Graft-versus-host disease is locally maintained in target tissues by resident progenitor-like T cells.

In allogeneic hematopoietic stem cell transplantation, donor αß T cells attack recipient tissues, causing graft-versus-host disease (GVHD), a major cause of morbidity and mortality. A central question has been how GVHD is sustained despite T cell exhaustion from chronic antigen stimulation. The current model for GVHD holds that disease is maintained through the continued recruitment of alloreactive effectors from blood into affected tissues. Here, we show, using multiple approaches including parabiosis of mice with GVHD, that GVHD is instead primarily maintained locally within diseased tissues. By tracking 1,203 alloreactive T cell clones, we fitted a mathematical model predicting that within each tissue a small number of progenitor T cells maintain a larger effector pool. Consistent with this, we identified a tissue-resident TCF-1+ subpopulation that preferentially engrafted, expanded, and differentiated into effectors upon adoptive transfer. These results suggest that therapies targeting affected tissues and progenitor T cells within them would be effective.

Early-childhood body mass index and its association with the COVID-19 pandemic, containment measures and islet autoimmunity in children with increased risk for type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to determine whether BMI in early childhood was affected by the COVID-19 pandemic and containment measures, and whether it was associated with the risk for islet autoimmunity. METHODS: Between February 2018 and May 2023, data on BMI and islet autoimmunity were collected from 1050 children enrolled in the Primary Oral Insulin Trial, aged from 4.0 months to 5.5 years of age. The start of the COVID-19 pandemic was defined as 18 March 2020, and a stringency index was used to assess the stringency of containment measures. Islet autoimmunity was defined as either the development of persistent confirmed multiple islet autoantibodies, or the development of one or more islet autoantibodies and type 1 diabetes. Multivariate linear mixed-effect, linear and logistic regression methods were applied to assess the effect of the COVID-19 pandemic and the stringency index on early-childhood BMI measurements (BMI as a time-varying variable, BMI at 9 months of age and overweight risk at 9 months of age), and Cox proportional hazard models were used to assess the effect of BMI measurements on islet autoimmunity risk. RESULTS: The COVID-19 pandemic was associated with increased time-varying BMI (ß = 0.39; 95% CI 0.30, 0.47) and overweight risk at 9 months (ß = 0.44; 95% CI 0.03, 0.84). During the COVID-19 pandemic, a higher stringency index was positively associated with time-varying BMI (ß = 0.02; 95% CI 0.00, 0.04 per 10 units increase), BMI at 9 months (ß = 0.13; 95% CI 0.01, 0.25) and overweight risk at 9 months (ß = 0.23; 95% CI 0.03, 0.43). A higher age-corrected BMI and overweight risk at 9 months were associated with increased risk for developing islet autoimmunity up to 5.5 years of age (HR 1.16; 95% CI 1.01, 1.32 and HR 1.68, 95% CI 1.00, 2.82, respectively). CONCLUSIONS/INTERPRETATION: Early-childhood BMI increased during the COVID-19 pandemic, and was influenced by the level of restrictions during the pandemic. Controlling for the COVID-19 pandemic, elevated BMI during early childhood was associated with increased risk for childhood islet autoimmunity in children with genetic susceptibility to type 1 diabetes.

Implementation of a treatment algorithm to decrease incidence of paralysis post endovascular thoracoabdominal aorta repair.

BACKGROUND: Spinal cord ischemia (SCI) is a rare but devastating complication following aortic repair. Despite improvements in operative management and critical care of aortic disease patients, SCI remains one of the most serious and common complications after these procedures. Early recognition and rescue interventions can augment the outcome and reduce the morbidity or avoid permanent dysfunction. This is a single institution experience of creating an evidence-based algorithm for the treatment of SCI in patients after thoracoabdominal endovascular aortic repair (TEVAR). INTERVENTION/METHODS: We implemented an evidence-based treatment algorithm for the management of acute SCI after TEVAR. A total of 131 TEVAR cases were reviewed, 59 cases preimplementation, and 72 cases postimplementation of an SCI treatment algorithm. RESULTS: Lower extremity motor and/or sensory deficits were identified in 5.1% of preimplementation and 4.2% of postimplementation cases. SCI treatment interventions included increasing the mean arterial pressure (MAP) (66% pre and 100% post), placing lumbar drain (33% pre and 33% post), performing carotid subclavian bypass (33% pre and 33% post), initiating naloxone drip (66% pre and 100% post), and administering glipizide (0% pre and 100% post, P < .05). Long-term paralysis occurred in 66% of preimplementation and 0% of postimplementation cases. CONCLUSIONS: By creating and implementing an SCI treatment algorithm we reduced both, time to detection and time to effective treatment of SCI and significantly improved our patients' neurological outcomes.

T cell exhaustion and a failure in antigen presentation drive resistance to the graft-versus-leukemia effect.

In hematopoietic cell transplants, alloreactive T cells mediate the graft-versus-leukemia (GVL) effect. However, leukemia relapse accounts for nearly half of deaths. Understanding GVL failure requires a system in which GVL-inducing T cells can be tracked. We used such a model wherein GVL is exclusively mediated by T cells that recognize the minor histocompatibility antigen H60. Here we report that GVL fails due to insufficient H60 presentation and T cell exhaustion. Leukemia-derived H60 is inefficiently cross-presented whereas direct T cell recognition of leukemia cells intensifies exhaustion. The anti-H60 response is augmented by H60-vaccination, an agonist αCD40 antibody (FGK45), and leukemia apoptosis. T cell exhaustion is marked by inhibitory molecule upregulation and the development of TOX+ and CD39-TCF-1+ cells. PD-1 blockade diminishes exhaustion and improves GVL, while blockade of Tim-3, TIGIT or LAG3 is ineffective. Of all interventions, FGK45 administration at the time of transplant is the most effective at improving memory and naïve T cell anti-H60 responses and GVL. Our studies define important causes of GVL failure and suggest strategies to overcome them.

High prevalence of chronic venous disease among health care workers in the United States.

BACKGROUND: Health care workers spend extended times standing and walking short distances and are at risk for development of chronic venous insufficiency (CVI). We conducted a hospital-wide venous screening program designed to measure the prevalence of and risk factors for clinical manifestations of CVI and ultrasound evidence of venous reflux or obstruction in health care workers. We also determined their risk for deep venous thrombosis (DVT). METHODS: Free venous screening and education were offered to all hospital employees; the program started in April 2016, and results are presented from the first year. Demographics, medical history, and use of compression stockings were recorded. A physical examination determined the clinical class of the Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) classification for clinical disease, and an ultrasound test evaluated for reflux or obstruction in the common femoral vein, popliteal vein, and saphenofemoral junction. The Caprini score was recorded to evaluate risk of DVT. Descriptive statistics were reported, and logistic regression was used for multivariate analysis of risk factors. RESULTS: We enrolled 636 participants (1272 legs); 93.0% were women. The median age was 42 years (interquartile range, 31-52 years), mean body mass index was 29.2 ± 6.6 kg/m2, and most participants were white (49.1%) or African American (39.5%); 18% reported having hypertension, 7.1% had diabetes, and 6.1% were current smokers. The majority reported occasional leg pain (72.7%) and evening leg swelling (42.3%). Only 2.7% used daily compression stockings. Clinical evidence of CVI was present in at least one leg in 69.1% (C1, 49.0%; C2, 17.7%; C3, 1.9%; C4, 0.2%; C5, 0.2%). Venous reflux was present in at least one leg in 82.1%; obstruction was rare (0.2%). Reflux in either the superficial (saphenofemoral junction) or the deep (femoral or popliteal) venous system was present in the majority (71.0%) of patients with CVI (clinical class ≥C1). Reflux and white race were risk factors for clinical disease; clinical disease, age, female sex, and white race were risk factors for reflux. On the basis of the Caprini score, 14.1% of participants were in the highest risk category for DVT when experiencing a high-risk situation (including 2.2% with history of DVT). CONCLUSIONS: Prevalence of clinical CVI and venous reflux is high among health care workers despite a low frequency of cardiovascular comorbidities. Increased awareness about CVI and DVT and preventive strategies for venous disease must be instituted in this high-risk cohort.

Reduced length of stay and 30-day readmission rate on an inpatient vascular surgery service.

As the cost of care for patients with specific diagnoses becomes fixed, hospitals must develop systems to reduce length of stay and optimize the use of hospital resources while maintaining a high quality of care. The goal of this study is to evaluate the implementation and efficacy of a system designed to reduce average length of stay on a vascular surgery service. To effectively reduce the average length of stay in our center, we restructured patient rounds, implemented multidisciplinary rounds, introduced clinical pathways to postoperative care, and expanded outpatient management of postoperative patients. A total of 1697 adult vascular surgery patients discharged while under the medical direction of a vascular surgeon between July 1, 2013, and June 30, 2016, were included in the study. Improving communication with critical staff and using procedural space outside of the main operating rooms led to a 2.8-day reduction in the length of stay (10.8 vs 8.0, P < .001). There was a trend toward a reduction in the 30-day readmission rate (12% vs 10%, respectively; P = .01) and no significant difference in the case-mix index as a measure of illness severity (2.5 vs 2.4, respectively; P = .15). Length of stay reductions were heterogeneous among the types of vascular diseases studied, with greater improvements seen in patients undergoing lower extremity amputation, lower extremity angiogram, and endovascular aneurysm repair for nonruptured abdominal aortic aneurysms. Less pronounced differences were observed in patients undergoing carotid artery endarterectomy or stenting and lower extremity bypasses. In conclusion, restructuring team rounds and instituting a multidisciplinary approach to discharge planning produced significant reductions in length of stay without a deleterious effect on patient care which may impact hospital profitability.

Infrainguinal wound infections in vascular surgery: An antiquated challenge without a modern solution.

Surgical site infections (SSIs) have always complicated recovery after surgery, being associated with increased cost of hospitalization, length of stay, and mortality. The most significant measure to reduce the incidence of SSI was the standardization of prophylactic antibiotic administration in patients undergoing surgical procedures. Since then, countless measures have been proposed to improve rates of SSI and patient outcome, but few have been as efficacious as prophylactic antibiotics. Therefore, SSI continues to plague clinicians and patients in modern health care. This review focuses on current and future efforts at SSI control.