The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource.

The NHGRI-EBI GWAS Catalog (www.ebi.ac.uk/gwas) is a FAIR knowledgebase providing detailed, structured, standardised and interoperable genome-wide association study (GWAS) data to >200 000 users per year from academic research, healthcare and industry. The Catalog contains variant-trait associations and supporting metadata for >45 000 published GWAS across >5000 human traits, and >40 000 full P-value summary statistics datasets. Content is curated from publications or acquired via author submission of prepublication summary statistics through a new submission portal and validation tool. GWAS data volume has vastly increased in recent years. We have updated our software to meet this scaling challenge and to enable rapid release of submitted summary statistics. The scope of the repository has expanded to include additional data types of high interest to the community, including sequencing-based GWAS, gene-based analyses and copy number variation analyses. Community outreach has increased the number of shared datasets from under-represented traits, e.g. cancer, and we continue to contribute to awareness of the lack of population diversity in GWAS. Interoperability of the Catalog has been enhanced through links to other resources including the Polygenic Score Catalog and the International Mouse Phenotyping Consortium, refinements to GWAS trait annotation, and the development of a standard format for GWAS data.

Burkholderia thailandensis Isolated from the Environment, United States.

Burkholderia thailandensis, an opportunistic pathogen found in the environment, is a bacterium closely related to B. pseudomallei, the cause of melioidosis. Human B. thailandensis infections are uncommon. We isolated B. thailandensis from water in Texas and Puerto Rico and soil in Mississippi in the United States, demonstrating a potential public health risk.

Acute hypoxaemic respiratory failure after treatment with lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal: long-term outcomes from the REST randomised trial.

INTRODUCTION: Lower tidal volume ventilation, facilitated by veno-venous extracorporeal carbon dioxide removal (vv-ECCO2R), does not improve 90-day mortality in patients with acute hypoxaemic respiratory failure (AHRF). The aim of this analysis was to evaluate the effect of this therapeutic strategy on long-term outcomes. METHODS: This was a prespecified analysis of the REST trial, a UK-wide multicentre randomised clinical trial that compared lower tidal volume ventilation, facilitated by vv-ECCO2R (intervention), with standard care in the treatment of patients with moderate-to-severe AHRF. Mortality to 2 years was assessed, while respiratory function, post-traumatic stress disorder, cognitive function and health-related quality of life were evaluated in survivors at 1 year using standardised questionnaires. RESULTS: Of 412 patients enrolled into the REST trial, 391 (95%) had 2-year mortality outcome data available. There was no difference in the time to death between intervention and standard care (HR 1.08 (0.81, 1.44); log-rank test p=0.61). 161 patients alive at 1 year provided at least one questionnaire response. There was no difference in respiratory function, post-traumatic stress disorder, cognitive dysfunction or health-related quality of life between patients allocated to intervention or standard care. CONCLUSION: Lower-tidal volume ventilation facilitated by vv-ECCO2R does not affect 1-year mortality in patients with moderate-to-severe AHRF. Of the patients who provided questionnaire responses, there was no treatment effect on long-term respiratory function, post-traumatic stress disorder, cognitive dysfunction or health-related quality of life. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02654327.

Do critical illness survivors with multimorbidity need a different model of care?

There is currently a lack of evidence on the optimal strategy to support patient recovery after critical illness. Previous research has largely focussed on rehabilitation interventions which aimed to address physical, psychological, and cognitive functional sequelae, the majority of which have failed to demonstrate benefit for the selected outcomes in clinical trials. It is increasingly recognised that a person's existing health status, and in particular multimorbidity (usually defined as two or more medical conditions) and frailty, are strongly associated with their long-term outcomes after critical illness. Recent evidence indicates the existence of a distinct subgroup of critical illness survivors with multimorbidity and high healthcare utilisation, whose prior health trajectory is a better predictor of long-term outcomes than the severity of their acute illness. This review examines the complex relationships between multimorbidity and patient outcomes after critical illness, which are likely mediated by a range of factors including the number, severity, and modifiability of a person's medical conditions, as well as related factors including treatment burden, functional status, healthcare delivery, and social support. We explore potential strategies to optimise patient recovery after critical illness in the presence of multimorbidity. A comprehensive and individualized approach is likely necessary including close coordination among healthcare providers, medication reconciliation and management, and addressing the physical, psychological, and social aspects of recovery. Providing patient-centred care that proactively identifies critical illness survivors with multimorbidity and accounts for their unique challenges and needs is likely crucial to facilitate recovery and improve outcomes.

Studying moral distress (MD) and moral injury (MI) among inpatient and outpatient healthcare professionals during the COVID-19 pandemic.

BACKGROUND: COVID-19 increased moral distress (MD) and moral injury (MI) among healthcare professionals (HCPs). MD and MI were studied among inpatient and outpatient HCPs during March 2022. OBJECTIVES: We sought to examine (1) the relationship between MD and MI; (2) the relationship between MD/MI and pandemic-related burnout and resilience; and (3) the degree to which HCPs experienced pandemic-related MD and MI based on their background. METHODS: A survey was conducted to measure MD, MI, burnout, resilience, and intent to leave healthcare at 2 academic medical centers during a 4-week period. A convenience sample of 184 participants (physicians, nurses, residents, respiratory therapists, advanced practice providers) completed the survey. In this mixed-methods approach, researchers analyzed both quantitative and qualitative survey data and triangulated the findings. RESULTS: There was a moderate association between MD and MI (r = .47, P < .001). Regression results indicated that burnout was significantly associated with both MD and MI (P = .02 and P < .001, respectively), while intent to leave was associated only with MD (P < .001). Qualitative results yielded 8 sources of MD and MI: workload, distrust, lack of teamwork/collaboration, loss of connection, lack of leadership, futile care, outside stressors, and vulnerability. CONCLUSIONS: While interrelated conceptually, MD and MI should be viewed as distinct constructs. HCPs were significantly impacted by the COVID-19 pandemic, with MD and MI being experienced by all HCP categories. Understanding the sources of MD and MI among HCPs could help to improve well-being and work satisfaction.

Anti-Interleukin-31 Receptor A Antibody for Atopic Dermatitis.

BACKGROUND: Interleukin-31 may play a role in the pathobiologic mechanism of atopic dermatitis and pruritus. We wanted to assess the efficacy and safety of nemolizumab (CIM331), a humanized antibody against interleukin-31 receptor A, in the treatment of atopic dermatitis. METHODS: In this phase 2, randomized, double-blind, placebo-controlled, 12-week trial, we assigned adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments to receive subcutaneous nemolizumab (at a dose of 0.1 mg, 0.5 mg, or 2.0 mg per kilogram of body weight) or placebo every 4 weeks or an exploratory dose of 2.0 mg of nemolizumab per kilogram every 8 weeks. The primary end point was the percentage improvement from baseline in the score on the pruritus visual-analogue scale (on which a negative change indicates improvement) at week 12. Secondary end points included changes in the score on the Eczema Area and Severity Index (EASI, on which a negative change indicates improvement), and body-surface area of atopic dermatitis. RESULTS: Of 264 patients who underwent randomization, 216 (82%) completed the study. At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were -43.7% in the 0.1-mg group, -59.8% in the 0.5-mg group, and -63.1% in the 2.0-mg group, versus -20.9% in the placebo group (P<0.01 for all comparisons). Changes on the EASI were -23.0%, -42.3%, and -40.9%, respectively, in the nemolizumab groups, versus -26.6% in the placebo group. Respective changes in body-surface area affected by atopic dermatitis were -7.5%, -20.0%, and -19.4% with nemolizumab, versus -15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks, treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1-mg group, in 9 of 54 (17%) in the 0.5-mg group, and in 7 of 52 (13%) in the 2.0-mg group, versus in 9 of 53 (17%) in the placebo group. CONCLUSIONS: In this phase 2 trial, nemolizumab at all monthly doses significantly improved pruritus in patients with moderate-to-severe atopic dermatitis, which showed the efficacy of targeting interleukin-31 receptor A. The limited size and length of the trial preclude conclusions regarding adverse events. (Funded by Chugai Pharmaceutical; XCIMA ClinicalTrials.gov number, NCT01986933 .).

Deficits of white matter axial diffusivity in bipolar disorder relative to major depressive disorder: No relationship to cerebral perfusion or body mass index.

OBJECTIVE: To compare white matter integrity (WMI) in bipolar disorder (BD) relative to healthy volunteers (HVs) and major depressive disorder (MDD). To determine the relationship of bipolar-specific differences in WMI to cerebral perfusion, body mass index (BMI), and blood pressure as indices of cardiovascular function. METHODS: Thirty-two participants with BD, 44 with MDD, and 41 HV were recruited. All BD and MDD participants were in a major depressive episode, and all but 12 BD participants were medication-free. 64-direction diffusion tensor imaging (DTI) and arterial spin labeling (ASL) sequences were obtained. Tract-based spatial statistics (TBSS) on four DTI indices were employed to distinguish patterns of DTI in BD relative to HV and MDD groups. BMI, blood pressure, and medical histories were also obtained for the BD participants. RESULTS: A cluster of lower axial diffusivity (AD) was found in BD participants in comparison to the HVs in the left posterior thalamic radiation, superior longitudinal fasciculus, inferior longitudinal fasciculus, fronto-occipital fasciculus, and internal capsule. Mean AD in the significant cluster was not associated with cerebral blood flow (CBF) in the region as measured by ASL, and was not associated with BMI or blood pressure. A cluster of lower AD was also found in the BD group when compared to MDD that had spatial overlap with the HV comparison. CONCLUSIONS: The results indicate a deficit of AD in BD when compared to MDD and HV groups. No association between AD values and either cerebral perfusion, BMI, or blood pressure was found in BD.

Large-scale estimation of random graph models with local dependence.

A class of random graph models is considered, combining features of exponential-family models and latent structure models, with the goal of retaining the strengths of both of them while reducing the weaknesses of each of them. An open problem is how to estimate such models from large networks. A novel approach to large-scale estimation is proposed, taking advantage of the local structure of such models for the purpose of local computing. The main idea is that random graphs with local dependence can be decomposed into subgraphs, which enables parallel computing on subgraphs and suggests a two-step estimation approach. The first step estimates the local structure underlying random graphs. The second step estimates parameters given the estimated local structure of random graphs. Both steps can be implemented in parallel, which enables large-scale estimation. The advantages of the two-step estimation approach are demonstrated by simulation studies with up to 10,000 nodes and an application to a large Amazon product recommendation network with more than 10,000 products.

Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics.

Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures.

White matter tract integrity is associated with antidepressant response to lurasidone in bipolar depression.

OBJECTIVES: Patients with bipolar disorder spend the most time in the depressed phase, and that phase is associated with the most morbidity and mortality. Treatment of bipolar depression lacks a test to determine who will respond to treatment. White matter disruptions have been found in bipolar disorder. Previous reports suggest that white matter disruptions may be associated with resistance to antidepressant medication, but this has never been investigated in a prospective study using a Food and Drug Administration (FDA)-approved medication. METHODS: Eighteen subjects with bipolar disorder who were in a major depressive episode and off all medications were recruited. Magnetic resonance imaging was acquired using a 64-direction diffusion tensor imaging sequence on a 3T scanner. Subjects were treated with 8 weeks of open-label lurasidone. The Montgomrey-Asberg Depression Rating Scale (MADRS) was completed weekly. Tract-Based Spatial Statistics were utilized to perform a regression analysis of fractional anisotropy (FA) data with treatment outcome as assessed by percent change in MADRS as a regressor while controlling for age and sex, using a threshold of P (threshold-free cluster enhancement-corrected) <.05. RESULTS: FA was positively correlated with antidepressant treatment response in multiple regions of the mean FA skeleton bilaterally, including tracts in the frontal and parietal lobes. CONCLUSIONS: Greater disruptions in the white matter tracts in bipolar disorder were associated with poorer antidepressant response to lurasidone. The disruptions may potentially indicate treatment with a different antidepressant medication class. These results are limited by the open-label study design, sample size and lack of a healthy control group.

Swallowing Disorders in Schizophrenia.

Disorders of swallowing are poorly characterized but quite common in schizophrenia. They are a source of considerable morbidity and mortality in this population, generally as a result of either acute asphyxia from airway obstruction or more insidious aspiration and pneumonia. The death rate from acute asphyxia may be as high as one hundred times that of the general population. Most swallowing disorders in schizophrenia seem to fall into one of two categories, changes in eating and swallowing due to the illness itself and changes related to psychotropic medications. Behavioral changes related to the illness are poorly understood and often involve eating too quickly or taking inappropriately large boluses of food. Iatrogenic problems are mostly related to drug-induced extrapyramidal side effects, including drug-induced parkinsonism, dystonia, and tardive dyskinesia, but may also include xerostomia, sialorrhea, and changes related to sedation. This paper will provide an overview of common swallowing problems encountered in patients with schizophrenia, their pathophysiology, and management. While there is a scarcity of quality evidence in the literature, a thorough history and examination will generally elucidate the predominant problem or problems, often leading to effective management strategies.

Tools for structured team communication in pre-registration health professions education: a Best Evidence Medical Education (BEME) review: BEME Guide No. 41.

INTRODUCTION: Calls for the inclusion of standardized protocols for information exchange into pre-registration health professions curricula have accompanied their introduction into clinical practice. In order to help clinical educators respond to these calls, we have reviewed educational interventions for pre-registration students that incorporate one or more of these ?tools for structured communication?. METHODS: Searches of 10 databases (1990?2014) were supplemented by hand searches and by citation searches (to January 2015). Studies evaluating an intervention for pre-registration students of any clinical profession and incorporating at least one tool were included. Quality of included studies was assessed using a checklist of 11 indicators and a narrative synthesis of findings undertaken. RESULTS: Fifty studies met our inclusion criteria. Of these, 21 evaluated the specific effect of a tool on educational outcomes, and 27 met seven or more quality indicators. CONCLUSIONS: Pre-registration students, particularly those in the US, are learning to use tools for structured communication either in specific sessions or integrated into more extensive courses or programmes; mostly 'Situation Background Assessment Recommendation' and its variants. There is some evidence that learning to use a tool can improve the clarity and comprehensiveness of student communication, their perceived self-confidence and their sense of preparedness for clinical practice. There is, as yet, little evidence for the transfer of these skills to the clinical setting or for any influence of teaching approach on learning outcomes. Educators will need to consider the positioning of such learning with other skills such as clinical reasoning and decision-making.

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression.

The oncogenic role of WNT is well characterized. Wntless (WLS) (also known as GPR177, or Evi), a key modulator of WNT protein secretion, was recently found to be highly overexpressed in malignant astrocytomas. We hypothesized that this molecule may be aberrantly expressed in other cancers known to possess aberrant WNT signaling such as ovarian, gastric, and breast cancers. Immunohistochemical analysis using a TMA platform revealed WLS overexpression in a subset of ovarian, gastric, and breast tumors; this overexpression was associated with poorer clinical outcomes in gastric cancer (P=0.025). In addition, a strong correlation was observed between WLS expression and human epidermal growth factor receptor 2 (HER2) overexpression. Indeed, 100% of HER2-positive intestinal gastric carcinomas, 100% of HER2-positive serous ovarian carcinomas, and 64% of HER2-positive breast carcinomas coexpressed WLS protein. Although HER2 protein expression or gene amplification is an established predictive biomarker for trastuzumab response in breast and gastric cancers, a significant proportion of HER2-positive tumors display resistance to trastuzumab, which may be in part explainable by a possible mechanistic link between WLS and HER2.

Behavioral activation therapy for return to work in medication-responsive chronic depression with persistent psychosocial dysfunction.

OBJECTIVE: Chronic depression is associated with significant impairment in work functioning, relationships, and health. Such impairment often persists following medication-induced remission of depressive symptoms. We adapted and tested Behavioral Activation therapy with a goal of return to work (BA-W) in subjects with chronic depression who had responded to medication treatment but remained unemployed. METHOD: Sixteen adults aged 18-65 with DSM-IV diagnosed Dysthymic Disorder or chronic Major Depression were recruited from clinical trials taking place at the New York State Psychiatric Institute between 4/2009 and 12/2012 and enrolled in 12 weeks of individual manual-driven BA-W. Functioning was measured at intake, post-treatment and at 24 week follow-up. RESULTS: Eighty-seven percent (n=14) of subjects completed the full 12 weeks of BA-W. Hours of work related activity (p<.005, d=0.83), hours of paid work (p<.0003, d=0.54), and work productivity (p<.0004, d=-0.48) increased significantly over the study period. Earned income increased post-treatment (p=.068) with significant changes by 24 week follow-up (p=.011). Secondary outcomes including behavioral avoidance (p<.004, d=-0.56), and global functioning (p<.0003, d=1.42) were also significantly improved post-treatment. Effect sizes, including for outcomes with non-significant changes, were generally in the range of 0.5-0.8. CONCLUSIONS: This pilot study provides preliminary evidence of the efficacy of a work-targeted psychotherapy to remediate vocational impairment in subjects with chronic depression. Data suggests that further testing of BA-W using a randomized controlled trial is warranted and may represent a significant advance in treatment for the residual disability present after successful pharmacotherapy.

Guided Imagery for Arthritis and Other Rheumatic Diseases: A Systematic Review of Randomized Controlled Trials.

Many individuals suffering from arthritis and other rheumatic diseases (AORD) supplement pharmacologic treatments with psychosocial interventions. One promising approach, guided imagery, has been reported to have positive results in randomized controlled trials (RCTs) and is a highly scalable treatment for those with AORD. The main purpose of this study was to conduct a systematic review of RCTs that have examined the effects of guided imagery on pain, function, and other outcomes such as anxiety, depression, and quality of life in adults with AORD. Ten electronic bibliographic databases were searched for reports of RCTs published between 1960 and 2013. Selection criteria included adults with AORD who participated in RCTs that used guided imagery as a partial or sole intervention strategy. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Instrument. Results were synthesized qualitatively. Seven studies representing 306 enrolled and 287 participants who completed the interventions met inclusion criteria. The average age of the participants was 62.9 years (standard deviation = 12.2). All interventions used guided imagery scripts that were delivered via audio technology. The interventions ranged from a one-time exposure to 16 weeks in duration. Risk of bias was low or unclear in all but one study. All studies reported statistically significant improvements in the observed outcomes. Guided imagery appears to be beneficial for adults with AORD. Future theory-based studies with cost-benefit analyses are warranted.

A qualitative understanding of patient falls in inpatient mental health units.

BACKGROUND: Falls are the leading cause of injury-related deaths among people age 65 and older, and fractures are the major category of serious injuries produced by falls. OBJECTIVE: Determine market segment-specific recommendations for "selling" falls prevention in acute inpatient psychiatry. DESIGN: Descriptive using focus groups. SETTING: One inpatient unit at a Veterans' hospital in the Southeastern United States and one national conference of psychiatric and mental health nurses. PATIENTS: A convenience sample of 22 registered nurses and advanced practice nurses, one physical therapist and two physicians participated in one of six focus groups. INTERVENTION: None. MEASUREMENTS: Focus groups were conducted by expert facilitators using a semistructured interview guide. Focus groups were recorded and transcribed. Content analysis was used to organize findings. RESULTS: Findings were grouped into fall risk assessment, clinical fall risk precautions, programmatic fall prevention, and "selling" fall prevention in psychiatry. Participants focused on falls prevention instead of fall injury prevention, were committed to reducing risk, and were receptive to learning how to improve safety. Participants recognized unique features of their patients and care settings that defined risk, and were highly motivated to work with other disciplines to keep patients safe. CONCLUSIONS: Selling fall injury prevention to staff in psychiatric settings is similar to selling fall injury prevention to staff in other health care settings. Appealing to the larger construct of patient safety will motivate staff in psychiatric settings to implement best practices and customize these to account for unique population needs characteristics.

Collaboration and growth in a large research cooperative: A network analytic approach.

Research networks encourage team science and facilitate collaboration within and across research teams. While many analyses have examined the output of these collaborative networks (e.g., authorship networks, publications, grant applications), less attention has been paid to the formative phases of these initiatives. This article presents analyses of a whole-network survey of investigators participating in a new research initiative, and examines the development of collaborative ties over the network's first year. In particular, we examine the influence of research center affiliation, seniority, and prior network experience on the number and structure of collaborative ties, including participants' bridging and broker roles. Such analyses can inform the overall management of the project in purposefully promoting new collaboration opportunities, and may ultimately predict the number of collaborative products generated by the network members.