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Background: In the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection.Methods: We performed a two-stage genetic association study of kidney allograft rejection. In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor-recipient pairs. We defined genomic collision as a specific donor-recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses.Results: In the discovery cohort, which included 705 recipients, we found a significant association with allograft rejection at the LIMS1 locus represented by rs893403 (hazard ratio with the risk genotype vs. nonrisk genotypes, 1.84; 95% confidence interval [CI], 1.35 to 2.50; P = 9.8×10-5). This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor-recipient pairs (hazard ratio, 1.55; 95% CI, 1.25 to 1.93; P = 6.5×10-5). In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype (hazard ratio, 1.63; 95% CI, 1.37 to 1.95; P = 4.7×10-8). We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses.Conclusions: We found that the LIMS1 locus appeared to encode a minor histocompatibility antigen. Genomic collision at this locus was associated with rejection of the kidney allograft and with production of anti-LIMS1 IgG2 and IgG3. (Funded by the Columbia University Transplant Center and others.). [ABSTRACT FROM AUTHOR]

BACKGROUND The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22qll.2; the genetic driver of the kidney defects is unknown. METHODS We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS We identified heterozygous deletions of 22qll.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5xl014). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS We identified a recurrent 370-kb deletion at the 22qll.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and is involved in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed a genome-wide association study of serum IgA levels in 41,263 individuals of diverse ancestries and identified 20 genome-wide significant loci, including 9 known and 11 novel loci. Co-localization analyses with expression QTLs prioritized candidate genes for 14 of 20 significant loci. Most loci encoded genes that produced immune defects and IgA abnormalities when genetically manipulated in mice. We also observed positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes, and body mass index, and negative correlations with celiac disease, inflammatory bowel disease, and several infections. Mendelian randomization supported elevated serum IgA as a causal factor in IgA nephropathy. African ancestry was consistently associated with higher serum IgA levels and greater frequency of IgA-increasing alleles compared to other ancestries. Our findings provide novel insights into the genetic regulation of IgA levels and its potential role in human disease., (© 2022. The Author(s).)

Even the best school physical education programs fall short of providing enough physical activity (PA) to meet students' PA guidelines thus increasing PA at other times throughout the school day could help students meet recommended PA levels. Unstructured leisure-time periods during the school day represent an opportunity to promote PA, particularly among students in underserved school districts. Between 2014 and 2018, we partnered with 14 elementary and 5 secondary schools in low-income Latino communities to increase students' leisure time moderate to vigorous physical activity (MVPA). Schools received consultation and technical assistance on their wellness policy, and some created wellness committees. Schools selected 1-2 PA/nutrition promotion activities for the academic year. Following the System for Observing Play and Leisure Activity in Youth protocol, we conducted a pre- vs. post- analysis of observations of school time student PA (levels of MVPA, energy expenditure, proportion of areas in which games and sports were prominent) in 4936 pre-intervention play areas and 4404 post-intervention areas before school, during lunch recess, and after school. We utilized linear and logistic regression analyses to test pre/post changes in these dependent variables using school area characteristics, period of observation, and temperature as covariates. Following our intervention, MVPA levels before school, during lunch recess, and after school increased significantly from 19.8% at baseline to 25.6% among elementary girls and from 25.4% to 33.2% among elementary boys. Decomposition of these effects suggested that the benefits were partially mediated by increased adult playground supervision. We did not observe any significant changes in PA levels among secondary school girls or boys. Our school-level intervention aimed at promoting PA was associated with modest but meaningful increases in leisure-time PA among elementary, but not secondary, school students. The effects were attributable in part to increased adult supervision on the playground., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Introduction: To examine the association of a novel disease-specific health plan, known as the Diabetes Health Plan (DHP), with emergency room (ER) and hospital utilization among patients with diabetes and pre-diabetes., Research Design and Methods: Quasi-experimental design, with employer group as the unit of analysis, comparing changes in any ER and inpatient hospital utilization over a 3-year period. Inverse probability weighting was used to control for differences between employers purchasing DHP versus standard plans. Estimated differences in utilization are calculated as average treatment effects on the treated. We used employees and dependents from employer groups contracting with a large, national private insurer between 2009 and 2012. Eligibility and claims data from continuously covered employees and dependents with diabetes and pre-diabetes (n=74 058) were aggregated to the employer level. The analysis included 9 DHP employers (n=7004) and 183 control employers (n=67 054)., Results: DHP purchase was associated with 2.4 and 1.8 percentage points absolute reduction in mean rates of any ER utilization, representing 13% and 10% relative reductions at 1 and 2 years post-DHP (p=0.012 and p=0.046, respectively). There was no significant association between DHP purchase and hospital utilization., Conclusion: Employers purchasing diabetes-specific health benefit designs may experience lower rates of resource-intensive services such as ER utilization., Competing Interests: Competing interests: TM received support from the Department of Veterans Affairs under grants QUE15-272, QUE15-286, and CSP2002, the NIH/National Istitute of Diabetes and Digestive and Kidnet Disease (NIDDK) under grant 1R01DK124503-01 and the Centers for Disease Control and Prevention (CDC) under grant U18DP006140.CMM and KD received support from the University of California at Los Angeles (UCLA), by the NIH/NIDDK under grant R18DK105464, the CDC under grant U18DP006140, and from the Patient-Centered Outcomes Research Institute (PCORI) under grant SDM-2018C2-13543. CMM also received support from NIH/National Center for Advancing Translational Sciences UCLA Clinical and Translational Science Institute under grant UL1TR001881. CMM holds the Barbara A Levey and Gerald S Levey Endowed Chair in Medicine, which partially supported her work. CMM is a member of the United States Preventive Services Task Force (USPSTF). KD also received support from the Terasaki Family Foundation under grant 20191425. CMM, KD and NS received support from the Resource Centers for Minority Aging Research Center for Health Improvement of Minority Elderly under National Institutes of Health (NIH)/NIA under grant P30AG021684., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The membrane proximal external region (MPER) of HIV-1 gp41 is targeted by several neutralizing antibodies (NAbs) and is of interest for vaccine design. In this study, we identified novel MPER peptide mimotopes and evaluated their reactivity with HIV + plasma antibodies to characterize the diversity of the immune responses to MPER during natural infection. We utilized phage display technology to generate novel mimotopes that fit antigen-binding sites of MPER NAbs 4E10, 2F5 and Z13. Plasma antibodies from 10 HIV + patients were mapped by phage immunoprecipitation, to identify unique patient MPER binding profiles that were distinct from, and overlapping with, those of MPER NAbs. 4E10 mimotope binding profiles correlated with plasma neutralization of HIV-2/HIV-1 MPER chimeric virus, and with overall plasma neutralization breadth and potency. When administered as vaccines, 4E10 mimotopes elicited low titer NAb responses in mice. HIV mimotopes may be useful for detailed analysis of plasma antibody specificity., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: Training in high-spending regions correlates with higher spending patterns among practicing physicians. This study aimed to evaluate whether trainees' exposure to a high-value care culture differed based on type of health system in which they trained., Method: In 2016, 517 internal medicine residents at 12 California graduate medical education programs (university, community, and safety-net medical centers) completed a cross-sectional survey assessing perceptions of high-value care culture within their respective training program. The authors used multilevel linear regression to assess the relationship between type of medical center and High-Value Care Culture Survey (HVCCS) scores. The correlation between mean institutional HVCCS and Centers for Medicare and Medicaid Services' Value-Based Purchasing (VBP) scores was calculated using Spearman rank coefficients., Results: Of 517 residents, 306 (59.2%), 83 (16.1%), and 128 (24.8%) trained in university, community, and safety-net programs, respectively. Across all sites, the mean HVCCS score was 51.2 (standard deviation [SD] 11.8) on a 0-100 scale. Residents reported lower mean HVCCS scores if they were from safety-net-based training programs (β = -4.4; 95% confidence interval: -8.2, -0.6) with lower performance in the leadership and health system messaging domain (P < .001). Mean institutional HVCCS scores among university and community sites positively correlated with institutional VBP scores (Spearman r = 0.71; P < .05)., Conclusions: Safety-net trainees reported less exposure to aspects of high-value care culture within their training environments. Tactics to improve the training environment to foster high-value care culture include training, increasing access to data, and improving open communication about value.

Background: School initiatives aimed at increasing physical activity (PA) may improve the health of children in low-income communities., Methods: Assessors completed 5909 observations of students' PA during leisure periods using a validated instrument in 19 schools in low-income Latino communities. We examined relationships between school environment factors (eg, presence of playground equipment) and levels of moderate-to-vigorous physical activity (MVPA)., Results: Overall, 16.4% of students were engaged in vigorous activity, lower than reported in prior analyses. Consistent with earlier reports, boys were more engaged in vigorous PA than girls (18.6% vs 13.2%). Playground equipment, such as balls and jump ropes, were present in 27.5% of activity areas. Supervision was present in 83.1% of observations; however, staff members were only observed leading organized activity in 1.7%. Playground equipment was associated with higher rates of MVPA, particularly among elementary boys (p < .0001). Staff supervision was not associated with MVPA, possibly because staff members rarely led organized activity., Conclusions: We found low rates of leisure time PA among students in this low-income Latino community. The presence of playground equipment was favorably associated with activity levels. Increasing the availability of playground equipment might promote activity among children in similar populations., (© 2019, American School Health Association.)

Background: Given the national emphasis on affordability, healthcare systems expect that their clinicians are motivated to provide high-value care. However, some hospitalists are reimbursed with productivity bonuses, and little is known about the effects of these reimbursements on the local culture of high-value care delivery., Objective: To evaluate if hospitalist reimbursement models are associated with high-value culture in university, community, and safety-net hospitals., Design, Setting, Patients: Internal medicine hospitalists from 12 hospitals across California completed a cross-sectional survey assessing their perceptions of high-value care culture within their institutions. Sites represented university, community, and safety-net centers with different performances as reflected by the Centers of Medicare and Medicaid Service's Value-based Purchasing (VBP) scores., Measurement: Demographic characteristics and High-Value Care Culture Survey (HVCCSTM) scores were evaluated using descriptive statistics, and associations were assessed through multilevel linear regression., Results: Of the 255 hospitalists surveyed, 147 (57.6%) worked in university hospitals, 85 (33.3%) in community hospitals, and 23 (9.0%) in safety-net hospitals. Across all 12 sites, 166 (65.1%) hospitalists reported payment with salary or wages, and 77 (30.2%) with salary plus productivity adjustments. The mean HVCCS score was 50.2 (SD 13.6) on a 0-100 scale. Hospitalists reported lower mean HVCCS scores if they reported payment with salary plus productivity (β = -6.2, 95% CI -9.9 to -2.5) than if they reported payment with salary or wages., Conclusions: Hospitalists paid with salary plus productivity reported lower high-value care culture scores for their institutions than those paid with salary or wages. High-value care culture and clinician reimbursement schemes are potential targets of strategies for improving quality outcomes at low cost., (© 2018 Society of Hospital Medicine.)

Background: Organisational culture affects physician behaviours. Patient safety culture surveys have previously been used to drive care improvements, but no comparable survey of high-value care culture currently exists. We aimed to develop a High-Value Care Culture Survey (HVCCS) for use by healthcare leaders and training programmes to target future improvements in value-based care., Methods: We conducted a two-phase national modified Delphi process among 28 physicians and nurse experts with diverse backgrounds. We then administered a cross-sectional survey at two large academic medical centres in 2015 among 162 internal medicine residents and 91 hospitalists for psychometric evaluation., Results: Twenty-six (93%) experts completed the first phase and 22 (85%) experts completed the second phase of the modified Delphi process. Thirty-eight items achieved ≥70% consensus and were included in the survey. One hundred and forty-one residents (83%) and 73 (73%) hospitalists completed the survey. From exploratory factor analyses, four factors emerged with strong reliability: (1) leadership and health system messaging (α=0.94); (2) data transparency and access (α=0.80); (3) comfort with cost conversations (α=0.70); and (4) blame-free environment (α=0.70). In confirmatory factor analysis, this four-factor model fit the data well (Bentler-Bonett Normed Fit Index 0.976 and root mean square residual 0.056). The leadership and health system messaging (r=0.56, p<0.001), data transparency and access (r=0.15, p<0.001) and blame-free environment (r=0.37, p<0.001) domains differed significantly between institutions and positively correlated with Value-Based Purchasing Scores., Conclusions: Our results provide support for the reliability and validity of the HVCCS to assess high-value care culture among front-line clinicians. HVCCS may be used by healthcare groups to identify target areas for improvements and to monitor the effects of high-value care initiatives., Competing Interests: Competing interests: RG is the Director of Outreach and Evaluation and the Director of the Teaching Value in Healthcare Learning Network at Costs of Care. She is supported by the VA Office of Academic Affiliations through the VA/Robert Wood Johnson Clinical Scholars Program. CM receives royalties from McGraw Hill for the textbook ‘Understanding Value-based Healthcare’, outside of the submitted work and is the Director of Implementation at Costs of Care. RDH was supported in part by grants from the NIA (No. P30-AG021684) and the NIMHD (No. P20-MD000182). CHB is the Vice Dean for Education at the David Geffen School of Medicine at UCLA and the chair of the American Board of Internal Medicine. RW reports that he is a member of the Lucian Leape Institute of the National Patient Safety Foundation (for which he receives no compensation); is currently chairing an advisory board to England's National Health Service reviewing the NHS’ digital health strategy (no compensation); has a contract to UCSF from the Agency for Healthcare Research and Quality to edit a patient-safety website; receives compensation from John Wiley and Sons for writing a blog; receives royalties from Lippincott Williams & Wilkins and McGraw-Hill for writing/editing several books; received a stipend and stock options for having previously served on the Board of Directors of IPC Healthcare; receives stock options for serving on the board of Accuity Medical Management Systems; serves on the scientific advisory boards for Amino.com, PatientSafe Solutions, QPID Health, Twine and EarlySense (for which he receives stock options); and holds the Benioff endowed chair in hospital medicine from Marc and Lynne Benioff. RG and CM had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

MHC class I dependent CD8(+) T cells are essential for protection induced by radiation-attenuated Plasmodium sporozoites (RAS) in murine malaria models. Apart from the mechanism of activation of CD8(+) T cells specific for the circumsporozoite protein, the major sporozoite antigen (Ag), CD8(+) T cells specific for other exoerythrocytic Ags that have been shown to mediate protection have not been thoroughly investigated. Specifically, mechanisms of processing and presentation of exoerythrocytic Ags, which includes liver stage (LS) Ags, remain poorly understood. We hypothesize that as exogenous proteins, LS Ags are processed by mechanisms involving either the TAP-dependent phagosomal-to-cytosol or TAP-independent vacuolar pathway of cross-presentation. We used TAP-deficient mice to investigate whether LS Ag mediated induction of naïve CD8(+) T cells and their recall during sporozoite challenge occur by the TAP-dependent or TAP-independent pathways. On the basis of functional attributes, CD8(+) T cells were activated via the TAP-independent pathway during immunizations with Plasmodium berghei RAS; however, IFN-γ(+) CD8(+) T cells previously induced by P. berghei RAS in TAP-deficient mice failed to be recalled against sporozoite challenge and the mice became parasitemic. On the basis of these observations, we propose that TAP-associated Ag processing is indispensable for sterile protection induced with P. berghei RAS., (Published 2015. This article is a U.S. Government work and is in the public domain in the USA.)

Aim: Identify what factors rural women perceived to influence their surgical choice for EBC., Background: Higher rates of mastectomy still remain for women with early breast cancer (EBC) in rural areas. While access to radiotherapy is a commonly identified barrier, there is growing debate around other factors which are also important influences on surgical choice., Methods: Qualitative study with 70 interviews with women diagnosed with EBC in rural Gippsland, Australia. Twenty-nine women had a mastectomy and 41 had breast conserving surgery (BCS)., Results: Patient led psychosocial and surgeon led factors influenced surgical choice. Psychosocial factors were a greater influence for the mastectomy group. These included a high fear of cancer recurrence and radiotherapy, negative views of the body and breast, a family history of cancer, wanting to avoid the negative treatment experiences they had seen significant others go through, and not wanting to travel for treatment. Surgeon led factors were a greater influence for the BCS group, in particular, the direct recommendation made by the surgeon for BCS. For both groups, urgency to act was a shared psychosocial factor. Trust and confidence in the expertise and reputation of the surgeon and their consultation style were surgeon led factors shared by the groups., Conclusions: To ensure women achieve the best treatment outcome, patients and clinicians need to work together to identify how important and influential the various factors are for the women and, if necessary, to seek support to ensure informed decisions are made., (© 2014 John Wiley & Sons Ltd.)

Objective: To determine opinions of faculty members with clinical appointments, clinical veterinarians, residents, and interns at a US veterinary teaching hospital regarding antimicrobial use and antimicrobial-resistant infections., Design: Cross-sectional survey., Sample: 71 veterinarians., Procedures: An online questionnaire was sent to all veterinarians with clinical service responsibilities at the North Carolina State University veterinary teaching hospital (n = 167). The survey included 23 questions regarding demographic information, educational experiences, current prescribing practices, and personal opinions related to antimicrobial selection, antimicrobial use, restrictions on antimicrobial use, and antimicrobial resistance., Results: Of the 167 veterinarians eligible to participate, 71 (43%) responded. When respondents were asked to rate their level of concern (very concerned = 1; not concerned = 5) about antimicrobial-resistant infections, most (41/70 [59%]) assigned a score of 1, with mean score for all respondents being 1.5. Most survey participants rated their immediate colleagues (mean score, 1.9) as more concerned than other veterinary medical professionals (mean score, 2.3) and their clients (mean score, 3.4). Fifty-nine of 67 (88%) respondents felt that antimicrobials were overprescribed at the hospital, and 32 of 69 (46%) respondents felt uncomfortable prescribing at least one class of antimicrobials (eg, carbapenems or glycopeptides) because of public health concerns., Conclusions and Clinical Relevance: Findings indicated that veterinarians at this teaching hospital were concerned about antimicrobial resistance, thought antimicrobials were overprescribed, and supported restricting use of certain antimicrobial classes in companion animals. Findings may be useful in educating future veterinarians and altering prescribing habits and antimicrobial distribution systems in veterinary hospitals.