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Tissue-resident macrophages are heterogeneous as a consequence of anatomical niche–specific functions. Many populations self-renew independently of bone marrow in the adult, but the molecular mechanisms of this are poorly understood. We determined a transcriptional profile for the major self-renewing population of peritoneal macrophages in mice. These cells specifically expressed the transcription factor Gata6. Selective deficiency of Gata6 in myeloid cells caused substantial alterations in the transcriptome of peritoneal macrophages. Gata6 deficiency also resulted in dysregulated peritoneal macrophage proliferative renewal during homeostasis and in response to inflammation, which was associated with delays in the resolution of inflammation. Our investigations reveal that the tissue macrophage phenotype is under discrete tissue-selective transcriptional control and that this is fundamentally linked to the regulation of their proliferation renewal.

Millions of experimental animals are widely used in the assessment of toxicological or biological effects of manufactured nanomaterials in medical technology. However, the animal consciousness has increased and become an issue for debate in recent years. Currently, the principle of the 3Rs (i.e., reduction, refinement, and replacement) is applied to ensure the more ethical application of humane animal research. In order to avoid unethical procedures, the strategy of alternatives to animal testing has been employed to overcome the drawbacks of animal experiments. This article provides current alternative strategies to replace or reduce the use of experimental animals in the assessment of nanotoxicity. The currently available alternative methods include in vitro and in silico approaches, which can be used as cost-effective approaches to meet the principle of the 3Rs. These methods are regarded as non-animal approaches and have been implemented in many countries for scientific purposes. The in vitro experiments related to nanotoxicity assays involve cell culture testing and tissue engineering, while the in silico methods refer to prediction using molecular docking, molecular dynamics simulations, and quantitative structure–activity relationship (QSAR) modeling. The commonly used novel cell-based methods and computational approaches have the potential to help minimize the use of experimental animals for nanomaterial toxicity assessments.

The general paradigm is that monocytes are recruited to sites of inflammation and terminally differentiate into macrophages. There has been no demonstration of proliferation of peripherally-derived inflammatory macrophages under physiological conditions. Here we show that proliferation of both bone marrow-derived inflammatory and tissue-resident macrophage lineage branches is a key feature of the inflammatory process with major implications for the mechanisms underlying recovery from inflammation. Both macrophage lineage branches are dependent on M-CSF during inflammation, and thus the potential for therapeutic interventions is marked. Furthermore, these observations are independent of Th2 immunity. These studies indicate that the proliferation of distinct macrophage populations provides a general mechanism for macrophage expansion at key stages during inflammation, and separate control mechanisms are implicated. Monocytes are recruited to sites of damage or infection where they differentiate into inflammatory macrophages. Here the authors demonstrate that, contrary to the prevailing model, these differentiated cells are able to proliferate at sites of inflammation.

The American Heart Association recently issued guidelines introducing the concept of cardiovascular-kidney-metabolic (CKM) syndrome to emphasize the importance of multidisciplinary approaches to prevention, risk stratification, and treatment for these diseases. This study assessed the prevalence of CKM syndrome stages and the mortality risk associated with its components in a large Asian cohort. We analyzed a retrospective cohort of 515,602 participants aged ≥20 years from a health screening program conducted between 1996 and 2017 in Taiwan. We assessed the associations of all-cause mortality, cardiovascular disease (CVD) mortality, and cause-specific mortality with CKM stages and its components-hypertension, diabetes mellitus, chronic kidney disease (CKD), metabolic syndrome, and hyperlipidemia. All participants were followed for a median of 16.5 years (interquartile range: 11.5, 21.2 years). Multivariate Cox proportional hazards models, adjusted for age, sex, educational level, smoking status, alcohol drinking status, and physical activity groups, were used to calculate hazard ratios (HRs). We used Chiang's life table method to estimate years of life lost due to each CKM component. Among all participants, 257,535 (49.9%) were female. The majority of participants (n = 368,578 participants, (71.5%)) met criteria for CKM syndrome, with prevalence rates of 19.5%, 46.3%, 1.9%, and 3.8% for stages 1, 2, 3, and 4, respectively. CKM syndrome was associated with higher risks of all-cause mortality (HR: 1.33; 95% confidence interval, CI: 1.28, 1.39), CVD mortality (HR: 2.81; 95% CI: 2.45, 3.22), and incident end-stage kidney disease (ESKD) (HR: 10.15; 95% CI: 7.54, 13.67). Each additional CKM component was associated with a 22% increase in the risk of all-cause mortality (HR: 1.22; 95% CI: 1.21, 1.23), a 37% increase in the risk of CVD mortality (HR: 1.37; 95% CI: 1.35, 1.40) compared with those without any CKM components. In addition, each additional component reduced average life expectancy by 3 years. The population-attributable fractions of CKM syndrome were 18.7% (95% CI: 15.8, 21.7) for all-cause mortality and 55.0% (95% CI: 49.0, 60.4) for CVD mortality. We estimated that failing to include CKD in CKM syndrome could result in the missed attribution of 11% of CVD deaths. The primary limitation is that our analysis relied on baseline measurements only, without accounting for longitudinal changes. In the large cohort study, the prevalence of CKM syndrome and its components were associated with risks of all-cause mortality, CVD mortality, and ESKD. These findings highlight the clinical need for integrated care within CKM health.

The benefits of rapidly up-titrating evidence-based treatments following heart failure (HF) hospitalizations were demonstrated in the The Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies (STRONG-HF) trial and emphasized in contemporary HF guidelines. We aimed to assess up-titration patterns of guideline-directed medical treatments in the Taiwanese HF population. Combining data from the Taiwan Society of Cardiology - Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry and the Treatment with Angiotensin Receptor neprilysin inhibitor for Taiwan Acute Heart Failure (TAROT-AHF) study cohort, we formed the “Taiwan real-world cohort”. We compared these data with subgroups of patients with left ventricular ejection fraction ≤40% in the STRONG-HF trial. Patients in the Taiwan cohort exhibited similar blood pressure, heart rate and N-terminal pro B-type natriuretic peptide levels at discharge compared with those in the STRONG-HF trial. A higher proportion of patients in the STRONG-HF high-intensity care group received up-titrations compared with those in the usual care group and the Taiwan cohort. Composite all-cause mortality or HF hospitalization at 180 days for patients in the high-intensity care group, usual care group, and Taiwan cohort were 17.4%, 23.7%, and 31.9%, respectively, with differences largely contributed by HF hospitalization (10.1%, 17.9%, and 27.6%, respectively), whereas all-cause mortality rates were similar (11.0%, 9.6%, and 9.3%, respectively). Gender did not affect this trend. In conclusion, our data highlights a treatment gap between the STRONG-HF trial and real-world practices in Taiwan, urging prompt optimization of HF therapy.

Pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD) contributes to mortality. Existing epidemiological research is limited in scale, leading to varied prevalence estimates. Hereby, we aim to evaluate the prevalence and impact of COPD-related PH in individuals with COPD. We used medical-claims data from the national health insurance database (NHIRD) of Taiwan (2009 to 2018). The index date was defined as the initial hospitalization for COPD. We identified patients above 40 year-old with a COPD diagnosis from inpatient claims data and stratified rates of COPD-related PH by gender, age, and COPD severity. We compared short- and long-term mortality between COPD patients with and without PH. To ensure the reliability of our findings, we performed a sensitivity analysis by excluding patients who had not undergone echocardiography. Among 215,292 patients hospitalized primarily for COPD, we found an average COPD-related PH prevalence of 39.9 per 1000 individuals. The annual trend significant declined in prevalence among men but was comparable among women. Furthermore, a higher frequency of COPD-related hospitalization or emergency department visits correlated with an elevated COPD-related PH prevalence, irrespective of age. In comparison to COPD patients without PH, those with this condition exhibited notably higher one-year, three-year, and five-year mortality rates. Collectively, despite a declining trend in COPD-related PH prevalence among COPD patients, its development is closely linked to the severity of COPD. Given the significantly increased mortality rates in COPD patients with PH, early detection of this condition and the implementation of related interventions should be prioritized.

Although some studies have assessed the cost-effectiveness of percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI), there has been a lack of nationwide real-world studies estimating life expectancy (LE), loss-of-LE, life-years saved, and lifetime medical costs. We evaluated the cost-effectiveness of PCI versus non-PCI therapy by integrating a survival function and mean-cost function over a lifelong horizon to obtain the estimations for AMI patients without major comorbidities. We constructed a longitudinal AMI cohort based on the claim database of Taiwan's National Health Insurance during 1999–2015. Taiwan's National Mortality Registry Database was linked to derive a survival function to estimate LE, loss-of-LE, life-years saved, and lifetime medical costs in both therapies. This study enrolled a total of 38,441 AMI patients; AMI patients receiving PCI showed a fewer loss-of-LE (3.6 versus 5.2 years), and more lifetime medical costs (US$ 49,112 versus US$ 43,532). The incremental cost-effectiveness ratio (ICER) was US$ 3488 per life-year saved. After stratification by age, the AMI patients aged 50–59 years receiving PCI was shown to be cost-saving. From the perspective of Taiwan's National Health Insurance, PCI is cost-effective in AMI patients without major comorbidities. Notably, for patients aged 50–59 years, PCI is cost-saving.

The outcome of acute kidney injury (AKI) as a result of aminoglycosides (AGs) use remains uncertain in patients without prior chronic kidney disease (CKD). Therefore, we explored the outcomes of AGs use on AKI episodes associated with renal recovery and progress in patients without prior CKD in Taiwan. This was a retrospective cohort study by using the Taipei Medical University Research Database from January 2008 to December 2019. 43,259 individuals without CKD who had received parenteral AGs were enrolled. The exposed and unexposed groups underwent propensity score matching for age, gender, patients in intensive care unit/emergency admission, and covariates, except serum hemoglobin and albumin levels. We identified an exposed group of 40,547 patients who used AGs (median age, 54.4 years; 44.3% male) and an unexposed group of 40,547 patients without AG use (median age, 55.7 years; 45.5% male). There was the risk for AKI stage 1 (adjusted hazard ratio [HR] 1.34; 95% confidence interval [CI] 1.00–1.79; p  = 0.05) in patients that used AGs in comparison with the control subjects. Moreover, patients using AGs were significantly associated neither with the progression to acute kidney disease (AKD) stages nor with the progression to end-stage renal disease (ESRD) on dialysis. Further analyzed, there was an increased risk of AKI episodes for serum albumin levels less than 3.0 g/dL and hemoglobin levels less than 11.6 g/dL. Among patients without prior CKD, AGs-used individuals were associated with AKI risks, especially those at relatively low albumin (< 3.0 g/dL) or low hemoglobin (< 11.6 g/dL). That could raise awareness of AGs prescription in those patients in clinical practice.

Postnatal kidney growth is substantial and involves expansion in kidney tubules without growth of new nephrons, which are the functional units of the kidney. Proliferation and differentiation pathways underpinning nephron elongation are not well defined. To address this, we performed sequential characterization of mouse kidney transcriptomics at the single cell level. Single nuclear RNA sequencing (snRNA-seq) was performed on kidney tissue from male and female mice at 1, 2, 4 and 12 weeks of age using the 10x Chromium platform. Unbiased clustering was performed on 68,775 nuclei from 16 animals. 31 discrete cellular clusters were seen, which were identified through comparison of their gene expression profiles to canonical markers of kidney cell populations. High levels of proliferation were evident at early time points in some cell types, especially tubular cells, but not in other cell types, for example podocytes. Proliferation was especially evident in Proximal Tubular Cells (PTCs) which are the most abundant cell type in the adult kidney. Uniquely when compared to other kidney cell types, PTCs demonstrated sex-specific expression profiles at late, but not early, time points. Mapping of PTC differentiation pathways using techniques including trajectory and RNA Velocity analyses delineated increasing PTC specialization and sex-specific phenotype specification. Our single-cell transcriptomics data characterise cellular states observed during kidney growth. We have identified PTC differentiation pathways that lead to sex-specific tubular cell phenotypes. Tubular proliferative responses are of central importance in postnatal kidney growth and have also been linked to kidney recovery versus fibrosis following injury. Our unbiased and comprehensive dataset of tubular cell development can be used to identify candidate pathways for therapeutic targeting.

There is little comprehensive education for people with end-stage renal disease (ESRD) progress. We investigated the differences in terms of outcomes between patients with CKD stages 3–5 who enrolled and did not enroll in the pre-ESRD care education in Taiwan. This retrospective cohort study was conducted using data from the National Health Insurance Research Database (NHIRD). All patients diagnosed with CKD stages 3–5 who received the pre-ESRD care education through the pay for performance (P4P) program were enrolled. Based on whether or not they participated in the program, they were categorized into P4P or non-P4P groups. All analyses were performed from January 2006 through December 2015. Study outcomes were risk of hemodialysis dependency, hospitalization, and all-cause mortality. In this study of 29,337 patients, those with CKD stages 3–5 in the P4P group had lower events of hemodialysis, hospitalization, and all-cause mortality compared to patients in the non-P4P group. This study suggested that pre-ESRD care education is associated with increased patient outcomes, resulting in lower hemodialysis and hospitalization events and a higher overall survival rate in patients with CKD stages 3–5. Patient education could raise opportunities to improve pre-ESRD care by reaching patients outside the traditional health care setting.