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PurposeTo evaluate functional and structural assessments as endpoints for clinical trials for USH2A-related retinal degeneration.MethodsPeople with biallelic disease-causing variants in USH2A, visual acuity ≥ 20/80, and visual field ≥ 10° diameter were enrolled in a 4-year, natural history study. Participants underwent static perimetry, microperimetry, visual acuity, fullfield stimulus testing (FST), and optical coherence tomography annually. Rates of change estimated from mixed-effects linear models and percentages of eyes with changes exceeding the coefficient of repeatability (CoR) or thresholds conforming with U.S. Food and Drug Administration (FDA) guidelines were evaluated.ResultsRates of change were generally more sensitive to change than proportions of eyes exceeding a threshold such as the CoR. Baseline ellipsoid zone area ≥ 3 mm2 was necessary to detect change. Mean sensitivity and volumetric hill of vision measures on static perimetry had similar properties and were the most sensitive to changes of the continuous measures. The highest 4-year proportions of eyes exceeding the CoR were from FST testing (47%) and microperimetry (32%). Specification of loci as functional transition points (FTPs) resulted in 45% (static perimetry) and 46% (microperimetry) at 4 years, meeting FDA guidelines for progression.ConclusionsRate of change of mean sensitivity on static perimetry was a sensitive perimetric continuous measure. Percentages of within-eye change were largest with FST testing and microperimetry. FTPs appear to be particularly sensitive to change. These results affect clinical trial design for USH2A-related retinal degeneration.Translational relevanceAnalyses of natural history data from the Rate of Progression in USH2A-Related Retinal Degeneration (RUSH2A) study can inform eligibility criteria and endpoints for clinical trials.

BackgroundDespite elevated rates of trauma exposure, substance misuse, mental health problems, and suicide, systems-impacted teens and their caregivers have limited access to empirically supported behavioral health services. Family-based interventions are the most effective for improving mental health, education, substance use, and delinquency outcomes, yet the familial and placement disruption that occurs during child welfare involvement can interfere with the delivery of family-based interventions.ObjectiveTo address this gap in access to services, we adapted an in-person, empirically supported, family-based affect management intervention using a trauma-informed lens to be delivered via telehealth to families impacted by the child welfare system (Family Telehealth Project). We describe the intervention adaptation process and an open trial to evaluate its feasibility, acceptability, and impact.MethodsAdaptations to the in-person, family-based affect management intervention were conducted iteratively with input from youth, caregivers, and systems partners. Through focus groups and collaborative meetings with systems partners, a caregiver-only version of the intervention was also developed. An open trial of the intervention was conducted to assess family perspectives of its acceptability and feasibility and inform further refinements prior to a larger-scale evaluation. Participants included English-speaking families involved in the child welfare system in the past 12 months with teens (aged 12-18 years). Caregivers were eligible to participate either individually (caregivers of origin, kinship caregivers, or foster parents; n=7) or with their teen (caregiver of origin only; n=6 dyads). Participants completed session feedback forms and surveys at pretreatment, posttreatment, and 3-month posttreatment time points. Qualitative exit interviews were conducted with a subset of participants (12/19, 63%) to further understand their experiences with the intervention.ResultsSession attendance was high, and both caregivers and teens reported high acceptability of clinicians and sessions on feedback forms. Families were comfortable with video technology, with very few (

BackgroundSmartphone apps may provide an opportunity to deliver mental health resources and interventions in a scalable and cost-effective manner. However, young people from marginalized and underserved groups face numerous and unique challenges to accessing, engaging with, and benefiting from these apps.ObjectiveThis study aims to better understand the acceptability (ie, perceived usefulness and satisfaction with an app) and feasibility (ie, the extent to which an app was successfully used) of mental health apps for underserved young people. A secondary aim was to establish whether adaptations can be made to increase the accessibility and inclusivity of apps for these groups.MethodsWe conducted 2 sequential studies, consisting of a systematic literature review of mental health apps for underserved populations followed by a qualitative study with underserved young male participants (n=20; age: mean 19). Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, an electronic search of 5 databases was conducted in 2021. The search yielded 18,687 results, of which 14 articles met the eligibility criteria.ResultsThe included studies comprised a range of groups, including those affected by homelessness, having physical health conditions, living in low- and middle-income countries, and those with sexual and gender minority identities. Establishing and maintaining user engagement was a pervasive challenge across mental health apps and populations, and dropout was a reported problem among nearly all the included studies. Positive subjective reports of usability, satisfaction, and acceptability were insufficient to determine users' objective engagement.ConclusionsDespite the significant amount of funding directed to the development of mental health apps, juxtaposed with only limited empirical evidence to support their effectiveness, few apps have been deliberately developed or adapted to meet the heterogeneous needs of marginalized and underserved young people. Before mental health apps are scaled up, a greater understanding is needed of the types of services that more at-risk young people and those in limited-resource settings prefer (eg, standard vs digital) followed by more rigorous and consistent demonstrations of acceptability, effectiveness, and cost-effectiveness. Adopting an iterative participatory approach by involving young people in the development and evaluation process is an essential step in enhancing the adoption of any intervention, including apps, in "real-world" settings and will support future implementation and sustainability efforts to ensure that marginalized and underserved groups are reached.Trial registrationPROSPERO CRD42021254241; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=254241.

We explored whether siblings can be engaged in PrEP promotion. We used the Information-Motivation-Behavior model to develop and conduct surveys and dyadic interviews with Latino men who have sex with men (LMSM) and their siblings (n = 31) and three sibling-only focus groups (n = 20). For LMSM, only n = 14 (45%) agreed they would benefit from taking PrEP, yet n = 22 (71%) would take PrEP to make their sibling worry less about them, and n = 23 (74%) requested a PrEP referral. For siblings, n = 20 (65%) believed PrEP would benefit their brother, and n = 19 (95%) in the focus groups said they would take PrEP to help their brother get started. Qualitative results include (1) siblings' support for PrEP use, (2) explicit conversations about sex were not necessary for discussing sexual health, and (3) siblings wanted to understand what they could do to encourage their brother to consider PrEP. We conclude siblings can be engaged in PrEP promotion.

OBJECTIVE: Adolescents commonly experience both fear of negative evaluation and weight/shape concerns. However, evidence concerning the prospective associations between these constructs during adolescence is limited. The current study examined the bidirectional relationships between fear of negative evaluation and weight/shape concerns over a 3-year period in adolescents. METHOD: Australian high school students (n = 2073; 55% girls) completed self-report measures at three timepoints, each 1 year apart. RESULTS: Findings showed a bidirectional relationship, whereby increases in fear of negative evaluation predicted exacerbated weight/shape concerns, and vice versa. Results point towards a vicious maintenance cycle between fear of negative evaluation and weight/shape concerns. DISCUSSION: Findings from the current study highlight the importance of considering both fear of negative evaluation and weight/shape concerns in the development of health promotion and prevention programs designed to reduce the occurrence and adverse effects of body dissatisfaction or improve general mental health. PUBLIC SIGNIFICANCE: Many adolescents experience some level of fear of negative evaluation (i.e., worry about being judged by others) and worry about their weight and/or shape. This study examined the prospective relationship between both constructs. Findings showed a bidirectional relationship, whereby higher fear of negative evaluation predicted increased weight/shape concerns, and vice versa. Programs designed to reduce body dissatisfaction might be improved by targeting both fear of negative evaluation and weight/shape concerns.

BackgroundFamily-based interventions are efficacious at preventing and controlling childhood overweight and obesity; however, implementation is often hindered by low parent engagement. The purpose of this study was to evaluate predictors of parent engagement in a family-based childhood obesity prevention and control intervention.MethodsPredictors were assessed in a clinic-based community health worker (CHW)-led Family Wellness Program consisting of in-person educational workshops attended by parents and children. This program was part of a larger effort known as the Childhood Obesity Research Demonstration projects. Participants included 128 adult caretakers of children ages 2-11 (98% female). Predictors of parent engagement (e.g., anthropometric, sociodemographic, psychosocial variables) were assessed prior to the intervention. Attendance at intervention activities was recorded by the CHW. Zero-inflated Poisson regression was used to determine predictors of non-attendance and degree of attendance.ResultsParents' lower readiness to make behavioral and parenting changes related to their child's health was the sole predictor of non-attendance at planned intervention activities in adjusted models (OR = 0.41, p

BackgroundReducing the burden of death due to infection is an urgent global public health priority. Previous studies have estimated the number of deaths associated with drug-resistant infections and sepsis and found that infections remain a leading cause of death globally. Understanding the global burden of common bacterial pathogens (both susceptible and resistant to antimicrobials) is essential to identify the greatest threats to public health. To our knowledge, this is the first study to present global comprehensive estimates of deaths associated with 33 bacterial pathogens across 11 major infectious syndromes.MethodsWe estimated deaths associated with 33 bacterial genera or species across 11 infectious syndromes in 2019 using methods from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, in addition to a subset of the input data described in the Global Burden of Antimicrobial Resistance 2019 study. This study included 343 million individual records or isolates covering 11 361 study-location-years. We used three modelling steps to estimate the number of deaths associated with each pathogen: deaths in which infection had a role, the fraction of deaths due to infection that are attributable to a given infectious syndrome, and the fraction of deaths due to an infectious syndrome that are attributable to a given pathogen. Estimates were produced for all ages and for males and females across 204 countries and territories in 2019. 95% uncertainty intervals (UIs) were calculated for final estimates of deaths and infections associated with the 33 bacterial pathogens following standard GBD methods by taking the 2·5th and 97·5th percentiles across 1000 posterior draws for each quantity of interest.FindingsFrom an estimated 13·7 million (95% UI 10·9-17·1) infection-related deaths in 2019, there were 7·7 million deaths (5·7-10·2) associated with the 33 bacterial pathogens (both resistant and susceptible to antimicrobials) across the 11 infectious syndromes estimated in this study. We estimated deaths associated with the 33 bacterial pathogens to comprise 13·6% (10·2-18·1) of all global deaths and 56·2% (52·1-60·1) of all sepsis-related deaths in 2019. Five leading pathogens-Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa-were responsible for 54·9% (52·9-56·9) of deaths among the investigated bacteria. The deadliest infectious syndromes and pathogens varied by location and age. The age-standardised mortality rate associated with these bacterial pathogens was highest in the sub-Saharan Africa super-region, with 230 deaths (185-285) per 100 000 population, and lowest in the high-income super-region, with 52·2 deaths (37·4-71·5) per 100 000 population. S aureus was the leading bacterial cause of death in 135 countries and was also associated with the most deaths in individuals older than 15 years, globally. Among children younger than 5 years, S pneumoniae was the pathogen associated with the most deaths. In 2019, more than 6 million deaths occurred as a result of three bacterial infectious syndromes, with lower respiratory infections and bloodstream infections each causing more than 2 million deaths and peritoneal and intra-abdominal infections causing more than 1 million deaths.InterpretationThe 33 bacterial pathogens that we investigated in this study are a substantial source of health loss globally, with considerable variation in their distribution across infectious syndromes and locations. Compared with GBD Level 3 underlying causes of death, deaths associated with these bacteria would rank as the second leading cause of death globally in 2019; hence, they should be considered an urgent priority for intervention within the global health community. Strategies to address the burden of bacterial infections include infection prevention, optimised use of antibiotics, improved capacity for microbiological analysis, vaccine development, and improved and more pervasive use of available vaccines. These estimates can be used to help set priorities for vaccine need, demand, and development.FundingBill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care, using UK aid funding managed by the Fleming Fund.

To develop and validate a new tissue-based biomarker that improves prediction of outcomes in localized prostate cancer by quantifying the host response to tumor. We use digital image analysis and machine learning to develop a biomarker of the prostate stroma called quantitative reactive stroma (qRS). qRS is a measure of percentage tumor area with a distinct, reactive stromal architecture. Kaplan Meier analysis was used to determine survival in a large retrospective cohort of radical prostatectomy samples. qRS was validated in two additional, distinct cohorts that include international cases and tissue from both radical prostatectomy and biopsy specimens. In the developmental cohort (Baylor College of Medicine, n = 482), patients whose tumor had qRS > 34% had increased risk of prostate cancer-specific death (HR 2.94; p = 0.039). This result was replicated in two validation cohorts, where patients with qRS > 34% had increased risk of prostate cancer-specific death (MEDVAMC; n = 332; HR 2.64; p = 0.02) and also biochemical recurrence (Canary; n = 988; HR 1.51; p = 0.001). By multivariate analysis, these associations were shown to hold independent predictive value when compared to currently used clinicopathologic factors including Gleason score and PSA. qRS is a new, validated biomarker that predicts prostate cancer death and biochemical recurrence across three distinct cohorts. It measures host-response rather than tumor-based characteristics, and provides information not represented by standard prognostic measurements.

BackgroundHuman immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) is still among the leading causes of disease burden and mortality in sub-Saharan Africa (SSA), and the world is not on track to meet targets set for ending the epidemic by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the United Nations Sustainable Development Goals (SDGs). Precise HIV burden information is critical for effective geographic and epidemiological targeting of prevention and treatment interventions. Age- and sex-specific HIV prevalence estimates are widely available at the national level, and region-wide local estimates were recently published for adults overall. We add further dimensionality to previous analyses by estimating HIV prevalence at local scales, stratified into sex-specific 5-year age groups for adults ages 15-59 years across SSA.MethodsWe analyzed data from 91 seroprevalence surveys and sentinel surveillance among antenatal care clinic (ANC) attendees using model-based geostatistical methods to produce estimates of HIV prevalence across 43 countries in SSA, from years 2000 to 2018, at a 5 × 5-km resolution and presented among second administrative level (typically districts or counties) units.ResultsWe found substantial variation in HIV prevalence across localities, ages, and sexes that have been masked in earlier analyses. Within-country variation in prevalence in 2018 was a median 3.5 times greater across ages and sexes, compared to for all adults combined. We note large within-district prevalence differences between age groups: for men, 50% of districts displayed at least a 14-fold difference between age groups with the highest and lowest prevalence, and at least a 9-fold difference for women. Prevalence trends also varied over time; between 2000 and 2018, 70% of all districts saw a reduction in prevalence greater than five percentage points in at least one sex and age group. Meanwhile, over 30% of all districts saw at least a five percentage point prevalence increase in one or more sex and age group.ConclusionsAs the HIV epidemic persists and evolves in SSA, geographic and demographic shifts in prevention and treatment efforts are necessary. These estimates offer epidemiologically informative detail to better guide more targeted interventions, vital for combating HIV in SSA.

Sensorineural hearing loss (SNHL) is characteristic of Usher syndrome type 2 (USH2), but less is known about SNHL in nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) and olfaction in USH2A-associated retinal degeneration. The Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) is a natural history study that enrolled 127 participants, 80 with USH2 and 47 with ARRP. Hearing was measured by pure-tone thresholds and word recognition scores, and olfaction by the University of Pennsylvania Smell Identification Test (UPSIT). SNHL was moderate in 72% of USH2 participants and severe or profound in 25%, while 9% of ARRP participants had moderate adult-onset SNHL. Pure-tone thresholds worsened with age in ARRP but not in USH2 participants. The degree of SNHL was not associated with other participant characteristics in either USH2 or ARRP. Median pure-tone thresholds in ARRP participants were significantly higher than the normative population (p

The magnitude and functional patterns of intraspecific transcriptional variation in the anophelines, including those of sex-biased genes underlying sex-specific traits relevant for malaria transmission, remain understudied. As a result, how changes in expression levels drive adaptation in these species is poorly understood. We sequenced the female, male, and larval transcriptomes of three populations of Anopheles arabiensis from Burkina Faso. One-third of the genes were differentially expressed between populations, often involving insecticide resistance-related genes in a sample type-specific manner, and with the females showing the largest number of differentially expressed genes. At the genomic level, the X chromosome appears depleted of differentially expressed genes compared with the autosomes, chromosomes harboring inversions do not exhibit evidence for enrichment of such genes, and genes that are top contributors to functional enrichment patterns of population differentiation tend to be clustered in the genome. Further, the magnitude of variation for the sex expression ratio across populations did not substantially differ between male- and female-biased genes, except for some populations in which male-limited expressed genes showed more variation than their female counterparts. In fact, female-biased genes exhibited a larger level of interpopulation variation than male-biased genes, both when assayed in males and females. Beyond uncovering the extensive adaptive potential of transcriptional variation in An. Arabiensis, our findings suggest that the evolutionary rate of changes in expression levels on the X chromosome exceeds that on the autosomes, while pointing to female-biased genes as the most variable component of the An. Arabiensis transcriptome.

BackgroundSustainable Development Goal 3.2 has targeted elimination of preventable child mortality, reduction of neonatal death to less than 12 per 1000 livebirths, and reduction of death of children younger than 5 years to less than 25 per 1000 livebirths, for each country by 2030. To understand current rates, recent trends, and potential trajectories of child mortality for the next decade, we present the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 findings for all-cause mortality and cause-specific mortality in children younger than 5 years of age, with multiple scenarios for child mortality in 2030 that include the consideration of potential effects of COVID-19, and a novel framework for quantifying optimal child survival.MethodsWe completed all-cause mortality and cause-specific mortality analyses from 204 countries and territories for detailed age groups separately, with aggregated mortality probabilities per 1000 livebirths computed for neonatal mortality rate (NMR) and under-5 mortality rate (U5MR). Scenarios for 2030 represent different potential trajectories, notably including potential effects of the COVID-19 pandemic and the potential impact of improvements preferentially targeting neonatal survival. Optimal child survival metrics were developed by age, sex, and cause of death across all GBD location-years. The first metric is a global optimum and is based on the lowest observed mortality, and the second is a survival potential frontier that is based on stochastic frontier analysis of observed mortality and Healthcare Access and Quality Index.FindingsGlobal U5MR decreased from 71·2 deaths per 1000 livebirths (95% uncertainty interval [UI] 68·3-74·0) in 2000 to 37·1 (33·2-41·7) in 2019 while global NMR correspondingly declined more slowly from 28·0 deaths per 1000 live births (26·8-29·5) in 2000 to 17·9 (16·3-19·8) in 2019. In 2019, 136 (67%) of 204 countries had a U5MR at or below the SDG 3.2 threshold and 133 (65%) had an NMR at or below the SDG 3.2 threshold, and the reference scenario suggests that by 2030, 154 (75%) of all countries could meet the U5MR targets, and 139 (68%) could meet the NMR targets. Deaths of children younger than 5 years totalled 9·65 million (95% UI 9·05-10·30) in 2000 and 5·05 million (4·27-6·02) in 2019, with the neonatal fraction of these deaths increasing from 39% (3·76 million [95% UI 3·53-4·02]) in 2000 to 48% (2·42 million; 2·06-2·86) in 2019. NMR and U5MR were generally higher in males than in females, although there was no statistically significant difference at the global level. Neonatal disorders remained the leading cause of death in children younger than 5 years in 2019, followed by lower respiratory infections, diarrhoeal diseases, congenital birth defects, and malaria. The global optimum analysis suggests NMR could be reduced to as low as 0·80 (95% UI 0·71-0·86) deaths per 1000 livebirths and U5MR to 1·44 (95% UI 1·27-1·58) deaths per 1000 livebirths, and in 2019, there were as many as 1·87 million (95% UI 1·35-2·58; 37% [95% UI 32-43]) of 5·05 million more deaths of children younger than 5 years than the survival potential frontier.InterpretationGlobal child mortality declined by almost half between 2000 and 2019, but progress remains slower in neonates and 65 (32%) of 204 countries, mostly in sub-Saharan Africa and south Asia, are not on track to meet either SDG 3.2 target by 2030. Focused improvements in perinatal and newborn care, continued and expanded delivery of essential interventions such as vaccination and infection prevention, an enhanced focus on equity, continued focus on poverty reduction and education, and investment in strengthening health systems across the development spectrum have the potential to substantially improve U5MR. Given the widespread effects of COVID-19, considerable effort will be required to maintain and accelerate progress.FundingBill & Melinda Gates Foundation.

There is an urgent need to measure the impacts of COVID-19 among gay men and other men who have sex with men (MSM). We conducted a cross-sectional survey with a global sample of gay men and other MSM (n = 2732) from April 16, 2020 to May 4, 2020, through a social networking app. We characterized the economic, mental health, HIV prevention and HIV treatment impacts of COVID-19 and the COVID-19 response, and examined whether sub-groups of our study population are disproportionately impacted by COVID-19. Many gay men and other MSM not only reported economic and mental health consequences, but also interruptions to HIV prevention and testing, and HIV care and treatment services. These consequences were significantly greater among people living with HIV, racial/ethnic minorities, immigrants, sex workers, and socio-economically disadvantaged groups. These findings highlight the urgent need to mitigate the negative impacts of COVID-19 among gay men and other MSM.

PurposeTo report baseline visual fields in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) study.DesignCross-sectional study within a natural history study.MethodsSetting: multicenter, international.Study populationUsher syndrome type 2 (USH2) (n = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP) (n = 47) associated with biallelic disease-causing sequence variants in USH2A.Observation proceduresRepeatability of full-field static perimetry (SP) and between-eye symmetry of kinetic perimetry (KP) were evaluated with intraclass correlation coefficients (ICCs). The association of demographic and clinical characteristics with total hill of vision (VTOT) was assessed with general linear models. Associations between VTOT and other functional and morphologic measures were assessed using Spearman correlation coefficients and t tests.Main outcome measuresVTOT (SP) and III4e isopter area (KP).ResultsUSH2 participants had more severe visual field loss than ARRP participants (P < .001, adjusting for disease duration, age of enrollment). Mean VTOT measures among 3 repeat tests were 32.7 ± 24.1, 31.2 ± 23.4, and 31.7 ± 23.9 decibel-steradians (intraclass correlation coefficient [ICC] = 0.96). Better VA, greater photopic ERG 30-Hz flicker amplitudes, higher mean microperimetry sensitivity, higher central subfield thickness, absence of macular cysts, and higher III4e seeing area were associated with higher VTOT (all r > .48; P < .05). Mean III4e isopter areas for left (4561 ± 4426 squared degrees) and right eyes (4215 ± 4300 squared degrees) were concordant (ICC = 0.94).ConclusionsUSH2 participants had more visual field loss than participants with USH2A-related ARRP, adjusting for duration of disease and age of enrollment. VTOT was repeatable and correlated with other functional and structural metrics, suggesting it may be a good summary measure of disease severity in patients with USH2A-related retinal degeneration.

PurposeThe purpose of this study was to evaluate baseline best corrected visual acuity (BCVA), full-field electroretinography (ERG), full-field stimulus thresholds (FST), and their relationship with baseline demographic and clinical characteristics in the Rate of Progression in Usher syndrome type 2 (USH2A)-related Retinal Degeneration (RUSH2A) multicenter study.MethodsParticipants had Usher syndrome type 2 (USH2, N = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP, N = 47) associated with biallelic variants in the USH2A gene. Associations of demographic and clinical characteristics with BCVA, ERG, and FST were assessed with regression models.ResultsIn comparison to ARRP, USH2 had worse BCVA (median 79 vs. 82 letters; P < 0.001 adjusted for age), lower rod-mediated ERG b-wave amplitudes (median 0.0 vs. 6.6 µV; P < 0.001) and 30 Hz flicker cone-mediated ERG amplitudes (median 1.5 vs. 3.1 µV; P = 0.001), and higher (white, blue, and red) FST thresholds (means [-26, -31, -23 dB] vs. [-39, -45, -28 dB]; P < 0.001 for all stimuli). After adjusting for age, gender, and duration of vision loss, the difference in BCVA between diagnosis groups was attenuated (P = 0.09). Only diagnosis was associated with rod- and cone-mediated ERG parameters, whereas both genders (P = 0.04) and duration of visual loss (P < 0.001) also were associated with FST white stimulus.ConclusionsUSH2 participants had worse BCVA, ERG, and FST than ARRP participants. FST was strongly associated with duration of disease; it remains to be determined whether it will be a sensitive measure of progression.Translational relevanceUsing standardized research protocols in RUSH2A, measures have been identified to monitor disease progression and treatment response and differentiate features of prognostic relevance between USH2 and ARRP participants with USH2A mutations.

Background and purposeSelf-management programs may improve quality of life and self-efficacy for stroke survivors, but participation is low. In a randomized controlled trial of a complex, multidisciplinary, team-based secondary stroke prevention intervention, we offered participants Chronic Disease Self-Management Program (CDSMP) workshops in addition to clinic visits and home visits. To enhance participation, workshops were facilitated by community health workers who were culturally and linguistically concordant with most participants and scheduled CDSMP sessions at convenient venues and times. Over time, we implemented additional strategies such as free transportation and financial incentives. In this study, we aimed to determine factors associated with CDSMP participation and attendance.MethodsFrom 2014 to 2018, 18 CDSMP workshop series were offered to 241 English and Spanish-speaking individuals (age ≥40 years) with recent stroke or transient ischemic attack. Zero-inflated Poisson regression was used to identify factors associated with participation and attendance (ie, number of sessions attended) in CDSMP. Missing values were imputed using multiple imputation methods.ResultsNearly one-third (29%) of intervention subjects participated in CDSMP. Moderate disability and more clinic/home visits were associated with participation. Participants with higher numbers of clinic and home visits (incidence rate ratio [IRR], 1.06 [95% CI, 1.01-1.12]), severe (IRR, 2.34 [95% CI, 1.65-3.31]), and moderately severe disability (IRR, 1.55 [95% CI, 1.07-2.23]), and who enrolled later in the study (IRR, 1.12 [95% CI, 1.08-1.16]) attended more sessions. Individuals with higher chaos scores attended fewer sessions (IRR, 0.97 [95% CI, 0.95-0.99]).ConclusionsLess than one-third of subjects enrolled in the SUCCEED (Secondary Stroke Prevention by Uniting Community and Chronic Care Model Teams Early to End Disparities) intervention participated in CDSMP; however, participation improved as transportation and financial barriers were addressed. Strategies to address social determinants of health contributing to chaos and engage individuals in healthcare may facilitate attendance. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01763203.

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3·5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.

BackgroundChild overweight prevalence is increasing globally, but micronutrient deficiencies persist.ObjectivesWe aimed to 1) describe the prevalence and distribution of intraindividual double burden of malnutrition (DBM), defined as coexistence of overweight or obesity (OWOB) and either micronutrient deficiencies or anemia, among preschool children; 2) assess the independence of DBM components, e.g., whether the prevalence of DBM is greater than what would be expected by chance; and 3) identify predictors of intraindividual DBM, to guide intervention targeting.MethodsWe analyzed data from 24 population-based surveys from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia project (separately by survey; n = 226 to n = 7166). We defined intraindividual DBM as coexisting OWOB and ≥1 micronutrient deficiency [e.g., Micronutrient Deficiency Index (MDI) > 0; DBM-MDI] or anemia (DBM-Anemia). We assessed independence of DBM components with the Rao-Scott chi-square test and examined predictors of DBM and its components with logistic regression.ResultsDBM prevalence ranged from 0% to 9.7% (median: 2.5%, DBM-MDI; 1.4%, DBM-Anemia), reflecting a lower prevalence of OWOB (range: 0%-19.5%) than of micronutrient deficiencies and anemia, which exceeded 20% in most surveys. OWOB was generally not significantly associated with micronutrient deficiencies or anemia. In more than half of surveys, children 6-23 mo of age, compared with ≥24 mo, had greater adjusted odds of DBM-Anemia, anemia, and micronutrient deficiencies. Child sex and household socioeconomic status, urban location, and caregiver education did not consistently predict DBM or its components.ConclusionsIntraindividual DBM among preschool children was low but might increase as child OWOB increases. The analysis does not support the hypothesis that DBM components cluster within individuals, suggesting that population-level DBM may be addressed by programs to reduce DBM components without targeting individuals with DBM.

Multiple sclerosis (MS) is a chronic, inflammatory autoimmune disease that affects the central nervous system (CNS) for which there is no cure. In MS, encephalitogenic T cells infiltrate the CNS causing demyelination and neuroinflammation; however, little is known about the role of regulatory T cells (Tregs) in CNS tissue repair. Transplantation of neural stem and progenitor cells (NSCs and NPCs) is a promising therapeutic strategy to promote repair through cell replacement, although recent findings suggest transplanted NSCs also instruct endogenous repair mechanisms. We have recently described that dampened neuroinflammation and increased remyelination is correlated with emergence of Tregs following human NPC transplantation in a murine viral model of immune-mediated demyelination. In the current study we utilized the prototypic murine autoimmune model of demyelination experimental autoimmune encephalomyelitis (EAE) to test the efficacy of hNSC transplantation. Eight-week-old, male EAE mice receiving an intraspinal transplant of hNSCs during the chronic phase of disease displayed remyelination, dampened neuroinflammation, and an increase in CNS CD4+CD25+FoxP3+ regulatory T cells (Tregs). Importantly, ablation of Tregs abrogated histopathological improvement. Tregs are essential for maintenance of T cell homeostasis and prevention of autoimmunity, and an emerging role for Tregs in maintenance of tissue homeostasis through interactions with stem and progenitor cells has recently been suggested. The data presented here provide direct evidence for collaboration between CNS Tregs and hNSCs promoting remyelination.

ObjectiveWe previously identified 4 empirically derived mild cognitive impairment (MCI) subtypes via cluster analysis within the Alzheimer's Disease Neuroimaging Initiative (ADNI) and demonstrated high correspondence between patterns of cortical thinning at baseline and each cognitive subtype. We aimed to determine whether our MCI subtypes demonstrate unique longitudinal atrophy patterns.MethodsADNI participants (295 with MCI and 134 cognitively normal [CN]) underwent annual structural MRI and neuropsychological assessments. General linear modeling compared vertex-wise differences in cortical atrophy rates between each MCI subtype and the CN group. Linear mixed models examined trajectories of cortical atrophy over 3 years within lobar regions of interest.ResultsCompared to the CN group, those with amnestic MCI (memory deficit) initially demonstrated greater atrophy rates within medial temporal lobe regions that became more widespread over time. Those with dysnomic/amnestic MCI (naming/memory deficits) showed greater atrophy rates largely localized to temporal lobe regions. The mixed MCI (impairment in all cognitive domains) group showed greater atrophy rates in widespread regions at all time points. The cluster-derived normal group, who had intact neuropsychological performance and normal cortical thickness at baseline despite their MCI diagnosis via conventional diagnostic criteria, continued to show normal cognition and minimal cortical atrophy over 3 years.ConclusionsADNI's purported amnestic MCI sample produced more refined cognitive subtypes with unique longitudinal cortical atrophy rates. These novel MCI subtypes reliably reflect underlying atrophy, reduce false-positive diagnostic errors, and improve prediction of clinical course. Such improvements have implications for the selection of participants for clinical trials and for providing more precise risk assessment for individuals diagnosed with MCI.

BACKGROUND AND OBJECTIVES: Early diagnosis of cerebral palsy (CP) is critical in obtaining evidence-based interventions when plasticity is greatest. In 2017, international guidelines for early detection of CP were published on the basis of a systematic review of evidence. Our study aim was to reduce the age at CP diagnosis throughout a network of 5 diverse US high-risk infant follow-up programs through consistent implementation of these guidelines. METHODS: The study leveraged plan-do-study-act and Lean methodologies. The primary outcome was age at CP diagnosis. Data were acquired during the corresponding 9-month baseline and quarterly throughout study. Balancing measures were clinic no-show rates and parent perception of the diagnosis visit. Clinic teams conducted strengths, weaknesses, opportunities, and threats analyses, process flow evaluations, standardized assessments training, and parent questionnaires. Performance of a 3- to 4-month clinic visit was a critical process step because it included a Hammersmith Infant Neurologic Examination, a General Movements Assessment, and standardized assessments of motor function. RESULTS: The age at CP diagnosis decreased from a weighted average of 19.5 (95% confidence interval 16.2 to 22.8) to 9.5 months (95% confidence interval 4.5 to 14.6), with P = .008; 3- to 4-month visits per site increased from the median (interquartile range) 14 (5.2-73.7) to 54 (34.5-152.0), with P < .001; and no-show rates were not different. Parent questionnaires revealed positive provider perception with improvement opportunities for information content and understandability. CONCLUSIONS: Large-scale implementation of international guidelines for early detection of CP is feasible in diverse high-risk infant follow-up clinics. The initiative was received positively by families and without adversely affecting clinic operational flow. Additional parent support and education are necessary.

Educational attainment is an important social determinant of maternal, newborn, and child health1-3. As a tool for promoting gender equity, it has gained increasing traction in popular media, international aid strategies, and global agenda-setting4-6. The global health agenda is increasingly focused on evidence of precision public health, which illustrates the subnational distribution of disease and illness7,8; however, an agenda focused on future equity must integrate comparable evidence on the distribution of social determinants of health9-11. Here we expand on the available precision SDG evidence by estimating the subnational distribution of educational attainment, including the proportions of individuals who have completed key levels of schooling, across all low- and middle-income countries from 2000 to 2017. Previous analyses have focused on geographical disparities in average attainment across Africa or for specific countries, but-to our knowledge-no analysis has examined the subnational proportions of individuals who completed specific levels of education across all low- and middle-income countries12-14. By geolocating subnational data for more than 184 million person-years across 528 data sources, we precisely identify inequalities across geography as well as within populations.

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders.

In situ transgenesis methods such as viruses and electroporation can rapidly create somatic transgenic mice but lack control over copy number, zygosity, and locus specificity. Here we establish mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely defined chromosomal loci. We provide a toolkit of MADR elements for combination labeling, inducible and reversible transgene manipulation, VCre recombinase expression, and transgenesis of human cells. Further, we demonstrate the versatility of MADR by creating glioma models with mixed reporter-identified zygosity or with "personalized" driver mutations from pediatric glioma. MADR is extensible to thousands of existing mouse lines, providing a flexible platform to democratize the generation of somatic mosaic mice. VIDEO ABSTRACT.

Both HIV infection and tenofovir disoproxil fumarate (TDF) treatment adversely impact bone metabolism and may lead to osteopenia, which has critical implications for youth with HIV (YWH). This study evaluates changes in the biomarkers of bone metabolism and inflammation among YWH receiving initial treatment with TDF- and non-TDF-containing antiretroviral therapies (ARTs). YWH [n = 23, median age 21 years (range 18-24), 87% male, 61% African American] were assessed for inflammatory and bone metabolism biomarkers at enrollment, after 48 weeks of TDF-containing ART, and 96 weeks of ART without TDF with continued viral suppression. Spearman's rank correlation evaluated biomarker associations. Bone alkaline phosphatase, parathyroid hormone, and osteopontin increased after TDF treatment. All fell after TDF was discontinued. Levels of RANKL and osteoprotegerin did not change throughout the study. There was little correlation between biomarkers of bone metabolism and either macrophage or lymphocyte activation at any time point. Our results establish baseline associations between bone metabolism and immune biomarkers for this population, and find that before CD4 T cell decline chronic inflammation does not perturb biomarkers of bone metabolism among YWH. The adverse effects of TDF on bone health may be marginal for YWH at the early stages of disease.

BackgroundNeurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders.MethodsWe estimated prevalence, incidence, deaths, and disability-adjusted life-years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs]) by age and sex for 15 neurological disorder categories (tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category for other less common neurological disorders) in 195 countries from 1990 to 2016. DisMod-MR 2.1, a Bayesian meta-regression tool, was the main method of estimation of prevalence and incidence, and the Cause of Death Ensemble model (CODEm) was used for mortality estimation. We quantified the contribution of 84 risks and combinations of risk to the disease estimates for the 15 neurological disorder categories using the GBD comparative risk assessment approach.FindingsGlobally, in 2016, neurological disorders were the leading cause of DALYs (276 million [95% UI 247-308]) and second leading cause of deaths (9·0 million [8·8-9·4]). The absolute number of deaths and DALYs from all neurological disorders combined increased (deaths by 39% [34-44] and DALYs by 15% [9-21]) whereas their age-standardised rates decreased (deaths by 28% [26-30] and DALYs by 27% [24-31]) between 1990 and 2016. The only neurological disorders that had a decrease in rates and absolute numbers of deaths and DALYs were tetanus, meningitis, and encephalitis. The four largest contributors of neurological DALYs were stroke (42·2% [38·6-46·1]), migraine (16·3% [11·7-20·8]), Alzheimer's and other dementias (10·4% [9·0-12·1]), and meningitis (7·9% [6·6-10·4]). For the combined neurological disorders, age-standardised DALY rates were significantly higher in males than in females (male-to-female ratio 1·12 [1·05-1·20]), but migraine, multiple sclerosis, and tension-type headache were more common and caused more burden in females, with male-to-female ratios of less than 0·7. The 84 risks quantified in GBD explain less than 10% of neurological disorder DALY burdens, except stroke, for which 88·8% (86·5-90·9) of DALYs are attributable to risk factors, and to a lesser extent Alzheimer's disease and other dementias (22·3% [11·8-35·1] of DALYs are risk attributable) and idiopathic epilepsy (14·1% [10·8-17·5] of DALYs are risk attributable).InterpretationGlobally, the burden of neurological disorders, as measured by the absolute number of DALYs, continues to increase. As populations are growing and ageing, and the prevalence of major disabling neurological disorders steeply increases with age, governments will face increasing demand for treatment, rehabilitation, and support services for neurological disorders. The scarcity of established modifiable risks for most of the neurological burden demonstrates that new knowledge is required to develop effective prevention and treatment strategies.FundingBill & Melinda Gates Foundation.

BackgroundGermline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls.MethodsIn this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger.FindingsWe analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02-2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06-3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05-2·44; p=0·04) and Asp294His (2·15, 1·05-4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants.InterpretationOur pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies.FundingSPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.

This study examined fruit and vegetable intake by food store type shopped among US Hispanics. Using National Health and Nutrition Examination Survey 2011-2012 data, T test and chi-square tests examined differences between Hispanic consumers by food store type. Negative binomial regression analyses estimated associations between fruit and vegetable intake and food store type. Hispanics who only purchased fruits and vegetables from convenience stores were younger and more likely US born. They reported lower intakes of fruit and vegetables than individuals who purchased these foods from supermarket/grocery stores. Those who primarily purchased fruits and vegetables from supermarkets/grocery stores consumed 0.92 (p

Recent work has implicated the Lateral Habenula (LHb) in the production of anxiogenic and aversive states. It is innervated by all the major monoamine neurotransmitter systems and has projections that have been shown to modulate the activity of both dopaminergic and serotonergic brain regions. Cocaine is a stimulant drug of abuse that potentiates neurotransmission in these monoamine systems and recent research suggests that the drug's behavioral effects may be related in part to its actions within the LHb. The present research was therefore devised to test the hypothesis that alterations in serotonin (5-HT) function within the LHb can affect the behavioral response to cocaine. Male rats were fitted with intracranial guide cannula and trained to traverse a straight alleyway once a day for a 1 mg/kg i.v. injection of cocaine. Intra-LHb pretreatment with the 5-HT1B agonist CP 94,253 (0, 0.1, or 0.25 μg/side) attenuated the development of approach/avoidance "retreat" behaviors known to be a consequence of cocaine's dual rewarding (approach) and anxiogenic (avoidance) properties. This effect was reversed by co-administration of a selective 5-HT1B antagonist, NAS-181 (0.1 μg/side), demonstrating drug specificity at the 5-HT1B receptor. These data suggest that 5-HT1B signaling within the LHb contributes to the anxiogenic effects of cocaine.

Nicolas Fernandez,1 Julian Chavarriaga,2 Paola Ayala,3 Adriana Pedraza,4 John Bolivar,5 Juan Guillermo Prada,6 Juan Guillermo Cataño,6 Herney Garcia,7 Juliana Villanueva,6 Daniela Varela,6 Ignacio Zarante3 1Division of Urology Seattle Children’s Hospital, University of Washington, Seattle, WA, USA; 2Division of Urology, Clínica Imbanaco - Quiron Salud, Cali, Colombia; 3Human Genetics Institute, Pontificia Universidad Javeriana, Bogota, Colombia; 4Division of Urology Clínica Desa, Cali, Colombia; 5Division of Urology, Department of Surgery, Hospital Universitario San Ignacio, Bogota, Colombia; 6Division of Urology, Hospital Universitario San Ignacio, Pontificia Universidad Javeriana, Bogota, Colombia; 7Division of Urology, Department of Surgery, Universidad del Valle, Cali, ColombiaCorrespondence: Nicolas Fernandez, Division of Urology, Seattle Children’s Hospital, University of Washington, 5801 Sand Point Way NE, Seattle, WA, 98105, USA, Tel +1 206 351 2618, Email nicolas.fernandez@seattlechildrens.orgPurpose: To identify micro-RNAs (miRNAs) expression profiles in peripheral blood plasma that could play a role as potential biomarkers in patients who progressed to castration-resistant prostate cancer (CRPC). Liquid biopsy analysis of miRNAs is a fast-developing field with a considerable likelihood to predict tumor progression and metastasis by targeting genes involved in oncogenesis.Patients and Methods: Differential expression analysis of miRNAs profile in CRPC patients was performed by creating small RNA libraries of circulating miRNAs using HiSeq2500 Illumina platform. A secondary analysis of aligned reads with miRNA identification and quantification was performed using miARmaSeq. Using the Bowtie algorithm, the selected variants were compared to reference nucleotide sequence GRCh38 and miRbase. Novel miRNA sequences were structurally analyzed using mirDeep2®.Results: A total of 16 patients with CRPC were included for analysis. Identified circulating miRNAs were hsa-miR-885-3p, hsa-miR-4467, hsa-miR-4686, hsa-miR-146a-3p, hsa-miR-6514-5p. Genes identified as regulated by these miRNAs were GPR56, BDNF, CTNND1, C17orf62, and DTNA.Conclusion: We explored the miRNA expression profile in patients with CRPC, identifying five miRNAs implicated in the regulation of genes involved in prostate cancer (PCa) oncogenesis and progression. We also found miRNA 855– 3p in peripheral blood for the first time, which has a critical role in tumor growth mechanisms and higher expression profile than in healthy individuals.Keywords: prostatic neoplasm, prostatic neoplasms, castration-resistant, microRNAs, biomarkers, genital neoplasms, male

BackgroundGlobal development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017.MethodsThe causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries-Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODEm), to generate cause fractions and cause-specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised.FindingsAt the broadest grouping of causes of death (Level 1), non-communicable diseases (NCDs) comprised the greatest fraction of deaths, contributing to 73·4% (95% uncertainty interval [UI] 72·5-74·1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional (CMNN) causes accounted for 18·6% (17·9-19·6), and injuries 8·0% (7·7-8·2). Total numbers of deaths from NCD causes increased from 2007 to 2017 by 22·7% (21·5-23·9), representing an additional 7·61 million (7·20-8·01) deaths estimated in 2017 versus 2007. The death rate from NCDs decreased globally by 7·9% (7·0-8·8). The number of deaths for CMNN causes decreased by 22·2% (20·0-24·0) and the death rate by 31·8% (30·1-33·3). Total deaths from injuries increased by 2·3% (0·5-4·0) between 2007 and 2017, and the death rate from injuries decreased by 13·7% (12·2-15·1) to 57·9 deaths (55·9-59·2) per 100 000 in 2017. Deaths from substance use disorders also increased, rising from 284 000 deaths (268 000-289 000) globally in 2007 to 352 000 (334 000-363 000) in 2017. Between 2007 and 2017, total deaths from conflict and terrorism increased by 118·0% (88·8-148·6). A greater reduction in total deaths and death rates was observed for some CMNN causes among children younger than 5 years than for older adults, such as a 36·4% (32·2-40·6) reduction in deaths from lower respiratory infections for children younger than 5 years compared with a 33·6% (31·2-36·1) increase in adults older than 70 years. Globally, the number of deaths was greater for men than for women at most ages in 2017, except at ages older than 85 years. Trends in global YLLs reflect an epidemiological transition, with decreases in total YLLs from enteric infections, respiratory infections and tuberculosis, and maternal and neonatal disorders between 1990 and 2017; these were generally greater in magnitude at the lowest levels of the Socio-demographic Index (SDI). At the same time, there were large increases in YLLs from neoplasms and cardiovascular diseases. YLL rates decreased across the five leading Level 2 causes in all SDI quintiles. The leading causes of YLLs in 1990-neonatal disorders, lower respiratory infections, and diarrhoeal diseases-were ranked second, fourth, and fifth, in 2017. Meanwhile, estimated YLLs increased for ischaemic heart disease (ranked first in 2017) and stroke (ranked third), even though YLL rates decreased. Population growth contributed to increased total deaths across the 20 leading Level 2 causes of mortality between 2007 and 2017. Decreases in the cause-specific mortality rate reduced the effect of population growth for all but three causes: substance use disorders, neurological disorders, and skin and subcutaneous diseases.InterpretationImprovements in global health have been unevenly distributed among populations. Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health. For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for NCDs, and the death rate for selected causes has increased in the past decade.FundingBill & Melinda Gates Foundation.

BackgroundThe Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data.MethodsWe estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting.FindingsGlobally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs s1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]).InterpretationGlobal all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury.FundingBill & Melinda Gates Foundation.

BackgroundThe Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk-outcome associations.MethodsWe used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.FindingsIn 2017, 34·1 million (95% uncertainty interval [UI] 33·3-35·0) deaths and 1·21 billion (1·14-1·28) DALYs were attributable to GBD risk factors. Globally, 61·0% (59·6-62·4) of deaths and 48·3% (46·3-50·2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10·4 million (9·39-11·5) deaths and 218 million (198-237) DALYs, followed by smoking (7·10 million [6·83-7·37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6·53 million [5·23-8·23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4·72 million [2·99-6·70] deaths and 148 million [98·6-202] DALYs), and short gestation for birthweight (1·43 million [1·36-1·51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4·9% (3·3-6·5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23·5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18·6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low.InterpretationBy quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning.FundingBill & Melinda Gates Foundation.

BackgroundHow long one lives, how many years of life are spent in good and poor health, and how the population's state of health and leading causes of disability change over time all have implications for policy, planning, and provision of services. We comparatively assessed the patterns and trends of healthy life expectancy (HALE), which quantifies the number of years of life expected to be lived in good health, and the complementary measure of disability-adjusted life-years (DALYs), a composite measure of disease burden capturing both premature mortality and prevalence and severity of ill health, for 359 diseases and injuries for 195 countries and territories over the past 28 years.MethodsWe used data for age-specific mortality rates, years of life lost (YLLs) due to premature mortality, and years lived with disability (YLDs) from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to calculate HALE and DALYs from 1990 to 2017. We calculated HALE using age-specific mortality rates and YLDs per capita for each location, age, sex, and year. We calculated DALYs for 359 causes as the sum of YLLs and YLDs. We assessed how observed HALE and DALYs differed by country and sex from expected trends based on Socio-demographic Index (SDI). We also analysed HALE by decomposing years of life gained into years spent in good health and in poor health, between 1990 and 2017, and extra years lived by females compared with males.FindingsGlobally, from 1990 to 2017, life expectancy at birth increased by 7·4 years (95% uncertainty interval 7·1-7·8), from 65·6 years (65·3-65·8) in 1990 to 73·0 years (72·7-73·3) in 2017. The increase in years of life varied from 5·1 years (5·0-5·3) in high SDI countries to 12·0 years (11·3-12·8) in low SDI countries. Of the additional years of life expected at birth, 26·3% (20·1-33·1) were expected to be spent in poor health in high SDI countries compared with 11·7% (8·8-15·1) in low-middle SDI countries. HALE at birth increased by 6·3 years (5·9-6·7), from 57·0 years (54·6-59·1) in 1990 to 63·3 years (60·5-65·7) in 2017. The increase varied from 3·8 years (3·4-4·1) in high SDI countries to 10·5 years (9·8-11·2) in low SDI countries. Even larger variations in HALE than these were observed between countries, ranging from 1·0 year (0·4-1·7) in Saint Vincent and the Grenadines (62·4 years [59·9-64·7] in 1990 to 63·5 years [60·9-65·8] in 2017) to 23·7 years (21·9-25·6) in Eritrea (30·7 years [28·9-32·2] in 1990 to 54·4 years [51·5-57·1] in 2017). In most countries, the increase in HALE was smaller than the increase in overall life expectancy, indicating more years lived in poor health. In 180 of 195 countries and territories, females were expected to live longer than males in 2017, with extra years lived varying from 1·4 years (0·6-2·3) in Algeria to 11·9 years (10·9-12·9) in Ukraine. Of the extra years gained, the proportion spent in poor health varied largely across countries, with less than 20% of additional years spent in poor health in Bosnia and Herzegovina, Burundi, and Slovakia, whereas in Bahrain all the extra years were spent in poor health. In 2017, the highest estimate of HALE at birth was in Singapore for both females (75·8 years [72·4-78·7]) and males (72·6 years [69·8-75·0]) and the lowest estimates were in Central African Republic (47·0 years [43·7-50·2] for females and 42·8 years [40·1-45·6] for males). Globally, in 2017, the five leading causes of DALYs were neonatal disorders, ischaemic heart disease, stroke, lower respiratory infections, and chronic obstructive pulmonary disease. Between 1990 and 2017, age-standardised DALY rates decreased by 41·3% (38·8-43·5) for communicable diseases and by 49·8% (47·9-51·6) for neonatal disorders. For non-communicable diseases, global DALYs increased by 40·1% (36·8-43·0), although age-standardised DALY rates decreased by 18·1% (16·0-20·2).InterpretationWith increasing life expectancy in most countries, the question of whether the additional years of life gained are spent in good health or poor health has been increasingly relevant because of the potential policy implications, such as health-care provisions and extending retirement ages. In some locations, a large proportion of those additional years are spent in poor health. Large inequalities in HALE and disease burden exist across countries in different SDI quintiles and between sexes. The burden of disabling conditions has serious implications for health system planning and health-related expenditures. Despite the progress made in reducing the burden of communicable diseases and neonatal disorders in low SDI countries, the speed of this progress could be increased by scaling up proven interventions. The global trends among non-communicable diseases indicate that more effort is needed to maximise HALE, such as risk prevention and attention to upstream determinants of health.FundingBill & Melinda Gates Foundation.

BackgroundRadiotherapy is increasingly used to treat oligometastatic patients. We sought to identify prognostic criteria in oligometastatic patients undergoing definitive hypofractionated image-guided radiotherapy (HIGRT).MethodsExclusively extracranial oligometastatic patients treated with HIGRT were pooled. Characteristics including age, sex, primary tumor type, interval to metastatic diagnosis, number of treated metastases and organs, metastatic site, prior systemic therapy for primary tumor treatment, prior definitive metastasis-directed therapy, and systemic therapy for metastasis associated with overall survival (OS), progression-free survival (PFS), and treated metastasis control (TMC) were assessed by the Cox proportional hazards method. Recursive partitioning analysis (RPA) identified prognostic risk strata for OS and PFS based on pretreatment factors.Results361 patients were included. Primary tumors included non-small cell lung (17%), colorectal (19%), and breast cancer (16%). Three-year OS was 56%, PFS was 24%, and TMC was 72%. On multivariate analysis, primary tumor, interval to metastases, treated metastases number, and mediastinal/hilar lymph node, liver, or adrenal metastases were associated with OS. Primary tumor site, involved organ number, liver metastasis, and prior primary disease chemotherapy were associated with PFS. OS RPA identified five classes: class 1: all breast, kidney, or prostate cancer patients (BKP) (3-year OS 75%, 95% CI 66-85%); class 2: patients without BKP with disease-free interval of 75+ months (3-year OS 85%, 95% CI 67-100%); class 3: patients without BKP, shorter disease-free interval, ≤ two metastases, and age < 62 (3-year OS 55%, 95% CI 48-64%); class 4: patients without BKP, shorter disease-free interval, ≥ three metastases, and age < 62 (3-year OS 38%, 95% CI 24-60%); class 5: all others (3-year OS 13%, 95% CI 5-35%). Higher biologically effective dose (BED) (p < 0.01) was associated with OS.ConclusionsWe identified clinical factors defining oligometastatic patients with favorable outcomes, who we hypothesize are most likely to benefit from metastasis-directed therapy.

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients' DBF risk within the validation dataset (c-index = 0.631) and Heller's explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p

We evaluated the impact on alcohol intake and blood alcohol concentration (BAC) of a multi-level structural intervention to increase the availability of free water, coupled with messaging on pacing alcohol intake and normative feedback of blood alcohol concentration in a convenience sample of gay bars in San Francisco. Participants (n = 1,293) were recruited among exiting patrons of four gay bars (two intervention bars and two control bars). Participants were surveyed on alcohol intake and BAC was measured by breathalyzer. Prior to the intervention there were no significant differences in baseline alcohol measures between intervention and control bars. Post-intervention there were significant differences on objective and subjective measures of alcohol consumption: 30% of intervention bar participants had BAC% levels over the legal driving limit (0.08%) compared to 43% of control bar participants, p

Retail food environments have received attention for their influence on dietary behaviors and for their nutrition intervention potential. To improve diet-related behaviors, such as fruit and vegetable (FV) purchasing, it is important to examine its relationship with in-store environmental characteristics. This study used baseline data from the "El Valor de Nuestra Salud" study to examine how in-store environmental characteristics, such as product availability, placement and promotion, were associated with FV purchasing among Hispanic customers in San Diego County. Mixed linear regression models indicated that greater availability of fresh FVs was associated with a $0.36 increase in FV purchasing (p = 0.01). Placement variables, specifically each additional square foot of display space dedicated to FVs (p = 0.01) and each additional fresh FV display (p = 0.01), were associated with a $0.02 increase and $0.29 decrease, respectively, in FV purchasing. Introducing FV promotions in the final model was not related to FV purchasing. Exploratory analyses indicated that men reported spending $3.69 fewer dollars on FVs compared to women, controlling for covariates (p = 0.02). These results can help inform interventions targeting in-store environmental characteristics to encourage FV purchasing among Hispanics.

Aggressive NK cell leukemia (ANKL) is an exceedingly rare form of leukemia and carries a poor prognosis, with a median survival of only 2 months. Using the Center for International Blood and Marrow Transplant Research database, we evaluated outcomes of allogeneic hematopoietic cell transplantation (alloHCT) in patients with ANKL. Twenty-one patients with a centrally confirmed diagnosis of ANKL were included. Median patient age was 42 years and 15 patients (71%) were Caucasian. Fourteen patients (67%) were in complete remission (CR) at the time of alloHCT, and 5 patients had active disease. Median follow-up of survivors was 25 months (range, 12 to 116). The 2-year estimates of nonrelapse mortality, relapse/progression, progression-free (PFS), and overall survival (OS) were 21%, 59%, 20%, and 24%, respectively. The 2-year PFS of patients in CR at the time of alloHCT was significantly better than that of patients with active disease at transplantation (30% versus 0%; P = .001). The 2-year OS in similar order was 38% versus 0% (P

The objective of this study was to observe parent-child interactions in tiendas, limited assortment food stores catering to Latinos in the United States, and to examine the extent to which child involvement influenced these interactions and their purchase outcomes. Two confederates, one posing as a tienda employee and one posing as a customer, observed the entire shopping trip of 100 Latino parent-child (mean age = 8 years) dyads and coded the following: number and type of parent- and child-initiated request interactions, types of purchase influence attempts used by children and how parents responded, and whether the product was purchased. Level of child involvement was examined as a potential influencing factor on purchasing. The observations were relatively short (mean duration of 10 minutes), reflecting the "quick trip" nature of the observed shopping trips. From the 100 parent-child dyads, 144 request interactions were observed, and among dyads with at least 1 request interaction during the shopping trip, the average number of request interactions per dyad was 2. Children initiated most of the request interactions by asking for a product or simply placing it in the basket; parents initiated 24% of the request interactions. Child involvement in shopping and checkout were associated with spending and purchase outcomes. These results indicate that children and parents influence each other during grocery shopping, and children who are more involved have greater influence over purchases. Furthermore, this study identified a number of targets for future family/parent and consumer food environment interventions.

This study aimed to understand how college students participating in a 2-year randomized controlled trial (Project SMART: Social and Mobile Approach to Reduce Weight; N = 404) engaged their social networks and used social and mobile technologies to try and lose weight. Participants in the present study (n = 20 treatment, n = 18 control) were approached after a measurement visit and administered semi-structured interviews. Interviews were analyzed using principles from grounded theory. Treatment group participants appreciated the timely support provided by the study and the integration of content across multiple technologies. Participants in both groups reported using non-study-designed apps to help them lose weight, and many participants knew one another outside of the study. Individuals talked about weight-loss goals with their friends face to face and felt accountable to follow through with their intentions. Although seeing others' success online motivated many, there was a range of perceived acceptability in talking about personal health-related information on social media. The findings from this qualitative study can inform intervention trials using social and mobile technologies to promote weight loss. For example, weight-loss trials should measure participants' use of direct-to-consumer technologies and interconnectivity so that treatment effects can be isolated and cross-contamination accounted for.

BackgroundThe sperm gene bindin encodes a gamete recognition protein, which plays an important role in conspecific fertilization and reproductive isolation of sea urchins. Molecular evolution of the gene has been extensively investigated with the attention focused on the protein coding regions. Intron evolution has been investigated to a much lesser extent. We have studied nucleotide variability in the complete bindin locus, including two exons and one intron, in the sea urchin Strongylocentrotus intermedius represented by two morphological forms. We have also analyzed all available bindin sequences for two other sea urchin species, S. pallidus and S. droebachiensis.ResultsThe results show that the bindin sequences from the two forms of S. intermedius are intermingled with no evidence of genetic divergence; however, the forms exhibit slightly different patterns in bindin variability. The level of the bindin nucleotide diversity is close for S. intermedius and S. droebachiensis, but noticeably higher for S. pallidus. The distribution of variability is non-uniform along the gene; however there are striking similarities among the species, indicating similar evolutionary trends in this gene engaged in reproductive function. The patterns of nucleotide variability and divergence are radically different in the bindin coding and intron regions. Positive selection is detected in the bindin coding region. The neutrality tests as well as the maximum likelihood approaches suggest the action of diversifying selection in the bindin intron.ConclusionsSignificant deviation from neutrality has been detected in the bindin coding region and suggested in the intron, indicating the possible functional importance of the bindin intron variability. To clarify the question concerning possible involvement of diversifying selection in the bindin intron evolution more data combining population genetic and functional approaches are necessary.

IntroductionEcological approaches to health behavior change require effective engagement from and coordination of activities among diverse community stakeholders. We identified facilitators of and barriers to implementation experienced by project leaders and key stakeholders involved in the Imperial County, California, Childhood Obesity Research Demonstration project, a multilevel, multisector intervention to prevent and control childhood obesity.MethodsA total of 74 semistructured interviews were conducted with project leaders (n = 6) and key stakeholders (n = 68) representing multiple levels of influence in the health care, early care and education, and school sectors. Interviews, informed by the Multilevel Implementation Framework, were conducted in 2013, approximately 12 months after year-one project implementation, and were transcribed, coded, and summarized.ResultsRespondents emphasized the importance of engaging parents and of ensuring support from senior leaders of participating organizations. In schools, obtaining teacher buy-in was described as particularly important, given lower perceived compatibility of the intervention with organizational priorities. From a program planning perspective, key facilitators of implementation in all 3 sectors included taking a participatory approach to the development of program materials, gradually introducing intervention activities, and minimizing staff burden. Barriers to implementation were staff turnover, limited local control over food provided by external vendors or school district policies, and limited availability of supportive resources within the broader community.ConclusionProject leaders and stakeholders in all sectors reported similar facilitators of and barriers to implementation, suggesting the possibility for synergy in intervention planning efforts.

PurposeImage guided radiation therapy (IGRT) is designed to ensure accurate and precise targeting, but whether improved clinical outcomes result is unknown.Methods and materialsA retrospective comparison of locally advanced lung cancer patients treated with and without IGRT from 2001 to 2012 was conducted. Median local failure-free survival (LFFS), regional, locoregional failure-free survival (LRFFS), distant failure-free survival, progression-free survival, and overall survival (OS) were estimated. Univariate and multivariate models assessed the association between patient- and treatment-related covariates and local failure.ResultsA total of 169 patients were treated with definitive radiation therapy and concurrent chemotherapy with a median follow-up of 48 months in the IGRT cohort and 96 months in the non-IGRT cohort. IGRT was used in 36% (62 patients) of patients. OS was similar between cohorts (2-year OS, 47% vs 49%, P = .63). The IGRT cohort had improved 2-year LFFS (80% vs 64%, P = .013) and LRFFS (75% and 62%, P = .04). Univariate analysis revealed IGRT and treatment year improved LFFS, whereas group stage, dose, and positron emission tomography/computed tomography planning had no impact. IGRT remained significant in the multivariate model with an adjusted hazard ratio of 0.40 (P = .01). Distant failure-free survival (58% vs 59%, P = .67) did not differ significantly.ConclusionIGRT with daily cone beam computed tomography confers an improvement in the therapeutic ratio relative to patients treated without this technology.

BackgroundStudies have shown self-monitoring can modify health behaviors, including physical activity (PA). This study tested the utility of a wearable sensor/device (Fitbit(®) One™; Fitbit Inc., San Francisco, CA) and short message service (SMS) text-messaging prompts to increase PA in overweight and obese adults.Materials and methodsSixty-seven adults wore a Fitbit One tracker for 6 weeks; half were randomized to also receive three daily SMS-based PA prompts. The Fitbit One consisted of a wearable tracker for instant feedback on performance and a Web site/mobile application (app) for detailed summaries. Outcome measures were objectively measured steps and minutes of PA by intensity using two accelerometers: Actigraph™ (Pensacola, FL) GT3X+ (primary measure) at baseline and Week 6 and Fitbit One (secondary measure) at baseline and Weeks 1, 2, 3, 4, 5, and 6.ResultsMixed-model repeated-measures analysis of primary measures indicated a significant within-group increase of +4.3 (standard error [SE]=2.0) min/week of moderate- to vigorous-intensity PA (MVPA) at 6-week follow-up (p=0.04) in the comparison group (Fitbit only), but no study group differences across PA levels. Secondary measures indicated the SMS text-messaging effect lasted for only 1 week: the intervention group increased by +1,266 steps (SE=491; p=0.01), +17.8 min/week MVPA (SE=8.5; p=0.04), and +38.3 min/week total PA (SE=15.9; p=0.02) compared with no changes in the comparison group, and these between-group differences were significant for steps (p=0.01), fairly/very active minutes (p

Huntington's Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motor decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible.

BackgroundDiffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.MethodsWe performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.ResultsUnsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.ConclusionsThe integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

BackgroundDespite recent declines among young children, obesity remains a public health burden in the United States, including among Latino/Hispanic children. The determining factors are many and are too complex to fully address with interventions that focus on single factors, such as parenting behaviors or school policies. In this article, we describe a multisector, multilevel intervention to prevent and control childhood obesity in predominantly Mexican-origin communities in Southern California, one of three sites of the CDC-funded Childhood Obesity Research Demonstration (CA-CORD) study.MethodsCA-CORD is a partnership between a university-affiliated research institute, a federally qualified health center, and a county public health department. We used formative research, advisory committee members' recommendations, and previous research to inform the development of the CA-CORD project. Our theory-informed multisector, multilevel intervention targets improvements in four health behaviors: fruit, vegetable, and water consumption; physical activity; and quality sleep. Intervention partners include 1200 families, a federally qualified health center (including three clinics), 26 early care and education centers, two elementary school districts (and 20 elementary schools), three community recreation centers, and three restaurants. Intervention components in these sectors target changes in behaviors, policies, systems, and the social and physical environment. Evaluation activities include assessment of the primary outcome, BMI z-score, at baseline, 12-, and 18-months post-baseline, and sector evaluations at baseline, 12, and 24 months.ConclusionsIdentifying feasible and effective strategies to prevent and control childhood obesity has the potential to effect real changes in children's current and future health status.

The deleterious effects of racism on a wide range of health outcomes, including HIV risk, are well documented among racial/ethnic minority groups in the United States. However, little is known about how men of color who have sex with men (MSM) cope with stress from racism and whether the coping strategies they employ buffer against the impact of racism on sexual risk for HIV transmission. We examined associations of stress and coping with racism with unprotected anal intercourse (UAI) in a sample of African American (N = 403), Asian/Pacific Islander (N = 393), and Latino (N = 400) MSM recruited in Los Angeles County, CA during 2008-2009. Almost two-thirds (65 %) of the sample reported being stressed as a consequence of racism experienced within the gay community. Overall, 51 % of the sample reported having UAI in the prior 6 months. After controlling for race/ethnicity, age, nativity, marital status, sexual orientation, education, HIV serostatus, and lifetime history of incarceration, the multivariate analysis found statistically significant main effects of stress from racism and avoidance coping on UAI; no statistically significant main effects of dismissal, education/confrontation, and social-support seeking were observed. None of the interactions of stress with the four coping measures were statistically significant. Although stress from racism within the gay community increased the likelihood of engaging in UAI among MSM of color, we found little evidence that coping responses to racism buffered stress from racism. Instead, avoidance coping appears to suggest an increase in UAI.