Citations

Abstract Skin fibrosis is a clinical problem with devastating impacts but limited treatment options. In the setting of diabetes, insulin administration often causes local dermal fibrosis, leading to a range of clinical sequelae including impeded insulin absorption. Mechanical forces are important drivers of fibrosis and, clinically, physical tension offloading at the skin level using an elastomeric patch significantly reduces wound scarring. However, it is not known whether tension offloading could similarly prevent skin fibrosis in the setting of pro-fibrotic injections. Here, we develop a porcine model using repeated local injections of bleomycin to recapitulate key features of insulin-induced skin fibrosis. Using histologic, tissue ultrastructural, and biomechanical analyses, we show that application of a tension-offloading patch both prevents and rescues existing skin fibrosis from bleomycin injections. By applying single-cell transcriptomic analysis, we find that the fibrotic response to bleomycin involves shifts in myeloid cell dynamics from favoring putatively pro-regenerative to pro-fibrotic myeloid subtypes; in a mechanomodulatory in vitro platform, we show that these shifts are mechanically driven and reversed by exogenous IL4. Finally, using a human foreskin xenograft model, we show that IL4 treatment mitigates bleomycin-induced dermal fibrosis. Overall, this study highlights that skin tension offloading, using an FDA cleared, commercially available patch, could have significant potential clinical benefit for the millions of patients dependent on insulin.

ImportanceEndovascular thrombectomy (EVT) is standard treatment for acute ischemic stroke (AIS) due to large-vessel occlusion (LVO), but optimal post-EVT blood pressure (BP) control remains debated.ObjectiveTo assess the association of different systolic BP targets following EVT with functional outcomes, mortality, and complications in patients with AIS due to LVO.Data SourcesSystematic review and meta-analysis of databases (PubMed, Embase, Web of Science, Scopus, and Cochrane Library) to September 8, 2023.Study SelectionInclusion criteria consisted of randomized clinical trials examining post-EVT management of systolic BP in patients with AIS and LVO comparing intensive vs conventional targets. Nonrandomized studies, observational studies, noninterventional trials, meeting abstracts, duplicate studies, studies with overlapping data, and non–English language studies were excluded. Two authors independently applied these criteria through a blinded review, with discrepancies resolved through consensus. The risk of bias in the included studies was assessed using the revised tool for assessing risk of bias in randomized trials.Data Extraction and SynthesisThis study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Three authors extracted data regarding study characteristics, baseline patient data, and outcomes of interest. The pooled data were analyzed using a random-effects meta-analysis.Main Outcomes and MeasuresRates of functional independence, 90-day mortality, symptomatic intracranial hemorrhage, and hypotensive events.ResultsA total of 4 randomized clinical trials with 1571 initially enrolled patients were included in the analysis. Lower functional independence rates were observed in the intensive control group (relative risk [RR], 0.81 [95% CI, 0.67-0.98]). No significant differences were found in 90-day mortality (RR, 1.18 [95% CI, 0.92-1.52]), symptomatic intracranial hemorrhage (RR, 1.12 [95% CI, 0.75-1.67]), or hypotensive events (RR, 1.80 [95% CI, 0.37-8.76]). There was minimal heterogeneity among the studies included in the functional independence outcome (I2 = 13% and τ2 = 0.003), which was absent among other outcomes (I2 = 0 and τ2 = 0).Conclusions and RelevanceThese findings suggest that intensive post-EVT BP reduction does not yield benefits and may carry risks. While awaiting the results of additional ongoing trials, a conservative BP management strategy after endovascular recanalization is favored in daily practice.

Exposure to high altitude results in hypobaric hypoxia, leading to physiological changes in the cardiovascular system that may result in limiting symptoms, including dyspnea, fatigue, and exercise intolerance. However, it is still unclear why some patients are more susceptible to high-altitude symptoms than others. Hypoxic simulation testing (HST) simulates changes in physiology that occur at a specific altitude by asking the patients to breathe a mixture of gases with decreased oxygen content. This study aimed to determine whether the use of transthoracic echocardiography (TTE) during HST can detect the rise in right-sided pressures and the impact of hypoxia on right ventricle (RV) hemodynamics and right to left shunts, thus revealing the underlying causes of high-altitude signs and symptoms. A retrospective study was performed including consecutive patients with unexplained dyspnea at high altitude. HSTs were performed by administrating reduced FiO2 to simulate altitude levels specific to patients’ history. Echocardiography images were obtained at baseline and during hypoxia. The study included 27 patients, with a mean age of 65 years, 14 patients (51.9%) were female. RV systolic pressure increased at peak hypoxia, while RV systolic function declined as shown by a significant decrease in the tricuspid annular plane systolic excursion (TAPSE), the maximum velocity achieved by the lateral tricuspid annulus during systole (S’ wave), and the RV free wall longitudinal strain. Additionally, right-to-left shunt was present in 19 (70.4%) patients as identified by bubble contrast injections. Among these, the severity of the shunt increased at peak hypoxia in eight cases (42.1%), and the shunt was only evident during hypoxia in seven patients (36.8%). In conclusion, the use of TTE during HST provides valuable information by revealing the presence of symptomatic, sustained shunts and confirming the decline in RV hemodynamics, thus potentially explaining dyspnea at high altitude. Further studies are needed to establish the optimal clinical role of this physiologic method.

Background The Woven Endo-Bridge (WEB) device revolutionized the treatment of wide-necked bifurcation aneurysms by intrasaccular flow diversion. The latest advancement is the WEB-17 system, offering greater flexibility with fewer wires, enabling treatment of smaller distal aneurysms using smaller microcatheters than the WEB-21 system. Methods We conducted a systematic review following preferred reporting items for systematic reviews and meta-analyses guidelines, analyzing data from seven retrospective cohort studies involving 483 aneurysms treated with the WEB-17 device. Statistical analysis computed pooled prevalence rates and 95% confidence intervals using appropriate models for each outcome and R software version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria). Results Technical success was achieved in 475 out of 483 aneurysms treated with the WEB-17 device, with a success rate of 98.34% (95% confidence interval (CI) = 96.72–99.17). Among the successful cases, 4.97% (95% CI = 1.60–14.39) required adjunctive devices. Adequate occlusion, defined as complete occlusion or neck remnants, was observed in 94.41% (95% CI = 88.17–97.46) of cases. Periprocedural complications were infrequent, with thromboembolic complications occurring in 4.93% (95% CI = 3.29–7.30) of cases, hemorrhagic complications in 1.28% (95% CI = 0.58–2.83), and postprocedural neurologic complications in 0.99% (95% CI = 0.31–3.14). Procedure-related morbidity was observed in 1.71% (95% CI = 0.86–3.39) of cases, and there was one procedure-related mortality reported at 0.21% (95% CI = .03–1.50). Mortality unrelated to the procedure occurred in 1% (95% CI = 0.23–4.15). Conclusion Our findings suggest that the WEB-17 device is associated with a high rate of technical success, favorable angiographic outcomes, and a low rate of periprocedural complications. Further research, including prospective trials, is needed to confirm these findings and establish its safety and efficacy definitively.

AbstractThis systematic review and meta‐analysis of randomised controlled trials (RCTs) aimed to evaluate the efficacy, safety, and tolerability of fluvoxamine for the outpatient management of COVID‐19. We conducted this review in accordance with the PRISMA 2020 guidelines. Literature searches were conducted in MEDLINE, EMBASE, International Pharmaceutical Abstracts, CINAHL, Web of Science, and CENTRAL up to 14 September 2023. Outcomes included incidence of hospitalisation, healthcare utilization (emergency room visits and/or hospitalisation), mortality, supplemental oxygen and mechanical ventilation requirements, serious adverse events (SAEs) and non‐adherence. Fluvoxamine 100 mg twice a day was associated with reductions in the risk of hospitalisation (risk ratio [RR] 0.75, 95% confidence interval [CI] 0.58–0.97; I 2 = 0%) and reductions in the risk of healthcare utilization (RR 0.68, 95% CI 0.53–0.86; I 2 = 0%). While no increased SAEs were observed, fluvoxamine 100 mg twice a day was associated with higher treatment non‐adherence compared to placebo (RR 1.61, 95% CI 1.22–2.14; I 2 = 53%). In subgroup analyses, fluvoxamine reduced healthcare utilization in outpatients with BMI ≥30 kg/m2, but not in those with lower BMIs. While fluvoxamine offers potential benefits in reducing healthcare utilization, its efficacy may be most pronounced in high‐risk patient populations. The observed non‐adherence rates highlight the need for better patient education and counselling. Future investigations should reassess trial endpoints to include outcomes relating to post‐COVID sequelaes. Registration: This review was prospectively registered on PROSPERO (CRD42023463829).

Current management of patients with congenital heart disease has increased their survival into adulthood. This is accompanied by potential cardiac complications, including pulmonary hypertension associated with congenital heart disease (PAH-CHD). PAH-CHD constitutes a challenging subgroup of pulmonary hypertension and requires expert management to improve quality of life and prognosis. Novel agents have shown a significant improvement in morbidity and mortality in patients with pulmonary arterial hypertension. However, the long-term effects of these medications on PAH-CHD patients remain somewhat uncertain, necessitating treatment plans largely founded on the clinical experience of the healthcare providers. The aim of this review is to summarize the current evidence and future perspectives regarding treatment strategies for PAH-CHD to help better guide management of this complex disease.

Introduction: At the forefront of post-heart transplant care is early detection of transplant rejection. However, the current gold standard for detecting acute cellular transplant rejection is recurrent invasive endomyocardial biopsies (EMB). We aimed at developing a non-invasive biomarker for acute cellular heart transplant rejection (ACR) using a plasma extracellular vesicle (EV) platform. Methods: Peripheral and coronary sinus plasma samples were prospectively collected from 183 (31.7% female) patients from 2020 to 2023 during routine surveillance EMB. A discovery cohort comprised five patients who displayed ISHLT 0-1R biopsy followed by an ISHLT 2R grade rejection event. Plasma EVs were isolated from the baseline (0-1R) and rejection (2R) time points. Subsequently, integrative analysis of plasma EV proteomic, miRNomic, and metabolomics was performed pairwise with the samples. Results: The study collected 943 sample time points from 183 patients. Of these sample collections, 43 (4.5%) cases were 2R rejections. Our proteomic analysis of the plasma EVs identified 28 proteins found explicitly during a grade 2R rejection and 87 differentially expressed proteins during a 2R rejection event. An Ingenuity Pathway Analysis (IPA) analysis of the upregulated proteins highlighted EVs mediated mTOR signaling and antigen presentation as central to rejection events. Although all patients in the discovery cohort were negative for antibody-mediated rejection (AMR), the proteomic findings also revealed increased B-cell receptor signaling, implying a mechanistic intersection of ACR and AMR. Conclusions: A distinct set of proteins were found in plasma EVs during ACR events, providing potentially specific and sensitive biomarkers to reduce the need for EMB that could be exploited for ACR diagnosis. The proteins identified formed an immune signaling network that suggests a novel role for EVs in ACR pathogenesis.

Abstract Background: Ventilator-associated pneumonia (VAP) is one of the leading causes of mortality in patients with critical care illness. Since obesity is highly prevalent, we wanted to study its impact on the outcomes of patients who develop VAP. Methods: Using the National Inpatient Sample (NIS) Database from 2017 to 2020, we conducted a retrospective study of adult patients with a principal diagnosis of VAP with a secondary diagnosis with or without obesity according to ICD-10 codes. Several demographics, including age, race, and gender, were analyzed. The primary endpoint was mortality, while the secondary endpoints included tracheostomy, length of stay in days, and patient charge in dollars. Multivariate logistic regression model analysis was used to adjust for confounders, with a p-value less than 0.05 considered statistically significant. Results: The study included 3832 patients with VAP, 395 of whom had obesity. The mean age in both groups was around 58 years, and 68% of the group with obesity were females compared to 40% in the control group. Statistically significant comorbidities in the obesity group included a Charlson Comorbidity Index score of three and above, Diabetes Mellitus, Hypertension, and chronic kidney disease. Rates and odds of mortality were not significantly higher in the collective obesity group 39 (10%) vs. 336 (8.5%), p-value 0.62, aOR 1.41, p-value 0.39). The rates and odds of tracheostomy were higher in the obesity group but not statistically significant. Obese patients were also found to have a longer and more expensive hospitalization. Conclusions: Obesity was not found to be an independent risk factor for worse outcomes in patients who develop VAP in the intensive care unit.

Background: Quadriceps muscle atrophy remains a limiting factor in returning to activity after anterior cruciate ligament reconstruction (ACLR). Blood flow restriction (BFR) therapy may accelerate quadriceps strengthening in the perioperative period. Purpose: To evaluate postoperative isometric quadriceps strength in patients who underwent ACLR with a perioperative BFR program. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Patients indicated for ACLR were randomized into 2 groups, BFR and control, at their initial clinic visit. All patients underwent 2 weeks of prehabilitation preoperatively, with the BFR group performing exercises with a pneumatic cuff set to 80% limb occlusion pressure placed over the proximal thigh. All patients also underwent a standardized postoperative 12-week physical therapy protocol, with the BFR group using pneumatic cuffs during exercise. Quadriceps strength was measured as peak and mean torque during seated leg extension and presented as quadriceps index (percentage vs healthy limb). Patient-reported outcomes (PROs), knee range of motion, and quadriceps circumference were also gathered at 6 weeks, 3 months, and 6 months postoperatively, and adverse effects were recorded. Results: Included were 46 patients, 22 in the BFR group (mean age, 25.4 ± 10.6 years) and 24 in the control group (mean age, 27.5 ± 12.0 years). At 6 weeks postoperatively, the BFR group demonstrated significantly greater strength compared with the controls (quadriceps index: 57% ± 24% vs 40% ± 18%; P = .029), and the BFR group had significantly better Patient-Reported Outcomes Measurement Information System–Physical Function (42.69 ± 5.64 vs 39.20 ± 5.51; P = .001) and International Knee Documentation Committee (58.22 ± 7.64 vs 47.05 ± 13.50; P = .011) scores. At 6 weeks postoperatively, controls demonstrated a significant drop in the peak torque generation of the operative versus nonoperative leg. There were no significant differences in strength or PROs at 3 or 6 months postoperatively. Three patients elected to drop out of the BFR group secondary to cuff intolerance during exercise; otherwise, no other severe adverse events were reported. Conclusion: Integrating BFR into perioperative physical therapy protocols led to improved strength and increased PROs at 6 weeks after ACLR. No differences in strength or PROs were found at 3 and 6 months between the 2 groups. Registration: NCT04374968 (ClinicalTrials.gov identifier).

Purpose To compare 3 separate blood flow restriction (BFR) systems in their capacity to reduce repetitions to failure, impact perceptual responses, and cause adverse events during a low‐load free‐flow exercise. Methods The study included healthy subjects aged 18 years or older who presented to an ambulatory‐care sports medicine clinic. On day 1, participants’ demographic characteristics and anthropomorphic measurements were recorded. Each participant performed dumbbell biceps curl repetitions to failure using 20% of his or her 1‐repetition maximum weight with each arm. Participants were exposed to 3 different tourniquet systems for familiarization. On day 2, each participant’s arm was randomized to a cuff system, and the participant performed 2 sets of biceps curl repetitions to failure with the cuff inflated. Repetitions to failure, rating of perceived effort (RPE), rating of perceived discomfort, and pulse oxygenation levels were recorded after each set. On day 3, participants completed a survey of their perceived delayed‐onset muscle soreness. Results The final analysis was performed on 42 arms, with 14 limbs per system. The study population had a mean age of 28.7 ± 2.4 years and a mean body mass index of 24.9 ± 4.3. All 3 systems successfully reduced repetitions to failure compared with unrestricted low‐load exercise from baseline to BFR set 1 and from baseline to BFR set 2. There were no significant between‐group differences among BFR systems regarding the number of repetitions to failure performed at baseline versus BFR set 1 or BFR set 2. The Delfi Personalized Tourniquet System (PTS) cohort had the greatest reductions in repetitions to failure from BFR set 1 to BFR set 2 ( P = .002) and reported the highest RPE after set 2 ( P = .025). Conclusions The Delfi PTS, SmartCuffs Pro, and BStrong BFR systems were each safe and were able to significantly reduce repetitions to failure compared with a low‐load free‐flow condition when used in a BFR exercise protocol. The Delfi PTS system may produce a higher RPE with prolonged use in comparison to the other systems. Level of Evidence Level II, prospective cohort study.