite international calls for efforts to reduce weight stigma in the medical community, cross-country research is lacking in this field. This study provides the first multinational investigation of associations between weight stigma and healthcare experiences across six Western countries. Methods Participants were 13,996 adults residing in Australia, Canada, France, Germany, the UK, and the US who were actively enrolled in an internationally available behavioral weight management program. Participants completed identical online surveys in the dominant language for their country that assessed experienced weight stigma, internalized weight bias, and healthcare behaviors and experiences including perceived quality of care, avoidance or delay of seeking care, experiences with providers, and perceived weight stigma from doctors. Results Among participants who reported a history of weight stigma (56–61%), two-thirds of participants in each country reported experiencing weight stigma from doctors. Across all six countries, after accounting for demographics, BMI, and experienced stigma, participants with higher internalized weight bias reported greater healthcare avoidance, increased perceived judgment from doctors due to body weight, lower frequency of obtaining routine checkups, less frequent listening and respect from providers, and lower quality of healthcare. Additionally, experienced weight stigma (from any source) was indirectly associated with poorer healthcare experiences through weight bias internalization, consistently across the six countries. Conclusions Weight stigma in healthcare is prevalent among adults actively engaged in weight management across different Western countries, and internalized weight bias has negative implications for healthcare even after controlling for BMI. The similar findings across all six countries underscore the negative consequences of weight stigma on healthcare behaviors and experiences, and emphasize the need for collective international efforts to address this problem.

© 2020 World Stroke Organization., [Background]: Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has been associated with a significant risk of thrombotic events in critically ill patients. [Aim]: To summarize the findings of a multinational observational cohort of patients with SARS-CoV-2 and cerebrovascular disease. [Methods]: Retrospective observational cohort of consecutive adults evaluated in the emergency department and/or admitted with coronavirus disease 2019 (COVID-19) across 31 hospitals in four countries (1 February 2020–16 June 2020). The primary outcome was the incidence rate of cerebrovascular events, inclusive of acute ischemic stroke, intracranial hemorrhages (ICH), and cortical vein and/or sinus thrombosis (CVST). [Results]: Of the 14,483 patients with laboratory-confirmed SARS-CoV-2, 172 were diagnosed with an acute cerebrovascular event (1.13% of cohort; 1130/100,000 patients, 95%CI 970–1320/100,000), 68/171 (40.5%) were female and 96/172 (55.8%) were between the ages 60 and 79 years. Of these, 156 had acute ischemic stroke (1.08%; 1080/100,000 95%CI 920–1260/100,000), 28 ICH (0.19%; 190/100,000 95%CI 130–280/100,000), and 3 with CVST (0.02%; 20/100,000, 95%CI 4–60/100,000). The in-hospital mortality rate for SARS-CoV-2-associated stroke was 38.1% and for ICH 58.3%. After adjusting for clustering by site and age, baseline stroke severity, and all predictors of in-hospital mortality found in univariate regression (p < 0.1: male sex, tobacco use, arrival by emergency medical services, lower platelet and lymphocyte counts, and intracranial occlusion), cryptogenic stroke mechanism (aOR 5.01, 95%CI 1.63–15.44, p < 0.01), older age (aOR 1.78, 95%CI 1.07–2.94, p ¼ 0.03), and lower lymphocyte count on admission (aOR 0.58, 95%CI 0.34–0.98, p ¼ 0.04) were the only independent predictors of mortality among patients with stroke and COVID-19. [Conclusions]: COVID-19 is associated with a small but significant risk of clinically relevant cerebrovascular events, particularly ischemic stroke. The mortality rate is high for COVID-19-associated cerebrovascular complications; therefore, aggressive monitoring and early intervention should be pursued to mitigate poor outcomes.

Purpose: Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown. Experimental Design: Patients with melanoma were prospectively offered tumor sequencing of 341–468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables. Results: A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P < 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months. Conclusions: Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor–refractory melanoma.

Despite substantial evidence documenting weight stigma toward people with higher body weight, international comparative studies are lacking in this field. The few studies that have compared weight stigma across different countries focus on explicit weight-biased attitudes rather than people's experiences of weight stigma. The present study conducted a multinational systematic comparison of weight stigma in six countries to assess experiences and interpersonal sources of weight stigma.Adults (N = 13,996) enrolled in WW International (formerly Weight Watchers), residing in Australia, Canada, France, Germany, the UK, and the US completed identical online anonymous surveys in the dominant language for their country. Surveys assessed their history of experiencing weight stigma, the onset of stigmatizing experiences and associated distress from stigma in different time periods, and interpersonal sources of weight stigma.More than half of participants (55.6-61.3%) across countries reported experiencing weight stigma. Participants with higher BMI were significantly more likely to report weight-stigmatizing experiences than individuals with lower BMI. In all countries, weight stigma experiences were most frequent in childhood and adolescence, with associated distress highest during these time periods. Participants in Germany reported a higher frequency of weight stigma across their whole life, but lower distress associated with stigmatizing experiences, compared to participants in the other five countries. High percentages of participants in each country experienced weight stigma from family members (76.0-87.8%), classmates (72.0-80.9%), doctors (62.6-73.5%), co-workers (54.1-61.7%), and friends (48.8-66.2%).Weight stigma is prevalent for adults actively engaged in weight management across different Western countries. There were more similarities than differences in the nature, frequency, and interpersonal sources of people's experiences of weight stigma across the six countries in this study. Findings underscore the need for multinational initiatives to address weight stigma and interventions to support individuals engaged in weight management who experience weight mistreatment.

Stargardt disease is one of the most common forms of inherited retinal disease and leads to permanent vision loss. A diagnostic feature of the disease is retinal flecks, which appear hyperautofluorescent in fundus autofluorescence (FAF) imaging. The size and number of these flecks increase with disease progression. Manual segmentation of flecks allows monitoring of disease, but is time-consuming. Herein, we have developed and validated a deep learning approach for segmenting these Stargardt flecks (1750 training and 100 validation FAF patches from 37 eyes with Stargardt disease). Testing was done in 10 separate Stargardt FAF images and we observed a good overall agreement between manual and deep learning in both fleck count and fleck area. Longitudinal data were available in both eyes from 6 patients (average total follow-up time 4.2 years), with both manual and deep learning segmentation performed on all (n = 82) images. Both methods detected a similar upward trend in fleck number and area over time. In conclusion, we demonstrated the feasibility of utilizing deep learning to segment and quantify FAF lesions, laying the foundation for future studies using fleck parameters as a trial endpoint.

Mutations in the splicing factor pre-messenger RNA processing factor 31 (Ophthalmic examination, optical coherence tomography, fundus autofluorescence and microperimetry were performed at baseline and every 6-12 months. Baseline and annual change in best-corrected visual acuity (BCVA), microperimetry mean sensitivity (MS) and number of scotoma loci, residual ellipsoid zone (EZ) span and hyperautofluorescent ring (HAR) area were reported. Next-generation and Sanger sequencing were performed in available members.12 affected members from three generations were examined. Mean (SD, range) age at onset of symptoms was 11 (4.5, 4-19) years. MS declined steadily from the third decade and EZ span and HAR area declined rapidly during the second decade. Serial microperimetry showed negligible change in MS over 2-3 years. However, mean EZ span, near-infrared and short-wavelength HAR area reduction was 203 (6.4%) µm/year, 1.8 (8.7%) mmOur findings suggest that in the studied cohort, the optimal window for therapeutic intervention is the second decade of life and residual EZ span and HAR area can be considered as efficacy outcome measures. Further studies on larger samples with different

Aim The diabetes and obesity fields have called for attention to the harmful role of stigma in obesity and diabetes, especially given that little is known about the extent and nature of diabetes stigma facing adults with type 2 diabetes, or the experience of weight stigma in this population. This study addresses this research gap by examining the prevalence and demographic correlates of weight stigma and diabetes stigma in individuals with type 2 diabetes. Methods Adults (N = 1212, Mage = 52) with type 2 diabetes living in the USA were recruited by a healthcare-oriented market research firm, and completed online questionnaires to assess their experiences with weight stigma and diabetes stigma, as well as their internalization of both forms of stigma. Rates of stigma and sociodemographic correlates (years with type 2 diabetes, age, education, income, gender, race and BMI) were examined. Results More than half of participants reported prior experiences of weight stigma, and 40-60% reported experiencing weight stigma in a healthcare context. Participants reported frequent experiences with diabetes-related stigma including blame and judgement, self-stigma and differential treatment. Women reported more weight stigma than men, and White women appeared particularly at risk for experiencing weight and diabetes related stigma relative to Black women. Conclusions Individuals with type 2 diabetes reported higher rates of weight stigma than the general population, experienced high rates of diabetes-related stigma, and many internalized these forms of stigma. Increased attention to stigma reduction is essential to ensuring equitable care for individuals with type 2 diabetes.

Purpose Lymphedema and fibrosis (LEF) are common yet overlooked late effects of head and neck cancer and its therapy. Lack of reliable and valid measures of head and neck LEF is a critical barrier to the timely identification and management of head and neck LEF. To fill this gap, we developed and pilot tested a 64-item patient-reported outcome measure ( Lymphedema Symptom Intensity and Distress Survey-Head and Neck, LSIDS-H&N). This article aims to report the process of further validation and refinement of the tool. Methods and Materials A prospective, longitudinal study was conducted, and 120 patients with oral cavity and oropharyngeal cancer were recruited. Participants completed the LSIDS-H&N at pretreatment, end of treatment, and every 3 months up to 12 months after treatment. SAS PROC VARCLUS was used to generate preliminary clusters of item responses. Internal consistency of the item responses within each cluster was assessed using Cronbach’s alpha. Results A total of 117 patients completed the study. The participants reported that the LSIDS-H&N was easy to understand and captured their symptoms and medical conditions. However, >50% of participants indicated that the survey was burdensome due to length. Thus, we proceeded with item reduction, and the shortened tool (33-item) was named Head and Neck Lymphedema and Fibrosis Symptom Inventory (HN-LEF Symptom Inventory). The subsequent exploration of symptom clusters identified 7 symptom domain clusters (eg, soft tissue and neurologic toxicity), all of which demonstrated good internal consistency. Conclusions The HN-LEF Symptom Inventory has been carefully developed and refined to allow clinicians and researchers to capture LEF-associated symptom burden and function impairments. Additional rigorous psychometric testing of the tool is ongoing to further validate the strength and internal validity of this tool.

Background and Aims Prevention of vaccine-preventable diseases is important in the care of patients with inflammatory bowel disease (IBD). Thus, accurate immunization histories are critical. Many providers rely on patient self-report when assessing immunization status. The primary aim of our study was to determine the accuracy of self-reported influenza vaccination status in a cohort of patients with IBD. Methods We conducted a prospective study of patients with IBD who answered a vaccination status questionnaire and compared their responses to the Wisconsin Immunization Registry, a state-wide electronic immunization information system. The primary outcome was the sensitivity and specificity of self-reported influenza vaccination status. A secondary outcome evaluated the sensitivity and specificity of pneumococcal vaccination status. Results A total of 200 patients with IBD were included in the study. Documented immunization rates were 74.5% for influenza vaccinations and 79.9% for pneumococcal vaccinations. Influenza vaccination self-report had a sensitivity of 98.7%, a specificity of 90.2%, a positive predictive value (PPV) of 96.7% and a negative predictive value (NPV) of 95.8%. In comparison, the sensitivity for pneumococcal vaccination was 83.5% with a specificity of 86.2%, PPV of 96.4%, and NPV of 54.3%. Conclusions Self-reported influenza immunization status is sensitive and specific in patients with IBD. Accuracy for pneumococcal vaccination is slightly lower, but responses were notable for a high PPV. Self-report is an effective way to determine influenza immunization status and provides useful information for receipt of pneumococcal vaccine in patients with IBD.