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Abstract Little is known about the prospective association between autosomal mosaic chromosomal alterations (mCAs), a group of large-scale somatic mutations on autosomes, and bladder cancer. Here we utilized data from 99,877 participants who were free of physician-diagnosed cancer at baseline (2004–2008) of the China Kadoorie Biobank to estimate the associations between autosomal mCAs and bladder cancer (ICD-10: C67). A total of 2874 autosomal mCAs events among 2612 carriers (2.6%) were detected. After a median follow-up of 12.4 years, we discovered that participants with all autosomal mCAs exhibited higher risks of bladder cancer, with a multivariable-adjusted hazard ratio (HR) (95% confidence interval [CI]) of 2.60 (1.44, 4.70). The estimate of such association was even stronger for mosaic loss events (HR [95% CI]: 6.68 [2.92, 15.30]), while it was not significant for CN-LOH events. Both expanded (cell fraction ≥10%) and non-expanded autosomal mCAs, as well as mosaic loss, were associated with increased risks of bladder cancer. Of interest, physical activity (PA) significantly modified the associations of autosomal mCAs and mosaic loss (P interaction = 0.038 and 0.012, respectively) with bladder cancer. The increased risks of bladder cancer were only observed with mCAs and mosaic loss among participants with a lower level of PA (HR [95% CI]: 5.11 [2.36, 11.09] and 16.30 [6.06, 43.81]), but not among participants with a higher level of PA. Our findings suggest that peripheral leukocyte autosomal mCAs may represent a novel risk factor for bladder cancer, and PA may serve as a potential intervention target for mCAs carriers.

Abstract DNA methylation (DNAm) has been implicated in acute coronary syndrome (ACS), but the causality remains unclear in cross-sectional studies. Here, we conduct a prospective epigenome-wide association study of incident ACS in two Chinese cohorts (discovery: 751 nested case-control pairs; replication: 476 nested case-control pairs). We identified and validated 26 differentially methylated positions (DMPs, false discovery rate [FDR]

Abstract Elevated blood pressure (BP) is major risk factor for cardiovascular diseases (CVD). Genome-wide association studies (GWAS) conducted predominantly in populations of European ancestry have identified >2,000 BP-associated loci, but other ancestries have been less well-studied. We conducted GWAS of systolic, diastolic, pulse, and mean arterial BP in 100,453 Chinese adults. We identified 128 non-overlapping loci associated with one or more BP traits, including 74 newly-reported associations. Despite strong genetic correlations between populations, we identified appreciably higher heritability and larger variant effect sizes in Chinese compared with European or Japanese ancestry populations. Using instruments derived from these GWAS, multivariable Mendelian randomisation demonstrated that BP traits contribute differently to the causal associations of BP with CVD. In particular, only pulse pressure was independently causally associated with carotid plaque. These findings reinforce the need for studies in diverse populations to understand the genetic determinants of BP traits and their roles in disease risk.

Abstract Background People with different types of dementia may have distinct symptoms and experiences that affect their quality of life. This study investigated whether quality of life varied across types of dementia and over time. Methods The participants were 1555 people with mild-to-moderate dementia and 1327 carers from the IDEAL longitudinal cohort study, recruited from clinical services. As many as possible were followed for up to 6 years. Diagnoses included were Alzheimer’s disease, vascular dementia, mixed Alzheimer’s and vascular dementia, Parkinson’s disease dementia, dementia with Lewy bodies, and frontotemporal dementia. Self- and informant-rated versions of the Quality of Life in Alzheimer’s Disease scale were used. A joint model, incorporating a mixed effects model with random effects and a survival model to account for dropout, was used to examine whether quality of life varied by dementia type at the time of diagnosis and how trajectories changed over time. Results The strongest associations between dementia type and quality of life were seen around the time of diagnosis. For both self-ratings and informant ratings, people with Parkinson’s disease dementia or dementia with Lewy bodies had lower quality of life scores. Over time there was little change in self-rated scores across all dementia types (− 0.15 points per year). Informant-rated scores declined over time (− 1.63 points per year), with the greatest decline seen in ratings by informants for people with dementia with Lewy bodies (− 2.18 points per year). Conclusions Self-rated quality of life scores were relatively stable over time whilst informant ratings showed a steeper decline. People with Parkinson’s disease dementia or dementia with Lewy bodies report particularly low levels of quality of life, indicating the importance of greater attention to the needs of these groups.

Aims: The purpose of this survey study was to examine the demographic and lifestyle factors of women currently in orthopaedic surgery. Methods: An electronic survey was conducted of practising female orthopaedic surgeons based in the USA through both the Ruth Jackson Society and the online Facebook group “Women of Orthopaedics”. Results: The majority of surveyed female orthopaedic surgeons reported being married (76.4%; 285/373) and having children (67.6%; 252/373). In all, 66.5% (247/373) were collegiate athletes; 82.0% (306/373) reported having no female orthopaedic surgeon mentors in undergraduate and medical school. Their mean height is 65.8 inches and average weight is 147.3 lbs. Conclusion: The majority of female orthopaedic surgeons did not have female mentorship during their training. Additionally, biometrically, their build is similar to that of the average American woman. Cite this article: Bone Jt Open 2024;5(5):419–425.

Abstract Despite the high prevalence of snoring in Asia, little is known about the genetic etiology of snoring and its causal relationships with cardiometabolic traits. Based on 100,626 Chinese individuals, a genome-wide association study on snoring was conducted. Four novel loci were identified for snoring traits mapped on SLC25A21, the intergenic region of WDR11 and FGFR, NAA25, ALDH2, and VTI1A, respectively. The novel loci highlighted the roles of structural abnormality of the upper airway and craniofacial region and dysfunction of metabolic and transport systems in the development of snoring. In the two-sample bi-directional Mendelian randomization analysis, higher body mass index, weight, and elevated blood pressure were causal for snoring, and a reverse causal effect was observed between snoring and diastolic blood pressure. Altogether, our results revealed the possible etiology of snoring in China and indicated that managing cardiometabolic health was essential to snoring prevention, and hypertension should be considered among snorers.

Abstract Objectives Longitudinal evidence documenting health conditions in spousal caregivers of people with dementia and whether these influence caregivers’ outcomes is scarce. This study explores type and number of health conditions over two years in caregivers of people with dementia and subgroups based on age, sex, education, hours of care, informant-rated functional ability, neuropsychiatric symptoms, cognition of the person with dementia, and length of diagnosis in the person with dementia. It also explores whether over time the number of health conditions is associated with caregivers’ stress, positive experiences of caregiving, and social networks Methods Longitudinal data from the IDEAL (Improving the experience of Dementia and Enhancing Active Life) cohort were used. Participants comprised spousal caregivers (n = 977) of people with dementia. Self-reported health conditions using the Charlson Comorbidity Index, stress, positive experiences of caregiving, and social network were assessed over two years. Mixed effect models were used Results On average participants had 1.5 health conditions at baseline; increasing to 2.1 conditions over two years. More health conditions were reported by caregivers who were older, had no formal education, provided 10 + hours of care per day, and/or cared for a person with more neuropsychiatric symptoms at baseline. More baseline health conditions were associated with greater stress at baseline but not with stress over time. Over two years, when caregivers’ health conditions increased, their stress increased whereas their social network diminished Discussion Findings highlight that most caregivers have their own health problems which require management to avoid increased stress and shrinking of social networks

Purpose: This case report seeks to highlight impressive photographs of amyloid staining with trypan blue that persisted after DMEK surgery with 3 years follow-up. This has only been reported in the literature twice previously, and may have contributed to visual symptoms in the early post-operative period of this patient. Observations: We report a case of an 82-year-old patient with concurrent Fuchs' corneal endothelial dystrophy and lattice corneal dystrophy who suffered permanent trypan blue staining of the amyloid deposits after descemet's membrane endothelial keratoplasty (DMEK) surgery. Conclusions and importance: Trypan blue staining of amyloid deposits in the corneal stroma is permanent, with research suggesting potential stimulation of progression or recurrence of amlyoid deposition. This is relevant for all anterior segment surgeons using trypan blue in the setting of primary (eg. lattice corneal dystrophy) or secondary amyloid deposition (eg. polymorphous amyloid degeneration, chronic inflammation, systemic disease). Trypan blue staining should be limited or alternative surgical options such as descemet's stripping automated endothelial keratoplasty (DSAEK) considered.

Abstract Background Most people with dementia have multiple health conditions. This study explores (1) number and type of health condition(s) in people with dementia overall and in relation to age, sex, dementia type, and cognition; (2) change in number of health conditions over two years; and (3) whether over time the number of health conditions at baseline is related to social isolation, loneliness, quality of life, and/or well-being. Methods Longitudinal data from the IDEAL (Improving the experience of Dementia and Enhancing Active Life) cohort were used. Participants comprised people with dementia (n = 1490) living in the community (at baseline) in Great Britain. Health conditions using the Charlson Comorbidity Index, cognition, social isolation, loneliness, quality of life, and well-being were assessed over two years. Mixed effects modelling was used. Results On average participants had 1.8 health conditions at baseline, excluding dementia; increasing to 2.5 conditions over two years. Those with vascular dementia or mixed (Alzheimer’s and vascular) dementia had more health conditions than those with Alzheimer’s disease. People aged ≥ 80 had more health conditions than those aged

Abstract Objectives A novel model of resilience was tested in caregivers of people with mild-to-moderate dementia and was extended to explore whether including self-efficacy, optimism, and self-esteem improved its predictive value. Design Cross-sectional. Setting Data from the IDEAL cohort were used. Participants The study comprised 1222 caregivers of people with dementia. Measurements A composite resilience score was calculated from five measures. Multivariable regressions were used to investigate factors associated with resilience. Results Greater resilience was associated with being older, being male, and caregiving for older people with dementia. Greater resilience was also observed when people with dementia had fewer functional difficulties and/or fewer neuropsychiatric symptoms, there was a stronger dyadic relationship, and the caregiver had fewer social restrictions, less neuroticism, and greater perceived competence. Surprisingly, caregiver self-efficacy, optimism, and self-esteem were unrelated to resilience. Conclusion Caregivers of people with mild-to-moderate dementia generally scored well for resilience. Resilience was associated with both the personal characteristics of caregivers and level of care need among people with dementia. Future work is needed to determine whether the caregivers in this cohort appeared resilient because the care recipients had relatively low care needs and consequently placed fewer demands on caregiver well-being than would be the case where dementia is more advanced.

Furin is an important proteolytic enzyme, converting several proteins from inactive precursors to their active forms. Recently, proteo-genomic analyses in European and East Asian populations suggested a causal association of furin with ischaemic heart disease, and there is growing interest in its role in cardiovascular disease (CVD) aetiology. In this narrative review, we present a critical appraisal of evidence from population studies to assess furin’s role in CVD risk and potential as a drug target for CVD. Whilst most observational studies report positive associations between furin expression and CVD risk, some studies report opposing effects, which may reflect the complex biological roles of furin and its substrates. Genetic variation in FURIN is also associated with CVD and its risk factors. We found no evidence of current clinical development of furin as a drug target for CVD, although several phase 1 and 2 clinical trials of furin inhibitors as a type of cancer immunotherapy have been completed. The growing field of proteo-genomics in large-scale population studies may inform the future development of furin and other potential drug targets to improve the treatment and prevention of CVD.

This two-article submission suggests a new lens through which to read and study the Bible. This lens generates new perspectives for teaching, preaching, and writing about the Bible. Called gender balance, the lens applies to both the Old and New Testament. Gender balance not only is simple, but also is in plain sight. If there is a story, passage, theme, or text about a man, look for a similar one about a woman; if there is a story, passage, theme, or text about a woman, look for a similar one about a man. The accounts often not only complement each other, but also provide additional details and insights. Combining canonical and literary methodologies, these two articles acknowledge the preponderance of biblical references to men. However, they show that a similar reference to a woman can usually be found quickly. Given that these two articles represent a survey with examples, an extensive exegesis is not provided. Comments on each gender balance entry are brief and framed in supplemental scholarship. The examples incorporate a conscious choice of looking for a similar story, passage, theme, or text about the opposite gender. The examples illustrate the premise that gender balance is clearly within the Scriptures. While a new way, a new lens of looking at the Bible, is presented, the first article supplies an extensive literature review showing it is a new idea. It then proceeds with examples of gender balance from the Old Testament and ends with a short conclusion and a bibliography. The second article contains New Testament examples of gender balance, a longer conclusion, and a bibliography. Contribution: The concept of looking at the Bible through a new lens – that of gender balance – may be both revolutionary and revitalising. It may be a tool for evangelism (for it consciously seeks to show stories about men and women); it may prove a more effective way to teach, preach, study, and write about the Bible (for it seeks complementary passages for both genders). These articles – by illustrating the concept through literary tools such as round and flat characterisation and literary categories such as epic tale – offer more ways to address the Bible’s wonderful diversity. These two articles advocate making gender balance a standard practice in reading the Bible. They illustrate that the lens of gender balance offers new perspectives and insights on the Bible. After all, it is in plain sight! Gender balance affirms the Bible’s glorious, wide-armed, concluding invitation to all – Jew or Greek, slave or free, rich or poor, male or female – ‘Come’ (Rv 22:17a).

Summary: Background: Previous observational studies established a positive relationship between snoring and stroke. We aimed to investigate the causal effect of snoring on stroke. Methods: Based on 82,339 unrelated individuals with qualified genotyping data of Asian descent from the China Kadoorie Biobank (CKB), we conducted a Mendelian randomization (MR) analysis of snoring and stroke. Genetic variants identified in the genome-wide association analysis (GWAS) of snoring in CKB and UK Biobank (UKB) were selected for constructing genetic risk scores (GRS). A two-stage method was applied to estimate the associations of the genetically predicted snoring with stroke and its subtypes. Besides, MR analysis among the non-obese group (body mass index, BMI

The US agricultural industry depends on immigrant farm labor, particularly in the specialty crop sector where tasks like harvesting require a lot of labor. Most US farmworkers are from other countries, and almost half are not authorized to work in the United States. The importance of immigrant labor in meeting the demand for workers in the nursery and floriculture production sector has been further highlighted with this industry's recent growth. This publication offers an overview of the increasing demand for H-2A workers in the ornamental horticulture industry, examines growers' challenges, and explores the underlying factors affecting workers’ participation in the H-2A program. It guides industry stakeholders to monitor changes in immigration policies and labor regulations, including the H-2A program and to adjust labor management practices accordingly. It includes strategies to address labor challenges and remain competitive in the marketplace

Introduction The INflammation and Small Vessel Disease (INSVD) study aims to investigate whether peripheral inflammation, immune (dys)regulation and blood–brain barrier (BBB) permeability relate to disease progression in cerebral small vessel disease (SVD). This research aims to pinpoint specific components of the immune response in SVD relating to disease progression. This could identify biomarkers of SVD progression, as well as potential therapeutic targets to inform the development and repurposing of drugs to reduce or prevent SVD, cognitive decline and vascular dementia.Methods and analysis INSVD is a prospective observational multicentre cohort study in individuals with symptomatic SVD. This longitudinal study combines comprehensive immunophenotyping of the peripheral blood immune compartment with advanced neuroimaging markers of SVD and BBB permeability. The main SVD marker of interest is white matter microstructure as determined by diffusion tensor imaging, a valuable marker of disease progression owing to its sensitivity to early alterations to white matter integrity. The research is being conducted in two sites—in the UK (Cambridge) and the Netherlands (Nijmegen)—with each site recruiting 100 participants (total n=200). Participants undergo clinical and cognitive assessments, blood draws, and brain MRI at baseline and 2-year follow-up.Ethics and dissemination This study received ethical approval from the local ethics boards (UK: East of England—Cambridge Central Research Ethics Committee (REC) ref: 22/EE/00141, Integrated Research Application System (IRAS) ID: 312 747. Netherlands: Medical Research Ethics Committee (MREC) Oost-Nederland, ref: 2022-13623, NL-number: NL80258.091.22). Written informed consent was obtained from all subjects before the study. Any participant-derived benefits resulting from this research, such as new insights into disease mechanisms or possible novel therapies, will be disseminated to study participants, patient groups and members of the public.Trial registration number NCT05746221.

Abstract Background Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited. Methods We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake. Results We identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke). Conclusion This study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.

Abstract. Background:. Several studies have reported that polygenic risk scores (PRSs) can enhance risk prediction of coronary artery disease (CAD) in European populations. However, research on this topic is far from sufficient in non-European countries, including China. We aimed to evaluate the potential of PRS for predicting CAD for primary prevention in the Chinese population. Methods:. Participants with genome-wide genotypic data from the China Kadoorie Biobank were divided into training (n = 28,490) and testing sets (n = 72,150). Ten previously developed PRSs were evaluated, and new ones were developed using clumping and thresholding or LDpred method. The PRS showing the strongest association with CAD in the training set was selected to further evaluate its effects on improving the traditional CAD risk-prediction model in the testing set. Genetic risk was computed by summing the product of the weights and allele dosages across genome-wide single-nucleotide polymorphisms. Prediction of the 10-year first CAD events was assessed using hazard ratios (HRs) and measures of model discrimination, calibration, and net reclassification improvement (NRI). Hard CAD (nonfatal I21-I23 and fatal I20-I25) and soft CAD (all fatal or nonfatal I20-I25) were analyzed separately. Results:. In the testing set, 1214 hard and 7201 soft CAD cases were documented during a mean follow-up of 11.2 years. The HR per standard deviation of the optimal PRS was 1.26 (95% CI:1.19-1.33) for hard CAD. Based on a traditional CAD risk prediction model containing only non-laboratory-based information, the addition of PRS for hard CAD increased Harrell's C index by 0.001 (-0.001 to 0.003) in women and 0.003 (0.001 to 0.005) in men. Among the different high-risk thresholds ranging from 1% to 10%, the highest categorical NRI was 3.2% (95% CI: 0.4-6.0%) at a high-risk threshold of 10.0% in women. The association of the PRS with soft CAD was much weaker than with hard CAD, leading to minimal or no improvement in the soft CAD model. Conclusions:. In this Chinese population sample, the current PRSs minimally changed risk discrimination and offered little improvement in risk stratification for soft CAD. Therefore, this may not be suitable for promoting genetic screening in the general Chinese population to improve CAD risk prediction.

Abstract. Background:. Severe liver disease (SLD), including cirrhosis and liver cancer, constitutes a major disease burden in China. We aimed to examine the association of genetic and healthy lifestyle factors with the incidence and prognosis of SLD. Methods:. The study population included 504,009 participants from the prospective China Kadoorie Biobank aged 30-79 years. The individuals were from 10 diverse areas in China without a history of cancer or liver disease at baseline. Cox regression was used to estimate adjusted hazard ratios (HRs) for incident SLD and death after SLD diagnosis associated with healthy lifestyle factors (smoking, alcohol, physical activity, and central adiposity). Additionally, the contribution of genetic risk for hepatitis B virus (HBV, assessed by genetic variants in major histocompatibility complex, class II, DP/DQ [HLA-DP/DQ] genes) was also estimated. Results:. Compared with those with 0-1 healthy lifestyle factor, participants with 2, 3, and 4 factors had 12% (HR 0.88 [95% confidence interval [CI] 0.85, 0.92]), 26% (HR 0.74 [95%CI: 0.69, 0.79]), and 44% (HR 0.56 [95%CI: 0.48, 0.65]) lower risks of SLD, respectively. Inverse associations were observed among participants with both low and high genetic risks (HR per 1-point increase 0.83 [95%CI: 0.74, 0.94] and 0.91 [95%CI: 0.82, 1.02], respectively; Pinteraction = 0.51), although with a non-significant trend among those with a high genetic risk. Inverse associations were also observed between healthy lifestyle factors and liver biomarkers regardless of the genetic risk. Despite the limited power, healthy lifestyle factors were associated with a lower risk of death after incident SLD among participants with a low genetic risk (HR 0.59 [95%CI: 0.37, 0.96]). Conclusions:. Lifestyle modification may be beneficial in terms of lowering the risk of SLD regardless of the genetic risk. Moreover, it is also important for improving the prognosis of SLD in individuals with a low genetic risk. Future studies are warranted to examine the impact of healthy lifestyles on SLD prognosis, particularly among individuals with a high genetic risk.

Abstract Previous studies have linked higher body mass index (BMI) to lower subjective well-being in adult European ancestry populations. However, our understanding of these relationships across different populations is limited. Here, we investigated the association between BMI and well-being in people of (a) East Asian and (b) European ancestry in the China Kadoorie Biobank (CKB) and UK Biobank (UKB), respectively. Mendelian randomisation (MR) methods were used to test the relationship between BMI with (a) health satisfaction and (b) life satisfaction. One-sample MR enabled us to test effects in men and women separately and to test the role of cultural contexts by stratifying our analyses by urban and rural home location in both China and the UK. Further, we implemented a control function method to test the linearity of the BMI-well-being relationship. We found evidence of different associations between BMI and well-being in individuals of East Asian versus European ancestry. For example, a genetically instrumented higher BMI tentatively associated with higher health satisfaction in people of East Asian ancestry, especially in females (ß: 0.041, 95% CI: 0.002, 0.081). In contrast, there was a robust inverse association between higher genetically instrumented BMI and health satisfaction in all European ancestry UKB participants (ß: −0.183, 95% CI: −0.200, −0.165, P difference

Abstract Background Cross-sectional evidence indicates that certain personality traits may influence how well people with dementia and their caregivers are able to live alongside the condition. However, no studies to date have explored these associations longitudinally. The present study aimed to explore whether each of the Five-Factor personality traits were associated with change over two years in perceptions of ‘living well’ for people with dementia and their caregivers. ‘Living well’ was conceptualized as a composite of quality of life, satisfaction with life, and subjective well-being. Methods Data were analyzed from 1487 people with dementia and 1234 caregivers who took part in the IDEAL cohort. Participants were categorized into low, medium, and high groups for each trait using stanine scores. Latent growth curve models investigated associations between these groups and ‘living well’ scores for each trait at baseline and at 12 and 24 months. Covariates included cognition in people with dementia and stress in caregivers. A Reliable Change Index was calculated against which to evaluate changes in ‘living well’ scores over time. Results At baseline, neuroticism was negatively associated with ‘living well’ scores for people with dementia, while conscientiousness, extraversion, openness, and agreeableness were positively associated. For caregivers, neuroticism was negatively associated with ‘living well’ scores at baseline while conscientiousness and extraversion were positively associated. ‘Living well’ scores were mostly stable over time with no influence of personality traits on observed changes. Conclusions Findings suggest that personality traits, particularly neuroticism, have a meaningful impact on how people with dementia and caregivers rate their capability to ‘live well’ at baseline. Over time ‘living well’ scores for each personality trait group were largely stable. Studies utilizing longer follow-up periods and more appropriate measures of personality are needed to corroborate and extend the findings of the present study.

ObjectiveFamily relationships influence how people appraise their own aging and how their appraisals impact their health. We analyzed felt age (FA) among family caregivers of people with dementia.Methods and measuresWe used a stratified sample of 1,020 spousal and 202 adult-child caregivers from the IDEAL study. We estimated cross-sectional associations and bidirectional influences between caregivers' FA and their health and wellbeing (depression, number of health conditions, stress, positive aspects of caregiving) over 2 years.ResultsAmong spousal caregivers, 25% had a younger FA and 36% had an older FA. Among adult-child caregivers, 21.8% had a younger FA and 36.1% had an older FA. In spousal and adult-child caregivers an older FA was cross-sectionally associated with higher depression, number of health conditions, and stress, and fewer positive aspects of caregiving. In spousal caregivers, hours of care per day moderated the association between FA and depression, and FA was associated with stress 1 year later.ConclusionCaregiving may impact FA and its relationship with health. We urge continued research on the connections between caregiving and FA, and how interventions might support caregivers' positive views on their own aging, which will translate views on aging scholarship to meaningfully improve caregivers' lives.

IntroductionThe discrepancy between caregiver-ratings and self-ratings of abilities is commonly used to assess awareness in people with dementia. We investigated the contribution of caregiver and dyadic characteristics to the difference in perspective between caregiver-informants and people with dementia about difficulties experienced, when considering awareness of condition.MethodsWe conducted exploratory cross-sectional analyses using data from the IDEAL cohort. Participants were 1,038 community-dwelling people with mild-to-moderate dementia, and coresident spouse/partner caregivers. The Representations and Adjustment to Dementia Index (RADIX) checklist reporting difficulties commonly experienced in dementia was completed by 960 caregiver-informants and 989 people with dementia. Difference in scores was calculated for 916 dyads. Demographic information, cognition, informant-rated functional ability and neuropsychiatric symptoms were recorded for the person with dementia. Self-reported data were collected on mood, comorbidity, religion, importance of religion, relationship quality, and caregiver stress.ResultsFor most dyads, caregivers reported more RADIX difficulties than people with dementia. Caregiver RADIX ratings were more closely associated with informant-rated functional ability and neuropsychiatric symptoms than with cognition. More RADIX difficulties and higher stress were reported by female caregivers. Greater RADIX difference was associated with more caregiver stress, and older age but less depression in people with dementia.ConclusionFew dyadic characteristics were important, but caregiver stress was higher where caregivers reported more RADIX difficulties and/or the difference in perspective was greater, whereas partners with dementia reported better mood. In addition to offering information about awareness of condition, the caregiver rating and difference in perspectives could indicate where more support is needed.

Abstract Background DNA methylation clocks emerged as a tool to determine biological aging and have been related to mortality and age-related diseases. Little is known about the association of DNA methylation age (DNAm age) with coronary heart disease (CHD), especially in the Asian population. Results Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip for 491 incident CHD cases and 489 controls in the prospective China Kadoorie Biobank. We calculated the methylation age using a prediction model developed among Chinese. The correlation between chronological age and DNAm age was 0.90. DNA methylation age acceleration (Δage) was defined as the residual of regressing DNA methylation age on the chronological age. After adjustment for multiple risk factors of CHD and cell type proportion, compared with participants in the bottom quartile of Δage, the OR (95% CI) for CHD was 1.84 (1.17, 2.89) for participants in the top quartile. One SD increment in Δage was associated with 30% increased risk of CHD (OR = 1.30; 95% CI 1.09, 1.56; Ptrend = 0.003). The average number of cigarette equivalents consumed per day and waist-to-hip ratio were positively associated with Δage; red meat consumption was negatively associated with Δage, characterized by accelerated aging in those who never or rarely consumed red meat (all P

The ornamental horticulture industry relies on workers to do myriad tasks, such as pruning, applying fertilizers, scouting, spraying pesticides, planting, harvesting, packing, and weeding. As a result of the perishable nature of horticultural goods, a skilled and accessible labor supply is imperative for continued industry growth and stability. The decreasing number of workers, followed by increasing wage rates, could be alarming for the economic well-being of the ornamental horticulture industry, which has already experienced a downward trend in revenue and profits. Combining 2014 and 2019 National Green Industry Survey data, this study investigates factors affecting ornamental growers’ decisions on hiring H-2A workers. Growers’ decisions are largely affected by their home state’s enforcement of the 287(g) program and the observed industry employment and total wage payment. Growers are more likely to participate in an H-2A workers program if their home state implemented the restrictive 287(g) program. Increasing industry employment of domestic workers will discourage participation in the H-2A workers program, but increasing industry wage costs will encourage participation. In contrast, individual firm characteristics play different roles in program participation and the number of H-2A workers hiring decision. Increasing farm sales value by $1 million merely increases the probability of hiring by a 0.1% point, revealing that large growers are the major beneficiaries of the H-2A workers program. After the participation hurdle is overcome, the number of H-2A workers hired is affected minimally by these factors. Our results suggest that the current H-2A program imposes a potential hurdle to participate, thus benefiting large growers.

Abstract Background Extensive evidence links higher body mass index (BMI) to higher odds of depression in people of European ancestry. However, our understanding of the relationship across different settings and ancestries is limited. Here, we test the relationship between body composition and depression in people of East Asian ancestry. Methods Multiple Mendelian randomisation (MR) methods were used to test the relationship between (a) BMI and (b) waist-hip ratio (WHR) with depression. Firstly, we performed two-sample MR using genetic summary statistics from a recent genome-wide association study (GWAS) of depression (with 15,771 cases and 178,777 controls) in people of East Asian ancestry. We selected 838 single nucleotide polymorphisms (SNPs) correlated with BMI and 263 SNPs correlated with WHR as genetic instrumental variables to estimate the causal effect of BMI and WHR on depression using the inverse-variance weighted (IVW) method. We repeated these analyses stratifying by home location status: China versus UK or USA. Secondly, we performed one-sample MR in the China Kadoorie Biobank (CKB) in 100,377 participants. This allowed us to test the relationship separately in (a) males and females and (b) urban and rural dwellers. We also examined (c) the linearity of the BMI-depression relationship. Results Both MR analyses provided evidence that higher BMI was associated with lower odds of depression. For example, a genetically-instrumented 1-SD higher BMI in the CKB was associated with lower odds of depressive symptoms [OR: 0.77, 95% CI: 0.63, 0.95]. There was evidence of differences according to place of residence. Using the IVW method, higher BMI was associated with lower odds of depression in people of East Asian ancestry living in China but there was no evidence for an association in people of East Asian ancestry living in the USA or UK. Furthermore, higher genetic BMI was associated with differential effects in urban and rural dwellers within China. Conclusions This study provides the first MR evidence for an inverse relationship between BMI and depression in people of East Asian ancestry. This contrasts with previous findings in European populations and therefore the public health response to obesity and depression is likely to need to differ based on sociocultural factors for example, ancestry and place of residence. This highlights the importance of setting-specific causality when using genetic causal inference approaches and data from diverse populations to test hypotheses. This is especially important when the relationship tested is not purely biological and may involve sociocultural factors.

Annie’s Project: Farming in New Jersey’s Cities and the Urban Fringe focused on the following five areas of risk identified by the US Department of Agriculture Economic Research Service: financial, production, marketing/price, legal/institutional, and human/personnel. Additional education regarding urban farming topics included securing suitable land, dealing with contaminated soils and alternative growing medias, and securing water for crop production. We delivered a series of six 3-hour evening classes to 23 producers. We administered a retrospective evaluation at the conclusion of the series and distributed an evaluation survey 6 months after training. Both evaluations found that participants increased their understanding of farm risks. Furthermore, they indicated they were better able to manage the impacts of the COVID-19 pandemic on their farm business activities.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Abstract Regulatory T cells (Treg) are vital to the maintenance of immune homeostasis. The genetic background of an inbred mouse strain can have a profound effect on the immune response in the animal, including Treg responses. Most Treg studies focus on animals created on the C57BL/6 or BALB/c background. Recent studies have demonstrated a difference in the phenotype and behavior of C57BL/6 and BALB/c Tregs. In this study, we have investigated the function of FVB/N Tregs compared to C57BL/6 and BALB/c. We observed that while FVB/N Tregs appear to suppress normally in a cell contact‐dependent system, FVB/N Tregs are less capable of suppressing when regulation depends on the secretion of a soluble factor. FVB/N Tregs produce IL‐10; however, TGF‐β was not detected in any culture from C57BL/6 or FVB/N. C57BL/6 Foxp3+ Tregs expressed more of the TGF‐β‐related proteins glycoprotein‐A repetitions predominant (GARP) and latency‐associated peptide (LAP) on the cell surface than both FVB/N and BALB/c, but C57BL/6 Tregs expressed significantly less Ctse (Cathepsin E) mRNA. Each strain displayed different abilities of thymic Tregs (tTreg) to maintain Foxp3 expression and had a varying generation of induced Tregs (iTregs). In vitro generated FVB/N iTregs expressed significantly less GARP and LAP. These results suggest Tregs of different strains have varying phenotypes and dominant mechanisms of action for the suppression of an immune response. This information should be taken into consideration when Tregs are examined in future studies, particularly for therapeutic purposes in a genetically diverse population.

We use 0.1″ observations from the Atacama Large Millimeter Array (ALMA), Hubble Space Telescope (HST), and JWST to study young massive clusters (YMCs) in their embedded “infant” phase across the central starburst ring in NGC 3351. Our new ALMA data reveal 18 bright and compact (sub-)millimeter continuum sources, of which 8 have counterparts in JWST images and only 6 have counterparts in HST images. Based on the ALMA continuum and molecular line data, as well as ancillary measurements for the HST and JWST counterparts, we identify 14 sources as infant star clusters with high stellar and/or gas masses (∼10 ^5 M _⊙ ), small radii (≲ 5 pc), large escape velocities (6–10 km s ^−1 ), and short freefall times (0.5–1 Myr). Their multiwavelength properties motivate us to divide them into four categories, likely corresponding to four evolutionary stages from starless clumps to exposed H ii region–cluster complexes. Leveraging age estimates for HST-identified clusters in the same region, we infer an evolutionary timeline, ranging from ∼1–2 Myr before cluster formation as starless clumps, to ∼4–6 Myr after as exposed H ii region–cluster complexes. Finally, we show that the YMCs make up a substantial fraction of recent star formation across the ring, exhibit a nonuniform azimuthal distribution without a very coherent evolutionary trend along the ring, and are capable of driving large-scale gas outflows.

Identifying determinants of broadly neutralizing antibodies against hepatitis C virus (HCV) may guide HCV vaccine design. Here, the authors discover new anti-HCV antibodies using computational screening and analyze the amino acid composition and sequence-structure relationships in this antibody family.

Summary: Background: This study aimed to: 1) assess the associations of biological age acceleration based on Klemera and Doubal's method (KDM-AA) with long-term risk of all-cause mortality; and 2) compare the association of KDM-AA with all-cause mortality among participants potentially at different stages of the cardiovascular disease (CVD) continuum. Methods: The present study was based on a subpopulation of the China Kadoorie Biobank, with baseline survey during 2004–08. A total of 12,377 participants free of ischemic heart disease, stroke, or cancer at baseline were included, in which 8180 participants were identified to develop major coronary event (MCE), ischemic stroke (IS), intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH), and 4197 remained free of these cardiovascular diseases before 1 January 2014. These participants were followed up until 1 Jan 2018. KDM-AA was calculated by regressing biological age measurement, which was constructed based on baseline 16 physical and 9 biochemical markers using Klemera and Doubal's method, on chronological age. We estimated the associations of KDM-AA with the mortality risk using the hazard ratio (HR) and 95% confidence interval (CI) from Cox proportional hazard models. We assessed discrimination performance by Harrell's C-index and net reclassification index (NRI). Findings: The participants who developed MCE (mean KDM-AA = 0.1 year, standard deviation [SD] = 1.6 years) or ICH/SAH (0.3 ± 1.5 years) during subsequent follow-up showed accelerated aging at baseline compared to those of IS (0.0 ± 1.2 years) and control (−0.3 ± 1.3 years) groups. The KDM-AA was positively associated with long-term risk of all-cause mortality (HR = 1.20; 95% CI: 1.17, 1.23), and the association was robust for participants potentially at different stages of the CVD continuum. Adding KDM-AA improved mortality prediction compared to the model only with sociodemographic and lifestyle factors in whole participants, with the Harrell's C-index increasing from 0.813 (0.807, 0.819) to 0.821 (0.815, 0.826) (NRI = 0.011; 95% CI: 0.003, 0.019). Interpretation: In this middle-aged and elderly Chinese population, the KDM-AA is a promising measurement for biological age, and can capture the difference in cardiovascular health and predict the risk of all-cause mortality over a decade. Funding: This work was supported by National Natural Science Foundation of China (82192904, 82192901, 82192900, 81941018). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z), grants (2016YFC0900500) from the National Key R&D Program of China, National Natural Science Foundation of China (81390540, 91846303), and Chinese Ministry of Science and Technology (2011BAI09B01).

Abstract As trainees consider future job options, they often have excellent examples of careers in academia. However, trainees usually do not have much exposure to career options in the biotechnology industry and they have limited network contacts to provide such information. This perspective is intended to provide some insights into working at a large and established biotechnology company. In addition, it will detail the author's observations on some of the major differences between careers in academia and biotechnology and give examples of skills that are critical for success in a biotechnology career.

Water availability, quality, and management, particularly under climate change constraints and fierce competition for water resources, are challenging the sustainability of intensively irrigated nursery crops. We created an online tool to estimate costs and benefits of a water recycling investment at a commercial nursery, given data on the operation input by the user. The online tool returns a “regulatory risk score” based on the user’s drought and pollution risk. Then, using a partial budget approach, it returns net present value of the investment, upfront capital cost, and expected change in annual cash flow. The present article seeks to cross-validate this computer model with results reported in the case study literature. We aggregated data on 38 nurseries and greenhouses profiled in five published studies into a meta study dataset. These data validated the computer tool’s assumptions about the relationship of operation size to total capital cost. Separate simulations on the profitability effects of varying public water rates and price premia due to green marketing corroborated the findings of earlier studies. A major finding of the simulation analysis not previously emphasized in the literature is that capital cost and profit vary significantly with the precise method that is used to size the recapture pond. A “minimalist” approach to this decision is likely to be the most cost-effective, but growers should also keep stormwater runoff and other issues of environmental best practices in mind.

Abstract Introduction: Most students in MD-PhD programs take a leave of absence from medical school to complete PhD training, which promotes a natural loss of clinical skills and knowledge and could negatively impact a student’s long-term clinical knowledge. To address this concern, clinical refresher courses in the final year of PhD training have traditionally been used; however, effectiveness of such courses versus a longitudinal clinical course spanning all PhD training years is unclear. Methods: The University of Alabama at Birmingham MD-PhD Program implemented a comprehensive continuing clinical education (CCE) course spanning PhD training years that features three course components: (1) clinical skills; (2) clinical knowledge; and (3) specialty exposure activities. To evaluate course effectiveness, data from an anonymous student survey completed at the end of each semester were analyzed. Results: Five hundred and ninety-seven surveys were completed by MD-PhD students from fall 2014 to 2022. Survey responses indicated that the majority of students found the course helpful to: maintain clinical skills and knowledge (544/597, 91% and 559/597, 94%; respectively), gain exposure to clinical specialties (568/597, 95%), and prepare them for responsibilities during clinical clerkships. During semesters following lockdowns from the COVID-19 pandemic, there were significant drops in students’ perceived preparedness. Conclusions: Positive student survey feedback and improved preparedness to return to clinic after development of the course suggests the CCE course is a useful approach to maintain clinical knowledge during research training.

The PHANGS collaboration has been building a reference data set for the multiscale, multiphase study of star formation and the interstellar medium (ISM) in nearby galaxies. With the successful launch and commissioning of JWST, we can now obtain high-resolution infrared imaging to probe the youngest stellar populations and dust emission on the scales of star clusters and molecular clouds (∼5–50 pc). In Cycle 1, PHANGS is conducting an eight-band imaging survey from 2 to 21 μ m of 19 nearby spiral galaxies. Optical integral field spectroscopy, CO(2–1) mapping, and UV-optical imaging for all 19 galaxies have been obtained through large programs with ALMA, VLT-MUSE, and Hubble. PHANGS–JWST enables a full inventory of star formation, accurate measurement of the mass and age of star clusters, identification of the youngest embedded stellar populations, and characterization of the physical state of small dust grains. When combined with Hubble catalogs of ∼10,000 star clusters, MUSE spectroscopic mapping of ∼20,000 H ii regions, and ∼12,000 ALMA-identified molecular clouds, it becomes possible to measure the timescales and efficiencies of the earliest phases of star formation and feedback, build an empirical model of the dependence of small dust grain properties on local ISM conditions, and test our understanding of how dust-reprocessed starlight traces star formation activity, all across a diversity of galactic environments. Here we describe the PHANGS–JWST Treasury survey, present the remarkable imaging obtained in the first few months of science operations, and provide context for the initial results presented in the first series of PHANGS–JWST publications.

We present a high-resolution view of bubbles within the Phantom Galaxy (NGC 628), a nearby (∼10 Mpc), star-forming (∼2 M _⊙ yr ^−1 ), face-on ( i ∼ 9°) grand-design spiral galaxy. With new data obtained as part of the Physics at High Angular resolution in Nearby GalaxieS (PHANGS)-JWST treasury program, we perform a detailed case study of two regions of interest, one of which contains the largest and most prominent bubble in the galaxy (the Phantom Void, over 1 kpc in diameter), and the other being a smaller region that may be the precursor to such a large bubble (the Precursor Phantom Void). When comparing to matched-resolution H α observations from the Hubble Space Telescope, we see that the ionized gas is brightest in the shells of both bubbles, and is coincident with the youngest (∼1 Myr) and most massive (∼10 ^5 M _⊙ ) stellar associations. We also find an older generation (∼20 Myr) of stellar associations is present within the bubble of the Phantom Void. From our kinematic analysis of the H I , H _2 (CO), and H ii gas across the Phantom Void, we infer a high expansion speed of around 15 to 50 km s ^−1 . The large size and high expansion speed of the Phantom Void suggest that the driving mechanism is sustained stellar feedback due to multiple mechanisms, where early feedback first cleared a bubble (as we observe now in the Precursor Phantom Void), and since then supernovae have been exploding within the cavity and have accelerated the shell. Finally, comparison to simulations shows a striking resemblance to our JWST observations, and suggests that such large-scale, stellar-feedback-driven bubbles should be common within other galaxies.

Large-scale bars can fuel galaxy centers with molecular gas, often leading to the development of dense ringlike structures where intense star formation occurs, forming a very different environment compared to galactic disks. We pair ∼0.″3 (30 pc) resolution new JWST/MIRI imaging with archival ALMA CO(2–1) mapping of the central ∼5 kpc of the nearby barred spiral galaxy NGC 1365 to investigate the physical mechanisms responsible for this extreme star formation. The molecular gas morphology is resolved into two well-known bright bar lanes that surround a smooth dynamically cold gas disk ( R _gal ∼ 475 pc) reminiscent of non-star-forming disks in early-type galaxies and likely fed by gas inflow triggered by stellar feedback in the lanes. The lanes host a large number of JWST-identified massive young star clusters. We find some evidence for temporal star formation evolution along the ring. The complex kinematics in the gas lanes reveal strong streaming motions and may be consistent with convergence of gas streamlines expected there. Indeed, the extreme line widths are found to be the result of inter-“cloud” motion between gas peaks; ScousePy decomposition reveals multiple components with line widths of 〈 σ _CO,scouse 〉 ≈ 19 km s ^−1 and surface densities of $\langle \,{{\rm{\Sigma }}}_{{{\rm{H}}}_{2},\mathrm{scouse}}\rangle \,\approx \,800\,{M}_{\odot }\,{\mathrm{pc}}^{-2}$ , similar to the properties observed throughout the rest of the central molecular gas structure. Tailored hydrodynamical simulations exhibit many of the observed properties and imply that the observed structures are transient and highly time-variable. From our study of NGC 1365, we conclude that it is predominantly the high gas inflow triggered by the bar that is setting the star formation in its CMZ.

Summary: Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.

Objective: To measure well-being at a community level using a valid instrument. Patients and Methods: Written surveys were mailed to a random sample of residents in Olmsted County, Minnesota, in 2015 and 2019 including the 5-item World Health Organization Well-being Index (0-100; for which 100 is the best imaginable well-being or quality of life). Multivariable hierarchical regression was used to evaluate the association between well-being and demographic characteristics, comorbid conditions, and environmental factors. Results: The survey was returned by 1232 of 4000 individuals (response rate, 30.80%). The average well-being score was 70.02. Impaired well-being was identified in 223/1187 individuals (18.79%). Adjusted regression models showed that impaired well-being was independently associated with household poverty, financial stress, reduced access to medical or mental health care, ever having depression diagnosed, living in an unsafe community, or being socially isolated. Conclusion: One in 5 people in a county in the US Midwest have impaired well-being. Well-being was associated with several modifiable factors. Data provide a rationale for policies that align transportation and housing and create opportunities for community members to connect and interact in a safe environment.

Abstract Background Both genetic and cardiovascular factors contribute to the risk of developing heart failure (HF), but whether idea cardiovascular health metrics (ICVHMs) offset the genetic association with incident HF remains unclear. Objectives To investigate the genetic association with incident HF as well as the modification effect of ICVHMs on such genetic association in Chinese and British populations. Methods An ICVHMs based on smoking, drinking, physical activity, diets, body mass index, waist circumference, blood pressure, blood glucose, and blood lipids, and a polygenic risk score (PRS) for HF were constructed in the China Kadoorie Biobank (CKB) of 96,014 participants and UK Biobank (UKB) of 335,782 participants which were free from HF and severe chronic diseases at baseline. Results During the median follow-up of 11.38 and 8.73 years, 1451 and 3169 incident HF events were documented in CKB and UKB, respectively. HF risk increased monotonically with the increase of PRS per standard deviation (CKB: hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07, 1.32; UKB: 1.07; 1.03, 1.11; P for trend < 0.001). Each point increase in ICVHMs was associated with 15% and 20% lower risk of incident HF in CKB (0.85; 0.81, 0.90) and UKB (0.80; 0.77, 0.82), respectively. Compared with unfavorable ICVHMs, favorable ICVHMs was associated with a lower HF risk, with 0.71 (0.44, 1.15), 0.41 (0.22, 0.77), and 0.48 (0.30, 0.77) in the low, intermediate, and high genetic risk in CKB and 0.34 (0.26, 0.44), 0.32 (0.25, 0.41), and 0.37 (0.28, 0.47) in UKB (P for multiplicative interaction > 0.05). Participants with low genetic risk and favorable ICVHMs, as compared with high genetic risk and unfavorable ICVHMs, had 56~72% lower risk of HF (CKB 0.44; 0.28, 0.70; UKB 0.28; 0.22, 0.37). No additive interaction between PRS and ICVHMs was observed (relative excess risk due to interaction was 0.05 [−0.22, 0.33] in CKB and 0.04 [−0.14, 0.22] in UKB). Conclusions In CKB and UKB, genetic risk and ICVHMs were independently associated with the risk of incident HF, which suggested that adherence to favorable cardiovascular health status was associated with a lower HF risk among participants with all gradients of genetic risk.

Abstract Background Alcohol consumption is an important risk factor for hepatic neoplastic and non-neoplastic diseases. Questions remain, however, about the relevance to disease risk of drinking patterns and alcohol tolerability, which differ appreciably between Chinese and Western populations. Methods The prospective China Kadoorie Biobank included 512,715 adults (41% men) aged 30–79 years recruited from ten areas during 2004–2008, recording alcohol intake, drinking patterns, and other characteristics. After median 10 years’ follow-up, 2531 incident liver cancer, 2040 liver cirrhosis, 260 alcoholic liver disease (ALD), and 1262 non-alcoholic fatty liver disease (NAFLD) cases were recorded among 492,643 participants without prior cancer or chronic liver disease at baseline. Cox regression was used to estimate adjusted hazard ratios (HR) relating alcohol intake and drinking patterns to each disease. Results Overall, 33% of men and 2% of women drank alcohol regularly (i.e. at least weekly) at baseline. Among male current regular drinkers, alcohol consumption showed positive dose-response associations with risks of several major chronic liver diseases, with HRs per 280 g/week (i.e. around four drinks/day) higher usual alcohol intake of 1.44 (95% CI 1.23–1.69) for liver cancer (n = 547), 1.83 (1.60–2.09) for liver cirrhosis (n = 388), 2.01 (1.77–2.28) for ALD (n = 200), 1.71 (1.35–2.16) for NAFLD (n = 198), and 1.52 (1.40–1.64) for total liver disease (n = 1775). The association with ALD appeared stronger among men reporting flushing (i.e., with low alcohol tolerance). After adjustment for the total amount of weekly alcohol consumption, daily drinkers had significantly increased risk of ALD (2.15, 1.40–3.31) compared with non-daily drinkers, and drinking without meals was associated with significantly greater risks of liver cancer (1.32, 1.01–1.72), liver cirrhosis (1.37, 1.02–1.85), and ALD (1.60, 1.09–2.33) compared with drinking with meals. Female current regular drinkers had significantly higher risk of ALD, but not other liver diseases, than female abstainers. Conclusions In Chinese men, alcohol intake was associated with significantly increased risks of several major chronic liver diseases, and certain drinking patterns (e.g. drinking daily, drinking without meals) may further exacerbate the disease risks.

Abstract Background People living with dementia vary in awareness of their abilities. We explored awareness of the condition and diagnosis in people with mild-to-moderate dementia, and how this relates to quality of life, well-being, life satisfaction, and caregiver stress. Methods This study was a cross-sectional exploratory analysis of data from the IDEAL cohort, which recruited people with dementia living at home and available caregivers from 29 research sites in Great Britain. Our study included 917 people with mild-to-moderate dementia and 755 carers. Low and high awareness groups were derived from self-reported responses to a dementia representation measure. Logistic regression was used to explore predictors of awareness of condition and diagnosis using demographic, cognitive, functional and psychological measures, and the relationship with quality of life, well-being and life satisfaction (‘living well’), and caregiver stress. Results There were 83 people with low awareness of their condition. The remaining 834 people showed some awareness and 103 of these had high awareness of their condition and diagnosis. Psychosocial factors were stronger predictors of awareness than cognitive and functional ability. Those with higher awareness reported lower mood, and lower scores on indices of living well as well as lower optimism, self-efficacy and self-esteem. Low awareness was more likely in those aged 80y and above, and living in more socially deprived areas. No relationship was seen between caregiver stress and awareness. Conclusions Awareness of the condition and diagnosis varies in people with mild-to-moderate dementia and is relevant to the capability to live well. Awareness should be considered in person-centered clinical care.

Adaptive plasticity of Breast Cancer stem cells (BCSCs) is strongly correlated with cancer progression and resistance, leading to a poor prognosis. In this study, we report the expression profile of several pioneer transcription factors of the Oct3/4 network associated with tumor initiation and metastasis. In the triple negative breast cancer cell line (MDA-MB-231) stably transfected with human Oct3/4-GFP, differentially expressed genes (DEGs) were identified using qPCR and microarray, and the resistance to paclitaxel was assessed using an MTS assay. The tumor-seeding potential in immunocompromised (NOD-SCID) mice and DEGs in the tumors were also assessed along with the intra-tumor (CD44+/CD24-) expression using flow cytometry. Unlike 2-D cultures, the Oct3/4-GFP expression was homogenous and stable in 3-D mammospheres developed from BCSCs. A total of 25 DEGs including Gata6, FoxA2, Sall4, Zic2, H2afJ, Stc1 and Bmi1 were identified in Oct3/4 activated cells coupled with a significantly increased resistance to paclitaxel. In mice, the higher Oct3/4 expression in tumors correlated with enhanced tumorigenic potential and aggressive growth, with metastatic lesions showing a >5-fold upregulation of DEGs compared to orthotopic tumors and variability in different tissues with the highest modulation in the brain. Serially re-implanting tumors in mice as a model of recurrence and metastasis highlighted the sustained upregulation of Sall4, c-Myc, Mmp1, Mmp9 and Dkk1 genes in metastatic lesions with a 2-fold higher expression of stem cell markers (CD44+/CD24-). Thus, Oct3/4 transcriptome may drive the differentiation and maintenance of BCSCs, promoting their tumorigenic potential, metastasis and resistance to drugs such as paclitaxel with tissue-specific heterogeneity.

ABSTRACT Yellow fever virus (YFV) causes sporadic outbreaks of infection in South America and sub-Saharan Africa. While live-attenuated yellow fever virus vaccines based on three substrains of 17D are considered some of the most effective vaccines in use, problems with production and distribution have created large populations of unvaccinated, vulnerable individuals in areas of endemicity. To date, specific antiviral therapeutics have not been licensed for human use against YFV or any other related flavivirus. Recent advances in monoclonal antibody (mAb) technology have allowed the identification of numerous candidate therapeutics targeting highly pathogenic viruses, including many flaviviruses. Here, we sought to identify a highly neutralizing antibody targeting the YFV envelope (E) protein as a therapeutic candidate. We used human B cell hybridoma technology to isolate mAbs from circulating memory B cells from human YFV vaccine recipients. These antibodies bound to recombinant YFV E protein and recognized at least five major antigenic sites on E. Two mAbs (designated YFV-136 and YFV-121) recognized a shared antigenic site and neutralized the YFV-17D vaccine strain in vitro. YFV-136 also potently inhibited infection by multiple wild-type YFV strains, in part, at a postattachment step in the virus replication cycle. YFV-136 showed therapeutic protection in two animal models of YFV challenge, including hamsters and immunocompromised mice engrafted with human hepatocytes. These studies define features of the antigenic landscape of the YFV E protein recognized by the human B cell response and identify a therapeutic antibody candidate that inhibits infection and disease caused by highly virulent strains of YFV. IMPORTANCE Yellow fever virus (YFV) is a mosquito-borne virus that occasionally causes outbreaks of severe infection and disease in South America and sub-Saharan Africa. There are very effective live-attenuated (weakened) yellow fever virus vaccines, but recent problems with their production and distribution have left many people in affected areas vulnerable. Here, we sought to isolate an antibody targeting the surface of the virus for possible use in the future as a biologic drug to prevent or treat YFV infection. We isolated naturally occurring antibodies from individuals who had received a YFV vaccine. We created antibodies and tested them. We found that the antibody with the most powerful antiviral activity was a beneficial treatment in two different small-animal models of human infection. These studies identified features of the virus that are recognized by the human immune system and generated a therapeutic antibody candidate that inhibits infection caused by highly virulent strains of YFV.

Collisions with human-made structures are responsible for billions of bird deaths each year, resulting in ecological damage as well as regulatory and financial burdens to many industries. Acoustic signals can alert birds to obstacles in their flight paths in order to mitigate collisions, but these signals should be tailored to the sensory ecology of birds in flight as the effectiveness of various acoustic signals potentially depends on the influence of background noise and the relative ability of various sound types to propagate within a landscape. We measured changes in flight behaviors from zebra finches released into a flight corridor containing a physical obstacle, either in no-additional-sound control conditions or when exposed to one of four acoustic signals. We selected signals to test two frequency ranges (4–6 kHz or 6–8 kHz) and two temporal modulation patterns (broadband or frequency-modulated oscillating) to determine whether any particular combination of sound attributes elicited the strongest collision avoidance behaviors. We found that, relative to control flights, all sound treatments caused birds to maintain a greater distance from hazards and to adjust their flight trajectories before coming close to obstacles. There were no statistical differences among different sound treatments, but consistent trends within the data suggest that the 4–6 kHz frequency-modulated oscillating signal elicited the strongest avoidance behaviors. We conclude that a variety of acoustic signals can be effective as avian collision deterrents, at least in the context in which we tested these birds. These results may be most directly applicable in scenarios when birds are at risk of collisions with solid structures, such as wind turbines and communication towers, as opposed to window collisions or collisions involving artificial lighting. We recommend the incorporation of acoustic signals into multimodal collision deterrents and demonstrate the value of using behavioral data to assess collision risk.

Background: Few studies have assessed the role of individual plasma cholesterol levels in the association between egg consumption and the risk of cardiovascular diseases. This research aims to simultaneously explore the associations of self-reported egg consumption with plasma metabolic markers and these markers with the risk of cardiovascular disease (CVD). Methods: Totally 4778 participants (3401 CVD cases subdivided into subtypes and 1377 controls) aged 30–79 were selected based on the China Kadoorie Biobank. Targeted nuclear magnetic resonance was used to quantify 225 metabolites in baseline plasma samples. Linear regression was conducted to assess associations between self-reported egg consumption and metabolic markers, which were further compared with associations between metabolic markers and CVD risk. Results: Egg consumption was associated with 24 out of 225 markers, including positive associations for apolipoprotein A1, acetate, mean HDL diameter, and lipid profiles of very large and large HDL, and inverse associations for total cholesterol and cholesterol esters in small VLDL. Among these 24 markers, 14 were associated with CVD risk. In general, the associations of egg consumption with metabolic markers and of these markers with CVD risk showed opposite patterns. Conclusions: In the Chinese population, egg consumption is associated with several metabolic markers, which may partially explain the protective effect of moderate egg consumption on CVD. Funding: This work was supported by the National Natural Science Foundation of China (81973125, 81941018, 91846303, 91843302). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key R&D Program of China, National Natural Science Foundation of China (81390540, 81390541, 81390544), and Chinese Ministry of Science and Technology (2011BAI09B01). The funders had no role in the study design, data collection, data analysis and interpretation, writing of the report, or the decision to submit the article for publication.

Abstract Background Accurately quantifying the risk of osteoporotic fracture is important for directing appropriate clinical interventions. While skeletal measures such as heel quantitative speed of sound (SOS) and dual-energy X-ray absorptiometry bone mineral density are able to predict the risk of osteoporotic fracture, the utility of such measurements is subject to the availability of equipment and human resources. Using data from 341,449 individuals of white British ancestry, we previously developed a genome-wide polygenic risk score (PRS), called gSOS, that captured 25.0% of the total variance in SOS. Here, we test whether gSOS can improve fracture risk prediction. Methods We examined the predictive power of gSOS in five genome-wide genotyped cohorts, including 90,172 individuals of European ancestry and 25,034 individuals of Asian ancestry. We calculated gSOS for each individual and tested for the association between gSOS and incident major osteoporotic fracture and hip fracture. We tested whether adding gSOS to the risk prediction models had added value over models using other commonly used clinical risk factors. Results A standard deviation decrease in gSOS was associated with an increased odds of incident major osteoporotic fracture in populations of European ancestry, with odds ratios ranging from 1.35 to 1.46 in four cohorts. It was also associated with a 1.26-fold (95% confidence interval (CI) 1.13–1.41) increased odds of incident major osteoporotic fracture in the Asian population. We demonstrated that gSOS was more predictive of incident major osteoporotic fracture (area under the receiver operating characteristic curve (AUROC) = 0.734; 95% CI 0.727–0.740) and incident hip fracture (AUROC = 0.798; 95% CI 0.791–0.805) than most traditional clinical risk factors, including prior fracture, use of corticosteroids, rheumatoid arthritis, and smoking. We also showed that adding gSOS to the Fracture Risk Assessment Tool (FRAX) could refine the risk prediction with a positive net reclassification index ranging from 0.024 to 0.072. Conclusions We generated and validated a PRS for SOS which was associated with the risk of fracture. This score was more strongly associated with the risk of fracture than many clinical risk factors and provided an improvement in risk prediction. gSOS should be explored as a tool to improve risk stratification to identify individuals at high risk of fracture.

Miscarriage affects around 15% of clinically confirmed pregnancies. Here the authors carry out a large genome-wide association study for sporadic and multiple consecutive miscarriage and suggest links with placental biology.