Search

AIMS CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

Functional bowel disorders refer to disorders of gut-brain interaction that affect the intestinal tract. Irritable bowel syndrome (IBS) is the most common functional bowel disorder and affects individuals regardless of age and gender. It can result in impaired quality of life and significant health care utilization and is therefore important to recognize and manage. The diagnosis of IBS is based on clinical symptoms. IBS is categorized based on predominant bowel habit (constipation, diarrhea, mixed, or unclassified), and the treatment of IBS is individually tailored based on subtype and symptom severity.

Background Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marr...

[Figure][1] Coronavirus disease 2019 (COVID-19) has had a profound effect on our health care system. In primary care, it has stymied the delivery of the preventive and routine services that keep people healthy and out of the hospital. This is no less true of reproductive health care, as

Purpose Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted. Methods We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record. Results Notably, 32% of patients had a genetic finding with clinical management implications, even after excluding PGx results, including 9% who were molecularly diagnosed with a Mendelian condition. Among surveyed physicians, 84% reported medical management changes based on these results, including specialist referrals, cardiac tests, and medication changes. LPA polymorphisms and high polygenic risk of CAD were found in 20% and 9% of patients, respectively, leading to diet, lifestyle, and other changes. Warfarin and simvastatin pharmacogenetic variants were present in roughly half of the cohort. Conclusion Our results support the use of genetic information in routine cardiovascular health management and provide a roadmap for accompanying research.

Rationale: Autologous bone marrow mesenchymal stem cells (MSCs) and c-kit + cardiac progenitor cells (CPCs) are 2 promising cell types being evaluated for patients with heart failure (HF) secondary to ischemic cardiomyopathy. No information is available in humans about the relative efficacy of MSCs and CPCs and whether their combination is more efficacious than either cell type alone. Objective: CONCERT-HF (Combination of Mesenchymal and c-kit + Cardiac Stem Cells As Regenerative Therapy for Heart Failure) is a phase II trial aimed at elucidating these issues by assessing the feasibility, safety, and efficacy of transendocardial administration of autologous MSCs and CPCs, alone and in combination, in patients with HF caused by chronic ischemic cardiomyopathy (coronary artery disease and old myocardial infarction). Methods and Results: Using a randomized, double-blinded, placebo-controlled, multicenter, multitreatment, and adaptive design, CONCERT-HF examines whether administration of MSCs alone, CPCs alone, or MSCs+CPCs in this population alleviates left ventricular remodeling and dysfunction, reduces scar size, improves quality of life, or augments functional capacity. The 4-arm design enables comparisons of MSCs alone with CPCs alone and with their combination. CONCERT-HF consists of 162 patients, 18 in a safety lead-in phase (stage 1) and 144 in the main trial (stage 2). Stage 1 is complete, and stage 2 is currently randomizing patients from 7 centers across the United States. Conclusions: CONCERT-HF will provide important insights into the potential therapeutic utility of MSCs and CPCs, given alone and in combination, for patients with HF secondary to ischemic cardiomyopathy. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02501811.

Objectives SENECA ( S t E m cell i N j EC tion in c A ncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC). Background AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium. Methods The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP). Conclusions This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome.

Background: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute–sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. Methods: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. Results: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] −0.6 to 2.5; P =0.238), collateral count (0.9±0.6 arteries; 95% CI, −0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, −0.8 to 0.8; P =0.978), and capillary perfusion (−0.2±0.6%; 95% CI, −1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1–2.9; P =0.047) in participants with completely occluded femoral arteries. Conclusions: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01774097.

Autologous bone marrow mononuclear cell (BM-MNC) therapy for patients with ST-segment elevation myocardial infarction (STEMI) has produced inconsistent results, possibly due to BM-MNC product heterogeneity. Patient-specific cardiovascular risk factors (CRFs) may contribute to variations in BM-MNC composition. We sought to identify associations between BM-MNC subset frequencies and specific CRFs in STEMI patients. Bone marrow was collected from 191 STEMI patients enrolled in the CCTRN TIME and LateTIME trials. Relationships between BM-MNC subsets and CRFs were determined with multivariate analyses. An assessment of CRFs showed that hyperlipidemia and hypertension were associated with a higher frequency of CD11b+ cells (P = 0.045 and P = 0.016, respectively). In addition, we found that females had lower frequencies of CD11b+ (P = 0.018) and CD45+CD14+ (P = 0.028) cells than males, age was inversely associated with the frequency of CD45+CD31+ cells (P = 0.001), smoking was associated with a decreased frequency of CD45+CD31+ cells (P = 0.013), glucose level was positively associated with the frequency of CD45+CD3+ cells, and creatinine level (an indicator of renal function) was inversely associated with the frequency of CD45+CD3+ cells (P = 0.015). In conclusion, the frequencies of monocytic, lymphocytic, and angiogenic BM-MNCs varied in relation to patients’ CRFs. These phenotypic variations may affect cell therapy outcomes and might be an important consideration when selecting patients for and reviewing results from autologous cell therapy trials.

Objective: Results from several randomized, controlled cell therapy trials suggest that the use of autologous bone marrow mononuclear cells (BMMNCs) results in only modest benefits in patients with ST-segment elevation myocardial infarction (STEMI). However, the patients in these trials had varying combinations of underlying cardiovascular risk factors (CVRFs) and comorbidities. The autologous BMMNC product administered to each patient was unique. Based on our previous findings, the purpose of this study was to identify potential associations between specific CVRFs and BMMNC subsets in patients with STEMI. Methods: This study evaluated a cohort of patients with STEMI who were enrolled in either the CCTRN TIME or LateTIME trials and underwent BMMNC or placebo treatment (N=139). Flow cytometric analysis targeting phenotypic markers (eg, CD45, CD14, CD11b, CD3, CD19, CD31, and CD34) was used to assess the frequency of BMMNC subsets at baseline. The GRACE ACS Risk Score 2.0 - 3 year death (GRS) was used to stratify patients according to cardiovascular risk (low: GRS 30%). Multivariable models were then applied to assess relationships between BMMNC subsets and CVRFs, including age, smoking, hypertension, hyperlipidemia, and sex. Results: Patients were grouped as low GRS (n=69, 49.6%), moderate GRS (n=49, 35.3%), and high GRS (n=21, 15.1%). Patients with a high GRS had significantly lower frequencies of CD45+CD31+ cells than those with a low GRS (35.6% vs 40.3%, respectively, P=0.041). In multivariable analyses, age was inversely associated with the frequencies of CD34+ (P=0.011) and CD45+CD31+ (P=0.001) cells, and smoking was associated with a decrease in CD45+CD31+ cells (P=0.022). In addition, higher frequencies of CD11b+ cells were associated with hypertension (P=0.010) and hyperlipidemia (P=0.029). In contrast, the CD11b+ cell frequency was less in females (P=0.005). Conclusions: This study identified associations between specific CVRFs and BMMNC subsets. These associations may contribute to the heterogeneity of the cell product received. Thus, differences in patients’ comorbidities should be considered when designing future autologous cell therapy trials.

Sporadic duodenal adenomas are uncommon. Prior studies show that patients with sporadic duodenal adenoma have increased risk of colorectal neoplasia and should undergo colorectal screening. However, the nature of the risk, location, and type of colorectal neoplasia are not well studied. We aimed to identify the risk of colorectal neoplasia in patients who have duodenal adenomas. A retrospective case–control study was conducted to identify sporadic duodenal adenoma patients using the databases at one academic center. Colonoscopic findings including histology and location of colorectal cancer neoplasia in sporadic duodenal adenoma patients were compared with a control group of patients without duodenal adenomas who underwent both gastroduodenoscopy and colonoscopy. Hundred and two patients with sporadic duodenal adenomas or adenocarcinomas were identified. Colonoscopy was performed in 47 patients (46 %), and colorectal neoplasia was present in 22 (46 %). There was a significantly higher rate of colorectal neoplasia in patients with sporadic duodenal adenoma (43 %) compared to the control group (24 %) odds ratio 4.8, 95 % confidence interval (1.7–7.4), but not for advanced colorectal adenoma (9 vs. 26 %, p = 0.17). Case patients had significantly more right-sided lesions than matched controls (p = 0.02). Single-center, retrospective study. Individuals with sporadic duodenal adenomas have a significantly higher risk of colorectal neoplasia and proximal location of neoplasia. Therefore, these patients should undergo colonoscopy with particular attention to the right colon.

Errorless learning (EL) procedures have been shown to be effective in teaching new information and new procedures to individuals with severe memory impairment. The published studies have been based on comparatively short-term interventions delivered to individuals with relatively circumscribed impairments. In this single case study, we explore the usefulness of errorless learning procedures used for seven years with an adult with profound and complicated memory and executive function impairments associated with three distinct aetiologies. In primary functional areas targeted by the intervention, outcome was documented by behavioural descriptions and a frequency rating scale. Caregiver burden was documented with qualitative descriptors. A financial cost-benefit analysis is also provided. In the absence of change in underlying neuropsychological impairments, DI's everyday functioning in critical areas improved substantially, with corresponding reduction in supports and improved quality of life. Caregiver burden was reduced to acceptable levels and cost-benefit analysis demonstrates substantial ongoing cost savings.

The anti-inflammatory agent, mesalamine (5-aminosalicylic acid) has been shown to decrease mucosal inflammation in ulcerative colitis. The effect of mesalamine in HIV-infected individuals, who exhibit abnormal mucosal immune activation and microbial translocation (MT), has not been established in a placebo-controlled trial. We randomized 33 HIV-infected subjects with CD4 counts

A 71-year-old woman with end-stage renal disease on hemodialysis, hypertension, diabetes, coronary artery disease, and ischemic cardiomyopathy, on hydralazine 300 mg daily for 2 years, presented with a new onset of vesiculobullous rash, dysphagia, odynophagia, throat pain/tightness, and hoarseness. Physical exam showed multiple vesicles in her upper and lower extremities with significant airway edema and ulcerations of floor of mouth, tongue, epiglottis, aryepiglottic folds, and arytenoid edema. On admission day 3, she had an episode of gastrointestinal bleeding. Upper endoscopy and capsule endoscopy found petechiae and melanosis in the proximal small bowel, including most of duodenum and proximal jejunum (Figure 1). Pathology revealed necrotizing neutrophil-rich venulitis and pseudomelanosis.