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Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (CADM3, NALCN, NLRC5, ZNF792, and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level (p

Background & aimsDiscerning whether laryngeal symptoms result from gastroesophageal reflux is clinically challenging and a reliable tool to stratify patients is needed. We aimed to develop and validate a model to predict the likelihood of gastroesophageal reflux disease (GERD) among patients with chronic laryngeal symptoms.MethodsThis multicenter international study collected data from adults with chronic laryngeal symptoms who underwent objective testing (upper gastrointestinal endoscopy and/or ambulatory reflux monitoring) between March 2018 and May 2023. The training phase identified a model with optimal receiver operating characteristic curves, and β coefficients informed a weighted model. The validation phase assessed performance characteristics of the weighted model.ResultsA total of 856 adults, 304 in the training cohort and 552 in the validation cohort, were included. In the training phase, the optimal predictive model (area under the curve, 0.68; 95% CI, 0.62-0.74), was the Cough, Overweight/obesity, Globus, Hiatal Hernia, Regurgitation, and male seX (COuGH RefluX) score, with a lower threshold of 2.5 and an upper threshold of 5.0 to predict proven GERD. In the validation phase, the COuGH RefluX score had an area under the curve of 0.67 (95% CI, 0.62-0.71), with 79% sensitivity and 81% specificity for proven GERD.ConclusionsThe externally validated COuGH RefluX score is a clinically practical model to predict the likelihood of proven GERD. The score classifies most patients with chronic laryngeal symptoms as low/high likelihood of proven GERD, with only 38% remaining as indeterminate. Thus, the COuGH RefluX score can guide diagnostic strategies and reduce inappropriate proton pump inhibitor use or testing for patients referred for evaluation of chronic laryngeal symptoms.

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p

BACKGROUND: Sedentary behavior (SB) is a recognized risk factor for many chronic diseases. ActiGraph and activPAL are two commonly used wearable accelerometers in SB research. The former measures body movement and the latter measures body posture. The goal of the current study is to quantify the pattern and variation of movement (by ActiGraph activity counts) during activPAL-identified sitting events, and examine associations between patterns and health-related outcomes, such as systolic and diastolic blood pressure (SBP and DBP). METHODS: The current study included 314 overweight postmenopausal women, who were instructed to wear an activPAL (at thigh) and ActiGraph (at waist) simultaneously for 24 hours a day for a week under free-living conditions. ActiGraph and activPAL data were processed to obtain minute-level time-series outputs. Multilevel functional principal component analysis (MFPCA) was applied to minute-level ActiGraph activity counts within activPAL-identified sitting bouts to investigate variation in movement while sitting across subjects and days. The multilevel approach accounted for the nesting of days within subjects. RESULTS: At least 90% of the overall variation of activity counts was explained by two subject-level principal components (PC) and six day-level PCs, hence dramatically reducing the dimensions from the original minute-level scale. The first subject-level PC captured patterns of fluctuation in movement during sitting, whereas the second subject-level PC delineated variation in movement during different lengths of sitting bouts: shorter (< 30 minutes), medium (30 -39 minutes) or longer (> 39 minute). The first subject-level PC scores showed positive association with DBP (standardized β ^ : 2.041, standard error: 0.607, adjusted p = 0.007), which implied that lower activity counts (during sitting) were associated with higher DBP. CONCLUSION: In this work we implemented MFPCA to identify variation in movement patterns during sitting bouts, and showed that these patterns were associated with cardiovascular health. Unlike existing methods, MFPCA does not require pre-specified cut-points to define activity intensity, and thus offers a novel powerful statistical tool to elucidate variation in SB patterns and health. TRIAL REGISTRATION: ClinicalTrials.gov NCT03473145; Registered 22 March 2018; https://clinicaltrials.gov/ct2/show/NCT03473145 ; International Registered Report Identifier (IRRID): DERR1-10.2196/28684.

BACKGROUND: Sedentary behavior is a recognized mortality risk factor. The novel and validated convolutional neural network hip accelerometer posture algorithm highly accurately classifies sitting and postural changes compared with accelerometer count cut points. We examined the prospective associations of convolutional neural network hip accelerometer posture-classified total sitting time and mean sitting bout duration with all-cause and cardiovascular disease (CVD) death. METHODS AND RESULTS: Women (n=5856; mean±SD age, 79±7 years; 33% Black women, 17% Hispanic or Latina women, 50% White women) in the Womens Health Initiative Objective Physical Activity and Cardiovascular Health (OPACH) Study wore the ActiGraph GT3X+ for ~7 days from May 2012 to April 2014 and were followed through February 19, 2022 for all-cause and CVD death. The convolutional neural network hip accelerometer posture algorithm classified total sitting time and mean sitting bout duration from GT3X+ output. Over follow-up (median, 8.4 years; range, 0.1-9.9), there were 1733 deaths (632 from CVD). Adjusted Cox regression hazard ratios (HRs) comparing women in the highest total sitting time quartile (>696 min/d) to those in the lowest (15 minutes) to the shortest (

Both wild-type and mutant tau proteins can misfold into prions and self-propagate in the central nervous system of animals and people. To extend the work of others, we investigated the molecular basis of tau prion-mediated neurodegeneration in transgenic (Tg) rats expressing mutant human tau (P301S); this line of Tg rats is denoted Tg12099. We used the rat Prnp promoter to drive the overexpression of mutant tau (P301S) in the human 0N4R isoform. In Tg12099(+/+) rats homozygous for the transgene, ubiquitous expression of mutant human tau resulted in the progressive accumulation of phosphorylated tau inclusions, including silver-positive tangles in the frontal cortices and limbic system. Signs of central nervous system dysfunction were found in terminal Tg12099(+/+) rats exhibiting severe neurodegeneration and profound atrophy of the amygdala and piriform cortex. The greatest increases in tau prion activity were found in the corticolimbic structures. In contrast to the homozygous Tg12099(+/+) rats, we found lower levels of mutant tau in the hemizygous rats, resulting in few neuropathologic changes up to 2 years of age. Notably, these hemizygous rats could be infected by intracerebral inoculation with recombinant tau fibrils or precipitated tau prions from the brain homogenates of sick, aged homozygous Tg12099(+/+) rats. Our studies argue that the regional propagation of tau prions and neurodegeneration in the Tg12099 rats resembles that found in human primary tauopathies. These findings seem likely to advance our understanding of human tauopathies and may lead to effective therapeutics for Alzheimer's disease and other tau prion disorders.

SNCAIP duplication may promote Group 4 medulloblastoma via induction of PRDM6, a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and tested PRDM6 as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.

Data curators play an important role in assessing data quality and take actions that may ultimately lead to better, more valuable data products. This study explores the curation practices of data curators working within US-based data repositories. We performed a survey in January 2021 to benchmark the levels of curation performed by repositories and assess the perceived value and impact of curation on the data sharing process. Our analysis included 95 responses from 59 unique data repositories. Respondents primarily were professionals working within repositories and examined curation performed within a repository setting. A majority 72.6% of respondents reported that data-level curation was performed by their repository and around half reported their repository took steps to ensure interoperability and reproducibility of their repositorys datasets. Curation actions most frequently reported include checking for duplicate files, reviewing documentation, reviewing metadata, minting persistent identifiers, and checking for corrupt/broken files. The most value-add curation action across generalist, institutional, and disciplinary repository respondents was related to reviewing and enhancing documentation. Respondents reported high perceived impact of curation by their repositories on specific data sharing outcomes including usability, findability, understandability, and accessibility of deposited datasets; respondents associated with disciplinary repositories tended to perceive higher impact on most outcomes. Most survey participants strongly agreed that data curation by the repository adds value to the data sharing process and that it outweighs the effort and cost. We found some differences between institutional and disciplinary repositories, both in the reported frequency of specific curation actions as well as the perceived impact of data curation. Interestingly, we also found variation in the perceptions of those working within the same repository regarding the level and frequency of curation actions performed, which exemplifies the complexity of a repository curation work. Our results suggest data curation may be better understood in terms of specific curation actions and outcomes than broadly defined curation levels and that more research is needed to understand the resource implications of performing these activities. We share these results to provide a more nuanced view of curation, and how curation impacts the broader data lifecycle and data sharing behaviors.

PURPOSE: Pregnancy intentions are associated with preconception health behaviors but are understudied among female adolescent and young adult (AYA) cancer survivors. Preconception health is critical for survivors because they face unique risks to fertility and pregnancy from late effects of cancer treatments. This study prospectively assessed the effect of pregnancy intention on physical activity (PA) and smoking behaviors among female AYA survivors. METHODS: A cohort of 1049 female AYA survivors were recruited between 2013 and 2017. Participants were 18-39 years and had completed primary cancer treatment. Longitudinal mixed effects analysis was conducted on participants who completed at least 2 of 4 questionnaires over 1.5 years. Two measures were used to capture multiple dimensions of pregnancy intention. The pregnancy intention score (PIS) captured wanting and planning dimensions and represented a scaled response of low to high intention. The trying dimension captured urgent intention and ranged from not trying, ambivalent (neither attempting nor avoiding pregnancy), and trying now. Intention change was assessed between each consecutive time points. Final analysis was conducted with multiple imputations. RESULTS: Survivors with increased intention measured by trying was associated with increased PA over time (adjusted B [95%CI]: 0.3 [0.01, 0.5]) compared to survivors with no changes or decreased trying intention. PIS was not significantly associated with preconception behaviors. No measure of intention was associated with smoking behavior. CONCLUSIONS: Increasingly urgent pregnancy intention (trying dimension) was associated with higher preconception PA. IMPLICATIONS FOR CANCER SURVIVORS: Screening for immediate intentions can identify AYA survivors in need of early preconception health promotion.

BACKGROUND: Metabolic syndrome varies by socio-demographic characteristics, with younger (18-29 years) and older (50-69 years) Hispanic/Latino having higher prevalence compared to other groups. While there is substantial research on neighborhood influences on cardiometabolic health, there are mixed findings regarding the effects of gentrification and few studies have included Hispanic/Latinos. The role of neighborhood income inequality on metabolic health remains poorly understood. OBJECTIVES: Examined associations of neighborhood gentrification and income inequality with metabolic syndrome (MetSyn) using data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). DESIGN, SETTING AND PARTICIPANTS: The HCHS/SOL is a community-based cohort of adults of Hispanic/Latinos (aged 18-74). Analyses included 6710 adults who did not meet criteria for MetsS at baseline (2008-2011) and completed the visit 2 examination (2014-2017). Poisson regressions estimated odds ratios (IRR) and 95% confidence intervals (CI) for neighborhood gentrification and change in income inequality with MetSyn incidence. MAIN OUTCOME AND EXPOSURE MEASURES: Gentrification was measured with an index that included changes (2000 to 2006-2010) in education, poverty, and income. Change in neighborhood income inequality (2005-2009 to 2012-2016) was measured using the Gini coefficient of income distribution. MetSyn was defined using National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: Among 6647 Hispanic/Latino adults, 23% (N = 1530) had incident MetSyn. In models adjusted for socio-demographic, health insurance status, and neighborhood characteristics, gentrification (IRR, 1.00, 95%CI, 0.96-1.03) and income inequality change (IRR, 1.00, 95%CI, 0.99-1.00) were not associated with MetSyn at visit 2. There was no association between cross-sectional income inequality (2005-2009) and MetSyn at visit 2 (IRR, 0.97, 95%CI, 0.82-1.15). CONCLUSION: Neighborhood gentrification and income inequality change were not associated with incidence of MetSyn over 6 years among Hispanic/Latino adults. This study demonstrated that income-based residential changes alone may not be sufficient to explain neighborhood influences on health outcomes among this population.

BACKGROUND/OBJECTIVES: Sedentary behavior (SB) has both movement and postural components, but most SB research has only assessed low movement, especially in children. The purpose of this study was to compare estimates and health associations of SB when derived from a standard accelerometer cut-point, a novel sitting detection technique (CNN Hip Accelerometer Posture for Children; CHAP-Child), and both combined. METHODS: Data were from the International Study of Childhood Obesity, Lifestyle, and the Environment (ISCOLE). Participants were 6103 children (mean ± SD age 10.4 ± 0.56 years) from 12 countries who wore an ActiGraph GT3X+ accelerometer on the right hip for approximately one week. We calculated SB time, mean SB bout duration, and SB breaks using a cut-point (SBmovement), CHAP-Child (SBposture), and both methods combined (SBcombined). Mixed effects regression was used to test associations of SB variables with pediatric obesity variables (waist circumference, body fat percentage, and body mass index z-score). RESULTS: After adjusting for MVPA, SBposture showed several significant obesity associations favoring lower mean SB bout duration (b = 0.251-0.449; all p

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

PURPOSE: Sleep-disordered breathing (SDB) is a common sleep disorder in veterans; however, limited research exists in women veterans. We sought to estimate patterns of care in terms of evaluation, diagnosis, and treatment among women veterans with factors associated with elevated SDB risk. METHODS: Within one VA healthcare system, women identified through electronic health record data as having one or more factors (e.g., age >50 years, hypertension) associated with SDB, completed telephone screening in preparation for an SDB treatment study and answered questions about prior care related to SDB diagnosis and treatment. RESULTS: Of 319 women, 111 (35%) reported having completed a diagnostic sleep study in the past, of whom 48 (43%) were diagnosed with SDB. Women who completed a diagnostic study were more likely to have hypertension or obesity. Those who were diagnosed with SDB based on the sleep study were more likely to have hypertension, diabetes, or be ≥50 years old. Of the 40 women who received treatment, 37 (93%) received positive airway pressure therapy. Only 9 (24%) had used positive airway pressure therapy in the prior week. Few women received other treatments such as oral appliances or surgery. CONCLUSIONS: Findings support the need for increased attention to identification and management of SDB in women veterans, especially those with conditions associated with elevated SDB risk.

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes.

INTRODUCTION: High-resolution manometry (HRM) and functional lumen imaging probe (FLIP) are primary and/or complementary diagnostic tools for the evaluation of esophageal motility. We aimed to assess the interrater agreement and accuracy of HRM and FLIP interpretations. METHODS: Esophageal motility specialists from multiple institutions completed the interpretation of 40 consecutive HRM and 40 FLIP studies. Interrater agreement was assessed using intraclass correlation coefficient (ICC) for continuous variables and Fleiss κ statistics for nominal variables. Accuracies of rater interpretation were assessed using the consensus of 3 experienced raters as the reference standard. RESULTS: Fifteen raters completed the HRM and FLIP studies. An excellent interrater agreement was seen in supine median integral relaxation pressure (ICC 0.96, 95% confidence interval 0.95-0.98), and a good agreement was seen with the assessment of esophagogastric junction (EGJ) outflow, peristalsis, and assignment of a Chicago Classification version 4.0 diagnosis using HRM (κ = 0.71, 0.75, and 0.70, respectively). An excellent interrater agreement for EGJ distensibility index and maximum diameter (0.91 [0.90-0.94], 0.92 [0.89-0.95]) was seen, and a moderate-to-good agreement was seen in the assignment of EGJ opening classification, contractile response pattern, and motility classification (κ = 0.68, 0.56, and 0.59, respectively) on FLIP. Rater accuracy for Chicago Classification version 4.0 diagnosis on HRM was 82% (95% confidence interval 78%-84%) and for motility diagnosis on FLIP Panometry was 78% (95% confidence interval 72%-81%). DISCUSSION: Our study demonstrates high levels of interrater agreement and accuracy in the interpretation of HRM and FLIP metrics and moderate-to-high levels for motility classification in FLIP, supporting the use of these approaches for primary or complementary evaluation of esophageal motility disorders.

Pancreatic cancer is difficult to resect due to its unique challenges, often leading to incomplete tumor resections. Fluorescence-guided surgery (FGS), also known as intraoperative molecular imaging and optical surgical navigation, is an intraoperative tool that can aid surgeons in complete tumor resection through an increased ability to detect the tumor. To target the tumor, FGS contrast agents rely on biomarkers aberrantly expressed in malignant tissue compared to normal tissue. These biomarkers allow clinicians to identify the tumor and its stage before surgical resection and provide a contrast agent target for intraoperative imaging. Mucins, a family of glycoproteins, are upregulated in malignant tissue compared to normal tissue. Therefore, these proteins may serve as biomarkers for surgical resection. Intraoperative imaging of mucin expression in pancreatic cancer can potentially increase the number of complete resections. While some mucins have been studied for FGS, the potential ability to function as a biomarker target extends to the entire mucin family. Therefore, mucins are attractive proteins to investigate more broadly as FGS biomarkers. This review summarizes the biomarker traits of mucins and their potential use in FGS for pancreatic cancer.

Human milk contains all of the essential nutrients required by the infant within a complex matrix that enhances the bioavailability of many of those nutrients. In addition, human milk is a source of bioactive components, living cells and microbes that facilitate the transition to life outside the womb. Our ability to fully appreciate the importance of this matrix relies on the recognition of short- and long-term health benefits and, as highlighted in previous sections of this supplement, its ecology (i.e., interactions among the lactating parent and breastfed infant as well as within the context of the human milk matrix itself). Designing and interpreting studies to address this complexity depends on the availability of new tools and technologies that account for such complexity. Past efforts have often compared human milk to infant formula, which has provided some insight into the bioactivity of human milk, as a whole, or of individual milk components supplemented with formula. However, this experimental approach cannot capture the contributions of the individual components to the human milk ecology, the interaction between these components within the human milk matrix, or the significance of the matrix itself to enhance human milk bioactivity on outcomes of interest. This paper presents approaches to explore human milk as a biological system and the functional implications of that system and its components. Specifically, we discuss study design and data collection considerations and how emerging analytical technologies, bioinformatics, and systems biology approaches could be applied to advance our understanding of this critical aspect of human biology.

As of March 31, 2023, more than 30,000 monkeypox (mpox) cases had been reported in the United States in an outbreak that has disproportionately affected gay, bisexual, and other men who have sex with men (MSM) and transgender persons (1). JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic) was approved by the Food and Drug Administration (FDA) in 2019 for the prevention of smallpox and mpox via subcutaneous injection as a 2-dose series (0.5 mL per dose, administered 4 weeks apart) (2). To expand vaccine access, an Emergency Use Authorization was issued by FDA on August 9, 2022, for dose-sparing intradermal injection of JYNNEOS as a 2-dose series (0.1 mL per dose, administered 4 weeks apart) (3). Vaccination was available to persons with known or presumed exposure to a person with mpox (postexposure prophylaxis [PEP]), as well as persons at increased risk for mpox or who might benefit from vaccination (preexposure mpox prophylaxis [PrEP]) (4). Because information on JYNNEOS vaccine effectiveness (VE) is limited, a matched case-control study was conducted in 12 U.S. jurisdictions,† including nine Emerging Infections Program sites and three Epidemiology and Laboratory Capacity sites,§ to evaluate VE against mpox among MSM and transgender adults aged 18-49 years. During August 19, 2022-March 31, 2023, a total of 309 case-patients were matched to 608 control patients. Adjusted VE was 75.2% (95% CI = 61.2% to 84.2%) for partial vaccination (1 dose) and 85.9% (95% CI = 73.8% to 92.4%) for full vaccination (2 doses). Adjusted VE for full vaccination by subcutaneous, intradermal, and heterologous routes of administration was 88.9% (95% CI = 56.0% to 97.2%), 80.3% (95% CI = 22.9% to 95.0%), and 86.9% (95% CI = 69.1% to 94.5%), respectively. Adjusted VE for full vaccination among immunocompromised participants was 70.2% (95% CI = -37.9% to 93.6%) and among immunocompetent participants was 87.8% (95% CI = 57.5% to 96.5%). JYNNEOS is effective at reducing the risk for mpox. Because duration of protection of 1 versus 2 doses remains unknown, persons at increased risk for mpox exposure should receive the 2-dose series as recommended by the Advisory Committee on Immunization Practices (ACIP),¶ regardless of administration route or immunocompromise status.

STUDY OBJECTIVES: We examined whether women service members and veterans who reported recent combat and/or sexual trauma experiences had a greater risk of insomnia compared with women who did not report these recent experiences, and whether insomnia would be associated with a greater risk of mental health outcomes. METHODS: We analyzed two waves of survey data (2011-2013, Time 1 [T1] and 2014-2016, Time 2 [T2]) from 26 443 current and former women service members from the Millennium Cohort Study. We assessed recent traumas in the past 3 years, and probable insomnia at T1 and probable post-traumatic stress disorder (PTSD) and depression at T2. A longitudinal mediation model was used to quantify separate indirect effects of recent traumas on mental health outcomes through probable insomnia. RESULTS: Women who had experienced recent sexual assault (odds ratio [OR] = 1.68; 95% CI = 1.24-2.10), sexual harassment (OR = 1.22; 95% CI = 1.05-1.41), and combat (OR = 1.34; 95% CI = 1.20-1.49) at T1 had a greater risk of probable insomnia at T1 compared with women who had not recently experienced these events. Probable insomnia at T1, in turn, was associated with probable depression (OR = 2.66; 95% CI = 2.31-3.06) and PTSD (OR = 2.57; 95% CI = 2.27-2.90) at T2. Recent combat experience did not moderate the associations of recent sexual trauma with insomnia or mental health outcomes. CONCLUSIONS: Insomnia contributes to the risk of subsequent mental health conditions following trauma. The diagnosis and treatment of post-trauma insomnia should be prioritized to mitigate the development of posttraumatic mental health conditions.

BACKGROUND: The functional lumen imaging probe (FLIP) evaluates esophagogastric junction (EGJ) opening and esophageal contractility. Both post hoc and real-time analyses are possible, but reproducibility and reliability of analysis remain undefined. This study assesses inter- and intra-rater agreement of normative FLIP measurements among novice and experienced users. METHODS: Eight motility experts from different institutions independently evaluated de-identified video recordings from 27 asymptomatic healthy subjects using FLIP. Interpretation methods simulating a post-procedure and a live procedure setting were tested. Novice FLIP users (n = 3) received training prior to post-procedure interpretation. Experienced FLIP users (n = 5) interpreted using both methods. Users recorded maximum EGJ and distal esophageal body diameter, distensive pressure, and EGJ distensibility index (EGJ-DI), at balloon fill volumes of 50-, 60-, and 70 ml, as well as repetitive antegrade contractions (RACs). Inter- and intra-rater agreements of diameters, distensive pressure and EGJ-DI were assessed by intra-class correlation coefficient (ICC) and Pearsons correlation coefficient (PCC). Percentage agreement evaluated inter- and intra-rater reliability for RACs. KEY RESULTS: Novice and experienced users acquired normative FLIP metrics. Good-to-excellent inter- and intra-rater reliability were achieved for all variables at 60 ml balloon fill volumes. Median parameters at 60 ml balloon fill volume were as follows: EGJ-DI 5.5 mm2 /mmHg, maximum EGJ diameter 18.6 mm, distensive pressure at maximum EGJ diameter 48.1 mmHg, and distal esophageal body diameter 19.5 mm. CONCLUSIONS AND INFERENCES: Normative FLIP parameters can be reliably extracted from FLIP videos using both real-time and post hoc analyses, with high reliability between experienced and novice users.

In several neurodegenerative disorders, the neuronal proteins tau and α-synuclein adopt aggregation-prone conformations capable of replicating within and between cells. To better understand how these conformational changes drive neuropathology, we compared the interactomes of tau and α-synuclein in the presence or the absence of recombinant fibril seeds. Human embryonic stem cells with an inducible neurogenin-2 transgene were differentiated into glutamatergic neurons expressing (1) WT 0N4R tau, (2) mutant (P301L) 0N4R tau, (3) WT α-synuclein, or (4) mutant (A53T) α-synuclein, each genetically fused to a promiscuous biotin ligase (BioID2). Neurons expressing unfused BioID2 served as controls. After treatment with fibrils or PBS, interacting proteins were labeled with biotin in situ and quantified using mass spectrometry via tandem mass tag labeling. By comparing interactions in mutant versus WT neurons and in fibril- versus PBS-treated neurons, we observed changes in protein interactions that are likely relevant to disease progression. We identified 45 shared interactors, suggesting that tau and α-synuclein function within some of the same pathways. Potential loci of shared interactions include microtubules, Wnt signaling complexes, and RNA granules. Following fibril treatment, physiological interactions decreased, whereas other interactions, including those between tau and 14-3-3 η, increased. We confirmed that 14-3-3 proteins, which are known to colocalize with protein aggregates during neurodegeneration, can promote or inhibit tau aggregation in vitro depending on the specific combination of 14-3-3 isoform and tau sequence.

Assessing health outcomes associated with exposure to polychlorinated biphenyls (PCBs) is important given their persistent and ubiquitous nature. PCBs are classified as a Group 1 carcinogen, but the full range of potential noncancer health effects from exposure to PCBs has not been systematically summarized and evaluated. We used systematic review methods to identify and screen the literature using combined manual review and machine learning approaches. A protocol was developed that describes the literature search strategy and Populations, Exposures, Comparators, and Outcomes (PECO) criteria used to facilitate subsequent screening and categorization of literature into a systematic evidence map of PCB exposure and noncancer health endpoints across 15 organs/systems. A comprehensive literature search yielded 62,599 records. After electronic prioritization steps, 17,037 studies were manually screened at the title and abstract level. An additional 900 studies identified by experts or supplemental searches were also included. After full-text screening of 3889 references, 1586 studies met the PECO criteria. Relevant study details such as the endpoints assessed, exposure duration, and species were extracted into literature summary tables. This review compiles and organizes the human and mammalian studies from these tables into an evidence map for noncancer health endpoints and PCB mixture exposure to identify areas of robust research as well as areas of uncertainty that would benefit from future investigation. Summary data are available online as interactive visuals with downloadable metadata. Sufficient research is available to inform PCB hazard assessments for most organs/systems, but the amount of data to inform associations with specific endpoints differs. Furthermore, despite many years of research, sparse data exist for inhalation and dermal exposures, which are highly relevant human exposure routes. This evidence map provides a foundation for future systematic reviews and noncancer hazard assessments of PCB mixtures and for strategic planning of research to inform areas of greater uncertainty.

PURPOSE: Examine the association between neighborhood segregation and 6-year incident metabolic syndrome (MetSyn) in the Hispanic Community Health Study/Study of Latinos. METHODS: Prospective cohort of adults residing in Miami, Chicago, the Bronx, and San Diego. The analytic sample included 6,710 participants who did not have MetSyn at baseline. The evenness and exposure dimensions of neighborhood segregation, based on the Gini and Isolation indices, respectively, were categorized into quintiles (Q). Racialized economic concentration was measured with the Index of Concentration at the Extremes (continuously and Q). RESULTS: Exposure, but not evenness, was associated with higher disease odds (Q1 (lower segregation) vs. Q4, OR = 1.53, 95% CI = 1.082.17; Q5, OR = 2.29, 95% CI = 1.493.52). Economic concentrationprivilege (continuous OR = 0.87, 95% CI = 0.770.98), racial concentrationracialized privilege (Q1 (greater concentration) vs. Q2 OR = 0.75, 95% CI = 0.541.04; Q3 OR = 0.68, 95% CI = 0.441.05; Q4 OR = 0.68, 95% CI = 0.451.01; Q5 OR = 0.64, 95% CI = 0.420.98)(continuous OR = 0.93, 95% CI = 0.821.04), and racialized economic concentrationprivilege (i.e., higher SES non-Hispanic White, continuous OR = 0.86, 95% CI = 0.760.98) were associated with lower disease odds. CONCLUSION: Hispanics/Latino adults residing in neighborhoods with high segregation had higher risk of incident MetSyn compared to those residing in neighborhoods with low segregation. Research is needed to identify the mechanisms that link segregation to poor metabolic health.

DISCLOSURES: Funding for this summary was contributed by Blue Cross Blue Shield of MA, California Healthcare Foundation, The Patrick and Catherine Weldon Donaghue Medical Research Foundation, Arnold Ventures, and Kaiser Foundation Health Plan Inc., to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, AbbVie, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy Solutions, Express Scripts, Genentech/ Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health First, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer. Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, Sun Life Financial, uniQure, and United Healthcare. Mr Nikitin, Ms McKenna, Ms Richardson, and Drs Rind and Pearson are employed by ICER. Through their affiliated institutions, Drs Makam, Carlson, and Suh received funding from ICER for the work described in this summary.

Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

Drug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly in a pandemic scenario. In response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. However, it is unknown if different statins exhibit consistent function or may have varying therapeutic benefit. A Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2. Top drug predictions included statins, which were then assessed using electronic medical records containing over 4,000 COVID-19 patients on statins to determine mortality risk in patients prescribed specific statins versus untreated matched controls. The same drugs were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus. Simvastatin was among the most highly predicted compounds (14/14 datasets) and five other statins, including atorvastatin, were predicted to be active in > 50% of analyses. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin. In vitro testing of SARS-CoV-2 infected cells revealed simvastatin to be a potent direct inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells. Statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared drug target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and clinically evaluate non-obvious mechanisms and derisk and accelerate drug repurposing opportunities.

Mobile devices offer a scalable opportunity to collect longitudinal data that facilitate advances in mental health treatment to address the burden of mental health conditions in young people. Sharing these data with the research community is critical to gaining maximal value from rich data of this nature. However, the highly personal nature of the data necessitates understanding the conditions under which young people are willing to share them. To answer this question, we developed the MindKind Study, a multinational, mixed methods study that solicits young people's preferences for how their data are governed and quantifies potential participants' willingness to join under different conditions. We employed a community-based participatory approach, involving young people as stakeholders and co-researchers. At sites in India, South Africa, and the UK, we enrolled 3575 participants ages 16-24 in the mobile app-mediated quantitative study and 143 participants in the public deliberation-based qualitative study. We found that while youth participants have strong preferences for data governance, these preferences did not translate into (un)willingness to join the smartphone-based study. Participants grappled with the risks and benefits of participation as well as their desire that the "right people" access their data. Throughout the study, we recognized young people's commitment to finding solutions and co-producing research architectures to allow for more open sharing of mental health data to accelerate and derive maximal benefit from research.

BackgroundType II achalasia (Ach2) is distinguished from other achalasia sub-types by the presence of panesophageal pressurization (PEP) of ≥30 mmHg in ≥20% swallows on high-resolution manometry (HRM). Variable manometric features in Ach2 have been observed, characterized by focal elevated pressures (FEPs) (focal/segmental pressures ≥70 mmHg within the PEP band) and/or high compression pressures (PEP ≥70 mmHg). This study aimed to examine clinical and physiologic variables among sub-groups of Ach2.MethodsThis retrospective single center study performed over 3 years (1/2019-1/2022) included adults with Ach2 on HRM who underwent endoscopic ultrasound (EUS), functional lumen imaging probe (FLIP), and/or barium esophagram (BE) prior to therapy. Patients were categorized into two overarching sub-groups: Ach2 without FEPs and Ach2 with FEPs. Demographic, clinical, and physiologic data were compared between these sub-groups utilizing unpaired univariate analyses.Key resultsOf 53 patients with Ach2, 40 (75%) were without FEPs and 13 (25%) had FEPs. Compared with the Ach2 sub-group without FEPs, the Ach2 sub-group with FEPs demonstrated a significantly thickened distal esophageal circular muscle on EUS (1.4 mm [SD 0.9] vs. 2.1 [0.7]; p = 0.02), higher prevalence of tertiary contractions on BE (46% vs. 100%; p = 0.0006), lower esophagogastric junction distensibility index (2.2mm2 /mmHg [0.9] vs 0.9 [0.4]; p = 0.0008) as well as higher distensive pressure (31.0 mmHg [9.8] vs. 55.4 [18.8]; p = 0.01) at 60 cc fill on FLIP, and higher prevalence of chest pain on Eckardt score (p = 0.03).Conclusions and inferencesWe identified a distinct sub-group of type II achalasia on HRM, defined as type II achalasia with focal elevated pressures. This sub-group uniquely exhibits spastic features and may benefit from personalized treatment approaches.

The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 is responsible for compaction of the ∼30-kb RNA genome in the ∼90-nm virion. Previous studies suggest that each virion contains 35 to 40 viral ribonucleoprotein (vRNP) complexes, or ribonucleosomes, arrayed along the genome. There is, however, little mechanistic understanding of the vRNP complex. Here, we show that N protein, when combined in vitro with short fragments of the viral genome, forms 15-nm particles similar to the vRNP structures observed within virions. These vRNPs depend on regions of N protein that promote protein-RNA and protein-protein interactions. Phosphorylation of N protein in its disordered serine/arginine region weakens these interactions to generate less compact vRNPs. We propose that unmodified N protein binds structurally diverse regions in genomic RNA to form compact vRNPs within the nucleocapsid, while phosphorylation alters vRNP structure to support other N protein functions in viral transcription.

Risk management has reduced vulnerability to floods and droughts globally1,2, yet their impacts are still increasing3. An improved understanding of the causes of changing impacts is therefore needed, but has been hampered by a lack of empirical data4,5. On the basis of a global dataset of 45 pairs of events that occurred within the same area, we show that risk management generally reduces the impacts of floods and droughts but faces difficulties in reducing the impacts of unprecedented events of a magnitude not previously experienced. If the second event was much more hazardous than the first, its impact was almost always higher. This is because management was not designed to deal with such extreme events: for example, they exceeded the design levels of levees and reservoirs. In two success stories, the impact of the second, more hazardous, event was lower, as a result of improved risk management governance and high investment in integrated management. The observed difficulty of managing unprecedented events is alarming, given that more extreme hydrological events are projected owing to climate change3.

IntroductionThis study examines the associations of neighborhood environments with BMI, HbA1c, and diabetes across 6 years in Hispanic/Latino adults.MethodsParticipants from the Hispanic Community Health Study/Study of Latinos San Diego site (n=3,851, mean age=39.4 years, 53.3% women, 94.0% Mexican heritage) underwent assessment of metabolic risk factors and diabetes status (categorized as normoglycemia, prediabetes, and diabetes) at baseline (2008-2011) and approximately 6 years later (2014-2017). In the Study of Latinos Community and Surrounding Areas Study ancillary study (2015-2020), participant baseline addresses were geocoded, and neighborhoods were defined using 800-meter circular buffers. Neighborhood variables representing socioeconomic deprivation, residential stability, social disorder, walkability, and greenness were created using Census and other public databases. Analyses were conducted in 2020-2021.ResultsComplex survey regression analyses revealed that greater neighborhood socioeconomic deprivation was associated with higher BMI (β=0.14, p

BackgroundThe availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.MethodsWe conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.ResultsTwo blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P

BackgroundA better understanding of the extent to which psychosocial and environmental correlates of physical activity are specific to locations would inform intervention optimization.PurposeTo investigate cross-sectional associations of location-general and location-specific variables with physical activity and sedentary time in three common locations adolescents spend time.MethodsAdolescents (N = 472,Mage = 14.1,SD = 1.5) wore an accelerometer and global positioning systems (GPS) tracker and self-reported on psychosocial (e.g., self-efficacy) and environmental (e.g., equipment) factors relevant to physical activity and sedentary time. We categorized each survey item based on whether it was specific to a location to generate psychosocial and environmental indices that were location-general or specific to either school, non-school, or home location. Physical activity (MVPA) and sedentary time were based on time/location match to home, school, or all "other" locations. Mixed-effects models investigated the relation of each index with location-specific activity.ResultsThe location-general and non-school physical activity psychosocial indices were related to greater MVPA at school and "other" locations. The school physical activity environment index was related to greater MVPA and less sedentary time at school. The home activity environment index was related to greater MVPA at home. The non-school sedentary psychosocial index was related to less sedentary time at home. Interactions among indices revealed adolescents with low support on one index benefited (i.e., exhibited more optimal behavior) from high support on another index (e.g., higher scores on the location-general PA psychosocial index moderated lower scores on the home PA environment index). Concurrent high support on two indices did not provide additional benefit.ConclusionsNo psychosocial or environment indices, including location-general indices, were related to activity in all locations. Most of the location-specific indices were associated with activity in the matching location(s). These findings provide preliminary evidence that psychosocial and environmental correlates of activity are location specific. Future studies should further develop location-specific measures and evaluate these constructs and whether interventions may be optimized by targeting location-specific psychosocial and environmental variables across multiple locations.

Despite experiencing health inequities, less is known about neighborhood environments and physical activity among Hispanic/Latino adults compared to other populations. We investigated this topic in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Hispanic/Latino adults in the San Diego, California area of the U.S. completed measures of overall moderate-to-vigorous physical activity (MVPA) via accelerometry and domain-specific MVPA via questionnaire at Visits 1 (2008-2011; n = 4086) and 2 (2014-2017; n = 1776), ~6 years apart. 800-m home neighborhood buffers were used to create objective measures of residential, intersection, and retail density, bus/trolley stops, greenness, parks, and recreation area at Visit 1. Regression models tested the association of each neighborhood feature with MVPA at Visit 1 and over 6 years, adjusting for individual characteristics and neighborhood socioeconomic deprivation. At Visit 1, those in neighborhoods with higher vs. lower retail density or recreation area (+1 vs. -1 standard deviation from the mean) engaged in 10% more overall MVPA and 12-22% more active transportation. Those in neighborhoods with higher vs. lower residential density engaged in 22% more active transportation. Those in neighborhoods with higher vs. lower greenness and park count engaged in 14-16% more recreational MVPA. Neighborhood features were unassociated with changes in MVPA over 6 years. Although changes in MVPA over time were similar across neighborhoods, Hispanic/Latino adults living in neighborhoods with design features supportive of walking and recreational activity (e.g., greater residential and retail density, more parks and recreation facilities) were consistently more active. Improving neighborhood environments appears important for supporting physical activity among Hispanic/Latino adults.

PurposeTo characterize current experiences with communication and decision-making practices when non-medical switching to a biosimilar trastuzumab is proposed or required by cancer center or insurer.MethodsWe developed and launched 60- and 51-item internet surveys to elicit US breast cancer patient and medical oncologist lived experiences with trastuzumab biosimilars and patient information needs and seeking practices. We recruited participants using social media and administered via REDCap in 2020-2021.Results143 breast cancer patients and 33 medical oncologists completed the surveys. 63.9% patients reported having switched to a trastuzumab biosimilar and 40.8% reported receiving no prior notification about switching. 44% of patients reported learning about biosimilars primarily through self-directed learning and 41% wanting more time to discuss with oncologist. None of the oncologists reported that the decision to switch a patient to a biosimilar was initiated by them, but rather more frequently by the insurer (45.2%). About 54.8% reported not receiving any pharmaceutical manufacturer material related to the selected biosimilar. Patients and oncologists diverged in their responses to items regarding patient opportunities to ask questions, adequacy of resources, effectiveness of treatment, patient worry, and magnitude of change.ConclusionThere is a need for tailored and effective patient and oncologist information and education on trastuzumab biosimilars, along with improved healthcare communication regarding switching. The discrepancy between patient-reported experiences and oncologist perceptions of the patient experience, suggests a lack of adequate information that may be a challenge not only to the uptake of trastuzumab biosimilars, but to the patient-oncologist relationship.

BackgroundMycoplasma hominis can cause significant infections after solid organ transplantation (SOT). Treatment should be guided by susceptibility testing, but conventional lab methods are laborious with prolonged turnaround time (TAT). This case series compares the phenotypic and genotypic susceptibility profiles of M. hominis isolates identified from SOT patients.MethodsThis is a single-center retrospective study evaluating SOT recipients with confirmed M. hominis infections. Patients' demographic, clinical, microbiological, and radiographic data were collected. Culture of M. hominis isolates was performed according to current Clinical and Laboratory Standards Institute guidelines. Phenotypic susceptibility testing was performed by University of Alabama Diagnostic Mycoplasma Laboratory. Whole genome sequencing (WGS) was performed followed by bioinformatic analysis of known genetic determinants of resistance.ResultsSeven SOT recipients with M. hominis infections were identified. Two out of seven (28.5%) patients had resistance detected by phenotypic susceptibility testing (Case 5 to levofloxacin and Case 7 to tetracycline). Genomic analyses confirmed the presence of mutations in the parC and parE topoisomerase genes at positions conferring to fluoroquinolone resistance in the isolate from Case 5, while the tetracycline-resistant isolate from Case 7 harbored the tetM gene. The median TAT from the date of specimen collection was 24 days for phenotypic susceptibility testing and 14 days for genotypic susceptibility testing. All seven patients received antimicrobials directed toward M. hominis and recovered with complete resolution of infection.ConclusionsWGS may offer a novel and more rapid methodology for M. hominis susceptibility testing to help optimize antimicrobial usage, but more data are needed.

BACKGROUND: Upper endoscopy (EGD) is frequently performed in patients with esophageal complaints following anti-reflux surgery such as fundoplication. Endoscopic evaluation of fundoplication wrap integrity can be challenging. Our primary aim in this pilot study was to evaluate the accuracy and confidence of assessing Nissen fundoplication integrity and hiatus herniation among gastroenterology (GI) fellows, subspecialists, and foregut surgeons. METHODS: Five variations of post-Nissen fundoplication anatomy were included in a survey of 20 sets of EGD images that was completed by GI fellows, general GI attendings, esophagologists, and foregut surgeons. Accuracy, diagnostic confidence, and inter-rater agreement across providers were evaluated. RESULTS: There were 31 respondents in the final cohort. Confidence in pre-survey diagnostics significantly differed by provider type (mean confidence out of 5 was 1.8 for GI fellows, 2.7 for general GI attendings, 3.6 for esophagologists, and 3.6 for foregut surgeons, P = 0.01). The mean overall accuracy was 45.9%, which significantly differed by provider type with the lowest rate among GI fellows (37%) and highest among esophagologists (53%; P = 0.01). The accuracy was highest among esophagologists across all wrap integrity variations. Inter-rater agreement was low across wrap integrity variations (Krippendorfs alpha

Interferon restricts SARS-CoV-2 replication in cell culture, but only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identify DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 and SARS-CoV replication in human cells. Basal expression of DAXX is sufficient to limit the replication of SARS-CoV-2, and DAXX over-expression further restricts infection. DAXX restricts an early, post-entry step of the SARS-CoV-2 life cycle. DAXX-mediated restriction of SARS-CoV-2 is independent of the SUMOylation pathway but dependent on its D/E domain, also necessary for its protein-folding activity. SARS-CoV-2 infection triggers the re-localization of DAXX to cytoplasmic sites and promotes its degradation. Mechanistically, this process is mediated by the viral papain-like protease (PLpro) and the proteasome. Together, these results demonstrate that DAXX restricts SARS-CoV-2, which in turn has evolved a mechanism to counteract its action.

Aims/hypothesisType 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA1c, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA1c in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study.MethodsWe conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA1c (n = 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci.ResultsFour novel associations were identified (p < 5 × 10-9), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known GCK locus and for fasting insulin at the known PPP1R3B locus in transethnic meta-analysis.Conclusions/interpretationOur findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations.Data availabilityFull summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog ( https://www.ebi.ac.uk/gwas/downloads/summary-statistics ).

ObjectiveThis study compared the benefits of cognitive-behavioral therapy for insomnia for sleep, mental health symptoms, and quality of life (QoL) in a sample of women veterans with and without probable post-traumatic stress disorder (PTSD) comorbid with insomnia disorder.MethodsSeventy-three women veterans (30 with probable PTSD) received a manual-based 5-week cognitive-behavioral therapy for insomnia treatment as part of a behavioral sleep intervention study. Measures were completed at baseline, post-treatment, and 3-month follow-up. Sleep measures included the Insomnia Severity Index, Pittsburgh Sleep Quality Index, sleep efficiency measured by actigraphy, and sleep efficiency and total sleep time measured by sleep diary. Mental health measures included the PTSD Checklist-5, nightmares per week, Patient Health Questionnaire-9, and Generalized Anxiety Disorder-7 scale. QoL was measured with the Short Form-12. Linear mixed models compared changes over time across groups. Independent t tests examined PTSD symptom changes in women veterans with probable PTSD.ResultsBoth groups demonstrated improvements across sleep (ps

Pancreatic ductal adenocarcinoma (PDA) is an extremely metastatic and lethal disease. Here, in both murine and human PDA, we demonstrate that extracellular matrix architecture regulates cell extrusion and subsequent invasion from intact ductal structures through tumor-associated collagen signatures (TACS). This results in early dissemination from histologically premalignant lesions and continual invasion from well-differentiated disease, and it suggests TACS as a biomarker to aid in the pathologic assessment of early disease. Furthermore, we show that pancreatitis results in invasion-conducive architectures, thus priming the stroma prior to malignant disease. Analysis in potentially novel microfluidic-derived microtissues and in vivo demonstrates decreased extrusion and invasion following focal adhesion kinase (FAK) inhibition, consistent with decreased metastasis. Thus, data suggest that targeting FAK or strategies to reengineer and normalize tumor microenvironments may have roles not only in very early disease, but also for limiting continued dissemination from unresectable disease. Likewise, it may be beneficial to employ stroma-targeting strategies to resolve precursor diseases such as pancreatitis in order to remove stromal architectures that increase risk for early dissemination.

BackgroundFemale adolescent and young adult (AYA) cancer survivors face higher infertility and pregnancy risks than peers with no cancer history. Preconception health behaviors such as physical activity (PA), tobacco smoking, and alcohol intake influence reproductive outcomes. In general populations, pregnancy intention is positively associated with healthy preconception behaviors, but it has not been studied among AYA survivors. The authors hypothesized that higher pregnancy intention would be associated with healthier behaviors, especially among AYA survivors with perceived infertility risk.MethodsA cross-sectional analysis was conducted with data collected between 2013 and 2017 from 1071 female AYA survivors aged 18 to 39 years who had completed their primary cancer treatment and enrolled in an ovarian function study. Self-reported intention dimensions were measured as a pregnancy intention score (PIS) and trying now to become pregnant. Multivariable linear (PA), binary (smoking), and ordinal (alcohol use) logistic regressions were used to estimate associations between intentions and preconception behaviors, with adjustments made for demographic and cancer characteristics. Effect modification by perceived infertility risk was assessed.ResultsThe mean PIS was 1.1 (SD, 0.77) on a 0 to 2 scale (2 = high intention), and 8.9% were attempting pregnancy now. A higher PIS was associated with increased PA (β, 0.08; 95% CI, 0.11-1.04), whereas ambivalence in pregnancy intention was associated with lower alcohol consumption (odds ratio, 0.72; 95% CI, 0.55-0.95). Pregnancy intentions were not associated with smoking. Perceived infertility risk strengthened the relationship between PIS and PA (P < .05).ConclusionsPregnancy intentions were associated with some healthier preconception behaviors in AYA survivors. Medical professionals caring for AYA survivors may consider pregnancy intention screening to guide conversations on preconception health.

BackgroundThe sarcoplasmic reticulum (SR) Ca2+-ATPase 2 (SERCA2) mediates Ca2+ reuptake into SR and thereby promotes cardiomyocyte relaxation, whereas the ryanodine receptor (RYR) mediates Ca2+ release from SR and triggers contraction. Ca2+/CaMKII (CaM [calmodulin]-dependent protein kinase II) regulates activities of SERCA2 through phosphorylation of PLN (phospholamban) and RYR through direct phosphorylation. However, the mechanisms for CaMKIIδ anchoring to SERCA2-PLN and RYR and its regulation by local Ca2+ signals remain elusive. The objective of this study was to investigate CaMKIIδ anchoring and regulation at SERCA2-PLN and RYR.MethodsA role for AKAP18δ (A-kinase anchoring protein 18δ) in CaMKIIδ anchoring and regulation was analyzed by bioinformatics, peptide arrays, cell-permeant peptide technology, immunoprecipitations, pull downs, transfections, immunoblotting, proximity ligation, FRET-based CaMKII activity and ELISA-based assays, whole cell and SR vesicle fluorescence imaging, high-resolution microscopy, adenovirus transduction, adenoassociated virus injection, structural modeling, surface plasmon resonance, and alpha screen technology.ResultsOur results show that AKAP18δ anchors and directly regulates CaMKIIδ activity at SERCA2-PLN and RYR, via 2 distinct AKAP18δ regions. An N-terminal region (AKAP18δ-N) inhibited CaMKIIδ through binding of a region homologous to the natural CaMKII inhibitor peptide and the Thr17-PLN region. AKAP18δ-N also bound CaM, introducing a second level of control. Conversely, AKAP18δ-C, which shares homology to neuronal CaMKIIα activator peptide (N2B-s), activated CaMKIIδ by lowering the apparent Ca2+ threshold for kinase activation and inducing CaM trapping. While AKAP18δ-C facilitated faster Ca2+ reuptake by SERCA2 and Ca2+ release through RYR, AKAP18δ-N had opposite effects. We propose a model where the 2 unique AKAP18δ regions fine-tune Ca2+-frequency-dependent activation of CaMKIIδ at SERCA2-PLN and RYR.ConclusionsAKAP18δ anchors and functionally regulates CaMKII activity at PLN-SERCA2 and RYR, indicating a crucial role of AKAP18δ in regulation of the heartbeat. To our knowledge, this is the first protein shown to enhance CaMKII activity in heart and also the first AKAP (A-kinase anchoring protein) reported to anchor a CaMKII isoform, defining AKAP18δ also as a CaM-KAP.

The tropomyosin receptor kinase (TRK) family of proteins is encoded by neurotrophic tyrosine receptor kinase (NTRK) genes and has a role in the development and normal functioning of the nervous system. NTRK gene fusions have been identified as oncogenic drivers in a wide range of tumors in both adult and pediatric patients. There has recently been a paradigm shift in cancer treatment toward biomarker-based targeted therapies, as an increasing number of actionable targets are being identified across different tumors and/or tumor histologies. These targeted agents offer greater comparative effectiveness and safety vs historical nontargeted standard therapies. The development of drugs that specifically target oncogenic drivers of cancer has led to the emergence of screening technologies to identify the patients most likely to benefit from targeted therapy. This review describes the role of NTRK gene fusions in cancer and outlines the epidemiology of NTRK gene fusions, the therapeutic benefits of targeting TRK fusions with small molecule inhibitors, and recommendations for NTRK gene fusion testing in adult and pediatric patients with cancer, in order to guide treatment decisions.

BACKGROUND AND AIMS: This study aimed to systematically evaluate a classification scheme of secondary peristalsis using functional luminal imaging probe (FLIP) panometry through comparison with primary peristalsis on high-resolution manometry (HRM). METHODS: 706 adult patients that completed FLIP and HRM for primary esophageal motility evaluation and 35 asymptomatic volunteers (controls) were included. Secondary peristalsis, that is, contractile responses (CRs), was classified on FLIP panometry by the presence and pattern of contractility as normal (NCR), borderline (BCR), impaired/disordered (IDCR), absent (ACR), or spastic-reactive (SRCR). Primary peristalsis on HRM was assessed according to the Chicago Classification. RESULTS: All 35 of the controls had antegrade contractions on FLIP panometry with either NCR (89%) or BCR (11%). The average percentages of normal swallows on HRM varied across contractile response patterns from 84% in NCR, 68% in BCR, 39% in IDCR, to 11% in ACR, as did the percentage of failed swallows on HRM: 4% in NCR, 12% in BCR, 36% in IDCR, and 79% in ACR. SRCR on FLIP panometry was observed in 18/57 (32%) patients with type III achalasia, 4/15 (27%) with distal esophageal spasm, and 7/15 (47%) with hypercontractile esophagus on HRM. CONCLUSIONS: The FLIP panometry contractile response patterns reflect a pathophysiologic transition from normal to abnormal esophageal peristaltic function with shared features with primary peristaltic function/dysfunction on HRM. Thus, these patterns of the contractile response to distension can facilitate the evaluation of esophageal motility using FLIP panometry.

BackgroundHip-worn accelerometer cut-points have poor validity for assessing children's sedentary time, which may partly explain the equivocal health associations shown in prior research. Improved processing/classification methods for these monitors would enrich the evidence base and inform the development of more effective public health guidelines. The present study aimed to develop and evaluate a novel computational method (CHAP-child) for classifying sedentary time from hip-worn accelerometer data.MethodsParticipants were 278, 8-11-year-olds recruited from nine primary schools in Melbourne, Australia with differing socioeconomic status. Participants concurrently wore a thigh-worn activPAL (ground truth) and hip-worn ActiGraph (test measure) during up to 4 seasonal assessment periods, each lasting up to 8 days. activPAL data were used to train and evaluate the CHAP-child deep learning model to classify each 10-s epoch of raw ActiGraph acceleration data as sitting or non-sitting, creating comparable information from the two monitors. CHAP-child was evaluated alongside the current practice 100 counts per minute (cpm) method for hip-worn ActiGraph monitors. Performance was tested for each 10-s epoch and for participant-season level sedentary time and bout variables (e.g., mean bout duration).ResultsAcross participant-seasons, CHAP-child correctly classified each epoch as sitting or non-sitting relative to activPAL, with mean balanced accuracy of 87.6% (SD = 5.3%). Sit-to-stand transitions were correctly classified with mean sensitivity of 76.3% (SD = 8.3). For most participant-season level variables, CHAP-child estimates were within ± 11% (mean absolute percent error [MAPE]) of activPAL, and correlations between CHAP-child and activPAL were generally very large (> 0.80). For the current practice 100 cpm method, most MAPEs were greater than ± 30% and most correlations were small or moderate (≤ 0.60) relative to activPAL.ConclusionsThere was strong support for the concurrent validity of the CHAP-child classification method, which allows researchers to derive activPAL-equivalent measures of sedentary time, sit-to-stand transitions, and sedentary bout patterns from hip-worn triaxial ActiGraph data. Applying CHAP-child to existing datasets may provide greater insights into the potential impacts and influences of sedentary time in children.

Chronic multisymptom illness (CMI) affects a subsection of elderly and war Veterans and is associated with systemic inflammation. Here, using a mouse model of CMI and a group of Gulf War (GW) Veterans' with CMI we show the presence of an altered host resistome. Results show that antibiotic resistance genes (ARGs) are significantly altered in the CMI group in both mice and GW Veterans when compared to control. Fecal samples from GW Veterans with persistent CMI show a significant increase of resistance to a wide class of antibiotics and exhibited an array of mobile genetic elements (MGEs) distinct from normal healthy controls. The altered resistome and gene signature is correlated with mouse serum IL-6 levels. Altered resistome in mice also is correlated strongly with intestinal inflammation, decreased synaptic plasticity, reversible with fecal microbiota transplant (FMT). The results reported might help in understanding the risks to treating hospital acquired infections in this population.

Neighborhood-level socioeconomic deprivation can increase risk for higher blood pressure or hypertension, while greater neighborhood safety and walkability may protect against hypertension. Large-scale prospective research, particularly among Hispanics/Latinos, is lacking. We examined cross-sectional and prospective associations between neighborhood environments and blood pressure and hypertension among 3851 Hispanic/Latinos enrolled in the Hispanic Community Health Study/Study of Latinos San Diego, CA cohort. Addresses from Visit 1 (2008-2011) were geocoded and neighborhood characteristics were determined as part of the SOL CASAS ancillary study. Home addresses were geocoded and home areas created using 800 m circular radial buffers. Neighborhood indices socioeconomic deprivation, residential stability, and social disorder were created using Census and other publicly available data. Walkability was computed as density of intersections, retail spaces, and residences. Greenness was measured via satellite imagery using the Normalized Difference Vegetation Index. Visit 1 and Visit 2 (2014-2017) clinical outcomes included systolic (SBP) and diastolic (DBP) blood pressure, as well as prevalent and 6-year incident hypertension, defined as SBP/DBP ≥140/90 mmHg or antihypertensive medication use. Complex survey regression models adjusted for covariates revealed cross-sectional associations between greater walkability and lower SBP (B = -0.05; 95% CI: -0.09, -0.003). In prospective analyses, greater neighborhood social disorder was related to increasing SBP (B = 0.05; 95% CI: 0.01, 0.09) and DBP (B = 0.07; 95% CI: 0.02, 0.12) over time. Greater socioeconomic deprivation (OR = 1.47; 95% CI: 1.06, 2.04) and greater social disorder (OR = 1.25; 95% CI: 1.02, 1.54) were associated with higher odds of incident hypertension. All other associations were not significant. Beyond individual-level characteristics, greater neighborhood social disorder and socioeconomic deprivation were related to adverse changes in blood pressure over 6 years among Hispanics/Latinos. Neighborhood social environment may help identify, or be an area for future intervention for, cardiovascular risk among Hispanics/Latinos.