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ImportancePrescription drug prices are a leading concern among patients and policy makers. There have been large and sharp price increases for some drugs, but the long-term implications of large drug price increases remain poorly understood.ObjectiveTo examine the association of the large 2010 price increase in colchicine, a common treatment for gout, with long-term changes in colchicine use, substitution with other drugs, and health care use.Design, setting, and participantsThis retrospective cohort study examined MarketScan data from a longitudinal cohort of patients with gout with employer-sponsored insurance from 2007 through 2019.ExposuresThe US Food and Drug Administration's discontinuation of lower-priced versions of colchicine from the market in 2010.Main outcomes and measuresMean price of colchicine; use of colchicine, allopurinol, and oral corticosteroids; and emergency department (ED) and rheumatology visits for gout in year 1 and over the first decade of the policy (through 2019) were calculated. Data were analyzed between November 16, 2021, and January 17, 2023.ResultsA total of 2 723 327 patient-year observations were examined from 2007 through 2019 (mean [SD] age of patients, 57.0 [13.8] years; 20.9% documented as female; 79.1% documented as male). The mean price per prescription of colchicine increased sharply from $11.25 (95% CI, $11.23-$11.28) in 2009 to $190.49 (95% CI, $190.07-$190.91) in 2011, a 15.9-fold increase, with the mean out-of-pocket price increasing 4.4-fold from $7.37 (95% CI, $7.37-$7.38) to $39.49 (95% CI, $39.42-$39.56). At the same time, colchicine use declined from 35.0 (95% CI, 34.6-35.5) to 27.3 (95% CI, 26.9-27.6) pills per patient in year 1 and to 22.6 (95% CI, 22.2-23.0) pills per patient in 2019. Adjusted analyses showed a 16.7% reduction in year 1 and a 27.0% reduction over the decade (P

ImportanceThere has been disappointing progress in enrollment of medical students from racial and ethnic groups underrepresented in medicine, including American Indian or Alaska Native, Black, and Hispanic students. Barriers that may influence students interested in medicine are understudied.ObjectiveTo examine racial and ethnic differences in barriers faced by students taking the Medical College Admission Test (MCAT).Design, setting, and participantsThis cross-sectional study used survey data (surveys administered between January 1, 2015, to December 31, 2018) from MCAT examinees linked with application and matriculation data from the Association of American Medical Colleges. Data analyses were performed from November 1, 2021, to January 31, 2023.Main variables and outcomesMain outcomes were medical school application and matriculation. Key independent variables reflected parental educational level, financial and educational barriers, extracurricular opportunities, and interpersonal discrimination.ResultsThe sample included 81 755 MCAT examinees (0.3% American Indian or Alaska Native, 21.3% Asian, 10.1% Black, 8.0% Hispanic, and 60.4% White; 56.9% female). There were racial and ethnic differences in reported barriers. For example, after adjustment for demographic characteristics and examination year, 39.0% (95% CI, 32.3%-45.8%) of American Indian or Alaska Native examinees, 35.1% (95% CI, 34.0%-36.2%) of Black examinees, and 46.6% (95% CI, 45.4%-47.9%) of Hispanic examinees reported having no parent with a college degree compared with 20.4% (95% CI, 20.0%-20.8%) of White examinees. After adjustment for demographic characteristics and examination year, Black examinees (77.8%; 95% CI, 76.9%-78.7%) and Hispanic examinees (71.3%; 95% CI, 70.2%-72.4%) were less likely than White examinees (80.2%; 95% CI, 79.8%-80.5%) to apply to medical school. Black examinees (40.6%; 95% CI, 39.5%-41.7%) and Hispanic examinees (40.2%; 95% CI, 39.0%-41.4%) were also less likely than White examinees (45.0%; 95% CI, 44.6%-45.5%) to matriculate at medical school. Examined barriers were associated with a lower likelihood of medical school application and matriculation (eg, examinees having no parent with a college degree had lower odds of applying [odds ratio, 0.65; 95% CI, 0.61-0.69] and matriculating [odds ratio, 0.63; 95% CI, 0.59-0.66]). Black-White and Hispanic-White disparities in application and matriculation were largely accounted for by differences in these barriers.Conclusions and relevanceIn this cross-sectional study of MCAT examinees, American Indian or Alaska Native, Black, and Hispanic students reported lower parental educational levels, greater educational and financial barriers, and greater discouragement from prehealth advisers than White students. These barriers may deter groups underrepresented in medicine from applying to and matriculating at medical school.

BACKGROUND: Non-Asian body mass index (BMI) classifications are commonly used as a risk factor for high fasting blood glucose (FBG). We investigated the incidence and factors associated with high FBG among people living with HIV in the Asia-Pacific region, using a World Health Organization BMI classification specific to Asian populations. METHODS: This study included people living with HIV enrolled in a longitudinal cohort study from 2003 to 2019, receiving antiretroviral therapy (ART), and without prior tuberculosis. BMI at ART initiation was categorized using Asian BMI classifications: underweight (25 kg/m2 were at increased risk of high FBG. This indicates that regular assessments should be performed in those with high BMI, irrespective of the classification used.

BACKGROUND: Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete. OBJECTIVE: We sought to determine phenotypic factors associated with FEV1 throughout childhood in the Severe Asthma Research Program 3 pediatric cohort. METHODS: Lung function was measured at baseline and annually. Multivariate linear mixed-effects models were constructed to assess the effect of baseline and time-varying predictors of prebronchodilator FEV1 at each assessment for up to 6 years. All models were adjusted for age, predicted FEV1 by Global Lung Function Initiative reference equations, race, sex, and height. Secondary outcomes included postbronchodilator FEV1 and prebronchodilator FEV1/forced vital capacity. RESULTS: A total of 862 spirometry assessments were performed for 188 participants. Factors associated with FEV1 include baseline Feno (B, -49 mL/log2 PPB; 95% CI, -92 to -6), response to a characterizing dose of triamcinolone acetonide (B, -8.4 mL/1% change FEV1 posttriamcinolone; 95% CI, -12.3 to -4.5), and maximal bronchodilator reversibility (B, -27 mL/1% change postbronchodilator FEV1; 95% CI, -37 to -16). Annually assessed time-varying factors of age, obesity, and exacerbation frequency predicted FEV1 over time. Notably, there was a significant age and sex interaction. Among girls, there was no exacerbation effect. For boys, however, moderate (1-2) exacerbation frequency in the previous 12 months was associated with -20 mL (95% CI, -39 to -2) FEV1 at each successive year. High exacerbation frequency (≥3) 12 to 24 months before assessment was associated with -34 mL (95% CI, -61 to -7) FEV1 at each successive year. CONCLUSIONS: In children with severe and nonsevere asthma, several clinically relevant factors predict FEV1 over time. Boys with recurrent exacerbations are at high risk of lower FEV1 through childhood.

ObjectiveTo assess inequities in mortality by race and sex for eight common surgical procedures (elective and non-elective) across specialties in the United States.DesignRetrospective cohort study.SettingUS, 2016-18.Participants1 868 036 Black and White Medicare beneficiaries aged 65-99 years undergoing one of eight common surgeries: repair of abdominal aortic aneurysm, appendectomy, cholecystectomy, colectomy, coronary artery bypass surgery, hip replacement, knee replacement, and lung resection.Main outcome measureThe main outcome measure was 30 day mortality, defined as death during hospital admission or within 30 days of the surgical procedure.ResultsPostoperative mortality overall was higher in Black men (1698 deaths, adjusted mortality rate 3.05%, 95% confidence interval 2.85% to 3.24%) compared with White men (21 833 deaths, 2.69%, 2.65% to 2.73%), White women (21 847 deaths, 2.38%, 2.35% to 2.41%), and Black women (1631 deaths, 2.18%, 2.04% to 2.31%), after adjusting for potential confounders. A similar pattern was found for elective surgeries, with Black men showing a higher adjusted mortality (393 deaths, 1.30%, 1.14% to 1.46%) compared with White men (5650 deaths, 0.85%, 0.83% to 0.88%), White women (4615 deaths, 0.82%, 0.80% to 0.84%), and Black women (359 deaths, 0.79%, 0.70% to 0.88%). This 0.45 percentage point difference implies that mortality after elective procedures was 50% higher in Black men compared with White men. For non-elective surgeries, however, mortality did not differ between Black men and White men (1305 deaths, 6.69%, 6.26% to 7.11%; and 16 183 deaths, 7.03%, 6.92% to 7.14%, respectively), although mortality was lower for White women and Black women (17 232 deaths, 6.12%, 6.02% to 6.21%; and 1272 deaths, 5.29%, 4.93% to 5.64%, respectively). These differences in mortality appeared within seven days after surgery and persisted for up to 60 days after surgery.ConclusionsPostoperative mortality overall was higher among Black men compared with White men, White women, and Black women. These findings highlight the need to understand better the unique challenges Black men who require surgery face.

ObjectivesFew surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic.DesignCross-sectional survey using four validated instruments.SettingSixty-two sites in Canada and the United States.SubjectsAttending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs.InterventionNone.Measurements and main resultsWe analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures.ConclusionsDespite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

SignificanceMetagenomic pathogen sequencing offers an unbiased approach to characterizing febrile illness. In resource-scarce settings with high biodiversity, it is critical to identify disease-causing pathogens in order to understand burden and to prioritize efforts for control. Here, metagenomic next-generation sequencing (mNGS) characterization of the pathogen landscape in Cambodia revealed diverse vector-borne and zoonotic pathogens irrespective of age and gender as risk factors. Identification of key pathogens led to changes in national program surveillance. This study is a "real world" example of the use of mNGS surveillance of febrile individuals, executed in-country, to identify outbreaks of vector-borne, zoonotic, and other emerging pathogens in a resource-scarce setting.

Exposure to tobacco smoke (TS) has been considered a risk factor for osteonecrosis of the femoral head (ONFH). Soluble epoxide hydrolase inhibitors (sEHIs) have been found to reduce inflammation and oxidative stress in a variety of pathologies. This study was designed to assess the effect of sEHI on the development of ONFH phenotypes induced by TS exposure in spontaneously hypertensive (SH) rats. SH and normotensive Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or TS (80 mg/m3 particulate concentration) 6 h/day, 3 days/week for 8 weeks. During this period, sEHI was delivered through drinking water at a concentration of 6 mg/L. Histology, immunohistochemistry, and micro-CT morphometry were performed for phenotypic evaluation. As results, TS exposure induced significant increases in adipocyte area, bone specific surface (BS/BV), and trabecular separation (Tb.SP), as well as significant decreases in bone mineral density (BMD), percent trabecular area (Tb.Ar), HIF-1a expression, bone volume fraction (BV/TV), trabecular numbers (Tb.N), and trabecular thickness (Tb.Th) in both SH and WKY rats. However, the protective effects of sEHI were mainly observed in TS-exposed SH rats, specifically in the density of osteocytes, BMD, Tb.Ar, HIF-1a expression, BV/TV, BS/BV, Tb.N, and Tb.SP. Our study confirms that TS exposure can induce ONFH especially in SH rats, and suggests that sEHI therapy may protect against TS exposure-induced osteonecrotic changes in the femoral head.

BackgroundWhether the presence of dementia in patients makes it difficult for physicians to assess the risk such patients might have for serious conditions such as pulmonary embolism (PE) is unknown. Our objective was to examine the differential association of four clinical factors (deep venous thrombosis (DVT)/PE, malignancy, recent surgery, and tachycardia) with PE testing for patients with dementia compared to patients without dementia.MethodsWe performed a cross-sectional study of emergency department (ED) visits to 104 Veterans Affairs (VA) hospitals from 2011 to 2018 by patients aged 60 years and over presenting with shortness of breath (SOB). Our outcomes were PE testing (CT scan and/or D-dimer) and subsequently diagnosed acute PE.ResultsThe sample included 593,001 patient visits for SOB across 7124 ED physicians; 5.6% of the sample had dementia, and 10.6% received PE testing. Three of the four clinical factors examined had a lower association with PE testing for patients with dementia. For example, after taking into account that at baseline, physicians were 0.9 percentage points less likely to test patients with dementia than patients without dementia for PE, physicians were an additional 2.6 percentage points less likely to test patients with dementia who had tachycardia than patients without dementia who had tachycardia. We failed to find evidence that any clinical factor examined had a differentially lower association with a subsequently diagnosed acute PE for patients with dementia.ConclusionsClinical factors known to be predictive of PE risk had a lower association with PE testing for patients with dementia compared to patients without dementia. These results may be consistent with physicians missing these clinical factors more often when evaluating patients with dementia, but also with physicians recognizing such factors but not using them in the decision-making process. Further understanding how physicians evaluate patients with dementia presenting with common acute symptoms may help improve the care delivered to such patients.

Study objectiveHeuristics, or rules of thumb, are hypothesized to influence the care physicians deliver. One such heuristic is the availability heuristic, under which assessments of an event's likelihood are affected by how easily the event comes to mind. We examined whether the availability heuristic influences physician testing in a common, high-risk clinical scenario: assessing patients with shortness of breath for the risk of pulmonary embolism.MethodsWe performed an event study from 2011 to 2018 of emergency physicians caring for patients presenting with shortness of breath to 104 Veterans Affairs (VA) hospitals. Our measures were physician rates of pulmonary embolism testing (D-dimer and/or computed tomography scan) for subsequent patients after having a patient visit with a pulmonary embolism discharge diagnosis, hypothesizing that physician rates of pulmonary embolism testing would increase after having a recent patient visit with a pulmonary embolism diagnosis due to the availability heuristic.ResultsThe sample included 7,370 emergency physicians who had 416,720 patient visits for shortness of breath. The mean rate of pulmonary embolism testing was 9.0%. For physicians who had a recent patient visit with a pulmonary embolism diagnosis, their rate of pulmonary embolism testing for subsequent patients increased by 1.4 percentage points (95% confidence interval 0.42 to 2.34) in the 10 days after, which is approximately 15% relative to the mean rate of pulmonary embolism testing. We failed to find statistically significant changes in rates of pulmonary embolism testing in the subsequent 50 days following these first 10 days.ConclusionAfter having a recent patient visit with a pulmonary embolism diagnosis, physicians increase their rates of pulmonary embolism testing for subsequent patients, but this increase does not persist. These results provide large-scale evidence that the availability heuristic may play a role in complex testing decisions.

Spontaneous control of HIV infection has been repeatedly linked to antiviral CD8+ T cells but is not always permanent. To address mechanisms of durable and aborted control of viremia, we evaluated immunologic and virologic parameters longitudinally among 34 HIV-infected subjects with differential outcomes. Despite sustained recognition of autologous virus, HIV-specific proliferative and cytolytic T cell effector functions became selectively and intrinsically impaired prior to aborted control. Longitudinal transcriptomic profiling of functionally impaired HIV-specific CD8+ T cells revealed altered expression of genes related to activation, cytokine-mediated signaling, and cell cycle regulation, including increased expression of the antiproliferative transcription factor KLF2 but not of genes associated with canonical exhaustion. Lymphoid HIV-specific CD8+ T cells also exhibited poor functionality during aborted control relative to durable control. Our results identify selective functional impairment of HIV-specific CD8+ T cells as prognostic of impending aborted HIV control, with implications for clinical monitoring and immunotherapeutic strategies.

ImportanceSubstantial patient racial and ethnic differences in opioid prescribing have been documented, but how much of these differences were attributable to physicians prescribing opioids differently to patients of racial and ethnic minority groups is unknown, particularly during the first wave of the opioid epidemic when the dangers of opioid prescribing and use were not as well known.ObjectiveTo examine associations of patient race and ethnicity with differences in opioid prescribing by the same primary care physician (PCP) for new low back pain episodes among older adults from 2007 to 2014.Design setting and participantsThis cross-sectional study used Medicare data of PCP office visits by Medicare beneficiaries who were 66 years or older with new low back pain.Main outcomes and measuresPrescribing of any opioid in the first year of a new low back pain episode (days 1-365) and subsequent long-term use of an opioid (prescribed for ≥180 days in days 366-730).ResultsAmong the study population of 274 771 patients (mean [SD] age, 77.1 [7.2] years; 192 105 [69.9%] women) with new low back pain, 15 285 (6%) were Asian or Pacific Islander, 16 079 (6%) were Black, 21 289 (8%) were Hispanic, and 222 118 (81%) were White, cared for by 63 494 physicians. In adjusted analysis, on average, 11.5% of the White patients (95% CI, 11.4 to 11.6) received an opioid prescription in the first year of new low back pain. The same prescribing physician was 1.5 percentage points (PP; 95% CI, -2.2 PP to -0.8 PP) less likely to prescribe an opioid if the patient was Black, 2.7 PP (95% CI, -3.5 PP to -1.8 PP) less likely if the patient was Asian or Pacific Islander, and 1.0 PP (95% CI, -1.7 PP to -0.3 PP) less likely if the patient was Hispanic. The same physician was more likely to prescribe a prescription nonsteroidal anti-inflammatory drug to a patient of a racial or ethnic minority group. White patients with new low back pain were more likely to develop subsequent long-term opioid use than patients of racial and ethnic minority groups (eg, 1.8% for White patients vs 0.5% for Hispanic patients).Conclusions and relevanceThis cross-sectional study found that from 2007 to 2014, primary care physicians prescribed opioids for new low back pain more often to White patients than to patients of racial and ethnic minority groups. These results suggest that there may have been unequal treatment of pain by physicians when less was known about the morbidity associated with opioid use.

Attention-deficit hyperactivity disorder (ADHD) is common in patients with (ADHD+PAE) and without (ADHD-PAE) prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD actually have covert PAE, a treatment-relevant distinction. To improve differential diagnosis, we sought to identify brain differences between ADHD+PAE and ADHD-PAE using neurobehavioral, magnetic resonance spectroscopy, and diffusion tensor imaging metrics that had shown promise in past research. Children 8-13 were recruited in three groups: 23 ADHD+PAE, 19 familial ADHD-PAE, and 28 typically developing controls (TD). Neurobehavioral instruments included the Conners 3 Parent Behavior Rating Scale and the Delis-Kaplan Executive Function System (D-KEFS). Two dimensional magnetic resonance spectroscopic imaging was acquired from supraventricular white matter to measure N-acetylaspartate compounds, glutamate, creatine + phosphocreatine (creatine), and choline-compounds (choline). Whole brain diffusion tensor imaging was acquired and used to to calculate fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity from the same superventricular white matter regions that produced magnetic resonance spectroscopy data. The Conners 3 Parent Hyperactivity/Impulsivity Score, glutamate, mean diffusivity, axial diffusivity, and radial diffusivity were all higher in ADHD+PAE than ADHD-PAE. Glutamate was lower in ADHD-PAE than TD. Within ADHD+PAE, inferior performance on the D-KEFS Tower Test correlated with higher neurometabolite levels. These findings suggest white matter differences between the PAE and familial etiologies of ADHD. Abnormalities detected by magnetic resonance spectroscopy and diffusion tensor imaging co-localize in supraventricular white matter and are relevant to executive function symptoms of ADHD.

This cross-sectional study examines national trends in representativeness in select health care occupations by race/ethnicity and sex.

This study estimates differences in influenza vaccination rates by patient race and sex between patients of female and male physicians working in the same outpatient practice.

Social interactions and relationships are often rewarding, but the neural mechanisms through which social interaction drives positive experience remain poorly understood. In this study, we developed an automated operant conditioning system to measure social reward in mice and found that adult mice of both sexes display robust reinforcement of social interaction. Through cell-type-specific manipulations, we identified a crucial role for GABAergic neurons in the medial amygdala (MeA) in promoting the positive reinforcement of social interaction. Moreover, MeA GABAergic neurons mediate social reinforcement behavior through their projections to the medial preoptic area (MPOA) and promote dopamine release in the nucleus accumbens. Finally, activation of this MeA-to-MPOA circuit can robustly overcome avoidance behavior. Together, these findings establish the MeA as a key node for regulating social reward in both sexes, providing new insights into the regulation of social reward beyond the classic mesolimbic reward system.

Ligands can induce G protein-coupled receptors (GPCRs) to adopt a myriad of conformations, many of which play critical roles in determining the activation of specific signaling cascades associated with distinct functional and behavioral consequences. For example, the 5-hydroxytryptamine 2A receptor (5-HT2AR) is the target of classic hallucinogens, atypical antipsychotics, and psychoplastogens. However, currently available methods are inadequate for directly assessing 5-HT2AR conformation both in vitro and in vivo. Here, we developed psychLight, a genetically encoded fluorescent sensor based on the 5-HT2AR structure. PsychLight detects behaviorally relevant serotonin release and correctly predicts the hallucinogenic behavioral effects of structurally similar 5-HT2AR ligands. We further used psychLight to identify a non-hallucinogenic psychedelic analog, which produced rapid-onset and long-lasting antidepressant-like effects after a single administration. The advent of psychLight will enable in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and the development of 5-HT2AR-dependent non-hallucinogenic therapeutics.

BackgroundFor unknown reasons, Hispanic patients with cystic fibrosis (CF) have more severe pulmonary disease than non-Hispanic white patients. In CF, the pulmonary pathogen Pseudomonas aeruginosa is associated with worse outcomes. We sought to determine if Hispanic patients with CF are at an increased risk of acquiring P. aeruginosa or acquire it earlier than non-Hispanic white patients.MethodsThis is a longitudinal study comparing the timing and risk of acquisition of different forms of P. aeruginosa between Hispanic and non-Hispanic white patients aged 0-21 years old with CF in the CF Foundation Patient Registry (CFFPR) in 2008-2013. The age at the initial acquisition of P. aeruginosa (initial acquisition, mucoid, chronic, multidrug-resistant) was summarized using Kaplan-Meier survival curves and analyzed using Cox proportional hazards regression models.ResultsOf 10,464 patients, 788 (7.5%) were Hispanic and 9,676 (92.5%) were non-Hispanic white. Hispanic patients acquired all forms of P. aeruginosa at a younger age than non-Hispanic white patients. Hispanic patients had a higher risk of acquiring P. aeruginosa than non-Hispanic white patients: the hazard ratio (HR) was 1.26 (95% CI 1.16-1.38, p

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

While several areas in the United States have asked nurses and physicians who are not in the labor force to return to help with the COVID-19 pandemic, little is known about the characteristics of these clinicians that may present barriers to returning. We studied age, disability, and household composition of clinicians not in the workforce using the American Community Survey from 2014 to 2018, a nationally-representative survey of US households administered by the US Census. Overall, we found that, for nurses and physicians not in the labor force, over three-quarters were 55 and over and about 15 percent had a disability. For female nurses and physicians not in the labor force, over half of those ages 20-54 had a child under 15 at home and over half of those ages 65+ had another adult 65 and over at home. These characteristics may present challenges and risks to returning.

Therapy-induced neuroendocrine prostate cancer (NEPC), an extremely aggressive variant of castration-resistant prostate cancer (CRPC), is increasing in incidence with the widespread use of highly potent androgen receptor (AR)-pathway inhibitors (APIs) such as Enzalutamide (ENZ) and Abiraterone and arises via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED). The molecular basis of NED is not completely understood leading to a lack of effective molecular markers for its diagnosis. Here, we demonstrate for the first time, that lineage switching to NE states is accompanied by key miRNA alterations including downregulation of miR-106a~363 cluster and upregulation of miR-301a and miR-375. To systematically investigate the key miRNAs alterations driving therapy-induced NED, we performed small RNA-NGS in a retrospective cohort of human metastatic CRPC clinical samples + PDX models with adenocarcinoma features (CRPC-adeno) vs those with neuroendocrine features (CRPC-NE). Further, with the application of machine learning algorithms to sequencing data, we trained a 'miRNA classifier' that could robustly classify 'CRPC-NE' from 'CRPC-Adeno' cases. The performance of classifier was validated in an additional cohort of mCRPC patients and publicly available PCa cohorts. Importantly, we demonstrate that miR-106a~363 cluster pleiotropically regulate cardinal nodal proteins instrumental in driving NEPC including Aurora Kinase A, N-Myc, E2F1 and STAT3. Our study has important clinical implications and transformative potential as our 'miRNA classifier' can be used as a molecular tool to stratify mCRPC patients into those with/without NED and guide treatment decisions. Further, we identify novel miRNA NED drivers that can be exploited for NEPC therapeutic targeting.

Alterations in diet can have significant impact on the host, with high-fat diet (HFD) leading to obesity, diabetes, and inflammation of the gut. Although membership and abundances in gut bacterial communities are strongly influenced by diet, substantially less is known about how viral communities respond to dietary changes. Examining fecal contents of mice as the mice were transitioned from normal chow to HFD, we found significant changes in the relative abundances and the diversity in the gut of bacteria and their viruses. Alpha diversity of the bacterial community was significantly diminished in response to the diet change but did not change significantly in the viral community. However, the diet shift significantly impacted the beta diversity in both the bacterial and viral communities. There was a significant shift away from the relatively abundant Siphoviridae accompanied by increases in bacteriophages from the Microviridae family. The proportion of identified bacteriophage structural genes significantly decreased after the transition to HFD, with a conserved loss of integrase genes in all four experimental groups. In total, this study provides evidence for substantial changes in the intestinal virome disproportionate to bacterial changes, and with alterations in putative viral lifestyles related to chromosomal integration as a result of shift to HFD.IMPORTANCE Prior studies have shown that high-fat diet (HFD) can have profound effects on the gastrointestinal (GI) tract microbiome and also demonstrate that bacteria in the GI tract can affect metabolism and lean/obese phenotypes. We investigated whether the composition of viral communities that also inhabit the GI tract are affected by shifts from normal to HFD. We found significant and reproducible shifts in the content of GI tract viromes after the transition to HFD. The differences observed in virome community membership and their associated gene content suggest that these altered viral communities are populated by viruses that are more virulent toward their host bacteria. Because HFD also are associated with significant shifts in GI tract bacterial communities, we believe that the shifts in the viral community may serve to drive the changes that occur in associated bacterial communities.

BackgroundRelative enlargement of the pulmonary artery (PA) on chest CT imaging is associated with respiratory exacerbations in patients with COPD or cystic fibrosis. We sought to determine whether similar findings were present in patients with asthma and whether these findings were explained by differences in ventricular size.MethodsWe measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left, and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI, and eETVVI, respectively). Associations between the cardiac and PA measures (PA-to-aorta [PA/A] ratio, eERVVI-to-eELVVI [eRV/eLV] ratio, eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed by Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated by multivariable linear and zero-inflated negative binomial regression.ResultsAsthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1 mL/m2 smaller eETVVI than healthy control subjects (P = .003) and 14.1 mL/m2 smaller eETVVI than those with mild/moderate disease (P = .011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57% higher rate of exacerbations during follow-up than those with eETVVI greater than the median (P = .020). Neither PA/A nor eRV/eLV was associated with asthma severity or exacerbations.ConclusionsIn patients with asthma, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations.Trial registryClinicalTrials.gov; No.: NCT01761630; URL: www.clinicaltrials.gov.

BackgroundTools for quantification of asthma severity are limited.ObjectiveWe sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations.MethodsBaseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics.ResultsASSESS scores ranged from 0 to 20 (8.78 ± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall.ConclusionsThe ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted.

ObjectiveThis study assesses the performance of the North American Association of Central Cancer Registries Asian/Pacific Islander Identification Algorithm (NAPIIA) to infer Hmong ethnicity.Design and settingAnalyses of electronic health records (EHRs) from 1 January 2011 to 1 October 2015. The NAPIIA was applied to the EHR data, and self-reported Hmong ethnicity from a questionnaire was used as the gold standard. Sensitivity, specificity, positive (PPV) and negative predictive values (NPVs) were calculated comparing the source data ethnicity inferred by the algorithm with the self-reported ethnicity from the questionnaire.ParticipantsEHRs indicating Hmong, Chinese, Vietnamese and Korean ethnicity who met the original study inclusion criteria were analysed.ResultsThe NAPIIA had a sensitivity of 78%, a specificity of 99.9%, a PPV of 96% and an NPV of 99%. The prevalence of Hmong population in the sample was 3.9%.ConclusionThe high sensitivity of the NAPIIA indicates its effectiveness in detecting Hmong ethnicity. The applicability of the NAPIIA to a multitude of Asian subgroups can advance Asian health disparity research by enabling researchers to disaggregate Asian data and unmask health challenges of different Asian subgroups.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.

BACKGROUND: We tested the safety and performance of the insulin-only configuration of the bionic pancreas (BP) closed-loop blood-glucose control system in a home-use setting to assess glycemic outcomes using different static and dynamic glucose set-points. METHOD: This is an open-label non-randomized study with three consecutive intervention periods. Participants had consecutive weeks of usual care followed by the insulin-only BP with (1) an individualized static set-point of 115 or 130 mg/dL and (2) a dynamic set-point that automatically varied within 110 to 130 mg/dL, depending on hypoglycemic risk. Human factors (HF) testing was conducted using validated surveys. The last five days of each study arm were used for data analysis. RESULTS: Thirteen participants were enrolled with a mean age of 28 years, mean A1c of 7.2%, and mean daily insulin dose of 0.6 U/kg (0.4-1.0 U/kg). The usual care arm had an average glucose of 145 ± 20 mg/dL, which increased in the static set-point arm (159 ± 8 mg/dL, P = .004) but not in the dynamic set-point arm (154 ± 10 mg/dL, P = ns). There was no significant difference in time spent in range (70-180 mg/dL) among the three study arms. There was less time

BackgroundOur objective was to determine those characteristics associated with reversibility of airflow obstruction and response to maximal bronchodilation in children with severe asthma through the Severe Asthma Research Program (SARP).MethodsWe performed a cross-sectional analysis evaluating children ages 6 to 17 years with nonsevere asthma (NSA) and severe asthma (SA). Participants underwent spirometry before and after 180 µg of albuterol to determine reversibility (≥12% increase in FEV1 ). Participants were then given escalating doses up to 720 µg of albuterol to determine their maximum reversibility.ResultsWe evaluated 230 children (n = 129 SA, n = 101 NSA) from five centers across the United States in the SARP I and II cohorts. SA (odds ratio [OR], 2.08, 95% confidence interval [CI], 1.05-4.13), second-hand smoke exposure (OR, 2.81, 95%CI, 1.23-6.43), and fractional exhaled nitric oxide (FeNO; OR, 1.97, 95%CI, 1.35-2.87) were associated with increased odds of airway reversibility after maximal bronchodilation, while higher prebronchodilator (BD) FEV1 % predicted (OR, 0.91, 95%CI, 0.88-0.94) was associated with decreased odds. In an analysis using the SARP III cohort (n = 186), blood neutrophils, immunoglobulin E (IgE), and FEV1 % predicted were significantly associated with BD reversibility. In addition, children with BD response have greater healthcare utilization. BD reversibility was associated with reduced lung function at enrollment and 1-year follow-up though less decline in lung function over 1 year compared to those without reversibility.ConclusionsLung function, that is FEV1 % predicted, is a predictor of BD response in children with asthma. Additionally, smoke exposure, higher FeNO or IgE level, and low peripheral blood neutrophils are associated with a greater likelihood of BD reversibility. BD response can identify a phenotype of pediatric asthma associated with low lung function and poor asthma control.

BackgroundHispanic subjects with cystic fibrosis (CF) have increased morbidity and mortality than non-Hispanic white subjects. The ethnic disparity in mortality varies by region. Factors influencing pulmonary function vary by both ethnicity and region.ObjectiveTo determine if the ethnic difference in pulmonary function varies by region.MethodsThis retrospective cohort study compared differences in longitudinal pulmonary function (percent-predicted forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1 ], forced expiratory flow at 25% to 75% [FEF25-75 ], FEV1 /FVC, and FEV1 decline) between Hispanic and non-Hispanic white subjects with CF by Census region of the United States (West, South, Midwest, and Northeast). Subjects were of ages 6 to 25 years and in the CF Foundation Patient Registry from 2008 to 2013. We used linear mixed effects models with subject-specific slopes and intercepts, adjusting for 14 demographic and clinical variables.ResultsOf 14 932 subjects, 1433 (9.6%) were Hispanic and 13 499 (90.4%) were non-Hispanic white. Hispanic subjects' FEV1 was 9.0% (8.3%-9.8%) lower than non-Hispanic white subjects in the West, while Hispanic subjects' FEV1 was only 4.0% (3.0%-5.0%) lower in the Midwest, 4.4% (3.1%-5.7%) lower in the Northeast, and 4.4% (3.2%-5.5%) lower in the South. Similarly, FVC and FEF25-75 were lower among Hispanic subjects compared to non-Hispanic white subjects in all US regions, with the biggest differences in the West. Only in the West was FEV1 /FVC significantly lower in Hispanic subjects (-0.019; -0.022 to -0.015). FEV1 decline was not significantly different between ethnicities in any region.ConclusionsIn CF, Hispanic subjects have lower pulmonary function than non-Hispanic white subjects in all geographic regions with the largest difference in occurring in the West.

Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α-XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or pharmacologic IRE1α kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138- cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1α inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1α for MM therapy.

BackgroundAttention deficit-hyperactivity disorder (ADHD) is common in fetal alcohol spectrum disorders (FASD) but also in patients without prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD may actually have ADHD and covert PAE, a treatment-relevant distinction.MethodsWe compared proton magnetic resonance spectroscopic imaging (MRSI; N = 44) and diffusion tensor imaging (DTI; N = 46) of the anterior corona radiata (ACR)-a key fiber tract in models of ADHD-at 1.5 T in children with ADHD with PAE (ADHD+PAE), children with ADHD without PAE (ADHD-PAE), children without ADHD with PAE (non-ADHD+PAE), and children with neither ADHD nor PAE (non-ADHD-PAE, i.e., typically developing controls). Levels of choline-compounds (Cho) were the main MRSI endpoint, given interest in dietary choline for FASD; the main DTI endpoint was fractional anisotropy (FA), as ACR FA may reflect ADHD-relevant executive control functions.ResultsFor ACR Cho, there was an ADHD-by-PAE interaction (p = 0.038) whereby ACR Cho was 26.7% lower in ADHD+PAE than in ADHD-PAE children (p

We investigated dengue virus (DENV) and asymptomatic DENV infections in rural villages of Kampong Cham Province, Cambodia, during 2012 and 2013. We conducted perifocal investigations in and around households for 149 DENV index cases identified through hospital and village surveillance. We tested participants 0.5-30 years of age by using nonstructural 1 rapid tests and confirmed DENV infections using quantitative reverse transcription PCR or nonstructural 1-capture ELISA. We used multivariable Poisson regressions to explore links between participants' DENV infection status and household characteristics. Of 7,960 study participants, 346 (4.4%) were infected with DENV, among whom 302 (87.3%) were

ObjectiveConventional, breath-holding magnetic resonance imaging (MRI) assesses body composition by measuring fat volumes and proton density fat fraction (PDFF). However, breath-holding MRI is not always feasible in children. This study's objective was to use free-breathing MRI to quantify visceral and subcutaneous fat volumes and PDFFs and correlate these measurements with hepatic PDFF.MethodsThis was an observational, hypothesis-forming study that enrolled 2 groups of children (ages 6-17 years), healthy children and overweight children with presumed nonalcoholic fatty liver disease. Free-breathing MRI was used to measure visceral and subcutaneous fat volumes and PDFFs, and hepatic PDFF. Imaging biomarkers were compared between groups, and correlations coefficients (r) and coefficients of determination (R) were calculated.ResultsWhen compared with the control group (n = 10), the overweight group (n = 9) had greater mean visceral (1843 vs 329 cm, P

BackgroundDespite advances in asthma care, disparities persist. Black patients are disproportionally affected by asthma and also have poorer outcomes compared with white patients.ObjectiveWe sought to determine associations between black and white patients and asthma-related health care use, accounting for complex relationships.MethodsThis study was completed as part of the National Heart, Lung, and Blood Institute's Severe Asthma Research Program, a prospective observational cohort. Between November 2012 and February 2015, it enrolled 579 participants 6 years and older with 1 year of observation time and complete data. Inverse probability of treatment weighting was used to balance racial groups with respect to community and family socioeconomic variables and environmental exposure variables. The primary outcome was emergency department (ED) use for asthma. Secondary outcomes included inhaled corticosteroid use, outpatient physician's office visits for asthma, and asthma-related hospitalization.ResultsBlack patients had greater odds of ED use over 1 year (odds ratio, 2.19; 95% CI, 1.43-3.35) but also differed in the majority (>50%) of baseline variables measured. After statistical balancing of the racial groups, the difference between black and white patients with respect to ED use no longer reached the level of significance. Instead, in secondary analyses black patients were less likely to see an outpatient physician for asthma management (adjusted odds ratio, 0.57; 95% CI, 0.38-0.85).ConclusionsThe disparity in ED use was eliminated after consideration of multiple variables. Social and environmental policies and interventions tailored to black populations with a high burden of asthma are critical to reduction (or elimination) of these disparities.

BackgroundDespite improved diagnostics, pulmonary pathogens in immunocompromised children frequently evade detection, leading to significant mortality. Therefore, we aimed to develop a highly sensitive metagenomic next-generation sequencing (mNGS) assay capable of evaluating the pulmonary microbiome and identifying diverse pathogens in the lungs of immunocompromised children.MethodsWe collected 41 lower respiratory specimens from 34 immunocompromised children undergoing evaluation for pulmonary disease at 3 children's hospitals from 2014-2016. Samples underwent mechanical homogenization, parallel RNA/DNA extraction, and metagenomic sequencing. Sequencing reads were aligned to the National Center for Biotechnology Information nucleotide reference database to determine taxonomic identities. Statistical outliers were determined based on abundance within each sample and relative to other samples in the cohort.ResultsWe identified a rich cross-domain pulmonary microbiome that contained bacteria, fungi, RNA viruses, and DNA viruses in each patient. Potentially pathogenic bacteria were ubiquitous among samples but could be distinguished as possible causes of disease by parsing for outlier organisms. Samples with bacterial outliers had significantly depressed alpha-diversity (median, 0.61; interquartile range [IQR], 0.33-0.72 vs median, 0.96; IQR, 0.94-0.96; P < .001). Potential pathogens were detected in half of samples previously negative by clinical diagnostics, demonstrating increased sensitivity for missed pulmonary pathogens (P < .001).ConclusionsAn optimized mNGS assay for pulmonary microbes demonstrates significant inoculation of the lower airways of immunocompromised children with diverse bacteria, fungi, and viruses. Potential pathogens can be identified based on absolute and relative abundance. Ongoing investigation is needed to determine the pathogenic significance of outlier microbes in the lungs of immunocompromised children with pulmonary disease.

BackgroundRecurrent preschool wheezing is a heterogeneous disorder with significant morbidity, yet little is known about phenotypic determinants and their impact on clinical outcomes.ObjectiveLatent class analysis (LCA) was used to identify latent classes of recurrent preschool wheeze and their association with future exacerbations and inhaled corticosteroid (ICS) treatment response.MethodsData from 5 clinical trials of 1708 children aged 12 to 71 months with recurrent wheezing were merged. LCA was performed on 10 demographic, exposure, and sensitization variables to determine the optimal number of latent classes. The primary outcome was the annualized rate of wheezing exacerbations requiring systemic corticosteroids during the study intervention period; the secondary outcome was the time to first exacerbation. Exploratory analyses examined the effect of daily ICS treatment on exacerbation outcomes.ResultsFour latent classes of recurrent wheezing were identified; these were not distinguished by current symptoms or historical exacerbations but differed with regard to allergen sensitization and/or exposures. Annualized exacerbation rates (mean ± SEM/year) were 0.65 ± 0.06 for class 1 ("minimal sensitization"), 0.93 ± 0.10 for class 2 ("sensitization with indoor pet exposure"), 0.60 ± 0.07 for class 3 ("sensitization with tobacco smoke exposure"), and 0.81 ± 0.10 for class 4 ("multiple sensitization and eczema") (P < .001). In a research setting of high adherence, daily ICS treatment improved exacerbation rates in classes 2 and 4 but not the other groups.ConclusionsSensitization and exposure assessments are useful in the prediction of future exacerbation and may identify children most likely to respond favorably to daily ICS treatment.

While human immunodeficiency virus (HIV) infection has become a treatable disease with the development of combination antiretroviral therapy (cART), chronic inflammation that affects the central nervous system and other organs is still common. Reliable methods are needed to study HIV-associated inflammatory biomarkers. In this study involving both plasma and cerebrospinal fluid (CSF), we compared multiplex bead array (MBA) to a relatively new technology based on microfluidics and glass nanoreactor (GNR) technology for the measurement of three commonly studied markers from HIV-infected individuals. We found that results correlated between the two platforms for MCP-1 in both fluids as well as for plasma TNFα (all p

The original Human Connectome Project yielded a rich data set on structural and functional connectivity in a large sample of healthy young adults using improved methods of data acquisition, analysis, and sharing. More recent efforts are extending this approach to include infants, children, older adults, and brain disorders. This paper introduces and describes the Human Connectome Project in Aging (HCP-A), which is currently recruiting 1200 + healthy adults aged 36 to 100+, with a subset of 600 + participants returning for longitudinal assessment. Four acquisition sites using matched Siemens Prisma 3T MRI scanners with centralized quality control and data analysis are enrolling participants. Data are acquired across multimodal imaging and behavioral domains with a focus on factors known to be altered in advanced aging. MRI acquisitions include structural (whole brain and high resolution hippocampal) plus multiband resting state functional (rfMRI), task fMRI (tfMRI), diffusion MRI (dMRI), and arterial spin labeling (ASL). Behavioral characterization includes cognitive (such as processing speed and episodic memory), psychiatric, metabolic, and socioeconomic measures as well as assessment of systemic health (with a focus on menopause via hormonal assays). This dataset will provide a unique resource for examining how brain organization and connectivity changes across typical aging, and how these differences relate to key characteristics of aging including alterations in hormonal status and declining memory and general cognition. A primary goal of the HCP-A is to make these data freely available to the scientific community, supported by the Connectome Coordination Facility (CCF) platform for data quality assurance, preprocessing and basic analysis, and shared via the NIMH Data Archive (NDA). Here we provide the rationale for our study design and sufficient details of the resource for scientists to plan future analyses of these data. A companion paper describes the related Human Connectome Project in Development (HCP-D, Somerville et al., 2018), and the image acquisition protocol common to both studies (Harms et al., 2018).

BackgroundMosquito-borne arboviruses, like dengue virus, continue to cause significant global morbidity and mortality, particularly in Southeast Asia. When the infectious mosquitoes probe into human skin for a blood meal, they deposit saliva containing a myriad of pharmacologically active compounds, some of which alter the immune response and influence host receptivity to infection, and consequently, the establishment of the virus. Previous reports have highlighted the complexity of mosquito vector-derived factors and immunity in the success of infection. Cumulative evidence from animal models and limited data from humans have identified various vector-derived components, including salivary components, that are co-delivered with the pathogen and play an important role in the dissemination of infection. Much about the roles and effects of these vector-derived factors remain to be discovered.Methods/designWe describe a longitudinal, pagoda (community)-based pediatric cohort study to evaluate the burden of dengue virus infection and document the immune responses to salivary proteins of Aedes aegypti, the mosquito vector of dengue, Zika, and chikungunya viruses. The study includes community-based seroprevalence assessments in the peri-urban town of Chbar Mon in Kampong Speu Province, Cambodia. The study aims to recruit 771 children between the ages of 2 and 9 years for a three year period of longitudinal follow-up, including twice per year (rainy and dry season) serosurveillance for dengue seroconversion and Ae. aegypti salivary gland homogenate antibody intensity determinations by ELISA assays. Diagnostic tests for acute dengue, Zika and chikungunya viral infections will be performed by RT-PCR.DiscussionThis study will serve as a foundation for further understanding of mosquito saliva immunity and its impact on Aedes-transmitted arboviral diseases endemic to Cambodia.Trial registrationNCT03534245 registered on 23 May 2018.

BackgroundAlthough pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch.MethodsTo examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6-18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression.ResultsFrom pre-/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV1% and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV1%, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV1% and FVC %.ConclusionsThese results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty.Trial registrationClinicalTrials.gov registration number: NCT01748175 .

Chinese Americans have low colorectal cancer (CRC) screening rates. It is unclear whether physicians should offer all CRC screening modalities (fecal occult blood test [FOBT], sigmoidoscopy, colonoscopy) to Chinese Americans to increase screening. Seven hundred and twenty-five Chinese Americans were asked in a survey if their physician had ever recommended CRC screening and to self-report receipt and type of CRC screening. Participants whose physician had recommended all CRC screening modalities were significantly more likely to report ever having screening (adjusted odds ratio 4.29, 95% CI 1.26-14.68) and being up-to-date (4.06, 95% CI 2.13-7.74) than those who reported that their physician only recommended FOBT. Participants who received a recommendation of only one type of screening did not report a significant difference in ever having or being up-to-date for screening. A potential strategy to increase CRC screening among Chinese Americans is for clinicians to recommend all available CRC screening modalities to each patient.

The goal of the study was to test the bidirectional associations between teacher-child relationship quality and behavior problems in an elementary school age sample of Chinese American immigrant children. A socioeconomically diverse sample (N = 258) of first- and second-generation Chinese American children (M ages = 7.4 and 9.2 years at Wave 1 and Wave 2, respectively; 48% girls) was recruited from schools and communities and followed for 1 to 2 years. Two waves of data on dimensions of teacher-child relationship quality (i.e., warmth, closeness, and conflict) and children's externalizing and internalizing problems were collected through parents', teachers', and children's report. Path analyses were conducted to test the bidirectional associations between teacher-child relationship quality and behavior problems, controlling for prior levels, child demographic characteristics, and teacher ethnicity. Transactional associations between teacher-child relationship quality and children's behavior problems were found for externalizing problems. That is, teacher-rated externalizing problems negatively predicted child-rated closeness, and teacher-rated conflict positively predicted parent-rated externalizing problems. On the other hand, teacher-child relationship quality did not predict subsequent internalizing problems. However, parent-rated internalizing problems negatively predicted teacher-rated warmth, and teacher-rated internalizing problems negatively predicted teacher-rated conflict. Using a multiple informant approach and a diverse sample of Chinese American immigrant children, this study extends our knowledge of the reciprocal associations between teacher-child relationship quality and children's behavior problems. Based on the results of this study, the authors provide recommendations for educators and future research with this understudied population.

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.

BackgroundWe performed a phase I modified 3 + 3 dose escalation study to evaluate the safety and activity of bevacizumab plus gemcitabine and nab-paclitaxel in patients with advanced solid tumours.MethodsPatients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed.ResultsThe study enrolled 110 patients who had undergone a median of 3 prior lines of therapy. The median age was 60 years (range, 17-85 years), and 55 patients (50%) had gemcitabine-refractory disease. We observed 3 dose-limiting toxicities during dose escalation and 3 DLTs in expansion cohorts. Dose escalation to 150 mg/m2 nab-paclitaxel and 15 mg/kg bevacizumab with 1000 mg/m2 of gemcitabine was well tolerated with no MTD. One patient with gemcitabine-refractory peritoneal papillary carcinoma had a complete response, 13 patients (13%) had partial responses, and 54 patients (52%) had stable disease ≥12 weeks. Exploratory VEGF single nucleotide polymorphism (SNP) analysis was performed on 13 patients.ConclusionsThe combination of gemcitabine, nab-paclitaxel, and bevacizumab is safe, well-tolerated, and has activity in advanced malignancies, including gemcitabine-refractory tumours. Based on this study, the recommended phase 2 dose is gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2, and bevacizumab 15 mg/kg. VEGF polymorphism data should be evaluated in future bevacizumab-based trials.

BACKGROUND:Ilorasertib (ABT-348) inhibits Aurora and VEGF receptor (VEGFR) kinases. Patients with advanced solid tumours participated in a phase 1 dose-escalation trial to profile the safety, tolerability, and pharmacokinetics of ilorasertib. METHODS:Ilorasertib monotherapy was administered at 10-180 mg orally once daily (Arm I, n = 23), 40-340 mg orally twice daily (Arm II, n = 28), or 8-32 mg intravenously once daily (Arm III, n = 7), on days 1, 8, and 15 of each 28-day cycle. RESULTS:Dose-limiting toxicities were predominantly related to VEGFR inhibition. The most frequent treatment-emergent adverse events ( > 30%) were: fatigue (48%), anorexia (34%), and hypertension (34%). Pharmacodynamic markers suggested that ilorasertib engaged VEGFR2 and Aurora B kinase, with the VEGFR2 effects reached at lower doses and exposures than Aurora inhibition effects. In Arm II, one basal cell carcinoma patient (40 mg twice daily (BID)) and one patient with adenocarcinoma of unknown primary site (230 mg BID) had partial responses. CONCLUSIONS:In patients with advanced solid tumours, ilorasertib treatment resulted in evidence of engagement of the intended targets and antitumour activity, but with maximum inhibition of VEGFR family kinases occurring at lower exposures than typically required for inhibition of Aurora B in tissue. CLINICAL TRIAL REGISTRATION:NCT01110486.

Depression is a commonly occurring symptom in obsessive-compulsive disorder (OCD), and is associated with worse functional impairment, poorer quality of life, and poorer treatment response. Understanding the underlying neurochemical and connectivity-based brain mechanisms of this important symptom domain in OCD is necessary for development of novel, more globally effective treatments. To investigate biopsychological mechanisms of comorbid depression in OCD, we examined effective connectivity and neurochemical signatures in the pregenual anterior cingulate cortex (pACC), a structure known to be involved in both OCD and depression. Resting-state functional magnetic resonance imaging (fMRI) and 1H magnetic resonance spectroscopy (MRS) data were obtained from participants with OCD (n=49) and healthy individuals of equivalent age and sex (n=25). Granger causality-based effective (directed) connectivity was used to define causal networks involving the right and left pACC. The interplay between fMRI connectivity, 1H MRS and clinical data was explored by applying moderation and mediation analyses. We found that the causal influence of the right dorsal anterior midcingulate cortex (daMCC) on the right pACC was significantly lower in the OCD group and showed significant correlation with depressive symptom severity in the OCD group. Lower and moderate levels of glutamate (Glu) in the right pACC significantly moderated the interaction between right daMCC-pACC connectivity and depression severity. Our results suggest a biochemical-connectivity-psychological model of pACC dysfunction contributing to depression in OCD, particularly involving intracingulate connectivity and glutamate levels in the pACC. These findings have implications for potential molecular and network targets for treatment of this multi-faceted psychiatric condition.

BackgroundAsthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited.MethodsWe studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids.ResultsThe rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06).ConclusionsIn children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

BackgroundThe effect of age on asthma severity is poorly understood.ObjectivesThe objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features.MethodsSARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity.ResultsCompared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma.ConclusionsThe phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age.

INTRODUCTION: The burden of influenza in Cambodia is not well known, but it would be useful for understanding the impact of seasonal epidemics and pandemics and to design appropriate policies for influenza prevention and control. The severe acute respiratory infection (SARI) surveillance system in Cambodia was used to estimate the national burden of SARI hospitalizations in Cambodia. METHODS: We estimated age-specific influenza-associated SARI hospitalization rates in three sentinel sites in Svay Rieng, Siem Reap and Kampong Cham provinces. We used influenza-associated SARI surveillance data for one year to estimate the numerator and hospital admission surveys to estimate the population denominator for each site. A national influenza-associated SARI hospitalization rate was calculated using the pooled influenza-associated SARI hospitalizations for all sites as a numerator and the pooled catchment population of all sites as denominator. National influenza-associated SARI case counts were estimated by applying hospitalization rates to the national population. RESULTS: The national annual rates of influenza-associated hospitalizations per 100 000 population was highest for the two youngest age groups at 323 for

BackgroundHispanic patients with cystic fibrosis (CF) have decreased life expectancy compared to non-Hispanic white patients. Pulmonary function is a main predictor of life expectancy in CF. Ethnic differences in pulmonary function in CF have been understudied. The objective was to compare longitudinal pulmonary function between Hispanic and non-Hispanic white patients with CF.MethodsThis cohort study of 15 018 6-25 years old patients in the CF Foundation Patient Registry from 2008 to 2013 compared FEV1 percent predicted and longitudinal change in FEV1 percent predicted in Hispanic to non-Hispanic white patients. We used linear mixed effects models with patient-specific slopes and intercepts, adjusting for 14 demographic and clinical variables. We did sub-analyses by CFTR class, F508del copies, and PERT use.ResultsHispanic patients had lower FEV1 percent predicted (79.9%) compared with non-Hispanic white patients (85.6%); (-5.8%, 95%CI -6.7% to -4.8%, P  0.05) or between F508del copies (None: -7.6%, Heterozygotes: -5.6%, Homozygotes: -5.3%, P > 0.05).ConclusionsDisparities in pulmonary function exist in Hispanic patients with CF early in life and then persist without improving or worsening over time. It is valuable to investigate the factors contributing to pulmonary function in Hispanic patients with CF.