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Rationale and Objectives Molecular studies have shown the changes in bone marrow fat in relation to altered hematopoiesis. This study aims to investigate the changes in the bone marrow fat in patients affected by β-thalassemia by using chemical shift-encoded (CSE)–MRI. Materials and Methods Twenty-three subjects, comprising of six healthy (17-31 years old) and 17 β-thalassemia subjects (19-39 years old), were scanned using a multiecho fast low angle shot sequence (0.94 × 0.94 × 3.00 mm3) and a stimulated echo acquisition mode sequence using 3T MRI. Bone marrow proton density fat fraction (PDFF) was quantified in the left femur of each subject. Regression and Bland-Altman analysis were used to analyze agreement between CSE-MRI and 1H-MRS. PDFF distribution was analyzed using Hartigan's dip test and the computed Wasserstein distances. Jonckheere-Terpstra trend analysis was performed to evaluate the effect of disease severity on PDFF distribution. Results An excellent agreement was found between PDFF measured using CSE-MRI with 1H-MRS (R2 = 0.91; bias =-1.41%). Healthy subjects showed left-skewed or bimodal PDFF distribution while β-thalassemia subjects showed bimodal, normal or right-skewed distribution. Jonckheere-Terpstra test shows that PDFF distribution was increasingly different from the norm as disease severity increased (TJT = 166.0, z = 3.806, p Conclusion CSE-MRI is a promising tool to demonstrate spatial changes and variability in marrow fat distribution, resulting from ineffective erythropoiesis.

Rationale: Comorbidity is a significant driver of health status and healthcare utilization in chronic obstructive pulmonary disease (COPD). Obstructive sleep apnea (OSA) portends poorer outcomes, whereas obesity is protective. Objectives: We describe the prevalence and influence of these comorbidities on COPD readmissions. Methods: We collated discharge records for COPD exacerbations spanning 2010-2016 from the Nationwide Readmissions Database using Medicare's Hospital Readmissions Reduction Program criteria, with OSA-COPD overlap identified by concomitant diagnosis code for OSA. We used mixed-effects logistic regression to predict readmission odds. A cross-sectional mediation analysis was performed to evaluate the extent that OSA attenuated obesity's impact on readmission. Results: Of 1,662,983 qualifying COPD discharges, 19.1% carried a diagnosis of obesity and 12.9% had OSA, with both diagnoses present in 7.8%. In unadjusted analyses, obesity (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.03-1.05; P

Microscopic hematuria is one of the most common office consults for urologists. While revised guidelines have risk-stratified patients to reduce unnecessary screening, they do not provide guidance concerning specimen quality. We sought to define "properly collected" specimens using catheterized urine samples as a reference to improve the utility of hematuria screening in women.We prospectively acquired same-visit voided and catheterized urine samples from 46 women referred for microscopic hematuria from September 2016 to March 2020. Characteristics of pre-referral urinalysis were compared to the matched specimens. True microscopic hematuria was defined as ≥3 red blood cells per high power field on catheterization.Catheterized urinalyses had significantly fewer red blood and squamous epithelial cells in comparison to both referral urinalyses (p=0.006, p=0.001, respectively) and same-day void urinalyses (p=0.02, p=0.04, respectively). As no catheterized sample had2 squamous epithelial cells, we applied this squamous epithelial cell threshold to referral urinalyses for analysis. Addition of this criterion for "properly collected specimen" increased the positive predictive value of referral urinalyses from 46.1% to 68.8% for true microscopic hematuria. Fewer than 2 squamous epithelial cells with elevated RBC was a significant predictor for true microscopic hematuria (p=0.003).Voided specimens in the urology clinic had significantly lower red blood cells than referral samples, indicating improved collection technique may reduce false positive urinalyses. Matched collection suggested that repeat collection by catheterization in women who present with2 squamous epithelial cells per high power field on referral urinalysis may prevent unnecessary future work-up.

Background High-cost high-need patients are typically defined by risk or cost thresholds which aggregate clinically diverse subgroups into a single ‘high-need high-cost’ designation. Programs have had limited success in reducing utilization or improving quality of care for high-cost high-need Medicaid patients, which may be due to the underlying clinical heterogeneity of patients meeting high-cost high-need designations. Methods Our objective was to segment a population of high-cost high-need Medicaid patients (N = 676,161) eligible for a national complex case management program between January 2012 and May 2015 to disaggregate clinically diverse subgroups. Patients were eligible if they were in the top 5 % of annual spending among UnitedHealthcare Medicaid beneficiaries. We used k-means cluster analysis, identified clusters using an information-theoretic approach, and named clusters using the patients’ pattern of acute and chronic conditions. We assessed one-year overall and preventable hospitalizations, overall and preventable emergency department (ED) visits, and cluster stability. Results Six clusters were identified which varied by utilization and stability. The characteristic condition patterns were: 1) pregnancy complications, 2) behavioral health, 3) relatively few conditions, 4) cardio-metabolic disease, and complex illness with relatively 5) low or 6) high resource use. The patients varied by cluster by average ED visits (2.3–11.3), hospitalizations (0.3–2.0), and cluster stability (32–91%). Conclusions We concluded that disaggregating subgroups of high-cost high-need patients in a large multi-state Medicaid sample identified clinically distinct clusters of patients who may have unique clinical needs. Segmenting previously identified high-cost high-need populations thus may be a necessary strategy to improve the effectiveness of complex case management programs in Medicaid.

Vaccination of the global population against COVID-19 is a great scientific, logistical, and moral challenge. Despite the rapid development and authorization of several full-length Spike (S) protein vaccines, the global demand outweighs the current supply and there is a need for safe, potent, high-volume, affordable vaccines that can fill this gap, especially in low- and middle-income countries. Whether SARS-CoV-2 S-protein receptor-binding domain (RBD)-based vaccines could fill this gap has been debated, especially with regards to its suitability to protect against emerging viral variants of concern. Given a predominance for elicitation of neutralizing antibodies (nAbs) that target RBD following natural infection or vaccination, a key biomarker of protection, there is merit for selection of RBD as a sole vaccine immunogen. With its high-yielding production and manufacturing potential, RBD-based vaccines offer an abundance of temperature-stable doses at an affordable cost. In addition, as the RBD preferentially focuses the immune response to potent and recently recognized cross-protective determinants, this domain may be central to the development of future pan-sarbecovirus vaccines. In this study, we review the data supporting the non-inferiority of RBD as a vaccine immunogen compared to full-length S-protein vaccines with respect to humoral and cellular immune responses against both the prototype pandemic SARS-CoV-2 isolate and emerging variants of concern.

This study aimed to determine which dietary factors were associated with habitual sleep duration in pre/peri- and post-menopausal women. Data from the 2007–2008 National Health and Nutrition Examination Survey were used ( N = 1,783). Habitual sleep duration was categorized as very short (

Background Schools and school climate are thought to influence academic outcomes as well as child and adolescent development, health and well-being. We sought to examine the relationship between several aspects of the school climate with adolescent social-emotional health outcomes. Methods We analysed data from the Reducing Inequities through Social and Educational change Follow-up (RISE UP) Study, a longitudinal natural experimental study of Los Angeles high school students collected from 2013 to 2018. We analysed data on the portion of the sample that completed the baseline, 10th grade and 11th grade surveys (n=1114). Students reported their perceptions of school climate at 10th grade and social-emotional outcomes including grit, self-efficacy, depression, hopelessness, and stress at baseline (9th grade) and at 11th grade. Multivariable regressions adjusted for student and parental demographics and baseline social-emotional states tested associations between school climate and each outcome. Results Students who reported being in authoritative school environments in 10th grade, one that is highly supportive and highly structured, had subsequently higher levels of self-efficacy (pp=0.01). They also had fewer depressive symptoms (p=0.008), and less hopelessness (p = 0.01), stress at school (p=0.002) and stress about the future (p=0.03) reported in 11th grade. Conclusions School climate, and particularly an authoritative school environment, is strongly associated with better social-emotional health among adolescents. Relationship with teachers and their disciplinary style may be a focus for future interventions to improve the social-emotional health of children.

Introduction: Trochlear dysplasia is a known risk factor for patellar dislocations yet normal trochlea development is not well described. This study will define the articular cartilage and subchondral trochlear morphology development in pediatric patients using MRI evaluation. Methods: Retrospective knee MRI review including patients aged 3-16 years with non-patellofemoral related diagnoses. ICD-9/ICD-10 codes identified eligible study patients. Measurements of the trochlea were made based on previously established methods using the axial MRI image just distal to the physis at the deepest portion of the trochlear groove. Three linear (Lateral Trochlear Height (LTH), Medial Trochlear Height (MTH), Central Trochlear Height (CTH)) and three angular (Sulcus Angle (SA), Lateral Trochlear Slope (LTS), Medial Trochlear Slope (MTS)) were made at the Articular Cartilage (AC) and Subchondral Bone (SCB) (Figure 1). Twelve measurements were made independently by two study authors. Interrater reliability was assessed. Trochlea measurements were summarized across age quartiles: 1st (age 5.1 - 8.3y), 2nd (8.3 - 11.5y), 3rd (11.5 - 14.3y), 4th (14.3 - 16.9y). Associations between age and trochlea measures were assessed using linear regression with Huber-White adjusted standard errors. Results: 246 knee MRIs from 230 patients were included in this study. 113 patients (51%) were female while 117 (49%) were male. 116 MRIs (47%) were of the Left knee and 130 (53%) were Right knee. Average patient age was 11.4±3.4 years. Interrater agreement was high (ICC values >0.7). Mean values for measurements are presented by age quartiles (Table 1). LTH, MTH, and CTH showed linear increase with age (range 2 to 2.6 mm per year, p0.05) however LTS and MTS measured at SCB showed significant increases with age (0.6 and 0.9 degrees per year, p0.05) however for MTH, LTH, and CTH, males were found to have a significantly greater growth rate (p

Background: Limited data about the frequency and outcomes of palliative care (PC) specialty consultations for patients with amyotrophic lateral sclerosis (ALS) are available. Methods: This study was a retrospective chart review. Patients with ALS admitted to 2 academic hospitals from 2013-2018 were included. We compared patients who were seen by an inpatient specialty PC service (PC group) with those who were not (NonPC group). Results: Twenty-four patients met inclusion criteria (9 PC group, 15 NonPC group). Patients in both groups were similar in age and had been diagnosed for a similar amount of time before admission. In the PC group, 6 patients were seen by more than 1 PC multidisciplinary team member (physician, social worker, spiritual care provider, clinical nurse specialist). PC consultations were requested for goals of care (GOC) (n = 7), pain (n = 4), hospice information/referral (n = 2), dyspnea (n = 1), and excessive oral secretions (n = 1). GOC topics addressed for both groups were code status, treatment preferences (tracheostomy placement, percutaneous endoscopic gastrostomy placement, change to comfort care), prognostication, and hospice information/referral. Patients in the PC group were significantly more likely to be discharged with GOC (89%, p = 0.02) and completed advance care planning (ACP) documents (89%, p = 0.04) than patients in the NonPC group (32%; 47%). Despite reason for consultation, at least 1 symptom was addressed for every patient seen by PC specialists. Conclusions: Inpatient specialty PC consultation for patients with ALS leads to greater documentation of GOC and ACP by discharge. PC consultants participate in symptom management in patients with ALS during hospitalization.

Background: β-thalassemia is a genetic disease that causes abnormal production of red blood cells (ineffective erythropoiesis, IE). IE is a condition known to change bone marrow composition. Purpose: To evaluate the effect of IE on the marrow fat content and fat unsaturation levels in the proximal femur using 1 H-MRS. Study Type: Prospective. Subjects: Twenty-three subjects were included in this study, seven control and 16 β-thalassemia subjects. Field Strength/Sequence: 3.0T; stimulated echo acquisition Mode (STEAM); magnetic resonance spectroscopy (MRS) sequence. Assessment: Multiecho MRS scans were performed in four regions of the proximal left femur of each subject, that is, diaphysis, femoral neck, femoral head, and greater trochanter. The examined regions were grouped into red (diaphysis and femoral neck) and yellow marrow regions (femoral head and greater trochanter). Statistical Tests: The Jonckheere–Terpstra test was used to evaluate the impact of increasing disease severity on bone marrow fat fraction (BMFF), marrow conversion index, and fat unsaturation index (UI). Pairwise comparison analysis was performed when a significant trend (P < 0.05) was found. K-means clustering analysis was used to examine the clusters observed when BMFF in the red and yellow regions were studied (diaphysis against greater trochanter). Results: BMFF showed a significant decreasing trend with increasing disease severity in both red (TJT = 109.00, z = –4.414, P < 0.05) and yellow marrow regions (TJT = 108.00, z = –4.438, P < 0.05). The opposite trend was observed in UI in both bone marrow regions (red marrow: TJT = 180.5, z = 3.515, P < 0.05; yellow marrow: TJT = 155.0, z = 2.282, P = 0.05). Three distinct forms of marrow adipogenesis were found when plotting BMFF diaphysis against BMFF greater trochanter: 1) normal (centroid: 80.4%, 66.6%), 2) partial disruption (centroid: 51.1%, 16.6%), and 3) total disruption (centroid: 2.6%, 1.6%). Data Conclusion: β-thalassemia is associated with decreased marrow fat, and increased marrow fat unsaturation level. Level of Evidence: 2 Technical Efficacy Stage: 3.

BACKGROUND Increased enrollment in government-based insurance plans has been reported. With youth sports injuries on the rise, increased ordering of advanced imaging such as magnetic resonance imaging (MRI) has occurred. This study sought to report on the impact of insurance type on access to and results of knee MRI in pediatric sports medicine patients. METHODS A retrospective review of 178 consecutive pediatric sports medicine clinics was completed. INCLUSION CRITERIA patients younger than 18 years, routine knee MRI ordered, sports medicine diagnosis, and insurance. Data included basic demographics, injury date, date and location (urgent care vs. clinic) of the first presentation, details of MRI ordering and approval, date and location of MRI follow-up, MRI results (negative, minor findings, major findings), and eventual treatment required. RESULTS A total of 168 charts underwent a complete review. The patients' average age was 14±3 years and 54% (N=90) were female. Ninety-eight had government insurance and 70 had commercial insurance. The time between injury and MRI completion was significantly longer with government insurance (34 vs. 67 d, P

Anemia is common in intestinal failure (IF), but it is unknown if anemia in IF is due to iron deficiency or another etiology. Understanding iron status is important, as deficiency and overload are both associated with multisystem morbidity and mortality. The objective was to determine the etiology of anemia in a cohort of patients with IF and characterize iron status with respect to multisystem outcomes. This was a single center retrospective cohort analysis of iron parameters from August 1998 to March 2018 in 54 IF patients (355 person years). Thirty-eight percent of measurements showed iron deficiency, 36% anemia of inflammation, 21% indeterminate iron status, and 5% suggested iron overload. Mean direct and total bilirubin were elevated when ferritin was > 200 ng/mL and in inflamed and overloaded patients compared with iron-deficient patients. For every 10% increase in Tsat, bilirubin increased by 0.58 mg/dL from baseline (p = 0.003). Tsat > 50% had a mean positive culture probability of 60%. The probability of renal disease increased over time and average GFR decreased over time (−3.14 ± 1.37 mL/min per 1.73 m2), and nearly one in five patients in this study had chronic kidney disease (CKD). Patients with IF are at risk for both iron deficiency anemia as well as anemia of inflammation, with at a portion of patients with anemia of inflammation and overload having elevated risk of cholestasis, CKD, and infection compared to their peers. Careful assessment of inflammation, risk of infection, and renal function should be performed prior to dosing iron to ensure safe and effective delivery of this essential micronutrient. Future directions include determination of extra-renal sources of inflammation in IF.

BACKGROUND: Hospital readmission rates decreased for myocardial infarction (AMI), heart failure (CHF), and pneumonia with implementation of the first phase of the Hospital Readmissions Reduction Program (HRRP). It is not established whether readmissions fell for chronic obstructive pulmonary disease (COPD), an HRRP condition added in 2014. OBJECTIVE: We sought to determine whether HRRP penalties influenced COPD readmissions among Medicare, Medicaid, or privately insured patients. DESIGN: We analyzed a retrospective cohort, evaluating readmissions across implementation periods for HRRP penalties (“pre-HRRP” January 2010–April 2011, “implementation” May 2011–September 2012, “partial penalty” October 2012–September 2014, and “full penalty” October 2014–December 2016). PATIENTS: We assessed discharged patients ≥ 40 years old with COPD versus those with HRRP Phase 1 conditions (AMI, CHF, and pneumonia) or non-HRRP residual diagnoses in the Nationwide Readmissions Database. INTERVENTIONS: HRRP was announced and implemented during this period, forming a natural experiment. MEASUREMENTS: We calculated differences-in-differences (DID) for 30-day COPD versus HRRP Phase 1 and non-HRRP readmissions. KEY RESULTS: COPD discharges for 1.2 million Medicare enrollees were compared with 22 million non-HRRP and 3.4 million HRRP Phase 1 discharges. COPD readmissions decreased from 19 to 17% over the study. This reduction was significantly greater than non-HRRP conditions (DID − 0.41%), but not HRRP Phase 1 (DID + 0.02%). A parallel trend was observed in the privately insured, with significant reduction compared with non-HRRP (DID − 0.83%), but not HRRP Phase 1 conditions (DID − 0.45%). Non-significant reductions occurred in Medicaid (DID − 0.52% vs. non-HRRP and − 0.21% vs. Phase 1 conditions). CONCLUSIONS: In Medicare, HRRP implementation was associated with reductions in COPD readmissions compared with non-HRRP controls but not versus other HRRP conditions. Parallel findings were observed in commercial insurance, but not in Medicaid. Condition-specific penalties may not reduce readmissions further than existing HRRP trends. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-020-05958-0) contains supplementary material, which is available to authorized users.

Author(s): Duru, O Kenrik; Harwood, Jessica; Moin, Tannaz; Jackson, Nicholas J; Ettner, Susan L; Vasilyev, Arseniy; Mosley, David G; O'Shea, Donna L; Ho, Sam; Mangione, Carol M | Abstract: BackgroundMedical, behavioral, and social determinants of health are each associated with high levels of emergency department (ED) visits and hospitalizations.ObjectiveThe objective of this study was to evaluate a care coordination program designed to provide combined "whole-person care," integrating medical, behavioral, and social support for high-cost, high-need Medicaid beneficiaries by targeting access barriers and social determinants.Research designIndividual-level interrupted time series with a comparator group, using person-month as the unit of analysis.SubjectsA total of 42,214 UnitedHealthcare Medicaid beneficiaries (194,834 person-months) age 21 years or above with diabetes, with Temporary Assistance to Needy Families, Medicaid expansion, Supplemental Security Income without Medicare, or dual Medicaid/Medicare.MeasuresOur outcome measures were any hospitalizations and any ED visits in a given month. Covariates of interest included an indicator for intervention versus comparator group and indicator and spline variables measuring changes in an outcome's time trend after program enrollment.ResultsOverall, 6 of the 8 examined comparisons were not statistically significant. Among Supplemental Security Income beneficiaries, we observed a larger projected decrease in ED visit risk among the intervention sample versus the comparator sample at 12 months postenrollment (difference-in-difference: -6.6%; 95% confidence interval: -11.2%, -2.1%). Among expansion beneficiaries, we observed a greater decrease in hospitalization risk among the intervention sample versus the comparator sample at 12 months postenrollment (difference-in-difference: -5.8%; 95% confidence interval: -11.4%, -0.2%).ConclusionA care coordination program designed to reduce utilization among high-cost, high-need Medicaid beneficiaries was associated with fewer ED visits and hospitalizations for patients with diabetes in selected Medicaid programs but not others.

Author(s): Moin, Tannaz; Harwood, Jessica M; Mangione, Carol M; Jackson, Nicholas; Ho, Sam; Ettner, Susan L; Duru, O Kenrik | Abstract: Background/objectivesMedicaid beneficiaries with diabetes have complex care needs. The Accountable Care Communities (ACC) Program is a practice-level intervention implemented by UnitedHealthcare to improve care for Medicaid beneficiaries. We examined changes in costs and utilization for Medicaid beneficiaries with diabetes assigned to ACC versus usual care practices.Research designInterrupted time series with concurrent control group analysis, at the person-month level. The ACC was implemented in 14 states, and we selected comparison non-ACC practices from those states to control for state-level variation in Medicaid program. We adjusted the models for age, sex, race/ethnicity, comorbidities, seasonality, and state-by-year fixed effects. We examined the difference between ACC and non-ACC practices in changes in the time trends of expenditures and hospital and emergency room utilization, for the 4 largest categories of Medicaid eligibility [Temporary Assistance to Needy Families, Supplemental Security Income (without Medicare), Expansion, Dual-Eligible].Subjects/measuresEligibility and claims data from Medicaid adults with diabetes from 14 states between 2010 and 2016, before and after ACC implementation.ResultsAnalyses included 1,200,460 person-months from 66,450 Medicaid patients with diabetes. ACC implementation was not associated with significant changes in outcome time trends, relative to comparators, for all Medicaid categories.ConclusionsMedicaid patients assigned to ACC practices had no changes in cost or utilization over 3 years of follow-up, compared with patients assigned to non-ACC practices. The ACC program may not reduce costs or utilization for Medicaid patients with diabetes.

Author(s): Buhr, Russell G; Jackson, Nicholas J; Dubinett, Steven M; Kominski, Gerald F; Mangione, Carol M; Ong, Michael K | Abstract: BackgroundReadmissions after exacerbations of chronic obstructive pulmonary disease (COPD) are penalized under the Hospital Readmissions Reduction Program (HRRP). Understanding attributable diagnoses at readmission would improve readmission reduction strategies.ObjectivesDetermine factors that portend 30-day readmissions attributable to COPD versus non-COPD diagnoses among patients discharged following COPD exacerbations.Design, setting, and participantsWe analyzed COPD discharges in the Nationwide Readmissions Database from 2010 to 2016 using inclusion and readmission definitions in HRRP.Main outcomes and measuresWe evaluated readmission odds for COPD versus non-COPD returns using a multilevel, multinomial logistic regression model. Patient-level covariates included age, sex, community characteristics, payer, discharge disposition, and Elixhauser Comorbidity Index. Hospital-level covariates included hospital ownership, teaching status, volume of annual discharges, and proportion of Medicaid patients.ResultsOf 1,622,983 (a weighted effective sample of 3,743,164) eligible COPD hospitalizations, 17.25% were readmitted within 30 days (7.69% for COPD and 9.56% for other diagnoses). Sepsis, heart failure, and respiratory infections were the most common non-COPD return diagnoses. Patients readmitted for COPD were younger with fewer comorbidities than patients readmitted for non-COPD. COPD returns were more prevalent the first two days after discharge than non-COPD returns. Comorbidity was a stronger driver for non-COPD (odds ratio [OR] 1.19) than COPD (OR 1.04) readmissions.ConclusionThirty-day readmissions following COPD exacerbations are common, and 55% of them are attributable to non-COPD diagnoses at the time of return. Higher burden of comorbidity is observed among non-COPD than COPD rehospitalizations. Readmission reduction efforts should focus intensively on factors beyond COPD disease management to reduce readmissions considerably by aggressively attempting to mitigate comorbid conditions.

Pulmonary vein isolation using cryoballoon ablation is an effective treatment for patients with atrial fibrillation. We sought to compare outcomes with the first and second generation cryoballoon, with the second generation balloon incorporating the Achieve Lasso catheter, in terms of freedom from symptomatic recurrence and major complications.The first 200 patients who underwent cryoballoon ablation with the first generation balloon were compared with the first 200 patients using the second-generation balloon. All patients had symptomatic atrial fibrillation and had failed at least one antiarrhythmic drug. The primary efficacy endpoint was freedom from symptomatic recurrence of atrial fibrillation (AF) after a single pulmonary vein isolation (PVI) procedure using the cryoballoon. The primary safety endpoint was major procedural complications.At 12 months, freedom from symptomatic AF after a single procedure in the first generation cohort was 64.3% compared with 78.6% in the second-generation cohort (p = 0.002). At 24 months, freedom from symptomatic AF in the first generation cohort was 51.3% compared with 72.6% in the second-generation cohort (p 0.001). Procedural time (150 min vs 101 min; p 0.001) and fluoroscopy time (32.5 min vs 21.4 min; p 0.001) was lower in the second-generation group. The rate of major complications was comparably low in both groups.The second-generation cryoballoon was associated with improved freedom from symptomatic AF with reduction in procedure and fluoroscopy time, with a similar low rate of major complications.

Zinc metallopeptidase STE24 (ZMPSTE24) is essential for the conversion of farnesyl–prelamin A to mature lamin A, a key component of the nuclear lamina. In the absence of ZMPSTE24, farnesyl–prelamin A accumulates in the nucleus and exerts toxicity, causing a variety of disease phenotypes. By ∼4 months of age, both male and female Zmpste24(−/−) mice manifest a near-complete loss of adipose tissue, but it has never been clear whether this phenotype is a direct consequence of farnesyl–prelamin A toxicity in adipocytes. To address this question, we generated a conditional knockout Zmpste24 allele and used it to create adipocyte-specific Zmpste24–knockout mice. To boost farnesyl–prelamin A levels, we bred in the “prelamin A–only” Lmna allele. Gene expression, immunoblotting, and immunohistochemistry experiments revealed that adipose tissue in these mice had decreased Zmpste24 expression along with strikingly increased accumulation of prelamin A. In male mice, Zmpste24 deficiency in adipocytes was accompanied by modest changes in adipose stores (an 11% decrease in body weight, a 23% decrease in body fat mass, and significantly smaller gonadal and inguinal white adipose depots). No changes in adipose stores were detected in female mice, likely because prelamin A expression in adipose tissue is lower in female mice. Zmpste24 deficiency in adipocytes did not alter the number of macrophages in adipose tissue, nor did it alter plasma levels of glucose, triglycerides, or fatty acids. We conclude that ZMPSTE24 deficiency in adipocytes, and the accompanying accumulation of farnesyl–prelamin A, reduces adipose tissue stores, but only modestly and only in male mice.

OBJECTIVES Discrimination has been shown to have profound negative effects on mental and behavioral health and may influence these outcomes early in adulthood. We aimed to examine short-term, long-term, and cumulative associations between different types of interpersonal discrimination (eg, racism, sexism, ageism, and physical appearance discrimination) and mental health, substance use, and well-being for young adults in a longitudinal nationally representative US sample. METHODS We used data from 6 waves of the Transition to Adulthood Supplement (2007–2017, 1834 participants) of the Panel Study of Income Dynamics. Outcome variables included self-reported health, drug use, binge drinking, mental illness diagnosis, Languishing and Flourishing score, and Kessler Psychological Distress Scale score. We used logistic regression with cluster-robust variance estimation to test cross-sectional and longitudinal associations between discrimination frequency (overall, cumulative, and by different reason) and outcomes, controlling for sociodemographics. RESULTS Increased discrimination frequency was associated with higher prevalence of languishing (relative risk [RR] 1.34 [95% CI 1.2–1.4]), psychological distress (RR 2.03 [95% CI 1.7–2.4]), mental illness diagnosis (RR 1.26 [95% CI 1.1–1.4]), drug use (RR 1.24 [95% CI 1.2–1.3]), and poor self-reported health (RR 1.26 [95% CI 1.1–1.4]) in the same wave. Associations persisted 2 to 6 years after exposure to discrimination. Similar associations were found with cumulative high-frequency discrimination and with each discrimination subcategory in cross-sectional and longitudinal analyses. CONCLUSIONS In this nationally representative longitudinal sample, current and past discrimination had pervasive adverse associations with mental health, substance use, and well-being in young adults.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as an unpleasant sensation perceived to be related to the bladder with associated urinary symptoms. Due to difficulties discriminating pelvic visceral sensation, IC/BPS likely represents multiple phenotypes with different etiologies that present with overlapping symptomatic manifestations, which complicates clinical management. We hypothesized that unique bladder pain phenotypes or “symptomatic clusters” would be identifiable using machine learning analysis (unsupervised clustering) of validated patient-reported urinary and pain measures. Patients (n = 145) with pelvic pain/discomfort perceived to originate in the bladder and lower urinary tract symptoms answered validated questionnaires [OAB Questionnaire (OAB-q), O'Leary-Sant Indices (ICSI/ICPI), female Genitourinary Pain Index (fGUPI), and Pelvic Floor Disability Index (PFDI)]. In comparison to asymptomatic controls (n = 69), machine learning revealed three bladder pain phenotypes with unique, salient features. The first group chiefly describes urinary frequency and pain with the voiding cycle, in which bladder filling causes pain relieved by bladder emptying. The second group has fluctuating pelvic discomfort and straining to void, urinary frequency and urgency without incontinence, and a sensation of incomplete emptying without urinary retention. Pain in the third group was not associated with voiding, instead being more constant and focused on the urethra and vagina. While not utilized as a feature for clustering, subjects in the second and third groups were significantly younger than subjects in the first group and controls without pain. These phenotypes defined more homogeneous patient subgroups which responded to different therapies on chart review. Current approaches to the management of heterogenous populations of bladder pain patients are often ineffective, discouraging both patients and providers. The granularity of individual phenotypes provided by unsupervised clustering approaches can be exploited to help objectively define more homogeneous patient subgroups. Better differentiation of unique phenotypes within the larger group of pelvic pain patients is needed to move toward improvements in care and a better understanding of the etiologies of these painful symptoms.

BACKGROUND This pilot assessed transfusion requirements during resuscitation with whole blood followed by standard component therapy (CT) versus CT alone, during a change in practice at a large urban Level I trauma center. METHODS This was a single-center prospective cohort pilot study. Male trauma patients received up to 4 units of cold-stored low anti-A, anti-B group O whole blood (LTOWB) as initial resuscitation followed by CT as needed (LTOWB + CT). A control group consisting of women and men who presented when LTOWB was unavailable, received CT only (CT group). Exclusion criteria included antiplatelet or anticoagulant medication and death within 24 hours. The primary outcome was total transfusion volume at 24 hours. Secondary outcomes were mortality, morbidity, and intensive care unit- and hospital-free days. RESULTS Thirty-eight patients received LTOWB, with a median of 2.0 (interquartile range [IQR] 1.0-3.0) units of LTOWB transfused. Thirty-two patients received CT only. At 24 hours after presentation, the LTOWB +CT group had received a median of 2,138 mL (IQR, 1,275-3,325 mL) of all blood products. The median for the CT group was 4,225 mL (IQR, 1,900-5,425 mL; p = 0.06) in unadjusted analysis. When adjusted for Injury Severity Score, sex, and positive Focused Assessment with Sonography for Trauma, LTOWB +CT group patients received 3307 mL of blood products, and CT group patients received 3,260 mL in the first 24 hours (p = 0.95). The adjusted median ratio of plasma to red cells transfused was higher in the LTOWB + CT group (0.85 vs. 0.63 at 24 hours after admission; p = 0.043. Adjusted mortality was 4.4% in the LTOWB + CT group, and 11.7% in the CT group (p = 0.19), with similar complications, intensive care unit-, and hospital-free days in both groups. CONCLUSION Beginning resuscitation with LTOWB results in equivalent outcomes compared with resuscitation with CT only. LEVEL OF EVIDENCE Therapeutic (Prospective study with 1 negative criterion, limited control of confounding factors), level III.

IntroductionAtrial fibrillation (AF) is the most common sustained arrhythmia worldwide. Direct current cardioversion is commonly used to restore sinus rhythm in patients with AF. Chest pressure may improve cardioversion success through decreasing transthoracic impedance and increasing cardiac energy delivery. We aim to assess the efficacy and safety of routine chest pressure with direct current cardioversion for AF.Methods and analysisMulticentre, double blind (patient and outcome assessment), randomised clinical trial based in New South Wales, Australia. Patients will be randomised 1:1 to control and interventional arms. The control group will receive four sequential biphasic shocks of 150 J, 200 J, 360 J and 360 J with chest pressure on the last shock, until cardioversion success. The intervention group will receive the same shocks with chest pressure from the first defibrillation. Pads will be placed in an anteroposterior position. Success of cardioversion will be defined as sinus rhythm at 1 min after shock. The primary outcome will be total energy provided. Secondary outcomes will be success of first shock to achieve cardioversion, transthoracic impedance and sinus rhythm at post cardioversion ECG.Ethics and disseminationEthics approval has been confirmed at all participating sites via the Research Ethics Governance Information System. The trial has been registered on the Australia New Zealand Clinical Trials Registry (ACTRN12620001028998). De-identified patient level data will be available to reputable researchers who provide sound analysis proposals.

Background Readmissions following exacerbations of chronic obstructive pulmonary disease (COPD) are prevalent and costly. Multimorbidity is common in COPD and understanding how comorbidity influences readmission risk will enable health systems to manage these complex patients. Objectives We compared two commonly used comorbidity indices published by Charlson and Elixhauser regarding their ability to estimate readmission odds in COPD and determine which one provided a superior model. Methods We analyzed discharge records for COPD from the Nationwide Readmissions Database spanning 2010 to 2016. Inclusion and readmission criteria from the Hospital Readmissions Reduction Program were utilized. Elixhauser and Charlson Comorbidity Index scores were calculated from published methodology. A mixed-effects logistic regression model with random intercepts for hospital clusters was fit for each comorbidity index, including year, patient-level, and hospital-level covariates to estimate odds of thirty-day readmissions. Sensitivity analyses included testing age inclusion thresholds and model stability across time. Results In analysis of 1.6 million COPD discharges, readmission odds increased by 9% for each half standard deviation increase of Charlson Index scores and 13% per half standard deviation increase of Elixhauser Index scores. Model fit was slightly better for the Elixhauser Index using information criteria. Model parameters were stable in our sensitivity analyses. Conclusions Both comorbidity indices provide meaningful information in prediction readmission odds in COPD with slightly better model fit in the Elixhauser model. Incorporation of comorbidity information into risk prediction models and hospital discharge planning may be informative to mitigate readmissions.

OBJECTIVE To determine the effect of age of packed RBCs on tissue oxygenation in children receiving extracorporeal membrane oxygenation support. DESIGN A retrospective study was done between March 2013 and August 2015. The following biomarkers were examined 6 hours before and 6 hours after the conclusion of a transfusion: serum and circuit hematocrits, serum and circuit venous saturations, serum lactate levels (mg/dL), and cerebral saturation via near-infrared spectroscopy. Biomarkers were examined with respect to time relative to transfusion using four discrete categories ( 3 hr). The association between age of blood transfusion and change in biomarkers was accessed analyzing time relative to transfusion as described above. In addition, the age of blood transfusion was analyzed similarly, using four discrete categories (0-7, 7-14, 14-21, and > 21 d). SETTING Twenty-four bed mixed pediatric medical and cardiac ICU at a tertiary care center. SUBJECTS Zero- to 18-year-old patients of required extracorporeal membrane oxygenation support. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Circuit venous saturation demonstrated an increase of 2.5% (p < 0.001) in first 3 hours posttransfusion. This was followed by a 1.4% decrease after the initial 3 hours posttransfusion. Serum venous saturation showed no statistically significant change with relation to transfusions. Neither lactate levels nor near-infrared spectroscopy demonstrated any observed statistical change with relation to transfusion. With regards to the relationship between the age of RBC transfusion and tissue oxygenation biomarkers, none of the biomarkers exhibited a consistent interaction. CONCLUSIONS Our study demonstrates that the age of packed RBC transfusion does not affect the degree tissue oxygenation in children receiving extracorporeal membrane oxygenation support, as measured by mixed venous oxygen saturation, lactate, and near-infrared spectroscopy. In addition, packed RBC transfusion, in general, did not produce any meaningful change in these markers of tissue oxygenation.

The CYD-TDV vaccine is licensed in multiple endemic countries based on vaccine efficacy (VE) against symptomatic, virologically confirmed dengue demonstrated in two phase 3 trials (CYD14, 2- to 14-year-olds, Asia; CYD15, 9- to 16-year-olds, Latin America). 50% plaque reduction neutralization test (PRNT(50)) titers at baseline and month 13 (post-vaccination) were associated with VE and may enable bridging VE to adults. Two phase 2 trials of CYD-TDV measured baseline and month 13 PRNT(50) titers: CYD22 (9- to 45-year-olds, Vietnam) and CYD47 (18- to 45-year-olds, India). 50% plaque reduction neutralization test distributions were compared between age cohorts, and four versions of an epidemiological bridging method were used to estimate VE against any serotype (dengue virus [DENV]-Any) and against each serotype over 25 months post first vaccination in a hypothetical CYD14 + CYD15 18- to 45-year-old cohort (bridging population 1) and in the actual CYD47 18- to 45-year-old cohort (bridging population 2). Baseline and month 13 geometric mean PRNT(50) titers to each serotype were significantly greater in 18- to 45-year-olds than 9- to 16-year-olds for all comparisons. The four methods estimated VE against DENV-Any at 75.3–86.0% (95% CIs spanning 52.5–100%) for bridging population 1 and 68.4–77.5% (95% CIs spanning 42.3–88.5%) for bridging population 2. The vaccine efficacy against serotype 1, 2, 3, and 4 was estimated at 56.9–76.9%, 68.3–85.8%, 91.4–95.0%, and 93.2–100% (bridging population 1) and 44.5–66.9%, 53.2–69.2%, 79.8–92.0%, and 90.6–95.0% (bridging population 2), respectively; thus, CYD-TDV would likely confer improved efficacy in adults than 9- to 16-year-olds. Using the same methods, we predicted VE against hospitalized DENV-Any over 72 months of follow-up, with estimates 59.1–73.5% (95% CIs spanning 40.9–92.2%) for bridging population 1 and 50.9–65.9% (95% CIs spanning 38.1–82.1%) for bridging population 2.

The recombinant yellow fever-17D-dengue virus, live, attenuated, tetravalent dengue vaccine (CYD-TDV) is licensed in several dengue-endemic countries. Although the vaccine provides protection against dengue, the level of protection differs by serotype and warrants further investigation. We characterized the antigenic properties of each vaccine virus serotype using highly neutralizing human monoclonal antibodies (hmAbs) that bind quaternary structure-dependent epitopes. Specifically, we monitored the binding of dengue virus-1 (DENV-1; 1F4), DENV-2 (2D22) or DENV-3 (5J7) serotype-specific or DENV-1-4 cross-reactive (1C19) hmAbs to the four chimeric yellow fever-dengue vaccine viruses (CYD-1-4) included in phase III vaccine formulations using a range of biochemical and functional assays (dot blot, ELISA, surface plasmon resonance and plaque reduction neutralization assays). In addition, we used the "classic" live, attenuated DENV-2 vaccine serotype, immature CYD-2 viruses and DENV-2 virus-like particles as control antigens for anti-serotype-2 reactivity. The CYD vaccine serotypes were recognized by each hmAbs with the expected specificity, moreover, surface plasmon resonance indicated a high functional affinity interaction with the CYD serotypes. In addition, the hmAbs provided similar protection against CYD and wild-type dengue viruses in the in vitro neutralization assay. Overall, these findings demonstrate that the four CYD viruses used in clinical trials display key conformational and functional epitopes targeted by serotype-specific and/or cross-reactive neutralizing human antibodies. More specifically, we showed that CYD-2 displays serotype- specific epitopes present only on the mature virus. This indicates that the CYD-TDV has the ability to elicit antibody specificities which are similar to those induced by the wild type DENV. Future investigations will be needed to address the nature of CYD-TDV-induced responses after vaccine administration, and how these laboratory markers relate to vaccine efficacy and safety.

Background The tetravalent dengue vaccine (CYD-TDV, Dengvaxia, Sanofi Pasteur) demonstrated efficacy in 2 previous phase III trials conducted in endemic countries. Neutralizing antibodies (NAbs) elicited by 3 doses of this vaccine have been associated with efficacy. Long-term follow-up data has shown that NAb immune responses tend to wane over time, after the third dose. This study compared the immune response elicited by a booster (4th) dose of CYD-TDV with the immune responses from the same participants obtained post-dose 3 of the primary series administered 4-5 years earlier. Methods This multicenter, observer-blind, randomized, placebo-controlled, phase II noninferiority trial was conducted in healthy adolescents and adults in dengue endemic countries of Latin America (Colombia, Honduras, Brazil, Mexico and Puerto Rico). All participants had been immunized with 3 doses of CYD-TDV in phase II studies conducted 4-5 years earlier. NAb levels against each dengue virus serotype 28 days postbooster or placebo injection were reported. Results A total of 187 participants received CYD-TDV and 64 received placebo. Prospectively defined noninferiority criteria for dengue NAbs after the booster dose compared with postdose 3 were met for all 4 serotypes. Prospectively defined superiority criteria were met for 3 of the 4 serotypes. Conclusions Antidengue NAb levels can be boosted to levels at least as high as, or higher than those observed after completion of the primary 3-dose series, with an additional dose of CYD-TDV 4-5 years after the standard 3-dose vaccination schedule.

INTRODUCTION Diversity has increased within youth sports. It is unknown whether these demographic or socioeconomic factors affect adolescent patients' and their guardians' preferences of sports medicine physicians and involvement in medial decision making. Demographic and socioeconomic factors may affect adolescent patient and guardian preferences for sports medicine physicians. METHODS Patients, age 10 to 18 years, and their guardians presenting to two sports medicine offices were asked to complete matched, anonymous surveys assessing their preferences for medical decision making, sports medicine physician gender, and personality characteristics. Analysis of demographic and socioeconomic effects on preferences was completed. RESULTS Matched survey responses were collected from 353 patients and 325 corresponding guardians. Patient average age was 14.6 years (SD 2.1), with 43% female. Guardian average age was 43.4 years (SD 8.3), with 79% female. For both patients and guardians, the highest valued physician characteristic was being a good listener. Overall, 21% of patients and 17% of guardians reported a physician gender preference that matched the gender of the patient. Among all female patients, 32% preferred a female physician. Among all male patients, 12% preferred a male physician (P < 0.001). Ninety-two percent of patients reported wanting to be involved, and 93% of guardians thought that their child should be involved in the decision-making process. Hispanic, non-White, non-English speaking, government or no insurance, or less than college level of education patients and guardians reported a significantly greater importance of the physician independently determining the treatment plan (P < 0.001). CONCLUSIONS Demographic and socioeconomic factors do affect adolescent patient and guardian preferences for sports medicine physicians. Young patients have a desire to be included in the medical decision-making process. Female adolescent patients may have a same-gender preference for their sports medicine physician. STUDY DESIGN This is a prospective, cohort study.

This longitudinal cohort study's aim was to detect whether larger increases in C‐reactive protein (CRP) predict greater amounts of subsequent bone loss in women transitioning from premenopause to postmenopause. Participants were initially 42 to 52 years of age and premenopausal or early perimenopausal. The sample included 1431 women who were not using hormone therapy and whose CRP values were not consistent with acute inflammation. Individual fixed effects (IFE) models estimated the association of log2 CRP with subsequent bone mineral density (BMD) decline rate, adjusted for menopause transition (MT) stage (1: premenopausal or early perimenopausal; 2: late perimenopausal or early postmenopausal; or 3: late postmenopausal), body mass index, diabetes, smoking, alcohol, bone active medications, and anti‐inflammatory medications. BMD decline at both the lumbar spine (LS) and femoral neck (FN) was faster for observations made in MT stage 2 than that during other stages (all p

Key Points Question Is a team-based community health worker and advanced practice clinician (including nurse practitioners or physician assistants) intervention emphasizing evidence-based care, self-management, lifestyle change, and medication adherence superior to usual care for controlling blood pressure after stroke in safety-net settings? Findings In this randomized clinical trial that included 487 adults with recent stroke or transient ischemic attack, there was no difference between usual care and the multifaceted team-based intervention in blood pressure control at 12 months. Meaning These findings suggest that additional research is needed to determine the optimal care model for controlling risk factors after stroke in safety-net settings., This randomized clinical trial examines the effect of a multifaceted team intervention vs usual care on systolic blood pressure (SBP) among patients with stroke or transient ischemic attack (TIA) in safety-net settings., Importance Few stroke survivors meet recommended cardiovascular goals, particularly among racial/ethnic minority populations, such as Black or Hispanic individuals, or socioeconomically disadvantaged populations. Objective To determine if a chronic care model–based, community health worker (CHW), advanced practice clinician (APC; including nurse practitioners or physician assistants), and physician team intervention improves risk factor control after stroke in a safety-net setting (ie, health care setting where all individuals receive care, regardless of health insurance status or ability to pay). Design, Setting, and Participants This randomized clinical trial included participants recruited from 5 hospitals serving low-income populations in Los Angeles County, California, as part of the Secondary Stroke Prevention by Uniting Community and Chronic Care Model Teams Early to End Disparities (SUCCEED) clinical trial. Inclusion criteria were age 40 years or older; experience of ischemic or hemorrhagic stroke or transient ischemic attack (TIA) no more than 90 days prior; systolic blood pressure (BP) of 130 mm Hg or greater or 120 to 130 mm Hg with history of hypertension or using hypertensive medications; and English or Spanish language proficiency. The exclusion criterion was inability to consent. Among 887 individuals screened for eligibility, 542 individuals were eligible, and 487 individuals were enrolled and randomized, stratified by stroke type (ischemic or TIA vs hemorrhagic), language (English vs Spanish), and site to usual care vs intervention in a 1:1 fashion. The study was conducted from February 2014 to September 2018, and data were analyzed from October 2018 to November 2020. Interventions Participants randomized to intervention were offered a multimodal coordinated care intervention, including hypothesized core components (ie, ≥3 APC clinic visits, ≥3 CHW home visits, and Chronic Disease Self-Management Program workshops), and additional telephone visits, protocol-driven risk factor management, culturally and linguistically tailored education materials, and self-management tools. Participants randomized to the control group received usual care, which varied by site but frequently included a free BP monitor, self-management tools, and linguistically tailored information materials. Main Outcomes and Measures The primary outcome was change in systolic BP at 12 months. Secondary outcomes were non–high density lipoprotein cholesterol, hemoglobin A1c, and C-reactive protein (CRP) levels, body mass index, antithrombotic adherence, physical activity level, diet, and smoking status at 12 months. Potential mediators assessed included access to care, health and stroke literacy, self-efficacy, perceptions of care, and BP monitor use. Results Among 487 participants included, the mean (SD) age was 57.1 (8.9) years; 317 (65.1%) were men, and 347 participants (71.3%) were Hispanic, 87 participants (18.3%) were Black, and 30 participants (6.3%) were Asian. A total of 246 participants were randomized to usual care, and 241 participants were randomized to the intervention. Mean (SD) systolic BP improved from 143 (17) mm Hg at baseline to 133 (20) mm Hg at 12 months in the intervention group and from 146 (19) mm Hg at baseline to 137 (22) mm Hg at 12 months in the usual care group, with no significant differences in the change between groups. Compared with the control group, participants in the intervention group had greater improvements in self-reported salt intake (difference, 15.4 [95% CI, 4.4 to 26.0]; P = .004) and serum CRP level (difference in log CRP, −0.4 [95% CI, −0.7 to −0.1] mg/dL; P = .003); there were no differences in other secondary outcomes. Although 216 participants (89.6%) in the intervention group received some of the 3 core components, only 35 participants (14.5%) received the intended full dose. Conclusions and Relevance This randomized clinical trial of a complex multilevel, multimodal intervention did not find vascular risk factor improvements beyond that of usual care; however, further studies may consider testing the SUCCEED intervention with modifications to enhance implementation and participant engagement. Trial Registration ClinicalTrials.gov Identifier: NCT01763203

BACKGROUND: Phenytoin has long been used to treat epilepsy and for some time as an antiarrhythmic drug (AAD). It is known that the diastolic calcium leakage through dysfunctional cardiac ryanodine receptors (RyR2) is a mechanism for arrhythmias in heart failure. Recent evidence suggests that phenytoin inhibits dysfunctional RyR2, reduces the calcium leak during diastole in heart failure, and may improve cardiac systolic function. This indicates the potential for repurposing phenytoin as an AAD in patients with heart failure.METHODS: A systematic search of MEDLINE, Embase, and the Cochrane Library databases was performed in March 2019. The search was limited to the studies published in the English language from 1946 to 2019. Studies on the antiarrhythmic effects of phenytoin in adults compared to no treatment or other AADs were included. Studies were excluded if there was insufficient clinical data regarding antiarrhythmic effects, dosing and administration of phenytoin and other ADDs. Conference abstracts, editorials, case studies and review articles were also excluded. RESULTS: A total of 157 non-duplicate titles were screened, and 25 articles underwent full-text review. 13 studies met the inclusion criteria, representing a total of 985 patients. Phenytoin was found to be effective in treating arrhythmias associated with digitalis toxicity, and in suppressing premature ventricular contractions (PVCs). In a recent animal study, phenytoin inhibited diastolic calcium leak through dysfunctional RyR2 in failing sheep hearts and improved cardiac systolic function without affecting normal functional RyR2.CONCLUSION: Phenytoin has an acceptable safety profile when used as an AAD. It has some utility in treating digitalis-induced arrhythmias and suppressing PVCs, however, further study is needed to determine its efficacy as an antiarrhythmic in heart failure patients given new evidence of its RyR2 stabilising properties.TRIAL REGISTRATION NUMBER: PROSPERO database (CRD42019129125).

SUMMARY We report a serum-free, 3D murine artificial thymic organoid (M-ATO) system that mimics normal murine thymopoiesis with the production of all T cell stages, from early thymic progenitors to functional single-positive (CD8SP and CD4SP) TCRαβ and TCRγδ cells. RNA sequencing aligns M-ATO-derived populations with phenotypically identical primary thymocytes. M-ATOs initiated with Rag1−/− marrow produce the same differentiation block as seen in the endogenous thymus, and Notch signaling patterns in M-ATOs mirror primary thymopoiesis. M-ATOs initiated with defined hematopoietic stem cells (HSCs) and lymphoid progenitors from marrow and thymus generate each of the downstream differentiation stages, allowing the kinetics of T cell differentiation to be tracked. Remarkably, single HSCs deposited into each M-ATO generate the complete trajectory of T cell differentiation, producing diverse TCR repertoires across clones that largely match endogenous thymus. M-ATOs represent a highly reproducible and efficient experimental platform for the interrogation of clonal thymopoiesis from HSCs., In Brief Montel-Hagen et al. develop a murine artificial thymic organoid (M-ATO) system to reproduce thymopoiesis in vitro from bone marrow stem and progenitor cells (HSPCs). This method efficiently recapitulates the phenotypic and transcriptional features of normal murine T cell development even when initiated with a single HSC., Graphical Abstract

Empirical approaches to targeting the ventricular tachycardia (VT) substrate include mapping of late potentials, local abnormal electrogram, pace-mapping and homogenisation of the abnormal signals. These approaches do not try to differentiate between the passive or active role of local signals as the critical components of the VT circuit. By not considering the functional components, these approaches often view the substrate as a fixed anatomical barrier. Strategies to improve the success of VT ablation need to include the identification of critical functional substrate. Decrement-evoked potential (DeEP) mapping has been developed to elucidate this using an extra-stimulus added to a pacing drive train. With knowledge translation in mind, the authors detail the evolution of the DeEP concept by way of a study of simultaneous panoramic endocardial mapping in VT ablation; an in silico modelling study to demonstrate the factors influencing DeEPs; a multicentre VT ablation validation study; a practical approach to DeEP mapping; the potential utility of DeEPs to identify arrhythmogenic atrial substrate; and, finally, other functional mapping strategies.

To determine incidence, risks factors for, and outcomes of idiopathic vitritis (IV) after Boston type 1 keratoprosthesis (KPro) implantation.Retrospective, consecutive case series. Risk factors were analyzed between IV group and No IV group.IV occurred in 32/350 procedures (9.1%), for an average incidence of 0.02 cases per procedure-year. Presumed infectious keratitis was the only risk factor identified (HR = 7.65) Corneal necrosis and retinal detachment occurred significantly more frequently in IV group (allIV is associated with infectious keratitis, indicating that the vitritis may not be a sterile process. The increased incidence of subsequent complications leads to significantly decreased visual acuity and KPro retention in affected eyes.

(1) Background: Internal medicine (IM) resident physicians need to be trained to care for older adults and transition them safely across care settings. Objective: The study purpose was to evaluate the efficacy of a curriculum in geriatrics assessment and communication skills for transitions of care (TOCs) to IM resident physicians. (2) Methods: IM residents rotated for 4 weeks on the geriatrics consult service at a large public teaching hospital, where they received didactic lectures and clinical experience in consultation and transitional care. The curriculum was designed to meet consensus guidelines for minimum geriatrics competencies expected of IM residents. Previously validated and published assessment tools were used for geriatrics knowledge and attitudes. Locally developed tools were used to directly observe and rate communication skills, and self-assess geriatrics assessment and health literacy skills. The curriculum was evaluated using a quasi-experimental, nonrandomized, single-group pre- and post-test observational design. Data on 31 subjects were collected over 18 months and analyzed using mixed-effects models. (3) Results: Average knowledge scores improved from 65% to 74% (&Delta, 9%, 95% CI 4&ndash, 13%, p &lt, 0.001). Communication skills improved by an average of 1.15 points (95% CI 0.66&ndash, 1.64, p &lt, 0.001) on a 9-point scale. Attitudes did not change significantly. Self-rated confidence in geriatrics assessment and health literacy skills improved modestly. (4) Conclusions: The curriculum is effective in teaching basic geriatrics knowledge and communication skills, and increasing self-confidence in geriatrics assessment skills. In settings where an inpatient geriatrics consult service is feasible, the curriculum may be a model for combining geriatrics and TOC training.

The use of upfront chemotherapy for primary localized soft tissue sarcoma (STS) of the extremity and trunk is debated. It remains unclear if chemotherapy adds clinical benefit, which patients are likely to benefit, and whether the timing of therapy affects outcomes. We used the National Cancer Database (NCDB) to examine the association between overall survival (OS) and chemotherapy in 5436 patients with the five most common subtypes of STS with primary disease localized to the extremity or trunk, mirroring the patient population of a modern phase 3 clinical trial of neoadjuvant chemotherapy. We then examined associations between timing of multi-agent chemotherapy (neoadjuvant or adjuvant) and OS. We used a Cox proportional hazards model and propensity score matching (PSM) to account for covariates including demographic, patient, clinical, treatment, and facility factors. In the overall cohort, we observed no association between multi-agent chemotherapy or its timing and improved OS. Multi-agent chemotherapy was associated with improved OS in several subgroups, including patients with larger tumors (&gt, 5 cm), those treated at high-volume centers, or those who received radiation. We also identified an OS benefit to multi-agent chemotherapy among the elderly (&gt, 70 years) and African American patients. Multi-agent chemotherapy was associated with improved survival for patients with tumors &gt, 5 cm, who receive radiation, or who receive care at high-volume centers. Neither younger age nor chemotherapy timing was associated with better outcomes. These &lsquo, real-world&rsquo, findings align with recent randomized trial data supporting the use of multi-agent chemotherapy in high-risk patients with localized STS.

INTRODUCTION Different endpoint criteria, different durations of follow-up and the completeness of follow-up can dramatically affect the perceived benefits of atrial fibrillation (AF) ablation. METHODS We defined three endpoints for recurrence of AF post ablation in a cohort of 200 patients with symptomatic AF, refractory to antiarrhythmic drugs (AADs). A 'Strict Endpoint' where patients were considered to have a recurrence with any symptomatic or documented recurrence for ≥30 seconds with no blanking period, and off their AADs, a 'Liberal Endpoint' where only documented recurrences after the blanking period, either on or off AADs were counted, and a 'Patient-defined Outcome endpoint' which was the same as the Liberal endpoint but allowed for up to two recurrences and one repeat ablation or DCCV during follow-up. We also surveyed 50 patients on the waiting list for an AF ablation and asked them key questions regarding what they would consider to be a successful result for them. RESULTS Freedom from recurrence of atrial tachyarrhythmias (AT) at 5 years was 62% for the Strict Endpoint, 73% for the Liberal Endpoint, and 80% for the Patient-defined Outcome endpoint (p

Objective Thrombophilia is a prothrombotic condition that increases the risk of venous thromboembolism. It is unclear whether the presence of thrombophilia alters the clinical outcomes after deep venous stenting. The aim of the present study was to examine the relationship between thrombophilia and outcomes after stenting for post-thrombotic syndrome. Methods Consecutive patients (2012-2017) receiving a nitinol venous stent for chronic post-thrombotic venous occlusive disease with a minimum of 18 months of follow-up in one center using the same anticoagulation protocol were included. The clinical history and thrombophilia testing results were reviewed. The outcomes were stent patency, which was assessed using duplex ultrasonography at 24 hours, 2 and 6 weeks, 3 months, 6 months, and annually thereafter; and reinterventions, which were performed when the stent diameter was Results Of the 136 patients who had undergone intervention, 55 (40%) had had a provoked deep vein thrombosis (DVT) and 81 (60%) had had an unprovoked DVT and had therefore undergone thrombophilia testing. Of the 81 patients, 38 (47%) had had either inherited (n = 19; 50%) or acquired (n = 19; 50%) thrombophilia. Of the 136 patients who had undergone stenting, 68 had required reintervention (50%) during follow-up to maintain stent patency. Of the 55 patients with a provoked DVT, 29 (53%) had required reintervention. Of the 81 patients with an unprovoked DVT, 39 (48%) had required reintervention (P = .420). Of the 38 patients with unprovoked DVT and thrombophilia, 17 (45%) had required reintervention. Of the 43 patients with unprovoked DVT and no thrombophilia, 22 (51%) had required reintervention (P = .766). The cumulative patency rate was 80% for patients with provoked DVT and 88% for those with unprovoked DVT (P = .193). The presence of thrombophilia was not associated with patency loss (92% cumulative patency for patients with thrombophilia and 84% for patients without thrombophilia; P = .307). Conclusions Using our anticoagulation protocol, patients with and without thrombophilia had similar clinical outcomes after deep venous stenting and should not be excluded from iliofemoral venous stenting. We found no significant differences in outcomes in conjunction with appropriate postoperative anticoagulation therapy.

Supplemental Digital Content is available in the text., Background and Purpose— Lowering blood pressure and cholesterol, antiplatelet/antithrombotic use, and smoking cessation reduce risk of recurrent stroke. However, gaps in risk factor control among stroke survivors warrant development and evaluation of alternative care delivery models that aim to simultaneously improve multiple risk factors. Randomized trials of care delivery models are rarely of sufficient duration or size to be powered for low-frequency outcomes such as observed recurrent stroke. This creates a need for tools to estimate how changes across multiple stroke risk factors reduce risk of recurrent stroke. Methods— We reviewed existing evidence of the efficacy of interventions addressing blood pressure reduction, cholesterol lowering, antiplatelet/antithrombotic use, and smoking cessation and extracted relative risks for each intervention. From this, we developed a tool to estimate reductions in recurrent stroke risk, using bootstrapping and simulation methods. We also calculated a modified Global Outcome Score representing the proportion of potential benefit (relative risk reduction) achieved if all 4 individual risk factors were optimally controlled. We applied the tool to estimate stroke risk reduction among 275 participants with complete 12-month follow-up data from a recently published randomized trial of a healthcare delivery model that targeted multiple stroke risk factors. Results— The recurrent stroke risk tool was feasible to apply, yielding an estimated reduction in the relative risk of ischemic stroke of 0.36 in both the experimental and usual care trial arms. Global Outcome Score results suggest that participants in both arms likely averted, on average, 45% of recurrent stroke events that could possibly have been prevented through maximal implementation of interventions for all 4 individual risk factors. Conclusions— A stroke risk reduction tool facilitates estimation of the combined impact on vascular risk of improvements in multiple stroke risk factors and provides a summary outcome for studies testing alternative care models to prevent recurrent stroke. Registration— URL: https://www.clinicaltrials.gov; Unique identifier: NCT00861081.

Background Trauma quality improvement (QI) has resulted in decreased trauma mortality and morbidity in high-income countries and has the potential to do the same in low- and middle-income countries. Effective implementation of QI programs relies on a foundational culture of patient safety; however, studies on trauma-related patient safety culture in Sub-Saharan Africa remain scarce. This study assesses baseline patient safety culture in Cameroon to best identify opportunities for improvement. Materials and methods Over a 3-week period, the Hospital Survey on Patient Safety Culture was administered in three hospitals in the Littoral region of Cameroon. Percentages of positive responses (PPRs) were calculated across 42 items in 12 survey dimensions. A mixed-effects logistic regression model was used to summarize dimension-level percentages and confidence intervals. Results A total of 179 trauma-related hospital personnel were surveyed with an overall response rate of 76.8%. High PPRs indicate favorable patient safety culture. Of the 12 dimensions evaluated by the Hospital Survey on Patient Safety Culture, nine had a PPR below 50%. Dimensions particularly pertinent in the context of QI include Nonpunitive Response to Errors with a PPR of 25.8% and Organization Learning—Continuous Improvement with a PPR of 64.7%. Conclusions The present study elucidates an opportunity for the development of trauma patient safety culture in Cameroon. Low PPR for Nonpunitive Response to Errors indicates a need to shift cultural paradigms from ascribing individual blame to addressing systemic shortcomings of patient care. Moving forward, data from this study will inform interventions to cultivate patient safety culture in partnering Cameroonian hospitals.