Our unique capacities for spoken and written language are fundamental features of what makes us human, yet the biological bases remain largely mysterious. We present a large-scale well-powered genome-wide association study meta-analysis of individual differences in reading- and language-related skills  in tens of thousands of participants. The findings prompt a major reevaluation of prior literature claiming candidate gene associations in much smaller samples. Moreover, we use the novel genetic data as windows into multiple aspects of the biology of these important abilities, revealing molecular links to individual differences in neuroanatomy of language-related brain areas and enriched heritability in archaic deserts of the human genome as well as in fetal brain enhancer regions. P = 1.098 × 10−8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures  in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009,  The processing and production of complex spoken and written language are capacities that appear to be distinct to our species . Such skROBO2 associated with expressive vocabulary in infancy , which encompasses the older definition of specific language impairment (SLI) . However infancy ; rs17663dyslexia .https://www.genlang.org/) together with several public datasets that have data available for the relevant phenotypes matched to genome-wide genotype information. Five quantitative traits were identified for which phenotype data could be aligned across different cohorts to yield sufficiently large sample sizes for GWAS: word reading, nonword reading, spelling, phoneme awareness, and nonword repetition. Univariate GWAS meta-analyses were performed for each of the phenotypes to identify genetic variation influencing these traits and to model genetic overlaps between them. For comparative purposes, a GWAS meta-analysis for performance intelligence quotient (IQ) was also performed in the same dataset. Together with publicly available GWAS summary statistics from prior studies of cognitive performance and educational attainment, these data were used to study genetic relationships between reading- and language-related traits, IQ, and educational attainment. A multivariate approach allowed us to optimize the power of GWAS meta-analysis for functional follow-ups, giving insights into the tissues, cell types, brain regions, and evolutionary signatures involved.Here, we present large-scale GWAS meta-analyses of a set of reading- and language-related traits, measured with psychometric tools. We captured variation across the phenotypic spectrum, extending beyond disorder. Our study focused on traits assessed using continuous measures in multiple cohorts from the international GenLang network . The cohorts connected in the GenLang network either were originally ascertained through a proband with a language/reading disorder (DLD/SLI or dyslexia) or were sampled from the general population; all cohorts include quantitative phenotypic data gathered via validated psychometric tests as well as genome-wide genotype data from the tested individuals. Some of the samples are birth cohorts, and some involve family or twin designs. The phenotype data were collected across an array of different ages, test instruments, and languages . We reduced heterogeneity of assessment age by excluding individuals over 18 y of age (except for three cohorts)  and where phenotype data were available from the same participant at multiple ages, by choosing the age that matched best with the assessment ages of the largest cohort(s). We limited the heterogeneity introduced by different test instruments by only including those that measured the phenotypes described in our analysis plan  and in cases where data from more than one test instrument were available, by selecting the test instrument that was used by the largest number of cohorts.Our study focused on five quantitative reading- and language-related traits: word reading accuracy, nonword reading accuracy, spelling accuracy, phoneme awareness, and nonword repetition accuracy . These tDataset S4). We tested those data for genetic correlations using linkage disequilibrium score regression (LDSC) . There was limited heterogeneity of GWAS meta-analysis results, as also evident in the Cochran Q statistics  and LDSC ratios (Dataset S4) for all traits except nonword repetition.We evaluated whether, despite efforts to minimize this, heterogeneity related to age and/or use of different test instruments remained in our data. To do so, we generated GWAS meta-analysis results for word and nonword reading stratified by age or test instrument (n (LDSC) , determiSI AppendixSupplemental Notes, Dataset S4). Given the lack of genetic heterogeneity, the remainder of the study involved analyses of the full non-stratified dataset, to ensure largest available sample size and maximal power.We also assessed effects of sex, observing high genetic correlations for female- and male-only subsets (P = 5 × 10−8), but also for multiple testing based on the correlation structure of our five reading-/language-related traits, as estimated using phenotypic Spectral Decomposition . The significance threshold for assessing the GWAS meta-analysis results was thus set to P = 5 × 10−8/2.15 independent traits = 2.33 × 10−8. We identified a genome-wide significant locus associated with word reading  . Notably, rs11208009 has not shown association with general cognitive performance or educational attainment, while other SNPs in linkage disequilibrium (LD) with rs11208009 (r2 > 0.6) have been associated with triglyceride and total cholesterol levels in blood in previous GWAS (Dataset S5). Three genes are located in the vicinity of rs11208009 and SNPs in LD (r2 > 0.6): DOCK7, encoding a guanine nucleotide exchange factor important for neurogenesis . Genome-wide significant loci were not identified for the other traits. Dataset S7 lists all results with P < 1 × 10−6.We performed univariate GWAS meta-analyses for the reading-/language-related traits in the full GenLang dataset as follows. For each phenotype, associations between SNPs and the quantitative trait were calculated in every cohort separately, then combined into a meta-analysis for that phenotype. This yielded five separate univariate GWAS datasets, one for each trait. For evaluating statistical significance of SNP associations, we determined an appropriate threshold that was adjusted not only for genome-wide screening , indicating that the captured common genetic variation accounts for a substantive proportion of the phenotypic variance. These observations allowed for follow-up analyses that are dependent on significant SNP heritability, including estimates of genetic correlations: a measure that quantifies the overall genetic similarity between two complex traits. Pairwise genetic correlation analyses showed significant overlap among the reading- and language-related traits (Dataset S4). Genetic correlation estimates were especially high for word reading, nonword reading, spelling, and phoneme awareness, ranging from 0.96 (SE = 0.07) to 1.06 (SE = 0.07).The individual effect size of our genome-wide significant hit is small, as is typical for genetically complex traits. We went on to make use of the complete GWAS signal considered in aggregate across the genome to gain insights into the genetic architecture of the reading-/language-related traits as well as relationships with other aspects of human biology. First, for each phenotype, we estimated SNP-based heritability: the proportion of trait variability explained by the SNPs included in the GWAS. All five traits showed significant SNP-based heritability, with LDSC-based estimates ranging from 0.13 for nonword repetition to 0.26 for nonword reading  . Only nonverbal subtests of general intelligence tests were used in this analysis (Dataset S1). Summary statistics were also obtained from another three sources: 1) genome-wide studies of full-scale IQ  and educational attainment  by the Social Science Genetic Association Consortium   that used a decomposition analysis to identify genetic associations with distinct domains of performance  ; and 3) formance .Dataset S8). Interestingly, genetic correlations with full-scale IQ were substantially higher for word reading (95% CI = 0.70 to 0.85) than nonword reading (95% CI = 0.50 to 0.68), likely reflecting the importance of reading skills for verbal tests of cognition. Genetic correlations of reading-/language-related traits with performance IQ (range = 0.20 to 0.35) were much lower than those for full-scale IQ, and the 95% CIs did not overlap. Indeed, only word reading showed a significant genetic correlation with performance IQ. These results indicate that reading-/language-related traits and IQ are at least partly based on distinct genetic factors. Significant trait-specific genetic correlations were observed for components 2 to 4 of the Danish school grade decomposition analysis , educational attainment (range = 0.54 to 0.68), and school performance (range = 0.54 to 0.81) . Exploratory factor models with one to four factors were fitted to the data, of which the three-factor model explained the majority of the variance. The three-factor model was followed up using confirmatory factor analysis in GenomicSEM. In the final model   is a metal model B, the fiDataset S10), and these have identified very few associations exceeding genome-wide significance. In those prior studies, a total of 48 independent SNPs met a less stringent threshold of P < 1 × 10−6 in the respective GWAS. We ran lookups of each of those SNPs in our GenLang GWAS meta-analysis results (Dataset S10). Where SNP associations passed a threshold adjusted for multiple testing of 48 SNPs and 2.15 independent GenLang traits (P < 4.84 × 10−4), we then reran the association analyses after exclusion of the original cohort(s) in which the association was first identified to evaluate independent effects beyond those of the respective earlier study. According to these criteria, only one SNP, rs1555839, previously associated with rapid automatized naming in the Genes, Reading, and Dyslexia (GRaD) cohort (P = 3.33 × 10−4). This SNP is one of five SNPs that reached the threshold for genome-wide significance in the original GWAS of the GRaD cohort.The number of previous GWAS on reading-/language-related traits and disorders is small  cohort  yielded Dataset S11 gives gene-based P values from our GenLang GWAS meta-analysis, calculated by Multi-marker Analysis of GenoMic Annotation (MAGMA) . DCDC2 was originally identified in a linkage region for dyslexia susceptibility, and SNPs in and near this gene were subsequently associated with dyslexia in candidate gene studies  (Dataset S11). These null findings highlight the importance of large-scale studies for robust identification of common DNA variation associated with reading-/language-related traits and disorders and warrant a reevaluation of the contributions of candidate genes that are prominent from prior literature.Some 20 genes have been described in the literature as candidate genes for reading-/language-related traits and disorders based on a range of mapping approaches and have been the focus of much of the prior published research in this area . Dataset (MAGMA) , for eac studies , althoug studies . No singSI Appendix, Fig. S4), the approach improved power for follow-up analyses in three ways: 1) by incorporating all available data from the different traits without increasing multiple testing burden; 2) by reducing error variance and thereby, increasing the proportion of phenotypic variability captured by genetic variations, with SNP-based heritability that was higher than any of the univariate estimates with a smaller SE ; and 3) because joint analysis of the different traits maximized the effective sample size of the dataset. Indeed, MTAG estimated the GWAS equivalent sample size of the multivariate results as 41,783 compared with 27,180 for the corresponding univariate results. These multivariate GenLang GWAS results were used for follow-up analyses utilizing not only genetic correlation approaches, but also other genome-based methods, such as gene property analysis and heritability partitioning, further explained below.To improve the power of our GWAS meta-analysis for follow-up analyses, we took advantage of the high genetic correlations between the traits by performing a multivariate GWAS analysis of word reading, nonword reading, spelling, and phoneme awareness with the Multi Trait Analysis of GWAS (MTAG) method . This apMaterials and Methods). This yielded 58 structural neuroimaging traits, including surface-based morphometry (surface area and thickness)  phenotypes and diffusion tensor imaging   results. Second, as many of these brain-based phenotypes were significantly correlated with each other, genetic correlations among their summary statistics were used to calculate the number of independent traits for multiple testing correction. Third, we performed genetic correlation analyses between the multivariate GenLang GWAS results and the 58 neuroimaging traits to identify genetic overlaps. One neuroimaging trait showed significant genetic correlation with the multivariate GenLang results (P < 0.05/24.85 independent traits = 2.01 × 10−3): the surface area of the banks of the superior temporal sulcus (STS) of the left hemisphere  (Dataset S12). This finding suggests the existence of shared genetic factors that contribute both to left STS surface area and to reading-/language-related skills, albeit without identifying which SNPs underlie the relationship. Functional MRI studies have linked this region to different aspects of written and spoken language processing (Dataset S12).The neurobiological circuitry involved in spoken and written language has been extensively investigated in prior literature, from pioneering postmortem studies of brain lesions through to the noninvasive structural and functional neuroimaging research that is now standard for the field , 27. Notocessing –36. To in = 257,828) were obtained as well. A total of 143 traits showed significant genetic correlations with the multivariate GenLang GWAS results after correction for multiple testing [P < 0.05/(535 × 2) = 4.67 × 10−5] (Dataset S13), while 245 traits were genetically correlated with full-scale IQ; 135 traits showed significant correlations with both our multivariate GWAS and full-scale IQ. Traits with strong genetic correlations were related to education, eyesight, chronotype, well-being, lifestyle, physical health and exercise, and socioeconomic status. Representative traits are plotted in Next, we assessed genetic correlations of our multivariate GWAS results with 20 cognitive, education, neurological, psychiatric, and sleeping-related traits and 515 additional UK Biobank traits using LD Hub. To further investigate overlaps with and differences from IQ, genetic correlations between these 535 traits and the published GWAS summary statistics for full-scale IQ  . The tested annotations included human gained enhancers active in fetal and adult brain tissue, ancient selective sweep regions, Neanderthal introgressed variants, and archaic introgression deserts . The latter two annotations relate to admixture events between Homo sapiens and Neanderthal populations that took place when the different hominins encountered each other outside Africa some 50,000 to 60,000 y ago, with the consequent gene flow leaving remnants (introgressed fragments) that can be detected in the genomes of living humans. Archaic deserts are long stretches in the human genome that, despite these admixture events, are significantly depleted for Neanderthal alleles in living humans, possibly due to critical functions of the genetic loci in H. sapiens and intolerance to gene flow (P < 0.01) (Dataset S14). Thus, our results suggest that common DNA variation in archaic deserts makes a larger contribution to individual differences in reading-/language-related traits within present-day populations than expected by chance.Writing and reading are relatively recent cultural innovations, but multiple lines of evidence indicate that the relevant skills, especially those involved in decoding as assessed here, are based on our capacities for spoken language, which emerged through biological evolution along the lineage that led to humans , 38. As ene flow . We obseP < 1.02 × 10−4), three annotations showed significant heritability enrichment: histone-3 lysine-4 monomethylation (H3K4me1) in two fetal brain samples and the adult brain germinal matrix . H3K4me1 is considered a marker for enhancer regions. These results indicate that SNPs associated with reading-/language-related traits are overrepresented in fetal brain enhancers.We next investigated whether regions of the genome with tissue-specific functions are involved in reading-/language-related traits, again using LDSC heritability partitioning. We used annotations reflecting chromatin signatures from a broad range of tissues, as most variants identified in GWAS are located outside coding regions and are often found enriched in tissue-specific functional regions of the genome, such as promoters, enhancers, and regions with open chromatin. After correction for testing of 489 annotations (P < 6.02 × 10−4), no relation was found with tissue-specific gene expression patterns of adult tissues from the Genotype-Tissue Expression (GTEx) project and brain tissues of a specific  time from Brainspan . In the cell type–specific gene expression analysis, three single-cell RNA-sequencing datasets of embryonic, fetal, and adult brain tissue were used. After correction for 142 cell types (P < 3.52 × 10−4), the multivariate GWAS results were significantly associated with one of the mature neurons from the fetal dataset: red nucleus neurons  . This observation could reflect an association with this specific nucleus or with the higher maturity of the neurons compared with the other cell types in the fetal dataset. The red nucleus is a large structure in the ventral midbrain that is part of the olivocerebellar and cerebello–thalamo–cortical systems. It plays roles in locomotion and nonmotor behavior in various animals, and in humans, it might also play a role in higher cortical functions  (45P = 1.10 × 10−8), highlighting DOCK7, ATG4C, ANGPTL3, and USP1 as potential candidates for involvement in this trait. Other SNPs from the locus have been associated with triglyceride and cholesterol levels  in sample sizes  that are substantially larger than previous genetic analyses of reading and/or language skills assessed with neuropsychological tools  –7, 45–47l levels  but may l levels , 50; psyl levels ; and bral levels  and cortl levels . They arl levels  and alcol levels . So, desOur work shows overlapping contributions of common genetic variants to individual differences in reading-/language-related and cognitive traits. Such overlaps are evident both from genetic correlation analyses and from the three-factor structural equation model, in which one factor explains most of the variation in word reading, nonword reading, spelling, and phoneme awareness. This is in line with the widespread pleiotropy found between many aspects of cognitive functioning, including language, reading, mathematics, and general cognitive ability , 55. We Further evidence of differences in trait etiology between the five reading-/language-related traits was observed in our genetic correlation analysis with GWAS results of components  from school grades in the Danish iPSYCH cohort  and withHuman abilities to process spoken and written language depend on an array of distributed brain circuits , 64–66. 6433H. sapiens, which took place through admixture events around 50,000 to 60,000 y ago , only  1 error . Regardi 1 error . OverallReading- and language-related phenotypes pose special challenges for scaling up genetic analysis since psychometric assessments can be labor intensive to administer and score and because of the heterogeneity introduced by differences in assessment tools, ages, populations, and languages, among other factors , 76. OneThis first wave of analysis from GenLang represents the largest GWAS meta-analyses for direct quantitative assessments of reading- and language-related abilities to date, including 22 cohorts with data available for at least one of the phenotypes. Nonetheless, although substantially increased over prior work in this area, sample sizes may still be considered relatively modest compared with the state of the art for genetic association analyses of other complex traits. While they captured a significant proportion of the genetic variation underlying each phenotype, yielding several insights into the associated biology, detection of individual genome-wide significant loci was still limited. In addition, when sufficiently large datasets become available, it would be valuable to validate the genetic correlation and heritability partitioning results in additional independent datasets. A number of phenotypes of interest, including those that tap into syntactic skills or that involve different modalities such as sign languages, could not (yet) be pursued due to inadequate sample sizes, even when combining data available from multiple cohorts. We note that despite our best efforts at harmonizing the included datasets and limited evidence of heterogeneity in the results based on Cochran Q statistics, LDSC intercepts, and genetic correlations between subsets of the data, we cannot fully exclude that heterogeneity is introduced by the inclusion of data from different assessment tools, languages, and ages. The choice of assessment tools for future collection of reading- and language-related phenotypes for genomic studies, to increase the sample sizes of these GWAS meta-analyses and also, to collect additional language-related phenotypes, should, therefore, be based at least partially on optimal matching with existing data. At the same time, we should invest in facilitating and simplifying the collection of language-related phenotypes, in part by developing and optimizing test batteries that could be reliably administered online in web/app-based settings. These are major areas of focus for the GenLang Consortium moving forward.H. sapiens may have been intolerant to gene flow from other archaic hominins. These efforts by GenLang open up avenues for deciphering the biological underpinnings of spoken and written language.In summary, our GWAS meta-analyses of five reading- and language-related phenotypes in sample sizes of up to ∼34,000 participants demonstrated significant SNP heritability for all traits and identified genome-wide significant associations with word reading on chromosome 1. Structural equation models revealed a single factor accounting for much of the genetic architecture underlying word reading, nonword reading, spelling, and phoneme awareness, prompting a multivariate GWAS analysis. The multivariate results were genetically correlated with cortical surface area of the banks of the left STS, a brain region where the processing of spoken and written language comes together. Partitioned heritability analyses showed enrichments in fetal brain enhancers, highlighting links to early brain development, and in archaic deserts depleted of Neanderthal ancestry, suggesting that genomic regions associated with emerging language-related skills in SI Appendix, Extended Methods.A more detailed version of the methods is provided in Dataset S1). Different measures for the reading- and language-related traits had been assessed in each cohort and could be included in the GWAS meta-analyses . Data from children, adolescents, and young adults aged 5 to 26 y were included. The phenotype data were standardized and then, adjusted for covariates ; the genotype data were subjected to stringent quality control according to a detailed analysis plan following standard procedures for GWAS and then imputed using the Haplotype Reference Consortium version 1.1 panel or the 1000 Genomes Project Phase 3 reference panel (Dataset S2). Univariate GWAS analyses were performed using linear regression methods with the imputed additive genotype dosages for the full dataset and for males and females separately.The meta-analyses included GWAS summary statistics from 22 independent cohorts .The summary statistics for each GWAS cohort for each trait were subjected to stringent quality control measures . Meta-analyses of the univariate GWAS results were performed with METAL (version March 2011), with effect size estimates weighted using the inverse of the corresponding SEs. For the follow-up analyses with LDSC, separate meta-analyses without genomic control correction  were perTo investigate the high genetic correlations between the summary statistics of the five reading- and language-related traits and with cognitive performance  and educA multivariate GWAS was performed on the univariate GWAS summary statistics of the four traits with the highest genetic correlations  using MTAG (v1.0.8) .LDSC  (v1.0.0)The FUMA platform (version 1.3.6a)  was usedP values and for gene-property analyses, to study relationships with tissue-specific and cell type–specific gene expression patterns. Several bulk RNA-sequencing and single-cell RNA-sequencing datasets of brain samples were assessed through FUMA (MAGMA  (versionugh FUMA .LDSC heritability partitioning  was usedSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary FileSupplementary File


This cross-sectional study assesses whether the Medicaid expansion implemented as part of the Patient Protection and Affordable Care Act was associated with changes in Medicare-financed hospitalizations for adults with incident kidney failure. Was Medicaid expansion under the Patient Protection and Affordable Care Act (ACA) associated with lower rates of Medicare-financed hospitalizations among adults with incident kidney failure?In this cross-sectional study of 188 671 US adults aged 19 to 64 years with kidney failure initiating dialysis, the ACA Medicaid expansion was associated with a reduction in the number of Medicare-financed hospitalizations in the first 3 months after dialysis initiation.Findings of this study suggest that decreases in Medicare-financed hospitalizations may indicate favorable spillover outcomes from the ACA’s Medicaid expansion to Medicare through reduced spending on hospitalizations among a clinically complex patient population. Although Medicare provides health insurance coverage for most patients with kidney failure in the US, Medicare beneficiaries who initiate dialysis without supplemental coverage are exposed to substantial out-of-pocket costs. The availability of expanded Medicaid coverage under the Patient Protection and Affordable Care Act (ACA) for adults with kidney failure may improve access to care and reduce Medicare-financed hospitalizations after dialysis initiation.To examine the implications of the ACA’s Medicaid expansion for Medicare-financed hospitalizations, health insurance coverage, and predialysis nephrology care among Medicare-covered adults aged 19 to 64 years with incident kidney failure in the first year after initiating dialysis.This cross-sectional study used a difference-in-differences approach to assess Medicare-financed hospitalizations among adults aged 19 to 64 years who initiated dialysis between January 1, 2010, and December 31, 2018, while covered by Medicare Part A (up to 5 years postexpansion). Data on patients were obtained from the Renal Management Information System’s End Stage Renal Disease Medical Evidence Report, which includes data for all patients initiating outpatient maintenance dialysis regardless of health insurance coverage, treatment modality, or citizenship status, and these data were linked with claims data from the Medicare Provider Analysis and Review. Data were analyzed from January to August 2022.Living in a Medicaid expansion state.Primary outcomes were number of Medicare-financed hospitalizations and hospital days in the first 3 months, 6 months, and 12 months after dialysis initiation. Secondary outcomes included dual Medicare and Medicaid coverage at 91 days after dialysis initiation and the presence of an arteriovenous fistula or graft at dialysis initiation for patients undergoing hemodialysis.P = .001) and hospital days , relative reductions of 8% for both outcomes. Medicaid expansion was associated with a 2.58–percentage point  increase in dual Medicare and Medicaid coverage at 91 days after dialysis initiation and a 1.65–percentage point  increase in arteriovenous fistula or graft at initiation.The study population included 188 671 adults, with 97 071 living in Medicaid expansion states  and 91 600 living in nonexpansion states . In the first 3 months after dialysis initiation, Medicaid expansion was associated with a significant decrease in Medicare-financed hospitalizations (−4.24  admissions per 100 patient-years; In this cross-sectional study with a difference-in-differences analysis, the ACA’s Medicaid expansion was associated with decreases in Medicare-financed hospitalizations and hospital days and increases in dual Medicare and Medicaid coverage. These findings suggest favorable spillover outcomes of Medicaid expansion to Medicare-financed care, which is the primary payer for patients with kidney failure. Medicare also provides health insurance coverage for most patients with kidney failure, and coverage begins at 91 days after initiating in-center hemodialysis or at the time of enrolling in training for home-based dialysis. In 2017, Medicare fee-for-service spending for all beneficiaries with kidney failure was approximately $36 billion .15 Medicaid expansion may facilitate access to predialysis nephrology care for adult patients initiating dialysis,8 thereby preventing complications and reducing the number of Medicare-financed hospitalizations and hospital days immediately after dialysis initiation. These implications may be evident among adults with low household incomes eligible for Medicaid after the ACA and for those who were previously eligible for Medicaid but enrolled in the program after the ACA expansions, a phenomenon sometimes referred to as the woodwork or welcome mat effect. The aim of the study was to examine the implications of Medicaid expansion for Medicare-financed hospitalizations, health insurance coverage, and receipt of predialysis nephrology care among Medicare-covered adults aged 19 to 64 years with incident kidney failure.In addition to providing assistance with Medicare premiums and cost sharing,17 Each state’s postexpansion period was defined by its own implementation date, which was January 1, 2014, for most states. The Brown University Institutional Review Board and the Centers for Medicare & Medicaid Services (CMS) Privacy Board approved the study protocol and waived the requirement for informed consent because only deidentified data were used. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.In this cross-sectional study, we used a difference-in-differences approach to compare changes in the number of Medicare-financed hospitalizations, health insurance coverage, and receipt of predialysis nephrology care over time in Medicaid expansion vs nonexpansion states. The study population included persons aged 19 to 64 years with kidney failure who initiated dialysis between January 1, 2010, and December 31, 2018, while covered by Medicare Part A. The study period included 4 years during which patients initiated treatment before Medicaid expansion (2010-2013) and 5 years after expansion (2014-2018). Consistent with previous work, we considered expansion states as those that implemented the ACA’s Medicaid expansion from 2014 and afterward and excluded 5 states that extended Medicaid eligibility to adults with low household incomes between 2010 and 2013 .19 Hospitalizations were assessed by linking the CMS 2728 data to the Medicare Provider Analysis and Review, which includes information about all Medicare-financed hospitalizations, including primary diagnoses and number of hospital days. Data sets were linked using patients’ Medicare beneficiary identifiers. We included patients with both traditional Medicare and Medicare Advantage because the Medicare Provider Analysis and Review includes more than 90% of hospitalizations for enrollees in Medicare Advantage.21 The 2009 to 2013 American Community Survey data provided the poverty rate in each patient’s US Census tract.We used data from the Renal Management Information System’s End Stage Renal Disease Medical Evidence Report (CMS 2728), which is completed for all people initiating outpatient maintenance dialysis regardless of health insurance coverage, treatment modality, or citizenship status.22 We attributed hospitalizations to the quarter of the patient’s date of dialysis initiation.The primary outcomes were the number of Medicare-financed acute care hospitalizations and number of acute care hospital days in the first 3 months, 6 months, and 12 months after initiation of dialysis. Secondary outcomes were dual Medicare and Medicaid coverage at 91 days after dialysis initiation, receipt of predialysis nephrology care, presence of arteriovenous fistula (AVF) or graft at dialysis initiation for patients undergoing hemodialysis, receipt of home dialysis, and dialysis type at initiation . We also assessed hospitalizations due to cardiovascular disease or infectious conditions using the US Renal Data System’s approach to classify these conditions.11 The CMS 2728 specifies that a patient’s race and ethnicity should be collected using patient self-report at treatment initiation and was classified as Hispanic or Latino, non-Hispanic African American or Black, non-Hispanic Asian, non-Hispanic White, or non-Hispanic other race . Consistent with previous work, for observations missing serum albumin and hemoglobin levels, we used the mean value of the covariates for nonmissing observations.11 All models included state and year-quarter fixed effects. Analyses were conducted in Stata, version 17 (StataCorp LLC) and used 2-tailed hypothesis testing with a significance threshold of P < .05.Data were analyzed from January to August 2022. We used a linear regression model with Huber-White robust SEs clustered at the state level. Covariates included age, sex, race and ethnicity, primary cause of kidney failure, presence of congestive heart failure, atherosclerotic heart disease, other cardiac disease, hypertension, diabetes, diabetic retinopathy, cancer, obesity , smoking status, alcohol dependence, and hemoglobin and serum albumin levels at dialysis initiation.We compared characteristics of persons with kidney failure aged 19 to 64 years who had Medicare Part A at treatment initiation vs those who did not during the study period to assess the generalizability of our findings. To assess the validity of the difference-in-differences study design and to test the robustness of the findings, we conducted several sensitivity analyses (eAppendix in the Supplement). First, we visually inspected preexpansion trends. Using quarterly data before 2014, we then tested the statistical significance of an expansion-by-time trend and separately used a categorical time specification. Second, we reran the analyses to include states that expanded Medicaid before January 1, 2014, or late-expanding states , and 91 600 resided in nonexpansion states  . The mosP = .001) and acute care hospital days , with relative reductions of 8% (P = .01) in the first 6 months after initiation of dialysis  in dual Medicare and Medicaid coverage at 91 days after dialysis initiation (a 6% relative increase) (P = .02) in the presence of an AVF or graft at dialysis initiation for patients undergoing hemodialysis (a 7% relative increase)  A. Althouncrease) , Medicaincrease) B.P = .04) (P < .001), 6 months , and 12 months  after dialysis initiation (P = .001) and 6 months  after dialysis initiation.Medicaid expansion was associated with a significant reduction in the number of hospital days for cardiac conditions in the 3 months after dialysis initiation  . Medicaiitiation . MedicaiP < .001) (eTables 7-15 in the P = .04)  aged 19 to 64 years with kidney failure who initiated dialysis had Medicare Part A coverage , but it is unlikely that these rules would differentially affect states by expansion status. Fifth, although the difference-in-differences approach and inclusion of state fixed effects account for secular trends and potential state-specific policy contexts, it is plausible that changes or differences in outcomes for patients who initiated treatment for kidney failure were not associated with a state’s decision to expand Medicaid. Sixth, for the outcome examining changes in dialysis type at initiation, it is possible that individuals switched their dialysis type  after initiation. Seventh, we were unable to assess differences in hospitalization-related out-of-pocket costs because the data set did not include information such as having supplemental coverage or hospital networks (for Medicare Advantage beneficiaries). However, additional work to understand the potential changes in out-of-pocket costs associated with Medicaid expansion among Medicare beneficiaries with kidney failure is warranted.In this cross-sectional study, Medicaid expansion was associated with decreases in Medicare-financed hospitalizations and fewer acute care hospital days in the first year after initiating dialysis, which is a high-risk period, as well as increases in dual Medicare and Medicaid coverage. This study suggests that there may have been favorable spillover outcomes of Medicaid expansion to Medicare-financed care, which is the primary payer for patients with kidney failure.


Antenatal Doppler disturbances are associated with fetal hypoxia and may induce a brain-sparing vascular redistribution at the expense of splanchnic circulation, possibly predisposing to gut complications. We aimed to compare several gastrointestinal outcomes among very-low-birthweight (VLBW) preterm infants with different antenatal Doppler features. VLBW infants born between 2010–2022 were retrospectively included and stratified into the following clusters based on antenatal Doppler characteristics: normal Doppler (controls); absent or reversed end-diastolic flow in the umbilical artery (UA-AREDF) alone or also in the ductus venosus (UA+DV-AREDF); and abnormal Doppler with or without brain-sparing redistribution. The following outcomes were evaluated: time to reach full enteral feeds (FEF), feeding intolerance (FI), necrotizing enterocolitis (NEC), and spontaneous intestinal perforation (SIP). Overall, 570 infants were included. Infants born following UA+DV-AREDF had significantly higher FI, NEC, and SIP rates and achieved FEF later compared to controls. Increased FI prevalence and a longer time to FEF compared to controls were also observed among UA-AREDF infants and in the presence of brain-sparing redistribution, which also increased NEC rates. Antenatal Doppler abnormalities exacerbate the gastrointestinal risks of preterm infants. Detailed knowledge of Doppler features can aid in identifying those at highest risk of intestinal complications who may benefit from tailored enteral feeding management. Placental vascular dysfunction results from an abnormal trophoblast invasion of spiral arteries, which leads to an increased resistance of the placental vessels and a reduced uteroplacental blood flow . This coDoppler ultrasonography of the umbilical artery (UA), middle cerebral artery (MCA), and ductus venosus (DV) is the gold-standard procedure to assess the extent of placental vascular insufficiency and the resulting impairment of fetal circulation ,6,7,8.The early Doppler sign of a pathological increase of placental vascular resistance is a decrease in the blood flow in the UA, which can progress to absent or reversed end-diastolic flow (UA-AREDF) ,9. This,Fetal splanchnic hypoperfusion first results from the chronic hypoxia associated with placental insufficiency and is further worsened by the compensatory hemodynamic changes associated with the brain-sparing phenomenon. This may contribute to increasing the risk of ischemic gut complications in such a vulnerable population as preterm neonates, who are intrinsically prone to developing adverse gastrointestinal (GI) outcomes due to their functional and anatomic gut immaturity . CurrentThis study aims to fill these gaps by comparing GI and nutritional outcomes in very-low-birth-weight (VLBW) preterm infants with different features of antenatal Doppler impairment and evaluating the impact of the severity of Doppler abnormalities and the vascular remodeling associated with brain sparing.This retrospective observational study included infants admitted to the Neonatal Intensive Care Unit (NICU) of IRCCS AOU Bologna , between January 2010 and March 2022, according to the following criteria: gestational age <32 weeks and/or a birth weight <1500 g, availability of antenatal Doppler data. Infants with major congenital abnormalities deceased within the first week of life or transferred to other hospitals before achieving any of the study outcomes were excluded.This study was conducted in conformity with the principles and regulations of the Helsinki Declaration. The protocol was approved by the Ethics Committee “Area Vasta Emilia Centro—AVEC”, Bologna, Italy (protocol no. 221/2022/Oss/AOUBo).Based on the available data on the features of antenatal Doppler, the study population was stratified into two grouping systems according to the following classifications based on the vessels involved by the Doppler disturbances or on the presence/absence of brain-sparing: (1) normal antenatal Doppler, abnormal UA Doppler (UA-AREDF), abnormal DV Doppler (UA+DV-AREDF); 2) normal antenatal Doppler, impaired antenatal Doppler with brain-sparing, impaired antenatal Doppler without brain-sparing [ normal aThe following outcomes were compared between the study groups: time to reach full enteral feeds  ; duratioSince, during the study period, a human milk bank was established in our local hospital, the feeding type administered to the study infants during their hospital stay (exclusive human feeding vs. any formula feeding) was noted and included in the multivariable analysis. Apgar scores at 5′ and the need for invasive respiratory support during the hospital stay were also collected.Based on the prevalence of NEC (any stage) observed at IRCCS AOU Bologna over the last 5 years, a minimum sample size of 241 was estimated using G*Power software v. 3.1.9.6, with power = 0.80, α = 0.05 and effect size w = 0.2.Data distribution was analyzed using a Shapiro–Wilk test. Numerical variables were summarized as mean ± standard deviation or median (interquartile range), as appropriate; categorical variables were summarized as frequencies and percentages. Since the data did not follow a normal distribution, non-parametric methods were used for statistical analysis. The comparison of the study outcomes between the different Doppler groups  was performed using a chi-square or Fisher’s exact test for categorical variables and a Kruskal–Wallis test with Bonferroni post-hoc correction for continuous variables.p value < 0.05 was considered statistically significant.The study outcomes that differed significantly among the Doppler groups at the univariate analysis were used to build different generalized linear models (GLMs) in which the type of Doppler alteration was included as a factor and potential confounders, including the neonatal variables that differed among groups, as covariates. The variance inflation factor (VIF) was used to assess multicollinearity between the model terms; a VIF < 5 indicates a low correlation of that predictor with other predictors, a value between 5 and 10 indicates a moderate correlation, while VIF values > 10 are a sign for high, non-tolerable correlation of model predictors. A p < 0.05.Statistical analysis was performed using Statistical Package for Social Science (SPSS) software, version 27 . The significance level was set at As shown in the enrolment flow-chart , 570 infn = 446, 78.2% of the whole study cohort) served as controls.Antenatal Doppler abnormalities were observed in 124 out of 570 infants (21.8%). Of these, 97 (78.2%) had evidence of UA-AREDF and 27 (21.8%) of UA+DV-AREDF. Brain sparing remodeling occurred in 54 (43.5%) of the 124 neonates with evidence of abnormal antenatal Doppler and, in particular, in 21 out of 27 (77.8%) infants with UA+DV-AREDF and in 33 out of 97 (34.0%) infants with UA-AREDF. Infants with normal antenatal Doppler (p = 0.007 at post-hoc comparison) and controls (post-hoc p = 0.004), while no difference was observed between the latter groups. Compared to the control group, BW and the related z-score were significantly lower in infants with UA-AREDF and UA+DV-AREDF . In the latter group, BW was also significantly lower than in the UA-AREDF group (post-hoc p = 0.045). The prevalence of a BW < 10th centile, which defines small gestational age (SGA) neonates, differed significantly between the study groups, being 53.6% in the UA-AREDF group, 51.9% in the UA+DV-AREDF group, and 13% among controls.Clinical characteristics of infants born following UA-AREDF or UA+DV-AREDF and controls are detailed in p = 0.002), being highest in the UA-AREDF (86.5%) and lowest in the UA+DV-AREDF group (63%). Notably, all the infants with evidence of antenatal Doppler alterations were born by cesarean section.The prevalence of maternal hypertension was significantly higher in the UA-AREDF and UA+DV-AREDF groups compared to controls . The percentage of infants in the UA-AREDF group who received a complete course of antenatal steroids significantly differed between the study groups (p = 0.037 at post-hoc comparison), requiring PN for longer periods (post-hoc p = 0.010), while no significant difference was observed either between UA+DV-AREDF and UA-AREDF or between the latter infants and controls. Furthermore, infants with UA+DV-AREDF had a longer hospitalization than UA-AREDF infants (post-hoc p = 0.049) and controls (post-hoc p = 0.003).In order to adjust the observed results for possible confounders and assess the independent effect of the UA and DV Doppler alterations on FI, NEC development, and time to FEF, specific multivariable GLM models were built see . Since np < 0.001) and UA-AREDF  compared to controls. An association between increasing time to FEF, decreasing GA , and the need for invasive respiratory support  were also observed, while no significant effects were observed for complete antenatal steroids administration, formula feeds during hospital stay, and year of birth.Time to FEF was significantly higher in the presence of UA+DV-AREDF  and, to a lesser extent, UA-AREDF  compared to controls. A lower GA  and formula feeding  were also independently associated with higher FI rates, while the remaining covariates showed no significant effects.FI significantly increased in the presence of antenatal UA+DV-AREDF  but not by UA-AREDF. Formula feeding  and the need for invasive respiratory support  were also significantly associated with NEC development. No association was observed for the remaining covariates.NEC prevalence (at any stage) was significantly increased by antenatal UA+DV-AREDF . Compared to controls, AREDF infants with and without brain sparing had a significantly lower BW and BW z-score . The SGA prevalence was similar in AREDF infants with and without brain sparing , but significantly higher than in the control group (13%). Similar findings were observed for the prevalence of maternal hypertension, which was significantly higher in AREDF infants with and without brain sparing compared to controls , and for the antenatal administration of a complete steroid course .Clinical characteristics of the study groups are provided in p = 0.020 at post-hoc comparison), while no significant difference was observed for the remaining outcomes.In order to adjust the observed results for possible confounders and assess the independent effect of brain sparing on FI and NEC development, we built specific multivariable GLM models, shown in p < 0.001) and without brain sparing . Decreasing GA  and formula feeding  posed an additional, independent risk for this condition, while no effect was observed for the year of birth and antenatal steroid administration.Compared to controls, FI prevalence was significantly increased in both AREDF infants with , in formula-fed infants , and among those who required invasive respiratory support , while the remaining covariates showed no effect.The risk of NEC (at any stage) was significantly increased in the presence of antenatal brain sparing ; nonetheless, the morbidity and mortality rates, along with the financial healthcare costs associated with this condition, are still remarkably high . In our An increased risk of NEC in UA-AREDF infants has been previously reported in a meta-analysis of 14 observational studies, which described a 2-fold increase of NEC risk in AREDF infants compared to controls with normal Doppler , and in Baschat et al. evaluated the prevalence of several neonatal outcomes, including NEC, among infants with UA-AREDF, UA-AREDF and brain sparing, and altered venous Doppler, which included both DV-AREDF and altered umbilical vein flowmetry and reflected an advanced deterioration of fetal haemodynamics with altered cardiac function, observing increased NEC rates in this latter group . ConversIn the present study, antenatal Doppler impairment with evidence of brain sparing was associated with a 2.5-fold increase in NEC risk compared to normal antenatal Doppler. Increased rates of composite adverse neonatal outcomes, including NEC, in IUGR infants with antenatal signs of vascular redistribution were also reported by the PORTO trials ,28; howeSIP shows different clinical and diagnostic features from NEC, as it generally occurs earlier and is characterized by focal necrotic areas, more often localized in the terminal ileum, while the remaining bowel appears grossly normal . In our In line with previous evidence ,33,34, wAccording to the results of the multivariable GLMs, a lower GA and formula feeding are independent risk factors for adverse GI outcomes. The anatomical and functional immaturity of the bowel tract affect gut motility, alter the barrier function of the intestinal mucosa, and hinder the adequacy of digestive and absorptive processes , thus inIn our cohort, infants with antenatal Doppler abnormalities received a complete course of antenatal steroids more frequently than controls, consistent with the closer surveillance of these pregnancies . The effA strict monitoring of Doppler flowmetry may help to determine the optimal timing of delivery in high-risk pregnancies ,46. The In the present cohort, the number of infants with major GI complications such as NEC stage ≥ 2a and SIP was small and thus represents a potential study limitation. In order to determine the number of these infants, we analyzed data from a 12-year period. The retrospective nature of this study and the advances that occurred in obstetrics and neonatal practice during this study period may have influenced the observed results; to address this potential bias, the year of birth was included in the GLMs, ruling out a possible effect of this variable on the study outcomes. Moreover, the Apgar score at 5 minutes and the need for invasive ventilation were also included in the multivariable analysis, as they may act as potential indicators of clinical severity.The relatively small number of infants with AREDF, especially with altered DV velocimetry, also needs to be acknowledged among the study limitations, as it did not allow to include both UA/DV Doppler status and brain sparing in a unique and adequately powered multivariable analysis. Moreover, despite the efforts made to adjust the observed results for possible confounding or influencing factors, hidden confounders or biases are still possible. A targeted multicenter trial, based on a larger cohort, may allow to validate the present results and to merge the two grouping systems into a unique classification based on four groups .To the best of our knowledge, this is the first study investigating the impact of specific antenatal Doppler abnormalities on multiple GI outcomes. Indeed, most of the available literature on this topic either uses SGA as a proxy for antenatal AREDF or assesses composite outcomes mixing GI conditions such as NEC with neonatal complications related to different organs or systems. Although the term SGA is often used as a synonym for IUGR, it includes both constitutively small infants and those who have not reached their genetically determined growth potential due to an impairment of placental vascularization. The present results, based on an accurate evaluation of antenatal Doppler data, demonstrate how a considerable proportion of AREDF infants had a BW > 10° percentile, thus being excluded by the SGA definition, while nearly 1 out of 6 infants with normal antenatal Doppler were SGA. Hence, the use of the SGA definition in place of an accurate assessment of antenatal Doppler features may under-represent the AREDF population, thus possibly affecting the accuracy of the performed assessments and contributing to the heterogenicity of the currently available literature.Placental vascular dysfunction significantly influences postnatal GI outcomes in preterm infants. A growing severity of the fetal haemodynamic compromise associated with this condition leads to a greater risk of adverse GI sequelae, adding to the noxious effects of intestinal immaturity associated with preterm birth. Hence, a careful assessment of antenatal Doppler features is of particular importance to estimate the individual intestinal risk of preterm neonates and to identify those at highest risk who would benefit from tailored management of enteral feeding, including the use of exclusive breast milk and strict monitoring of their feeding tolerance, to reduce the clinical and healthcare burden of GI complications.


COVID-19 messenger RNA (mRNA) vaccines have demonstrated efficacy and effectiveness in preventing symptomatic COVID-19, while being relatively safe in trial studies. However, vaccine breakthrough infections have been reported.This study aims to identify risk factors associated with COVID-19 breakthrough infections among fully mRNA-vaccinated individuals.We conducted a series of observational retrospective analyses using the electronic health records (EHRs) of the Columbia University Irving Medical Center/New York Presbyterian (CUIMC/NYP) up to September 21, 2021. New York City (NYC) adult residences with at least 1 polymerase chain reaction (PCR) record were included in this analysis. Poisson regression was performed to assess the association between the breakthrough infection rate in vaccinated individuals and multiple risk factors—including vaccine brand, demographics, and underlying conditions—while adjusting for calendar month, prior number of visits, and observational days in the EHR.The overall estimated breakthrough infection rate was 0.16 (95% CI 0.14-0.18). Individuals who were vaccinated with Pfizer/BNT162b2  were male  and had compromised immune systems  were at the highest risk for breakthrough infections. Among all underlying conditions, those with primary immunodeficiency, a history of organ transplant, an active tumor, use of immunosuppressant medications, or Alzheimer disease were at the highest risk.Although we found both mRNA vaccines were effective, Moderna/mRNA-1273 had a lower incidence rate of breakthrough infections. Immunocompromised and male individuals were among the highest risk groups experiencing breakthrough infections. Given the rapidly changing nature of the SARS-CoV-2 pandemic, continued monitoring and a generalizable analysis pipeline are warranted to inform quick updates on vaccine effectiveness in real time. The ongoing global COVID-19 pandemic has infected hundreds of millions of people worldwide, imposing a tremendous burden on the global health care system. COVID-19 vaccines are currently the best defense against the rapidly evolving SARS-CoV-2, having demonstrated efficacy in preventing symptomatic COVID-19, while being relatively safe in trial studies . In addiThe Centers for Disease Control and Prevention (CDC) has reported vaccine breakthrough infections, defined as a fully vaccinated person getting infected with COVID-19 . SARS-CoThe study adhered to the principles set out in the Declaration of Helsinki, with informed consent obtained from all participants. The Columbia University Health Sciences Institutional Review Board (IRB) reviewed and approved the study (IRB AAAR3954). The analysis in this study was conducted on the deidentified data.-December 2021) variant waves but did not include data from the B.1.1.529  wave [We used EHR data obtained from the NYP/CUIMC data warehouse. The NYP/CUIMC is a quaternary care academic medical center that includes an academic hospital, a children’s hospital, and a community-based hospital serving a diverse patient population in northern Manhattan, New York City (NYC). EHR data were collected and stored in the data warehouse during routine clinical care at the CUIMC/NYP. The EHR data were converted to the Observational Medical Outcomes Partnership (OMOP) common data model (CDM) version 5.0 . All datnt) wave . Due to nt) wave , we onlyIndividuals over the age of 18 years who resided in NYC were included in this study. OMOP concepts related to vaccines were used to identify vaccinated individuals who received 2 doses of Pfizer/BNT162b2 or Moderna/mRNA-1273. To minimize potential bias resulting from missing vaccination records, vaccines records in our data warehouse were obtained from both CUIMC EHR data and the NYC vaccine registry. We required individuals to complete their 2-dose administration with a time interval of 20-23 days for Pfizer/BNT162b2 and 27-31 days for Moderna/mRNA-1273; individuals with 2 doses with 14 days of available follow-up after their second dose were considered fully vaccinated. Individuals who received doses from more than 1 manufacturer or only received 1 vaccine dose were excluded. We defined COVID-19-positive cases by using the OMOP measurement concepts and corresponding value concepts related to detect positive RNA using polymerase chain reaction (PCR). Individuals with at least 1 positive SARS-CoV-2 PCR test were flagged as COVID-19 positive. To balance the cofounding between positive cases and negative cases, we adopted a test-negative design—only individuals with at least 1 negative PCR test were included as COVID-19-negative cases. To reduce the potential false positives in the negative cohort, we additionally established stringent criteria to further exclude individuals with any evidence of a prior SARS-CoV-2 infection: (1) a positive SARS-CoV-2 PCR test, (2) a positive SARS-CoV-2 antibody test, or (3) a concept indicating SARS-CoV-2 infection. The details of OMOP concepts used for the cohort definition are available in Based on the vaccine and SARS-CoV-2 status, we then constructed 6 cohorts based on evidence of COVID-19 breakthrough infection  and vaccination status , as shown in condition_era and drug_era tables. To avoid extracting condition/drug concepts potentially caused by the SARS-CoV-2 infection itself, we added a 90-day washout period . To identify individuals who might have compromised immune systems, we compiled a list of conditions and drugs, including active solid tumors and hematologic malignancies (within 2 years), solid-organ or hematopoietic stem cell transplant, primary immunodeficiencies, HIV infection, immunosuppressive therapies , and CKD [For each cohort, we extracted individuals' demographic data, including age, gender, ethnicity, and race. For the vaccinated cohorts, the vaccine brand and corresponding administration dates were also extracted. To approximate the available observation time, we extracted the total number of prior EHR visits and days of observation periods between clinical encounters for each individual. We extracted all previous condition and drug concepts from the  and CKD ; see Mul and CKD .P value [We compared the Vax-positive and Vax-negative cohorts to identify potential risk factors associated with breakthrough infections . The entP value .For the Vax cohorts, the entry date was defined similarly to the entry date for the risk factor analysis. For the Unvax cohorts, the entry date was defined as January 18, 2021 , and individuals were then followed up until the first positive PCR test  or the date when they received their first dose, whichever came first . We 1:1-As shown in The overall estimated breakthrough infection rate was 0.16 (95% CI 0.14-0.18). For the underlying conditions and drug usage analysis, a total of 1359 and 536 unique candidate conditions and drugs were available for investigation, respectively. Concepts needed a minimum of 100 individuals to be considered. We analyzed the protective effect of vaccination in the Vax cohort using 2 matched Prevax and Unvax cohorts. When comparing the Vax cohort with the Prevax cohort, the risk of COVID-19 infection in vaccinated individuals was significantly lower , which was also the case when stratifying by age, gender, and immunocompromised status . SimilarBy comparing the breakthrough cohort  against the no-breakthrough cohort , we found a number of medical commodities were associated with an increased risk of breakthrough infection. First, we found that immunosuppressive therapy is associated with higher rates of breakthrough infection. Individuals with active tumors also had higher rates of breakthrough infection, suggesting that the effects of active malignancy or chemotherapy lead to a reduced immune response. There was a statistically not significant increase in individuals with a history of tumors, suggesting that individuals whose cancers are in remission are more similar to the average population in terms of immune response. Our findings are in line with prior studies of solid organ transplant recipients who have shown weaker immune responses in patients who are immunosuppressed and undergo vaccination against COVID-19 ,45. For Although our findings reaffirmed the high protection of mRNA vaccines against COVID-19 infection, we found that Moderna/mRNA-1273 had an overall higher effectiveness in preventing SARS-CoV-2 infections. A previous high-quality prospective study  involvinIt is important to provide constant public health surveillance of vaccine protection. By leveraging EHR data from various health systems, we can provide more robust and generalizable evidence of vaccine effectiveness. Unfortunately, it is not always easy to aggregate the medical data from multiple institutions due to Health Insurance Portability and Accountability Act of 1996 (HIPPA) constrains. Therefore, we developed an entirely CDM-based analysis pipeline, making it easily transferable to dozens of other health care databases compatible with it . We haveGiven the high level of missingness typically found in EHR data, it is challenging to estimate the absolute incidence rate of breakthrough infections. In our study, the incidence rate among the vaccinated cohort was estimated to be 0.16 per 1000 person-days. This potentially overestimates the incidence rate  and B.1.617.2 (delta) variants were prevalent. Our findings cannot be generalized to other newly emerged variants of concerns, including B.1.1.529 (omicron) for which the existing mRNA vaccines may have differing effectiveness. However, this is not unique to our study, as the pandemic has often evolved faster than high-quality analyses can be performed. Even a recent systematic review of the efficacy and effectiveness of the COVID-19 vaccines published in January 2022 included only papers before April 2021 (the data collected in those papers can be from even earlier). The conflict between the speed of scientific publication and the rapid evolution of the pandemic remains a significant challenge for the overall research community.Finally, the CUIMC/NYP is an academic medical center in NYC, which might not represent the general American population or other potential patient groups of interest. In particular, the overall population in our study is sicker than the general population, as evidenced by the high rate of comorbidities and older age of our patient cohort.We performed a retrospective analysis to investigate risk factors contributing to COVID-19 breakthrough infections among vaccinated individuals. We found those who are male, immunocompromised, or have preexisting pulmonary disease are at a higher risk of COVID-19 breakthrough infection. Although both vaccines are highly effective in preventing SARS-CoV-2 infection, Moderna/mRNA-1273 is associated with a lower risk of breakthrough infection than Pfizer/BNT162b2. Multiple medical institutions’ data are warranted to better link the PCR test results and vaccination information. Those with an OMOP instance of their data can reapply our analysis to check the robustness of our results .


A significant relationship was found between parents’ resilience and both their COVID-19-related stressors and family stressors. Parents described stressors challenging their resilience, including impacts on their mental health, managing occupational and educational responsibilities, social isolation, and economic setbacks, while also noting the impacts of social isolation, missing extracurricular activities, and lacking routines for their children. Overall, Ontario parents high in resilience are likely better positioned to adapt to pandemic-related stressors.Resilience, or the ability to bounce back despite facing adversities, may influence parents’ abilities to handle the multitude of parent-specific COVID-19-related challenges that have faced them. This cross-sectional study examined (1) the relationship between parents’ resilience and their COVID-19-related family stressors; (2) parents’ perceptions of their greatest stressors throughout the pandemic; and (3) non-school-related challenges and their resultant impact on parents’ and children's resilience. Via an online survey, data was collected from 63 parents (M The World Health Organization (WHO) declared COVID-19 a pandemic on March 11th, 2020 . By Marcn = 107; 80.4% female) in Singapore, n = 1049; 89.6% female) exerted a direct and negative effect on their general perceived distress resulting from the pandemic, such that higher resilience among parents indicated lower levels of perceived distress. This relationship between resilience and perceived distress also positively impacted depression and anxiety screenings, resulting in higher resilience among parents being associated with a lower incidence of depression and anxiety  in China, Ren and colleagues (2020) found that less social support was significantly related to increased parenting stress during the pandemic. A qualitative study conducted by n = 29) described the increased stress and exhaustion resulting from navigating pandemic-related changes without their usual support networks. The financial impacts of the pandemic on families have also been emphasized by many , it is plausible that Ontario parents may have experienced different challenges to their resilience than parents in other provinces of Canada. Moreover, while some studies have explored parents’ resilience and psychological distress during the pandemic, to date, no studies have examined parents’ resilience in relation to COVID-19-specific stressors. While still valuable, these studies were not focused specifically on whether the stress experienced by parents was due to COVID-19, or a result of other contextual factors; therefore, the relationship between resilience and specific COVID-19-related stressors remains largely unexplored. Gaining insights into the experiences of parents will allow for a better understanding of the breadth and severity of pandemic-induced stressors as determined by the population members themselves. This timely study is designed to address this research gap to help understand Ontario parents’ capacity to survive and thrive throughout the pandemic, while also providing insights into the experiences of Ontario parents and children. Implications of this research could serve to benefit families of over one million elementary school-aged children who have been impacted by the COVID-19 pandemic in Ontario .The three-fold purpose of this study was to examine: (1) the relationship between Ontario parents’ resilience and their COVID-19 family stressors; (2) Ontario parents’ perceptions of the greatest stressors challenging their resilience throughout the pandemic; and (3) non-school-related challenges that have surfaced throughout the pandemic and their resultant impact on the resilience of Ontario parents and children (as perceived and reported by parents).This cross-sectional study was conducted from January 17th–February 14th, 2022. The study received ethics approval from the host institution's Non-Medical Research Ethics Board. The data that support the findings of this study are available from the corresponding author, Julia Yates, upon reasonable request.XM . The study's letter of information and eligibility criteria were outlined first, and upon providing informed and voluntary consent, the survey instructions and content appeared. To diminish social desirability bias, honesty demands (per Study participants were English-speaking Ontarians residing in the province and a parent of at least one child in an English-speaking kindergarten (Junior or Senior), Primary (grades 1–3), or Junior (grades 4–6) elementary school . Participants were recruited via online advertisements  through a total of 153 ads posted by the research team. Upon clicking the online advertisement and QR code, interested parents were directed to the study's online survey hosted on qualtricsands per  were empThe online survey consisted of a short demographic questionnaire, the previously validated 10-item Connor-Davidson Resilience Scale  “Reflecting on your experiences during the COVID-19 pandemic, what, in your role as a parent, has been the single greatest stressor that has challenged your resilience?”; (2) “Reflecting on your experiences during the COVID-19 pandemic, what would you classify as the top three most influential, non-school-related challenges that have surfaced in your child(ren)'s life that has impacted their resilience?”; and (3) “In what ways have these non-school-related challenges that your child(ren) has/have experienced impacted your own resilience?”. To conceptualize these questions, a definition of resilience was provided on the questionnaire prior to the questions: “In this study, resilience is conceptualized as a dynamic process in which psychosocial and environmental factors interact to enable an individual to survive, grow, and thrive despite exposure to adversity.”All analyses were completed in RStudio  overall COVID-19 family stressors; (2) family stress; (3) income stress; and (4) chaos stress.To identify any emergent patterns, themes, and categories within the responses to the open-ended, inductive content analysis was conducted independently by two researchers per . To helpSD = 5.64). Most parents identified as female , of European descent , and most frequently reported completing a college or university degree  or higher . Just over half of the parents were employed full-time prior to COVID-19  and at the time of completing the survey , with working conditions for most remaining the same during COVID-19 . The average annual household income was between $80,000 and $110,000 . Most commonly, parents reported having two children  and living in a two-parent household . The mean age of the participants’ children was 7.01 years (SD = 3.47). See The online survey was completed by 63 parents with a mean age of 37.09 years (SD = 6.19). The scores of individual items can be found in Based on responses from the CD-RISC-10, the mean resilience score of this sample was 27.44 (SD = 6.67). The mean scores on each domain of the CoFaSS across parents were 13.00 (SD = 3.44), 7.97 (SD = 2.94), and 8.14 (SD = 1.92) for the family, income, and chaos stress subscales, respectively. The average scores of each item can be found in The mean total score on the CoFaSS scale was 29.11 (r (61) = −0.27, p = .04; r (61) = −0.33, p = .009; Results from the Pearson product-moment correlations indicated evidence of a significant negative relationship between parents’ resilience and their overall COVID-19-related psychological stressors  mental health impacts; (2) managing occupational and educational responsibilities; (3) lack of social interactions; and (4) economic impacts. Specifically, parents stressed the challenges of the constant uncertainty surrounding the pandemic and the resulting exhaustion. Further, the feeling of being responsible for their children's well-being was mentioned by many. Regarding occupational and educational responsibilities, parents noted the struggles of educational transitions and trying to find a balance between their seemingly ever-changing responsibilities throughout the pandemic. The lack of social interactions also challenged parents’ resilience in terms of having to navigate family relationships and attempting to maintain connections for their children. Finally, economic impacts were noted by many parents who stressed the challenges of dealing with job losses and barriers to accessing financial support. Parents reported the most influential, non-school-related challenges impacting their children's resilience as a lack of connection within both peer and family relationships, the absence of extracurricular activities, and a dearth of routine. Quotes illustrating these themes can be found in When asked how the above-noted challenges have impacted parents’ own resilience, some participants noted an increase in inner strength, specifically in relation to family connection/cohesion and personal growth. Parents also mentioned feelings of burnout resulting from feeling discouraged and an overall lack of time to spend on self-care activities, as well as prolonged impacts on their well-being. Finally, parents shared the impact of having to bear the weight of their children's emotions, rending many to experience a state of constant worry for their children while striving to make up for missed opportunities. Descriptive quotations of these findings can be found in The purpose of this study was three-fold: (1) to examine the relationship between parents’ resilience and their COVID-19 family stressors; (2) to examine parents’ perceptions of the greatest stressors challenging their resilience throughout the pandemic; and (3) to assess non-school-related challenges that have surfaced throughout the pandemic and their resultant impact on the resilience of parents and children (as perceived and reported by parents).n = 353; Mage = 42.15; 64% female) in Italy by age = 9.28). The authors reported that parents’ distress due to COVID-19 was significantly and negatively associated with their resilience . The parents with high resilience scores were less likely to have scores indicating problematic levels of stress  when compared to parents scoring lower on resilience  in the context of COVID-19. Similar to the current study, these authors highlighted that family functioning is impacted by the COVID-19 pandemic. More specifically, problematic family functioning  was noted in almost 80% of families in their sample  living in Greece. Although conducted pre-pandemic, authors of this study on parental resilience and family well-being noted that those parents who reported high levels of resilience were more likely to report higher levels of family well-being compared to parents reporting low levels of resilience  compared to the median after-tax income of Ontarians in 2019, which was $66,600 . Moreoven = 11; 82% female) in the United States, participants echoed the feelings of those in the current study regarding the difficulties of managing multiple roles and shouldering prolonged concern for their children's well-being. Specifically, participants expressed the difficulties of transitioning from in-person to online school, changing routines and priorities, the constant vacillating of emotions, and a loss of connection and support due to physical and social isolation  and children  living in Ontario, with a specific focus on their physical activity and sport-related behaviors during the pandemic. Via semi-structured interviews, children noted challenges with being unable to see friends at extracurriculars as well as the closure of outdoor spaces and activity facilities , honesty demands, which help to encourage truthful responses, were employed to limit this risk per . DespiteOntario parents high in resilience may be better equipped to adapt to pandemic-related stressors, including overall psychological stressors and family-related stress. Further, based on first-hand accounts of pandemic experiences, Ontario parents and children appear to be impacted by a myriad of challenges, many of which may be hindering their resilience. These impacts of the pandemic on Ontario parents and children must be taken into account when making future public health-related decisions. It is evident that parents and children could benefit from immediate and ongoing support throughout future periods of adversity.


Despite some improvement in lowering HIV incidence, HIV-related challenges, such as intimate partner violence (IPV), remain unacceptably high among women in South Africa. For decades, researchers and activists have pointed to the complex and intertwined reality of the substance abuse, violence and AIDS (SAVA) syndemic that endangers women. However, more recent systematic review/meta-analysis evidence points to inconclusive association between IPV and alcohol use. Furthermore, much of the evidence is often non-population-based that focuses on the co-occurrence rather than synergistic SAVA interaction. In this study, using the latest data from the South Africa Demographic and Health Survey (SA-DHS), we identified geographic synergistic clustering of IPV associated with HIV and substance abuse in South Africa as a measure of population-level interactions among these factors. The SA-DHS is a nationally representative sample that includes wide-ranging data on health, social challenges and household geo-locations of 5,874 women who participated in the domestic violence module. First, geographical IPV, harmful alcohol use (as the substance abuse measure available in SA-DHS) and HIV clusters were identified using the Kulldorff spatial scan statistic in SaTScan. Second, synergistic interactions related to recent IPV  with harmful alcohol use and HIV challenge were measured using RERI [Relative excess risk due to interaction], AP [attributable proportion] and S [Synergy index]. In our results, we spatially identified geographical physical IPV syndemic interactions in parts of the Eastern Cape/Free State Provinces (RERI = 4.42 [95% CI: 2.34–6.51], AP = 0.56 [95% CI: 0.44–0.68], S = 2.77 [95% CI: 2.01–3.84], but not in other forms of IPV. Although IPV, based on decade old concept of SAVA syndemic, was less common/widespread than expected from the national scale population-based data, we identified population-level physical violence syndemic occurring in South Africa. Our study highlights the need to prioritize public health response targeting vulnerable populations residing in these high-risk areas of syndemic mechanisms linking these synergistic epidemics that women face in South Africa. South Africa, home to one of the largest HIV epidemics in the world (estimated 4.7 million women aged 15 + were living with HIV in 20195), is no exception. According to the latest UNAIDS report in 2020, HIV-related death among women aged 15 + stood at 33,000 cases in 20195, a remarkable achievement, though still unacceptably high, compared to the 120,000 cases in 20056, when the national ART programs  roll-out was gaining momentum in South Africa.The global antiretroviral therapy (ART) community scale-up witnessed over the past decade has been a ‘game changer’8, HIV incidence remains unacceptably and chronically high among women in South Africa4. One of the reasons behind this trend could be the lack of progress in addressing excessively high levels of gender-based violence (GBV). When intimate partner violence (IPV), the most common form of GBV that includes physical, sexual and emotional abuse, is viewed as one barometer of gender inequality, the magnitude of the challenge in South Africa is alarming. According to the 2018 World Health Organization estimate, as many as 24% of women in South Africa experience IPV in their lifetime9.Despite the population health benefit of ART11. Syndemic theory12 posits that vulnerable populations often suffer from the effect of synergistic clustering of 2 + population health conditions, which are fueled by macrolevel social, environmental and economic adversities. In the era of the ageing HIV epidemic where the attention to focuses on chronic health challenges (i.e. non-communicable diseases) associated with longer life expectancy with the advent of ART for individuals living with HIV13, the challenge of addressing the SAVA syndemic needs to be re-assessed. In light of recent evidence from a systematic review and meta-analysis, which points to no association between IPV and alcohol use 14, this calls into question the relevance of decades old concept in SAVA syndemics, with a clear need to reassess whether synergistic clustering of IPV associated with HIV and substance use still matters in South Africa. Furthermore, to the best of our knowledge and literature review, there is no national-level epidemiological evidence that identifies and empirically quantifies the synergistic interactions of IPV associated with HIV and substance use in South Africa at population level to date. As a developing nation in sub-Saharan Africa, South African health system is overburdened and under-resourced15, which ultimately requires allocation of limited resources to be targeted to prioritized intervention in vulnerable populations residing in high-risk areas16. Towards informing a geographic targeted intervention, we conducted this investigation to first identify geographical IPV syndemic clustering, and then empirically investigate whether HIV and substance use synergistically interact to fuel population-level IPV among women in South Africa.The dual burden of the HIV and IPV epidemics facing women is sadly nothing new. Since the beginning of the global HIV epidemic, public health experts have been warning about the dangers of the substance abuse, violence and HIV/AIDS (SAVA) syndemic, the inseparability of the HIV challenge that is concurring, intersecting and mutually reinforcing the entrenched IPV and substance abuse epidemic17, a nationally representative sample of households that provides unique national-representative insights into population-level socio-demographic profiles and health needs, as well as data on spatial information of the sampled household locations  which became publicly available in 2019. The SA-DHS employed a stratified, two-stage cluster sampling design to reach a nationally representative sample of households17. Briefly, the SA-DHS followed a sampling design with a probability proportional to the sample size of primary sampling units (PSUs) at the first stage, and systematic sampling of residential dwelling units (DUs) in each PSU at the second stage. In terms of data collection, field workers interviewed all households at the selected DUs, with women ages 18 + ever partnered being eligible for the Domestic Violence Module. With an overall response rate of 76%, data on 5,874 (weighted) ever-partnered women were available from the domestic violence module. Thereafter, socio-demographic, clinical and household data were linked to the 5,874 women, which were obtained using other questionnaires [described in the Measures section below]. The use of the data was approved by the University of KwaZulu-Natal Biomedical Research Ethics Committee (00007107).We used publicly available cross-sectional data from the South Africa Demographic and Health Survey (SA-DHS)Intimate Partner Violence (Domain #1)Recent IPV was the primary focus of our study, with the SA-DHS collecting information on whether types of IPV women had experienced within the past 12 months, based on self-report. Our work focused on three types of IPV, namely: physical, sexual, and emotional violence.Substance Abuse (Domain #2)18, substance abuse refers to the harmful/hazardous use of psychoactive substances, including alcohol. We utilized a standard measure of potential problems with alcohol abuse based on a 4-item questionnaire from the Concern/Cut-down, Anger, Guilt, and Eye-Opener (CAGE) test. Two ‘Yes’ responses in the CAGE were considered to be risk positive for harmful alcohol use19.According to the WHOHIV (Domain #3)17.The SA-DHS also collected blood samples, with HIV status being determined based on a parallel ELISA (enzyme-linked immunosorbent assay) testing algorithm. The GenScreen HIV 1/2 Combi Assay (Bio-Rad), E411 Cobas HIV 1/2 Combi Assay (Roche), and Geenius HIV1/2 Assay (Bio-Rad) were used for appropriate concordant and discordant confirmatory rapid test results. Further details of the HIV testing algorithm are described in the SA-DHS reportThree health challenges relevant for the concept of SAVA syndemic, and available from the SA-DHS, were included in our study, namely (1) IPV, (2) substance use, (3) HIV.21 implemented in SaTScan software22. The space permutation model identifies geographical clusters by imposing a circular window with varying radii continuously for each GPS coordinate of the SA-DHS households, and testing whether or not the given health challenge studied is significantly adjacent and unlikely to have arisen by chance, based on a likelihood ratio test. This step of identifying clusters was repeated for each of the abovementioned health challenges and social driver (i.e. poverty). When a geographical cluster was identified (p < 0.05), the strength of the cluster (comparing the risks of events inside/outside) was estimated using relative risk (RR). The spatial locations of the geographical cluster identified were mapped using QGIS 3.10.823. Study participants were subsequently classified as exposed to a cluster (i.e. residing in a household located within a cluster) or unexposed (i.e. residing in a household located outside the cluster) as a dichotomized measure.Geographical clusters for each of the above mentioned three health challenges were identified separately using the Kulldorff spatial scan statistic25. RERI > 0, AP > 0 and S > 1 are indications of interactions, with geographical clusters overlap of IPV, harmful alcohol use and HIV being referred to as ‘IPV syndemic’ in this investigation. Third, we undertook bivariate and multivariable logistic regression to identify significant Socio-demographic correlates of population-level IPV syndemics . The analyses were adjusted by Domestic Violence Module survey weight provided by SA-DHS, with STATA 17 being used for analysis.Three analyses were conducted in our study. First, a descriptive analysis of the participant’s socio-demographics in the Domestic Violence Module was conducted. As the norm of large population-based research, percentages were reported for categorical data. Second, in the event that geographical clusters overlapping IPV, harmful alcohol use and HIV were identified, its additive interaction, which fits the logistic regression , particularly in areas where all these health challenges collide identified in this study.Based on a nationally representative community sample in South Africa, our study empirically identified geographic synergistic clustering of physical IPV associated with HIV and alcohol use , suggesting a population-level interaction among these factors. Although more recent systematic review/meta-analysis evidence point to an inconclusive association between IPV and alcohol use29.A syndemic that methodologically requires a vast number of population-based samples, along with detailed geospatial data to construct different disease clusters, remains an under-investigated topic in resource-limited settings. To the best of our knowledge, this is the first study in SSA that attempted to identify the spatial variability of syndemic health challenges, including the population-based IPV syndemic, based on the concept of SAVA syndemics, at a national scale, thus making comparison difficult with other studies. Nonetheless, a recent large population-based South African multi-morbidity study in a high HIV prevalence rural setting (at the time of this report) identified similar findings of the convergence of an infectious and non-communicable disease epidemic setting, although no measures of substance use, including harmful alcohol use, were available30, there are a number of designated informal settlements located in Wilsonia, Mdantsane, and Zwelitsha along and adjacent to the N2 National Road corridor. In the Free State, IPV spatial synergistic clusters were detected in SA-DHS households from the urban nodes/centers of Dewetsdorp to the southern parts of Manguang via the Regional Route R702. According to the Mangaung Municipal Spatial Development Framework report of 202031 there are number of highlighted informal settlements in Mangaung and Dewetsdorp close to Regional Route R702. Although we cannot fully pinpoint that spatial synergistic clusters of IPV given that the DHS randomly displaces the urban GPS positions for a maximum of two kilometers to protect participant confidentiality32 , the unique and unfortunate legacy of informal settlements cannot easily be dismissed33. Informal settlements, high population density areas at the outskirts of urban areas and other economic centers in South Africa often lack formal built infrastructure, and have little or no access to basic services, such as water, electricity and sanitation34. These areas exist historically (and continue to exist) as consequences of apartheid regime’s urban planning policy, which neglected the housing needs of migrants that industries relied upon for the country’s economic development35.IPV spatial synergistic clustering in parts of the Eastern Cape and Free State Provinces warrants further discussion. In Eastern Cape, these were detected in SA-DHS households from the western part of East London (i.e. Wilsonia) towards Qonce/Zwelitsha, passing through Mdantsane via the N2 National Road. According to the Buffalo City Municipal Spatial Development Framework report of 202037. In this surveillance area, HIV incidence among young women is persistently high 38. In the current investigation, we found that study participants residing in IPV spatial synergistic cluster communities were mainly young, Black African females (98.4%) often single (the largest group being ages 18–24: 20.4%), unemployed (68.1%), and had not completed secondary school (74.0%). Our study highlights the need to prioritize public health responses for socioeconomically vulnerable young women in the high-risk syndemic areas in South Africa.Although it could easily be argued that the detection of spatial synergistic cluster near the national roadway, or adjacent to the province’s economic hubs, can be attributed to ease of sampling by SA-DHS, other geospatial studies from South Africa also note similar challenges in informal settlements that are historically, and continues to be neglected. For example, several South African studies from the Africa Health Research Institute Demographic and Health Surveillance System (2016–2019), located in the Umkhanyakude District of the northern KwaZulu-Natal Province, point to clusters of HIV infections in informal settlement communities near the National Road that links the city of Durban with Mozambique, Swaziland and Mpumalanga Province in the north42. Second, our study was based on a cross-sectional design, with further studies being needed to establish temporal relationships between syndemics and IPV. Notwithstanding these limitations, this investigation identified the spatial heterogeneity of health syndemics at a national scale in South Africa, with a significant link between these syndemic health challenges and IPV among women.There are several limitations that warrant discussion. First, not all health challenges of the study participants were based on laboratory or diagnostic tests. Given the vast number of study participants and health domains available for assessment in the SA-DHS, it is common in large population-based studies to rely on self-reported data. We acknowledge the possible underreporting of health and IPV challenges in our study, as is commonly detected in other population-based studies43 that address complex challenges individual face in their respective community. The findings from our study, which geographically identified at-risk IPV syndemic communities, are an essential first step towards implementing people-centered interventions in the era of an aging HIV epidemic. Although more further studies are needed about the role of informal settlements, public health intervention should (re-)focus on alcohol reduction and HIV prevention at-risk impoverish communities that drive IPV among women in South Africa.Although IPV, based on decade old concept of SAVA syndemic, was less common/widespread than expected from the nationally representative population-based data, we nonetheless identified physical violence syndemic occurring in South Africa which speaks to the relevance of intertwined reality of the substance abuse, violence and AIDS (SAVA) syndemic in South Africa. In recent years, there has been a growing call for people-centered policies