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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) efficacy is complicated by graft-versus-host disease (GVHD), a leading cause of morbidity and mortality. Regulatory T cells (Tregs) have shown efficacy in preventing GVHD. However, high Treg doses are often required, necessitating substantial ex vivo or in vivo expansion that may diminish suppressor function. To enhance in vivo suppressor function, murine Tregs were transduced to express an anti–human CD19 chimeric antigen receptor (hCAR19) and infused into lethally irradiated, hCD19-transgenic recipients for allo-HSCT. Compared with recipients receiving control transduced Tregs, those receiving hCAR19 Tregs had a marked decrease in acute GVHD lethality. Recipient hCD19 B cells and murine hCD19 TBL12-luciferase (TBL12 luc ) lymphoma cells were both cleared by allogeneic hCAR19 Tregs, which was indicative of graft-versus-tumor (GVT) maintenance and potentiation. Mechanistically, hCAR19 Tregs killed syngeneic hCD19 + but not hCD19 – murine TBL12 luc cells in vitro in a perforin-dependent, granzyme B–independent manner. Importantly, cyclophosphamide-treated, hCD19-transgenic mice given hCAR19 cytotoxic T lymphocytes without allo-HSCT experienced rapid lethality due to systemic toxicity that has been associated with proinflammatory cytokine release; in contrast, hCAR19 Treg suppressor function enabled avoidance of this severe complication. In conclusion, hCAR19 Tregs are a potentially novel and effective strategy to suppress GVHD without loss of GVT responses.

Abstract With aging, somatic mutations in hematopoietic stem and progenitor cells (HSPC) can give rise to clonal hematopoiesis of indeterminate potential (CHIP), a premalignant state associated with diverse age-related diseases. Here we report the largest multi-ancestry genome-wide analysis of CHIP to date (N = 1,018,305), including individuals of African (N = 85,978), Admixed American (N = 191,371), East Asian (N = 13,532), European (N = 694,015), and South Asian (N = 13,193) ancestry. Multi-ancestry meta-analyses identified 72 genome-wide significant loci, including 44 novel associations implicating genes such as AFF1 , ATF7IP , ATP8B4 , BCL2 , CEBPA , CYRIA , DNM2 , ELF1 , NKX2-3 , PIK3CB , PRDM16 , RPN1 , TERC , and TRIM4 . Notably, variants at MECOM and PHF20L1 showed opposite allelic effects between DNMT3A - and non- DNMT3A -driven CHIP, highlighting driver-specific germline influences. Implicated loci converge on pathways regulating telomere maintenance, cell-cycle control, hematopoietic transcription, DNA damage response and immune signaling. These findings support a model in which germline variation both expands the HSPC pool and biases clonal selection in a driver-dependent manner, providing a mechanistic basis for inter-individual heterogeneity in CHIP. Phenome-wide association analyses further linked CHIP to hematologic, neoplastic, and circulatory traits, with enrichment across hematopoietic and non-hematopoietic cell types. Together, this work expands the genomic and phenomic landscape of CHIP and reveals germline–somatic interactions that shape clonal evolution during aging.

Background: Diagnosis and treatment of posterior shoulder instability (PSI) has improved with advances in imaging and surgical technique. However, the relationship between PSI and osteoarthritis (OA) remains unclear. Purpose: To evaluate a population-based cohort to (1) determine the rate of symptomatic OA, (2) identify patient characteristic risk factors for OA, and (3) evaluate the effect of posterior capsulolabral repair on OA progression. Study Design: Case-control study; Level of evidence, 3. Methods: After review of 324 patient records, we included 115 patients (14 female, 101 male) diagnosed with PSI between January 1994 and July 2012 with an average follow-up of 12.5 years (range, 5-23 years). Medical records were reviewed for patient characteristics, injury characteristics, surgical details (if any), and radiographic progression of OA. Kaplan-Meier survival was used to estimate survival free of OA; characteristics associated with OA progression were determined via univariate Cox regression models, and associated 95% CIs and hazard ratios (HRs) are presented. Results: Overall, 14% (16/115) of patients had radiographic progression of symptomatic glenohumeral arthritis, with 5-year survival of 88.3% (95% CI, 79.7%-97.3%). Older age at the time of instability diagnosis was associated with arthritis progression (10-year unit HR, 1.95; 95% CI, 1.26-3.03). Patients who underwent surgery demonstrated increased radiographic progression of OA (HR, 4.03; 95% CI, 1.23-13.23). There was a trend of increased OA in patients treated with labral debridement compared with repair despite lower baseline levels of OA; however, this difference was not statistically significant ( P = .09). Conclusion: Symptomatic glenohumeral arthritis is not seen routinely in patients with PSI. Although uncommon, an age of at least 30 years at the time of diagnosis and surgical intervention were identified as risk factors for developing symptomatic arthritis at long-term follow-up.

Background Patients with self-reported antibiotic allergies have a higher cost of care, more frequent infections with resistant bacteria and worse health outcomes than patients without antibiotic allergies. Ultimately, less than 5% of patients who report a penicillin allergy have a clinically significant immune-mediated hypersensitivity reaction when tested. As 10%–30% of the population of pregnant patients are colonised for group B Streptococcus (GBS) and guidelines recommend penicillin as the treatment of choice for GBS, current recommendations support penicillin allergy testing in pregnant patients who report an allergy. Methods and intervention In this quality improvement project, nursing staff used an algorithm outlining inclusion and exclusion criteria to determine which patients were eligible to have penicillin allergy testing completed. Penicillin allergy testing consisted of a skin test using benzylpenicilloyl polylysine (Pre-Pen), penicillin G potassium, amoxicillin and alkaline hydrolysis mix (penicilloate) as a prick skin test, followed by intradermal skin test and finally an oral challenge with either amoxicillin or penicillin. Patient outcomes were analysed to evaluate the impact of the intervention. Results Of the 1266 patients receiving prenatal care during the intervention, 236 (19%) reported a history of penicillin allergy, and 212 if these were eligible for testing. 150 of the eligible patients were offered penicillin allergy testing. 101 patients (67%) completed testing and 49 (33%) declined testing. Seven patients (7%) had positive penicillin allergy testing, while 94 patients (93%) had negative penicillin allergy testing and were immediately de-labelled as penicillin allergic. Seventeen of the de-labelled patients subsequently tested positive for GBS colonisation, and all received intrapartum penicillin without adverse events. Conclusions Pursuing penicillin allergy testing for pregnant patients with reported penicillin allergy is a safe and feasible approach, allowing for allergy de-labelling and safe, guideline-driven antimicrobial therapy during subsequent labour and delivery hospitalisations. Cost-effectiveness of the allergy testing and impact on later episodes of care should be further investigated.

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.

Objectives:Introduction: Wrestling is a physically demanding sport with young athletes prone to anterior cruciate ligament (ACL) injuries. However, there is a paucity of data evaluating the results of ACL reconstruction (ACLR) in this cohort. Purpose: To assess patient-reported outcomes, reoperation rates, graft survival, and return to play (RTP) following ACLR in a large cohort of competitive wrestlers Methods: All competitive wrestlers (high school, collegiate, or professional) with a history of an ACLR at a single institution between 2000 and 2019 were retrospectively identified. Graft failure was defined as a re-tear determined by clinical or advanced imaging evaluation, and/or revision ACL reconstruction. All patients were contacted for determination of reinjury rates, current sport status, visual analog scale (VAS), International Knee Documentation Committee (IKDC) and Tegner activity scores. Results: 118 knees in 114 wrestlers were included at a median follow-up time of 5.8 years (IQR: 3.6 – 10.3). The median age was 17 years (15 – 18) with 116 (98%) males. ACLR was most often performed with bone-patellar tendon-bone (BTB) autograft (n = 64; 54%) or hamstring tendon (HT) autograft (n = 43; 36%). At final follow-up, 80% of athletes were able to RTP at a median of 273 days (IQR: 203 – 379). Graft failure occurred in 17 (14%) patients at a median time of 1.4 years (IQR: 0.8 – 4.7) after the index ACLR. BTB autograft demonstrated a lower failure rate compared to HT autograft (8% vs. 21%; P = 0.044). Kaplan-Meier survivorship free from graft failure for the entire cohort was 95.3% at 1 year, 92.5% at 2 years, 89.8% at 5 years, 84.6 at 10 years, 77.6 at 20 years. BTB autograft was associated with better survival than HT autograft up to 15 years after the index ACLR (90.4% vs. 76.3%; P = 0.030). Conclusions: Return to competitive wrestling was observed in 80% of athletes after ACLR, with 14% of wrestlers experiencing graft failure. BTB autograft reconstruction may serve as a more durable graft for competitive wrestlers with lower rates of failure when compared to HT autograft even up to 15 years after surgery. [Table: see text][Figure: see text][Figure: see text][Figure: see text]

Objectives: Distal biceps tendon tears, although rare, significantly impair patient’s elbow mobility and function. There is a paucity of contemporary literature reporting long term outcomes of distal biceps (DB) injuries. Therefore, the authors sought to identify magnetic resonance imaging (MRI) confirmed distal bicep tears and report on (1) patient demographics and injury characteristics of all patients with distal bicep pathology, (2) outcomes of all patients with non-operatively managed DB pathology, and (3) outcomes of all patients with operatively managed DB pathology. Methods: Patients with an MRI-confirmed distal biceps rupture from 1996 to 2016 were identified through an institutional image database. Patients from the initial search were then cross-referenced with the [REDACTED] 1 to ensure record availability. Patients were included if they had complete medical records and ≥5 years of clinical follow-up. Patients with inflammatory arthritis and enthesitis, polytrauma, or incidental findings without clinical assessment were excluded. Medical records were reviewed to confirm the diagnosis of distal biceps tears and obtain further subject details. Results: A total of 158 patients (22 female, 136 male) with a mean age 51.5 years (44.8-61.2) were identified and included. Baseline patient demographics including BMI, smoking status, dominant-handedness, laborer occupation, and gender were gathered (Table 1). Patients had a mean clinical follow-up of almost 14 years (Table 1, range 8.4 -17.8). Outcomes of the 52 non-operative and 106 operatively managed patients, included severe complications, functional outcomes, and health-related productivity loss are reported in Table 2. There were 7 re-operations (4%), 5 re-ruptures (3%), and overall 35% of the operatively treated cohort experienced a complication. Conclusions: Patients with distal bicep pathology tended to be a male laborer in their 50s without clinically significantly associated risk factors. The majority of patients regained full ROM, and 83% were able to return to work without modifications, irregardless of operative or non-operative management. At long term follow up, patients treated operatively were more likely to report missing time from work and averaged more days missed than their non-operatively treated counterparts. Additionally, operative patients had no statistically significant gains functional outcomes, and were subject to potential post-operative complications. Surgeon bias may play a role in deciding treatment for distal biceps tears. As such, careful patient selection for surgical intervention for distal biceps pathology should be employed; surgeons should consider restricting surgical intervention to patients who have significant clinical symptoms or fail non-operative management. [Table: see text][Table: see text]

Objectives: Background: Although they are common, there remains a paucity of data regarding traumatic anterior shoulder dislocations (ASI) associated with anteroinferior glenoid rim fractures (AGRF) in older patients. Purpose: To describe the incidence of AGRF in this population following ASI, identify risk factors for AGRF, compare treatment strategies, and compare clinical outcomes of patients with and without an associated AGRF. Methods: An established geographic medical record system was used to identify patients >50 years of age with ASI between 1994 and 2016. Patients with radiographic evidence of AGRF were identified and matched 1:1 to patients without AGRF. Comparative analysis was conducted to determine differences between groups. Results: Overall, 186 patients were identified with a mean follow-up of 10.4 years (range, 2.0 – 25.4). Of these, 42 (22.6%) had AGRF and were matched to 42 control patients without AGRF. Average age was 58.9 and 58.2 years for the AGRF and control groups, respectively. Rates of surgical intervention (29% vs. 43%), recurrent instability (14% vs. 17%), progression of osteoarthritis (34% vs. 39%), and conversion to arthroplasty (2% vs. 5%) were similar between AGRF and control cohorts. Control patients were more likely to report recurrent pain (p=.046). For patients with AGRF, increased bone fragment size (OR 1.1) and increased BMI (OR 1.2) correlated with an increased risk for surgery. The cut-off value for surgery in patients with AGRF was a fragment size ≥33% of the glenoid width. Conclusions: In patients ≥ 50 years at presentation of ASI, 22.6% presented with an associated AGRF. Increased fragment size and greater patient BMI were significant factors associated with undergoing surgical intervention; however, most patients did not require surgery. Patients without AGRF were more likely to report recurrent pain, possibly due to a higher prevalence of rotator cuff derangement. Overall, the presence of an AGRF did not portend a worse prognosis as treatment strategies and long-term outcomes in terms of recurrent instability, progression of osteoarthritis, and conversion to arthroplasty were similar between patients with and without AGRF at the time of ASI diagnosis.

Objectives: Anterior shoulder instability (ASI) is a well-studied topic in young patients, however there is a dearth of knowledge about older patients with this pathology. The goals of this study were to describe patient demographics, injury characteristics and outcomes in patients >50 years old with anterior shoulder instability along with historical trends in diagnosis and treatment. Methods: An established geographic database was used to identify 179 patients who experienced new onset anterior shoulder instability after the age 50 between 1994-2016. Mean age was 59.7 years, mean BMI was 31.3 and 54.2% were female. The dominant arm was involved in 62.2% of instability events. 26.8% of our study population were laborers and 50% reported current or former smoking habits. The primary etiology for ASI involved trauma in 96.6% of cases. Comparative analysis was performed to identify differences between age groups. Mean follow up time was 11 years. Results: The overall incidence of ASI in our study population was 28.8/100,000 person years with the highest incidence in the age cohort 60-64 at 38.9/100,000 person years. At initial presentation, 73% of all patients were found to have a lesion apparent on either XR or MRI. Rotator cuff tears were found in 92.4% of all patients undergoing MRIs. 26.2% ultimately progressed to surgery at a mean time of 1.57 years after injury. 53% of all surgical procedures involved a rotator cuff repair whereas only 25% were performed for instability. In terms of historical trends, the one-year rate of obtaining an MRI after an ASI event has increased from 10% in the late 1990s to 46% in 2015-16. Similarly, the one-year rate of performing surgery has increased from 5.1% to 47% from 1994-1999 to 2015-2016. Conclusions: In our cohort, patients over the age of 50 with ASI were found to often have concomitant pathology on imaging, however only ¼ of all patients required surgery. Although the rate of ASI has stayed relatively stable over the last 20 years, the rate of obtaining an MRI and of surgical management has increased. [Figure: see text]