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The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.

The BCL2 inhibitor venetoclax promotes apoptosis in blood cancer cells and is approved for treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, multiple myeloma cells are frequently more dependent on MCL-1 for survival, conferring resistance to venetoclax. Here we report that mevalonate pathway inhibition with statins can overcome resistance to venetoclax in multiple myeloma cell lines and primary cells. In addition, statins sensitize to apoptosis induced by MCL-1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in multiple myeloma, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize multiple myeloma cells to venetoclax by upregulating two proapoptotic proteins: PUMA via a p53-independent mechanism and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in multiple myeloma.SignificanceBH3 mimetics including venetoclax hold promise for treatment of multiple myeloma but rational combinations are needed to broaden efficacy. This study presents mechanistic and clinical data to support addition of pitavastatin to venetoclax regimens in myeloma. The results open a new avenue for repurposing statins in blood cancer.

Premature dropout from posttraumatic stress disorder treatment (PTSD) hinders treatment response. Studies have primarily used quantitative methodology to identify factors that contribute to Veterans' premature dropout, which has yielded mixed results. Qualitative methods provide rich data and generate additional hypotheses about why Veterans discontinue PTSD treatment. This study aimed to understand Veterans' reasons for dropping out of prolonged exposure therapy (PE) and to examine if there are differences in reasons for dropout between three delivery modalities: in-home, in-person (IHIP), office-based telehealth (OBT), or home-based telehealth (HBT). Twenty-two Veterans who dropped out of PE from a parent randomized clinical trial participated in individual qualitative interviews about potential contextual and individual factors related to discontinuation. Team-based coding was used to conduct open and focused coding. Themes were generated that described factors that influenced Veterans' dropout from PE and constant comparison was used to explore differences in reasons between the three modalities. Most Veterans had multiple reasons for dropping out and reasons were similar across delivery modalities with few differences. Practical barriers (e.g., scheduling difficulties), attitudes toward mental health providers and therapy (e.g., stigma), psychological and physical health factors (e.g., perceived worsening of symptoms, pain), and the therapeutic context (e.g., disliking aspects of PE) contributed to Veterans' decisions to drop out from PE. Veterans in OBT reported more types of practical barriers than Veterans in HBT and IHIP. These findings can help generate hypotheses about interventions that may promote engagement and future studies should continue to study how to reduce dropout. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

ObjectivesWhat sonographic variables are most predictive for acute cholecystitis? What variables differentiate acute and chronic cholecystitis?MethodsThe surgical pathology database was reviewed to identify adult patients who underwent cholecystectomy for cholecystitis and had a preceding ultrasound of the right upper quadrant within 7 days. A total of 236 patients were included in the study. A comprehensive imaging review was performed to assess for gallstones, gallbladder wall thickening, gallbladder distension, pericholecystic fluid, gallstone mobility, the sonographic Murphy's sign, mural hyperemia, and the common hepatic artery peak systolic velocity.ResultsOf 236 patients with a cholecystectomy, 119 had acute cholecystitis and 117 had chronic cholecystitis on surgical pathology. Statistical models were created for prediction. The simple model consists of three sonographic variables and has a sensitivity of 60% and specificity of 83% in predicting acute versus chronic cholecystitis. The most predictive variables for acute cholecystitis were elevated common hepatic artery peak systolic velocity, gallbladder distension, and gallbladder mural abnormalities. If a patient had all three of these findings on their preoperative ultrasound, the patient had a 96% chance of having acute cholecystitis. Two of these variables gave a 73-93% chance of having acute cholecystitis. One of the three variables gave a 40-76% chance of having acute cholecystitis. If the patient had 0 of 3 of the predictor variables, there was a 29% chance of having acute cholecystitis.ConclusionsGallbladder distension, gallbladder mural abnormalities, and elevated common hepatic artery peak systolic velocity are the most important sonographic variables in predicting acute versus chronic cholecystitis.

Immune checkpoint inhibitors (ICIs), including CTLA-4- and PD-1-blocking antibodies, can have profound effects on tumor immune cell infiltration that have not been consistent in biopsy series reported to date. Here, we analyze seven molecular datasets of samples from patients with advanced melanoma (N = 514) treated with ICI agents to investigate clinical, genomic, and transcriptomic features of anti-PD-1 response in cutaneous melanoma. We find that prior anti-CTLA-4 therapy is associated with differences in genomic, individual gene, and gene signatures in anti-PD-1 responders. Anti-CTLA-4-experienced melanoma tumors that respond to PD-1 blockade exhibit increased tumor mutational burden, inflammatory signatures, and altered cell cycle processes compared with anti-CTLA-4-naive tumors or anti-CTLA-4-experienced, anti-PD-1-nonresponsive melanoma tumors. We report a harmonized, aggregate resource and suggest that prior CTLA-4 blockade therapy is associated with marked differences in the tumor microenvironment that impact the predictive features of PD-1 blockade therapy response.

In this review, we synthesize evidence to highlight cognitive appraisal as an important developmental antecedent of individual differences in emotion differentiation and adept emotion regulation. Emotion differentiation is the degree to which emotions are experienced in a nuanced or "granular" way-as specific and separable phenomena. More extensive differentiation is related to positive wellbeing and has emerged as a correlate of emotion regulation skill among adults. We argue that the cognitive appraisal processes that underlie these facets of emotional development are instantiated early in the first year of life and tuned by environmental input and experience. Powerful socializing input in the form of caregivers' contingent and selective responding to infants' emotional signals carves and calibrates the infant's appraisal thresholds for what in their world ought to be noticed, deemed as important or personally meaningful, and responded to (whether and how). These appraisal thresholds are thus unique to the individual child despite the ubiquity of the appraisal process in emotional responding. This appraisal infrastructure, while plastic and continually informed by experience across the lifespan, likely tunes subsequent emotion differentiation, with implications for children's emotion regulatory choices and skills. We end with recommendations for future research in this area, including the urgent need for developmental emotion science to investigate the diverse sociocultural contexts in which children's cognitive appraisals, differentiation of emotions, and regulatory responses are being built across childhood.

This paper describes the evaluation of a longitudinal peer-support program developed to address loneliness and isolation among low-income, urban community-dwelling older adults in San Francisco. Our objective was to determine barriers, challenges, and successful strategies in implementation of the program. In-depth qualitative interviews with clients (n = 15) and peers (n = 6) were conducted and analyzed thematically by program component. We identified barriers and challenges to engagement and outlined strategies used to identify clients, match them with peers, and provide support to both peers and clients. We found that peers played a flexible, non-clinical role and were perceived as friends. Connections to community resources helped when clients needed additional support. We also documented creative strategies used to maintain inter-personal connections during the COVID-19 pandemic. This study fills a gap in understanding how a peer-support program can be designed to address loneliness and social isolation, particularly in low-income, urban settings.

BackgroundInternationally, strategies focusing on reducing alcohol-related harms in homeless populations with severe alcohol use disorder (AUD) continue to gain acceptance, especially when conventional modalities focused on alcohol abstinence have been unsuccessful. One such strategy is the managed alcohol program (MAP), an alcohol harm reduction program managing consumption by providing eligible individuals with regular doses of alcohol as a part of a structured program, and often providing resources such as housing and other social services. Evidence to the role of MAPs for individuals with AUD, including how MAPs are developed and implemented, is growing. Yet there has been limited collective review of literature findings.MethodsWe conducted a scoping review to answer, "What is being evaluated in studies of MAPs? What factors are associated with a successful MAP, from the perspective of client outcomes? What are the factors perceived as making them a good fit for clients and for communities?" We first conducted a systematic search in PubMed, Embase, PsycINFO, CINAHL, Sociological Abstracts, Social Services Abstracts, and Google Scholar. Next, we searched the gray literature (through focused Google and Ecosia searches) and references of included articles to identify additional studies. We also contacted experts to ensure relevant studies were not missed. All articles were independently screened and extracted.ResultsWe included 32 studies with four categories of findings related to: (1) client outcomes resulting from MAP participation, (2) client experience within a MAP; (3) feasibility and fit considerations in MAP development within a community; and (4) recommendations for implementation and evaluation. There were 38 established MAPs found, of which 9 were featured in the literature. The majority were located in Canada; additional research works out of Australia, Poland, the USA, and the UK evaluate potential feasibility and fit of a MAP.ConclusionsThe growing literature showcases several outcomes of interest, with increasing efforts aimed at systematic measures by which to determine the effectiveness and potential risks of MAP. Based on a harm reduction approach, MAPs offer a promising, targeted intervention for individuals with severe AUD and experiencing homelessness. Research designs that allow for longitudinal follow-up and evaluation of health- and housing-sensitive outcomes are recommended.

ObjectiveLinked metabolic and cardiovascular comorbidities are prevalent in hyperuricemia and gout. For mechanistic insight into impact on inflammatory processes and cardiometabolic risk factors of xanthine oxidase inhibitor urate-lowering therapy (ULT) titration to target, we performed a prospective study of gout serum metabolomes from a ULT trial.MethodsSera of gout patients meeting the 2015 ACR/EULAR gout classification criteria (n = 20) and with hyperuricemia were studied at time zero and weeks 12 and 24 of febuxostat or allopurinol dose titration ULT. Ultrahigh performance liquid chromatography-tandem mass spectroscopy acquired the serum spectra. Data were assessed using the Metabolon and Metaboloanalyst software. Lipolysis validation assays were done in febuxostat and/or colchicine-treated 3T3-L1 differentiated adipocytes.ResultsSerum urate decreased from time zero (8.21 ±1.139 SD) at weeks 12 (5.965 ± 1.734 SD) and 24 (5.655 ±1.763 SD). Top metabolites generated by changes in nucleotide and certain amino acid metabolism and polyamine pathways were enriched at 12 and 24 weeks ULT, respectively. Decreases in multiple fatty acid metabolites were observed at 24 weeks, linked with obesity. In cultured adipocytes, febuxostat significantly decreased while colchicine increased the lipolytic response to β-adrenergic-agonism or TNF.ConclusionMetabolomic profiles linked xanthine oxidase inhibitor-based ULT titration to target with reduced serum free fatty acids. In vitro validation studies revealed that febuxostat, but not colchicine, reduced lipolysis in cultured adipocytes. Since soluble urate, xanthine oxidase inhibitor treatment, and free fatty acids modulate inflammation, our findings suggest that by suppressing lipolysis, ULT could regulate inflammation in gout and comorbid metabolic and cardiovascular disease.

Rationale: Although the contribution of air pollution to lung cancer risk is well characterized, few studies have been conducted in racially, ethnically, and socioeconomically diverse populations. Objectives: To examine the association between traffic-related air pollution and risk of lung cancer in a racially, ethnically, and socioeconomically diverse cohort. Methods: Among 97,288 California participants of the Multiethnic Cohort Study, we used Cox proportional hazards regression to examine associations between time-varying traffic-related air pollutants (gaseous and particulate matter pollutants and regional benzene) and lung cancer risk (n = 2,796 cases; average follow-up = 17 yr), adjusting for demographics, lifetime smoking, occupation, neighborhood socioeconomic status (nSES), and lifestyle factors. Subgroup analyses were conducted for race, ethnicity, nSES, and other factors. Measurements and Main Results: Among all participants, lung cancer risk was positively associated with nitrogen oxide (hazard ratio [HR], 1.15 per 50 ppb; 95% confidence interval [CI], 0.99-1.33), nitrogen dioxide (HR, 1.12 per 20 ppb; 95% CI, 0.95-1.32), fine particulate matter with aerodynamic diameter  0.21), although participants residing in low-SES neighborhoods had increased lung cancer risk associated with nitrogen oxides, and no association was observed among those in high-SES neighborhoods. Conclusions: These findings in a large multiethnic population reflect an association between lung cancer and the mixture of traffic-related air pollution and not a particular individual pollutant. They are consistent with the adverse effects of air pollution that have been described in less racially, ethnically, and socioeconomically diverse populations. Our results also suggest an increased risk of lung cancer among those residing in low-SES neighborhoods.

Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.

Cost-effectiveness analysis, the most common type of economic evaluation, estimates a new option's additional outcome in relation to its extra costs. This is crucial to study within the clinical setting because funding for new treatments and interventions is often linked to whether there is evidence showing they are a good use of resources. This article describes how to analyze a cost-effectiveness dataset using the framework of a net benefit regression. The process of creating estimates and characterizing uncertainty is demonstrated using a hypothetical dataset. The results are explained and illustrated using graphs commonly employed in cost-effectiveness analyses. We conclude with a call to action for researchers to do more person-level cost-effectiveness analysis to produce evidence of the value of new treatments and interventions. Researchers can utilize cost-effectiveness analysis to compare new and existing treatment mechanisms.

Rationale: Knowledge gaps exist regarding health implications of sleep-disordered breathing (SDB) identified in pregnancy and/or after delivery. Objectives: To determine whether SDB in pregnancy and/or after delivery is associated with hypertension (HTN) and metabolic syndrome (MS). Methods: nuMoM2b-HHS (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be Heart Health Study) (N = 4,508) followed participants initially recruited during their first pregnancy. Participants returned for a visit 2-7 years after pregnancy. This study examined a subgroup who underwent SDB assessments during their first pregnancy (n = 1,964) and a repeat SDB assessment after delivery (n = 1,222). Two SDB definitions were considered: 1) apnea-hypopnea index (AHI) ⩾ 5 and 2) oxygen desaturation index (ODI) ⩾ 5. Associations between SDB and incident HTN and MS were evaluated with adjusted risk ratios (aRRs). Measurements and Main Results: The aRR for MS given an AHI ⩾ 5 during pregnancy was 1.44 (95% confidence interval [CI], 1.08-1.93), but no association with HTN was found. ODI ⩾ 5 in pregnancy was associated with both an increased risk for HTN (aRR, 2.02; 95% CI, 1.30-3.14) and MS (aRR, 1.53; 95% CI, 1.19-1.97). Participants with an AHI ⩾ 5 in pregnancy that persisted after delivery were at higher risk for both HTN (aRR, 3.77; 95% CI, 1.84-7.73) and MS (aRR, 2.46; 95% CI, 1.59-3.76). Similar associations were observed for persistent ODI ⩾ 5 after delivery. Conclusions: An AHI ⩾ 5 in pregnancy was associated with an increased risk of MS. An ODI ⩾ 5 in pregnancy was significantly associated with both HTN and MS. Participants with persistent elevations in AHI and ODI during pregnancy and at 2-7 years after delivery were at the highest risk for HTN and MS. Clinical trial registered with www.clinicaltrials.gov (NCT02231398).

The role of plasticity and epigenetics in shaping cancer evolution and response to therapy has taken center stage with recent technological advances including single cell sequencing. This roadmap article is focused on state-of-the-art mathematical and experimental approaches to interrogate plasticity in cancer, and addresses the following themes and questions: is there a formal overarching framework that encompasses both non-genetic plasticity and mutation-driven somatic evolution? How do we measure and model the role of the microenvironment in influencing/controlling non-genetic plasticity? How can we experimentally study non-genetic plasticity? Which mathematical techniques are required or best suited? What are the clinical and practical applications and implications of these concepts?

BackgroundWithin the Multiethnic Cohort (MEC), we examined the association between air pollution and mortality among African American, European American, Japanese American, and Latina American women diagnosed with breast cancer.MethodsWe used a land use regression (LUR) model and kriging interpolation to estimate nitrogen oxides (NOx , NO2) and particulate matter (PM2.5, PM10) exposures for 3,089 breast cancer cases in the MEC, who were diagnosed from 1993 through 2013 and resided largely in Los Angeles County, California. Cox proportional hazards models were used to examine the association of time-varying air pollutants with all-cause, breast cancer, cardiovascular disease (CVD), and non-breast cancer/non-CVD mortality, accounting for key covariates.ResultsWe identified 1,125 deaths from all causes (474 breast cancer, 272 CVD, 379 non-breast cancer/non-CVD deaths) among the 3,089 breast cancer cases with 8.1 years of average follow-up. LUR and kriged NOX (per 50 ppb) and NO2 (per 20 ppb), PM2.5 (per 10 µg/m3), and PM10 (per 10 µg/m3) were positively associated with risks of all-cause (Hazard Ratio (HR) range = 1.13-1.25), breast cancer (HR range = 1.19-1.45), and CVD mortality (HR range = 1.37-1.60). Associations were statistically significant for LUR NOX and CVD mortality (HR = 1.60; 95% CI: 1.08-2.37) and kriged NO2 and breast cancer mortality (HR = 1.45; 95% CI 1.02-2.07). Gaseous and PM pollutants were positively associated with breast cancer mortality across racial/ethnic group.ConclusionIn this study, air pollutants have a harmful impact on breast cancer survival. Additional studies should evaluate potential confounding by socioeconomic factors. These data support maintaining clean air laws to improve survival for women with breast cancer.

The degree to which COVID-19 has disrupted the advances in reducing new HIV infections and preventing AIDS-related deaths is unknown. We present findings related to the effect COVID-19 had on HIV, sexual health and harm reduction service delivery in the state of California. We conducted a qualitative rapid assessment with health care providers, as well as representatives from non-medical support service agencies serving clients living with HIV in a range of counties in California. Some organizations adapted fairly easily while others struggled or were unable to adapt at all. Clinics were better positioned than community-based organizations to accommodate COVID restrictions and to quickly reestablish services. Influential forces that softened or calcified the hardships created by COVID-19 included influx of funding, flexibility in managing funds, networking and relationships, and workforce vulnerabilities. These data clearly suggest that an enhanced level of flexibility within funding streams and reporting requirements should be continued.

BackgroundEvidence-based interventions addressing loneliness and social isolation are needed, including among low-income, community-dwelling older adults of diverse racial and ethnic backgrounds. Our objective was to assess the effect of a peer intervention in addressing loneliness, isolation, and behavioral health needs in this population.MethodsWe conducted a mixed-method, two-year longitudinal study of a peer-outreach intervention in 74 low-income older adults recruited via an urban senior center in San Francisco. Structured participant surveys were conducted at baseline and every 6 months for up to 2 years. Outcomes included loneliness (3-item UCLA loneliness scale), social interaction (10-item Duke index), self-perceived socializing barriers (range: 0-10), and depression (PHQ-2 screen). Data were analyzed using mixed-effects linear and logistic regression adjusted for age and gender. Qualitative, semi-structured interviews with participants (N = 15) and peers (N = 6) were conducted in English and Spanish and analyzed thematically.ResultsParticipants were on average 71 years old (range: 59-96 years), with 58% male, 15% LGBT, 18% African American, 19% Latinx, 8% Asian, 86% living alone, and 36% with an ADL impairment. On average, 43 contact visits (IQR: 31-97 visits) between participants and peers occurred over the first year. Loneliness scores decreased by, on average, 0.8 points over 24 months (p = 0.015). Participants reported reduced depression (38%-16%, p

Adipocytes increase energy expenditure in response to prolonged sympathetic activation via persistent expression of uncoupling protein 1 (UCP1)1,2. Here we report that the regulation of glycogen metabolism by catecholamines is critical for UCP1 expression. Chronic β-adrenergic activation leads to increased glycogen accumulation in adipocytes expressing UCP1. Adipocyte-specific deletion of a scaffolding protein, protein targeting to glycogen (PTG), reduces glycogen levels in beige adipocytes, attenuating UCP1 expression and responsiveness to cold or β-adrenergic receptor-stimulated weight loss in obese mice. Unexpectedly, we observed that glycogen synthesis and degradation are increased in response to catecholamines, and that glycogen turnover is required to produce reactive oxygen species leading to the activation of p38 MAPK, which drives UCP1 expression. Thus, glycogen has a key regulatory role in adipocytes, linking glucose metabolism to thermogenesis.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4-9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.

ObjectiveThe aim of the study was to determine the prevalence of clinically important masses among incidental hyperenhancing liver observations on portal venous phase computed tomography (CT) in patients without known malignancy or liver disease.MethodsRetrospective search of portal venous phase CTs was performed to identify hyperenhancing liver observations in patients without cancer or liver disease. Observations were assigned a morphology of homogeneous, hemangioma, or heterogeneous. The reference standard was pathology (n = 2), liver protocol CT/magnetic resonance imaging (n = 40), follow-up portal venous phase CT for 2 years or more (n = 81), or clinical follow-up for 5 years or more (n = 107).ResultsThere were no clinically important masses among 83 observations with homogeneous morphology or 110 with hemangioma morphology. There were 2 clinically important masses (1 hepatocellular carcinoma and 1 hepatic adenoma) among 37 (5.4%) heterogeneous morphology observations.ConclusionsIncidental hyperenhancing liver observations on portal venous phase CT with homogeneous or typical hemangioma morphology in patients without known cancer or liver disease are highly likely benign.

Despite signs of infection-including taste loss, dry mouth and mucosal lesions such as ulcerations, enanthema and macules-the involvement of the oral cavity in coronavirus disease 2019 (COVID-19) is poorly understood. To address this, we generated and analyzed two single-cell RNA sequencing datasets of the human minor salivary glands and gingiva (9 samples, 13,824 cells), identifying 50 cell clusters. Using integrated cell normalization and annotation, we classified 34 unique cell subpopulations between glands and gingiva. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry factors such as ACE2 and TMPRSS members were broadly enriched in epithelial cells of the glands and oral mucosae. Using orthogonal RNA and protein expression assessments, we confirmed SARS-CoV-2 infection in the glands and mucosae. Saliva from SARS-CoV-2-infected individuals harbored epithelial cells exhibiting ACE2 and TMPRSS expression and sustained SARS-CoV-2 infection. Acellular and cellular salivary fractions from asymptomatic individuals were found to transmit SARS-CoV-2 ex vivo. Matched nasopharyngeal and saliva samples displayed distinct viral shedding dynamics, and salivary viral burden correlated with COVID-19 symptoms, including taste loss. Upon recovery, this asymptomatic cohort exhibited sustained salivary IgG antibodies against SARS-CoV-2. Collectively, these data show that the oral cavity is an important site for SARS-CoV-2 infection and implicate saliva as a potential route of SARS-CoV-2 transmission.

ObjectiveOur objective was to incorporate social and built environment factors into a compendium of multilevel factors among a cohort of very low birth weight infants to understand their contributions to inequities in NICU quality of care and support providers and NICUs in addressing these inequities via development of a health equity dashboard.Study designWe examined bivariate associations between NICU patient pool and NICU catchment area characteristics and NICU quality of care with data from a cohort of 15,901 infants from 119 NICUs in California, born 2008-2011.ResultNICUs with higher proportion of minority racial/ethnic patients and lower SES patients had lower quality scores. NICUs with catchment areas of lower SES, higher composition of minority residents, and more household crowding had lower quality scores.ConclusionMultilevel social factors impact quality of care in the NICU. Their incorporation into a health equity dashboard can inform providers of their patients' potential resource needs.

Social neuroscience research has demonstrated that those who are like-minded are also 'like-brained.' Studies have shown that people who share similar viewpoints have greater neural synchrony with one another, and less synchrony with people who 'see things differently.' Although these effects have been demonstrated at the 'group level,' little work has been done to predict the viewpoints of specific 'individuals' using neural synchrony measures. Furthermore, the studies that have made predictions using synchrony-based classification at the individual level used expensive and immobile neuroimaging equipment (e.g. functional magnetic resonance imaging) in highly controlled laboratory settings, which may not generalize to real-world contexts. Thus, this study uses a simple synchrony-based classification method, which we refer to as the 'neural reference groups' approach, to predict individuals' dispositional attitudes from data collected in a mobile 'pop-up neuroscience' lab. Using functional near-infrared spectroscopy data, we predicted individuals' partisan stances on a sociopolitical issue by comparing their neural timecourses to data from two partisan neural reference groups. We found that partisan stance could be identified at above-chance levels using data from dorsomedial prefrontal cortex. These results indicate that the neural reference groups approach can be used to investigate naturally occurring, dispositional differences anywhere in the world.

RATIONALE & OBJECTIVE: Kidney biopsy data inform us about pathologic processes associated with infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We conducted a multicenter evaluation of kidney biopsy findings in living patients to identify various kidney disease pathology findings in patients with coronavirus disease 2019 (COVID-19) and their association with SARS-CoV-2 infection. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We identified 14 native and 3 transplant kidney biopsies performed for cause in patients with documented recent or concurrent SARS-CoV-2 infection treated at 7 large hospital systems in the United States. OBSERVATIONS: Men and women were equally represented in this case series, with a higher proportion of Black (n=8) and Hispanic (n=5) patients. All 17 patients had SARS-CoV-2 infection confirmed by reverse transcriptase-polymerase chain reaction, but only 3 presented with severe COVID-19 symptoms. Acute kidney injury (n=15) and proteinuria (n=11) were the most common indications for biopsy and these symptoms developed concurrently or within 1 week of COVID-19 symptoms in all patients. Acute tubular injury (n=14), collapsing glomerulopathy (n=7), and endothelial injury/thrombotic microangiopathy (n=6) were the most common histologic findings. 2 of the 3 transplant recipients developed active antibody-mediated rejection weeks after COVID-19. 8 patients required dialysis, but others improved with conservative management. LIMITATIONS: Small study size and short clinical follow-up. CONCLUSIONS: Cases of even symptomatically mild COVID-19 were accompanied by acute kidney injury and/or heavy proteinuria that prompted a diagnostic kidney biopsy. Although acute tubular injury was seen among most of them, uncommon pathology such as collapsing glomerulopathy and acute endothelial injury were detected, and most of these patients progressed to irreversible kidney injury and dialysis.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals working with cancer survivors to ensure that each survivor's complex and varied needs are addressed. The Guidelines provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment; recommendations to help promote healthful lifestyle behaviors, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes the recommendations regarding employment and return to work for cancer survivors that were added in the 2021 version of the NCCN Guidelines.

Consoling touch is a powerful form of social support that has been repeatedly demonstrated to reduce the experience of physical pain. However, it remains unknown whether touch reduces emotional pain in the same way that it reduces physical pain. The present research sought to understand how handholding with a romantic partner shapes experiences of emotional pain and comfort during emotional recollection, as well as how it shapes lasting emotional pain associated with emotional experiences. Participants recalled emotionally painful memories or neutral memories with their partners, while holding their partner's hand or holding a squeeze-ball. They additionally completed a follow-up survey to report how much emotional pain they associated with the emotional experiences after recalling them in the lab with their partners. Although consoling touch did not reduce emotional pain during the task, consoling touch increased feelings of comfort. Moreover, participants later recalled emotional memories that were paired with touch as being less emotionally painful than those that were not paired with touch. These findings suggest that touch does not decrease the immediate experience of emotional pain and may instead support adaptive processing of emotional experiences over time.

Hepatic TANK (TRAF family member associated NFκB activator)-binding kinase 1 (TBK1) activity is increased during obesity, and administration of a TBK1 inhibitor reduces fatty liver. Surprisingly, liver-specific TBK1 knockout in mice produces fatty liver by reducing fatty acid oxidation. TBK1 functions as a scaffolding protein to localize acyl-CoA synthetase long-chain family member 1 (ACSL1) to mitochondria, which generates acyl-CoAs that are channeled for β-oxidation. TBK1 is induced during fasting and maintained in the unphosphorylated, inactive state, enabling its high affinity binding to ACSL1 in mitochondria. In TBK1-deficient liver, ACSL1 is shifted to the endoplasmic reticulum to promote fatty acid re-esterification in lieu of oxidation in response to fasting, which accelerates hepatic lipid accumulation. The impaired fatty acid oxidation in TBK1-deficient hepatocytes is rescued by the expression of kinase-dead TBK1. Thus, TBK1 operates as a rheostat to direct the fate of fatty acids in hepatocytes, supporting oxidation when inactive during fasting and promoting re-esterification when activated during obesity.

PurposePediatric genitalia injury represents 0.6% of all pediatric trauma. It is crucial for providers to understand whether pediatric patients are at risk for violent mechanisms, such as rape, assault, or other abuse. Therefore, we sought to perform a large database analysis of pediatric and adolescent female genitalia trauma, comparing mechanisms of injury (i.e., sexual abuse) and need for operative intervention between adolescent and pediatric cohorts.MethodsThe National Trauma Data Bank was queried (years 2007-2015) for female patients ≤ 16 years old with external genitalia (vaginal or vulvar) trauma. Two groups were compared: pediatrics (

Hydroxyurea is an efficacious treatment for sickle cell disease (SCD), but adoption is low among individuals with SCD. The objective of this study was to examine barriers to patients' adherence to hydroxyurea use regimens by using the intentional and unintentional medication nonadherence framework. We interviewed individuals with SCD age 15 to 49.9 years who were participants in the Sickle Cell Disease Implementation Consortium (SCDIC) Needs Assessment. The intentional and unintentional medication nonadherence framework explains barriers to using hydroxyurea and adds granularity to the understanding of medication adherence barriers unique to the SCD population. In total, 90 semi-structured interviews were completed across 5 of the 8 SCDIC sites. Among interviewed participants, 57.8% (n = 52) were currently taking hydroxyurea, 28.9% (n = 26) were former hydroxyurea users at the time of the interview, and 13.3% (n = 12) had never used hydroxyurea but were familiar with the medication. Using a constructivist grounded theory approach, we discovered important themes that contributed to nonadherence to hydroxyurea, which were categorized under unintentional (eg, Forgetfulness, External Influencers) and intentional (Negative Perceptions of Hydroxyurea, Aversion to Taking Any Medications) nonadherence types. Participants more frequently endorsed adherence barriers that fell into the unintentional nonadherence type (70%) vs intentional nonadherence type (30%). Results from this study will help SCD health care providers understand patient choices and decisions as being either unintentional or intentional, guide tailored clinical discussions regarding hydroxyurea therapy, and develop specific, more nuanced interventions to address nonadherence factors.

Noncoding RNAs (ncRNAs) direct a remarkable number of diverse functions in development and disease through their regulation of transcription, RNA processing and translation. Leading the charge in the RNA revolution is a class of ncRNAs that are synthesized at active enhancers, called enhancer RNAs (eRNAs). Here, we review recent insights into the biogenesis of eRNAs and the mechanisms underlying their multifaceted functions and consider how these findings could inform future investigations into enhancer transcription and eRNA function.

PurposeTreatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution.Patients and methodsWe report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial.ResultsThe most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n = 1); seizure, somnolence, and delirium (n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects.ConclusionsDespite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.

BackgroundThe United States HIV care workforce is shrinking, which could complicate service delivery to people living with HIV (PLWH). In this study, we examined the impact of practice transformations, defined as efficiencies in structures and delivery of care, on demonstration project sites within the Workforce Capacity Building Initiative, a Health Resources and Services Administration (HRSA) Ryan White HIV/AIDS Program Special Projects of National Significance (SPNS).Methods and findingsData were collected at 14 demonstration project sites in 7 states and the District of Columbia. Organizational assessments were completed at sites once before and 4 times after implementation. They captured 3 transformation approaches: maximizing the HIV care workforce (efforts to increase the number of existing healthcare workforce members involved in the care of PLWH), share-the-care (team-based care giving more responsibility to midlevel providers and staff), and enhancing client engagement in primary HIV care to reduce emergency and inpatient care (e.g., care coordination). We also obtained Ryan White HIV/AIDS Program Services Reports (RSRs) from sites for calendar years (CYs) 2014-2016, corresponding to before, during, and after transformation. The RSR include data on client retention in HIV care, prescription of antiretroviral therapy (ART), and viral suppression. We used generalized estimating equation (GEE) models to analyze changes among sites implementing each practice transformation approach. The demonstration projects had a mean of 18.5 prescribing providers (SD = 23.5). They reported data on more than 13,500 clients per year (mean = 969/site, SD = 1,351). Demographic characteristics remained similar over time. In 2014, a majority of clients were male (71% versus 28% female and 0.2% transgender), with a mean age of 47 (interquartile range [IQR] 37-54). Racial/ethnic characteristics (48% African American, 31% Hispanic/Latino, 14% white) and HIV risk varied (31% men who have sex with men; 31% heterosexual men and women; 7% injection drug use). A substantial minority was on Medicaid (41%). Across sites, there was significant uptake in practices consistent with maximizing the HIV care workforce (18% increase, p < 0.001), share-the-care (25% increase, p < 0.001), and facilitating patient engagement in HIV primary care (13% increase, p < 0.001). There were also significant improvements over time in retention in HIV care (adjusted odds ratio [aOR] = 1.03; 95% confidence interval [CI] 1.02-1.04; p < 0.001), ART prescription levels (aOR = 1.01; 95% CI 1.00-1.01; p < 0.001), and viral suppression (aOR = 1.03; 95% CI 1.02-1.04; p < 0.001). All outcomes improved at sites that implemented transformations to maximize the HIV care workforce or improve client engagement. At sites that implemented share-the-care practices, only retention in care and viral suppression outcomes improved. Study limitations included use of demonstration project sites funded by the Ryan White HIV/AIDS Program (RWHAP), which tend to have better HIV outcomes than other US clinics; varying practice transformation designs; lack of a true control condition; and a potential Hawthorne effect because site teams were aware of the evaluation.ConclusionsIn this study, we found that practice transformations are a potential strategy for addressing anticipated workforce challenges among those providing care to PLWH. They hold the promise of optimizing the use of personnel and ensuring the delivery of care to all in need while potentially enhancing HIV care continuum outcomes.

Head and neck squamous cell carcinomas (HNSCCs) are malignancies that originate in the mucosal lining of the upper aerodigestive tract. Despite advances in therapeutic interventions, survival rates among HNSCC patients have remained static for years. Cancer stem cells (CSCs) are tumor-initiating cells that are highly resistant to treatment, and are hypothesized to contribute to a significant fraction of tumor recurrences. Consequently, further investigations of how CSCs mediate recurrence may provide insights into novel druggable targets. A key element of recurrence involves the tumor's ability to evade immunosurveillance. Recent published reports suggest that CSCs possess immunosuppressive properties, however, the underlying mechanism have yet to be fully elucidated. To date, most groups have focused on the role of CSC-derived secretory proteins, such as cytokines and growth factors. Here, we review the established immunoregulatory role of exosomes derived from mixed tumor cell populations, and propose further study of CSC-derived exosomes may be warranted. Such studies may yield novel insights into new druggable targets, or lay the foundation for future exosome-based diagnostics.

Previous studies using different exposure methods to assess air pollution and breast cancer risk among primarily whites have been inconclusive. Air pollutant exposures of particulate matter and oxides of nitrogen were estimated by kriging (NOx , NO2 , PM10 , PM2.5 ), land use regression (LUR, NOx , NO2 ) and California Line Source Dispersion model (CALINE4, NOx , PM2.5 ) for 57,589 females from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993-1996) through 2010. Cox proportional hazards models were used to examine the associations between time-varying air pollution and breast cancer incidence adjusting for confounding factors. Stratified analyses were conducted by race/ethnicity and distance to major roads. Among all women, breast cancer risk was positively but not significantly associated with NOx (per 50 parts per billion [ppb]) and NO2 (per 20 ppb) determined by kriging and LUR and with PM2.5 and PM10 (per 10 μg/m3 ) determined by kriging. However, among women who lived within 500 m of major roads, significantly increased risks were observed with NOx (hazard ratio [HR] = 1.35, 95% confidence interval [95% CI]: 1.02-1.79), NO2 (HR = 1.44, 95% CI: 1.04-1.99), PM10 (HR = 1.29, 95% CI: 1.07-1.55) and PM2.5 (HR = 1.85, 95% CI: 1.15-2.99) determined by kriging and NOx (HR = 1.21, 95% CI:1.01-1.45) and NO2 (HR = 1.26, 95% CI: 1.00-1.59) determined by LUR. No overall associations were observed with exposures assessed by CALINE4. Subgroup analyses suggested stronger associations of NOx and NO2 among African Americans and Japanese Americans. Further studies of multiethnic populations to confirm the effects of air pollution, particularly near-roadway exposures, on the risk of breast cancer is warranted.

We aimed to identify neural regions where ischemia acutely after stroke is associated with impairment in phoneme discrimination, and to determine whether such deficits are associated with impairment of spoken word comprehension. We evaluated 33 patients within 48 h of left hemisphere ischemic stroke onset with tests of phoneme discrimination and word-picture matching. We identified Pearson correlations between accuracy in phoneme discrimination and accuracy of word comprehension and identified areas where the percentage of infarcted tissue was associated with severity of phoneme discrimination deficit. We found that 54% had deficits in phoneme discrimination relative to healthy controls. Accuracy in phoneme discrimination correlated with accuracy on word comprehension tests. Damage to left intraparietal sulcus and hypoperfusion and/or infarct of left superior temporal gyrus were associated with phoneme discrimination deficits acutely, although patients with these lesions showed improvement or resolution of the deficit by six months.

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates glucose, lipid, and energy homeostasis. While gene expression of FGF21 is regulated by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha in the fasted state, little is known about the regulation of trafficking and secretion of FGF21. We show that mice with a mutation in the Yip1 domain family, member 6 gene (Klein-Zschocher [KLZ]; Yipf6KLZ/Y ) on a high-fat diet (HFD) have higher plasma levels of FGF21 than mice that do not carry this mutation (controls) and hepatocytes from Yipf6KLZ/Y mice secrete more FGF21 than hepatocytes from wild-type mice. Consequently, Yipf6KLZ/Y mice are resistant to HFD-induced features of the metabolic syndrome and have increased lipolysis, energy expenditure, and thermogenesis, with an increase in core body temperature. Yipf6KLZ/Y mice with hepatocyte-specific deletion of FGF21 were no longer protected from diet-induced obesity. We show that YIPF6 binds FGF21 in the endoplasmic reticulum to limit its secretion and specifies packaging of FGF21 into coat protein complex II (COPII) vesicles during development of obesity in mice. Levels of YIPF6 protein in human liver correlate with hepatic steatosis and correlate inversely with levels of FGF21 in serum from patients with nonalcoholic fatty liver disease (NAFLD). YIPF6 is therefore a newly identified regulator of FGF21 secretion during development of obesity and could be a target for treatment of obesity and NAFLD.

BackgroundInhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response.ObjectiveWe aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings.MethodsA meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10-6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations.ResultsA total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10-6 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10-3 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10-3 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified.Conclusions and clinical relevanceThis study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.

ObjectiveTo assess the effect of cannabis legalisation on health effects and healthcare utilisation in Colorado (CO), the first state to legalise recreational cannabis, when compared with two control states, New York (NY) and Oklahoma (OK).DesignWe used the 2010 to 2014 Healthcare Cost and Utilisation Project (HCUP) inpatient databases to compare changes in rates of healthcare utilisation and diagnoses in CO versus NY and OK.SettingPopulation-based, inpatient.ParticipantsHCUP state-wide data comprising over 28 million individuals and over 16 million hospitalisations across three states.Main outcome measuresWe used International Classification of Diseases-Ninth Edition codes to assess changes in healthcare utilisation specific to various medical diagnoses potentially treated by or exacerbated by cannabis. Diagnoses were classified based on weight of evidence from the National Academy of Science (NAS). Negative binomial models were used to compare rates of admissions between states.ResultsIn CO compared with NY and OK, respectively, cannabis abuse hospitalisations increased (risk ratio (RR) 1.27, 95% CI 1.26 to 1.28 and RR 1.16, 95% CI 1.15 to 1.17; both p

ObjectiveHealth literacy is critical for understanding information from health-care providers and correct use of medications and includes the capacity to filter other information in navigating health care systems. Older adults with low health literacy exhibit more chronic health conditions, worse physical functioning, and poorer mental health. This study examined the relationship between sociodemographic variables and health literacy, and the impact of cognitive training on change in health literacy over 10 years in older adults.MethodsParticipants (N = 2,802) aged 65 years and older completed assessments, including reading and numeracy health literacy items, as part of the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study. We evaluated baseline sociodemographic variables and change in health literacy over a 10-year period in individuals exposed to cognitive training in reasoning, processing speed, memory, or a no-contact control condition.ResultsAge, sex, race, education level, and general cognitive functioning at baseline were all associated with baseline health literacy in older adults. Predictors of change in health literacy over the 10-year follow-up were age, race, education level, general cognitive functioning, and neighborhood income; disparities in health literacy because of race attenuated over time, while the effect of age increased over time. Health literacy was generally stable across the ACTIVE intervention groups over 10 years.ConclusionsThe present study showed important disparities in health literacy level and change over 10 years. Cognitive training did not significantly impact health literacy, suggesting that alternative approaches are needed to reduce the disparities.

This manuscript describes the experiences of three state departments of health (SDoH) that successfully launched data sharing interventions involving surveillance and/or patient data collected in clinics to improve care outcomes among people living with HIV. We examined 58 key informant interviews, gathered at two time points, to describe the development and implementation of data sharing interventions. We identified three common themes across states' experiences: creating standard practices, fostering interoperability, and negotiating the policy environment. Projects were successful when state teams adapted to changing circumstances and were committed to a consistent communication process. Once implemented, the interventions streamlined processes to promote linkage and retention in care among low-income populations living with HIV. Despite using routinely collected data, key informants emphasized the labor-intensive process to develop and sustain the interventions. Lessons learned from these three state experiences can help inform best practices for other SDoH that are considering launching similar interventions.

Ensuring continuity of and retention in care after release from prison is critical for optimizing health outcomes among people living with HIV. As part of a large federal initiative, we conducted qualitative interviews (n = 24) with individuals living with HIV and recently released from prison in four states to understand their experiences in different navigation interventions to improve access to HIV care post-release. Interventions were delivered only in prison, only in the community, or in both settings. While the interventions varied by design, overall, participants appreciated the breadth of support received from interventionists, including health system navigation, case management and social support. Even when individuals leaving prison were returning to clinics that they were familiar with, systems navigation supported continuity of care. Our findings elucidate why navigational support was instrumental, and underscore the value of a variety of types of navigation programs in facilitating continuity of care and reintegration post-prison.

ObjectivesTo describe the epidemiology, response to therapy, and outcomes of Kawasaki disease in a multiethnic community with a large Hispanic and Asian population.Study designWe analyzed prospectively collected data from 788 unselected patients with Kawasaki disease diagnosed and treated at a single medical center over a 10-year period.ResultsThe average incidence of Kawasaki disease in children

BackgroundSecondhand smoke (SHS) exposures have been linked to asthma-related outcomes but quantitative dose-responses using biomarkers of exposure have not been widely reported.ObjectivesAssess dose-response relationships between plasma cotinine-determined SHS exposure and asthma outcomes in minority children, a vulnerable population exposed to higher levels of SHS and under-represented in the literature.MethodsWe performed analyses in 1172 Latino and African-American children with asthma from the mainland USA and Puerto Rico. We used logistic regression to assess relationships of cotinine levels ≥0.05 ng/mL with asthma exacerbations (defined as asthma-related hospitalisations, emergency room visits or oral steroid prescription) in the previous year and asthma control. The shape of dose-response relationships was assessed using a continuous exposure variable in generalised additive logistic models with penalised splines.ResultsThe OR for experiencing asthma exacerbations in the previous year for cotinine levels ≥0.05 ng/mL, compared with

The non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and inhibitor of nuclear factor kappa-B kinase ε (IKKε) play a key role in insulin-independent pathways that promote energy storage and block adaptive energy expenditure during obesity. Utilizing docking calculations and the x-ray structure of TBK1 bound to amlexanox, an inhibitor of these kinases with modest potency, a series of analogues was synthesized to develop a structure activity relationship (SAR) around the A- and C-rings of the core scaffold. A strategy was developed wherein R7 and R8 A-ring substituents were incorporated late in the synthetic sequence by utilizing palladium-catalyzed cross-coupling reactions on appropriate bromo precursors. Analogues display IC50 values as low as 210 nM and reveal A-ring substituents that enhance selectivity toward either kinase. In cell assays, selected analogues display enhanced phosphorylation of p38 or TBK1 and elicited IL-6 secretion in 3T3-L1 adipocytes better than amlexanox. An analogue bearing a R7 cyclohexyl modification demonstrated robust IL-6 production in 3T3-L1 cells as well as a phosphorylation marker of efficacy and was tested in obese mice where it promoted serum IL-6 response, weight loss, and insulin sensitizing effects comparable to amlexanox. These studies provide impetus to expand the SAR around the amlexanox core toward uncovering analogues with development potential.

Chronic low-grade inflammation is a hallmark of obesity, which is a risk factor for the development of type 2 diabetes. The drug amlexanox inhibits IκB kinase ε (IKKε) and TANK binding kinase 1 (TBK1) to promote energy expenditure and improve insulin sensitivity. Clinical studies have demonstrated efficacy in a subset of diabetic patients with underlying adipose tissue inflammation, albeit with moderate potency, necessitating the need for improved analogs. Herein we report crystal structures of TBK1 in complex with amlexanox and a series of analogs that modify its carboxylic acid moiety. Removal of the carboxylic acid or mutation of the adjacent Thr156 residue significantly reduces potency toward TBK1, whereas conversion to a short amide or ester nearly abolishes the inhibitory effects. IKKε is less affected by these modifications, possibly due to variation in its hinge that allows for increased conformational plasticity. Installation of a tetrazole carboxylic acid bioisostere improved potency to 200 and 400 nM toward IKKε and TBK1, respectively. Despite improvements in the in vitro potency, no analog produced a greater response in adipocytes than amlexanox, perhaps because of altered absorption and distribution. The structure-activity relationships and cocrystal structures described herein will aid in future structure-guided inhibitor development using the amlexanox pharmacophore for the treatment of obesity and type 2 diabetes.

The bromodomain and extra-terminal motif (BET) protein BRD4 binds to acetylated histones at enhancers and promoters via its bromodomains (BDs) to regulate transcriptional elongation. In human colorectal cancer cells, we found that BRD4 was recruited to enhancers that were co-occupied by mutant p53 and supported the synthesis of enhancer-directed transcripts (eRNAs) in response to chronic immune signaling. BRD4 selectively associated with eRNAs that were produced from BRD4-bound enhancers. Using biochemical and biophysical methods, we found that BRD4 BDs function cooperatively as docking sites for eRNAs and that the BDs of BRD2, BRD3, BRDT, BRG1, and BRD7 directly interact with eRNAs. BRD4-eRNA interactions increased BRD4 binding to acetylated histones in vitro and augmented BRD4 enhancer recruitment and transcriptional cofactor activities. Our results suggest a mechanism by which eRNAs are directly involved in gene regulation by modulating enhancer interactions and transcriptional functions of BRD4.

Monomethylation of histone H3 lysine 4 (H3K4me1) is enriched at enhancers that are primed for activation and the levels of this histone mark are frequently altered in various human cancers. Yet, how alterations in H3K4me1 are established and the consequences of these epigenetic changes in tumorigenesis are not well understood. Using ChIP-Seq in human colon cancer cells, we demonstrate that mutant p53 depletion results in decreased H3K4me1 levels at active enhancers that reveal a striking colocalization of mutant p53 and the H3K4 monomethyltransferase MLL4 following chronic tumor necrosis factor alpha (TNFα) signaling. We further reveal that mutant p53 forms physiological associations and direct interactions with MLL4 and promotes the enhancer binding of MLL4, which is required for TNFα-inducible H3K4me1 and histone H3 lysine 27 acetylation (H3K27ac) levels, enhancer-derived transcript (eRNA) synthesis, and mutant p53-dependent target gene activation. Complementary in vitro studies with recombinant chromatin and purified proteins demonstrate that binding of the MLL3/4 complex and H3K4me1 deposition is enhanced by mutant p53 and p300-mediated acetylation, which in turn reflects a MLL3/4-dependent enhancement of mutant p53 and p300-dependent transcriptional activation. Collectively, our findings establish a mechanism in which mutant p53 cooperates with MLL4 to regulate aberrant enhancer activity and tumor-promoting gene expression in response to chronic immune signaling.

RationaleAlbuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.ObjectivesTo identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.MethodsWe performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.Measurements and main resultsWe identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P

BackgroundExperimental and epidemiologic data suggest that among nonpregnant adults, sleep duration may be an important risk factor for chronic disease. Although pregnant women commonly report poor sleep, few studies objectively evaluated the quality of sleep in pregnancy or explored the relationship between sleep disturbances and maternal and perinatal outcomes.ObjectiveOur objective was to examine the relationship between objectively assessed sleep duration, timing, and continuity (measured via wrist actigraphy) and maternal cardiovascular and metabolic morbidity specific to pregnancy.Study designThis was a prospective cohort study of nulliparous women. Women were recruited between 16 0/7 and 21 6/7 weeks' gestation. They were asked to wear a wrist actigraphy monitor and complete a daily sleep log for a period of 7 consecutive days. The primary sleep exposure variables were the averages of the following over the total valid nights (minimum 5, maximum 7 nights): short sleep duration during the primary sleep period (5 am), and top quartile of minutes of wake time after sleep onset and sleep fragmentation index. The primary outcomes of interest were a composite of hypertensive disorders of pregnancy (mild, severe, or superimposed preeclampsia; eclampsia; or antepartum gestational hypertension) and gestational diabetes mellitus. We used χ2 tests to assess associations between sleep variables and categorical baseline characteristics. Crude odds ratios and 95% confidence intervals were estimated from univariate logistic regression models to characterize the magnitude of the relationship between sleep characteristics and hypertensive disorders of pregnancy and gestational diabetes. For associations significant in univariate analysis, multiple logistic regression was used to explore further the association of sleep characteristics with pregnancy outcomes.ResultsIn all, 901 eligible women consented to participate; 782 submitted valid actigraphy studies. Short sleep duration and a later sleep midpoint were associated with an increased risk of gestational diabetes (odds ratio, 2.24; 95% confidence interval, 1.11-4.53; and odds ratio, 2.58; 95% confidence interval, 1.24-5.36, respectively) but not of hypertensive disorders. A model with both sleep duration and sleep midpoint as well as their interaction term revealed that while there was no significant interaction between these exposures, the main effects of both short sleep duration and later sleep midpoint with gestational diabetes remained significant (adjusted odds ratio, 2.06; 95% confidence interval, 1.01-4.19; and adjusted odds ratio, 2.37; 95% confidence interval, 1.13-4.97, respectively). Additionally, after adjusting separately for age, body mass index, and race/ethnicity, both short sleep duration and later sleep midpoint remained associated with gestational diabetes. No associations were demonstrated between the sleep quality measures (wake after sleep onset, sleep fragmentation) and hypertensive disorders or gestational diabetes.ConclusionOur results demonstrate a relationship between short sleep duration and later sleep midpoint with gestational diabetes. Our data suggest independent contributions of these 2 sleep characteristics to the risk for gestational diabetes in nulliparous women.