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In his 1972 paper 'The apportionment of human diversity', Lewontin showed that, when averaged over loci, genetic diversity is predominantly attributable to differences among individuals within populations. However, selection can alter the apportionment of diversity of specific genes or genomic regions. We examine genetic diversity at the human leucocyte antigen (HLA) loci, located within the major histocompatibility complex (MHC) region. HLA genes code for proteins that are critical to adaptive immunity and are well-documented targets of balancing selection. The single-nucleotide polymorphisms (SNPs) within HLA genes show strong signatures of balancing selection on large timescales and are broadly shared among populations, displaying low 𝐹𝑆𝑇 values. However, when we analyse haplotypes defined by these SNPs (which define 'HLA alleles'), we find marked differences in frequencies between geographic regions. These differences are not reflected in the 𝐹𝑆𝑇 values because of the extreme polymorphism at HLA loci, illustrating challenges in interpreting 𝐹𝑆𝑇. Differences in the frequency of HLA alleles among geographic regions are relevant to bone-marrow transplantation, which requires genetic identity at HLA loci between patient and donor. We discuss the case of Brazil's bone marrow registry, where a deficit of enrolled volunteers with African ancestry reduces the chance of finding donors for individuals with an MHC region of African ancestry. This article is part of the theme issue 'Celebrating 50 years since Lewontin's apportionment of human diversity'.

What are the social consequences of the recent expansion of newborn screening in the United States? The adoption of new screening technologies has generated diagnostic uncertainty about the nature of screening targets, making it unclear not only whether a newborn will develop a disease but also what the condition actually is. Based on observations in a genetics clinic and in-depth interviews with parents and geneticists, we examine how parents and clinical staff work out the social significance of uncertain newborn screening results. We find that some newborns will experience a specific trajectory of prolonged liminality between a state of normal health and pathology. Based on a review of related literatures, we suggest \"patients-in-waiting\" as an umbrella concept for those under medical surveillance between health and disease.

As researchers categorize issues facing Black women’s health, obesity and physical exercise continue to be significant topics of debate. General interventions targeted toward Black women to address obesity and increase physical exercise have been largely ineffective. In this article, I situate the current public health discourse on obesity and related interventions within a sociocultural context of body appearance, with a specific focus on hair. Why do some African American women feel such strong ties to their hair that they will avoid exercise? What can be done to understand this phenomenon and address alternatives that may make both hair maintenance and regular exercise feasible? I map a theoretical argument for why hair matters for some women, and discuss how physical activity intervention strategies might be improved by considering such complexities.

The gender paradox in mortality—where men die earlier than women despite having more socioeconomic resources—may be partly explained by men's lower levels of preventive health care. Stereotypical notions of masculinity reduce preventive health care; however, the relationship between masculinity, socioeconomic status (SES), and preventive health care is unknown. Using the Wisconsin Longitudinal Study, the authors conduct a population-based assessment of masculinity beliefs and preventive health care, including whether these relationships vary by SES. The results show that men with strong masculinity beliefs are half as likely as men with more moderate masculinity beliefs to receive preventive care. Furthermore, in contrast to the well-established SES gradient in health, men with strong masculinity beliefs do not benefit from higher education and their probability of obtaining preventive health care decreases as their occupational status, wealth, and/or income increases. Masculinity may be a partial explanation for the paradox of men's lower life expectancy, despite their higher SES.

Functional cure for chronic hepatitis B (CHB) remains challenging due to the lack of direct intervention methods for hepatic inflammation. Multi‐omics research offers a promising approach to understand hepatic inflammation mechanisms in CHB. A Bayesian linear model linked gene expression with clinical parameters, and population‐specific expression analysis (PSEA) refined bulk gene expression into specific cell types across different clinical phases. These models were integrated into our analysis of key factors like inflammatory cells, immune activation, T cell exhaustion, chemokines, receptors, and interferon‐stimulated genes (ISGs). Validation through multi‐immune staining in liver specimens from CHB patients bolstered our findings. In CHB patients, increased gene expression related to immune cell activation and migration was noted. Marker genes of macrophages, T cells, immune‐negative regulators, chemokines, and ISGs showed a positive correlation with serum alanine aminotransferase (ALT) levels but not hepatitis B virus DNA levels. The PSEA model confirmed T cells as the source of exhausted regulators, while macrophages primarily contributed to chemokine expression. Upregulated ISGs (ISG20, IFI16, TAP2, GBP1, PSMB9) in the hepatitis phase were associated with T cell and macrophage infiltration and positively correlated with ALT levels. Conversely, another set of ISGs (IFI44, ISG15, IFI44L, IFI6, MX1) mainly expressed by hepatocytes and B cells showed no correlation with ALT levels. Our study presents a multi‐omics analysis integrating bulk transcriptomic, single‐cell sequencing data, and clinical data from CHB patients to decipher the cause of intrahepatic inflammation in CHB. The findings confirm that macrophages secrete chemokines like CCL20, recruiting exhausted T cells into liver tissue; concurrently, hepatocyte innate immunity is suppressed, hindering the antiviral effects of ISGs. This study integrates liver bulk transcriptomic data, single‐cell sequencing data, and clinical data to analyze the factors that induce hepatic inflammation in chronic hepatitis B from a multi‐omics perspective by Bayesian regression. Macrophages secrete chemokines like CCL20 and CXCL8 to recruit immune‐exhausted T lymphocytes (CTLA4, TIGIT) into liver tissue. Innate immunity within hepatocytes is suppressed, impeding interferon‐stimulated genes from initiating antiviral effects. Activation of innate immune pathways in infiltrating T cells and macrophages further exacerbates inflammation formation. Highlights This study integrates liver bulk transcriptomic data, single‐cell sequencing data, and clinical data to analyze the factors inducing hepatic inflammation in chronic hepatitis B from a multi‐omics perspective by Bayesian regression. Macrophages secrete chemokines like CCL20 and CXCL8 to recruit immune‐exhausted T lymphocytes (CTLA4, TIGIT) into liver tissue. Innate immunity within hepatocytes is suppressed, impeding interferon‐stimulated genes from initiating antiviral effects. Activation of innate immune pathways in infiltrating T cells and macrophages further exacerbates inflammation formation.

In Western countries, clinical trials on prostate cancer screening demonstrated a limited benefit for patient survival. In the Asia-Pacific region, including Japan, the rate of prostate-specific antigen (PSA) testing remains very low compared with Western countries, and the benefits of population-based screening remain unclear. This review describes the current status of population screening and diagnosis for prostate cancer in Japan and discusses the efficacy of population screening for the Asian population. Since the 1990s, screening systems have been administered by each municipal government in Japan, and decreases in the prostate cancer mortality rate are expected in some regions where the exposure rate to PSA screening has increased markedly. A population-based screening cohort revealed that the proportion of metastatic disease in cancer detected by screening gradually decreased according to the increased exposure rate, and a decreasing trend in the proportion of cancer with high serum PSA levels after population screening was started. The prognosis of the prostate cancer detected by population screening was demonstrated to be more favorable than those diagnosed outside of the population screening. Recent results in screening cohorts demonstrated the efficacy of PSA. These recent evidences regarding population-based screening in Japan may contribute to establishing the optimal prostate cancer screening system in Asian individuals.

Accurate ultrasound estimated fetal weight (EFW) supports key perinatal decisions. This study aimed to compare the accuracy of a population-specific formula with that of a widely used global model in pregnancies examined near delivery. This was a secondary analysis of a prospective Japanese cohort study to develop a new fetal ultrasound biometry reference chart. Fetal ultrasound measurements were obtained by Japan Society of Ultrasonics in Medicine-certified sonographers or under their supervision and submitted to the coordinating center, where EFW was calculated using the Shinozuka and Hadlock-3 formulas. Analyses were restricted to cases with EFW available from both formulas. The primary analysis included examinations within 7 days before delivery; a sensitivity analysis restricted the interval to ≤3 days. A subgroup analysis was performed in fetuses classified as small for gestational age (SGA). In the primary analysis (n = 310), the median signed error was -75.8 g for Shinozuka and -223.3 g for Hadlock-3 (Wilcoxon p < 0.001). The median absolute percentage signed error was 4.81% for Shinozuka and 7.93% for Hadlock-3 (Wilcoxon p < 0.001). The proportion within ±10% of BW was 83.9% with Shinozuka versus 61.6% with Hadlock-3 (McNemar p < 0.001). In the sensitivity analysis (n = 176), similar findings were observed. In the SGA subgroup (n = 40), the signed error and absolute percentage error were significantly lower with the Shinozuka formula than with Hadlock-3. In this multicenter cohort examined near delivery, the population-specific Shinozuka formula produced EFW closer to BW and a higher proportion within ±10% than Hadlock-3, which showed greater systematic underestimation. These findings support the use of locally validated, population-specific EFW formulas when available, particularly for clinical decision-making near delivery.

This study examined two types of potential sources of racial-ethnic disparities in medical care: implicit biases and time pressure. Eighty-one family physicians and general internists responded to a case vignette describing a patient with chest pain. Time pressure was manipulated experimentally. Under high time pressure, but not under low time pressure, implicit biases regarding blacks and Hispanics led to a less serious diagnosis. In addition, implicit biases regarding blacks led to a lower likelihood of a referral to specialist when physicians were under high time pressure. The results suggest that when physicians face stress, their implicit biases may shape medical decisions in ways that disadvantage minority patients.

This article introduces the rationale and methods for explicitly considering health equity in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology for development of clinical, public health, and health system guidelines. We searched for guideline methodology articles, conceptual articles about health equity, and examples of guidelines that considered health equity explicitly. We held three meetings with GRADE Working Group members and invited comments from the GRADE Working Group listserve. We developed three articles on incorporating equity considerations into the overall approach to guideline development, rating certainty, and assembling the evidence base and evidence to decision and/or recommendation. Clinical and public health guidelines have a role to play in promoting health equity by explicitly considering equity in the process of guideline development.

Conventional genome-wide association study (GWAS) thresholds, notably 5 × 10⁻⁸, were established under assumptions that may not hold across diverse populations and whole-genome sequencing (WGS) analyses. Given the complex linkage disequilibrium structure of the human genome, a single fixed threshold risks inadequate type I error control. Here, we sought to derive minor allele frequency (MAF)-specific, population-tailored significance thresholds using the Li-Ji method across European, African, and Asian cohorts from the 1000 Genomes Project. We partitioned the genome into natural linkage disequilibrium (LD) blocks defined by the LDetect database and applied rigorous quality control measures before generating LD matrices. Using the Li-Ji method—we estimated the effective number of independent tests for each block across six MAF thresholds and then aggregated the results for each population. The resulting effective tests were used to calculate Bonferroni-adjusted significance thresholds. Our analysis revealed that for common variants (MAF ≥ 0.05), the significance thresholds in European and Asian populations were somewhat lower than the conventional 5 × 10⁻⁸ benchmark, whereas the African population required considerably more stringent corrections. The inclusion of rarer variants further increased the effective number of independent tests across all groups, thereby shifting the significance thresholds to levels even more stringent than the 5 × 10⁻⁸ benchmark. By applying the Li-Ji method, this study establishes that MAF-specific and population-specific significance thresholds provide a more accurate framework for GWAS analyses. Our findings suggest that the conventional 5 × 10⁻⁸ threshold may be suboptimal, particularly when evaluating rare variants or diverse populations, with important implications for future biobank-scale and precision genomic research.