Emergence of highly profibrotic and proinflammatory Lrat+Fbln2+ HSC subpopulation in alcoholic hepatitis.

BACKGROUND AND AIMS: Relative roles of HSCs and portal fibroblasts in alcoholic hepatitis (AH) are unknown. We aimed to identify subpopulations of collagen type 1 alpha 1 (Col1a1)-expressing cells in a mouse AH model by single-cell RNA sequencing (scRNA-seq) and filtering the cells with the HSC (lecithin retinol acyltransferase [Lrat]) and portal fibroblast (Thy-1 cell surface antigen [Thy1] and fibulin 2 [Fbln2]) markers and vitamin A (VitA) storage. APPROACH AND RESULTS: Col1a1-green fluorescent protein (GFP) mice underwent AH, CCl 4 , and bile duct ligation (BDL) procedures to have comparable F1-F2 liver fibrosis. Col1a1-expressing cells were sorted via FACS by VitA autofluorescence and GFP for single-cell RNA sequencing. In AH, approximately 80% of Lrat+Thy1-Fbln2- activated HSCs were VitA-depleted (vs. ~13% in BDL and CCl 4 ). Supervised clustering identified a subset co-expressing Lrat and Fbln2 (Lrat+Fbln2+), which expanded 44-fold, 17-fold, and 1.3-fold in AH, BDL, and CCl 4 . Lrat+Fbln2+ cells had 3-15-times inductions of profibrotic, myofibroblastic, and immunoregulatory genes versus Lrat+Fbln2- cells, but 2-4-times repressed HSC-selective genes. AH activated HSCs had up-regulated inflammatory (chemokine [C-X-C motif] ligand 2 [Cxcl2], chemokine [C-C motif] ligand 2), antimicrobial (Il-33, Zc3h12a), and antigen presentation (H2-Q6, H2-T23) genes versus BDL and CCl 4 . Computational deconvolution of AH versus normal human bulk-liver RNA-sequencing data supported an expansion of LRAT+FBLN2+ cells in AH; AH patient liver immunohistochemistry showed FBLN2 staining along fibrotic septa enriched with LRAT+ cells; and in situ hybridization confirmed co-expression of FBLN2 with CXCL2 and/or human leukocyte antigen E in patient AH. Finally, HSC tracing in Lrat-Cre;Rosa26mTmG mice detected GFP+FBLN2+ cells in AH. CONCLUSION: A highly profibrotic, inflammatory, and immunoregulatory Lrat+Fbln2+ subpopulation emerges from HSCs in AH and may contribute to the inflammatory and immunoreactive nature of AH.

Characterizing longitudinal change in accelerometry-based moderate-to-vigorous physical activity in the Hispanic Community Health Study/Study of Latinos and the Framingham Heart Study.

BACKGROUND: Physical activity promotes health and is particularly important during middle and older age for decreasing morbidity and mortality. We assessed the correlates of changes over time in moderate-to-vigorous physical activity (MVPA) in Hispanic/Latino adults from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL: mean [SD] age 49.2 y [11.5]) and compared them to a cohort of primarily White adults from the Framingham Heart Study (FHS: mean [SD] 46.9 y [9.2]). METHODS: Between 2008 and 2019, we assessed accelerometry-based MVPA at two time points with an average follow-up of: 7.6 y, SD 1.3 for HCHS/SOL, and 7.8 y, SD 0.7 for FHS. We used multinomial logistic regression to relate socio-demographic and health behaviors with changes in compliance with 2018 US recommendations for MVPA from time 1 to time 2 (remained active or inactive; became active or inactive) across the two cohorts. RESULTS: In HCHS/SOL mean MVPA was 22.6 (SD, 23.8) minutes at time 1 and dropped to 16.7 (19.0) minutes at time 2. In FHS Mean MVPA was 21.7 min (SD, 17.7) at time 1 and dropped to 21.3 min (SD, 19.2) at time 2. Across both cohorts, odds of meeting MVPA guidelines over time were about 6% lower in individuals who had lower quality diets vs. higher, about half in older vs. younger adults, about three times lower in women vs. men, and 9% lower in individuals who had a higher vs. lower BMI at baseline. Cohorts differed in how age, gender, income, education, depressive symptoms, marital status and perception of general health and pain associated with changes in physical activity. High income older Hispanics/Latino adults were more likely to become inactive at the follow-up visit as were HCHS/SOL women who were retired and FHS participants who had lower levels of education and income. Higher depressive symptomology was associated with becoming active only in HCHS/SOL women. Being male and married was associated with becoming inactive in both cohorts. Higher perception of general health and lower perception of pain were associated with remaining active only in FHS adults. CONCLUSIONS: These findings highlight potentially high-risk groups for targeted MVPA intervention.

Improving Postpartum Attendance among Women with Gestational Diabetes Using the Medical Home Model of Care.

OBJECTIVE: Poor attendance at the 6-week postpartum (PP) visit has been well reported. Attendance at this visit is crucial to identify women who have persistent diabetes mellitus (DM) following pregnancies affected by gestational DM (GDM). The medical home model has eliminated barriers to care in various other settings. This study sought to improve PP attendance among women with GDM by jointly scheduling PP visits and the 2-month well infant visits. STUDY DESIGN: All patients with a diagnosis of GDM who received care at a New York City-based publicly insured hospital clinic and delivered between October 2017 and June 2019 were eligible. Data were obtained via chart review. The primary outcome was attendance at the PP visit compared with previously published historical controls. Secondary outcomes were rates of PP glucose screening and well infant attendance. RESULTS: Of the 74 patients enrolled, 41.9% were Hispanic and 17.6% were Black, mean age was 31.6 years, and 58.1% delivered vaginally. Attendance at the 6-week PP visit was 68.9%, and attendance at the infant visit was 55.1%. PP glucose testing was ordered for 76.5% of attendees at the PP visit, and of those ordered, 43.6% of attendees completed testing. All patients had joint visits requested, though only 70.3% of visits were scheduled jointly. Among those who were jointly scheduled, 71.2% of women attended, 57.7% of infants attended, and 7.7% of pairs attended on the same day. The PP visit attendance rate was not significantly different than the prior attendance rate (p = 0.84). CONCLUSION: This study was unable to improve PP visit attendance among women with GDM by jointly scheduling the 6-week PP visit and the 2-month well-infant visit. Future research could be directed toward a shared space where both women and children can be seen to attempt to increase PP visit attendance and monitoring for women with GDM. KEY POINTS: · Attendance at the PP visit is poor, and without a visit, women with pregnancies affected by gestational diabetes remain unscreened for PP dysglycemia.. · Jointly scheduling women and their infants to eliminate barriers to care studied by this group, however, were unable to improve attendance.. · Innovative strategies are needed to improve PP attendance among women with pregnancies affected by GDM..

Acute Kidney Injury Following Pediatric Liver Transplant.

OBJECTIVE: To determine the incidence, severity, and risk factors of postoperative acute kidney injury in pediatric liver transplant patients with and without inborn errors of metabolism. DESIGN: Retrospective cohort study. SETTING: Single-center PICU. PATIENTS: All children less than or equal to 18 years old who received a liver transplant between January 2009 and July 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Following exclusion criteria there were 92 transplant encounters. After excluding patients who received combined kidney-liver transplantation, acute kidney injury occurred in 57% of patients (N = 49), with 25.6% (N = 22) stage 1, 15.1% (N = 13) stage 2, and 16.3% (N = 14) stage 3. In an adjusted analysis, metabolic indication for transplant was not significantly associated with presence of acute kidney injury (p = 0.45). For the subset of patients without inborn errors of metabolism, the odds of having acute kidney injury was 1.50 (95% CI: 1.00-2.26) for each 1-unit increase in preoperative INR after adjusting for the covariates of age, preoperative albumin, CMV status of donor, and preoperative creatinine. In the full cohort, as well as the sample of children without inborn errors of metabolism, presence of acute kidney injury was associated with longer total hospital stay as well as number of ICU days. CONCLUSIONS: Acute kidney injury in the early postoperative period is common in pediatric liver transplant patients (57%), 31.4% of whom had severe disease. In patients without inborn errors of metabolism, each unit increase in preoperative INR suggests a higher risk of acute kidney injury after adjusting for covariates including preoperative creatinine. This finding suggests an association between the severity of preoperative synthetic liver function and the risk of developing postoperative acute kidney injury which requires further investigation.

Screening and managing obesity: understanding paediatric residents' knowledge, attitudes and practice.

STUDY PURPOSE: Prior studies have identified paediatric attending physicians' screening and management patterns related to overweight/obesity, but less is known about resident physicians' behaviour. The objective was to understand paediatric resident physicians' knowledge, attitude and practice patterns of overweight/obesity screening and management. STUDY DESIGN: We performed a retrospective chart review of preventive visits conducted by residents between August and October 2019. Charts of patients 2-18 years with body mass index ≥85th percentile at the visit were reviewed (85th-<95th for age and sex defined as overweight, ≥95th defined as obese). A survey was distributed to residents assessing knowledge, attitudes and barriers towards obesity management. RESULTS: Of 1250 visits reviewed, 405 (32%) patients met the criteria for overweight or obesity. 39% were identified correctly by the provider, 53% were not identified and 8% were identified incorrectly. 89% of patients had diet history, 31% had physical activity and 43% had family history documented. Patients with obesity received physical activity documentation/counselling, portion size counselling, at least one referral, laboratory tests and a diagnosis more often than overweight patients. 84% of residents completed the survey. Although the majority of residents felt 'somewhat' or 'very' well prepared to counsel families about overweight/obesity, the majority thought their counselling on overweight/obesity was 'not at all' or 'slightly' effective. CONCLUSION: Despite residents feeling prepared and comfortable discussing overweight/obesity with patients, these diagnoses were often under-recognised or incorrectly made and appropriate counselling was lacking. Future work will focus on specific strategies to improve diagnosis, screening and management of overweight/obesity and include educational interventions and electronic medical record adaptations.

From Pruritus to Cholestasis: Building a Statistical Model and Online Application to Predict a Diagnosis Prior to Bile Acid Determination.

OBJECTIVE: This study aimed to create a statistical model using clinical and laboratory parameters to predict which patients presenting with pruritus in pregnancy will have elevated total bile acids (TBA) and thus, have a high risk of intrahepatic cholestasis of pregnancy (ICP). STUDY DESIGN: Retrospective cohort study of patients presenting with pruritus in pregnancy and had TBA sent from a single public hospital from January 1, 2017, to December 31, 2017. Primary outcome is TBA ≥ 10 µmol/L. Multivariate logistic regression with stepwise and backward variable selection were used to create predictive models. Four models were compared using Akaike information criterion (AIC), C-statistic, and the DeLong nonparametric approach to test for differences between area under the curve (AUC) of receiver operating characteristic (ROC) curves. Internal validation was performed via fivefold cross-validation technique on the best-fitting, most parsimonious model. RESULTS: Of the 320 patients with pruritus, 153 (47.8%) had elevated bile acid levels ≥10 µmol/L. Sixty-nine variables were assessed for association with the primary outcome. Five variables were significantly associated with elevated TBA: pruritus of palms and soles (adjusted odds ratio [aOR]: 2.35 [95% confidence interval, CI: 1.22, 4.54]), gestational hypertension (aOR: 0.10 [95% CI: 0.02, 0.60]), log of total bilirubin (aOR: 4.71 [95% CI: 2.28, 9.75]), systolic blood pressure (aOR: 0.97 [95% CI: 0.94, 0.99]), and alanine aminotransferase (aOR: 1.05 [95% CI: 1.02, 1.07]). The final model was chosen for being parsimonious while having the lowest AIC with highest AUC (0.85; 95% CI: 0.81, 0.89). Internal validation using a probability threshold of 50% demonstrated a sensitivity of 65.5%, specificity of 83.5%, and accuracy of 75.1%. CONCLUSION: We provide a predictive model using five simple variables to determine the probability that a patient presenting with pruritus in pregnancy carries the diagnosis of ICP. This tool, available via a web app, is designed to aid providers and enhance clinical judgment in difficult triage situations. KEY POINTS: · Currently, no standard method to triage pruritus in pregnancy exists.. · We present a predictive statistical model using five readily available clinical variables.. · Final calculator yields probability of having intrahepatic cholestasis of pregnancy..

Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients.

Alcoholic hepatitis (AH) continues to be a disease with high mortality and no efficacious medical treatment. Although severe AH is presented as acute on chronic liver failure, what underlies this transition from chronic alcoholic steatohepatitis (ASH) to AH is largely unknown. To address this question, unbiased RNA sequencing and proteomic analyses were performed on livers of the recently developed AH mouse model, which exhibits the shift to AH from chronic ASH upon weekly alcohol binge, and these results are compared to gene expression profiling data from AH patients. This cross-analysis has identified Casp11 (CASP4 in humans) as a commonly up-regulated gene known to be involved in the noncanonical inflammasome pathway. Immunoblotting confirms CASP11/4 activation in AH mice and patients, but not in chronic ASH mice and healthy human livers. Gasdermin-D (GSDMD), which induces pyroptosis (lytic cell death caused by bacterial infection) downstream of CASP11/4 activation, is also activated in AH livers in mice and patients. CASP11 deficiency reduces GSDMD activation, bacterial load in the liver, and severity of AH in the mouse model. Conversely, the deficiency of interleukin-18, the key antimicrobial cytokine, aggravates hepatic bacterial load, GSDMD activation, and AH. Furthermore, hepatocyte-specific expression of constitutively active GSDMD worsens hepatocellular lytic death and polymorphonuclear leukocyte inflammation. CONCLUSION: These results implicate pyroptosis induced by the CASP11/4-GSDMD pathway in the pathogenesis of AH. (Hepatology 2018;67:1737-1753).

The correlation between morphology and implantation of euploid human blastocysts.

RESEARCH QUESTION: Does the composite morphology score or a particular developmental component (expansion stage, inner cell mass [ICM] or trophectoderm [TE]) of euploid blastocysts undergoing single frozen embryo transfer (FET) impact ongoing pregnancy/live birth (OP/LB) rates? DESIGN: Retrospective cohort study including a total of 2236 embryos from 1629 patients who underwent single euploid FET between 2012 and 2017. RESULTS: Embryos with an ICM grade of A compared with C had a higher OP/LB rate (55.6% versus 32.3%, P < 0.001). Blastocysts with a TE grade of A or B compared with C had a higher likelihood of OP/LB (A versus C: odds ratio [OR] 1.6, 99% confidence interval [CI] 1.1-2.3, B versus C: OR 1.5, 99% CI 1.1-2.1), and blastocysts with a developmental stage of 4 or 5 compared with 6 had higher odds of OP/LB (4 versus 6: OR 1.6, 99% CI 1.2-2.2, 5 versus 6: OR 1.6, 99% CI 1.2-2.3). CONCLUSIONS: Among euploid embryos, ICM morphology is the best predictor of sustained implantation; however, a composite score may provide additional guidance. While there is a known benefit in genomic screening prior to embryo selection, morphology provides individualized, prognostic information about implantation potential.

Comparing pregnancy outcomes and loss rates in elective twin pregnancy reduction with ongoing twin gestations in a large contemporary cohort.

BACKGROUND: As compared with singleton gestations, twin pregnancies are associated with a significantly higher risk of preterm birth and maternal complications as well as fetal and neonatal morbidity and mortality. Multifetal pregnancy reduction is a technique developed in the 1980s to reduce the fetal number in higher-order multiple pregnancies to reduce the risk of adverse pregnancy outcomes, most importantly preterm birth. OBJECTIVE: The objective of the study was to compare pregnancy outcomes and loss rates in elective twin pregnancy reduction to ongoing twin gestations in a large contemporary cohort. STUDY DESIGN: This was a retrospective review of dichorionic diamniotic twin gestations that underwent first-trimester ultrasound at our institution from January 2008 to September 2016. Planned elective 2-to-1 multifetal pregnancy reductions at less than 15 weeks' gestation were compared with ongoing dichorionic diamniotic twin gestations. Data were collected via chart review. Demographics between 2-to-1 reduced singletons and ongoing twins were assessed using a Student t test or a Wilcoxon rank-sum test, as appropriate, for continuous variables and χ2 or Fisher exact tests, as appropriate, for categorical variables. Univariable and multivariable logistic regressions were used to compare pregnancy outcomes between ongoing twins and reduced singletons adjusting for maternal age, body mass index, race, in vitro fertilization, use of chorionic villus sampling, prior term birth, and prior preterm birth. RESULTS: Of 1070 dichorionic diamniotic twin pregnancies identified, completed follow-up data were available and analyzed for 855 patients (79.9%). Among those, 250 (29.2%) were 2-to-1 singletons and 605 (70.8%) were ongoing twins. Reduced singleton patients were slightly older, more likely white, and had lower body mass index. They were also more likely to have undergone in vitro fertilization (63.6% vs 48.8%), had chorionic villus sampling (92% vs 37.5%), and had prior term births (54% vs 35.7%). Compared with 2-to-1 singletons, the adjusted odds of having preterm delivery at 37 weeks for ongoing twins were 5.62 times (95% confidence interval, 3.67-8.61; P < .001) and 2.22 times (95% confidence interval, 1.20-4.11; P < .001) at 34 weeks. While intrauterine growth restriction, placental abruption, and gestational diabetes were not significant, ongoing twins were more likely to have a cesarean delivery (odds ratio, 5.53, 95% confidence interval, 3.60-8.49; P < .001) and preeclampsia (odds ratio, 3.33, 95% confidence interval, 1.60-6.96; P < .001) after adjusting for maternal characteristics. There were also significant differences between groups for preterm premature rupture of membranes and low birthweight at less than the fifth and 10th percentiles. Total pregnancy loss (at 24 and 20 weeks) was similar between singleton and ongoing twins (4% vs 2.5%, P = .23, and 3.6% vs 1.7%, P = .09 for respective weeks). There were no significant differences in the rate of unintended pregnancy loss (2.4% vs 2.3%; P = .94) and the rate of intrauterine fetal death greater than 24 weeks (1.2% vs 0.7%; P = .43) in reduced singleton versus ongoing twin group, respectively. CONCLUSION: In our study, patients who elected to reduce to a singleton pregnancy had a higher gestational age of delivery and lower rates of preterm birth and pregnancy complications without an increased risk of pregnancy loss.

Increasing living donation by implementing the Kidney Coach Program.

Candidates for living donor kidney transplantation (LDKT) find it difficult to discuss living donation with people in their social network, and there is a lack of useful interventions to train them. The Kidney Coach Program (KCP) was developed to equip individuals (advocates for candidates and candidate themselves) with the tools needed to find potential donors. The purpose of this pilot study is to evaluate the effects of the KCP on increasing the number of people considering living donation. METHODS: Candidates for the KCP were recruited. Data were collected on the number of live donor inquiries in the coach group compared to listed patients (historical controls). RESULTS: Over a 12-month period, 20 transplant candidates enrolled in the KCP were compared to 50 controls. Eighty percent of the participants in the KCP had at least one donor inquiry compared to 38% of controls (P = 0.001). Significantly, more Caucasian candidates participated in the KCP compared to other racial groups. CONCLUSIONS: The KCP can be an effective method to increase awareness of a patient's need for LDKT. Existing clinical staff successfully implemented the program. Transplant programs should provide training to candidates and their supports on effective ways to find a living donor.

ICU Risk Stratification Models Feasible for Use in Sub-Saharan Africa Show Poor Discrimination in Malawi: A Prospective Cohort Study.

BACKGROUND: Critical illness disproportionately affects people in low-income countries (LICs). Efforts to improve critical care in LICs must account for differences in demographics and infrastructure compared to high-income settings. Part of this effort includes the development and validation of intensive care unit (ICU) risk stratification models feasible for use in LICs. The purpose of this study was to validate and compare the performance of ICU mortality models developed for use in sub-Saharan Africa. MATERIALS AND METHODS: This was a prospective, observational cohort study of ICU patients in a referral hospital in Malawi. Models were selected for comparison based on a Medline search for studies which developed ICU mortality models based on cohorts in sub-Saharan Africa. Model discrimination was evaluated using the area under the curve with 95% confidence intervals (CI). RESULTS: During the study, 499 patients were admitted to the study ICU, and after exclusions, there were 319 patients. The cohort was 62% female, with the mean age 31 years (IQR: 23-41), and 74% had surgery preceding ICU admission. Discrimination for hospital mortality ranged from 0.54 (95% CI 0.48, 0.60) for the Universal Vital Assessment (UVA) to 0.72 (95% CI 0.66, 0.78) for the Malawi Intensive care Mortality Evaluation (MIME). After tenfold cross-validation, these results were unchanged. CONCLUSIONS: The MIME outperformed other models in this prospective study. Most ICU models developed for LICs had poor to modest discrimination for hospital mortality. Future research may contribute to a better risk stratification model for LICs by refining and enhancing the MIME.

Intraoperative Mortality in Malawi.

BACKGROUND: Surgical care is essential to improving population health, but metrics to monitor and evaluate the continuum of surgical care delivery have rarely been applied in low-resource settings, and improved efforts at benchmarking progress are needed. The objective of this study was to measure the intraoperative mortality at a Central Referral Hospital in Malawi, evaluate whether there have been changes in intraoperative mortality between 2 time periods, and assess factors associated with intraoperative mortality. METHODS: This was a retrospective cohort study of patients undergoing surgery at Kamuzu Central Hospital in Lilongwe, Malawi. Data describing daily consecutive operative cases were collected prospectively during 2 time periods: 2004-2006 (early cohort) and 2015-2016 (late cohort). The primary outcome was intraoperative mortality. Inverse probability of treatment weighting was used to analyze the association of intraoperative mortality with time using logistic regression models. Multivariable logistic models were performed to evaluate factors associated with intraoperative mortality. RESULTS: There were 21,090 surgeries performed during the 2 time periods, with 15,846 (75%) and 5244 (25%) completed from 2004 to 2006 and 2015 to 2016, respectively. Intraoperative mortality in the early cohort was 57 deaths per 100,000 surgeries (95% confidence interval [CI], 26-108) and in the late cohort was 133 per 100,000 surgeries (95% CI, 56-286), with 76 per 100,000 surgeries (95% CI, 44-124) overall. After applying inverse probability of treatment weighting, there was no evidence of an association between time periods and intraoperative mortality (odds ratio [OR], 1.6; 95% CI, 0.9-2.8; P = .08). Factors associated with intraoperative mortality, adjusting for demographics, included American Society of Anesthesiology physical status III or IV versus I or II (OR, 4.4; 95% CI, 1.5-12.5; P = .006) and emergency versus elective surgery (OR, 7.7; 95% CI, 2.5-23.6; P < .001). CONCLUSIONS: Intraoperative mortality in the study hospital in Malawi is high and has not improved over time. These data demonstrate an urgent need to improve the safety and quality of perioperative care in developing countries and integrate perioperative care into global health efforts.

Quadratus lumborum blocks: Two cases of associated hematoma.

A quadratus lumborum block associated complication is a rare event. We report two cases of hematoma following the performance of quadratus lumorum blocks in two patients. Performing this block requires additional consideration of abdominal wall anatomy and patient coagulation status.

Variation in Cervical Length over Time during a Single Transvaginal Ultrasound Examination.

OBJECTIVE: To quantify the degree of change in cervical length (CL) over a 3-minute transvaginal ultrasound. STUDY DESIGN: We conducted a prospective observational study of nulliparous patients who underwent routine transvaginal CL screening at the time of their second-trimester ultrasound. We recorded CL at four time points (0, 1, 2, 3 minutes) and compared these values to determine the minute-to-minute change within a single patient. RESULTS: A total of 771 patients were included. The mean gestational age was 20.8 weeks (±0.84). We used a linear mixed effect model to assess if each minute during the ultrasound is associated with a change in CL. The intraclass correlation coefficient between minute 0 to minute 3 was 0.82 (95% confidence interval: 0.80, 0.84). This indicates that there is a relatively high within-patient correlation in CL during their ultrasound. Additionally, we stratified patients based on their starting CL; the intraclass correlation coefficient remained high for all groups. We additionally compared CL at each minute. Although there is a statistically significant difference between several time points, the actual difference is small and not clinically meaningful. CONCLUSION: The variation in CL over a 3-minute transvaginal ultrasound examination is not clinically significant. It may be reasonable to conduct this examination over a shorter period.

The role of doxycycline in the management of chronic rhinosinusitis with nasal polyps.

INTRODUCTION: Many theories on the pathophysiology of chronic rhinosinusitis with nasal polyposis (CRSwNP) exist. The most effective management of CRSwNP has not been elucidated. Doxycycline, which has anti-inflammatory and anti-bacterial properties, has shown durable effects; however, its efficacy in combination with standard therapy has not been examined. We hypothesized that its addition to the standard anti-inflammatory regimen would improve patient outcomes. METHODS: We performed a double-blind, placebo-controlled trial at a tertiary level institution. Patients with moderate or severe CRSwNP were randomized into two groups, each receiving a 20-day course of oral corticosteroids and doxycycline or placebo. The 22-item Sinonasal Outcome Test (SNOT-22), nasal polyp scores, and visual analog scale (VAS) scores were recorded at the initial, 3-, 8- and 12-week visits. RESULTS: 49 patients were enrolled, 24 in the experimental and 25 in the placebo group with 3 moderate disease patients in each group. There were 12 dropouts in the treatment group and 14 in the placebo group. The most common reasons for dropout were severe CRS and asthma exacerbations. There was no significant difference in SNOT-22 scores, nasal polyp scores, and VAS scores between the two arms. CONCLUSIONS: Non-surgical management of patients with CRSwNP remains challenging. Our conclusions are limited given the high dropout rate and thus, limited sample size with inadequate power. This study is important, however, because a high dropout rate of mostly severe disease patients may illustrate that this patient population may not be optimally managed with medical therapy alone.

Intramyocardial Injection of Mesenchymal Precursor Cells and Successful Temporary Weaning From Left Ventricular Assist Device Support in Patients With Advanced Heart Failure: A Randomized Clinical Trial.

Importance: Left ventricular assist device (LVAD) therapy improves myocardial function, but few patients recover sufficiently for explant, which has focused attention on stem cells to augment cardiac recovery. Objective: To assess efficacy and adverse effects of intramyocardial injections of mesenchymal precursor cells (MPCs) during LVAD implant. Design, Setting, and Participants: A randomized phase 2 clinical trial involving patients with advanced heart failure, undergoing LVAD implant, at 19 North American centers (July 2015-August 2017). The 1-year follow-up ended August 2018. Interventions: Intramyocardial injections of 150 million allogeneic MPCs or cryoprotective medium as a sham treatment in a 2:1 ratio (n = 106 vs n = 53). Main Outcomes and Measures: The primary efficacy end point was the proportion of successful temporary weans (of 3 planned assessments) from LVAD support within 6 months of randomization. This end point was assessed using a Bayesian analysis with a predefined threshold of a posterior probability of 80% to indicate success. The 1-year primary safety end point was the incidence of intervention-related adverse events (myocarditis, myocardial rupture, neoplasm, hypersensitivity reactions, and immune sensitization). Secondary end points included readmissions and adverse events at 6 months and 1-year survival. Results: Of 159 patients (mean age, 56 years; 11.3% women), 155 (97.5%) completed 1-year of follow-up. The posterior probability that MPCs increased the likelihood of successful weaning was 69%; below the predefined threshold for success. The mean proportion of successful temporary weaning from LVAD support over 6 months was 61% in the MPC group and 58% in the control group (rate ratio [RR], 1.08; 95% CI, 0.83-1.41; P = .55). No patient experienced a primary safety end point. Of 10 prespecified secondary end points reported, 9 did not reach statistical significance. One-year mortality was not significantly different between the MPC group and the control group (14.2% vs 15.1%; hazard ratio [HR], 0.89; 95%, CI, 0.38-2.11; P = .80). The rate of serious adverse events was not significantly different between groups (70.9 vs 78.7 per 100 patient-months; difference, -7.89; 95% CI, -39.95 to 24.17; P = .63) nor was the rate of readmissions (0.68 vs 0.75 per 100 patient-months; difference, -0.07; 95% CI, -0.41 to 0.27; P = .68). Conclusions and Relevance: Among patients with advanced heart failure, intramyocardial injections of mesenchymal precursor cells, compared with injections of a cryoprotective medium as sham treatment, did not improve successful temporary weaning from left ventricular assist device support at 6 months. The findings do not support the use of intramyocardial mesenchymal stem cells to promote cardiac recovery as measured by temporary weaning from device support. Trial Registration: clinicaltrials.gov Identifier: NCT02362646.