Citations

Congenital heart diseases, including single ventricle circulations, are clinically challenging due to chronic pressure overload and the inability of the myocardium to compensate for lifelong physiological demands. To determine the clinical relevance of autologous umbilical cord blood–derived mononuclear cells (UCB-MNCs) as a therapy to augment cardiac adaptation following surgical management of congenital heart disease, a validated model system of right ventricular pressure overload due to pulmonary artery banding (PAB) in juvenile pigs has been employed. PAB in a juvenile porcine model and intramyocardial delivery of UCB-MNCs was evaluated in three distinct 12-week studies utilizing serial cardiac imaging and end-of-study pathology evaluations. PAB reproducibly induced pressure overload leading to chronic right ventricular remodeling including significant myocardial fibrosis and elevation of heart failure biomarkers. High-dose UCB-MNCs (3 million/kg) delivered into the right ventricular myocardium did not cause any detectable safety issues in the context of arrhythmias or abnormal cardiac physiology. In addition, this high-dose treatment compared with placebo controls demonstrated that UCB-MNCs promoted a significant increase in Ki-67-positive cardiomyocytes coupled with an increase in the number of CD31+ endothelium. Furthermore, the incorporation of BrdU-labeled cells within the myocardium confirmed the biological potency of the high-dose UCB-MNC treatment. Finally, the cell-based treatment augmented the physiological adaptation compared with controls with a trend toward increased right ventricular mass within the 12 weeks of the follow-up period. Despite these adaptations, functional changes as measured by echocardiography and magnetic resonance imaging did not demonstrate differences between cohorts in this surgical model system. Therefore, this randomized, double-blinded, placebo-controlled pre-clinical trial establishes the safety of UCB-MNCs delivered via intramyocardial injections in a dysfunctional right ventricle and validates the induction of cardiac proliferation and angiogenesis as transient paracrine mechanisms that may be important to optimize long-term outcomes for surgically repaired congenital heart diseases.

Abstract Introduction Patients with hematologic malignancies (HM) who are eligible for allogeneic hematopoietic cell transplant (allo-HCT) often lack an HLA-matched related donor (MRD) and rely on unrelated donors for a matched or mismatched unrelated donor (MUD or MMUD) or on umbilical cord blood (UCB). It is well known that racial minorities are underrepresented in donor registries. Objective Omidubicel, an advanced cell therapy for allo-HCT, demonstrated superior hematopoietic recovery and clinical outcomes compared with standard UCB (NCT02730299). We hypothesized the impact of omidubicel access on racial and ethnic health disparities in a projection model. Methods A model was developed to project allo-HCT access and clinical outcomes in a hypothetical population of 10,000 allo-HCT-eligible US patients with HM lacking an HLA-MRD. Outcomes associated with omidubicel, MUD, MMUD, haploidentical or UCB HCT, or no transplant were assessed by race/ethnic group. Model inputs, including clinical outcomes for each HCT type, were drawn from clinical trials, public CIBMTR and US Department of Health and Human Services data, and published studies. Increasing omidubicel use was modeled, with proportional reductions in other allo-HCT types or no transplant. Results In a modeled population of 10,000 patients, 5,956 (60%) received allo-HCT utilizing current donor sources (MUD, MMUD, haploidentical, UCB) with no omidubicel (status quo). While 80% of white patients underwent allo-HCT, only 40% of Hispanic, 32% of Asian, and 22% of Black patients underwent allo-HCT. Mean time from selecting graft to HCT was 11.5 weeks. Including those not transplanted, 1-year OS was 62% overall, ranging from 56% (Black) to 65% (White). Modeled increases in omidubicel use in eligible patients were associated with higher proportions of patients undergoing allo-HCT, decreased time to HCT, and increased 1-year OS. Improvements were greatest among racial minorities. Assuming 20% omidubicel use, the proportion of patients receiving allo-HCT increased by 71% in Black, 43% in Asian, 30% in Hispanic, and 5% in White patients. Modeled time to allo-HCT improved as well. Discussion Access to omidubicel is projected to decrease time to allo-HCT, improve outcomes overall, with greatest improvements among racial and ethnic groups underserved by the status quo, thus helping to reduce racial disparities and improving health equity in allo-HCT.

Abstract There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19), with rapidly changing efficacy and safety evidence from trials. The objective was to develop evidence-based, rapid, living guidelines intended to support patients, clinicians, and other healthcare professionals in their decisions about treatment and management of patients with COVID-19. In March 2020, the Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise to regularly review the evidence and make recommendations about the treatment and management of persons with COVID-19. The process used a living guideline approach and followed a rapid recommendation development checklist. The panel prioritized questions and outcomes. A systematic review of the peer-reviewed and grey literature was conducted at regular intervals. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. Based on the most recent search conducted on 31 May 2022, the IDSA guideline panel has made 32 recommendations for the treatment and management of the following groups/populations: pre- and postexposure prophylaxis, ambulatory with mild-to-moderate disease, and hospitalized with mild-to-moderate, severe but not critical, and critical disease. As these are living guidelines, the most recent recommendations can be found online at: https://idsociety.org/COVID19guidelines. At the inception of its work, the panel has expressed the overarching goal that patients be recruited into ongoing trials. Since then, many trials were conducted that provided much-needed evidence for COVID-19 therapies. There still remain many unanswered questions as the pandemic evolved, which we hope future trials can answer.

Background Many patients with symptomatic severe aortic stenosis do not undergo aortic valve replacement (AVR) despite clinical guidelines. This study analyzed the association of managing provider type with cardiac specialist follow‐up, AVR, and mortality for patients with newly diagnosed severe aortic stenosis (sAS). Methods and Results We identified adults with newly diagnosed sAS per echocardiography performed between January 2017 and March 2019 using Optum electronic health record data. We then selected from those meeting all eligibility criteria patients managed by a primary care provider (n=1707 [25%]) or cardiac specialist (n=5039 [75%]). We evaluated the association of managing provider type with cardiac specialist follow‐up, AVR, and mortality, as well as the independent association of cardiac specialist follow‐up and AVR with mortality, within 1 year of echocardiography detecting sAS. A subgroup analysis was limited to patients with symptomatic sAS. Patient characteristics and comorbidities at baseline were used for covariate‐adjusted cause‐specific and multivariable Cox proportional hazard models assessing group differences in outcomes by managing provider type. An adjusted Cox proportional hazard model with additional time‐dependent covariates for follow‐up and AVR was used to assess these practices' association with mortality. Within 1 year of echocardiography detecting sAS, data revealed that primary care provider management was associated with lower rates of cardiac specialist follow‐up (hazard ratio [HR], 0.47 [95% CI, 0.43–0.50], P <0.0001) and AVR (HR, 0.58 [95% CI, 0.53–0.64], P <0.0001) and with higher 1‐year mortality (HR, 1.45 [95% CI, 1.26–1.66], P <0.0001). Cardiac specialist follow‐up and AVR were independently associated with lower mortality (follow‐up: HR, 0.55 [95% CI, 0.48–0.63], P <0.0001; AVR: HR, 0.70 [95% CI, 0.60–0.83], P <0.0001). Results were similar for patients with symptomatic sAS. All analyses were adjusted for baseline patient characteristics and comorbidities. Conclusions For patients newly diagnosed with sAS, we observed differences in rates of cardiac specialist follow‐up and AVR and risk of mortality between primary care provider‐ versus cardiologist‐managed patients with sAS. In addition, a lower likelihood of receiving follow‐up and AVR was independently associated with higher mortality.

AbstractBackgroundPatient Safety Indicator (PSI)‐12, a hospital quality measure designed by Agency for Healthcare Research and Quality (AHRQ) to capture potentially preventable adverse events, captures perioperative venous thromboembolism (VTE). It is unclear how COVID‐19 has affected PSI‐12 performance.ObjectiveWe sought to compare the cumulative incidence of PSI‐12 in patients with and without acute COVID‐19 infection.Design, Setting, and ParticipantsThis was a retrospective cohort study including PSI‐12‐eligible events at three Mayo Clinic medical centers (4/1/2020‐10/5/2021).Exposure, Main Outcomes, and MeasuresWe compared the unadjusted rate and adjusted risk ratio (aRR) for PSI‐12 events among patients with and without COVID‐19 infection using Fisher's exact χ2 test and the AHRQ risk‐adjustment software, respectively. We summarized the clinical outcomes of COVID‐19 patients with a PSI‐12 event.ResultsOur cohort included 50,400 consecutive hospitalizations. Rates of PSI‐12 events were significantly higher among patients with acute COVID‐19 infection (8/257 [3.11%; 95% confidence interval {CI}, 1.35%–6.04%]) compared to patients without COVID‐19 (210/50,143 [0.42%; 95% CI, 0.36%–0.48%]) with a PSI‐12 event during the encounter (p < .001). The risk‐adjusted rate of PSI‐12 was significantly higher in patients with acute COVID‐19 infection (1.50% vs. 0.38%; aRR, 3.90; 95% CI, 2.12–7.17; p < .001). All COVID‐19 patients with PSI‐12 events had severe disease and 4 died. The most common procedure was tracheostomy (75%); the mean (SD) days from surgical procedure to VTE were 0.12 (7.32) days.ConclusionPatients with acute COVID‐19 infection are at higher risk for PSI‐12. The present definition of PSI‐12 does not account for COVID‐19. This may impact hospitals' quality performance if COVID‐19 infection is not accounted for by exclusion or risk adjustment.

Irritable bowel syndrome is a globally prevalent disorder categorized into constipation, diarrhea or mixed (IBS‐C, IBD‐D, IBS‐M) based on the predominant stool form/frequency. While the gut microbiome is recognized as an important factor underlying the pathophysiology of IBS, the specific mechanisms remain an area of active investigation. In our recent longitudinal multi‐omics study in IBS patients, we found bacteria‐derived hypoxanthine was significantly decreased in stool from IBS‐C patients. The aim of this study was to determine if IBS‐C relevant molecular pathways are affected by hypoxanthine. We hypothesized that hypoxanthine acts on enterochromaffin (EC) cells to stimulate serotonin (5‐HT) release, where 5‐HT is an important determinant of gastrointestinal (GI) transit time. We used Ca 2+ imaging in QGP cells (EC model), T84 cells (colonocyte model), primary cells and organoids from NeuroD1‐cre;GCaMP5‐tdTomato mice [NeuroD1 is a marker for enteroendocrine cells (EECs) which express calcium indicator GCaMP in these mice] in the absence or presence of receptor antagonists, and in ex vivo colon preparations with intact innervation from E2aCre:GCaMP6s mice (GCaMP is expressed in neuronal and non‐neuronal cells), to test the effect of hypoxanthine. The physiologic relevance of hypoxanthine signaling was assessed by measuring whole gut transit time. We found hypoxanthine increased Ca 2+ influx in QGP cells [using Cal520 (qualitative) and Fura‐2AM (quantitative)], primary EECs and EECs within organoids (previous research showed that the majority of these EECs are EC cells), but not in T84 cells. Hypoxanthine‐evoked Ca 2+ response was absent in Ca 2+ ‐free medium (n=6‐8, t‐test, P <0.0001), inhibited by G αi/o ‐GPCR antagonist (pertussis toxin; n=8‐14, t‐test, P <0.01)), Transient Receptor Potential Cation Channel Subfamily C Member 4 (TRPC4) antagonist (ML204; n=14‐15, t‐test, P <0.0001) and TRPC4 siRNA (n=5‐21, t‐test, P <0.01), and was accompanied by increased 5‐HT release (measured using 5‐HT biosensor). In ex vivo experiments, luminal application of hypoxanthine activated a subset of epithelial cells (likely EC cells) followed by subsets of neurons (latency to response onset, n=4, Mann‐Whitney, P <0.0001), as well as movement of the imaging field, which indicates smooth muscle contraction/relaxation. Our in vitro findings were confirmed by in vivo experiments showing that germ‐free mice colonized with hypoxanthine‐producing bacteria had faster whole gut transit and higher stool 5‐HT level compared to hypoxanthine‐consuming bacteria (n=7‐8, t‐test, P <0.05). In summary, hypoxanthine increases Ca 2+ influx specifically in EC cells by activating a signaling cascade involving a G αi/o ‐GPCR and TRPC4 channels, which results in 5‐HT release. The delay in activation of myenteric neurons and motor activity suggests that EC cell 5‐HT release likely induces neurogenic motor patterns and may underlie the shorter GI transit time seen with increased bacterial hypoxanthine production. While the current empirically designed probiotics have proven ineffective in IBS, our findings will allow development of novel mechanism‐based probiotic therapies for IBS‐C using hypoxanthine‐producing bacteria.

Introduction Rheumatoid arthritis (RA) affects approximately 0.5%–1% of the general population. Clinically significant interstitial lung diseases (ILD) develops in just under 10% of people with RA, and subclinical disease is more common. Little is known about RA-ILD in New Zealand (NZ), or the number of persons with RA in Canterbury, NZ. This study aims to determine: (1) incidence and prevalence of RA, (2) incidence and prevalence of RA-ILD, (3) clinical characteristics and risk factors for the development of RA-ILD, (4) long-term outcomes of RA-ILD, in the population resident within the Canterbury District Health Board (CDHB) catchment area. Methods and analysis Persons aged 18 years of age and older, and resident in the region covered by the CDHB with RA as well as RA-ILD will be identified by retrospective review of medical records. Prevalent as well as incident cases of RA between 1 January 2006 and 31 December 2008 and between 1 January 2011 and 31 December 2013 will be identified, and followed until 30 June 2019. Existing as well as incident cases of RA-ILD during this time will be identified. The association between the development of ILD and clinical characteristics and environmental exposures will be examined using Cox-proportional hazard models. Kaplan-Meier methods will be used to estimate survival rates for patients with RA-ILD. Mortality for people with RA and RA-ILD will also be compared with the general population of the CDHB. Ethics and dissemination Data will be obtained by retrospective review of medical records. Deidentified patient data will be stored in a secure online database. Data on individual patients will not be released, and all results will only be published in aggregate. Ethical approval has been obtained from the University of Otago Human Research Ethics Committee (REF HD18/079). Results will be published in peer-reviewed medical journals and presented at conferences. Trial registration number ACTRN12619001310156; Pre-results.

Cardiovascular (CV) disease (CVD) is the major health burden and cause of death for women. Marked disparities exist in CVD diagnosis, prevention, and treatment between women and men – as well as lack of female-specific data. Population, physiologic, translational, and clinical trial studies of sex and gender differences in CVD [[Unable to Display Character: &#8211;]] even when only women are studied[[Unable to Display Character: &#8211;]] often do not collect relevant data specific to women that could inform study outcomes. The ISIS CVD Network of the Society for Women’s Health Research compiled an inventory of items specific for women across the lifespan, together with references for methods and strategies to gather and evaluate this information; some items comprise robust measures, others are in development. The objective is to enhance usefulness of CVD research data in understanding sex and gender differences, thereby optimizing healthcare delivery and outcomes for women. Included are hormonal variables (menstrual cycle phase, hormone levels) oral contraceptive use, pregnancy history/complications, polycystic ovary syndrome (PCOS) components, measures of menopause, and menopausal hormone therapy, variables generally not collected in research studies, but essential to determine their role as sex-specific contributors to CV health and disease. Clear associations exist between reproductive health and CV health and disease. For example 25-33% of women experience complications of pregnancy that may precede and predispose to CVD. Vascular complications during pregnancy, antecedent risk factors and subsequent clinical CVD can be ascertained using medical records, birth registries, and/or maternal recall. Evaluating compilations of patient data with known hormonal or menopausal status using reference standards and patient data for PCOS could inform relationships to subsequent CV outcomes. Variables predominant among women that preferentially disadvantage them should be considered; e.g. psychosocial issues and elderly age. Depressive disorders are twice as common among women as men. They adversely affect CVD outcomes in women, yet the effect of reproductive life cycle and of hormonal fluctuations on depression and etiologic contributions of depression to CVD are inadequately explored. In addition to traditional CVD risk factors, diabetes mellitus, chronic inflammatory disorders, oxidative stress, vasomotor dysfunction, coronary microvascular disorders, and other novel risk variables that preferentially impact women should be explored. Along with increased enrollment of women in CVD research studies and analysis of clinical and genetic studies by sex, improvements and expansion of study design must include these understudied uniquely or predominantly female characteristics. This will enhance the quality and quantity of evidence-based medicine to guide CVD care in women and men thereby setting the stage for personalized approach to medicine.