A global perspective on bacterial diversity in the terrestrial deep subsurface.

While recent efforts to catalogue Earth's microbial diversity have focused upon surface and marine habitats, 12-20 % of Earth's biomass is suggested to exist in the terrestrial deep subsurface, compared to ~1.8 % in the deep subseafloor. Metagenomic studies of the terrestrial deep subsurface have yielded a trove of divergent and functionally important microbiomes from a range of localities. However, a wider perspective of microbial diversity and its relationship to environmental conditions within the terrestrial deep subsurface is still required. Our meta-analysis reveals that terrestrial deep subsurface microbiota are dominated by Betaproteobacteria, Gammaproteobacteria and Firmicutes, probably as a function of the diverse metabolic strategies of these taxa. Evidence was also found for a common small consortium of prevalent Betaproteobacteria and Gammaproteobacteria operational taxonomic units across the localities. This implies a core terrestrial deep subsurface community, irrespective of aquifer lithology, depth and other variables, that may play an important role in colonizing and sustaining microbial habitats in the deep terrestrial subsurface. An in silico contamination-aware approach to analysing this dataset underscores the importance of downstream methods for assuring that robust conclusions can be reached from deep subsurface-derived sequencing data. Understanding the global panorama of microbial diversity and ecological dynamics in the deep terrestrial subsurface provides a first step towards understanding the role of microbes in global subsurface element and nutrient cycling.

"Triple-low" radiation dose bronchial artery CT angiography before bronchial artery embolisation: a feasibility study.

AIM: To explore the feasibility of a "triple-low" dose (low tube voltage, low tube current, and low contrast agent volume) bronchial artery computed tomography (CT) angiography (CTA) to replace routine dose bronchial artery CTA before bronchial artery embolisation (BAE). MATERIALS AND METHODS: CTA was obtained from 60 patients with body mass index (BMI) < 30 kg/m2 using a 256 multi-section iCT system, and they were divided into two groups: (1) group A: 100 kVp, 100 mAs, 50 ml contrast medium (CM); (2) group B: 120 kVp, automatic tube current modulation (ACTM), 80 ml CM. CT attenuation of the thoracic aorta, image noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated, and subjective image quality scores and traceability scores assessed. The effective radiation dose was calculated. RESULTS: The radiation dose was reduced by 79.7% in group A compared to group B (p<0.05). The CT attenuation of the thoracic aorta was increased by approximately 13% in group A compared to group B (p<0.05). Higher image noise, lower SNR, and CNR were obtained in group A compared to group B (all p<0.05). Both subjective image quality scores and traceability scores did not differ between groups A and B (both p>0.05). CONCLUSION: It is feasible to use the "triple-low" dose CTA protocol for patients with a body mass index (BMI) < 30 kg/m2. The radiation dose was reduced by 79.7%, and the dose of contrast medium was reduced by 37.5% to ensure the diagnostic value.

The use of ultrapure molecular hydrogen enriched with atomic hydrogen in apparatuses of artificial lung ventilation in the fight against virus COVID-19.

COVID-19 is a disease caused by the SARS-CoV virus. It stands for severe acute respiratory syndrome, which affects the lungs. The process of replication and progression of the COVID-19 virus causes the formation of an excessive amount of reactive oxygen species and inflammation. Many studies have been carried out that have demonstrated that hydrogen has strong anti-inflammatory properties. It reduces hypotension and other symptoms by reducing inflammation and oxidative stress. Oxygen mixture, enriched with Hydrogen, - helps to reduce the resistance of the respiratory tract and frees up access to the pulmonary alveolus, which improves the penetration of oxygen into the lungs. Since hydrogen is an antioxidant, it helps to reduce the burden on the immune system, helps to maintain the body's health and its ability to quickly recover. When electrolysers are used to produce an oxygen-hydrogen mixture, alkaline mist and other impurities can enter the patient's lungs and cause poisoning and chemical burns. For this reason, the use of atomic hydrogen obtained from metal hydride sources for ventilation of the lungs will be more effective for treating COVID-19 than a molecular hydrogen-oxygen mixture from an electrolyzer. A functional diagram of a metal hydride source of atomic hydrogen to an artificial lung ventilator is shown. It is possible to create a series of hydrogen storage tanks of various capacities.

The telomere bouquet is a hub where meiotic double-strand breaks, synapsis, and stable homolog juxtaposition are coordinated in the zebrafish, Danio rerio.

Meiosis is a cellular program that generates haploid gametes for sexual reproduction. While chromosome events that contribute to reducing ploidy (homologous chromosome pairing, synapsis, and recombination) are well conserved, their execution varies across species and even between sexes of the same species. The telomere bouquet is a conserved feature of meiosis that was first described nearly a century ago, yet its role is still debated. Here we took advantage of the prominent telomere bouquet in zebrafish, Danio rerio, and super-resolution microscopy to show that axis morphogenesis, synapsis, and the formation of double-strand breaks (DSBs) all take place within the immediate vicinity of telomeres. We established a coherent timeline of events and tested the dependence of each event on the formation of Spo11-induced DSBs. First, we found that the axis protein Sycp3 loads adjacent to telomeres and extends inward, suggesting a specific feature common to all telomeres seeds the development of the axis. Second, we found that newly formed axes near telomeres engage in presynaptic co-alignment by a mechanism that depends on DSBs, even when stable juxtaposition of homologous chromosomes at interstitial regions is not yet evident. Third, we were surprised to discover that ~30% of telomeres in early prophase I engage in associations between two or more chromosome ends and these interactions decrease in later stages. Finally, while pairing and synapsis were disrupted in both spo11 males and females, their reproductive phenotypes were starkly different; spo11 mutant males failed to produce sperm while females produced offspring with severe developmental defects. Our results support zebrafish as an important vertebrate model for meiosis with implications for differences in fertility and genetically derived birth defects in males and females.

Institutional Betrayal and Closeness Among Women Veteran Survivors of Military Sexual Trauma: Associations with Self-Directed Violence and Mental Health Symptoms.

Institutional betrayal is defined as harm caused by an institution to an individual in the context of trust and dependence. High institutional betrayal is associated with poorer health outcomes, and high levels of trust, dependence, or identification with the institution (institutional closeness) may exacerbate the negative effects of institutional betrayal. While military sexual trauma is prevalent among women Veterans and associated with high rates of institutional betrayal, studies of the impact of military sexual trauma-related institutional betrayal have been limited in size and scope and have not examined the potential role of institutional closeness. We conducted a secondary analysis of national survey data collected from women Veterans who screened positive for military sexual trauma (n = 229). Hierarchical logistic and linear regression were used to examine associations between predictor variables (institutional betrayal, institutional closeness, and their interaction) and outcomes of interest and adjusted for age, education, and military sexual assault history. Institutional betrayal was associated with increased odds of suicidal ideation and suicide attempt during or following military service, as well as more severe symptoms of depression and posttraumatic stress disorder (PTSD). Institutional betrayal was not associated with non-suicidal self-injury or lifetime substance misuse. Counter to hypotheses, institutional closeness did not moderate relationships between institutional betrayal and mental health symptoms or self-directed violence. Results underscore the necessity of preventing and addressing institutional betrayal among women Veterans who experience military sexual trauma.

Bimodal expression of potential drug target CLL-1 (CLEC12A) on CD34+ blasts of AML patients.

OBJECTIVES: This study aims to retrospectively assess C-lectin-like molecule 1 (CLL-1) bimodal expression on CD34+ blasts in acute myeloid leukemia (AML) patients (total N = 306) and explore potential CLL-1 bimodal associations with leukemia and patient-specific characteristics. METHODS: Flow cytometry assays were performed to assess the deeper immunophenotyping of CLL-1 bimodality. Cytogenetic analysis was performed to characterize the gene mutation on CLL-1-negative subpopulation of CLL-1 bimodal AML samples. RESULTS: The frequency of a bimodal pattern of CLL-1 expression of CD34+ blasts ranged from 8% to 65% in the different cohorts. Bimodal CLL-1 expression was most prevalent in patients with MDS-related AML (P = .011), ELN adverse risk (P = .002), NPM1 wild type (WT, P = .049), FLT3 WT (P = .035), and relatively low percentages of leukemia-associated immunophenotypes (P = .006). Additional immunophenotyping analysis revealed the CLL-1- subpopulation may consist of pre-B cells, immature myeloblasts, and hematopoietic stem cells. Furthermore, (pre)-leukemic mutations were detected in both CLL-1+ and CLL-1- subfractions of bimodal samples (N = 3). CONCLUSIONS: C-lectin-like molecule 1 bimodality occurs in about 25% of AML patients and the CLL-1- cell population still contains malignant cells, hence it may potentially limit the effectiveness of CLL-1-targeted therapies and warrant further investigation.

Texture analysis applied in T1 maps and extracellular volume obtained using cardiac MRI in the diagnosis of hypertrophic cardiomyopathy and hypertensive heart disease compared with normal controls.

AIM: To assess the potential of texture analysis (TA) applied in T1 maps and extracellular volume (ECV) obtained using cardiac magnetic resonance (CMR) in the diagnosis of hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) compared with normal controls (NC). Strain parameters were analysed to compare with final TA models. MATERIALS AND METHODS: This retrospective study included 66 HCM patients, 39 HHD patients, and 41 NC. Step-wise dimension reduction and feature selection were performed by reproducibility, machine learning, collinearity, and multivariable regression analysis to select the texture features that enable diagnosis of and differentiation between HCM and HHD. Strain parameters were calculated by short-axis and three long-axis cine sequences. RESULTS: Independent features in T1 maps and ECV analysis allowed for the differentiation between patients (HCM and HHD) and NC. Of the best-calculated model, the areas under the receiver operating curve (AUCs) were as follows: 0.969 for T1 map and 0.964 for ECV. To distinguish HCM from HHD, two independent features were screened out for both T1 and ECV maps. The AUCs were as follows: 0.793 for T1 map and 0.894 for ECV. Radial, circumferential, and longitudinal strain parameters could differentiate patients from NC, but only longitudinal strain parameters was significantly different between HCM and HHD. CONCLUSIONS: Texture analysis of T1 maps and ECV shows high accuracy in differentiating hypertrophic myocardium from NC, and HCM from HHD. Strain parameters are able to demonstrate the difference between patients and NC, but were less impressive in differentiating HCM and HHD.

Shaky scaffolding: Age differences in cerebellar activation revealed through activation likelihood estimation meta-analysis.

Cognitive neuroscience research has provided foundational insights into aging, but has focused primarily on the cerebral cortex. However, the cerebellum is subject to the effects of aging. Given the importance of this structure in the performance of motor and cognitive tasks, cerebellar differences stand to provide critical insights into age differences in behavior. However, our understanding of cerebellar functional activation in aging is limited. Thus, we completed a meta-analysis of neuroimaging studies across task domains. Unlike in the cortex where an increase in bilateral activation is seen during cognitive task performance with advanced age, there is less overlap in cerebellar activation across tasks in older adults (OAs) relative to young. Conversely, we see an increase in activation overlap in OAs during motor tasks. We propose that this is due to inputs for comparator processing in the context of control theory (cortical and spinal) that may be differentially impacted in aging. These findings advance our understanding of the aging mind and brain.

Biventricular tissue tracking demonstrating associations between left ventricular myocardial extracellular volume, pulmonary artery pressure, and reduced right ventricular ejection fraction in patients with systemic lupus erythematosus using cardiovascular MRI.

AIM: To investigate the feasibility and prognostic value of biventricular strain analysis for patients with systemic lupus erythematosus (SLE) and relationship to left ventricular (LV) myocardial fibrosis, pulmonary hypertension (PAH), and right ventricular (RV) ejection fraction (RVEF). MATERIALS AND METHODS: A total of 50 SLE patients (47 women; 34.4±12 years) and 15 controls (13 women; 32.9±8.6 years) were imaged via echocardiography and a 3 T magnetic resonance imaging (MRI). Pulmonary artery systolic pressure (sPAP) was assessed using echocardiography. Biventricular global circumferential strain (GCS), global longitudinal strain (GLS), global circumferential strain rate (GCSR), and global longitudinal strain rate (GLSR) as well as LV myocardial extracellular volume (ECV) were derived for each subject. RESULTS: Elevated LV ECV was significantly associated with LV GCS (beta -0.428, p=0.000), GLS (beta 0.404, p=0.000), GCSR (beta -0.350, p=0.006), GLSR (beta -0.445, p=0.000) and RV GCS (beta -0.373, p=0.000), and the presence of reduced RVEF was significantly associated with LV GCS (beta -0.338, p=0.002), GLS (beta -0.465, p=0.000) and RV GCS (beta -0.465, p=0.000). Raised sPAP was significantly associated with RV GLS (beta 0.445, p=0.000) and GCSR (beta -0.387, p=0.001). Moreover, there were significantly correlations between LV and RV strain and strain rate. CONCLUSIONS: Biventricular strain analysis may be a better prognostic tool for patients with SLE as it allows greater comprehensive analysis and more definitive treatment planning compared to separate assessment of LV or RV contractility.

Complete genome sequence and genetic organization of a Garlic virus D infecting garlic (Allium sativum) from northern India.

The present paper describes first full genome sequence of the Garlic virus D (GarV-D) from northern India with a genome size of 8425 bp long ssRNA. The infected leaves and bulbs of garlic variety Yamuna Safed (G-282) plants suspected for GarV-D infection were collected with the aim to identify contagion virus during March, 2018. The total RNA was extracted from the pooled garlic plants using TRIzol reagent and sequenced using an Illumina HiSeq 2000 platform. BLASTn search in the NCBI database identified contagion as GarV-D (MK518067). It shared 83.63-85.83% nucleotide sequence identities with other (GarV-D) isolates from Argentina (KF550407, KF555653, KR819505) and 83.15% with isolates from China (MF795136, MF363012). Keywords: Allium sativum; Allexivirus; Garlic virus D; India.

Cortical thinning in epilepsy patients with postictal generalized electroencephalography suppression.

BACKGROUND AND PURPOSE: The aim was to investigate the brain microstructural abnormalities in epilepsy patients with postictal generalized electroencephalographic suppression (PGES) using a cortical surface-based analysis. METHODS: According to the video-electroencephalography records of epilepsy patients with generalized convulsive seizures, 30 patients with PGES (PGES+) and 21 patients without PGES (PGES-) were recruited. High-resolution T1-weighted images were acquired from each patient and 30 matched healthy control subjects. Cortical thickness was compared amongst the three groups using FreeSurfer software. RESULTS: Patients with PGES showed reduced cortical thickness in the right paracentral lobule, inferior parietal lobule, supramarginal gyrus and middle temporal lobe compared with patients without PGES. In relation to healthy control subjects, the PGES+ group presented reduced cortical thickness in the right superior parietal lobule and supramarginal gyrus, whilst the PGES- group presented reduced cortical thickness in the left precuneus, precentral gyrus, lateral occipital gyrus, parahippocampal gyrus, superior parietal lobule and right caudal middle frontal gyrus. CONCLUSIONS: Patients with PGES exhibited characteristic brain microstructural abnormalities, corroborating the PGES mechanisms at the brain level. The right-sided predominance of the detected PGES-related cortical thinning was the same as that of sudden unexpected death in epilepsy (SUDEP) cases and patients at high risk for SUDEP, implying that PGES and SUDEP may share a common abnormal brain substrate that is involved in the pathophysiology of these conditions.

[Research progress of deubiquitinating enzyme CYLD to regulate liver-related diseases].

Cylindromatosis gene is a kind of tumor suppressor genes, whose mutation or deletion will lead to the development of a cylindrical tumor. The deubiquitinating enzyme CYLD protein encoded by it is a member of the deubiquitinating enzyme family. CYLD alters the function of the target molecules by removing the ubiquitin chain linked to the substrate protein K63, and participates in the regulation of signaling pathways, such as NF-κB, JNK and Wnt. This article reviews the recent year's research progress of CYLD, especially its negative regulatory role in the progression of liver-related diseases.

Reduction of myeloid-derived suppressor cells reinforces the anti-solid tumor effect of recipient leukocyte infusion in murine neuroblastoma-bearing allogeneic bone marrow chimeras.

Allogeneic hematopoietic stem cell transplantation is an emerging treatment option for solid tumors because of its capacity to elicit immune graft-versus-tumor effects. However, these are often limited and associated with GvHD. Adoptive recipient leukocyte infusion (RLI) was shown to enhance anti-tumor responses of allogeneic bone marrow transplantation in murine neuroblastoma (Neuro2A)-bearing chimeras. In contrast to the clinically used donor leukocyte infusion, the RLI anti-tumor effect-elicited by host-versus-graft lymphohematopoietic reactivity-does not cause GvHD; however, the tumor growth-inhibitory effect is incomplete, because overall survival is not prolonged. Here, we studied the anti-solid tumor mechanisms of RLI with the objective to improve its efficacy. Host-versus-graft reactivity following RLI was associated with a systemic cytokine storm, lymph node DC activation, and systemic expansion of host-derived IFN-γ-expressing CD4+ T cells and IFN-γ-and granzyme B-expressing CD8+ T cells, which acquired killing activity against Neuro2A and third-party tumor cells. The tumor showed up-regulation of MHC class I and a transient accumulation of IFN-γ-and granzyme B-expressing CD8+ T cells: the intra-tumor decline in cytotoxic CD8+ T cells coincided with a systemic-and to a lesser extent intra-tumoral-expansion of MDSC. In vivo MDSC depletion with 5-FU significantly improved the local tumor growth-inhibitory effect of RLI as well as overall survival. In conclusion, the RLI-induced alloreactivity gives rise to a host-derived cytotoxic T-cell anti-neuroblastoma response, but also drives an expansion of host-type MDSC that counteracts the anti-tumor effect. This finding identifies MDSC as a novel target to increase the effectiveness of RLI, and possibly other cancer immunotherapies.

Disrupted intrinsic and remote functional connectivity in heterotopia-related epilepsy.

OBJECTIVES: Several neuroimaging studies have examined neural interactions in patients with periventricular nodular heterotopia (PNH). However, features of the underlying functional network remain poorly understood. In this study, we examined alterations in the local (regional) and remote (interregional) cerebral networks in this disorder. METHODS: Twenty-eight subjects all having suffered from PNH with epilepsy, as well as 28 age- and sex- matched healthy controls, were enrolled in this study. Amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) were calculated to detect regional neural function and functional network integration, respectively. RESULTS: Compared with healthy controls, patients with PNH-related epilepsy showed decreased ALFF in the ventromedial prefrontal cortex (vmPFC) and precuneus areas. ALFF values in both areas were negative correlated with epilepsy duration (P < .05, Bonferroni-corrected). Furthermore, patients with PNH-related epilepsy had increased remote interregional FC mainly in bilateral prefrontal and parietal cortices, supramarginal gyrus, dorsal cingulate gyrus, and right insula; lower FC was found in posterior brain regions including bilateral parahippocampal gyrus and inferior temporal gyrus. CONCLUSIONS: Focal spontaneous hypofunction, as assessed by ALFF, correlates with epilepsy duration in patients with PNH-related epilepsy. Abnormalities existed both within the default-mode network and then across the whole brain, demonstrating that intrinsic brain dysfunction may be related to specific network interactions. Our findings provide novel understanding of the connectivity-based pathophysiological mechanisms of PNH.

Effect of viral suppression on hepatic venous pressure gradient in hepatitis C with cirrhosis and portal hypertension.

Portal hypertension is a predictor of liver-related clinical events and mortality in patients with hepatitis C and cirrhosis. The effect of interferon-free hepatitis C treatment on portal pressure is unknown. Fifty patients with Child-Pugh-Turcotte (CPT) A and B cirrhosis and portal hypertension (hepatic venous pressure gradient [HVPG] >6 mm Hg) were randomized to receive 48 weeks of open-label sofosbuvir plus ribavirin at Day 1 or after a 24-week observation period. The primary endpoint was sustained virologic response 12 weeks after therapy (SVR12) in patients who received ≥1 dose of treatment. Secondary endpoints included changes in HVPG, laboratory parameters, and MELD and CPT scores. A subset of patients was followed 48 weeks posttreatment to determine late changes in HVPG. SVR12 occurred in 72% of patients (33/46). In the 37 patients with paired HVPG measurements at baseline and the end of treatment, mean HVPG decreased by -1.0 (SD 3.97) mm Hg. Nine patients (24%) had ≥20% decreases in HVPG during treatment. Among 39 patients with pretreatment HVPG ≥12 mm Hg, 27 (69%) achieved SVR12. Four of the 33 (12%) patients with baseline HVPG ≥12 mm Hg had HVPG <12 mm Hg at the end of treatment. Of nine patients with pretreatment HVPG ≥12 mm Hg who achieved SVR12 and completed 48 weeks of follow-up, eight (89%) had a ≥20% reduction in HVPG, and three reduced their pressure to <12 mm Hg. Patients with chronic HCV and compensated or decompensated cirrhosis who achieve SVR can have clinically meaningful reductions in HVPG at long-term follow-up. (EudraCT 2012-002457-29).

Perilesional and contralateral white matter evolution and integrity in patients with periventricular nodular heterotopia and epilepsy: a longitudinal diffusion tensor imaging study.

BACKGROUND AND PURPOSE: This study aimed to assess the evolution of perinodular and contralateral white matter abnormalities in patients with periventricular nodular heterotopia (PNH) and epilepsy. METHODS: Diffusion tensor imaging (DTI) (64 directions) and 3 T structural magnetic resonance imaging were performed in 29 PNH patients (mean age 27.3 years), and 16 patients underwent a second scan (average time between the two scans 1.1 years). Fractional anisotropy and mean diffusivity were measured within the perilesional and contralateral white matter. RESULTS: Longitudinal analysis showed that white matter located 10 mm from the focal nodule displayed characteristics intermediate to tissue 5 mm away, and normal-appearing white matter (NAWM) also established evolution profiles of perinodular white matter in different cortical lobes. Compared to 29 age- and sex-matched healthy controls, significant decreased fractional anisotropy and elevated mean diffusivity values were observed in regions 5 and 10 mm from nodules (P < 0.01), whilst DTI metrics of the remaining NAWM did not differ significantly from controls. Additionally, normal DTI metrics were shown in the contralateral region in patients with unilateral PNH. CONCLUSIONS: Periventricular nodular heterotopia is associated with microstructural abnormalities within the perilesional white matter and the extent decreases with increasing distance from the nodule. In the homologous contralateral region, white matter diffusion metrics were unchanged in unilateral PNH. These findings have clinical implications with respect to the medical and surgical interventions of PNH-related epilepsy.

Hypertrophic cardiomyopathy and left ventricular hypertrophy in hypertensive heart disease with mildly reduced or preserved ejection fraction: insight from altered mechanics and native T1 mapping.

AIM: To explore the relationship between extracellular volume (ECV), native T1, and systolic strain in hypertrophic cardiomyopathy (HCM) and hypertensive patients with left ventricular hypertrophy (HTN LVH) with mildly reduced or preserved ejection fraction. MATERIALS AND METHODS: T1 mapping was performed in 45 patients with late gadolinium enhancement positive (LGE+) HCM (mean age, 53±6 years), 11 patients with LGE- (LGE-) HCM (mean age, 56±5 years), and 20 patients with HTN LVH (mean age, 55±6 years) on at 3 T magnetic resonance imaging (MRI) using the modified look-locker inversion-recovery (MOLLI) pulse sequence. Mean T1 value, ECV and circumferential strain parameters were determined for each patient. RESULTS: Overall, the HCM patients had higher native T1 values (1242.92±68.94) and ECV (0.31±0.05) in comparison to those of the HTN LVH patients (1197±46.80, 0.27±0.04; p<0.05). In the subgroup analysis, the HCM LGE+ patients had the highest native T1 values among the three groups. The HCM LGE+ patients had higher ECV than the LGE- patients. HCM LGE- patients had higher ECV than HTN LVH patients (p<0.05). Peak systolic circumferential strain and early diastolic strain rates were reduced in the HCM LGE+ patients in comparison to the HCM LGE- and HTN LVH patients (p<0.05). Reduced peak systolic and early diastolic circumferential strain rates were associated with increased levels of ECV and native T1 values among all the patients. CONCLUSION: HCM LGE+ patients had higher native T1 values, higher ECV, and an associated reduction in early diastolic strain rates and peak systolic circumferential strains when compared to the HCM LGE- and HTN LVH patients with mildly reduced or preserved ejection fraction.

[A retrospective analysis of clinical characteristics and outcomes of heart failure patients with different left ventricular ejection fractions].

Objective: To compare the clinical characteristics, and outcomes of patients with heart failure with different left ventricular ejection fractions (LVEF). Methods: A total of 1 182 hospitalized patients with heart failure (HF) were enrolled and retrospectively studied in the present study. The patients were stratified by LVEF as reduced (HFrEF, LVEF<40%, n=313), mid-range (HFmrEF, 40% ≤LVEF <50%, n=287) and preserved (HFpEF, LVEF≥50%, n=582) ejection fraction groups. Among the 1 182 cases, 941 of them (81.3%, 84.9%, and 84.0% inHFrEF, HFmrEF and HFpEF groups, respectively) were followed up for an median duration of 27.3 months. Results: (1) Among the study patients, 26.5% were in HFrEF, 24.3% in HFmrEF, and 49.2% in HFpEF groups. (2) Ischemic heart disease with HFmrEF was more frequent than that in patients with HFrEF. The average age, percentage of female subjects, systolic blood pressure, uric acid, N terminal B-type natriuretic peptide precursor (NT-proBNP), hemoglobin, and the incidence of hypertensive heart disease, anemia, atrial fibrillation in patients with HFmrEF were higher than those in patients with HFrEF, but lower than those in patients with HFpEF (all P<0.01). (3) The all-cause cumulative mortality was 10.8% at 1 year, 20.6% at 2 years and 35.9% at 5 years. No difference was observed in the all-cause cumulative mortality at 1 year, 2 years, 5 years among the three groups (all P>0.05). Conclusions: The HFmrEF patients, as a new and distinct group, were with many intermediate characteristics compared with HFrEF and HFpEF subjects. However, the all-cause mortality was not significantly different among HF patients with different LVEF.

Myocardial Protection against Ischemic and Reperfusion Injuries (Experimental Study).

The effects of hypoxic, hyperoxic, and hypoxic-hyperoxic preconditioning were examined in the prospective study on narcotized and artificially ventilated rabbits. Under artificial circulation, acute myocardial ischemia was modeled by ligation of anterior descending coronary artery, which was followed by reperfusion. The degree of ventricular arrhythmias was assessed, and the ischemic area was evaluated in percent of the area at risk. Microscopic characterization of the myocardium was employed to assess the cardioprotective effect of hypoxic and/or hyperoxic preconditioning. According to Kruskal-Wallis test, the greatest resistance of the myocardium to ischemic and reperfusion injury was observed after hypoxic-hyperoxic preconditioning (H=42.459; p=0.009). The rabbits subjected to this type of preconditioning demonstrated the least damaged myocardium in comparison with nonconditioned controls.

GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study.

GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.