Search

Abstract Background During the first nine months of the COVID-19 emergency, patients were encouraged to use virtual versus clinic visits if in-person care was not deemed necessary by clinical staff. This study examined the association of spoken language preference and ethnicity with use of video versus phone virtual visits by US Latino and Chinese adult patients who got care in the same healthcare system. Methods We analyzed electronic health record data for four groups of adults aged 26-85y who had ≥ 1 primary or specialty care outpatient clinician visits during April-December 2020: 80,869 Latino adults preferring Spanish (LEP Latino); 214,765 Latino adults preferring English (non-LEP Latino); 23,430 Chinese adults preferring a Chinese dialect (LEP Chinese); and 49,710 Chinese adults preferring English (non-LEP Chinese). Prevalence of the following utilization outcomes were compared by language preference (LEP/non-LEP) within ethnicity and by ethnicity within language preference for four age subgroups (26-39y, 40-64y, 65-75y, and 76-85y): ≥ 1 virtual (video or phone) visit, ≥ 1 video visit, ≥ 1 phone visit, ≥ 1 clinic visit, video visits only, and phone visits only. We also compared ethnicity x language group differences within age subgroups using absolute difference and adjusted prevalence ratios derived from modified log-Poisson regression models that controlled for age and sex. Results Among virtual users, LEP Latino and Chinese adults were significantly less likely to use video visits and more likely to use phone visits than non-LEP Latino and Chinese adults in the same age strata. The LEP/non-LEP difference in video visit use was significantly larger among Latino than Chinese patients, with no similar ethnic group difference observed for phone visits. Within the LEP and non-LEP language groups, Chinese adults were significantly more likely than Latino adults to use video visits and less likely to use phone visits. Conclusions During the first nine months of the COVID-19 pandemic, uptake of video and phone virtual visits by Latino and Chinese adults significantly differed by LEP/non-LEP status within ethnicity and by ethnicity within LEP/non-LEP language group. These findings underscore the importance of disaggregating data by ethnicity and language preference when attempting to understand and study patient use of different virtual visit modalities.

Objective Surveys are a commonly used tool in quality improvement (QI) projects, but little is known about the standards to which they are designed and applied. We aimed to investigate the quality of surveys used within a QI collaborative, and to characterise the common errors made in survey design.Methods Five reviewers (two research methodology and QI, three clinical and QI experts) independently assessed 20 surveys, comprising 250 survey items, that were developed in a North American cystic fibrosis lung transplant transition collaborative. Content Validity Index (CVI) scores were calculated for each survey. Reviewer consensus discussions decided an overall quality assessment for each survey and survey item (analysed using descriptive statistics) and explored the rationale for scoring (using qualitative thematic analysis).Results 3/20 surveys scored as high quality (CVI >80%). 19% (n=47) of survey items were recommended by the reviewers, with 35% (n=87) requiring improvements, and 46% (n=116) not recommended. Quality assessment criteria were agreed upon. Types of common errors identified included the ethics and appropriateness of questions and survey format; usefulness of survey items to inform learning or lead to action, and methodological issues with survey questions, survey response options; and overall survey design.Conclusion Survey development is a task that requires careful consideration, time and expertise. QI teams should consider whether a survey is the most appropriate form for capturing information during the improvement process. There is a need to educate and support QI teams to adhere to good practice and avoid common errors, thereby increasing the value of surveys for evaluation and QI. The methodology, quality assessment criteria and common errors described in this paper can provide a useful resource for this purpose.

BackgroundPatient engagement with secure messaging (SM) via digital patient portals has been associated with improved diabetes outcomes, including increased patient satisfaction and better glycemic control. Yet, disparities in SM uptake exist among older patients and racial and ethnic underserved groups. Care partners (family members or friends) may provide a means for mitigating these disparities; however, it remains unclear whether and to what extent care partners might enhance SM use. ObjectiveWe aim to examine whether SM use differs among older patients with diabetes based on the involvement of care partner proxies. MethodsThis is a substudy of the ECLIPPSE (Employing Computational Linguistics to Improve Patient-Provider Secure Emails) project, a cohort study taking place in a large, fully integrated health care delivery system with an established digital patient portal serving over 4 million patients. Participants included patients with type 2 diabetes aged ≥50 years, newly registered on the patient portal, who sent ≥1 English-language message to their clinician between July 1, 2006, and December 31, 2015. Proxy SM was identified by having a registered proxy. To identify nonregistered proxies, a computational linguistics algorithm was applied to detect words and phrases more likely to appear in proxy messages compared to patient-authored messages. The primary outcome was the annual volume of secure messages (sent or received); secondary outcomes were the length of time to the first SM sent by patient or proxy and the number of annual SM exchanges (unique message topics generating ≥1 reply). ResultsThe mean age of the cohort (N=7659) at this study’s start was 61 (SD 7.16) years; 75% (n=5573) were married, 15% (n=1089) identified as Black, 10% (n=747) Chinese, 12% (n=905) Filipino, 13% (n=999) Latino, and 30% (n=2225) White. Further, 49% (n=3782) of patients used a proxy to some extent. Compared to nonproxy users, proxy users were older (P

IntroductionAdolescent girls and young women (AGYW) face a high burden of gender-based violence (GBV) worldwide. The COVID-19 pandemic and associated policies led to global increases in GBV, decreased access to resources, and disruptions of pathways to care. We aimed to understand the effects of COVID-19 on AGYW affected by GBV in Kisumu, Kenya, as well as to identify possible interventions to mitigate those effects.MethodsFocus group discussions (FGDs) were conducted with AGYW aged 15–25 with a history of exposure to GBV. AGYW were split into age-matched groups; aged 15–19 for younger groups and 19–25 for older groups. Discussions focused on how COVID-19 affected experiences of GBV, access to care services, economic and social outcomes, and opportunities for interventions to mitigate negative impacts of COVID-19 and violence.ResultsFive FGDs with 46 AGYW were completed in June-September 2021. AGYW described increases in all types of GBV, particularly sexual abuse and intimate partner violence. Early marriage and subsistence transactional sex also increased. AGYW described violence as both a cause and effect of poor economic, social and health consequences related to the pandemic. Notably, AGYW emphasized stress, lack of mental health support and increased substance use as risk factors for violence, and discussed the deleterious mental health effects of violence—particularly in the wake of disruption of mental health services. COVID-19 disrupted referrals to violence-related services, and reduced access to both medical services and psychosocial services. AGYW believed that interventions focused on improving mental health as well as economic empowerment would be the most feasible and acceptable in mitigating the negative effects of COVID-19 and related exacerbations in violence.DiscussionAGYW reported increases in almost all forms of GBV during the pandemic, with related exacerbation in mental health. Concurrently, AGYW endorsed decreased access to care services. As there is no evidence that violence and mental health challenges will quickly resolve, there is an urgent need to identify and implement interventions to mitigate these negative effects.

Pesticides are highly tested and regulated chemicals. There is currently great interest in the role that pesticides may play in childhood neurodevelopment. The objective was to identify and describe the body of evidence and to assess the ability to synthesize effect estimates. The epidemiologic literature from 2011 to 2022 was searched for publications on the association between pesticide exposure and neurodevelopment, behavior, and/or cognition in children. We identified 114 publications, representing 67 unique studies. While organochlorine and other insecticides were the most common classes of pesticides studied, up to 159 different metabolites or active ingredients were reported. Nine pesticides or their metabolites were reported in >10 publications. Similarly, multiple assessment methods were administered across studies to evaluate outcomes in neurodevelopment at ages which ranged from birth to 18 years of age. This scoping review reveals the heterogeneity among published studies with respect to exposures and health outcomes, in the methods used to assess and classify them, and in combinations of the two. This limits the adequacy of the evidence to evaluate specific risk estimates for a particular exposure-outcome pair. Intentional coordination among researchers to increase consistency in methodologies would facilitate the synthesis of results across studies. Research opportunities also exist to validate assumptions in exposure and outcome assessment which are implicit in many of the studies reviewed. In conclusion, there are many ongoing epidemiologic studies with a focus on pesticides and neurodevelopment. The variety of exposures, exposure assessment methods and tests for each outcome can be overwhelming. Interdisciplinary collaboration is recommended to harmonize data collection and to enable meaningful interpretation of the study results across populations.

Abstract Objective Most outpatients with pulmonary embolism (PE) are diagnosed in the emergency department (ED). The relationship between means of arrival, site of diagnosis, and disposition in ED patients with PE is unknown. We compared discharge home between patients arriving by emergency medical services (EMS) and those arriving by other means. Within the EMS cohort, we compared those with a recent PE diagnosis in the outpatient clinic setting to those who were diagnosed with PE in the ED. Methods This study was a secondary analysis of a retrospective cohort that included all adult, non‐pregnant ED patients treated for acute PE across 21 community EDs from January 2013 to April 2015. The primary outcome was discharge home within 24 h of ED registration; we also examined mortality. We described associations with patient arrival method and other patient characteristics. Results Among 2996 ED patient encounters with acute PE, 644 (21.5%) arrived by EMS. This group had a lower frequency of discharge (9.2% vs 26.4%) and higher 30‐day all‐cause mortality (8.7% vs 3.1%) than their counterparts (p

ABSTRACTVisceral hypersensitivity, a fundamental mechanism of chronic visceral pain disorders, can result from both central or peripheral factors, or their combination. As an important regulator of normal gut function, the gut microbiota has been implicated as a key peripheral factor in the pathophysiology of visceral hypersensitivity. Patients with chronic gastrointestinal disorders, such as irritable bowel syndrome, often present with abdominal pain secondary to adverse reactions to dietary components. As both long- and short-term diets are major determinants of gut microbiota configuration that can result in changes in microbial metabolic output, it is becoming increasingly recognized that diet–microbiota interactions play an important role in the genesis of visceral sensitivity. Changes in pain signaling may occur via diet-induced changes in secretion of mediators by both the microbiota and/or host cells. This review will examine the peripheral influence of diet–microbiota interactions underlying increased visceral sensitivity.

Abstract Background Substantial resources are invested by Health Departments worldwide in introducing National Clinical Audits (NCAs). Yet, there is variable evidence on the NCAs’ effectiveness and little is known on factors underlying the successful use of NCAs to improve local practice. This study will focus on a single NCA (the National Audit of Inpatient Falls -NAIF 2017) to explore: (i) participants’ perspectives on the NCA reports, local feedback characteristics and actions undertaken following the feedback underpinning the effective use of the NCA feedback to improve local practice; (ii) reported changes in local practice following the NCA feedback in England and Wales. Methods Front-line staff perspectives were gathered through interviews. An inductive qualitative approach was used. Eighteen participants were purposefully sampled from 7 of the 85 participating hospitals in England and Wales. Analysis was guided by constant comparative techniques. Results Regarding the NAIF annual report, interviewees valued performance benchmarking with other hospitals, the use of visual representations and the inclusion of case studies and recommendations. Participants stated that feedback should target front-line healthcare professionals, be straightforward and focused, and be delivered through an encouraging and honest discussion. Interviewees highlighted the value of using other relevant data sources alongside NAIF feedback and the importance of continuous data monitoring. Participants reported that engagement of front-line staff in the NAIF and following improvement activities was critical. Leadership, ownership, management support and communication at different organisational levels were perceived as enablers, while staffing level and turnover, and poor quality improvement (QI) skills, were perceived as barriers to improvement. Reported changes in practice included increased awareness and attention to patient safety issues and greater involvement of patients and staff in falls prevention activities. Conclusions There is scope to improve the use of NCAs by front-line staff. NCAs should not be seen as isolated interventions but should be fully embedded and integrated into the QI strategic and operational plans of NHS trusts. The use of NCAs could be optimised, but knowledge of them is poor and distributed unevenly across different disciplines. More research is needed to provide guidance on key elements to consider throughout the whole improvement process at different organisational levels.

Nitidulidae trapping performed from 2018 to 2021 to characterize flight behaviors of potential vectors of the oak wilt pathogen yielded three new species records for Canada, six new species records for Ontario, and three new species records for Manitoba. The new records for Canada include Carpophilus (Ecnomorphus) corticinus reported from Ontario, C. (Myothorax) nepos reported from Ontario and Manitoba, and Glischrochilus (Librodor) obtusus reported from Ontario. In addition, the following species are first recorded in Ontario: Carpophilus (Ecnomorphus) antiquus, C. (Megacarpolus) sayi, Stelidota coenosa; and also in Manitoba: Carpophilus (Megacarpolus) lugubris and Cychramus adustus. Collection data is provided for the two provinces and national records.

Abstract Background Management of adults with atrial fibrillation (AF) or atrial flutter in the emergency department (ED) includes rate reduction, cardioversion, and stroke prevention. Different approaches to these components of care may lead to variation in frequency of hospitalization and stroke prevention actions, with significant implications for patient experience, cost of care, and risk of complications. Standardization using evidence-based recommendations could reduce variation in management, preventable hospitalizations, and stroke risk. Methods We describe the rationale for our ED-based AF treatment recommendations. We also describe the development of an electronic clinical decision support system (CDSS) to deliver these recommendations to emergency physicians at the point of care. We implemented the CDSS at three pilot sites to assess feasibility and solicit user feedback. We will evaluate the impact of the CDSS on hospitalization and stroke prevention actions using a stepped-wedge cluster randomized pragmatic clinical trial across 13 community EDs in Northern California. Discussion We hypothesize that the CDSS intervention will reduce hospitalization of adults with isolated AF or atrial flutter presenting to the ED and increase anticoagulation prescription in eligible patients at the time of ED discharge and within 30 days. If our hypotheses are confirmed, the treatment protocol and CDSS could be recommended to other EDs to improve management of adults with AF or atrial flutter. Trial registration ClinicalTrials.gov NCT05009225 . Registered on 17 August 2021.

Abstract Dysferlin is a Ca2+-activated lipid binding protein implicated in muscle membrane repair. Recessive variants in DYSF result in dysferlinopathy, a progressive muscular dystrophy. We showed previously that calpain cleavage within a motif encoded by alternatively spliced exon 40a releases a 72 kDa C-terminal minidysferlin recruited to injured sarcolemma. Herein we use CRISPR/Cas9 gene editing to knock out murine Dysf exon 40a, to specifically assess its role in membrane repair and development of dysferlinopathy. We created three Dysf exon 40a knockout (40aKO) mouse lines that each express different levels of dysferlin protein ranging from ~ 90%, ~ 50% and ~ 10–20% levels of wild-type. Histopathological analysis of skeletal muscles from all 12-month-old 40aKO lines showed virtual absence of dystrophic features and normal membrane repair capacity for all three 40aKO lines, as compared with dysferlin-null BLAJ mice. Further, lipidomic and proteomic analyses on 18wk old quadriceps show all three 40aKO lines are spared the profound lipidomic/proteomic imbalance that characterises dysferlin-deficient BLAJ muscles. Collective results indicate that membrane repair does not depend upon calpain cleavage within exon 40a and that ~ 10–20% of WT dysferlin protein expression is sufficient to maintain the muscle lipidome, proteome and membrane repair capacity to crucially prevent development of dysferlinopathy.

Facial emotion recognition (ER) difficulties are associated with mental health and neurodevelopmental conditions, including autism and poorer social functioning. ER interventions may therefore have clinical potential. We investigated the efficacy of ER training (ERT). We conducted three online studies with healthy volunteers completing one ERT session. Studies 1 and 2 included active and control/sham training groups and tested the efficacy of (i) four-emotion ERT (angry, happy, sad and scared) (n = 101), and (ii) six-emotion ERT (adding disgusted and surprised) (n = 109). Study 3 tested generalizability of ERT to non-trained stimuli with groups trained and tested on the same stimuli, or different stimuli (n = 120). Training effects on total correct hits were estimated using linear mixed effects models. We did not observe clear evidence of improvement in study 1 but note the effect was in the direction of improvement (b = 0.02, 95% confidence interval (CI) = −0.02 to 0.07). Study 2 indicated greater total hits following training (b = 0.07, 95% CI = 0.03–0.12). Study 3 demonstrated similar improvement across groups (b = −0.01, 95% CI = −0.05 to 0.02). Our results indicate improved ER (as measured by our task), which generalizes to different facial stimulus sets. Future studies should further explore generalizability, longer-term effects and ERT in populations with known ER difficulties.

Abstract Objectives Efficient and accurate emergency department (ED) triage is critical to prioritize the sickest patients and manage department flow. We explored the use of electronic health record data and advanced predictive analytics to improve triage performance. Methods Using a data set of over 5 million ED encounters of patients 18 years and older across 21 EDs from 2016 to 2020, we derived triage models using deep learning to predict 2 outcomes: hospitalization (primary outcome) and fast‐track eligibility (exploratory outcome), defined as ED discharge with

Abstract Single-cell assays have enriched our understanding of hematopoiesis and, more generally, stem and progenitor cell biology. However, these single-end-point approaches provide only a static snapshot of the state of a cell. To observe and measure dynamic changes that may instruct cell fate, we developed an approach for examining hematopoietic progenitor fate specification using long-term (> 7-day) single-cell time-lapse imaging for up to 13 generations with in situ fluorescence staining of primary human hematopoietic progenitors followed by algorithm-assisted lineage tracing. We analyzed progenitor cell dynamics, including the division rate, velocity, viability, and probability of lineage commitment at the single-cell level over time. We applied a Markov probabilistic model to predict progenitor division outcome over each generation in culture. We demonstrated the utility of this methodological pipeline by evaluating the effects of the cytokines thrombopoietin and erythropoietin on the dynamics of self-renewal and lineage specification in primary human bipotent megakaryocytic-erythroid progenitors (MEPs). Our data support the hypothesis that thrombopoietin and erythropoietin support the viability and self-renewal of MEPs, but do not affect fate specification. Thus, single-cell tracking of time-lapse imaged colony-forming unit assays provides a robust method for assessing the dynamics of progenitor self-renewal and lineage commitment.

While checkpoint inhibitor therapy has revolutionized the treatment landscape of some solid tumors, it has shown limited efficacy in metastatic castration-resistant prostate cancers (mCRPC). A small (~3–5%) but clinically distinct subset of mCRPC tumors have a DNA mismatch repair deficiency (dMMR) and develop a hypermutation phenotype with elevated tumor mutational burden and high microsatellite instability (MSI-H). Retrospective analyses have shown dMMR/MSI-H status to be a predictive biomarker for response to pembrolizumab in prostate tumors. Here, in this report, we present a case of a patient with mCRPC harboring a somatic dMMR who had progressed on pembrolizumab after an initial response. He enrolled on a clinical trial with JNJ-081, a prostate-specific membrane antigen-CD3 bispecific T-cell engager antibody and experienced a partial response with course complicated by cytokine release syndrome. On progression, he was reinitiated on pembrolizumab and experienced an exceptional second response, with his prostate-specific antigen falling from a high of 20.01 to undetectable after 6 weeks and remaining undetectable for >11 months. To our knowledge, this represents the first reported case of bispecific T-cell engager-mediated re-sensitization to checkpoint inhibitor therapy in any cancer.

Abstract Background Artificial intelligence (AI) for healthcare presents potential solutions to some of the challenges faced by health systems around the world. However, it is well established in implementation and innovation research that novel technologies are often resisted by healthcare leaders, which contributes to their slow and variable uptake. Although research on various stakeholders’ perspectives on AI implementation has been undertaken, very few studies have investigated leaders’ perspectives on the issue of AI implementation in healthcare. It is essential to understand the perspectives of healthcare leaders, because they have a key role in the implementation process of new technologies in healthcare. The aim of this study was to explore challenges perceived by leaders in a regional Swedish healthcare setting concerning the implementation of AI in healthcare. Methods The study takes an explorative qualitative approach. Individual, semi-structured interviews were conducted from October 2020 to May 2021 with 26 healthcare leaders. The analysis was performed using qualitative content analysis, with an inductive approach. Results The analysis yielded three categories, representing three types of challenge perceived to be linked with the implementation of AI in healthcare: 1) Conditions external to the healthcare system; 2) Capacity for strategic change management; 3) Transformation of healthcare professions and healthcare practice. Conclusions In conclusion, healthcare leaders highlighted several implementation challenges in relation to AI within and beyond the healthcare system in general and their organisations in particular. The challenges comprised conditions external to the healthcare system, internal capacity for strategic change management, along with transformation of healthcare professions and healthcare practice. The results point to the need to develop implementation strategies across healthcare organisations to address challenges to AI-specific capacity building. Laws and policies are needed to regulate the design and execution of effective AI implementation strategies. There is a need to invest time and resources in implementation processes, with collaboration across healthcare, county councils, and industry partnerships.

Abstract Respiratory viruses are transmitted and acquired via the nasal mucosa, and thereby may influence the nasal metabolome composed of biochemical products produced by both host cells and microbes. Studies of the nasal metabolome demonstrate virus-specific changes that sometimes correlate with viral load and disease severity. Here, we evaluate the nasopharyngeal metabolome of COVID-19 infected individuals and report several small molecules that may be used as potential therapeutic targets. Specimens were tested by qRT-PCR with target primers for three viruses: Influenza A (INFA), respiratory syncytial virus (RSV), and SARS-CoV-2, along with unaffected controls. The nasopharyngeal metabolome was characterized using an LC–MS/MS-based screening kit capable of quantifying 141 analytes. A machine learning model identified 28 discriminating analytes and correctly categorized patients with a viral infection with an accuracy of 96% (R2 = 0.771, Q2 = 0.72). A second model identified 5 analytes to differentiate COVID19-infected patients from those with INFA or RSV with an accuracy of 85% (R2 = 0.442, Q2 = 0.301). Specifically, Lysophosphatidylcholines-a-C18:2 (LysoPCaC18:2) concentration was significantly increased in COVID19 patients (P

Background: The present study explores trauma-related factors (human trafficking or physical or sexual violence during transactional sex) associated with interest in future community mobilization around health and human rights. Community mobilization among persons selling sex aims to help participants overcome trauma and increase self-reliance through peer advocacy and collective action for improved human conditions. However, how violence and human trafficking impact community mobilization participation among men and women selling sex is less known. Methods: The current study uses data (n = 96) from the baseline survey of participants in the pilot Kapihan community mobilization intervention, which recruited 37 men and 59 women from Metro Manila, Philippines. Multiple logistic regression was used to analyze factors (violence, human trafficking) independently associated with the desire to participate in community mobilization, adjusting for socio-demographic variables. Results: An increased interest in participating in community mobilization around health and human rights was significantly associated with having experienced physical or sexual abuse in the sex trade (AOR = 10.86; CI 1.48–79.69) and less history of trafficking (AOR = 0.14; 95% CI 0.02–0.97), adjusting for age, gender, income, number of children, and whether they considered group goals or had previously participated in community mobilization. Conclusion: Understanding the impact of experiences with physical and sexual violence and human trafficking on health and human rights mobilization participation can inform the design and recruitment for future community-based interventions. Further investigation needs to explore why experiences with human trafficking, having more children, or being a woman lessened the desire to mobilize in this Philippines context. Findings imply that trauma may be more complex. More work is needed to better identify interventions for those with a history of being trafficked or victimized by physical or sexual violence during transactional sex exchanges.

This contribution introduces the special issue commemorating the 60th anniversary of International Migration Review. We first review the scholarly themes of articles published in the journal during the last 10 years, since the 50th-anniversary issue. We identify seven broad trends and aspects of international population movements, migration, and the migrant experience, including mixed migration, access to asylum, climate migration, South-South models of integration and assistance, studies of legal and liminal status, and attitudes and national political response to immigrants, as key themes represented in the last decade of IMR articles. We then discuss the process of creating the special issue and introduce the scholars and their contributions to the issue around the analytical and conceptual themes of (i) knowledge, expertise, and policy; (ii) migration theory; (iii) methods and analysis; (iv) assimilation and transnationalism; (v) borders and bordering; (vi) legal statuses and in-between experiences; and (vii) migrant well-being and health. Finally, we reflect on what we have accomplished so far, but also challenges IMR as a journal and the broader community of international migration scholars, practitioners, and advocates to continue to work toward further diversity, interdisciplinarity, innovation, and collaboration in our work. [ABSTRACT FROM AUTHOR]

Abstract The mismatch between when individuals breed and when we think they should breed has been a long‐standing problem in evolutionary ecology. Price et al. is a classic theory paper in this field and is mainly cited for its most obvious result: if individuals with high nutritional condition breed early, then the advantage of breeding early may be overestimated when information on nutritional condition is absent. Price at al.'s less obvious result is that individuals, on average, are expected to breed later than the optimum. Here, we provide an explanation of their non‐intuitive result in terms of hard selection, and go on to show that neither of their results are expected to hold if the relationship between breeding date and nutrition is allowed to evolve. By introducing the assumption that the advantage of breeding early is greater for individuals in high nutritional condition, we show that their most cited result can be salvaged. However, individuals, on average, are expected to breed earlier than the optimum, not later. More generally, we also show that the hard selection mechanisms that underpin these results have major implications for the evolution of plasticity: when environmental heterogeneity becomes too great, plasticity is selected against, prohibiting the evolution of generalists.

Both mast cells and microbiota play important roles in the pathogenesis of Irritable Bowel Syndrome (IBS), however the precise mechanisms are unknown. Using microbiota-humanized IBS mouse model, we show that colonic mast cells and mast cells co-localized with neurons were higher in mice colonized with IBS microbiota compared with those with healthy control (HC) microbiota. In situ hybridization showed presence of IBS, but not control microbiota, in the lamina propria and RNAscope demonstrated frequent co-localization of IBS bacteria and mast cells. TLR4 and H4 receptor expression was higher in mice with IBS microbiota, and in peritoneal-derived and bone marrow-derived mast cells (BMMCs) stimulated with IBS bacterial supernatant, which also increased BMMCs degranulation, chemotaxis, adherence and histamine release. While both TLR4 and H4 receptor inhibitors prevented BMMCs degranulation, only the latter attenuated their chemotaxis. We provide novel insights into the mechanisms, which contribute to gut dysfunction and visceral hypersensitivity in IBS.

Poorer performance in tasks testing executive function (EF) is associated with a range of psychopathologies such as schizophrenia, major depressive disorder (MDD) and anxiety, as well as smoking and alcohol consumption. We used two-sample bidirectional Mendelian randomization to examine whether these may reflect causal relationships and the direction of causation. We used genome-wide association study summary data (N = 17 310 to 848 460) for a common EF factor score (cEF), schizophrenia, MDD, anxiety, smoking initiation, alcohol consumption, alcohol dependence and cannabis use disorder (CUD). We found evidence of increased cEF on reduced schizophrenia liability (OR = 0.10; CI: 0.05 to 0.19; p-value = 3.43 × 10−12), MDD liability (OR = 0.52; CI: 0.38 to 0.72; p-value = 5.23 × 10−05), drinks per week (β = –0.06; CI: –0.10 to −0.02; p-value = 0.003) and CUD liability (OR = 0.27; CI: 0.12 to 0.61; p-value = 1.58 × 10−03). We also found evidence of increased schizophrenia liability (β = −0.04; CI: −0.04 to −0.03; p-value = 3.25 × 10−27) and smoking initiation on decreased cEF (β = −0.06; CI: −0.09 to −0.03; p-value = 6.11 × 10−05). Our results indicate potential causal relationships between cEF and mental health and substance use. Further studies are required to improve our understanding of the underlying mechanisms of these effects, but our results suggest that EF may be a promising intervention target for mental health and substance use.

NK cell deficiencies (NKD) are a type of primary immune deficiency in which the major immunologic abnormality affects NK cell number, maturity, or function. Since NK cells contribute to immune defense against virally infected cells, patients with NKD experience higher susceptibility to chronic, recurrent, and fatal viral infections. An individual with recurrent viral infections and mild hypogammaglobulinemia was identified to have an X-linked damaging variant in the transcription factor gene ELF4. The variant does not decrease expression but disrupts ELF4 protein interactions and DNA binding, reducing transcriptional activation of target genes and selectively impairing ELF4 function. Corroborating previous murine models of ELF4 deficiency (Elf4–/–) and using a knockdown human NK cell line, we determined that ELF4 is necessary for normal NK cell development, terminal maturation, and function. Through characterization of the NK cells of the proband, expression of the proband’s variant in Elf4–/– mouse hematopoietic precursor cells, and a human in vitro NK cell maturation model, we established this ELF4 variant as a potentially novel cause of NKD.

Engaging students in research is critical to their development as atmospheric scientists [...]

Abstract Background Admission rates for emergency department (ED) patients with acute heart failure (AHF) remain elevated. Use of a risk stratification tool could improve disposition decision making by identifying low‐risk patients who may be safe for outpatient management. Methods We performed a secondary analysis of a retrospective, multi‐center cohort of 26,189 ED patients treated for AHF from January 1, 2017 to December 31, 2018. We applied a 30‐day risk model we previously developed and grouped patients into 4 categories (low, low/moderate, moderate, and high) of predicted 30‐day risk of a serious adverse event (SAE). SAE consisted of death or cardiopulmonary resuscitation (CPR), intra‐aorta balloon pump, endotracheal intubation, renal failure requiring dialysis, or acute coronary syndrome. We measured the 30‐day mortality and composite SAE rates among patients by risk category according to ED disposition: direct discharge, discharge after observation, and hospital admission. Results The observed 30‐day mortality and total SAE rates were less than 1% and 2%, respectively, among 25% of patients in the low and low/moderate risk groups. These rates did not vary significantly by ED disposition. An additional 23% of patients were moderate risk and experienced an approximate 2% 30‐day mortality rate. Conclusion Use of a risk stratification tool could help identify lower risk AHF patients who may be appropriate for ED discharge. These findings will help inform prospective testing to determine how this risk tool can augment ED decision making.

The Early Pleistocene was a critical time period in the evolution of eastern African mammal faunas, but fossil assemblages sampling this interval are poorly known from Ethiopia’s Afar Depression. Field work by the Hadar Research Project in the Busidima Formation exposures (~2.7–0.8 Ma) of Hadar in the lower Awash Valley, resulted in the recovery of an early Homo maxilla (A.L. 666-1) with associated stone tools and fauna from the Maka’amitalu basin in the 1990s. These assemblages are dated to ~2.35 Ma by the Bouroukie Tuff 3 (BKT-3). Continued work by the Hadar Research Project over the last two decades has greatly expanded the faunal collection. Here, we provide a comprehensive account of the Maka’amitalu large mammals (Artiodactyla, Carnivora, Perissodactyla, Primates, and Proboscidea) and discuss their paleoecological and biochronological significance. The size of the Maka’amitalu assemblage is small compared to those from the Hadar Formation (3.45–2.95 Ma) and Ledi-Geraru (2.8–2.6 Ma) but includes at least 20 taxa. Bovids, suids, and Theropithecus are common in terms of both species richness and abundance, whereas carnivorans, equids, and megaherbivores are rare. While the taxonomic composition of the Maka’amitalu fauna indicates significant species turnover from the Hadar Formation and Ledi-Geraru deposits, turnover seems to have occurred at a constant rate through time as taxonomic dissimilarity between adjacent fossil assemblages is strongly predicted by their age difference. A similar pattern characterizes functional ecological turnover, with only subtle changes in dietary proportions, body size proportions, and bovid abundances across the composite lower Awash sequence. Biochronological comparisons with other sites in eastern Africa suggest that the taxa recovered from the Maka’amitalu are broadly consistent with the reported age of the BKT-3 tuff. Considering the age of BKT-3 and biochronology, a range of 2.4–1.9 Ma is most likely for the faunal assemblage.

BackgroundYersinia pestis is the causative agent of plague, a zoonosis associated with small mammals. Plague is a severe disease, especially in the pneumonic and septicemic forms, where fatality rates approach 100% if left untreated. The bacterium is primarily transmitted via flea bite or through direct contact with an infected host. The 2017 plague outbreak in Madagascar resulted in more than 2,400 cases and was highlighted by an increased number of pneumonic infections. Standard diagnostics for plague include laboratory-based assays such as bacterial culture and serology, which are inadequate for administering immediate patient care for pneumonic and septicemic plague.Principal findingsThe goal of this study was to develop a sensitive rapid plague prototype that can detect all virulent strains of Y. pestis. Monoclonal antibodies (mAbs) were produced against two Y. pestis antigens, low-calcium response V (LcrV) and capsular fraction-1 (F1), and prototype lateral flow immunoassays (LFI) and enzyme-linked immunosorbent assays (ELISA) were constructed. The LFIs developed for the detection of LcrV and F1 had limits of detection (LOD) of roughly 1-2 ng/mL in surrogate clinical samples (antigens spiked into normal human sera). The optimized antigen-capture ELISAs produced LODs of 74 pg/mL for LcrV and 61 pg/mL for F1 when these antigens were spiked into buffer. A dual antigen LFI prototype comprised of two test lines was evaluated for the detection of both antigens in Y. pestis lysates. The dual format was also evaluated for specificity using a small panel of clinical near-neighbors and other Tier 1 bacterial Select Agents.ConclusionsLcrV is expressed by all virulent Y. pestis strains, but homologs produced by other Yersinia species can confound assay specificity. F1 is specific to Y. pestis but is not expressed by all virulent strains. Utilizing highly reactive mAbs, a dual-antigen detection (multiplexed) LFI was developed to capitalize on the diagnostic strengths of each target.

Objective Veterans Healthcare Administration (VHA) conducted a large demonstration project of a holistic Whole Health approach to care in 18 medical centers, which included making complementary and integrative health (CIH) therapies more widely available. This evaluation examines patterns of service use among Veterans with chronic pain, comparing those with and without PTSD. Methods We assessed the use of Whole Health services in a cohort of Veterans with co-occurring chronic pain and PTSD ( n = 1698; 28.9%), comparing them to Veterans with chronic musculoskeletal pain only (n = 4170; 71.1%). Data was gathered from VA electronic medical records and survey self-report. Whole Health services were divided into Core Whole Health services (e.g., Whole Health coaching) and CIH services (e.g., yoga). Logistic regression was used to determine whether Veterans with co-occurring chronic pain and PTSD utilized more Whole Health services compared to Veterans with chronic pain but without PTSD. Results A total of 40.1% of Veterans with chronic pain and PTSD utilized Core Whole Health services and 53.2% utilized CIH therapies, compared to 28.3% and 40.0%, respectively, for Veterans with only chronic pain. Adjusting for demographics and additional comorbidities, Veterans with comorbid chronic pain and PTSD were 1.24 ( 95% CI : 1.12, 1.35, P ≤ .001) times more likely than Veterans with chronic pain only to use Core Whole Health services, and 1.23 ( 95% CI: 1.14, 1.31, P ≤ .001) times more likely to use CIH therapies. Survey results also showed high interest levels in Core Whole Health services and CIH therapies among Veterans who were not already using these services. Conclusion Early implementation efforts in VHA led to high rates of use of Core Whole Health and CIH therapy use among Veterans with co-occurring chronic pain and PTSD. Future assessments should examine how well these additional services are meeting the needs of Veterans in both groups.

Background Resource utilization among emergency department (ED) patients with possible coronary chest pain is highly variable. Methods and Results Controlled cohort study amongst 21 EDs of an integrated healthcare system examining the implementation of a graded coronary risk stratification algorithm (RISTRA‐ACS [risk stratification for acute coronary syndrome]). Thirteen EDs had access to RISTRA‐ACS within the electronic health record (RISTRA sites) beginning in month 24 of a 48‐month study period (January 2016 to December 2019); the remaining 8 EDs served as contemporaneous controls. Study participants had a chief complaint of chest pain and serum troponin measurement in the ED. The primary outcome was index visit resource utilization (observation unit or hospital admission, or 7‐day objective cardiac testing). Secondary outcomes were 30‐day objective cardiac testing, 60‐day major adverse cardiac events (MACE), and 60‐day MACE‐CR (MACE excluding coronary revascularization). Difference‐in‐differences analyses controlled for secular trends with stratification by estimated risk and adjustment for risk factors, ED physician and facility. A total of 154 914 encounters were included. Relative to control sites, 30‐day objective cardiac testing decreased at RISTRA sites among patients with low (≤2%) estimated 60‐day MACE risk (−2.5%, 95% CI −3.7 to −1.2%, P2%) estimated risk (+2.8%, 95% CI +0.6 to +4.9%, P=0.014), without significant overall change (−1.0%, 95% CI −2.1 to 0.1%, P=0.079). There were no statistically significant differences in index visit resource utilization, 60‐day MACE or 60‐day MACE‐CR. Conclusions Implementation of RISTRA‐ACS was associated with better allocation of 30‐day objective cardiac testing and no change in index visit resource utilization or 60‐day MACE. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03286179.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. From the onset of the pandemic, rapid antigen tests have quickly proved themselves to be an accurate and accessible diagnostic platform. The initial (and still most commonly used antigen tests) for COVID-19 diagnosis were constructed using monoclonal antibodies (mAbs) specific to severe acute respiratory syndrome coronavirus (SARS-CoV) nucleocapsid protein (NP). These mAbs are able to bind SARS-CoV-2 NP due to high homology between the two viruses. However, since first being identified in 2019, SARS-CoV-2 has continuously mutated, and a multitude of variants have appeared. These mutations have an elevated risk of leading to possible diagnostic escape when using tests produced with SARS-CoV-derived mAbs. Here, we established a library of 18 mAbs specific to SARS-CoV-2 NP and used two of these mAbs (1CV7 and 1CV14) to generate a prototype antigen-detection lateral flow immunoassay (LFI). A side-by-side analysis of the 1CV7/1CV14 LFI and the commercially available BinaxNOWTM COVID-19 Antigen CARD was performed. Results indicated the 1CV7/1CV14 LFI outperformed the BinaxNOWTM test in the detection of BA.2, BA.2.12.1, and BA.5 Omicron sub-variants when testing remnant RT-PCR positive patient nasopharyngeal swabs diluted in viral transport media.

Hospital admissions for patients with acute heart failure (AHF) remain high. There is an opportunity to improve alignment between patient risk and admission decision. We recently developed a machine learning (ML)-based model that stratifies emergency department (ED) patients with AHF based on predicted risk of a 30-day severe adverse event. Prior to deploying the algorithm and paired clinical decision support, we sought to understand barriers and opportunities regarding successful implementation. We conducted semi-structured interviews with eight front-line ED providers and surveyed 67 ED providers. Audio-recorded interviews were transcribed and analyzed using thematic analysis, and we had a 65% response rate to the survey. Providers wanted decision support to be streamlined into workflows with minimal disruptions. Most providers wanted assistance primarily with ED disposition decisions, and secondarily with medical management and post-discharge follow-up care. Receiving feedback on patient outcomes after risk tool use was seen as an opportunity to increase acceptance, and few providers (