Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection: The STOP-PASC Randomized Clinical Trial.

Importance: There is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC). Objective: To assess the efficacy of a 15-day course of nirmatrelvir-ritonavir in reducing the severity of select PASC symptoms. Design, Setting, and Participants: This was a 15-week blinded, placebo-controlled, randomized clinical trial conducted from November 2022 to September 2023 at Stanford University (California). The participants were adults with moderate to severe PASC symptoms of 3 months or longer duration. Interventions: Participants were randomized 2:1 to treatment with oral nirmatrelvir-ritonavir (NMV/r, 300 mg and 100 mg) or with placebo-ritonavir (PBO/r) twice daily for 15 days. Main Outcomes and Measures: Primary outcome was a pooled severity of 6 PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) based on a Likert scale score at 10 weeks. Secondary outcomes included symptom severity at different time points, symptom burden and relief, patient global measures, Patient-Reported Outcomes Measurement Information System (PROMIS) measures, orthostatic vital signs, and sit-to-stand test change from baseline. Results: Of the 155 participants (median [IQR] age, 43 [34-54] years; 92 [59%] females), 102 were randomized to the NMV/r group and 53 to the PBO/r group. Nearly all participants (n = 153) had received the primary series for COVID-19 vaccination. Mean (SD) time between index SARS-CoV-2 infection and randomization was 17.5 (9.1) months. There was no statistically significant difference in the model-derived severity outcome pooled across the 6 core symptoms at 10 weeks between the NMV/r and PBO/r groups. No statistically significant between-group differences were found at 10 weeks in the Patient Global Impression of Severity or Patient Global Impression of Change scores, summative symptom scores, and change from baseline to 10 weeks in PROMIS fatigue, dyspnea, cognitive function, and physical function measures. Adverse event rates were similar in NMV/r and PBO/r groups and mostly of low grade. Conclusions and Relevance: The results of this randomized clinical trial showed that a 15-day course of NMV/r in a population of patients with PASC was generally safe but did not demonstrate a significant benefit for improving select PASC symptoms in a mostly vaccinated cohort with protracted symptom duration. Further studies are needed to determine the role of antivirals in the treatment of PASC. Trial Registration: ClinicalTrials.gov Identifier: NCT05576662.

Influence of hospital-level and surgeon factors on the outcomes after ileo-anal pouch surgery for inflammatory bowel disease: systematic review.

BACKGROUND: Ileal pouch-anal anastomosis ('pouch surgery') provides a chance to avoid permanent ileostomy after proctocolectomy, but can be associated with poor outcomes. The relationship between hospital-level/surgeon factors (including volume) and outcomes after pouch surgery is of increasing interest given arguments for increasing centralization of these complex procedures. The aim of this systematic review was to appraise the literature describing the influence of hospital-level and surgeon factors on outcomes after pouch surgery for inflammatory bowel disease. METHODS: A systematic review was performed of studies reporting outcomes after pouch surgery for inflammatory bowel disease. The MEDLINE (Ovid), Embase (Ovid), and Cochrane CENTRAL databases were searched (1978-2022). Data on outcomes, including mortality, morbidity, readmission, operative approach, reconstruction, postoperative parameters, and pouch-specific outcomes (failure), were extracted. Associations between hospital-level/surgeon factors and these outcomes were summarized. This systematic review was prospectively registered in PROSPERO, the international prospective register of systematic reviews (CRD42022352851). RESULTS: A total of 29 studies, describing 41 344 patients who underwent a pouch procedure, were included; 3 studies demonstrated higher rates of pouch failure in lower-volume centres, 4 studies demonstrated higher reconstruction rates in higher-volume centres, 2 studies reported an inverse association between annual hospital pouch volume and readmission rates, and 4 studies reported a significant association between complication rates and surgeon experience. CONCLUSION: This review summarizes the growing body of evidence that supports centralization of pouch surgery to specialist high-volume inflammatory bowel disease units. Centralization of this technically demanding surgery that requires dedicated perioperative medical and nursing support should facilitate improved patient outcomes and help train the next generation of pouch surgeons.

Cloud-Based Machine Learning Platform to Predict Clinical Outcomes at Home for Patients With Cardiovascular Conditions Discharged From Hospital: Clinical Trial.

BACKGROUND: Hospitalizations account for almost one-third of the US $4.1 trillion health care cost in the United States. A substantial portion of these hospitalizations are attributed to readmissions, which led to the establishment of the Hospital Readmissions Reduction Program (HRRP) in 2012. The HRRP reduces payments to hospitals with excess readmissions. In 2018, >US $700 million was withheld; this is expected to exceed US $1 billion by 2022. More importantly, there is nothing more physically and emotionally taxing for readmitted patients and demoralizing for hospital physicians, nurses, and administrators. Given this high uncertainty of proper home recovery, intelligent monitoring is needed to predict the outcome of discharged patients to reduce readmissions. Physical activity (PA) is one of the major determinants for overall clinical outcomes in diabetes, hypertension, hyperlipidemia, heart failure, cancer, and mental health issues. These are the exact comorbidities that increase readmission rates, underlining the importance of PA in assessing the recovery of patients by quantitative measurement beyond the questionnaire and survey methods. OBJECTIVE: This study aims to develop a remote, low-cost, and cloud-based machine learning (ML) platform to enable the precision health monitoring of PA, which may fundamentally alter the delivery of home health care. To validate this technology, we conducted a clinical trial to test the ability of our platform to predict clinical outcomes in discharged patients. METHODS: Our platform consists of a wearable device, which includes an accelerometer and a Bluetooth sensor, and an iPhone connected to our cloud-based ML interface to analyze PA remotely and predict clinical outcomes. This system was deployed at a skilled nursing facility where we collected >17,000 person-day data points over 2 years, generating a solid training database. We used these data to train our extreme gradient boosting (XGBoost)-based ML environment to conduct a clinical trial, Activity Assessment of Patients Discharged from Hospital-I, to test the hypothesis that a comprehensive profile of PA would predict clinical outcome. We developed an advanced data-driven analytic platform that predicts the clinical outcome based on accurate measurements of PA. Artificial intelligence or an ML algorithm was used to analyze the data to predict short-term health outcome. RESULTS: We enrolled 52 patients discharged from Stanford Hospital. Our data demonstrated a robust predictive system to forecast health outcome in the enrolled patients based on their PA data. We achieved precise prediction of the patients' clinical outcomes with a sensitivity of 87%, a specificity of 79%, and an accuracy of 85%. CONCLUSIONS: To date, there are no reliable clinical data, using a wearable device, regarding monitoring discharged patients to predict their recovery. We conducted a clinical trial to assess outcome data rigorously to be used reliably for remote home care by patients, health care professionals, and caretakers.

Optimizing theatre utilization for abscess drainage: going beyond priority categories.

BACKGROUND: Day-only emergency surgery for abscess drainage is poorly implemented in Australia. This study assessed the feasibility, outcomes, cost, and impact of an acute day-only surgery (ADOS) program. METHOD: A retrospective pre-post implementation study of patients requiring abscess drainage in theatre was performed. Following implementation of an ADOS program for abscess management, eligible patients were discharged from the emergency department and prioritized first on the following day's emergency list. Outcomes from the first 12 months of the ADOS era were compared with those of the preceding 6 months (pre-ADOS). Primary outcome was length of hospital stay (LOS). Secondary outcomes included 30-day complications, admission costs, and impact on overall emergency theatre workflow (measured by emergency appendicectomy metrics). RESULTS: Overall, 266 patients during the ADOS era (including 95 eligible for the ADOS pathway) were compared with 115 patients during the pre-ADOS era. Baseline characteristics were comparable. Median LOS was shorter during the ADOS era (21.9 h (IQR 11.8-43.3) vs. 30.1 h (IQR 24.7-48.8), P < 0.001). Median LOS was 10.2 h (IQR 8.9-13.1) for patients on the ADOS pathway. There were no significant differences in 30-day complications (9.3% vs. 9.5%), emergency department re-presentations (7.4% vs. 5.1%), or abscess recurrence (5.6% vs. 5.7%). Average cost per patient was lower during the ADOS era ($4155 vs. $4916, p = 0.005). ADOS did not appear to materially impact other emergency procedures. CONCLUSION: ADOS for abscess drainage is feasible, safe, and produces cost savings, while being implemented without significant additional resources.

Restoration of intestinal continuity following emergency sigmoid colectomy for sigmoid volvulus: An American College of Surgeons National Surgical Quality Improvement Program analysis using coarsened exact matching.

BACKGROUND: There is limited data to guide decision-making between performing a primary anastomosis and fashioning an end colostomy following emergency sigmoid colectomy for patients with sigmoid volvulus. The aim of this study was to compare the outcomes of these two approaches. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2006 to 2021 was retrospectively analyzed. Missing data were multiply imputed, and coarsened exact matching was performed to generate matched cohorts. Rates of major complications and other postoperative outcomes were evaluated among patients who had a primary anastomosis as compared with matched controls who had an end colostomy following emergency sigmoid colectomy. RESULTS: Overall, 4041 patients who had a primary anastomosis and 1240 who had an end colostomy met the inclusion criteria. After multiple imputation and coarsened exact matching, 895 patients who had a primary anastomosis had a matched control. The rate of major complications was lower in patients who had an end colostomy (33.2% vs. 36.7%), but this difference was not statistically significant (OR 0.86, 95% CI 0.70-1.05). Results were similar in subgroup analyses of higher-risk patients. There were no significant differences in overall complication rate, mortality, length of hospital stay, or readmission rate. Patients with a colostomy were more likely to be discharged to a care facility (OR 1.35, 95% CI 1.09-1.67). CONCLUSION: Differences in rates of major complications and many other outcomes after primary anastomosis as compared with end colostomy were not statistically significant following emergency sigmoid colectomy for sigmoid volvulus.

Optimizing care delivery in expanding health systems: Views from clinical leaders.

INTRODUCTION: In response to intense market pressures, many hospitals have consolidated into systems. However, evidence suggests that consolidation has not led to the improvements in clinical quality promised by proponents of mergers. The challenges to delivering care within expanding health systems and the opportunities posed to surgical leaders remains largely unexplored. METHODS: Semistructured interviews with 30 surgical leaders at teaching hospitals affiliated with health systems from August-December 2019. Interviews were transcribed verbatim and coded in an iterative process using MaxQDA software. Attitudes and strategies toward redesigning health care delivery across expanding systems were analyzed using thematic analysis. RESULTS: Leaders reported challenges to redesigning care delivery across the system ranging from resource constraints (e.g. hospital beds and operating rooms) to evolving market demands (e.g., patient preferences to receive care close to home). However, participants also highlighted that system expansion provided multiple opportunities to increase access (e.g. decant low-complexity care to affiliated centers) and improve quality of care (e.g. standardize best practices) for diverse populations including the potential to leverage their health system to expand access and improve quality. CONCLUSIONS: Though evidence suggests that hospital consolidation has not led to redesigned care delivery or improved clinical quality at a national level, leaders are pursuing varying sets of strategies aimed at leveraging system expansion in order to improve access and quality of care.

Sex Influences the Safety and Therapeutic Efficacy of Cardiac Nanomedicine Technologies.

Nanomedicine technologies are being developed for the prevention, diagnosis, and treatment of cardiovascular disease (CVD), which is the leading cause of death worldwide. Before delving into the nuances of cardiac nanomedicine, it is essential to comprehend the fundamental sex-specific differences in cardiovascular health. Traditionally, CVDs have been more prevalent in males, but it is increasingly evident that females also face significant risks, albeit with distinct characteristics. Females tend to develop CVDs at a later age, exhibit different clinical symptoms, and often experience worse outcomes compared to males. These differences indicate the need for sex-specific approaches in cardiac nanomedicine. This Perspective discusses the importance of considering sex in the safety and therapeutic efficacy of nanomedicine approaches for the prevention, diagnosis, and treatment of CVD.

Dialectical Behavior Therapy in Juvenile Correctional and Detention Facilities: A Scoping Review.

Dialectical behavior therapy (DBT) has shown preliminary success in the treatment of youth in forensic settings. However, the implementation of DBT varies considerably from facility to facility. A scoping review was conducted to detail DBT intervention protocols in juvenile correctional and detention facilities. We described eight works' treatment setting, study design, youth characteristics, staff training, DBT approach, DBT skills modules, and main findings. All works involved DBT skills sessions, but few incorporated other DBT components such as individual therapy or skills coaching. Outcomes included reducing problematic behaviors such as aggression, improving mental health, and largely positive feedback regarding the DBT intervention from youth and staff. Our results consolidate the existing literature regarding DBT intervention in forensic settings for youth and inform future implementation and research of DBT in such facilities.

Using AI to measure Parkinson's disease severity at home.

We present an artificial intelligence (AI) system to remotely assess the motor performance of individuals with Parkinson's disease (PD). In our study, 250 global participants performed a standardized motor task involving finger-tapping in front of a webcam. To establish the severity of Parkinsonian symptoms based on the finger-tapping task, three expert neurologists independently rated the recorded videos on a scale of 0-4, following the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The inter-rater reliability was excellent, with an intra-class correlation coefficient (ICC) of 0.88. We developed computer algorithms to obtain objective measurements that align with the MDS-UPDRS guideline and are strongly correlated with the neurologists' ratings. Our machine learning model trained on these measures outperformed two MDS-UPDRS certified raters, with a mean absolute error (MAE) of 0.58 points compared to the raters' average MAE of 0.83 points. However, the model performed slightly worse than the expert neurologists (0.53 MAE). The methodology can be replicated for similar motor tasks, providing the possibility of evaluating individuals with PD and other movement disorders remotely, objectively, and in areas with limited access to neurological care.

Anti-breast cancer-induced cardiomyopathy: Mechanisms and future directions.

With the progression of tumor treatment, the 5-year survival rate of breast cancer is close to 90%. Cardiovascular toxicity caused by chemotherapy has become a vital factor affecting the survival of patients with breast cancer. Anthracyclines, such as doxorubicin, are still some of the most effective chemotherapeutic agents, but their resulting cardiotoxicity is generally considered to be progressive and irreversible. In addition to anthracyclines, platinum- and alkyl-based antitumor drugs also demonstrate certain cardiotoxic effects. Targeted drugs have always been considered a relatively safe option. However, in recent years, some random clinical trials have observed the occurrence of subclinical cardiotoxicity in targeted antitumor drug users, which may be related to the effects of targeted drugs on the angiotensin converting enzyme, angiotensin receptor and ß receptor. The use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and beta-blockers may prevent clinical cardiotoxicity. This article reviews the toxicity and mechanisms of current clinical anti-breast cancer drugs and proposes strategies for preventing cardiovascular toxicity to provide recommendations for the clinical prevention and treatment of chemotherapy-related cardiomyopathy.

Impact of obesity on patients undergoing surgery for rectal cancer in Australia and New Zealand.

PURPOSE: Patients with obesity undergoing rectal cancer surgery may have an increased risk of developing complications, though evidence is inconclusive. The aim of this study was to determine the direct impact of obesity on postoperative outcomes using data from a large clinical registry. METHOD: The Binational Colorectal Cancer Audit registry was used to identify patients who underwent rectal cancer surgery in Australia and New Zealand from 2007-2021. Primary outcomes were inpatient surgical and medical complications. Logistic regression models were developed to describe the association between body-mass index (BMI) and outcomes. RESULTS: Among 3,708 patients (median age 66 years [IQR 56.75-75], 65.0% male), 2.0% had a BMI < 18.5 kg/m2, 35.4% had a BMI of 18.5-24.9 kg/m2, 37.6% had a BMI of 25.0-29.9 kg/m2, 16.7% had a BMI of 30.0-34.9 kg/m2, and 8.2% had a BMI ≥ 35.0 kg/m2. Surgical complications occurred in 27.7% of patients with a BMI of 18.5-24.9 kg/m2, 26.6% of patients with a BMI of 25.0-29.9 kg/m2 (OR 0.91, 95% CI 0.76-1.10), 28.5% with a BMI of 30.0-34.9 kg/m2 (OR 0.96, 95% CI 0.76-1.21), and 33.2% with a BMI ≥ 35.0 kg/m2 (OR 1.27, 95% CI 0.94-1.71). Modelling BMI as a continuous variable confirmed a J-shaped relationship. The association between BMI and medical complications was more linear. CONCLUSION: Risk of postoperative complications is increased in patients with obesity undergoing rectal cancer surgery.

Relative Meaningfulness and Impacts of Symptoms in People with Early-Stage Parkinson's Disease.

BACKGROUND: Patient perspectives on meaningful symptoms and impacts in early Parkinson's disease (PD) are lacking and are urgently needed to clarify priority areas for monitoring, management, and new therapies. OBJECTIVE: To examine experiences of people with early-stage PD, systematically describe meaningful symptoms and impacts, and determine which are most bothersome or important. METHODS: Forty adults with early PD who participated in a study evaluating smartwatch and smartphone digital measures (WATCH-PD study) completed online interviews with symptom mapping to hierarchically delineate symptoms and impacts of disease from "Most bothersome" to "Not present," and to identify which of these were viewed as most important and why. Individual symptom maps were coded for types, frequencies, and bothersomeness of symptoms and their impacts, with thematic analysis of narratives to explore perceptions. RESULTS: The three most bothersome and important symptoms were tremor, fine motor difficulties, and slow movements. Symptoms had the greatest impact on sleep, job functioning, exercise, communication, relationships, and self-concept- commonly expressed as a sense of being limited by PD. Thematically, most bothersome symptoms were those that were personally limiting with broadest negative impact on well-being and activities. However, symptoms could be important to patients even when not present or limiting (e.g., speech, cognition). CONCLUSION: Meaningful symptoms of early PD can include symptoms that are present or anticipated future symptoms that are important to the individual. Systematic assessment of meaningful symptoms should aim to assess the extent to which symptoms are personally important, present, bothersome, and limiting.

Mapping Relevance of Digital Measures to Meaningful Symptoms and Impacts in Early Parkinson's Disease.

BACKGROUND: Adoption of new digital measures for clinical trials and practice has been hindered by lack of actionable qualitative data demonstrating relevance of these metrics to people with Parkinson's disease. OBJECTIVE: This study evaluated of relevance of WATCH-PD digital measures to monitoring meaningful symptoms and impacts of early Parkinson's disease from the patient perspective. METHODS: Participants with early Parkinson's disease (N = 40) completed surveys and 1:1 online-interviews. Interviews combined: 1) symptom mapping to delineate meaningful symptoms/impacts of disease, 2) cognitive interviewing to assess content validity of digital measures, and 3) mapping of digital measures back to personal symptoms to assess relevance from the patient perspective. Content analysis and descriptive techniques were used to analyze data. RESULTS: Participants perceived mapping as deeply engaging, with 39/40 reporting improved ability to communicate important symptoms and relevance of measures. Most measures (9/10) were rated relevant by both cognitive interviewing (70-92.5%) and mapping (80-100%). Two measures related to actively bothersome symptoms for more than 80% of participants (Tremor, Shape rotation). Tasks were generally deemed relevant if they met three participant context criteria: 1) understanding what the task measured, 2) believing it targeted an important symptom of PD (past, present, or future), and 3) believing the task was a good test of that important symptom. Participants did not require that a task relate to active symptoms or "real" life to be relevant. CONCLUSION: Digital measures of tremor and hand dexterity were rated most relevant in early PD. Use of mapping enabled precise quantification of qualitative data for more rigorous evaluation of new measures.

Evaluating the impact of metabolic surgery on patients with prior opioid use.

BACKGROUND: Metabolic surgery is the most effective treatment for obesity and may improve obesity-related pain syndromes. However, the effect of surgery on the persistent use of opioids in patients with a history of prior opioid use remains unclear. OBJECTIVE: To determine the effect of metabolic surgery on opioid use behaviors in patients with prior opioid use. SETTING: A consortium of public and private hospitals in Michigan. METHODS: Using a statewide metabolic-specific data registry, we identified 16,820 patients who self-reported opioid use before undergoing metabolic surgery between 2006 and 2020 and analyzed the 8506 (50.6%) patients who responded to 1-year follow-up. We compared patient characteristics, risk-adjusted 30-day postoperative outcomes, and weight loss between patients who self-reported discontinuing opioid use 1 year after surgery and those who did not. RESULTS: Among patients who self-reported using opioids before metabolic surgery, 3864 (45.4%) discontinued use 1 year after surgery. Predictors of persistent opioid use included an annual income of <$10,000 (odds ratio [OR] = 1.24; 95% confidence interval [CI], 1.06-1.44; P = .006), Medicare insurance (OR = 1.48; 95% CI, 1.32-1.66; P < .0001), and preoperative tobacco use (OR = 1.36; 95% CI, 1.16-1.59; P = .0001). Patients with persistent use were more likely to have a surgical complication (9.6% versus 7.5%, P = .0328) and less percent excess weight loss (61.6% versus 64.4%, P < .0001) than patients who discontinued opioids after surgery. There were no differences in the morphine milligram equivalents prescribed within the first 30 days following surgery between groups (122.3 versus 126.5, P = .3181). CONCLUSIONS: Nearly half of patients who reported taking opioids before metabolic surgery discontinued use at 1 year. Targeted interventions aimed at high-risk patients may increase the number of patients who discontinue opioid use after metabolic surgery.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic.

Background: The global prevalence of PASC is estimated to be present in 0·43 and based on the WHO estimation of 470 million worldwide COVID-19 infections, corresponds to around 200 million people experiencing long COVID symptoms. Despite this, its clinical features are not well-defined. Methods: We collected retrospective data from 140 patients with PASC in a post-COVID-19 clinic on demographics, risk factors, illness severity (graded as one-mild to five-severe), functional status, and 29 symptoms and principal component symptoms cluster analysis. The Institute of Medicine (IOM) 2015 criteria were used to determine the Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) phenotype. Findings: The median age was 47 years, 59.0% were female; 49.3% White, 17.2% Hispanic, 14.9% Asian, and 6.7% Black. Only 12.7% required hospitalization. Seventy-two (53.5%) patients had no known comorbid conditions. Forty-five (33.9%) were significantly debilitated. The median duration of symptoms was 285.5 days, and the number of symptoms was 12. The most common symptoms were fatigue (86.5%), post-exertional malaise (82.8%), brain fog (81.2%), unrefreshing sleep (76.7%), and lethargy (74.6%). Forty-three percent fit the criteria for ME/CFS, majority were female, and obesity (BMI > 30 Kg/m2) (P = 0.00377895) and worse functional status (P = 0.0110474) were significantly associated with ME/CFS. Interpretations: Most PASC patients evaluated at our clinic had no comorbid condition and were not hospitalized for acute COVID-19. One-third of patients experienced a severe decline in their functional status. About 43% had the ME/CFS subtype.

Extracellular vesicle-derived circCEBPZOS attenuates postmyocardial infarction remodeling by promoting angiogenesis via the miR-1178-3p/PDPK1 axis.

Emerging studies indicate that extracellular vesicles (EVs) and their inner circular RNAs (circRNAs), play key roles in the gene regulatory network and cardiovascular repair. However, our understanding of EV-derived circRNAs in cardiac remodeling after myocardial infarction (MI) remains limited. Here we show that the level of circCEBPZOS is downregulated in serum EVs of patients with the adverse cardiac remodeling compared with those without post-MI remodeling or normal subjects. Loss-of-function approaches in vitro establish that circCEBPZOS robustly promote angiogenesis. Overexpression of circCEBPZOS in mice attenuates MI-induced left ventricular dysfunction, accompanied by a larger functional capillary network at the border zone. Further exploration of the downstream target gene indicates that circCEBPZOS acts as a competing endogenous RNA by directly binding to miR-1178-3p and thereby inducing transcription of its target gene phosphoinositide-dependent kinase-1 (PDPK1). Together, our results reveal that circCEBPZOS attenuates detrimental post-MI remodeling via the miR-1178-3p/PDPK1 axis, which facilitates revascularization, ultimately improving the cardiac function.

Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases.

Extracellular vesicles (EVs) carry diverse bioactive components including nucleic acids, proteins, lipids and metabolites that play versatile roles in intercellular and interorgan communication. The capability to modulate their stability, tissue-specific targeting and cargo render EVs as promising nanotherapeutics for treating heart, lung, blood and sleep (HLBS) diseases. However, current limitations in large-scale manufacturing of therapeutic-grade EVs, and knowledge gaps in EV biogenesis and heterogeneity pose significant challenges in their clinical application as diagnostics or therapeutics for HLBS diseases. To address these challenges, a strategic workshop with multidisciplinary experts in EV biology and U.S. Food and Drug Administration (USFDA) officials was convened by the National Heart, Lung and Blood Institute. The presentations and discussions were focused on summarizing the current state of science and technology for engineering therapeutic EVs for HLBS diseases, identifying critical knowledge gaps and regulatory challenges and suggesting potential solutions to promulgate translation of therapeutic EVs to the clinic. Benchmarks to meet the critical quality attributes set by the USFDA for other cell-based therapeutics were discussed. Development of novel strategies and approaches for scaling-up EV production and the quality control/quality analysis (QC/QA) of EV-based therapeutics were recognized as the necessary milestones for future investigations.

Microvascular obstruction identifies a subgroup of patients who benefit from stem cell therapy following ST-elevation myocardial infarction.

BACKGROUND: Microvascular obstruction (MVO) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction following ST-elevation myocardial infarction (STEMI). We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction. METHODS AND RESULTS: We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs or placebo / control as part of 4 randomized clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot, the multicenter French BONAMI trial and SWISS-AMI trials. A total of 327 patients had paired imaging data at 1 year. All patients received 100 to 150 million intracoronary autologous BMCs or placebo / control 3 to 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n = 210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n = 146) (P < .01). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference = 2.7%; P < .05). Similarly, left-ventricular end-diastolic (LVEDVI) and end-systolic volume indices (LVESVI) demonstrated significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo. In contrast, no improvement in LVEF or LV volumes was observed in those patients without MVO who received BMCs compared to placebo. CONCLUSIONS: The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who benefit from intracoronary stem cell therapy.

High-resolution, respiratory-resolved coronary MRA using a Phyllotaxis-reordered variable-density 3D cones trajectory.

PURPOSE: To develop a respiratory-resolved motion-compensation method for free-breathing, high-resolution coronary magnetic resonance angiography (CMRA) using a 3D cones trajectory. METHODS: To achieve respiratory-resolved 0.98 mm resolution images in a clinically relevant scan time, we undersample the imaging data with a variable-density 3D cones trajectory. For retrospective motion compensation, translational estimates from 3D image-based navigators (3D iNAVs) are used to bin the imaging data into four phases from end-expiration to end-inspiration. To ensure pseudo-random undersampling within each respiratory phase, we devise a phyllotaxis readout ordering scheme mindful of eddy current artifacts in steady state free precession imaging. Following binning, residual 3D translational motion within each phase is computed using the 3D iNAVs and corrected for in the imaging data. The noise-like aliasing characteristic of the combined phyllotaxis and cones sampling pattern is leveraged in a compressed sensing reconstruction with spatial and temporal regularization to reduce aliasing in each of the respiratory phases. RESULTS: In initial studies of six subjects, respiratory motion compensation using the proposed method yields improved image quality compared to non-respiratory-resolved approaches with no motion correction and with 3D translational correction. Qualitative assessment by two cardiologists and quantitative evaluation with the image edge profile acutance metric indicate the superior sharpness of coronary segments reconstructed with the proposed method (P < 0.01). CONCLUSION: We have demonstrated a new method for free-breathing, high-resolution CMRA based on a variable-density 3D cones trajectory with modified phyllotaxis ordering and respiratory-resolved motion compensation with 3D iNAVs.