The hazards of genotype imputation when mapping disease susceptibility variants.

BACKGROUND: The cost-free increase in statistical power of using imputation to infer missing genotypes is undoubtedly appealing, but is it hazard-free? This case study of three type-2 diabetes (T2D) loci demonstrates that it is not; it sheds light on why this is so and raises concerns as to the shortcomings of imputation at disease loci, where haplotypes differ between cases and reference panel. RESULTS: T2D-associated variants were previously identified using targeted sequencing. We removed these significantly associated SNPs and used neighbouring SNPs to infer them by imputation. We compared imputed with observed genotypes, examined the altered pattern of T2D-SNP association, and investigated the cause of imputation errors by studying haplotype structure. Most T2D variants were incorrectly imputed with a low density of scaffold SNPs, but the majority failed to impute even at high density, despite obtaining high certainty scores. Missing and discordant imputation errors, which were observed disproportionately for the risk alleles, produced monomorphic genotype calls or false-negative associations. We show that haplotypes carrying risk alleles are considerably more common in the T2D cases than the reference panel, for all loci. CONCLUSIONS: Imputation is not a panacea for fine mapping, nor for meta-analysing multiple GWAS based on different arrays and different populations. A total of 80% of the SNPs we have tested are not included in array platforms, explaining why these and other such associated variants may previously have been missed. Regardless of the choice of software and reference haplotypes, imputation drives genotype inference towards the reference panel, introducing errors at disease loci.

Dearomative Access to (-)-Thebaine and Derivatives.

A synthesis of the natural product thebaine is reported in eight steps from commercially available starting materials, hinging on the dearomatization and coupling of simple aromatic starting materials. This provides divergent access to two unnatural opioid derivatives and is aimed at the long-term development of synthetic opioid analogs of the "wonderdrug" Naloxone. Additionally, a formal enantioselective synthesis of all reported targets is disclosed that leverages a catalytic asymmetric dearomatization via anion-pairing catalysis.

Microvascular maturation of the septal capillary layers takes place in parallel to alveolarization in human lungs.

Primary and secondary septa formed during lung development contain a double-layered capillary network. To improve gas exchange, the capillary network is remodeled into a single-layered one, a process that is called microvascular maturation (MVM). It takes place during classical and continued alveolarization. Classical alveolarization is defined as a formation of new septa from immature septa and continued alveolarization as a formation from mature septa. Until now, MVM was never quantitatively evaluated in human lungs. To correlate alveolarization and MVM, and to determine the transition point from classical to continued alveolarization, the degree of MVM was stereologically estimated. In 12 human lungs (0.1-15 yr), the alveolar surface area of immature and mature septa was estimated stereologically by intersection counting. An MVM-quotient (RMVM) was defined as the mature alveolar surface area over total alveolar surface area. The MVM-quotient increased logarithmically over age and showed a biphasic increase similar to alveolarization. It did not reach 100% maturity in these samples. A linear correlation between the MVM-quotient and the logarithm of the number of alveoli was observed. We conclude that MVM increased logarithmically and biphasically in parallel to alveolarization until alveolarization ceased. However, at 2-3 yr of age three-quarters of the alveolar microvasculature are mature. This result may explain a previous postulate that MVM is finished at this age. We hypothesize that as long as alveolarization takes place, MVM will take place in parallel. We propose that the transition from classical to continued alveolarization takes place between the ages of 1-3 yr in humans.NEW & NOTEWORTHY Newly formed alveolar septa contain a double-layered capillary network. To optimize gas exchange, the two layers fuse to a single-layered capillary network during microvascular maturation. Because its timing is unknow in humans, microvascular maturation was stereologically estimated throughout postnatal human lung development. It is shown that maturation of the microvascular and alveolar septa takes place in parallel to alveolarization. At an age of 2-3 yr three-quarters of the septa are mature.

Self-Compassion, Minority Stress, and Mental Health in Sexual and Gender Minority Populations: A Meta-Analysis and Systematic Review.

Sexual and gender minority (SGM) populations report numerous mental health disparities relative to heterosexual and cisgender populations, due in part to the effects of minority stress. This article evaluated self-compassion as a coping resource among SGM populations by (a) meta-analyzing the associations between self-compassion, minority stress, and mental health; and (b) synthesizing evidence for the mediating effects of self-compassion between minority stress and mental health. Systematic searches of databases identified 21 papers for the systematic review and 19 for the meta-analysis. Significant meta-analytic associations were found between self-compassion and minority stress (n = 4,296, r = -.29), psychological distress (n = 3,931, r = -.59), and well-being (n = 2,493, r = .50). The research synthesis identified supporting evidence for self-compassion as a coping resource for SGM people. The results of this review warrant further self-compassion research, particularly longitudinal research, for SGM populations.

The Heart of Rett Syndrome: A Quantitative Analysis of Cardiac Repolarization.

Background: Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies. Electrocardiogram (ECG) abnormalities, such as prolonged heart-rate corrected QT (QTc) interval, are markers of cardiac repolarization and are associated with potentially lethal ventricular arrhythmias. This study investigates the cardiac repolarization characteristics of RTT patients, including QTc and T-wave morphology characteristics. Methods: A retrospective quantitative analysis on 110 RTT patients and 124 age and sex-matched healthy controls was conducted. Results: RTT patients had longer QTc, more abnormal T-wave morphology, and greater heterogeneity of cardiac repolarization parameters compared to controls. Even RTT patients without prolonged QTc had more abnormal ECG and T-wave characteristics than controls. Among RTT patients, MECP2 patients had prolonged QTc compared to CDKL5 and FOXG1 patients. A subset of five RTT patients who died had normal QTc, but more abnormal T-wave morphology than the remaining RTT patients. Conclusions: Cardiac repolarization abnormalities are present in RTT patients, even without long QTc. T-wave morphology is related to RTT genotype and may be predictive of mortality. These findings could be used to help the management and monitoring of RTT patients.

Epidemiologic Features of the Monkeypox Outbreak and the Public Health Response - United States, May 17-October 6, 2022.

On May 17, 2022, the Massachusetts Department of Health announced the first suspected case of monkeypox associated with the global outbreak in a U.S. resident. On May 23, 2022, CDC launched an emergency response (1,2). CDC's emergency response focused on surveillance, laboratory testing, medical countermeasures, and education. Medical countermeasures included rollout of a national JYNNEOS vaccination strategy, Food and Drug Administration (FDA) issuance of an emergency use authorization to allow for intradermal administration of JYNNEOS, and use of tecovirimat for patients with, or at risk for, severe monkeypox. During May 17-October 6, 2022, a total of 26,384 probable and confirmed* U.S. monkeypox cases were reported to CDC. Daily case counts peaked during mid-to-late August. Among 25,001 of 25,569 (98%) cases in adults with information on gender identity,† 23,683 (95%) occurred in cisgender men. Among 13,997 cisgender men with information on recent sexual or close intimate contact,§ 10,440 (75%) reported male-to-male sexual contact (MMSC) ≤21 days preceding symptom onset. Among 21,211 (80%) cases in persons with information on race and ethnicity,¶ 6,879 (32%), 6,628 (31%), and 6,330 (30%) occurred in non-Hispanic Black or African American (Black), Hispanic or Latino (Hispanic), and non-Hispanic White (White) persons, respectively. Among 5,017 (20%) cases in adults with information on HIV infection status, 2,876 (57%) had HIV infection. Prevention efforts, including vaccination, should be prioritized among persons at highest risk within groups most affected by the monkeypox outbreak, including gay, bisexual, and other men who have sex with men (MSM); transgender, nonbinary, and gender-diverse persons; racial and ethnic minority groups; and persons who are immunocompromised, including persons with advanced HIV infection or newly diagnosed HIV infection.

Inhibition of bromodomain extraterminal histone readers alleviates skin fibrosis in experimental models of scleroderma.

Binding of the bromodomain and extraterminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. We sought to determine the antifibrotic efficacy and potential mechanisms of BET inhibition in systemic sclerosis (SSc). Blockade of BETs was done using a pan-BET inhibitor, JQ1; BRD2 inhibitor, BIC1; or BRD4 inhibitors AZD5153 or ARV825. BET inhibition, specifically BRD4 blockade, showed antifibrotic effects in an animal model of SSc and in patient-derived diffuse cutaneous SSc (dcSSc) fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium (Ca2+) signaling. The antifibrotic effect of BRD4 inhibition was mediated at least in part by downregulation of Ca2+/calmodulin-dependent protein kinase II α and reduction of intracellular Ca2+ concentrations. On the basis of these results, we propose targeting Ca2+ pathways or BRD4 as potentially novel therapeutic approaches for progressive tissue fibrosis.

Transgender and Gender Diverse Fertility Choices: Supporting the Decision-Making Process for Adolescents and Young Adults.

OBJECTIVE: To qualitatively examine the fertility-related decision making process of transgender and gender diverse (TGD) adolescents and young adults (AYAs) and their parents, in the setting of pursing gender affirming treatments. STUDY DESIGN: Twenty-five TGD AYAs and 6 parents of TGD AYAs participated in a focus group or individual semistructured interviews focused on participants' experience learning about the effects of gender affirming treatments on fertility as well as the process of making a fertility preservation decision. Using open coding, data were analyzed in an iterative process identifying emerging themes and relationships. A decisional satisfaction score was collected and/or coded for each participant. RESULTS: Four broad themes related to the decision-making process were identified: (1) Critical steps include awareness, gathering information, and conversations; (2) External constraints limit choices; (3) Expanding the conversation beyond preservation; and (4) Emotional distress, conflict, and decisional satisfaction. Despite reporting emotional distress or conflict during the decision, TGD AYAs and parents of TGD AYAs generally reported a high level of satisfaction with their fertility preservation decision. CONCLUSIONS: There are specific ways health care professionals and family members can support TGD AYAs in their fertility-related decision making process. Decisional satisfaction was common, regardless of whether TGD AYAs chose to pursue fertility preservation or not.

The hazards of genotype imputation in chromosomal regions under selection: A case study using the Lactase gene region.

Although imputation of missing SNP results has been widely used in genetic studies, claims about the quality and usefulness of imputation have outnumbered the few studies that have questioned its limitations. But it is becoming clear that these limitations are real-for example, disease association signals can be missed in regions of LD breakdown. Here, as a case study, using the chromosomal region of the well-known lactase gene, LCT, we address the issue of imputation in the context of variants that have become frequent in a limited number of modern population groups only recently, due to selection. We study SNPs in a 500 bp region covering the enhancer of LCT, and compare imputed genotypes with directly genotyped data. We examine the haplotype pairs of all individuals with discrepant and missing genotypes. We highlight the nonrandom nature of the allelic errors and show that most incorrect imputations and missing data result from long haplotypes that are evolutionarily closely related to those carrying the derived alleles, while some relate to rare and recombinant haplotypes. We conclude that bias of incorrectly imputed and missing genotypes can decrease the accuracy of imputed results substantially.

Effect of Bone Coverage on Acetabular Implant Stresses in Standard and Dual-Mobility Total Hip Arthroplasty Constructs: A Finite Element Model.

Although mechanical stress in total hip arthroplasty modular head-neck junctions is thought to contribute to the risk of trunnionosis and related metal ion disease in total hip arthroplasty, little is known about mechanical stress in the modular acetabular components. Recent retrieval analyses of dual-mobility constructs have demonstrated corrosion between liner and shell in some dual-mobility acetabular components. The objective of this study was to evaluate acetabular stress as a function of acetabular bone coverage, component modularity, and femoral head diameter. A parametric finite element model was created. The acetabulum was set at 40° of abduction and 15° of anteversion; superolateral bone loss up to 50° was modeled; and 28-mm, 32-mm, 36-mm, and 40-mm head sizes were simulated in stance phase of gait. Fixed polyethylene-bearing, monoblock and modular dual-mobility (MDM) acetabular components were evaluated. For traditional fixed-bearing components, the largest peak stress, 49.5 MPa, was observed with 50° of bone loss and a 28-mm head. The lowest peak stress, 6.3 MPa, occurred with complete bone coverage and a 36-mm head. Peak stress in the MDM construct, 25.1 MPa, concentrated in the chromium-cobalt portion of the construct. Larger head diameters are associated with decreased stress in the acetabular component when bone loss is present. An MDM construct with a stiff inner liner may decrease overall stress in the acetabular construct, but focally increased stress near the rim of uncovered acetabular components may increase the risk of metal-on-metal corrosion. [Orthopedics. 2021;44(5):280-284.].

Increased Load to Failure in Biceps Tenodesis With All-Suture Suture Anchor Compared With Interference Screw: A Cadaveric Biomechanical Study.

PURPOSE: To compare the biomechanical characteristics of a single radially expanding all-suture anchor with an interference screw for open subpectoral long head of biceps tendon (LHBT) tenodesis. METHODS: Eighteen fresh-frozen matched-pair human cadaveric humeri were used for this biomechanical study. The matched pair humeri were randomly assigned into 2 experimental biceps tenodesis groups: conventional interference screw (CIS) or all-suture suture anchor (ASSA). Open subpectoral LHBT tenodesis was then performed and biomechanical testing was performed using a servohydraulic test frame. A preload of 5 N was applied for 2 minutes before cyclic loading. Displacement was recorded at cycle 300 (D300) and cycle 500 (D500) and at ultimate failure. Data recorded included displacement, load to failure, displacement at failure. Paired t test was used for analysis. RESULTS: Decreased displacement was observed for the CIS group at D300 (1.67 ± 0.57 mm vs 3.35 ± 2.24 mm; P = .04), D500 (2.00 ± 0.76 mm vs 3.87 ± 2.20 mm; P = .04), and at failure (5.17 ± 3.05 mm vs 10.76 ± 2.66 mm; P < .001). Load to failure was lower in CIS specimens (170 ± 24.5 N vs 217.8 ± 51.54 N; P = .02). Failure in each case was tendon pullout for all CIS specimens; in ASSA 6 specimens failed as the suture pulled through the tendon, 2 specimens failed by suture breakage. No difference in stiffness was observed between the 2 groups (CIS = 98.33 ± 22.98 N/m vs ASSA = 75.94 ± 44.83 N/m; P = .20). CONCLUSIONS: Our study found that open subpectoral biceps tenodesis performed with an ASSA construct results in increased load to failure as compared with CIS. However, the CIS did demonstrate decreased displacement as compared to ASSA in this cadaveric biomechanical study. CLINICAL RELEVANCE: ASSA and CIS at time zero provide fixation as indicated by the provider intraoperatively for LHBT tenodesis. ASSA, however, does remove less cortical bone than does CIS and therefore produces a smaller stress riser in the proximal humerus. Further testing as to the integrity of ASSA is warranted to determine the integrity of the tenodesis with cyclical loading.

Group-based pharmacogenetic prediction: is it feasible and do current NHS England ethnic classifications provide appropriate data?

Inter-individual variation of drug metabolising enzymes (DMEs) leads to variable efficacy of many drugs and even adverse drug responses. Consequently, it would be desirable to test variants of many DMEs before drug treatment. Inter-ethnic differences in frequency mean that the choice of SNPs to test may vary across population groups. Here we examine the utility of testing representative groups as a way of assessing what variants might be tested. We show that publicly available population information is potentially useful for determining loci for pre-treatment genetic testing, and for determining the most prevalent risk haplotypes in defined groups. However, we also show that the NHS England classifications have limitations for grouping for these purposes, in particular for people of African descent. We conclude: (1) genotyping of hospital patients and people from the hospital catchment area confers no advantage over using samples from appropriate existing ethnic group collections or publicly available data, (2) given the current NHS England Black African grouping, a decision as to whether to test, would have to apply to all patients of recent Black African ancestry to cover reported risk alleles and (3) the current scarcity of available genome and drug effect data from Africans is a problem for both testing and treatment decisions.

Organized lymphatic tissue (BALT) in lungs of rhesus monkeys after air pollutant exposure.

The presence of bronchus-associated lymphoid tissue (BALT) and its size in humans largely depends upon age. It is detected in 35% of children less than 2 years of age, but absent in the healthy adult lung. Environmental gases or allergens may have an effect on the number of BALT. Lungs of rhesus macaque monkeys were screened by histology for the presence, size, and location of BALT after exposure to filtered air for 2, 6, 12, or 36 months or 12 and 36 months to ozone or 2, 12, or 36 months of house dust mite or a combination of ozone and house dust mite for 12 months. In the lungs of monkeys housed in filtered air for 2 months, no BALT was identified. After 6, 12, or 36 months, the number of BALT showed a significantly increased correlation with age in monkeys housed in filtered air. After 2 months of episodic house dust mite (HDM) exposure, no BALT was found. Monkeys exposed to HDM or HDM + ozone did not show a significant increase in BALT compared to monkeys housed in filtered air. However, monkeys exposed to ozone alone did show significant increases in BALT compared to all other groups. In particular, there were frequent accumulations of lymphocytes in the periarterial space of ozone exposed animals. In conclusion, BALT in rhesus monkeys housed under filtered air conditions is age-dependent. BALT significantly increased in monkeys exposed to ozone in comparison with monkeys exposed to HDM.

Mindfulness for healthcare providers fosters professional quality of life and mindful attention among emergency medical technicians.

OBJECTIVE: Emergency medical service (EMS) providers are systematically subjected to intense stimuli in their work that may result in distress and emotional suffering. While it is known that mindfulness-based stress reduction (MBSR) helps to foster well-being in healthcare workers, the effectiveness of MBSR among EMS providers is less understood. We explored the impact of a modified version of MBSR for healthcare workers called Mindfulness for Healthcare Providers (MHP) on reducing distress and promoting wellbeing in EMS providers. METHODS: A one-arm pilot study was conducted. We implemented eight two-and-a-half hour sessions of Mindfulness for Healthcare Providers with an additional day-long retreat at the end. Feasibility, perceived stress, professional quality of life, and trait mindfulness were assessed prior to and after the intervention. The professional quality of life scale includes measures of compassion satisfaction, burnout, and secondary trauma. RESULTS: Fifteen veteran EMS providers enrolled in the course; four participants dropped out. Prior to initiation of the study, no significant differences were revealed between those who did not participate (n = 48) and those who did (n = 11). After the intervention EMS providers endorsed statistically significant increases in compassion satisfaction, trait mindfulness, and decreases in burnout compared to the beginning of the program. These changes were sustained at six months post-completion. No significant changes over time were found for secondary trauma or perceived stress. CONCLUSIONS: To our knowledge, this study is the first to employ Mindfulness for Healthcare Providers in an EMS population and to demonstrate a positive impact on self-reported compassion, trait mindfulness, and burnout in this population. Additional research regarding mindfulness training within EMS populations should be conducted to further understand the relationship between mindfulness and perceived stress over time.

Zoledronic Acid Improves Muscle Function in Healthy Mice Treated with Chemotherapy.

Carboplatin is a chemotherapy drug used to treat solid tumors but also causes bone loss and muscle atrophy and weakness. Bone loss contributes to muscle weakness through bone-muscle crosstalk, which is prevented with the bisphosphonate zoledronic acid (ZA). We treated mice with carboplatin in the presence or absence of ZA to assess the impact of bone resorption on muscle. Carboplatin caused loss of body weight, muscle mass, and bone mass, and also led to muscle weakness as early as 7 days after treatment. Mice treated with carboplatin and ZA lost body weight and muscle mass but did not lose bone mass. In addition, muscle function in mice treated with ZA was similar to control animals. We also used the anti-TGFß antibody (1D11) to prevent carboplatin-induced bone loss and showed similar results to ZA-treated mice. We found that atrogin-1 mRNA expression was increased in muscle from mice treated with carboplatin, which explained muscle atrophy. In mice treated with carboplatin for 1 or 3 days, we did not observe any bone or muscle loss, or muscle weakness. In addition, reduced caloric intake in the carboplatin treated mice did not cause loss of bone or muscle mass, or muscle weakness. Our results show that blocking carboplatin-induced bone resorption is sufficient to prevent skeletal muscle weakness and suggests another benefit to bone therapy beyond bone in patients receiving chemotherapy. © 2019 American Society for Bone and Mineral Research.

Benefits of Using The Pause after Death in Emergency Departments: A Delphi Study.

OBJECTIVE: The Pause is a short-term, microbreak created by an emergency nurse in 2009. It provides care team members a few seconds of silence to honor a patient who has died while also honoring the efforts of the team. It is used now on four continents as a standard of care. We investigated how it is being used and why. METHODS: We used a modified Delphi methodology with purposive sampling and a descriptive approach. During the three-round Delphi, we created a data display using open, then axial coding to develop a thematic analysis. Member checking and reflexivity exercises were used to build reliability and trustworthiness of findings. RESULTS: We analyzed 21 transcripts. The Pause is reported to be an ongoing practice in at least 23 health systems globally. Key themes such as Benefits, Self-Care, and Support of other Patients were most pertinent in our analysis. CONCLUSION: The Pause is a low-risk, grassroots intervention that can be led by any member of a care team in emergency settings. It offers self-care for the individual and team. It helps emergency providers feel grounded after a death before going to treat another patient. According to our sample, The Pause helps reduce caregiver stress, which may decrease the risk for burnout. Although further research is recommended, we assert that The Pause be used as a standard of care in emergency departments across the United States.

Inhibition of EZH2 Ameliorates Lupus-Like Disease in MRL/lpr Mice.

OBJECTIVE: We previously identified a role for EZH2, a transcriptional regulator in inducing proinflammatory epigenetic changes in lupus CD4+ T cells. This study was undertaken to investigate whether inhibiting EZH2 ameliorates lupus-like disease in MRL/lpr mice. METHODS: EZH2 expression levels in multiple cell types in lupus patients were evaluated using flow cytometry and messenger RNA expression data. Inhibition of EZH2 in MRL/lpr mice was achieved by intraperitoneal 3'-deazaneplanocin (DZNep) administration using a preventative and a therapeutic treatment model. Effects of DZNep on animal survival, anti-double-stranded DNA (anti-dsDNA) antibody production, proteinuria, renal histopathology, cytokine production, and T and B cell numbers and percentages were assessed. RESULTS: EZH2 expression levels were increased in whole blood, neutrophils, monocytes, B cells, and CD4+ T cells in lupus patients. In MRL/lpr mice, inhibition of EZH2 by DZNep was confirmed by significant reduction of EZH2 and H3K27me3 in splenocytes. Inhibiting EZH2 with DZNep treatment before or after disease onset improved survival and significantly reduced anti-dsDNA antibody production. DZNep-treated mice displayed a significant reduction in renal involvement, splenomegaly, and lymphadenopathy. Lymphoproliferation and numbers of double-negative T cells were significantly reduced in DZNep-treated mice. Concentrations of circulating cytokines and chemokines, including tumor necrosis factor, interferon-γ, CCL2, RANTES/CCL5, interleukin-10 (IL-10), keratinocyte-derived chemokine/CXCL1, IL-12, IL-12p40, and CCL4/macrophage inflammatory protein 1ß, were decreased in DZNep-treated mice. CONCLUSION: EZH2 is up-regulated in multiple cell types in lupus patients. Therapeutic inhibition of EZH2 abrogates lupus-like disease in MRL/lpr mice, suggesting that EZH2 inhibitors may be repurposed as a novel therapeutic option for lupus patients.

"The Pause": A Delphi Methodology Examining an End-of-Life Practice.

"The Pause" was first practiced by a nurse at a Level 1 trauma center to honor the death of a deceased patient. This practice has spread internationally and is used in emergency departments, intensive care, transplant, and oncology units, in addition to pre-hospital settings. There is a paucity of research published on the effects of The Pause for health care workers. We used a three-staged Delphi methodology to understand the barriers, benefits, and language used in The Pause. Analyses of email communication and interview transcripts suggest that The Pause poses minimal risk and has considerable benefits. Benefits include increased perceived team cohesion, a moment for reflection, and a method by which to honor a deceased patient. The Pause allows nurses to feel more present to meet the needs of the next patient they care for during a shift. Further research is merited.

Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells.

OBJECTIVE: We examined genome-wide DNA methylation changes in CD8+ T cells from patients with lupus and controls and investigated the functional relevance of some of these changes in lupus. METHODS: Genome-wide DNA methylation of lupus and age, sex and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR. Inhibiting STAT1 and CIITA was performed using fludarabine and CIITA siRNA, respectively. RESULTS: Lupus CD8+ T cells had 188 hypomethylated CpG sites compared with healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. CIITA knockdown and STAT1 inhibition experiments revealed that HLA-DRB1 expression in lupus CD8+ T cells is dependent on CIITA and STAT1 signalling. Coincubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69 and cytokine production, in patients with lupus but not in healthy controls. This can be blocked by neutralising antibodies targeting HLA-DR. CONCLUSIONS: Lupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in patients with lupus. A possible pathogenic role for CD8+ T cells in lupus that is dependent on a high type-I interferon environment and epigenetic priming warrants further characterisation.

Epidemiology of Surgical Treatment of Adolescent Sports Injuries in the United States: Analysis of the MarketScan Commercial Claims and Encounters Database.

PURPOSE: To determine whether there is increasing surgical management of adolescent sports injuries and whether the average age of surgical patients is decreasing. METHODS: The Truven Health MarketScan Database was searched from 2008 to 2014 for patients 10 to 19 years of age using the International Classification of Disease, 9th Revision codes and Current Procedure Terminology, 4th Edition, codes for operative treatment for the following conditions: anterior cruciate ligament (ACL) injuries, knee collateral ligament (KCL) injuries, meniscal injuries, Osgood-Schlatter syndrome, and elbow ulnar collateral ligament injuries. Patients identified were characterized by sex, age, year of injury, and type of residence (urban vs rural) based on metropolitan statistical areas. RESULTS: A total of 516,892 patients sustained 1 of the identified injuries, and 133,541 (25.8%) patients underwent a related surgery. KCL and meniscal injuries demonstrated a consistent increase in the rate of surgical intervention (P < .0001). Average age of surgical intervention did not increase or decrease overall for any diagnosis. Female adolescents were more likely to undergo surgery for KCL injuries (adjusted odds ratio [aOR] 1.7, 95% confidence interval [CI] 1.58-1.79, P < .0001), Osgood-Schlatter syndrome (aOR 1.8, 95% CI 1.38-2.39, P < .0001), and ACL injuries (aOR 1.5, 95% CI 1.45-1.52, P < .0001), whereas male adolescents were more likely to undergo surgery for meniscal injuries (aOR 1.3, 95% CI 1.24-1.30, P < .0001) and ulnar collateral ligament injuries (aOR 1.1, 95% CI 1.06-1.23, P < .0005). Patients in rural areas were more likely to undergo surgical intervention for ACL and meniscal injuries (P < .0001) and KCL injuries (P = .02). CONCLUSIONS: We found that surgical treatment of 5 common sports injuries remains stable, with only KCL injuries and meniscal injuries showing an increase in surgical incidence. Average age of surgical intervention did not change significantly over the 7-year time span for any diagnosis. LEVEL OF EVIDENCE: Level IV, Cross Sectional Study.