Biomaterial-enhanced treg cell immunotherapy: A promising approach for transplant medicine and autoimmune disease treatment.

Regulatory T cells (Tregs) are crucial for preserving tolerance in the body, rendering Treg immunotherapy a promising treatment option for both organ transplants and autoimmune diseases. Presently, organ transplant recipients must undergo lifelong immunosuppression to prevent allograft rejection, while autoimmune disorders lack definitive cures. In the last years, there has been notable advancement in comprehending the biology of both antigen-specific and polyclonal Tregs. Clinical trials involving Tregs have demonstrated their safety and effectiveness. To maximize the efficacy of Treg immunotherapy, it is essential for these cells to migrate to specific target tissues, maintain stability within local organs, bolster their suppressive capabilities, and ensure their intended function's longevity. In pursuit of these goals, the utilization of biomaterials emerges as an attractive supportive strategy for Treg immunotherapy in addressing these challenges. As a result, the prospect of employing biomaterial-enhanced Treg immunotherapy holds tremendous promise as a treatment option for organ transplant recipients and individuals grappling with autoimmune diseases in the near future. This paper introduces strategies based on biomaterial-assisted Treg immunotherapy to enhance transplant medicine and autoimmune treatments.

Claustrum projections to the anterior cingulate modulate nociceptive and pain-associated behavior.

The anterior cingulate cortex (ACC) is critical for the perception and unpleasantness of pain.1,2,3,4,5,6 It receives nociceptive information from regions such as the thalamus and amygdala and projects to several cortical and subcortical regions of the pain neuromatrix.7,8 ACC hyperexcitability is one of many functional changes associated with chronic pain, and experimental activation of ACC pyramidal cells produces hypersensitivity to innocuous stimuli (i.e., allodynia).9,10,11,12,13,14 A less-well-studied projection to the ACC arises from a small forebrain region, the claustrum.15,16,17,18,19,20 Stimulation of excitatory claustrum projection neurons preferentially activates GABAergic interneurons, generating feed-forward inhibition onto excitatory cortical networks.21,22,23,24 Previous work has shown that claustrocingulate projections display altered activity in prolonged pain25,26,27; however, it remains unclear whether and how the claustrum participates in nociceptive processing and high-order pain behaviors. Inhibition of ACC activity reverses mechanical allodynia in animal models of persistent and neuropathic pain,1,9,28 suggesting claustrum inputs may function to attenuate pain processing. In this study, we sought to define claustrum function in acute and chronic pain. We found enhanced claustrum activity after a painful stimulus that was attenuated in chronic inflammatory pain. Selective inhibition of claustrocingulate projection neurons enhanced acute nociception but blocked pain learning. Inversely, chemogenetic activation of claustrocingulate neurons had no effect on basal nociception but rescued inflammation-induced mechanical allodynia. Together, these results suggest that claustrocingulate neurons are a critical component of the pain neuromatrix, and dysregulation of this connection may contribute to chronic pain.

Synthetic biology approaches for enhancing safety and specificity of CAR-T cell therapies for solid cancers.

CAR-T cell therapies have been successful in treating numerous hematologic malignancies as the T cell can be engineered to target a specific antigen associated with the disease. However, translating CAR-T cell therapies for solid cancers is proving more challenging due to the lack of truly tumor-associated antigens and the high risk of off-target toxicities. To combat this, numerous synthetic biology mechanisms are being incorporated to create safer and more specific CAR-T cells that can be spatiotemporally controlled with increased precision. Here, we seek to summarize and analyze the advancements for CAR-T cell therapies with respect to clinical implementation, from the perspective of synthetic biology and immunology. This review should serve as a resource for further investigation and growth within the field of personalized cellular therapies.

Natural history of visceral branch artery dissections and the influence of concurrent aortic dissection on overall and intervention-free survival.

OBJECTIVE: Visceral branch artery dissection (VBAD) is uncommon and may occur with or without an associated aortic dissection (AD). We hypothesized that isolated VBAD would have a more benign clinical course than those with concurrent AD and compared survival outcomes stratified based on aortic involvement. METHODS: VBAD over a 5-year period were identified using International Classification of Diseases codes. Data related to patient demographics, comorbid conditions, clinical presentation, management (including procedural interventions), and survival were obtained from medical records. Anatomic imaging studies were reviewed to characterize anatomy, including the presence or absence of concurrent AD. Overall survival and intervention-free survival were evaluated using Kaplan-Meier and Cox proportional hazards models. RESULTS: A total of 299 VBAD were identified, 174 of which were isolated VBAD and 125 were associated with concurrent AD. Seventy-one percent of patients were men, 77% were White, and 85% were non-Hispanic. The mean age was 61.1 ± 14.4 years. The mean follow-up was 53.2 ± 50.0 months. The estimated overall survival was 88.2% and the estimated overall intervention-free survival was 55.6% at 12 months. Isolated VBAD had better overall survival than those with concurrent AD (69.2% vs 32.4%; P < .001). Concurrent AD was also associated with inferior intervention-free survival (57.5% vs 7.3%; P < .001). Acute presentation was associated with decreased intervention-free survival (86.1% vs 13.4%; P < .001). Acute presentation was also associated with decreased overall survival in patients with isolated VBAD (60.8% vs 80.0% at 180 months; P < .001) and inferior intervention-free survival (48.4% vs 69.5% at 180 months; P < .001) in the subgroup of patients with isolated VBAD. Multivariable Cox models identified that age (hazard ratio [HR]: 1.05, standard deviation [SD]: 0.02; P = .001) was associated with inferior survival and renal dissections (HR: 3.08, SD: 0.99; P = .001) or mesenteric and renal dissections (HR: 3.39, SD: 1.44; P = .004) were associated with inferior intervention-free survival. CONCLUSIONS: Isolated VBAD has superior overall and intervention-free survival to those associated with concurrent AD. The absence vs presence of aortic involvement is useful for risk stratification and may support tailored approaches to the frequency of imaging surveillance.

Disparities and Trends in Routine Adult Vaccination Rates Among Disaggregated Asian American Subgroups, National Health Interview Survey 2006-2018.

Introduction: Vaccination rates may be improved through culturally tailored messages, but little is known about them among disaggregated Asian American subgroups. We assessed the vaccination rates for key vaccines among these subgroups. Methods: Using the National Health Interview Survey, we analyzed recent vaccination rates (2015-2018, n=188,250) and trends (2006-2018) among Asians (Chinese [n=3,165], Asian Indian [n=3,525], Filipino [n=3,656], other Asian [n=5,819]) and non-Hispanic White adults (n=172,085) for 6 vaccines (the human papillomavirus, hepatitis B, pneumococcal, influenza, tetanus-diphtheria [tetanus], and shingles vaccines). We controlled demographic, socioeconomic, and health-related variables in multivariable logistic regression and predicted marginal modeling analyses. We also computed vaccination rates among Asian American subgroups on the 2015-2018 National Health Interview Survey data stratified by foreign-born and U.S.-born status. We used Joinpoint regression to analyze trends in vaccination rates. All analyses were conducted in 2021 and 2022. Results: Among Asians, shingles (29.2%; 95% CI=26.6, 32.0), tetanus (53.7%; 95% CI=51.8, 55.6), and pneumococcal (53.8%; 95% CI=50.1, 57.4) vaccination rates were lower than among non-Hispanic Whites. Influenza (47.9%; 95% CI=46.2, 49.6) and hepatitis B (40.5%; 95% CI=39.0, 42.7) vaccination rates were similar or higher than among non-Hispanic Whites (48.4%; 95% CI=47.9, 48.9 and 30.7%; 95% CI=30.1, 31.3, respectively). Among Asians, we found substantial variations in vaccination rates and trends. For example, Asian Indian women had lower human papillomavirus vaccination rates (12.9%; 95% CI=9.1, 18.0) than all other Asian subgroups (Chinese: 37.9%; 95% CI=31.1, 45.2; Filipinos: 38.7%; 95% CI=29.9, 48.3; other Asians: 30.4%; 95% CI=24.8, 36.7) and non-Hispanic Whites (36.1%; 95% CI=34.8, 37.5). Being male, having lower educational attainment and income, having no health insurance or covered by public health insurance only, and lower frequency of doctor visits were generally associated with lower vaccine uptakes. Foreign-born Asian aggregate had lower vaccination rates than U.S.-born Asian aggregate for all vaccines except for influenza. We also found subgroup-level differences in vaccination rates between foreign-born and U.S.-born Asians. We found that (1) foreign-born Chinese, Asian Indians, and other Asians had lower human papillomavirus and hepatitis B vaccination rates; (2) foreign-born Chinese and Filipinos had lower pneumococcal vaccination rates; (3) foreign-born Chinese and Asian Indians had lower influenza vaccination rates; and (4) all foreign-born Asian subgroups had lower tetanus vaccination rates. Conclusions: Vaccination rates and trends differed among Asian American subgroups. Culturally tailored messaging and interventions may improve vaccine uptakes.

Factors associated with HIV Testing within the National Health Interview Survey (2006-2018).

The Centers for Disease Control and Prevention recommends that individuals aged 13-64 test for HIV at least once during their lifetime. However, screening has been disproportionate among racial/ethnic populations. Using the National Health Interview Survey data (2006-2018), we examined HIV screening prevalence within racial/ethnic groups in the United States (US), and factors associated with testing among 301,191 individuals. This consisted of 195,696 White, 42,409 Black, 47,705 Hispanic and 15,381 Asian individuals. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) to estimate the association between ever testing for HIV and demographic, socioeconomic and health-related factors. Approximately 36% of White, 61% of Black, 47% of Hispanic and 36% of Asian individuals reported ever testing for HIV. Hispanic (OR = 1.28, 95% CI [1.25-1.32]) and Black individuals (OR = 2.44, 95% CI [2.38-2.50]) had higher odds of HIV testing, whereas Asian individuals (OR = 0.74, 95% CI [0.71-0.77]) had lower odds of HIV testing compared to White individuals. Individuals who identified as males, married, between the ages of 18-26 years or greater than or equal to 50 years were less likely to ever test for HIV compared to their counterparts. Similarly, those with lower education, lower income, better self-reported health, no health professional visits or living in the midwestern US were less likely to ever test for HIV compared to their counterparts (OR range: 0.14-0.92). Understanding the factors associated with HIV testing opens opportunities to increase testing rates for all and reduce health disparities in HIV detection.

Factors Associated With the Development of Dyslipidemia Among Pediatric Patients With Diabetes: A Single-centre-based Study.

OBJECTIVES: The prevalence of pediatric diabetes is increasing. Dyslipidemia is an important modifiable cardiovascular disease risk factor often present in children with diabetes. In this study, we evaluated the adherence to Diabetes Canada 2018 lipid screening guidelines in a pediatric diabetes program to determine the prevalence of dyslipidemia in youth with diabetes and to identify risk factors related to dyslipidemia. METHODS: This retrospective chart review included patients at McMaster Children's Hospital with diabetes (types 1 and 2), who were at least 12 years of age as of January 1, 2019. Extracted data included age, sex, family history of diabetes or dyslipidemia, date of diagnosis, body mass index, glycemia monitoring system used, lipid profile, glycated hemoglobin (A1C), and thyroid-stimulating hormone values at the time the lipid profile was measured. Statistical methods included descriptive statistics and logistic regression modelling. RESULTS: Of the 305 patients included, 61% had a lipid profile measured according to guidelines, 29% had lipid screening completed outside of the recommended window, and 10% had no lipid profile on record. Among screened patients, 45% had dyslipidemia, most commonly hypertriglyceridemia (35%). Dyslipidemia was highest amongst those with type 2 diabetes, obesity, older age, short duration of diabetes, higher A1C, and those who used capillary blood glucose for monitoring (p<0.05). CONCLUSIONS: A high proportion of patients were screened for dyslipidemia, but many outside the recommended window. Dyslipidemia is highly prevalent in this patient population and was associated with the presence of obesity, but 44% of patients without obesity also had dyslipidemia.

Community-based organization perspectives on participating in state-wide community canvassing program aimed to reduce COVID-19 vaccine disparities in California.

BACKGROUND: Inequities in COVID-19 vaccine accessibility and reliable COVID-related information disproportionately affected marginalized racial and ethnic communities in the U.S. The Get Out the Vaccine (GOTVax) program, an innovative statewide government-funded COVID-19 vaccine canvassing program in California, aimed to reduce structural barriers to COVID-19 vaccination in high-risk communities with low vaccination rates. GOTVax consisted of a community-academic-government partnership with 34 local trusted community-based organizations' (CBOs) to conduct COVID-19 vaccine outreach, education, and vaccine registration. The purpose of this qualitative evaluation study was to explore the barriers and facilitators of using local CBOs to deploy a geographically, racially, and ethnically diverse state-wide COVID-19 vaccine outreach program. METHODS: Semi-structured online interviews were conducted with participating GOTVax CBO leaders from November 2021 to January 2022. Transcripts were analyzed using reflexive thematic analysis. RESULTS: Thirty-one of 34 CBOs participated (91% response rate). Identified themes encompassed both facilitators and barriers to program participation. Key facilitators included leveraging trust through recognized entities; promoting empathetic, tailored outreach; and flexibility of milestone-based CBO funding contracts for rapid program implementation. Barriers included navigating community sociopolitical, geographic, and cultural factors; managing canvassers' safety; desiring metrics for self-evaluation of outreach success; mitigating canvassing technology challenges; and concerns of program infrastructure initially limiting outreach. CBOs problem-solved barriers with academic and government partners. CONCLUSIONS: Between May and December 2021, the GOTVax program reached over 2 million California residents and registered over 60,000 residents for COVID-19 vaccination. Public health campaigns may improve benefits from leveraging the expertise of community-trusted CBOs and universities by providing flexible infrastructure and funding, allowing CBOs to seamlessly tailor outreach most applicable to local minoritized communities.

A review of vascular endothelial growth factor and its potential to improve functional outcomes following spinal cord injury.

Spinal cord injuries (SCI) are traumatic events with limited treatment options. Following injury, the lesion site experiences a drastic change to both its structure and vasculature which reduces its ability for tissue regeneration. Despite the lack of clinical options, researchers are investigating therapies to induce neuronal regeneration. Cell-based therapies have long been assessed in the context of SCI to promote neuronal protection and repair. Vascular endothelial growth factor (VEGF) not only demonstrates this ability, but also demonstrates angiogenic potential to promote blood vessel formation. While there have been numerous animal studies investigating VEGF, further research is still warranted to pinpoint its role following SCI. This review aims to discuss the literature surrounding the role of VEGF following SCI and its potential in promoting functional recovery.

Toward precision sleep medicine: variations in sleep outcomes among disaggregated Asian Americans in the National Health Interview Survey (2006-2018).

STUDY OBJECTIVES: Asian Americans report higher rates of insufficient sleep than non-Hispanic Whites (NHWs). It is unclear how sleep outcomes differ among disaggregated Asian subgroups. METHODS: The National Health Interview Survey (2006-2018) was used to analyze self-reported sleep duration and quality measures for Asian American subgroups (Chinese [n = 11,056], Asian Indian [n = 11,249], Filipino [n = 13,211], and other Asians [n = 21,767]). Outcomes included hours of sleep per day, the number of days reporting trouble falling asleep, staying asleep, waking up rested, and taking sleep medication in the past week. Subsetted multivariate logistic regression was used to assess factors impacting sleep outcomes by ethnicity. RESULTS: 29.2% of NHWs, 26.4% of Chinese, 24.5% of Asian Indians, and 38.4% of Filipinos reported insufficient sleep duration. Filipinos were less likely to report sufficient sleep duration (odds ratio 0.55, [confidence interval 95% 0.50-0.59]) and more likely to report trouble falling asleep (1.16 [1.01-1.33]) than NHWs. Chinese and Asian Indians had less trouble staying asleep (0.67 [0.58-0.77], 0.51 [0.44-0.59]) and falling asleep (0.77 [0.66-0.89], 0.72, [0.62-0.82]) than NHWs, and Asian Indians were more likely to wake feeling well rested (1.66 [1.48-1.87]). All Asian subgroups were less likely to report using sleep medications than NHWs. Foreign-born status had a negative association with sufficient sleep duration in Filipinos but a positive association in Asian Indians and Chinese. CONCLUSIONS: Filipinos report the highest burden of poor sleep outcomes, and Asian Indians report significantly better sleep outcomes. These findings highlight the importance of disaggregating Asian ethnic subgroups to address their health needs. CITATION: Wang RZ, Jamal A, Wang Z, et al. Toward precision sleep medicine: variations in sleep outcomes among disaggregated Asian Americans in the National Health Interview Survey (2006-2018). J Clin Sleep Med. 2023;19(7):1259-1270.

Factors associated with successful median arcuate ligament release in an international, multi-institutional cohort.

OBJECTIVE: Prior research on median arcuate ligament syndrome has been limited to institutional case series, making the optimal approach to median arcuate ligament release (MALR) and resulting outcomes unclear. In the present study, we compared the outcomes of different approaches to MALR and determined the predictors of long-term treatment failure. METHODS: The Vascular Low Frequency Disease Consortium is an international, multi-institutional research consortium. Data on open, laparoscopic, and robotic MALR performed from 2000 to 2020 were gathered. The primary outcome was treatment failure, defined as no improvement in median arcuate ligament syndrome symptoms after MALR or symptom recurrence between MALR and the last clinical follow-up. RESULTS: For 516 patients treated at 24 institutions, open, laparoscopic, and robotic MALR had been performed in 227 (44.0%), 235 (45.5%), and 54 (10.5%) patients, respectively. Perioperative complications (ileus, cardiac, and wound complications; readmissions; unplanned procedures) occurred in 19.2% (open, 30.0%; laparoscopic, 8.9%; robotic, 18.5%; P < .001). The median follow-up was 1.59 years (interquartile range, 0.38-4.35 years). For the 488 patients with follow-up data available, 287 (58.8%) had had full relief, 119 (24.4%) had had partial relief, and 82 (16.8%) had derived no benefit from MALR. The 1- and 3-year freedom from treatment failure for the overall cohort was 63.8% (95% confidence interval [CI], 59.0%-68.3%) and 51.9% (95% CI, 46.1%-57.3%), respectively. The factors associated with an increased hazard of treatment failure on multivariable analysis included robotic MALR (hazard ratio [HR], 1.73; 95% CI, 1.16-2.59; P = .007), a history of gastroparesis (HR, 1.83; 95% CI, 1.09-3.09; P = .023), abdominal cancer (HR, 10.3; 95% CI, 3.06-34.6; P < .001), dysphagia and/or odynophagia (HR, 2.44; 95% CI, 1.27-4.69; P = .008), no relief from a celiac plexus block (HR, 2.18; 95% CI, 1.00-4.72; P = .049), and an increasing number of preoperative pain locations (HR, 1.12 per location; 95% CI, 1.00-1.25; P = .042). The factors associated with a lower hazard included increasing age (HR, 0.99 per increasing year; 95% CI, 0.98-1.0; P = .012) and an increasing number of preoperative diagnostic gastrointestinal studies (HR, 0.84 per study; 95% CI, 0.74-0.96; P = .012) Open and laparoscopic MALR resulted in similar long-term freedom from treatment failure. No radiographic parameters were associated with differences in treatment failure. CONCLUSIONS: No difference was found in long-term failure after open vs laparoscopic MALR; however, open release was associated with higher perioperative morbidity. These results support the use of a preoperative celiac plexus block to aid in patient selection. Operative candidates for MALR should be counseled regarding the factors associated with treatment failure and the relatively high overall rate of treatment failure.

Characterizing patient-reported claudication treatment goals to support patient-centered treatment selection and measurement strategies.

OBJECTIVE: Patient-reported outcomes (PRO) have been increasingly emphasized for peripheral artery disease (PAD). Patient-defined treatment goals and expectations, however, are poorly understood and might not be achievable or aligned with guidelines or clinical outcomes. We evaluated the patient-reported treatment goals among patients with claudication and the associations between patient characteristics, goals, and PAD-specific PRO scores. METHODS: Patients with a diagnosis of claudication were prospectively recruited. Patient-defined treatment goals and outcomes related to walking distance, duration, and speed were quantified using multiple-choice survey items. Free-text items were used to identify activities other than walking distance, duration, or speed associated with symptoms and treatment goals. The peripheral artery disease quality of life and walking impairment questionnaire instruments were included as PRO. The treatment goal categories were compared with the PRO percentile scores using 95% confidence intervals (CIs), categorical tests, and logistic regression models. Associations between the patient characteristics and PRO were evaluated using linear and ordinal logistic regression models. RESULTS: A total of 150 patients meeting the inclusion criteria were included in the present study. Of these 150 patients, 144 (96%) viewed the entire survey. Their mean age was 70.0 ± 11.3 years, and 32.9% were women. Most of the respondents had self-reported their race as White (n = 135), followed by Black (n = 3), Asian (n = 2), Native American (n = 2), and other/unknown (n = 2). Two participants self-reported Hispanic ethnicity. The primary treatment goals were an increased walking distance or duration without stopping (62.0%), the ability to perform a specific activity or task (23.0%), an increased walking speed (8.0%), or other/none of the above (7.0%). The specific activities associated with symptoms or goals included outdoor recreation (38.5%), labor-related tasks (30.7%), sports (26.9%), climbing stairs (23.1%), uphill walking (19.2%), and shopping (6%). Among the patients choosing an increased walking distance and duration as the primary goals, 64% had indicated that a distance of ≥0.5 mile (2640 ft) and 59% had indicated a duration of ≥30 minutes would be a minimum increase consistent with meaningful improvement. Increasing age was associated with lower odds of a distance improvement goal of ≥0.5 mile (odds ratio [OR], 0.68 per 5 years; 95% CI, 0.51-0.92; P = .012) or duration improvement goal of ≥30 minutes (OR, 0.76 per 5 years; 95% CI, 0.58-0.99; P = .047). Patient characteristics associated with PAD Quality of Life percentile scores included age, ankle brachial index, and gender. Ankle brachial index was the only patient characteristic associated with the walking impairment questionnaire percentile scores. CONCLUSIONS: Patients define treatment goals according to their desired activities and expectations, which may influence their goals and perceived outcomes. Patients' expectations of minimum increases in walking distance and duration consistent with meaningful improvement exceeded reported minimum important difference criteria for many patients and would not be captured using common clinic-based walking tests. Patient age was associated with both treatment goals and PRO scores, and the related floor and ceiling effects could influence sensitivity to PRO changes for younger and older patients, respectively. Heterogeneity in treatment goals supports consideration of tailored decision-making and outcomes informed by patient characteristics and perspectives.

The Inequitable Experiences of Left-Handed Medical Students in Surgical Education.

PURPOSE: Left-handed medical students contend with unique educational barriers within surgery, such as lack of educational resources, lack of left-handed-specific training, and widespread stigmatization of surgical left-handedness. This study aimed to highlight the surgical experiences of left-handed medical students so educators may be empowered to act with greater care and appreciation of these students' circumstances. METHOD: In this qualitative study, the authors conducted semistructured interviews on surgical experiences during medical school between January 31, 2021, and June 20, 2021, on 31 current surgical residents and fellows from 15 U.S. institutions and 6 surgical specialties. Left-handed trainees were included regardless of their surgical hand dominance. RESULTS: The authors identified 3 themes related to left-handed medical students' surgical experience: (1) disorienting advice from faculty or residents, (2) discouraging right-handed pressures and left-handed stigmatization, and (3) educational wishes of left-handed medical students. Trainees describe dialogues during medical school in which their handedness was directly addressed by residents and faculty with disorienting and nonbeneficial advice. Often trainees were explicitly told which hand to use, neglecting any preferences of the left-handed student. Participants also described possible changes in future surgical clerkships, including normalization of left-handedness, tangible mentorship, or granular and meaningful instruction. CONCLUSIONS: Left-handed medical students encounter unique challenges during their surgical education. These students report being disoriented by the variability of advice provided by mentors, discouraged by how pressured they feel to operate right-handed, and burdened by the need to figure things out by themselves in the absence of adequate left-handed educational resources. Surgical education leadership should detail the unique problems left-handed learners face, impartially elicit the learner's current operative hand preference, take responsibility for their left-handed students, promote acceptance and accommodation strategies of left-handed surgical trainees, and endeavor to improve the breadth of left-handed surgical resources.

Comparison of surgical interventions for the treatment of early-onset scoliosis: a systematic review and meta-analysis.

OBJECTIVE: Several growth-preserving surgical techniques are employed in the management of early-onset scoliosis (EOS). The authors' objective was to compare the use of traditional growing rods (TGRs), magnetically controlled growing rods (MCGRs), Shilla growth guidance techniques, and vertically expanding prosthetic titanium ribs (VEPTRs) for the management of EOS. METHODS: A systematic review of electronic databases, including Ovid MEDLINE and Cochrane, was performed. Outcomes of interest included correction of Cobb angle, T1-S1 distance, and complication rate, including alignment, hardware failure and infection, and planned and unplanned reoperation rates. The percent changes and 95% CIs were pooled across studies using random-effects meta-analysis. RESULTS: A total of 67 studies were identified, which included 2021 patients. Of these, 1169 (57.8%) patients underwent operations with TGR, 178 (8.8%) Shilla growth guidance system, 448 (22.2%) MCGR, and 226 (11.1%) VEPTR system. The mean ± SD age of the cohort was 6.9 ± 1.2 years. The authors found that the Shilla technique provided the most significant improvement in coronal Cobb angle immediately after surgery (mean [95% CI] 64.3% [61.4%-67.2%]), whereas VEPTR (27.6% [22.7%-33.6%]) performed significantly worse. VEPTR also performed significantly worse than the other techniques at final follow-up. The techniques also provided comparable gains in T1-S1 height immediately postoperatively (mean [95% CI] 10.7% [8.4%-13.0%]); however, TGR performed better at final follow-up (21.4% [18.7%-24.1%]). Complications were not significantly different among the patients who underwent the Shilla, TGR, MCGR, and VEPTR techniques, except for the rate of infections. The TGR technique had the lowest rate of unplanned reoperations (mean [95% CI] 15% [10%-23%] vs 24% [19%-29%]) but the highest number of planned reoperations per patient (5.31 [4.83-5.82]). The overall certainty was also low, with a high risk of bias across studies. CONCLUSIONS: This analysis suggested that the Shilla technique was associated with a greater early coronal Cobb angle correction, whereas use of VEPTR was associated with a lower correction rate at any time point. TGR offered the most significant height gain at final follow-up. The complication rates were comparable across all surgical techniques. The optimal surgical approach should be tailored to individual patients, taking into consideration the strengths and limitations of each option.

Use of Direct Oral Anticoagulant and Associated Bleeding and Thrombotic Complication after Lower Extremity Bypass.

BACKGROUND: Therapeutic anticoagulation with either a vitamin K antagonist (VKA) or direct anticoagulant (DOAC) is often newly prescribed to patients undergoing lower extremity bypass (LEB) to aid in graft patency when risk factors for thrombosis are present or to treat postoperative venous thromboembolism or atrial fibrillation. There is a gap in knowledge as to how DOAC usage impacts postoperative outcomes compared with the standard-of-care VKAs. STUDY DESIGN: To determine temporal trends in DOAC prescription after infrainguinal LEB, impact on length of stay (LOS), and associated bleeding and thrombotic complications, patients undergoing elective LEB were identified from the Vascular Quality Initiative between January 2013 and May 2019. Postoperative bleeding, LOS, and graft occlusion for patients receiving VKA compared with DOAC were evaluated. RESULTS: A total of 24,459 LEBs were performed during the study period. Among 2,656 patients newly prescribed an anticoagulant, 78.0% (n = 2,072) received VKA and 22.0% (n = 584) received a DOAC, with DOAC use increasing throughout the study period. There was no significant difference in postoperative bleeding (VKA 2.3%, DOAC 1.7%, p = 0.413) or graft occlusion (VKA 1.2%, DOAC 1.4%, p = 0.762) between the anticoagulant classes. LOS was shorter in the DOAC group than in the VKA group (5.7 vs 6.8 days; p < 0.001). CONCLUSIONS: This analysis demonstrates that DOAC use is increasing with time in Vascular Quality Initiative centers. DOACs are a safe and comparable alternative to VKAs in the postoperative setting with similar rates of bleeding complications and early graft patency and are associated with a reduced postoperative LOS.

Prophylactic administration of miR-451 inhibitor decreases osteoarthritis severity in rats.

Transfection of chondrocytes with microRNA-451(miR-451), present in growth zone cartilage of the growth plate, upregulates production of enzymes association with extracellular matrix degradation. miR-451 is also present in articular cartilage and exacerbates IL-1ß effects in articular chondrocytes. Moreover, when osteoarthritis (OA) was induced in Sprague Dawley rats via bilateral anterior cruciate ligament transection (ACLT), miR-451 expression was increased in OA cartilage compared to control, suggesting its inhibition might be used to prevent or treat OA. To examine the prophylactic and therapeutic potential of inhibiting miR-451, we evaluated treatment with miR-451 power inhibitor (451-PI) at the onset of joint trauma and treatment after OA had developed. The prophylactic animal cohort received twice-weekly intra-articular injections of either 451-PI or a negative control (NC-PI) beginning on post-surgical day 3. OA was allowed to develop for 24 days in the therapeutic cohort before beginning injections. All rats were killed on day 45. Micro-CT, histomorphometrics, OARSI scoring, and muscle force testing were performed on samples. 451-PI mitigated OA progression compared to NC-PI limbs in the prophylactic cohort based on histomorphometric analysis and OARSI scoring, but no differences were detected by micro-CT. 451-PI treatment beginning 24 days post-surgery was not able to reduce OA severity. Prophylactic administration of 451-PI mitigates OA progression in a post-trauma ACLT rat model supporting its potential to prevent OA development following an ACLT injury clinically.

Quantitative immunopeptidomics reveals a tumor stroma-specific target for T cell therapy.

T cell receptor (TCR)-based immunotherapy has emerged as a promising therapeutic approach for the treatment of patients with solid cancers. Identifying peptide-human leukocyte antigen (pHLA) complexes highly presented on tumors and rarely expressed on healthy tissue in combination with high-affinity TCRs that when introduced into T cells can redirect T cells to eliminate tumor but not healthy tissue is a key requirement for safe and efficacious TCR-based therapies. To discover promising shared tumor antigens that could be targeted via TCR-based adoptive T cell therapy, we employed population-scale immunopeptidomics using quantitative mass spectrometry across ~1500 tumor and normal tissue samples. We identified an HLA-A*02:01-restricted pan-cancer epitope within the collagen type VI α-3 (COL6A3) gene that is highly presented on tumor stroma across multiple solid cancers due to a tumor-specific alternative splicing event that rarely occurs outside the tumor microenvironment. T cells expressing natural COL6A3-specific TCRs demonstrated only modest activity against cells presenting high copy numbers of COL6A3 pHLAs. One of these TCRs was affinity-enhanced, enabling transduced T cells to specifically eliminate tumors in vivo that expressed similar copy numbers of pHLAs as primary tumor specimens. The enhanced TCR variants exhibited a favorable safety profile with no detectable off-target reactivity, paving the way to initiate clinical trials using COL6A3-specific TCRs to target an array of solid tumors.