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ObjectiveBody mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population.SubjectsUsing eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models.ResultsWe replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

Background: Despite introduction of autologous chondrocyte therapy for repair of hyaline articular cartilage injury in 1994, microfracture remains a primary standard of care. NeoCart, an autologous cartilage tissue implant, was compared with microfracture in a multisite prospective, randomized trial of a tissue-engineered bioimplant for treating articular cartilage injuries in the knee.Methods: Thirty patients were randomized at a ratio of two to one (two were treated with an autologous cartilage tissue implant [NeoCart] for each patient treated with microfracture) at the time of arthroscopic confirmation of an International Cartilage Repair Society (ICRS) grade-III lesion(s). Microfracture or cartilage biopsy was performed. NeoCart, produced by seeding a type-I collagen matrix scaffold with autogenous chondrocytes and bioreactor treatment, was implanted six weeks following arthroscopic cartilage biopsy. Standard evaluations were performed with validated clinical outcomes measures.Results: Three, six, twelve, and twenty-four-month data are reported. The mean duration of follow-up (and standard deviation) was 26 ± 2 months. There were twenty-one patients in the NeoCart group and nine in the microfracture group. The mean age (40 ± 9 years), body mass index (BMI) (28 ± 4 kg/m2), duration between the first symptoms and treatment (3 ± 5 years), and lesion size (287 ± 138 mm2 in the NeoCart group and 252 ± 135 mm2 in the microfracture group) were similar between the groups. Adverse event rates per procedure did not differ between the treatment arms. The scores on the Short Form-36 (SF-36), Knee Injury and Osteoarthritis Outcome Score (KOOS) activities of daily living (ADL) scale, and International Knee Documentation Committee (IKDC) form improved from baseline (p < 0.05) to two years postoperatively in both treatment groups. In the NeoCart group, improvement, compared with baseline, was significant (p < 0.05) for all measures at six, twelve, and twenty-four months. Improvement in the NeoCart group was significantly greater (p < 0.05) than that in the microfracture group for the KOOS pain score at six, twelve, and twenty-four months; the KOOS symptom score at six months; the IKDC, KOOS sports, and visual analog scale (VAS) pain scores at twelve and twenty-four months; and the KOOS quality of life (QOL) score at twenty-four months. Analysis of covariance (ANCOVA) at one year indicated that the change in the KOOS pain (p = 0.016) and IKDC (p = 0.028) scores from pretreatment levels favored the NeoCart group. Significantly more NeoCart-treated patients (p = 0.0125) had responded to therapy (were therapeutic responders) at six months (43% versus 25% in the microfracture group) and twelve months (76% versus 22% in the microfracture group). This trend continued, as the proportion of NeoCart-treated patients (fifteen of nineteen) who were therapeutic responders at twenty-four months was greater than the proportion of microfracture-treated participants (four of nine) who were therapeutic responders at that time.Conclusions: This randomized study suggests that the safety of autologous cartilage tissue implantation, with use of the NeoCart technique, is similar to that of microfracture surgery and is associated with greater clinical efficacy at two years after treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Optimal management of congenital talipes equinovarus continues to be controversial. There is a dramatically renewed emphasis on non-operative management partly because there has been a high recurrence rate among operated feet. Our hypothesis is that early, extensive subtalar ligament release as the cornerstone of aggressive hindfoot realignment prevents recurrence and retains mobility. MATERIALS AND METHODS: Twenty-two congenital clubfeet (14 patients) corrected by one surgeon were evaluated using two validated patient-based outcome instruments, dynamic pedobarographic analysis, hindfoot mobility, and weightbearing radiographs. Pedobarographic analysis consisted of quantifying peak plantar forces and pressures during the gait cycle in 22 corrected feet and 24 control feet using the FSCAN in-shoe device. RESULTS: The mean age at surgery was 8 months and mean followup was 10 years. No patients experienced recurrence of deformity. Reported foot function and satisfaction were very high for all patients and were comparable to reported normal population values. AP and lateral talocalcaneal angles for each foot were within normal limits for age. Hindfoot range of motion, including dorsiflexion, was preserved in all feet. Peak regional forces throughout the gait cycle and plantar pressures at foot flat were mildly, but statistically significantly, higher in the midfoot of corrected feet suggesting slight flattening of the arch. One patient had tendon transfers for bilateral calcaneal deformity and one patient had surgical correction of a bilateral valgus deformity. CONCLUSION: Aggressive hindfoot realignment provides definitive treatment of an equinovarus deformity, but care must be taken to avoid overcorrection. [ABSTRACT FROM AUTHOR]

Several genome-wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups. As part of the ‘Population Architecture using Genomics and Epidemiology (PAGE)’ Consortium, we investigated the association between thirteen GWAS-identified SNPs and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African-Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI-increasing allele of each SNP, we calculated beta coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI ≥ 30) followed by fixed-effects meta-analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and adjusted for age, sex, and current smoking. We defined “replicating SNPs” (in European Americans) and “generalizing SNPs” (in other racial/ethnic groups) as those associated with an allele frequency-specific increase in BMI. By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians. Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine-mapping in large samples is needed to comprehensively explore these loci in diverse populations.

Objective: To collate current literature pertaining to the published reports of indications for, and outcomes of, osteochondral allograft (OCA) transplantations in the shoulder so as to guide surgeons in the management of various etiologies of osteochondral lesions in this joint., Design: A systematic review of the current literature was performed in February 2022 in the PubMed, Cochrane, and EMBASE databases using specific search terms and predetermined inclusion/exclusion criteria., Results: One-hundred-twenty-three articles were initially identified, 30 full-text articles were assessed for eligibility, and 17 articles met inclusion criteria. Data were collected for study characteristics, etiology, lesion size/location, intervention/type of graft used, follow-up, and outcomes. In total, 83 shoulders were included ( n = 83) in the review with an average follow-up of 45.7 months. Nine specific indications for OCA transplantation in the shoulder included: reverse Hill-Sachs lesions (33), Hill-Sachs lesions (22), pain pump chondrolysis (10), recurrent shoulder instability (7), osteoarthritis/degenerative changes (5), radiofrequency chondrolysis (2), prominent suture anchors (2), glenoid lesion (1), and osteochondritis dissecans (1). Seventeen patients had concomitant surgeries and two patients were lost to follow-up. Of the total 83 shoulders, 68 had favorable outcomes and 13 had unfavorable outcomes as determined by graft incorporation, pain scores, functionality/ROM, patient-reported satisfaction, and/or requirement for revision/arthroplasty. Of the 13 with unfavorable outcomes, a disproportionate number had concomitant surgeries and/or were performed for pain pump chondrolysis (6)., Conclusions: The use of OCAs appears to be a viable option for a variety of difficult-to-treat shoulder pathologies, particularly those characterized by isolated osteochondral injuries., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: There is no standardized rehabilitation protocol after osteochondral allograft (OCA) transplantation surgery to the distal femur. The spectrum of recommendations includes restrictions to toe-touch weightbearing (TTWB) for 6 weeks and immediate weightbearing as tolerated (WBAT)., Purpose/hypothesis: The purpose of this study was to compare outcomes for immediate unrestricted WBAT to restricted TTWB after OCA transplantation to the distal femur. It was hypothesized that the immediate WBAT protocol would be noninferior to delayed, restricted TTWB., Study Design: Retrospective cohort study., Methods: A total of 74 patients who underwent press-fit, dowel technique OCA transplantation to the femoral condyle(s) for contained (International Cartilage Repair Society grade 3-4) lesions were identified in the Metrics of Osteochondral Allograft multicenter database: 36 patients (18 women/18 men) who were prescribed TTWB were allocated to the control cohort and 38 patients (21 women/17 men) who were prescribed WBAT were allocated to the test cohort. Baseline characteristics were similar except for larger grafts in test patients (3.4 vs 2.7 cm 2 ; P = .004) and higher body mass index (BMI) in control patients (27.8 vs 24.9 kg/m 2 ; P = .01). Failure rates, final patient-reported outcome (PRO) scores, and PRO score changes from baseline were compared between the cohorts. Multiple regression was used to control for potential confounders and investigate noninferiority using minimal clinically important differences (MCIDs)., Results: The mean follow-up was 2 years (range, 1-5 years) in both cohorts. Both cohorts showed significant improvement in all PRO scores, with no significant between-group differences in failure rates, final PRO scores, or PRO changes from baseline. There were 3 cases of failure in each cohort (control cohort: allograft revision [n = 2], debridement [n = 1]; test cohort: chondroplasty [n = 2], conversion to total knee arthroplasty [n = 1]). Regression analysis showed that adjusted differences in final PRO scores based on weightbearing protocol were minor and less than MCIDs when controlling for age, sex, graft size, BMI, and allograft location. Analysis of the MCIDs with respect to the lower bounds of the confidence intervals indicated that WBAT was noninferior to TTWB with a reasonable degree of confidence (range, 84.1%-99.9% confidence)., Conclusion: Results indicated that immediate unrestricted WBAT after OCA transplantation to the distal femur was equally safe and effective compared to restricted TTWB., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: B.J.C. has received consulting fees from Endo Pharmaceuticals, Acumed, Aesculap Biologics, Arthrex, Bioventus, DJO, Vericel, Anika Therapeutics, Ossio, and Pacira Pharmaceuticals; nonconsulting fees from Arthrex, Vericel, Terumo BCT, and Pacira Pharmaceuticals; royalties from Arthrex; education payments from Endo Pharmaceuticals; hospitality payments from GE Healthcare; and honoraria from Vericel. A.B.Y. has received consulting fees from Stryker, JRF Ortho, and Olympus America; nonconsulting fees from Arthrex; education payments from Medwest Associates; and honoraria from JRF Ortho. D.C.C. has received consulting fees from JRF Ortho and Vericel, nonconsulting fees from Arthrex, education payments from Steelhead Surgical, and honoraria from JRF Ortho. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2024.)

Electronic health records (EHRs) contain a vast array of phenotypic data on large numbers of individuals, often collected over decades. Due to the wealth of information, EHR data have emerged as a powerful resource to make first discoveries and identify disparities in our healthcare system. While the number of EHR-based studies has exploded in recent years, most of these studies are directed at associations with disease rather than pharmacotherapeutic outcomes, such as drug response or adverse drug reactions. This is largely due to challenges specific to deriving drug-related phenotypes from the EHR. There is great potential for EHR-based discovery in clinical pharmacology research, and there is a critical need to address specific challenges related to accurate and reproducible derivation of drug-related phenotypes from the EHR. This review provides a detailed evaluation of challenges and considerations for deriving drug-related data from EHRs. We provide an examination of EHR-based computable phenotypes and discuss cutting-edge approaches to map medication information for clinical pharmacology research, including medication-based computable phenotypes and natural language processing. We also discuss additional considerations such as data structure, heterogeneity and missing data, rare phenotypes, and diversity within the EHR. By further understanding the complexities associated with conducting clinical pharmacology research using EHR-based data, investigators will be better equipped to design thoughtful studies with more reproducible results. Progress in utilizing EHRs for clinical pharmacology research should lead to significant advances in our ability to understand differential drug response and predict adverse drug reactions., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Efficacy of exercise to improve renal health and filtration remains understudied in adults with moderate-stages (stages G3a-b) of chronic kidney disease (CKD). Acute exercise may contribute clinically relevant information for exercise-related augmentation of renal health and filtration in CKD. Urine epidermal growth factor (uEGF) and cystatin C (CyC) are proposed to be more direct biomarkers of renal health and filtration. This study aimed to determine the influence of continuous moderate-intensity exercise (CMIE) and high-intensity interval exercise (HIIE) on traditional and novel biomarkers of renal health and filtration in moderate-stages of CKD. Methods: Twenty CKD participants completed 30 minutes of both CMIE and HIIE. Blood and urine samples were obtained pre, 1-hour, and 24-hours post-exercise. Traditional-serum creatinine (sCr) urine creatinine, novel-uEGF, uEGF ratio (uEGFr), and CyC. Estimates of glomerular filtration rate (eGFR)-modification of diet in renal disease (MDRD) and the CKD-Epidemiology (CKD-EPI)-responses were compared pre, 1 hr, and 24 hr post-exercise. Results: Relative to pre-exercise measures, uEGF remained unchanged in both exercise conditions. However, uEGFr was 5.4% greater 24-hours after HIIE ( P = .05), while uEGFr remained unchanged with CMIE. sCr decreased 6 to 19% 1-hour post-exercise in both conditions ( P = .009). On average renal filtration increased in eGFR-MDRD (7.2 ± 2.0 ml/min/1.73 m 2 ) ( P = .007) and eGFR-CKD-EPI (8.6 ± 2.3 ml/min/1.73 m 2 ) 1-hour post-exercise ( P = .009). Conclusion: By clinical estimates, renal filtration in CKD was not normalized but transiently improved regardless of exercise condition, with HIIE eliciting transient improvements in renal health.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Clostridioides difficile (C. diff.) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. diff. do not develop any infection while others develop severe or recurrent infections. To identify common genetic variants associated with CDI, we performed a genome-wide association analysis in 19,861 participants (1349 cases; 18,512 controls) from the Electronic Medical Records and Genomics (eMERGE) Network. Using logistic regression, we found strong evidence for genetic variation in the DRB locus of the MHC (HLA) II region that predisposes individuals to CDI (P > 1.0 × 10 -14 ; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring susceptibility to this opportunistic enteric pathogen., (© 2023. The Author(s).)

Purpose: The aim of this study was to assess risk for demographic variables and other health conditions that are associated with Fuchs endothelial corneal dystrophy (FECD)., Methods: We developed a FECD case-control algorithm based on structured electronic health record data and confirmed accuracy by individual review of charts at 3 Veterans Affairs (VA) Medical Centers. This algorithm was applied to the Department of VA Million Veteran Program cohort from whom sex, genetic ancestry, comorbidities, diagnostic phecodes, and laboratory values were extracted. Single-variable and multiple variable logistic regression models were used to determine the association of these risk factors with FECD diagnosis., Results: Being a FECD case was associated with female sex, European genetic ancestry, and a greater number of comorbidities. Of 1417 diagnostic phecodes evaluated, 213 had a significant association with FECD, falling in both ocular and nonocular conditions, including diabetes mellitus (DM). Five of 69 laboratory values were associated with FECD, with the direction of change for 4 being consistent with DM. Insulin dependency and type 1 DM raised risk to a greater degree than type 2 DM, like other microvascular diabetic complications., Conclusions: Female sex, European ancestry, and multimorbidity increased FECD risk. Endocrine/metabolic clinic encounter codes and altered patterns of laboratory values support DM increasing FECD risk. Our results evoke a threshold model in which the FECD phenotype is intensified by DM and potentially other health conditions that alter corneal physiology. Further studies to better understand the relationship between FECD and DM are indicated and may help identify opportunities for slowing FECD progression., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Genome-wide association studies (GWAS) revolutionized our understanding of common genetic variation and its impact on common human disease and traits. Developed and adopted in the mid-2000s, GWAS led to searchable genotype-phenotype catalogs and genome-wide datasets available for further data mining and analysis for the eventual development of translational applications. The GWAS revolution was swift and specific, including almost exclusively populations of European descent, to the neglect of the majority of the world's genetic diversity. In this narrative review, we recount the GWAS landscape of the early years that established a genotype-phenotype catalog that is now universally understood to be inadequate for a complete understanding of complex human genetics. We then describe approaches taken to augment the genotype-phenotype catalog, including the study populations, collaborative consortia, and study design approaches aimed to generalize and then ultimately discover genome-wide associations in non-European descent populations. The collaborations and data resources established in the efforts to diversify genomic findings undoubtedly provide the foundations of the next chapters of genetic association studies with the advent of budget-friendly whole-genome sequencing.

Competing Interests: The authors declare no competing financial interests.

Purpose: To evaluate the 5-year rate of survival without undergoing arthroplasty or high tibial osteotomy (HTO) in subjects with mild-to-moderate medial compartment knee osteoarthritis (OA) who were treated with an implantable shock absorber (ISA) system., Methods: Three prospective, sequential, multicenter, international, single-arm clinical trials were conducted comprising subjects who received an ISA for symptomatic medial knee OA after failing ≥ 6 months of conservative therapy. Study outcomes were analyzed cumulatively and by enrollment group when all subjects' follow-up data exceeded the 2-year threshold after ISA implantation. Primary outcome was survival rate without conversion to arthroplasty/HTO. Secondary outcomes were changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores after ISA implantation., Results: All 171 enrolled subjects (age 51 ± 9 years, body-mass index 28.5 ± 3.5 kg/m 2 , 38% female; study knee Kellgren-Lawrence score 2.7 ± 0.9 points) were followed for a minimum of 2, and up to 5, years after device implantation. Overall, 90.6% (155/171) of subjects survived without requiring arthroplasty/HTO at last follow-up (mean 3.2 ± 1.6 years). The Kaplan-Meyer median 3- and 5-year survival-without-arthroplasty point estimates were 89.8% (95% CI 86.5‒95.7%) and 84.9% (95% CI 75.1‒91.1%), respectively. The median 3-year estimated survival rate for the most recent study (n = 81) was 97.3%. The mean WOMAC Pain score decreased 71% from baseline to last follow-up after ISA implantation, from 58 ± 13 to 16 ± 17 points (p < 0.0001). The Function score improved 69%, decreasing from 56 ± 18 to 17 ± 17 points (p < 0.0001)., Conclusions: In younger patients with mild-to-moderate symptomatic medial compartment knee OA, implantation of the ISA device resulted in a 5-year survival rate of 85% from undergoing arthroplasty or HTO. The ISA system may be an effective treatment option for working-age patients with medial knee OA who are not candidates for or do not desire more invasive surgical approaches., Level of Evidence: II., (© 2023. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS 269 ). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS 269 developed from multi-ancestry GWASs and fine-mapping., Competing Interests: Declaration of interests The authors have no conflicts of interest to disclose., (Copyright © 2023 American Society of Human Genetics. All rights reserved.)

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility., Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry., Design, Setting, and Participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry., Outcome Measurements and Statistical Analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness., Results and Limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10 -4 )., Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry., Patient Summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Up to 10 million Americans below the age of 65 years have symptomatic knee osteoarthritis (OA) and may not yet be candidates for arthroplasty. In response, a subcutaneous implantable shock absorber (ISA) that unloads the knee has been developed. The safety and effectiveness of ISA treatment were compared against a surgical unloading control, high tibial osteotomy (HTO)., Design: This was a prospective open-label cohort study with a historical control arm. Subjects underwent ISA placement or HTO. The primary endpoint was a composite variable combining pain, function, specific adverse events, integrity of implant or hardware, and conversion to subsequent surgery. Pain and function outcomes (Western Ontario and McMaster Universities Arthritis Index scores) were assessed through 24 months. Adverse events were tracked., Results: The primary endpoint demonstrated superiority of the ISA arm versus the HTO arm, with 85.6% of ISA subjects meeting all criteria compared with 65.5% of HTO subjects. In addition, all 5 secondary endpoints showed superiority of ISA over HTO. At 24 months, the proportions of subjects considered responders were 95.8% (ISA) versus 87.9% (HTO) for pain and 91.7% (ISA) versus 81.3% (HTO) for function. The ISA procedure was well tolerated, with 13.4 days to full weightbearing status versus 58.0 days for the HTO arm., Conclusions: Treatment with an ISA demonstrated noninferiority and superiority versus treatment with HTO in subjects aged 25-65 years who had OA of the medial knee. Treatment with ISA has high clinical benefit and is durable through at least 24 months.

Although diet is an important route of exposure for brominated flame retardants (BFRs), little is known of their presence in US food. Therefore, we purchased meat, fish, and dairy product samples ( n = 72) in Bloomington, IN, from 3 stores representing national retail chains at different price levels. Composite samples ( n = 42) were analyzed for polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCDD), novel BFRs (NBFRs), and dechlorane plus (DP). Concentrations of total halogenated flame retardants (HFRs) ranged between 54 and 1,400 pg/g ww, with PBDEs being the predominant compounds. Concentrations of NBFRs, but not PBDEs, in US food items were significantly impacted by price, raising the issue of environmental justice. Nonorganic food generally had a higher abundance of BDE-209 than organic food items. Estimates of dietary exposure revealed that meat and cheese consumption contribute most to the overall HFR intake and that intakes are highest for children and for non-Hispanic Asians. Taking into account several caveats and limitations of this study, these results as a whole suggest that health burdens from dietary exposure to HFRs have become minimal for US citizens, highlighting the positive impact of regulatory efforts., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Polygenic risk scores (PRS) based on genome-wide discoveries are promising predictors or classifiers of disease development, severity, and/or progression for common clinical outcomes. A major limitation of most risk scores is the paucity of genome-wide discoveries in diverse populations, prompting an emphasis to generate these needed data for trans-population and population-specific PRS construction. Given diverse genome-wide discoveries are just now being completed, there has been little opportunity for PRS to be evaluated in diverse populations independent from the discovery efforts. To fill this gap, we leverage here summary data from a recent genome-wide discovery study of lipid traits (HDL-C, LDL-C, triglycerides, and total cholesterol) conducted in diverse populations represented by African Americans, Hispanics, Asians, Native Hawaiians, Native Americans, and others by the Population Architecture using Genomics and Epidemiology (PAGE) Study. We constructed lipid trait PRS using PAGE Study published genetic variants and weights in an independent African American adult patient population linked to de-identified electronic health records and genotypes from the Illumina Metabochip ( n  = 3,254). Using multi-population lipid trait PRS, we assessed levels of association for their respective lipid traits, clinical outcomes (cardiovascular disease and type 2 diabetes), and common clinical labs. While none of the multi-population PRS were strongly associated with the tested trait or outcome, PRS LDL-C was nominally associated with cardiovascular disease. These data demonstrate the complexity in applying PRS to real-world clinical data even when data from multiple populations are available., Competing Interests: The authors declare there are no competing interests., (©2023 Drouet et al.)

Background: Minimal change disease (MCD) is the major cause of childhood idiopathic nephrotic syndrome, which is characterized by massive proteinuria and debilitating edema. Proteinuria in MCD is typically rapidly reversible with corticosteroid therapy, but relapses are common, and children often have many adverse events from the repeated courses of immunosuppressive therapy. The pathobiology of MCD remains poorly understood. Prior clinical observations suggest that abnormal T-cell function may play a central role in MCD pathogenesis. Based on these observations, we hypothesized that T-cell responses to specific exposures or antigens lead to a clonal expansion of T-cell subsets, a restriction in the T-cell repertoire, and an elaboration of specific circulating factors that trigger disease onset and relapses., Methods: To test these hypotheses, we sequenced T-cell receptors in fourteen MCD, four focal segmental glomerulosclerosis (FSGS), and four membranous nephropathy (MN) patients with clinical data and blood samples drawn during active disease and during remission collected by the Nephrotic Syndrome Study Network (NEPTUNE). We calculated several T-cell receptor diversity metrics to assess possible differences between active disease and remission states in paired samples., Results: Median productive clonality did not differ between MCD active disease (0.0083; range: 0.0042, 0.0397) and remission (0.0088; range: 0.0038, 0.0369). We did not identify dominant clonotypes in MCD active disease, and few clonotypes were shared with FSGS and MN patients., Conclusions: While these data do not support an obvious role of the adaptive immune system T-cells in MCD pathogenesis, further study is warranted given the limited sample size. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Precision medicine requires a deep understanding of complex biomedical and healthcare data, which is being generated at exponential rates and increasingly made available through public biobanks, electronic medical record systems and biomedical databases and knowledgebases. The complexity and sheer amount of data prohibit manual manipulation. Instead, the field depends on artificial intelligence approaches to parse, annotate, evaluate and interpret the data to enable applications to patient healthcare At the 2023 Pacific Symposium on Biocomputing (PSB) session entitled "Precision Medicine: Using Artificial Intelligence (AI) to improve diagnostics and healthcare", we spotlight research that develops and applies computational methodologies to solve biomedical problems.

A major goal of precision medicine is to stratify patients based on their genetic risk for a disease to inform future screening and intervention strategies. For conditions like primary open-angle glaucoma (POAG), the genetic risk architecture is complicated with multiple variants contributing small effects on risk. Following the tepid success of genome-wide association studies for high-effect disease risk variant discovery, genetic risk scores (GRS), which collate effects from multiple genetic variants into a single measure, have shown promise for disease risk stratification. We assessed the application of GRS for POAG risk stratification in Hispanic-descent (HIS) and European-descent (EUR) Veterans in the Million Veteran Program. Unweighted and cross-ancestry meta-weighted GRS were calculated based on 127 genomic variants identified in the most recent report of cross-ancestry POAG meta-analyses. We found that both GRS types were associated with POAG case-control status and performed similarly in HIS and EUR Veterans. This trend was also seen in our subset analysis of HIS Veterans with less than 50% EUR global genetic ancestry. Our findings highlight the importance of evaluating GRS based on known POAG risk variants in different ancestry groups and emphasize the need for more multi-ancestry POAG genetic studies.

The availability of electronic health record (EHR)-linked biobank data for research presents opportunities to better understand complex ocular diseases. Developing accurate computable phenotypes for ocular diseases for which gold standard diagnosis includes imaging remains inaccessible in most biobank-linked EHRs. The objective of this study was to develop and validate a computable phenotype to identify primary open-angle glaucoma (POAG) through accessing the Department of Veterans Affairs (VA) Computerized Patient Record System (CPRS) and Million Veteran Program (MVP) biobank. Accessing CPRS clinical ophthalmology data from VA Medical Center Eye Clinic (VAMCEC) patients, we developed and iteratively refined POAG case and control algorithms based on clinical, prescription, and structured diagnosis data (ICD-CM codes). Refinement was performed via detailed chart review, initially at a single VAMCEC (n = 200) and validated at two additional VAMCECs (n = 100 each). Positive and negative predictive values (PPV, NPV) were computed as the proportion of CPRS patients correctly classified with POAG or without POAG, respectively, by the algorithms, validated by ophthalmologists and optometrists with access to gold-standard clinical diagnosis data. The final algorithms performed better than previously reported approaches in assuring the accuracy and reproducibility of POAG classification (PPV >83% and NPV >97%) with consistent performance in Black or African American and in White Veterans. Applied to the MVP to identify cases and controls, genetic analysis of a known POAG-associated locus further validated the algorithms. We conclude that ours is a viable approach to use combined EHR-genetic data to study patients with complex diseases that require imaging confirmation.

Purpose: Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS)., Design: Cross-sectional study., Participants: MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls., Methods: We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS., Main Outcome Measures: Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS., Results: GRS were significantly associated with POAG (P < 5 × 10 -5 ) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases., Conclusions: Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment., (Published by Elsevier Inc.)

Purpose: To define the criteria for coverage for a cartilage restoration procedure and osteochondral allograft (OCA) transplantation and to investigate coverage for OCA procedures among private payer medical policies., Methods: A systematic search of private payer websites was conducted to identify publicly available 2018 OCA medical policies. Medical criteria related to patient demographics, defect characteristics, and previous treatment were analyzed. Trends in coverage for treatment of talus and patella and the extent of restrictiveness of medical policies were evaluated from 2016 to 2018. The extent of restrictiveness of a policy was defined by number of medical criteria established by payer policies. Policies with >5, 3-5, and <3 specified criteria for OCAs were considered strongly, moderately, and weakly restrictive, respectively., Results: In total, 49 private payer medical policies for OCA transplantation were identified. Extracted criteria varied greatly between medical policies. Ten different defect size ranges were reported across payer policies. Criteria for patient body mass index was specified in 63% of policies. Criteria for failed arthroscopic or traditional surgical procedure were identified in 20% of the policies. More than one half of policies (51%) specified knee defect location to load-bearing surfaces. Analysis of trends in positive coverage statements and restrictiveness showed an increase from 4.7% in 2016 to 39.5% for talus, 4.7% to 7.0% for patella, and a slight shift (4.7% of payers) toward weakly restrictive medical policies., Conclusions: This study demonstrates wide variability and inconsistencies in published criteria among OCA medical policies., Clinical Relevance: This study informs clinicians of the current state of coverage for OCA transplantation, providing insights into the variability of payer policies and potential impact., (© 2022 The Authors.)

Background: Although osteochondral allograft (OCA) transplantation has been a standard treatment for patients with osteochondral lesions, there is a disagreement in commercial payers' medical criteria regarding the definition of medical suitability and thus authorization for OCA transplantation. The primary goal of this study was to understand where consensus between a committee of experienced cartilage restoration surgeon scientists and payer policies existed and where there was significant disagreement., Methods: U.S. private payers were identified by reviewing health insurance market research literature. Medical criteria were then obtained from publicly available payer medical polices. A literature review was conducted to identify supporting evidence for consensus statements based on private payer medical criteria. The MOCA (Metrics of Osteochondral Allograft) Committee, 30 experienced surgeons and subject-matter experts in OCA transplantation, used a Likert scale of 1 (strongly disagree) to 5 (strongly agree) to rank each statement. The extent of agreement and disagreement among participants was measured for each statement. Consensus was defined as agreement or disagreement of >75%., Results: Fifty-seven statements regarding relevant medical criteria for OCA transplantation were included in the survey. All 30 MOCA Committee members completed the survey (100% response rate). Over half of the statements (52.6%) did not reach consensus. Of the remaining 27 statements that reached consensus, respondents agreed or strongly agreed with 16 statements, and disagreed or strongly disagreed with 11 statements. Inconsistent voting was observed for statements related to osteoarthritis, inflammation, and degenerative changes., Conclusions: Commercial payers are not consistent in the medical criteria used to define patient eligibility for authorization of OCA transplantation. In contrast, an expert panel of cartilage surgeons reached a consensus that OCA transplantation was clearly suitable for a variety of specific indications. This study demonstrates the need to standardize medical criteria for cartilage restoration based on the most current literature, as well as in conjunction with experienced cartilage restoration experts., Level of Evidence: Therapeutic Level V . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H181 )., (Copyright © 2022 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10 -4 ), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3-9.5, p = 2 × 10 -5 ; stage T3/T4: OR = 4.5, 95% CI = 2.0-10.0, p = 2 × 10 -4 ; metastatic disease: OR = 5.1, 95% CI = 1.9-13.7, p = 0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. PATIENT SUMMARY: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry., (Copyright © 2022. Published by Elsevier B.V.)

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RC has received research support from Intercept Pharmaceuticals, Inc and Merck & Co. SMD receives research support from RenalytixAI and personal consulting fees from Calico Labs, outside the scope of the current research. MDR is on the scientific advisory board for Goldfinch Bio and Cipherome. CO’D is an employee of Novartis Institute for Biomedical Research. PN reports grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Genentech, and Novartis, and spousal employment at Vertex, all unrelated to the present work.

In the past 10 years since its introduction, phenome-wide association studies (PheWAS) have uncovered novel genotype-phenotype relationships. Along the way, PheWAS have evolved in many aspects as a study design with the expanded availability of large data repositories with genome-wide data linked to detailed phenotypic data. Advancement in methods, including algorithms, software, and publicly available integrated resources, makes it feasible to more fully realize the potential of PheWAS, overcoming the previous computational and analytical limitations. We review here the most recent improvements and notable applications of PheWAS since the second half of the decade from its inception. We also note the challenges that remain embedded along the entire PheWAS analytical pipeline that necessitate further development of tools and resources to further advance the understanding of the complex genetic architecture underlying human diseases and traits., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

More than 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data. Furthermore, 54% of the rare variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association between rare variants and phenotypes. To best use missense rare variants and investigate their biological effect, we examine their association with phenotypes in the context of protein structures. We developed a protein structure-based approach, protein optimized kernel evaluation of missense nucleotides (POKEMON), which evaluates rare missense variants based on their spatial distribution within a protein rather than their allele frequency. The hypothesis behind this test is that the three-dimensional spatial distribution of variants within a protein structure provides functional context to power an association test. POKEMON identified three candidate genes ( TREM2 , SORL1 , and EXOC3L4 ) and another suggestive gene from the ADSP WES data. For TREM2 and SORL1 , two known Alzheimer's disease (AD) genes, the signal from the spatial cluster is stable even if we exclude known AD risk variants, indicating the presence of additional low-frequency risk variants within these genes. EXOC3L4 is a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size., (© 2022 Jin et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets., Methods: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured., Results: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively., Conclusions: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations., (© 2022. The Author(s).)

Background: Multiple cartilage repair techniques are available for chondral defects in the knee. Optimal treatment is controversial., Purpose: To evaluate change from baseline in the 5 Knee injury and Osteoarthritis Outcome Score (KOOS) subscales among different cartilage repair techniques of the knee., Study Design: Systematic review and meta-analysis; Level of evidence, 1A., Methods: Medline and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for randomized controlled trials with minimum 1 year follow-up reporting change from baseline KOOS (delta KOOS) subscale values. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. A meta-analysis was performed on the following surgery types: microfracture (Mfx); augmented microfracture techniques (Mfx+Augment); and culture-based therapies, including autologous chondrocyte implantation (ACI) and matrix-assisted autologous chondrocyte implantation (MACI). A random-effects metaregression model was used., Results: A total of 14 randomized trials with a total of 775 patients were included. The KOOS Sport and Recreation (Sport) and KOOS Quality of Life (QOL) were the 2 most responsive subscales after operative intervention. Outcomes from Mfx and Mfx+Augment were not different in any of the 5 KOOS subscales (minimum P > .3). The mean delta KOOS Sport after ACI/MACI was 9.9 points greater than after Mfx ( P = .021) and 11.7 points greater than after Mfx+Augment ( P = .027). Longer follow-up time correlated with greater delta KOOS Sport ( P = .028). Larger body mass index led to greater delta KOOS QOL ( P = .045). Larger cartilage defect size correlated with greater delta KOOS Pain and KOOS Activities of Daily Living scores ( P = .023 and P = .002, respectively)., Conclusion: The KOOS Sport and QOL were the most responsive subscales after cartilage restoration surgery of the knee. Culture-based therapies (ACI/MACI) led to clinically relevant improvements in the KOOS Sport score compared with marrow stimulation and may be a more appropriate treatment in younger and more active individuals. There were no benefits to Mfx+Augment over Mfx alone in any of the KOOS subscales.

SARS-CoV-2 has caused symptomatic COVID-19 and widespread death across the globe. We sought to determine genetic variants contributing to COVID-19 susceptibility and hospitalization in a large biobank linked to a national United States health system. We identified 19,168 (3.7%) lab-confirmed COVID-19 cases among Million Veteran Program participants between March 1, 2020, and February 2, 2021, including 11,778 Whites, 4,893 Blacks, and 2,497 Hispanics. A multi-population genome-wide association study (GWAS) for COVID-19 outcomes identified four independent genetic variants (rs8176719, rs73062389, rs60870724, and rs73910904) contributing to COVID-19 positivity, including one novel locus found exclusively among Hispanics. We replicated eight of nine previously reported genetic associations at an alpha of 0.05 in at least one population-specific or the multi-population meta-analysis for one of the four MVP COVID-19 outcomes. We used rs8176719 and three additional variants to accurately infer ABO blood types. We found that A, AB, and B blood types were associated with testing positive for COVID-19 compared with O blood type with the highest risk for the A blood group. We did not observe any genome-wide significant associations for COVID-19 severity outcomes among those testing positive. Our study replicates prior GWAS findings associated with testing positive for COVID-19 among mostly White samples and extends findings at three loci to Black and Hispanic individuals. We also report a new locus among Hispanics requiring further investigation. These findings may aid in the identification of novel therapeutic agents to decrease the morbidity and mortality of COVID-19 across all major ancestral populations., Competing Interests: CD is now an employee of Novartis. MA received industry research grant support from Guardant Health and Genentech during the conduct of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Peloso, Tcheandjieu, McGeary, Posner, Ho, Zhou, Hilliard, Joseph, O’Donnell, Efird, Crawford, Wu, Arjomandi, Sun, Assimes and Huffman.)

Background: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ., Materials and Methods: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC., Results: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings., Conclusion: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The continued generation of large amounts of data within healthcare-from imaging to electronic medical health records to genomics and multi-omics -necessitates tools and methods to parse and interpret these data to improve healthcare outcomes. Artificial intelligence, and in particular deep learning, has enabled researchers to gain new insights from large scale and multimodal data. At the 2022 Pacific Symposium on Biocomputing (PSB) session entitled "Precision Medicine: Using Artificial Intelligence to Improve Diagnostics and Healthcare", we showcase the latest research, influenced and inspired by the idea of using technology to build a more fair, tailored, and cost-effective healthcare system after the COVID-19 pandemic.

Objective: Hypertension is more prevalent in African Americans (AA) than other ethnic groups. Genome-wide association studies (GWAS) have identified loci associated with hypertension and other cardio-metabolic traits like type 2 diabetes, coronary artery disease, and body mass index (BMI), however the AA population is underrepresented in these studies. In this study, we examined a large AA cohort for the generalizability of 14 Metabochip array SNPs with previously reported European hypertension associations., Methods: To evaluate associations, we analyzed genotype data of 14 SNPs for their associations with a diagnosis of hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in a case-control study of an AA population (N = 9,534). We also performed an age-stratified analysis (>30, 30≥59 and ≥60 years) following the hypertension definition described by the 8th Joint National Committee (JNC). Associations were adjusted for BMI, age, age2, sex, clinical confounders, and genetic ancestry using multivariable regression models to estimate odds ratios (ORs) and beta-coefficients. Analyses stratified by sex were also conducted. Meta-analyses (including both BioVU and COGENT-BP cohorts) were performed using a random-effects model., Results: We found rs880315 to be associated with systolic hypertension (SBP≥140 mmHg) in the entire cohort (OR = 1.14, p = 0.003) and within women only (OR = 1.16, p = 0.012). Variant rs17080093 associated with lower SBP and DBP (β = -2.99, p = 0.0352 and - β = 1.69, p = 0.0184) among younger individuals, particularly in younger women (β = -3.92, p = 0.0025 and β = -1.87, p = 0.0241 for SBP and DBP respectively). SNP rs1530440 associated with higher SBP and DBP measurements (younger individuals β = 4.1, p = 0.039 and β = 2.5, p = 0.043 for SBP and DBP; (younger women β = 4.5, p = 0.025 and β = 2.9, p = 0.028 for SBP and DBP), and hypertension risk in older women (OR = 1.4, p = 0.050). rs16948048 increases hypertension risk in younger individuals (OR = 1.31, p = 0.011). Among mid-age women rs880315 associated with higher risk of hypertension (OR = 1.20, p = 0.027). rs1361831 associated with DBP (β = -1.96, p = 0.02) among individuals older than 60 years. rs3096277 increases hypertension risk among older individuals (OR = 1.26 p = 0.0015), however, this variant also reduces SBP among younger women (β = -2.63, p = 0.0102)., Conclusion: These findings suggest that European-descent and AA populations share genetic loci that contribute to blood pressure traits and hypertension. However, the OR and beta-coefficient estimates differ, and some are age-dependent. Additional genetic studies of hypertension in AA are warranted to identify new loci associated with hypertension and blood pressure traits in this population., Competing Interests: Co-author Dana C. Crawford is a PLOS ONE Editorial Board member. Co-author William S. Bush is a PLOS ONE Statistical Advisory Board member. These memberships do not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.