Clinical profile of patients presenting with heart failure with preserved ejection fraction

Background: Evaluate the clinical profile of patients presenting with heart failure having normal or preserved ejection fraction and to determine the prevalence of comorbid illnesses in these patients.Methods: The study was carried out on patients that presented with heart failure at the Vadilal Sarabhai hospital, Ahmedabad between September 2014-2016. Heart failure patients with normal ejection fraction (>50%) were selected. Socio-demographic, vital signs, data of 2D Echocardiography and Tissue Doppler study were collected. The patients were classified as per the Echocardiographic study into four categories. Different laboratory parameters were compared in patients with respect to (a) grade of Hypertension (b), grade of anemia (c), HbA1c levels. Statistical analysis was done using the SPSS software v20. Mann-Whitney and Kruskal-Wallis tests were performed to compare the means between different study groups.Results: Out of the 70 patients, a majority (47%) belonged to the Grade 2 (pseudo-normalized) group of diastolic dysfunctions with most of them having only dyspnea and pedal edema (33%). 58.6% patients required intensive care for at least one day. Regarding co-morbidities 27 (38.6%) had hypertension, 34 (48.6%) were diabetic and 49(70%) had anemia. Patients with higher grade of dysfunction had higher HbA1c (p=0.023) and worsening anemia (p=0.003).Conclusions: Authors concluded that it is of prime importance to find, prevent and treat the comorbidities along with targeted therapies for HFpEF. Further evaluation can be done for clinical applicability of different markers including HbA1c and U.ACR for renal dysfunction in HFpEF

Development and Validation of a Clinical Scoring System to Differentiate Patients with Inflammatory Bowel Disease and Diarrhea-Predominant Irritable Bowel Disease

Background: There is no validated scoring system for differentiating inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS). Studies variably report clinical measures such as radiology, endoscopy, inflammatory markers, and symptoms to separate IBS from IBD. Our study seeks to create a system to IBD patients from IBS. The “REBISS” score incorporates various clinical criteria used commonly for diagnosis. We also studied a second system called “REBISS-PCP” focusing on a subset of criteria that are available to PCPs when faced with this challenge. Methods: This study was approved by the UMass IRB. Two cohorts were identified: 24 IBD patients (Group1) and 24 IBS patients (Group2). Subjects in Group1 were patients with Crohn’s or ulcerative colitis. Subjects in Group2 were identified as having IBS based on ROME III criteria. Retrospective analysis was performed and a score was calculated. One point is assigned for having: radiological findings consistent with IBD, endoscopic findings of inflammation or ulceration, biopsy findings consistent with IBD, elevated inflammatory markers, weight loss, hematochezia, extra-intestinal signs/symptoms, palpable mass on exam, and perianal disease. The maximum score is 10 points. For the REBISS-PCP score, the same clinical criteria were studied with the exclusion of endoscopic and biopsy findings. Maximum score for that system is 8 points. A likelihood ratio chi-square test was performed for both cohorts and scoring systems. Results: The REBISS scoring system showed a significant differentiation of the two cohorts in regards to scoring distribution (chi-square value = 59.8; p\u3c0.0001). The REBISS-PCP scoring system also found a significant differentiation of the two cohorts (chi-square value = 35.7;p\u3c 0.0001). Discussion: The REBISS scoring system could be used to standardize IBD and IBSd populations in an academic research setting, while both the REBISS and REBISS-PCP scoring system could be used as a screening tool in clinical practice

Jet Breaks in Short Gamma-Ray Bursts. I: The Uncollimated Afterglow of GRB 050724

We report the results of the \chandra observations of the \swift-discovered short Gamma-Ray Burst GRB 050724. \chandra observed this burst twice, about two days after the burst and a second time three weeks later. The first \chandra pointing occurred at the end of a strong late-time flare. About 150 photons were detected during this 49.3 ks observation in the 0.4-10.0 keV range. The spectral fit is in good agreement with spectral analysis of earlier \swift XRT data. In the second \chandra pointing the afterglow was clearly detected with 8 background-subtracted photons in 44.6 ks. From the combined \swift XRT and \chandra-ACIS-S light curve we find significant flaring superposed on an underlying power-law decay slope of $\alpha$=0.98$^{+0.11}_{-0.09}$. There is no evidence for a break between about 1 ks after the burst and the last \chandra pointing about three weeks after the burst. The non-detection of a jet break places a lower limit of 25$^{\circ}$ on the jet opening angle, indicating that the outflow is less strongly collimated than most previously-reported long GRBs. This implies that the beaming corrected energy of GRB 050724 is at least $4\times 10^{49}$ ergs.Comment: 7 pages, ApJ acceped, scheduled for December 20, 2006, ApJ, 65

Assessing the Safety of Stem Cell Therapeutics

Unprecedented developments in stem cell research herald a new era of hope and expectation for novel therapies. However, they also present a major challenge for regulators since safety assessment criteria, designed for conventional agents, are largely inappropriate for cell-based therapies. This article aims to set out the safety issues pertaining to novel stem cell-derived treatments, to identify knowledge gaps that require further research, and to suggest a roadmap for developing safety assessment criteria. It is essential that regulators, pharmaceutical providers, and safety scientists work together to frame new safety guidelines, based on “acceptable risk,” so that patients are adequately protected but the safety “bar” is not set so high that exciting new treatments are lost

Reverse Myocardial Remodeling Following Valve Repair in Patients With Chronic Severe Primary Degenerative Mitral Regurgitation

OBJECTIVES: The aims of this study were to quantify preoperative myocardial fibrosis using late gadolinium enhancement (LGE), extracellular volume fraction (ECV%), and indexed extracellular volume (iECV) on cardiac magnetic resonance; determine whether this varies following surgery; and examine the impact on postoperative outcomes. BACKGROUND: Myocardial fibrosis complicates chronic severe primary mitral regurgitation and is associated with left ventricular dilatation and dysfunction. It is not known if this nonischemic fibrosis is reversible following surgery or if it affects ventricular remodeling and patient outcomes. METHODS: A multicenter prospective study was conducted among 104 subjects with primary mitral regurgitation undergoing mitral valve repair. Cardiac magnetic resonance and cardiopulmonary exercise stress testing were performed preoperatively and ≥6 months after surgery. Symptoms were assessed using the Minnesota Living With Heart Failure Questionnaire. RESULTS: Mitral valve repair was performed for Class 2a indications in 65 patients and Class 1 indications in 39 patients. Ninety-three patients were followed up at 8.8 months (interquartile range: 7.4 months-10.6 months). Following surgery, there were significant reductions in both ECV% (from 27.4% to 26.6%; P = 0.027) and iECV (from 17.9 to 15.4 mL/m2; P < 0.001), but the incidence of LGE was unchanged. Neither preoperative ECV% nor LGE affected postoperative function, but iECV predicted left ventricular end-systolic volume index (β = 1.04; 95% CI: 0.49 to 1.58; P < 0.001) and left ventricular ejection fraction (β = -0.61; 95% CI: -1.05 to -0.18; P = 0.006). Patients with above-median iECV of ≥17.6 mL/m2 had significantly larger postoperative values of left ventricular end-systolic volume index (30.5 ± 12.7 mL/m2 vs 23.9 ± 8.0 mL/m2; P = 0.003), an association that remained significant in subcohort analyses of patients in New York Heart Association functional class I. CONCLUSIONS: Mitral valve surgery results in reductions in ECV% and iECV, which are surrogates of diffuse myocardial fibrosis, and preoperative iECV predicts the degree of postoperative remodeling irrespective of symptoms. (The Role of Myocardial Fibrosis in Degenerative Mitral Regurgitation; NCT02355418)

Restoring tumour selectivity of the bioreductive prodrug pr-104 by developing an analogue resistant to aerobic metabolism by human aldo-keto reductase 1c3

PR-104 is a phosphate ester pre-prodrug that is converted in vivo to its cognate alcohol, PR-104A, a latent alkylator which forms potent cytotoxins upon bioreduction. Hypoxia selectivity results from one-electron nitro reduction of PR-104A, in which cytochrome P450 oxidoreductase (POR) plays an important role. However, PR-104A also undergoes ‘off-target’ two-electron reduction by human aldo-keto reductase 1C3 (AKR1C3), resulting in activation in oxygenated tissues. AKR1C3 expression in human myeloid progenitor cells probably accounts for the dose-limiting myelotoxicity of PR-104 documented in clinical trials, resulting in human PR-104A plasma exposure levels 3.4- to 9.6-fold lower than can be achieved in murine models. Structure-based design to eliminate AKR1C3 activation thus represents a strategy for restoring the therapeutic window of this class of agent in humans. Here, we identified SN29176, a PR-104A analogue resistant to human AKR1C3 activation. SN29176 retains hypoxia selectivity in vitro with aerobic/hypoxic IC(50) ratios of 9 to 145, remains a substrate for POR and triggers γH2AX induction and cell cycle arrest in a comparable manner to PR-104A. SN35141, the soluble phosphate pre-prodrug of SN29176, exhibited superior hypoxic tumour log cell kill (>4.0) to PR-104 (2.5–3.7) in vivo at doses predicted to be achievable in humans. Orthologues of human AKR1C3 from mouse, rat and dog were incapable of reducing PR-104A, thus identifying an underlying cause for the discrepancy in PR-104 tolerance in pre-clinical models versus humans. In contrast, the macaque AKR1C3 gene orthologue was able to metabolise PR-104A, indicating that this species may be suitable for evaluating the toxicokinetics of PR-104 analogues for clinical development. We confirmed that SN29176 was not a substrate for AKR1C3 orthologues across all four pre-clinical species, demonstrating that this prodrug analogue class is suitable for further development. Based on these findings, a prodrug candidate was subsequently identified for clinical trials

Myocardial fibrosis in asymptomatic and symptomatic chronic severe primary mitral regurgitation and relationship to tissue characterisation and left ventricular function on cardiovascular magnetic resonance

Background: Myocardial fbrosis occurs in end-stage heart failure secondary to mitral regurgitation (MR), but it is not known whether this is present before onset of symptoms or myocardial dysfunction. This study aimed to characterise myocardial fbrosis in chronic severe primary MR on histology, compare this to tissue characterisation on cardiovascular magnetic resonance (CMR) imaging, and investigate associations with symptoms, left ventricular (LV) function, and exercise capacity. Methods: Patients with class I or IIa indications for surgery underwent CMR and cardiopulmonary exercise testing. LV biopsies were taken at surgery and the extent of fbrosis was quantifed on histology using collagen volume fraction (CVFmean) compared to autopsy controls without cardiac pathology. Results: 120 consecutive patients (64±13 years; 71% male) were recruited; 105 patients underwent MV repair while 15 chose conservative management. LV biopsies were obtained in 86 patients (234 biopsy samples in total). MR patients had more fbrosis compared to 8 autopsy controls (median: 14.6% [interquartile range 7.4–20.3] vs. 3.3% [2.6–6.1], P<0.001); this diference persisted in the asymptomatic patients (CVFmean 13.6% [6.3–18.8], P<0.001), but severity of fbrosis was not signifcantly higher in NYHA II-III symptomatic MR (CVFmean 15.7% [9.9–23.1] (P=0.083). Fibrosis was patchy across biopsy sites (intraclass correlation 0.23, 95% CI 0.08–0.39, P=0.001). No signifcant relationships were identifed between CVFmean and CMR tissue characterisation [native T1, extracellular volume (ECV) or late gadolinium enhancement] or measures of LV function [LV ejection fraction (LVEF), global longitudinal strain (GLS)]. Although the range of ECV was small (27.3±3.2%), ECV correlated with multiple measures of LV function (LVEF: Rho=−0.22, P=0.029, GLS: Rho=0.29, P=0.003), as well as NTproBNP (Rho=0.54, P<0.001) and exercise capacity (%PredVO2max: R=−0.22, P=0.030). Conclusions: Patients with chronic primary MR have increased fbrosis before the onset of symptoms. Due to the patchy nature of fbrosis, CMR derived ECV may be a better marker of global myocardial status. Clinical trial registration Mitral FINDER study; Clinical Trials NCT02355418, Registered 4 February 2015, https://clinicaltr ials.gov/ct2/show/NCT0235541

Comparative assessment of multiple COVID-19 serological technologies supports continued evaluation of point-of-care lateral flow assays in hospital and community healthcare settings

There is a clear requirement for an accurate SARS-CoV-2 antibody test, both as a complement to existing diagnostic capabilities and for determining community seroprevalence. We therefore evaluated the performance of a variety of antibody testing technologies and their potential use as diagnostic tools. Highly specific in-house ELISAs were developed for the detection of anti-spike (S), -receptor binding domain (RBD) and -nucleocapsid (N) antibodies and used for the cross-comparison of ten commercial serological assays-a chemiluminescence-based platform, two ELISAs and seven colloidal gold lateral flow immunoassays (LFIAs)-on an identical panel of 110 SARS-CoV-2-positive samples and 50 pre-pandemic negatives. There was a wide variation in the performance of the different platforms, with specificity ranging from 82% to 100%, and overall sensitivity from 60.9% to 87.3%. However, the head-to-head comparison of multiple sero-diagnostic assays on identical sample sets revealed that performance is highly dependent on the time of sampling, with sensitivities of over 95% seen in several tests when assessing samples from more than 20 days post onset of symptoms. Furthermore, these analyses identified clear outlying samples that were negative in all tests, but were later shown to be from individuals with mildest disease presentation. Rigorous comparison of antibody testing platforms will inform the deployment of point-of-care technologies in healthcare settings and their use in the monitoring of SARS-CoV-2 infections

The metabolic enzyme hexokinase 2 localizes to the nucleus in AML and normal haematopoietic stem and progenitor cells to maintain stemness

Thomas, Egan et al. report that hexokinase 2 localizes to the nucleus of leukaemic and normal haematopoietic cells to maintain stemness by interacting with nuclear proteins and modulating chromatin accessibility independently of its kinase activity. Mitochondrial metabolites regulate leukaemic and normal stem cells by affecting epigenetic marks. How mitochondrial enzymes localize to the nucleus to control stem cell function is less understood. We discovered that the mitochondrial metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus in leukaemic and normal haematopoietic stem cells. Overexpression of nuclear HK2 increases leukaemic stem cell properties and decreases differentiation, whereas selective nuclear HK2 knockdown promotes differentiation and decreases stem cell function. Nuclear HK2 localization is phosphorylation-dependent, requires active import and export, and regulates differentiation independently of its enzymatic activity. HK2 interacts with nuclear proteins regulating chromatin openness, increasing chromatin accessibilities at leukaemic stem cell-positive signature and DNA-repair sites. Nuclear HK2 overexpression decreases double-strand breaks and confers chemoresistance, which may contribute to the mechanism by which leukaemic stem cells resist DNA-damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes influence stem cell function independently of their metabolic function