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In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis. The primary efficacy end-point was sputum culture negative conversion. Totally, 93 patients were included in the modified intention-to-treat population. The rates of sputum culture conversion were 65.2% (30/46) and 87.2% (41/47) for short-course and standard regimen group, respectively. There was no difference on two-month culture conversion rates, time to culture conversion, nor early bactericidal activity (P > 0.05). However, patients on short-course regimen were observed with lower rates of radiological improvement or recovery and sustained treatment success, which was mainly attributed to higher percent of patients permanently changed assigned regimen (32.1% vs. 12.3%, P = 0.012). The main cause for it was drug-induced hepatitis (16/17). Although lowering the dose of prothionamide was approved, the alternative option of changing assigned regimen was chosen in this study. While in per-protocol population, sputum culture conversion rates were 87.0% (20/23) and 94.4% (34/36) for the respective groups. Overall, the short-course regimen appeared to have inferior efficacy and higher incidence of hepatitis but desired efficacy in per-protocol population. It provides the first proof-of-concept in humans of the capacity of the short-course approach to identify drug regimens that can shorten the treatment time for tuberculosis.

BackgroundConstrictive pericarditis (CP) is an uncommon disease that limits both cardiac relaxation and contraction. Patients often present with right-sided heart failure as the pericardium thickens and impedes cardiac filling. Pericardiectomy is the treatment of choice for improving hemodynamics in CP patients; however, the procedure carries a high morbidity and mortality, and the anesthetic management can be challenging. Acute heart failure, bleeding and arrhythmias are all concerns postoperatively.MethodsAfter IRB approval, we performed the retrospective analysis of 66 consecutive patients with CP who underwent pericardiectomy from July 2018 to May 2022.ResultsMost patients had significant preoperative comorbidities, including congestive hepatopathy (75.76%), New York Heart Association Type III/IV heart failure (59.09%) and atrial fibrillation (51.52%). Despite this, 75.76% of patients were extubated within the first 24 h and all but 2 of the patients survived to discharge (96.97%).ConclusionsAnesthetic management, including a thorough understanding of the pathophysiology of CP, the use of advanced monitoring and transesophageal echocardiography (TEE) guidance, all played an important role in patient outcomes.

Abstract The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is a critical clinical issue. Although previous studies have suggested macrophages as a key player in promoting inflammation and fibrosis during this transition, the heterogeneity and dynamic characterization of macrophages are still poorly understood. Here, we used integrated single‐cell RNA sequencing and spatial transcriptomic to characterize the spatiotemporal heterogeneity of macrophages in murine AKI‐to‐CKD model of unilateral ischemia‐reperfusion injury. A marked increase in macrophage infiltration at day 1 was followed by a second peak at day 14 post AKI. Spatiotemporal profiling revealed that injured tubules and macrophages co‐localized early after AKI, whereas in late chronic stages had spatial proximity to fibroblasts. Further pseudotime analysis revealed two distinct lineages of macrophages in this transition: renal resident macrophages differentiated into the pro‐repair subsets, whereas infiltrating monocyte‐derived macrophages contributed to chronic inflammation and fibrosis. A novel macrophage subset, extracellular matrix remodeling‐associated macrophages (EAMs) originating from monocytes, linked to renal fibrogenesis and communicated with fibroblasts via insulin‐like growth factors (IGF) signalling. In sum, our study identified the spatiotemporal dynamics of macrophage heterogeneity with a unique subset of EAMs in AKI‐to‐CKD transition, which could be a potential therapeutic target for preventing CKD development.

This study focused on the effect of a typical phenolic inhibitor, vanillin, on the growth and ethanol production of Starmerella bacillaris R5, as well as the effect of varying levels of glucose on its growth and fermentation performance. The results indicated that when the vanillin concentration was fixed at 3 g/L, increasing glucose concentration in the medium from 2% to 6% shorten the lag phage by 25.92%, increased the specific growth rate by 82.1%, and the ethanol conversion rate by 17.88%. Further analysis showed that increased glucose concentration resulted in an increase in the proportion of cells containing reactive oxygen species (ROS), a decrease in membrane permeability, and a reduction in intracellular H2O2 content. In addition, the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) increased by 58%, 35.5%, and 2.3 times, respectively. Intracellular glycerol content increased by 1.82 times. The activity of pyruvate kinase (PK), related to glucose metabolism, decreased by 54.5%, and the activity of hexokinase (HK) and 6-phosphate glucose dehydrogenase (6-PGDH) increased by 4.16 and 11.8 times, respectively. The content of reduced nicotinamide adenine dinucleotide phosphate (NADPH) increased by 19.4%. The gene expression levels of hexokinase (HK), 6-phosphate fructose kinase (PFK), isocitrate dehydrogenase (IDH3), 6-phosphate glucose dehydrogenase (PGD), ethanol dehydrogenase (ADH5), pyruvate decarboxylase (PDC) and glycerol dehydrogenase 1 (GCY1) were up-regulated by 4.6, 2.5, 13.9, 12.2, 17.5, 34.8, and 34.9 times, respectively. In summary, increasing glucose concentration increased the activity of intracellular antioxidant enzymes, attenuated oxidative damage, and provided more adenosine triphosphate (ATP) and reducing powder to cope with environmental stress, thereby increasing the conversion rate of ethanol. The results of this study could provide new ideas for utilizing S. bacillaris for bioethanol production.

Macrophages are a rich source of macrophage migration inhibitory factor (MIF). It is well established that macrophages and MIF play a pathogenic role in anti-glomerular basement membrane crescentic glomerulonephritis (anti-GBM CGN). However, whether macrophages mediate anti-GBM CGN via MIF-dependent mechanism remains unexplored, which was investigated in this study by specifically deleting MIF from macrophages in MIFf/f−lysM−cre mice. We found that compared to anti-GBM CGN induced in MIFf/f control mice, conditional ablation of MIF in macrophages significantly suppressed anti-GBM CGN by inhibiting glomerular crescent formation and reducing serum creatinine and proteinuria while improving creatine clearance. Mechanistically, selective MIF depletion in macrophages largely inhibited renal macrophage and T cell recruitment, promoted the polarization of macrophage from M1 towards M2 via the CD74/NF-κB/p38MAPK-dependent mechanism. Unexpectedly, selective depletion of macrophage MIF also significantly promoted Treg while inhibiting Th1 and Th17 immune responses. In summary, MIF produced by macrophages plays a pathogenic role in anti-GBM CGN. Targeting macrophage-derived MIF may represent a novel and promising therapeutic approach for the treatment of immune-mediated kidney diseases.