Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons.

Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by the deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD. We identified disease phenotypes in FTD neurons carrying the MAPT-N279K mutation, which were related to oxidative stress, oxidative phosphorylation, and neuroinflammation with an upregulation of the inflammation-associated protein osteopontin (OPN). Human FTD neurons survived less and elicited an increased microglial response after transplantation into the mouse forebrain, which we further characterized by single nucleus RNA sequencing of microdissected grafts. Notably, downregulation of OPN in engrafted FTD neurons resulted in improved engraftment and reduced microglial infiltration, indicating an immune-modulatory role of OPN in patient neurons, which may represent a potential therapeutic target in FTD.

Identification of complier and noncomplier average causal effects in the presence of latent missing-at-random (LMAR) outcomes: a unifying view and choices of assumptions.

The study of treatment effects is often complicated by noncompliance and missing data. In the one-sided noncompliance setting where of interest are the complier and noncomplier average causal effects, we address outcome missingness of the latent missing at random type (LMAR, also known as latent ignorability). That is, conditional on covariates and treatment assigned, the missingness may depend on compliance type. Within the instrumental variable (IV) approach to noncompliance, methods have been proposed for handling LMAR outcome that additionally invoke an exclusion restriction-type assumption on missingness, but no solution has been proposed for when a non-IV approach is used. This article focuses on effect identification in the presence of LMAR outcomes, with a view to flexibly accommodate different principal identification approaches. We show that under treatment assignment ignorability and LMAR only, effect nonidentifiability boils down to a set of two connected mixture equations involving unidentified stratum-specific response probabilities and outcome means. This clarifies that (except for a special case) effect identification generally requires two additional assumptions: a specific missingness mechanism assumption and a principal identification assumption. This provides a template for identifying effects based on separate choices of these assumptions. We consider a range of specific missingness assumptions, including those that have appeared in the literature and some new ones. Incidentally, we find an issue in the existing assumptions, and propose a modification of the assumptions to avoid the issue. Results under different assumptions are illustrated using data from the Baltimore Experience Corps Trial.

Evaluation of colitis induced by immune-checkpoint inhibitors therapy in melanoma patients by an overall grading scale.

BACKGROUND: Colitis was the third most common immune-related adverse effect in melanoma patients treated with immune-checkpoint inhibitor (ICI). With the limitation of real-world data in the UK population, this study was conducted in a UK hospital where a fresh colitis guidance was introduced to evaluate the overall grading (OG) to assess colitis severity and guide the treatment. AIMS: This study aimed to investigate colitis severity by Common Terminology Criteria for Adverse Events (CTCAE) grade and overall grade at time of presentation. Colitis treatment and outcome were evaluated to compare the impact of these two categories. METHODS: A single-center, retrospective observational study was performed in melanoma patient developing colitis symptoms. RESULTS: A total of 44 advanced melanoma patient with colitis symptoms were included. Median time to colitis onset was 67 days (range 4-890). Majority of patients developed G1/ G2 of CTCAE scale (70.4%) but moderate or severe overall grade (84.1%). There were 65.9% of patients treated with steroids, and 38.2% with infliximab and 4.5% with vedolizumab. The median time of colitis resolution was 28 days (range 0-282). Both treatment modality and time to resolution were associated with severity of colitis assessed by complete OG(p<0.0001) rather than CTCAE grading (p>0.05). CONCLUSIONS: This study provided a comprehensive description about ICI-induced colitis management in a single center of the UK. The more completed OG was proposed to stratify colitis patient and guide the investigation and treatment decision at presenting time, replacing the old CTCAE grading.

Anti-Staphylococcus aureus potential of compounds from Ganoderma sp.: A comprehensive molecular docking and simulation approaches.

In this study, a series of secondary metabolites from Ganoderma sp. were screened against Staphylococcus aureus protein targets, including as phosphotransacetylase, clumping factor A, and dihydrofolate reductase, using molecular docking simulations. The chemicals that showed the strongest binding energy with the targeted proteins were ganodermanontriol, lucidumol B, ganoderic acid J, ergosterol, ergosterol peroxide, 7-oxoganoderic acid Z, ganoderic acid AM1, ganosinoside A, ganoderic acid D, and 24R-ergosta-7,2E-diene-3ß,5α,6ß-triol. Interestingly, ganosinoside A showed the greatest affinity for the protein clumping factor A, a result validated by molecular dynamic simulation. Additionally, three natural Ganoderma sp. Strains as Ganoderma lingzhi VNKKK1903, Ganoderma lingzhi VNKK1905A2, and Amauroderma subresinosum VNKKK1904 were collected from Kon Ka Kinh National Park in central land of Vietnam and evaluated for their antibacterial activity against Staphylococcus aureus using an agar well diffusion technique. These results suggest that the fungal extracts and secondary metabolites may serve as valuable sources of antibiotics against Staphylococcus aureus. These findings provided an important scientific groundwork for further exploration of the antibacterial mechanisms of compounds derived from Ganoderma sp. in future research.

Unraveling reproductive and maternal health challenges of women living with HIV/AIDS in Vietnam: a qualitative study.

BACKGROUND: Human Immunodeficiency Virus (HIV) remains a significant public health concern worldwide. Women living with HIV/AIDS (WLHA) have the additional and unique need to seek sexual and reproductive health services. WLHA's maternal health journeys can be shaped by the cultural norms and resources that exist in their society. This study sought to understand if and how WLHA's family planning, pregnancy, and motherhood experiences could be influenced by the patriarchal culture, gender roles, and HIV stigma in Vietnam, specifically. METHODS: Between December 2021 and March 2022, 30 WLHA with diverse socioeconomic backgrounds and childbirth experiences were interviewed in Hanoi, Vietnam. These semi-structured interviews covered topics including HIV stigma, gender norms, pregnancy experiences, and child-rearing challenges. Interviews were audio recorded, transcribed, and analysed using ATLAS.ti. RESULTS: Qualitative analyses of participant quotes revealed how limited information on one's health prospects and reproductive options posed a significant challenge to family planning. Societal and familial expectations as well as economic circumstances also influenced reproductive decision-making. WLHA often encountered substandard healthcare during pregnancy, labor, and delivery. Stigma and lack of provider attentiveness resulted in cases where women were denied pain relief and other medical services. Communication breakdowns resulted in failure to administer antiretroviral therapy for newborns. Motherhood for WLHA was shadowed by concerns for not only their own health, but also the wellbeing of their children, as HIV stigma affected their children at school and in society as well. Many WLHA highlighted the constructive or destructive role that family members could play in their childbirth decision-making and care-giving experiences. CONCLUSIONS: Overall, this study underscores the complex ways that cultural expectations, family support, and stigma in healthcare impact WLHA. Efforts to educate and engage families and healthcare providers are warranted to better understand and address the needs of WLHA, ultimately improving their reproductive and maternal health.

HIV-related stigma and discrimination have consequential impacts on health and quality of life for women living with HIV (WLHA). WLHA in Vietnam must navigate the additional challenges of a traditionally patriarchal and hierarchical society. Women typically face less educational and occupational opportunities and are often expected to defer to expectations of family and virtue. Stigma among family members, friends, employers, and healthcare providers poses a significant challenge to WLHA autonomy, especially as it relates to their reproductive health decision-making and maternal health experiences. This study aims to better understand the experiences of WLHA throughout family planning, pregnancy, and motherhood. The findings will hopefully shed light on strategies to empower WLHA and to combat HIV- and gender-based stigma not only in Vietnam, but also globally.

Viral reprogramming of host transcription initiation.

Viruses are master remodelers of the host cell environment in support of infection and virus production. For example, viruses typically regulate cell gene expression through modulating canonical cell promoter activity. Here, we show that Epstein Barr virus (EBV) replication causes 'de novo' transcription initiation at 29674 new transcription start sites throughout the cell genome. De novo transcription initiation is facilitated in part by the unique properties of the viral pre-initiation complex (vPIC) that binds a TATT[T/A]AA, TATA box-like sequence and activates transcription with minimal support by additional transcription factors. Other de novo promoters are driven by the viral transcription factors, Zta and Rta and are influenced by directional proximity to existing canonical cell promoters, a configuration that fosters transcription through existing promoters and transcriptional interference. These studies reveal a new way that viruses interact with the host transcriptome to inhibit host gene expression and they shed light on primal features driving eukaryotic promoter function.

Navigating cultural and gender aspects of stigma among women living with HIV in Vietnam.

Women living with HIV often face intersecting challenges of stigma and gender inequality. In Vietnam, this issue is potentially exacerbated by the patriarchal culture. From December 2021 to March 2022, we conducted in-depth interviews with 30 women living with HIV in Hanoi to better understand their experiences and the coping mechanisms to navigate HIV stigma, cultural beliefs and gender norms. The interviews explored various topics including women's social and family roles in Vietnam, HIV-related beliefs, stigma and its impact on one's health and coping strategies. Participants reported stereotypes that assumed that women living with HIV had either engaged in sex work or behaved promiscuously. These stereotypes render them vulnerable to judgement and discrimination owing to widespread expectations of female virtue. As a result, women living with HIV often enacted non-disclosure and self-isolation to avoid stigma. This self-stigmatisation negatively impacted their healthcare-seeking, employment opportunities and ability to fulfil traditional family-caring roles. Conversely, many participants exhibited resilience with the support of family and peers. Overall, the complex interplay between gender, culture and HIV stigma underscores the importance of developing culturally appropriate, multifaceted approaches to engaging family and peers, modifying gender-based discriminatory social practices and enhancing women's self-efficacy and empowerment in Vietnam.

OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.

Glioblastoma (GBM) remains an incurable disease, requiring more effective therapies. Through interrogation of publicly available CRISPR and RNAi library screens, we identified the α-ketoglutarate dehydrogenase (OGDH) gene, which encodes an enzyme that is part of the tricarboxylic acid (TCA) cycle, as essential for GBM growth. Moreover, by combining transcriptome and metabolite screening analyses, we discovered that loss of function of OGDH by the clinically validated drug compound CPI-613 was synthetically lethal with Bcl-xL inhibition (genetically and through the clinically validated BH3 mimetic, ABT263) in patient-derived xenografts as well neurosphere GBM cultures. CPI-613-mediated energy deprivation drove an integrated stress response with an upregulation of the BH3-only domain protein, Noxa, in an ATF4-dependent manner, as demonstrated by genetic loss-of-function experiments. Consistently, silencing of Noxa attenuated cell death induced by CPI-613 in model systems of GBM. In patient-derived xenograft models of GBM in mice, the combination treatment of ABT263 and CPI-613 suppressed tumor growth and extended animal survival more potently than each compound on its own. Therefore, combined inhibition of Bcl-xL along with disruption of the TCA cycle might be a treatment strategy for GBM.

Effect of gibberellin on crown root development in the mutant of the rice plasmodesmal Germin-like protein OsGER4.

Rice is an essential but highly stress-susceptible crop, whose root system plays an important role in plant development and stress adaptation. The rice root system architecture is controlled by gene regulatory networks involving different phytohormones including auxin, jasmonate, and gibberellin. Gibberellin is generally known as a molecular clock that interacts with different pathways to regulate root meristem development. The exogenous treatment of rice plantlets with Gibberellin reduced the number of crown roots, whilst the exogenous jasmonic acid treatment enhanced them by involving a Germin-like protein OsGER4. Due to those opposite effects, this study aims to investigate the effect of Gibberellin on crown root development in the rice mutant of the plasmodesmal Germin-like protein OsGER4. Under exogenous gibberellin treatment, the number of crown roots significantly increased in osger4 mutant lines and decreased in the OsGER4 overexpressed lines. GUS staining showed that OsGER4 was strongly expressed in rice root systems, particularly crown and lateral roots under GA3 application. Specifically, OsGER4 was strongly expressed from the exodermis, epidermis, sclerenchyma to the endodermis layers of the crown root, along the vascular bundle and throughout LR primordia. The plasmodesmal protein OsGER4 is suggested to be involved in crown root development by maintaining hormone homeostasis, including Gibberillin.

Synergy of machine learning and density functional theory calculations for predicting experimental Lewis base affinity and Lewis polybase binding atoms.

Investigation of Lewis acid-base interactions has been conducted by ab initio calculations and machine learning (ML) models. This study aims to resolve two critical tasks that have not been quantitatively investigated. First, ML models developed from density functional theory (DFT) calculations predict experimental BF3 affinity with Pearson correlation coefficients around 0.9 and mean absolute errors around 10 kJ mol-1 . The ML models are trained by DFT-calculated BF3 affinity of more than 3000 adducts, with input features readily obtained by rdkit. Second, the ML models have the capability of predicting the relative strength of Lewis base binding atoms in Lewis polybases, which is either an extremely challenging task to conduct experimentally or a computationally expensive task for ab initio methods. The study demonstrates and solidifies the potential of combining DFT calculations and ML models to predict experimental properties, especially those that are scarce and impractical to empirically acquire.

The Potential Teeth Bleaching and Halitosis Prevention Effects of Pediococcus inopinatus THK-30, a Kimchi-Derived Lactic Acid Bacterium: In Vitro Study.

BACKGROUND: Recent developments in addressing dental aesthetic concerns, encompassing issues like teeth discoloration and halitosis, underscore the demand for safer alternative solutions. PURPOSE: This study aims to confirm the effects of lactic acid bacteria (LAB) from kimchi on artificial teeth bleaching and their potential impact in terms of preventing halitosis-related bacteria. MATERIALS AND METHODS: To evaluate the antimicrobial effects against oral pathogens, disc diffusion tests and broth microdilution methods were used. Additionally, crystal violet analysis was performed to confirm the biofilm inhibition effect. The bleaching effects on stained artificial teeth were analyzed using the CIEDE2000 colorimetric method. Statistical analyses were performed using GraphPad Prism 9 with one-way and two-way ANOVA, with the significance level set at α < 0.05. RESULTS: The strain THK-30, isolated from kimchi, exhibited antibacterial activity against Streptococcus mutans, Porphyromonas gingivalis, and Fusobacterium nucleatum, and was identified as Pediococcus inopinatus. Moreover, THK-30 showed a synergistic antibacterial effect against Gram-negative oral pathogens with 8% sodium hexametaphosphate (SHMP). In the stained artificial teeth bleaching test and artificial teeth biofilm inhibition test, the cell-free supernatant of THK-30 displayed significant teeth bleaching effects and caused the inhibition of biofilm formation, both independently and in combination with SHMP 8%. CONCLUSIONS: This study has demonstrated the potential applicability of LAB in teeth discoloration and halitosis. These findings are poised to provide a foundation for the development of research pertaining to the control of oral bacteria.

Direct observations of microbial community succession on sinking marine particles.

Microbial community dynamics on sinking particles control the amount of carbon that reaches the deep ocean and the length of time that carbon is stored, with potentially profound impacts on Earth's climate. A mechanistic understanding of the controls on sinking particle distributions has been hindered by limited depth- and time-resolved sampling and methods that cannot distinguish individual particles. Here, we analyze microbial communities on nearly 400 individual sinking particles in conjunction with more conventional composite particle samples to determine how particle colonization and community assembly might control carbon sequestration in the deep ocean. We observed community succession with corresponding changes in microbial metabolic potential on the larger sinking particles transporting a significant fraction of carbon to the deep sea. Microbial community richness decreased as particles aged and sank; however, richness increased with particle size and the attenuation of carbon export. This suggests that the theory of island biogeography applies to sinking marine particles. Changes in POC flux attenuation with time and microbial community composition with depth were reproduced in a mechanistic ecosystem model that reflected a range of POC labilities and microbial growth rates. Our results highlight microbial community dynamics and processes on individual sinking particles, the isolation of which is necessary to improve mechanistic models of ocean carbon uptake.

Early transcriptomic responses of rice leaves to herbivory by Spodoptera frugiperda.

During herbivory, chewing insects deposit complex oral secretions (OS) onto the plant wound. Understanding how plants respond to the different cues of herbivory remains an active area of research. In this study, we used an herbivory-mimick experiment to investigate the early transcriptional response of rice plants leaves to wounding, OS, and OS microbiota from Spodoptera frugiperda larvae. Wounding induced a massive early response associated to hormones such as jasmonates. This response switched drastically upon OS treatment indicating the activation of OS specific pathways. When comparing native and dysbiotic OS treatments, we observed few gene regulation. This suggests that in addition to wounding the early response in rice is mainly driven by the insect compounds of the OS rather than microbial. However, microbiota affected genes encoding key phytohormone synthesis enzymes, suggesting an additional modulation of plant response by OS microbiota.

Economic burden of chronic obstructive pulmonary disease: A systematic review.

Objectives: Globally, providing evidence on the economic burden of Chronic Obstructive Pulmonary Disease (COPD) is becoming essential to assist health authorities in improving resource allocation. This study aimed to summarize the literature's economic burden evidence for COPD from 1990 to 2019. Methods: This study, spanning from 1990 to 2019, examined the economic burden of COPD through a systematic review of online databases, including Web of Science, PubMed/Medline, Scopus, and the Cochrane Library. After meticulous screening of 12,734 studies, 43 articles meeting inclusion criteria were identified. General study information and data on direct, indirect, and intangible costs were extracted and converted to 2018 international dollars (Int$). Results: Findings revealed a range of total direct costs from Int$ 52.08 (India) to Int$ 13,776.33 (Canada) across 16 studies, with drug costs spanning from Int$ 70.07 (Vietnam) to Int$ 8,706.9 (China) in eleven studies. Eight studies explored indirect costs, while one highlighted caregivers' direct costs at approximately Int$ 1,207.8 (Greece). This study underscores the limited research on COPD caregivers' economic burdens, particularly in developing countries, emphasizing the importance of increased research support, particularly in high-resource settings. Conclusions: This study provides information about the cost and demographics of the COPD economic burden from 1990 to 2019. More strategies to reduce the frequency of hospital admissions and acute care services should be implemented to improve COPD patients' lives and control the disease's rising cost and burden.

Facile synthesis of gold nanostars for the duplex detection of pesticide residues in grapes using SERS.

In recent years, concerns have been raised regarding the contamination of grapes with pesticide residues. As consumer demand for safer food products grows, regular monitoring of pesticide residues in food has become essential. This study sought to develop a rapid and sensitive technique for detecting two specific pesticides (phosmet and paraquat) present on the grape surface using the surface-enhanced Raman spectroscopy (SERS) method. Gold nanostars (AuNS) particles were synthesized, featuring spiky tips that act as hot spots for localized surface plasmon resonance, thereby enhancing Raman signals. Additionally, the roughened surface of AuNS increases the surface area, resulting in improved interactions between the substrate and analyte molecules. Prominent Raman peaks of mixed contaminants were acquired and used to characterize and quantify the pesticides. It was observed that the SERS intensity of the Raman peaks changed in proportion to the concentration ratio of phosmet and paraquat. Moreover, AuNS exhibited superior SERS enhancement compared to gold nanoparticles. The results demonstrate that the lowest detectable concentration for both pesticides on grape surfaces is 0.5 mg/kg. These findings suggest that SERS coupled with AuNS constitutes a practical and promising approach for detecting and quantifying trace contaminants in food. PRACTICAL APPLICATION: This research established a novel surface-enhanced Raman spectroscopy (SERS) method coupled with a simplified extraction protocol and gold nanostar substrates to detect trace levels of pesticides in fresh produce. The detection limits meet the maximum residue limits set by the EPA. This substrate has great potential for rapid measurements of chemical contaminants in foods.

Human Milk-Derived Enterococcus faecalis HM20: A Potential Alternative Agent of Antimicrobial Effect against Methicillin-Resistant Staphylococcus aureus (MRSA).

The increasing global impact of skin diseases, fueled by methicillin-resistant Staphylococcus aureus (MRSA), emphasizes the necessity for alternative therapies with lower toxicity, such as lactic acid bacteria (LAB). This study aims to isolate potential LAB from human milk and evaluate their efficacy against MRSA using various methods, including well diffusion, microdilution, crystal violet assay, enzymatic characterization, SDS-PAGE, and scanning electron microscopy (SEM). Among the 26 LAB screened, the human milk-derived strain HM20 exhibited significant antimicrobial activity against S. aureus CCARM 3089 (MRSA), which is a highly resistant skin pathogen. Through 16S rRNA sequencing, strain HM20 was identified as closely related to Enterococcus faecalis ATCC 19433T, which was subsequently designated as Enterococcus faecalis HM20. The minimum inhibitory concentration (MIC) of the cell-free supernatant (CFS) of HM20 against S. aureus KCTC 3881 and S. aureus CCARM 3089 was determined to be 6.25% and 12.5%, respectively. Furthermore, the effective inhibition of biofilm formation in S. aureus KCTC 3881 and S. aureus CCARM 3089 was observed at concentrations of 12.5% and 25% or higher, respectively. The antibacterial effect of the CFS was attributed to the presence of organic acids, hydrogen peroxide, and bacteriocins. Additionally, the antimicrobial peptides produced by HM20 were found to be stable under heat treatment and analyzed to have a size below 5 kDa. SEM image observations confirmed that the CFS of HM20 caused damage to the cell wall, forming pores and wrinkles on S. aureus KCTC 3881 and S. aureus CCARM 3089. This comprehensive investigation on strain HM20 conducted in this study provides foundational data for potential developments in functional materials aimed at addressing skin infections and antibiotic-resistant strains in the future.

Depression and associated factors among HIV-positive smokers receiving care at HIV outpatient clinics in Vietnam: a cross-sectional analysis.

OBJECTIVES: To assess the prevalence of depressive symptoms and associated factors among people living with HIV (PLWH) who were current cigarette smokers and receiving treatment at HIV outpatient clinics (OPCs) in Vietnam. DESIGN: A cross-sectional survey of smokers living with HIV. SETTING: The study was carried out in 13 HIV OPCs located in Ha Noi, Vietnam. PARTICIPANTS: The study included 527 PLWH aged 18 and above who were smokers and were receiving treatment at HIV OPCs. OUTCOME MEASURES: The study used the Centre for Epidemiology Scale for Depression to assess depressive symptoms. The associations between depressive symptoms, tobacco dependence and other characteristics were explored using bivariate and Poisson regression analyses. RESULTS: The prevalence of depressive symptoms among smokers living with HIV was 38.3%. HIV-positive smokers who were female (prevalence ratio, PR 1.51, 95% CI 1.02 to 2.22), unmarried (PR 2.06, 95% CI 1.54 to 2.76), had a higher level of tobacco dependence (PR 1.06, 95% CI 1.01 to 1.11) and reported their health as fair or poor (PR 1.66, 95% CI 1.22 to 2.26) were more likely to have depression symptoms compared with HIV-positive smokers who were male, married, had a lower level of tobacco dependence and self-reported their health as good, very good or excellent. CONCLUSION: The prevalence of depressive symptoms among smokers receiving HIV care at HIV OPCs was high. Both depression and tobacco use screening and treatment should be included as part of ongoing care treatment plans at HIV OPCs.

Comparison of methods that combine multiple randomized trials to estimate heterogeneous treatment effects.

Individualized treatment decisions can improve health outcomes, but using data to make these decisions in a reliable, precise, and generalizable way is challenging with a single dataset. Leveraging multiple randomized controlled trials allows for the combination of datasets with unconfounded treatment assignment to better estimate heterogeneous treatment effects. This article discusses several nonparametric approaches for estimating heterogeneous treatment effects using data from multiple trials. We extend single-study methods to a scenario with multiple trials and explore their performance through a simulation study, with data generation scenarios that have differing levels of cross-trial heterogeneity. The simulations demonstrate that methods that directly allow for heterogeneity of the treatment effect across trials perform better than methods that do not, and that the choice of single-study method matters based on the functional form of the treatment effect. Finally, we discuss which methods perform well in each setting and then apply them to four randomized controlled trials to examine effect heterogeneity of treatments for major depressive disorder.

Estimation of place-based vulnerability scores for HIV viral non-suppression: an application leveraging data from a cohort of people with histories of using drugs.

The relationships between place (e.g., neighborhood) and HIV are commonly investigated. As measurements of place are multivariate, most studies apply some dimension reduction, resulting in one variable (or a small number of variables), which is then used to characterize place. Typical dimension reduction methods seek to capture the most variance of the raw items, resulting in a type of summary variable we call "disadvantage score". We propose to add a different type of summary variable, the "vulnerability score," to the toolbox of the researchers doing place and HIV research. The vulnerability score measures how place, as known through the raw measurements, is predictive of an outcome. It captures variation in place characteristics that matters most for the particular outcome. We demonstrate the estimation and utility of place-based vulnerability scores for HIV viral non-suppression, using data with complicated clustering from a cohort of people with histories of injecting drugs.

Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health.

The human retina is a multilayered tissue that offers a unique window into systemic health. Optical coherence tomography (OCT) is widely used in eye care and allows the noninvasive, rapid capture of retinal anatomy in exquisite detail. We conducted genotypic and phenotypic analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed OCT layer cross-phenotype association analyses (OCT-XWAS), associating retinal thicknesses with 1866 incident conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association studies (GWASs), identifying inherited genetic markers that influence retinal layer thicknesses and replicated our associations among the LIFE-Adult Study (N = 6313). Last, we performed a comparative analysis of phenome- and genome-wide associations to identify putative causal links between retinal layer thicknesses and both ocular and systemic conditions. Independent associations with incident mortality were detected for thinner photoreceptor segments (PSs) and, separately, ganglion cell complex layers. Phenotypic associations were detected between thinner retinal layers and ocular, neuropsychiatric, cardiometabolic, and pulmonary conditions. A GWAS of retinal layer thicknesses yielded 259 unique loci. Consistency between epidemiologic and genetic associations suggested links between a thinner retinal nerve fiber layer with glaucoma, thinner PS with age-related macular degeneration, and poor cardiometabolic and pulmonary function with a thinner PS. In conclusion, we identified multiple inherited genetic loci and acquired systemic cardio-metabolic-pulmonary conditions associated with thinner retinal layers and identify retinal layers wherein thinning is predictive of future ocular and systemic conditions.