Summary
Background
Interventional treatment for overt hepatic encephalopathy (OHE), includes non‐absorbable disaccharides, neomycin, rifaximin, L‐ornithine‐L‐aspartate and branched chain amino acids ...(BCAA). However, the optimum regimen remains inconclusive.
Aim
To compare interventions in terms of patients’ adverse events and major clinical outcomes.
Methods
Literature search of PubMed, Embase, Scopus, and Cochrane Library studies published up to July 31 2014. RCTs of above interventions in OHE patients were included. Network meta‐analysis combined direct and indirect evidence to estimate odds ratios (ORs) and mean difference (MD) between treatments and the probabilities of ranking for treatment based on clinical outcomes.
Results
Twenty eligible RCTs were included. When compared with observation, only L‐ornithine‐L‐aspartate (OR 3.71, P < 0.001) and BCAA (OR 3.37, P < 0.001) improved clinical efficacy significantly. However, when L‐ornithine‐L‐aspartate was compared with BCAA, non‐absorbable disaccharides and neomycin, there was a trend suggesting that L‐ornithine‐L‐aspartate may be the most effective intervention with respect to clinical improvement (OR 1.10), rifaximin (OR 1.31), non‐absorbable disaccharides (OR 2.75), neomycin (OR 2.22). In addition, L‐ornithine‐L‐aspartate (MD −20.18, 95% CI −40.12 to −0.27) provided a significant reduction in blood ammonia concentration compared with observation. Neomycin appeared to be associated with more adverse events in comparison with non‐absorbable disaccharides (OR 10.15), rifaximin (OR 17.31), L‐ornithine‐L‐aspartate (OR 3.16) or BCAA (OR 7.69).
Conclusions
L‐ornithine‐L‐aspartate treatment may show a trend in superiority for clinical efficacy among standard interventions for OHE. Rifaximin shows the greatest reduction in blood ammonia concentration, and treatment with neomycin demonstrates a higher probability in causing adverse effects among the five compared interventions.
Early detection of cancer offers the opportunity to identify candidates when curative treatments are achievable. The THUNDER study (THe UNintrusive Detection of EaRly-stage cancers, NCT04820868) ...aimed to evaluate the performance of enhanced linear-splinter amplification sequencing, a previously described cell-free DNA (cfDNA) methylation-based technology, in the early detection and localization of six types of cancers in the colorectum, esophagus, liver, lung, ovary, and pancreas.
A customized panel of 161 984 CpG sites was constructed and validated by public and in-house (cancer: n = 249; non-cancer: n = 288) methylome data, respectively. The cfDNA samples from 1693 participants (cancer: n = 735; non-cancer: n = 958) were retrospectively collected to train and validate two multi-cancer detection blood test (MCDBT-1/2) models for different clinical scenarios. The models were validated on a prospective and independent cohort of age-matched 1010 participants (cancer: n = 505; non-cancer: n = 505). Simulation using the cancer incidence in China was applied to infer stage shift and survival benefits to demonstrate the potential utility of the models in the real world.
MCDBT-1 yielded a sensitivity of 69.1% (64.8%-73.3%), a specificity of 98.9% (97.6%-99.7%), and tissue origin accuracy of 83.2% (78.7%-87.1%) in the independent validation set. For early-stage (I-III) patients, the sensitivity of MCDBT-1 was 59.8% (54.4%-65.0%). In the real-world simulation, MCDBT-1 achieved a sensitivity of 70.6% in detecting the six cancers, thus decreasing late-stage incidence by 38.7%-46.4%, and increasing 5-year survival rate by 33.1%-40.4%, respectively. In parallel, MCDBT-2 was generated at a slightly low specificity of 95.1% (92.8%-96.9%) but a higher sensitivity of 75.1% (71.9%-79.8%) than MCDBT-1 for populations at relatively high risk of cancers, and also had ideal performance.
In this large-scale clinical validation study, MCDBT-1/2 models showed high sensitivity, specificity, and accuracy of predicted origin in detecting six types of cancers.
•MCDBT-1 had a sensitivity of 69.1% and a specificity of 98.9% in detecting six cancers.•In the real world, MCDBT-1 decreased late-stage incidence by 38.7%-46.4% and increased 5-year survival rate by 33.1%-40.4%.•In parallel, MCDBT-2 was set at a lower specificity but a higher sensitivity than MCDBT-1 and had an ideal performance.
Persistent excessive sympathetic activation greatly contributes to the pathogenesis of chronic heart failure (CHF) and hypertension. Cardiac sympathetic afferent reflex (CSAR) is a sympathoexcitatory ...reflex with positive feedback characteristics. Humoral factors such as bradykinin, adenosine and reactive oxygen species produced in myocardium due to myocardial ischaemia stimulate cardiac sympathetic afferents and thereby reflexly increase sympathetic activity and blood pressure. The CSAR is enhanced in myocardial ischaemia, CHF and hypertension. The enhanced CSAR at least partially contributes to the sympathetic activation and pathogenesis of these diseases. Nucleus of the solitary tract (NTS), hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla are the most important central sites involved in the modulation and integration of the CSAR. Angiotensin II, AT1 receptors and NAD(P)H oxidase‐derived superoxide anions pathway in the PVN are mainly responsible for the enhanced CSAR in CHF and hypertension. Central angiotensin‐(1‐7), nitric oxide, endothelin, intermedin, hydrogen peroxide and several other signal molecules are involved in regulating CSAR. Blockade of the CSAR shows beneficial effects in CHF and hypertension. This review focuses on the anatomical and physiological basis of the CSAR, the interaction of CSAR with baroreflex and chemoreflex, and the role of enhanced CSAR in the pathogenesis of CHF and hypertension.
To compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual ...glucose dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist) to previously existing treatment options.
Systematic review and network meta-analysis.
Ovid Medline, Embase, and Cochrane Central up to 14 October 2022.
Eligible randomised controlled trials compared drugs of interest in adults with type 2 diabetes. Eligible trials had a follow-up of 24 weeks or longer. Trials systematically comparing combinations of more than one drug treatment class with no drug, subgroup analyses of randomised controlled trials, and non-English language studies were deemed ineligible. Certainty of evidence was assessed following the GRADE (grading of recommendations, assessment, development and evaluation) approach.
The analysis identified 816 trials with 471 038 patients, together evaluating 13 different drug classes; all subsequent estimates refer to the comparison with standard treatments. Sodium glucose cotransporter-2 (SGLT-2) inhibitors (odds ratio 0.88, 95% confidence interval 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (0.88, 0.82 to 0.93; high certainty) reduce all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduce mortality (0.89, 0.79 to 1.00; moderate certainty); other drugs may not. The study confirmed the benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Finerenone probably reduces admissions to hospital for heart failure and end stage kidney disease, and possibly cardiovascular death. Only GLP-1 receptor agonists reduce non-fatal stroke; SGLT-2 inhibitors are superior to other drugs in reducing end stage kidney disease. GLP-1 receptor agonists and probably SGLT-2 inhibitors and tirzepatide improve quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2 inhibitors, severe gastrointestinal adverse events with tirzepatide and GLP-1 receptor agonists, hyperkalaemia leading to admission to hospital with finerenone). Tirzepatide probably results in the largest reduction in body weight (mean difference -8.57 kg; moderate certainty). Basal insulin (mean difference 2.15 kg; moderate certainty) and thiazolidinediones (mean difference 2.81 kg; moderate certainty) probably result in the largest increases in body weight. Absolute benefits of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone vary in people with type 2 diabetes, depending on baseline risks for cardiovascular and kidney outcomes (https://matchit.magicevidence.org/230125dist-diabetes).
This network meta-analysis extends knowledge beyond confirming the substantial benefits with the use of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing adverse cardiovascular and kidney outcomes and death by adding information on finerenone and tirzepatide. These findings highlight the need for continuous assessment of scientific progress to introduce cutting edge updates in clinical practice guidelines for people with type 2 diabetes.
PROSPERO CRD42022325948.
Excessive sympathetic activity contributes to the pathogenesis of hypertension and the progression of the related organ damage. Adipose afferent reflex (AAR) is a sympatho‐excitatory reflex that the ...afferent activity from white adipose tissue (WAT) increases sympathetic outflow and blood pressure. Hypothalamic paraventricular nucleus (PVN or PVH) is one of the central sites in the control of the AAR, and ionotropic glutamate receptors in the nucleus mediate the AAR. The AAR is enhanced in obesity and obesity hypertension. Enhanced WAT afferent activity and AAR contribute to the excessive sympathetic activation and hypertension in obesity. Blockage of the AAR attenuates the excessive sympathetic activity and hypertension. Leptin may be one of sensors in the WAT for the AAR, and is involved in the enhanced AAR in obesity and hypertension. This review focuses on the neuroanatomical basis and physiological functions of the AAR, and the important role of the enhanced AAR in the pathogenesis of obesity hypertension.
The aim of this study was to develop a widely accepted prognostic nomogram for extranodal NK/T-cell lymphoma, nasal-type (NKTCL). The clinical data from 1383 patients with NKTCL treated at 10 ...participating institutions between 2000 and 2011 were reviewed. A nomogram was developed that predicted overall survival (OS) based on the Cox proportional hazards model. To contrast the utility of the nomogram against the widely used Ann Arbor staging system, the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI), we used the concordance index (C-index) and a calibration curve to determine its predictive and discriminatory capacity. The 5-year OS rate was 60.3% for the entire group. The nomogram included five important variables based on a multivariate analysis of the primary cohort: stage; age; Eastern Cooperative Oncology Group performance status; lactate dehydrogenase; and primary tumor invasion. The calibration curve showed that the nomogram was able to predict 5-year OS accurately. The C-index of the nomogram for OS prediction was 0.72 for both cohorts, which was superior to the predictive power (range, 0.56-0.64) of the Ann Arbor stage, IPI and KPI in the primary and validation cohorts. The proposed nomogram provides an individualized risk estimate of OS in patients with NKTCL.
The pressure-induced superconductivity and structural evolution of Bi2Se3 single crystals are studied. The emergence of superconductivity at an onset transition temperature (Tc) of about 4.4 K is ...observed at around 12 GPa. Tc increases rapidly to a maximum of 8.2 K at 17.2 GPa, decreases to around 6.5 K at 23 GPa, and then remains almost constant with further increases in pressure. Variations in Tc with respect to pressure are closely related to the carrier density, which increases by over two orders of magnitude from 2 to 23 GPa. High-pressure synchrotron radiation measurements reveal structural transitions at around 12, 20, and above 29 GPa. A phase diagram of superconductivity versus pressure is also constructed.
Dysbiotic oral microbiota has been associated with multiple sclerosis. However, the role and mechanism of oral microbiota in the development of multiple sclerosis are still elusive. Here, we ...demonstrated that ligature-induced periodontitis (LIP) aggravated experimental autoimmune encephalomyelitis (EAE) in mice, and this was likely dependent on the expansion of T helper 17 (Th17) cells. LIP increased the splenic richness of Enterobacter sp., which was able to induce the expansion of splenic Th17 cells and aggravate EAE in mice. LIP also led to enrichment of Erysipelotrichaceae sp. in the gut and increased Th17 cells in the large intestinal lamina propria of EAE mice. Fecal microbiota transplantation from EAE mice with LIP also promoted EAE symptoms. In conclusion, periodontitis exacerbates EAE, likely through ectopic colonization of oral pathobionts and expansion of Th17 cells.
In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and ...neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.