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Iron metabolism is closely associated with the pathogenesis of obesity. However, the mechanism of the iron-dependent regulation of adipocyte differentiation remains unclear. Here, we show that iron is essential for rewriting of epigenetic marks during adipocyte differentiation. Iron supply through lysosome-mediated ferritinophagy was found to be crucial during the early stage of adipocyte differentiation, and iron deficiency during this period suppressed subsequent terminal differentiation. This was associated with demethylation of both repressive histone marks and DNA in the genomic regions of adipocyte differentiation-associated genes, including Pparg, which encodes PPARγ, the master regulator of adipocyte differentiation. In addition, we identified several epigenetic demethylases to be responsible for iron-dependent adipocyte differentiation, with the histone demethylase jumonji domain-containing 1A and the DNA demethylase ten-eleven translocation 2 as the major enzymes. The interrelationship between repressive histone marks and DNA methylation was indicated by an integrated genome-wide association analysis, and was also supported by the findings that both histone and DNA demethylation were suppressed by either the inhibition of lysosomal ferritin flux or the knockdown of iron chaperone poly(rC)-binding protein 2. In summary, epigenetic regulations through iron-dependent control of epigenetic enzyme activities play an important role in the organized gene expression mechanisms of adipogenesis.

T1R3 is a class C G protein-coupled receptor family member that forms heterodimeric umami and sweet taste receptors with T1R1 and T1R2, respectively, in the taste cells of taste buds. T1R3 is expressed in 3T3-L1 cells in homomeric form and negatively regulates adipogenesis in a Gαs-dependent but cAMP-independent manner. Although T1R3 expression is markedly upregulated during adipogenesis, its physiological role in mature adipocytes remains obscure. Here, we show that stimulation of T1R3 with sucralose or saccharin induces microtubule disassembly in differentiated 3T3-L1 adipocytes. The effect was reproduced by treatment with cholera toxin or isoproterenol but not with forskolin. Treatment with sucralose or saccharin for 3 h inhibited insulin-stimulated glucose uptake by 32% and 45% in differentiated adipocytes, respectively, similar to the inhibitory effect of nocodazole (by 33%). Isoproterenol treatment inhibited insulin-stimulated glucose transport by 26%, whereas sucralose did not affect the intrinsic activity of the glucose transporter, indicating that it inhibited insulin-induced GLUT4 translocation to the plasma membrane. Immunostaining analysis showed that insulin-stimulated GLUT4 accumulation on the plasma membrane was abrogated in sucralose-treated cells, in association with depolymerization of microtubules. Sucralose-mediated inhibition of GLUT4 translocation was reversed by the overexpression of dominant-negative Gαs (Gαs-G226A) or knockdown of Gαs. Additionally, membrane fractionation analysis showed that sucralose treatment reduced GLUT4 levels in the plasma membrane fraction from insulin-stimulated adipocytes. We have identified a novel non-gustatory role for homomeric T1R3 in adipocytes, and activation of the T1R3 receptor negatively regulates insulin action of glucose transport via Gαs-dependent microtubule disassembly.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder of the vasculature, characterized by epistaxis, telangiectasia and arteriovenous malformations in multiple organs. We herein report a 49-year-old woman with a history of early-onset myocardial infarction and intracranial aneurysms, in whom we incidentally detected multiple hepatic vascular abnormalities. We subsequently diagnosed her with HHT after discovering gastrointestinal telangiectases and a pulmonary arteriovenous fistula along with a history of recurrent epistaxis. Whole-exome sequencing revealed a novel pathogenic variant in SMAD4, a relatively rare causative gene for HHT. This case highlights the fact that HHT patients may present with asymptomatic liver lesions.

Hepatokines, secretory proteins from the liver, mediate inter-organ communication to maintain a metabolic balance between food intake and energy expenditure. However, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli are largely unknown. Here, we unravel CNOT6L deadenylase switches off hepatokine expression after responding to the stimuli (e.g., exercise and food) to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, increasing corresponding serum protein levels. The resulting up-regulation of GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Despite the potential of hepatokines to treat metabolic disorders, their administration therapies have been challenging. Using small-molecule screening, we identified a CNOT6L inhibitor enhancing GDF15 and FGF21 hepatokine levels, which dramatically improves diet-induced metabolic syndrome. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic syndrome.

Aim Ventilator-associated pneumonia (VAP) is the most common intensive care unit (ICU)-acquired infection. The current study aimed to assess the efficacy of mechanical insufflation-exsufflation (MI-E) in preventing VAP in critically ill patients. Materials and methods This retrospective cohort study was conducted at the ICU of Chiba University Hospital between January 2014 and September 2017. The inclusion criteria were patients who required invasive mechanical ventilation ≥48 hours and those who underwent rehabilitation, including chest physical therapy (CPT). In 2015, the study institution started the use of MI-E in patients with impaired cough reflex. From January to December 2014, patients undergoing CPT were classified under the historical control group, and those who received treatment using MI-E from January 2015 to September 2017 were included in the intervention group. The patients received treatment using MI-E via the endotracheal or tracheostomy tube, with insufflation-exsufflation pressure of 15-40 cm H2O. The treatment frequency was one to three sessions daily, and a physical therapist who is experienced in using MI-E facilitated the treatment. Results From January 2015 to September 2017, 11 patients received treatment using MI-E. Of the 169 patients screened in 2014, 19 underwent CPT. The incidence of VAP was significantly different between the CPT and MI-E groups (84.2% [16/19] vs 26.4% [3/11], p = 0.011). After adjusting for covariates, a multivariate logistic regression analysis was performed, and results showed that the covariates were not associated with the incidence of VAP. Conclusion This retrospective cohort study suggests that the use of MI-E in critically ill patients is independently associated with a reduced incidence of VAP. Clinical significance Assessing the efficacy of MI-E to prevent VAP. How to cite this article Kuroiwa R, Tateishi Y, Oshima T, Inagaki T, Furukawa S, Takemura R, et al. Mechanical Insufflation-exsufflation for the Prevention of Ventilator-associated Pneumonia in Intensive Care Units: A Retrospective Cohort Study. Indian J Crit Care Med 2021;25(1):62-66.

Protein kinase A promotes beige adipogenesis downstream from β-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion resulted in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1β also dephosphorylates myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ which directly stimulates Ucp1 gene expression. Preadipocyte specific Mypt1 deficiency increases cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice, confirming this regulatory mechanism in vivo. Thus, we have uncovered new regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of the mechano-sensitive YAP/TAZ transcriptional co-activators.

Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis., How enhancers transition from a hypoacetylated primed state to a hyperacetylated-active state in response to differentiation stimuli is incompletely understood. Here the authors show that SETD5 forms a complex with NCoR-HDAC3 co-repressor to prevent histone acetylation of master adipogenic gene enhancers, while SETD5 degradation triggers enhancer hyperacetylation and transition to active state.

Dietary intervention is one of the most important approaches for the treatment of metabolic diseases such as diabetes mellitus. Fasting and caloric restriction have profound effects on systemic metabolism. The energy source-producing organs, such as the liver, and peripheral tissues rewire their metabolism to meet the energy demands of the whole body. Glycogenolysis, fatty acid oxidation, and ketone body production are characteristic metabolic changes that occur during fasting and caloric restriction. These metabolic changes are regulated by various signaling cascades including PPARα and FGF21. Moderate fasting and caloric restriction have also been implicated in extending the lifespan in a variety of organisms from nematodes to vertebrates. Intensive research has unveiled several regulatory mechanisms of longevity including metabolic regulators such as mTOR and sirtuins. The epigenome has been attracting attention as a mechanism underlying metabolic diseases and longevity. The epigenome is the concept that involves covalent modifications of DNA, histones, and RNA, which are mediated by the action of epigenetic enzymes. The activity of these enzymes is regulated by energy states, i.e. metabolites including ketone bodies and intermediates of various metabolic pathways. Thus, energy states are recorded in cells as an epigenetic memory, which may cause future onset of metabolic diseases and affect lifespan.

Tsukamurella spp. causes mainly bacteremia and central venous catheter-related bloodstream infections. To the best of our knowledge, there is no documented evidence that Tsukamurella ocularis causes catheter-related bloodstream infections like other species of Tsukamurella. We present a novel case of T. ocularis bacteremia in a 69-year-old woman with malignant cancer, wherein the patient was successfully treated with a peripherally inserted central venous catheter. We administered combination antimicrobial therapy to the patient, which was terminated only after confirming the absence of infection. We identified T. ocularis by sequencing three housekeeping genes that could not be identified using conventional mass spectrometry and 16S rRNA gene analysis.

α-Ketoglutarate (α-KG) also known as 2-oxoglutarate (2-OG) is an intermediate metabolite in the tricarboxylic acid (TCA) cycle and is also produced by the deamination of glutamate. It is an indispensable cofactor for a series of 2-oxoglutarate-dependent oxygenases including epigenetic modifiers such as ten-eleven translocation DNA demethylases (TETs) and JmjC domain-containing histone demethylases (JMJDs). Since these epigenetic enzymes target genomic DNA and histone in the nucleus, the nuclear concentration of α-KG would affect the levels of transcription by modulating the activity of the epigenetic enzymes. Thus, it is of great interest to measure the nuclear concentration of α-KG to elucidate the regulatory mechanism of these enzymes. Here, we report a novel fluorescence resonance energy transfer (FRET)-based biosensor with multiple nuclear localization signals (NLSs) to measure the nuclear concentration of α-KG. The probe contains the α-KG-binding GAF domain of NifA protein from Azotobacter vinelandii fused with EYFP and ECFP. Treatment of 3T3-L1 preadipocytes expressing this probe with either dimethyl-2-oxoglutarate (dimethyl-2-OG), a cell-permeable 2-OG derivative, or citrate elicited time- and dose-dependent changes in the FRET ratio, proving that this probe functions as an α-KG sensor. Measurement of the nuclear α-KG levels in the 3T3-L1 cells stably expressing the probe during adipocyte differentiation revealed that the nuclear concentration of α-KG increased in the early stage of differentiation and remained high thereafter. Thus, this nuclear-localized α-KG probe is a powerful tool for real-time monitoring of α-KG concentrations with subcellular resolution in living cells and is useful for elucidating the regulatory mechanisms of epigenetic enzymes.

The lysine methyltransferase SETDB1, an enzyme responsible for methylation of histone H3 at lysine 9, plays a key role in H3K9 tri-methylation-dependent silencing of endogenous retroviruses and developmental genes. Recent studies have shown that ubiquitination of human SETDB1 complements its catalytic activity and the silencing of endogenous retroviruses in human embryonic stem cells. However, it is not known whether SETDB1 ubiquitination is essential for its other major role in epigenetic silencing of developmental gene programs. We previously showed that SETDB1 contributes to the formation of H3K4/H3K9me3 bivalent chromatin domains that keep adipogenic Cebpa and Pparg genes in a poised state for activation and restricts the differentiation potential of pre-adipocytes. Here, we show that ubiquitin-resistant K885A mutant of SETDB1 represses adipogenic genes and inhibits pre-adipocyte differentiation similar to wild-type SETDB1. We show this was due to a compensation mechanism for H3K9me3 chromatin modifications on the Cebpa locus by other H3K9 methyltransferases Suv39H1 and Suv39H2. In contrast, the K885A mutant did not repress other SETDB1 target genes such as Tril and Gas6 suggesting SETDB1 represses its target genes by two mechanisms; one that requires its ubiquitination and another that still requires SETDB1 but not its enzyme activity.

Adipose tissue harbors plasticity to adapt to environmental thermal changes. While brown adipocyte is a thermogenic cell which produces heat acutely in response to cold stimuli, beige (or brite) adipocyte is an inducible form of thermogenic adipocytes which emerges in the white adipose depots in response to chronic cold exposure. Such adaptability of adipocytes is regulated by epigenetic mechanisms. Among them, histone methylation is chemically stable and thus is an appropriate epigenetic mark for mediating cellular memory to induce and maintain the beige adipocyte characteristics. The enzymes that catalyze the methylation or demethylation of H3K27 and H3K9 regulate brown adipocyte biogenesis through their catalytic activity-dependent and -independent mechanisms. Resolving the bivalency of H3K4me3 and H3K27me3 as well as "opening" the chromatin structure by demethylation of H3K9 both mediate beige adipogenesis. In addition, it is recently reported that maintenance of beige adipocyte, beige-to-white transition, and cellular memory of prior cold exposure in beige adipocyte are also regulated by histone methylation. A further understanding of the epigenetic mechanism of beige adipocyte biogenesis would unravel the mechanism of the cellular memory of environmental stimuli and provide a novel therapeutics for the metabolic disorders such as obesity and diabetes that are influenced by environmental factors.

Laminin, a major basement membrane protein, comprises three subunit chains: α, β, and γ chains. Among these chains, only the laminin α chain is capable of signaling via laminin receptors. Although laminin isoforms containing the α5 chain were reported to be the first laminin produced during rat anterior pituitary gland development, the functions of these isoforms are unknown. We used immunohistochemical techniques to localize the laminin α5 chain and its specific receptor, basal cell adhesion molecule (BCAM), in fetal and adult pituitary gland. Laminin α5 chain immunoreactivity was observed in the basement membrane of the primordial adenohypophysis at embryonic days 12.5 to 19.5. Double immunostaining showed that BCAM was present and co-localized with the laminin α5 chain in the tissue. Quantitative analysis showed that the laminin α5 chain and BCAM were expressed in the anterior pituitary gland during postnatal development and in adulthood (postnatal day 60). In the adult gland, co-localization of the laminin α5 chain and BCAM was observed, and BCAM was detected in both the folliculo-stellate cells and endothelial cells. These results suggest that laminin α5 chain signaling via BCAM occurs in both the fetal adenohypophysis and adult anterior pituitary gland.

Subaru Telescope, an 8­meter class optical telescope located in Hawaii, has been using a high ­availability commodity cluster as a platform for our Observation Control System for many years.1 A concerted attempt to virtualize this infrastructure using conventional virtual machines2 was eventually scuttled due to performance impacts on the observation software under sustained use. With the ascendance of container­-based virtualization, and its promise of high­-efficiency, we recently attempted this effort anew, and have found success with an approach that employs Linux (LXC) containers. This has provided immediate benefits in maintenance, risk ­management and availability. In this paper, we document our transition and discuss the rationale for this choice vs. the arguably more popular Docker containerization scheme. We list some of the issues we encountered and solved to realize a successful transition to containers. We have also recently converted our software stack to being based on Miniconda, a popular, open­source, cross­platform software distribution service. This move basically decoupled our software completely from the operating system platform, and provides a virtualized software stack with many desirable benefits. The combination of the LXC containers and Miniconda gives us an orthogonal three-­axis virtualization scheme with extreme flexibility. We present our system for managing Miniconda environments, the benefits that accrue, and how this three­-axis approach to virtualization has altered our deployment and management strategies.

The Subaru Telescope recently celebrated its 20th year of operation. Despite that lengthy period of successful operation, it has never had a proper simulator for its telescope control system. This fact complicates the development and testing of observing scripts that need to send commands and receive realistic feedback from both telescope and instrument systems. The Subaru telescope control system was developed by a subcontractor and there was no requirement for it to be able to run in simulation mode. Furthermore, the source code is proprietary and is not accessible by current Subaru software engineers. These two facts greatly complicated the development of a telescope simulator. Prior to the current effort, the telescope simulator consisted of a “yes-man” interface, i.e., the rudimentary simulator would just respond that it received the command but would not simulate telescope motion or set any status items to provide feedback to the observing scripts. The telescope simulator developed in this effort currently simulates the following components: telescope and instrument rotator motion, focal station configuration, autoguide camera images and pointing errors, as well as facility hardware like dome shutters and mirror covers. We have plans to further refine all those components and implement features like simulated environmental conditions based on historical weather data. The simulator has already proven useful in testing observation scripts. In addition, the simulator will also be a good training aid for new telescope operators.

Hypertension leads to structural remodeling of cerebral blood vessels, which has been implicated in the pathophysiology of cerebrovascular diseases. The remodeling and progression of arteriolosclerosis under hypertension involve fibrosis along with the production of type I collagen around cerebral arterioles. However, the source and regulatory mechanisms of this collagen production remain elusive. In this study, we examined if perivascular macrophages (PVMs) are involved in collagen production around cerebral small vessels in hypertensive SHRSP/Izm rats. Immunoreactivity for type I collagen around cerebral small vessels in 12-week-old hypertensive rats tended to higher than those in 4-week-old hypertensive and 12-week-old control rats. In ultrastructural analyses using transmission electron microscopy, the substantial deposition of collagen fibers could be observed in the intercellular spaces around PVMs near the arterioles of rats with prolonged hypertension. In situ hybridization analyses revealed that cells positive for mRNA of Col1a1, which comprises type I collagen, were observed near cerebral small vessels. The Col1a1-positive cells around cerebral small vessels were colocalized with immunoreactivity for CD206, a marker for PVMs, but not with those for glial fibrillary acidic protein or desmin, markers for other perivascular cells such as astrocytes and vascular smooth muscle cells. These results demonstrated that enhanced production of type I collagen is observed around cerebral small vessels in rats with prolonged hypertension and Col1a1 is expressed by PVMs, and support the concept that PVMs are involved in collagen production and vascular fibrosis under hypertensive conditions.

Herein, we report the interim vaccine effectiveness (VE) of a quadrivalent inactivated influenza vaccine, during the 2019/2020 influenza season, in Japan. We conducted a retrospective observational cohort study of 381 patients aged >= 15 years, who were enrolled with influenza like illnesses and examined via the rapid influenza diagnostic test, at the Ambulatory Care unit of the National Center for Global Health and Medicine in Tokyo, Japan, from the beginning of October 2019 to the end of January 2020. VE was estimated using a test-negative design. VE was calculated as (1 - odds ratio) x 100%, comparing influenza A test positivity between vaccinated and unvaccinated patients. Of the 381 patients initially screened for inclusion, 314 were enrolled in the study. Of these, 105 were vaccinated, 98 were diagnosed with influenza A, and 5 were diagnosed with influenza B. Overall VE against influenza A was 27.6% (95% confidence interval [CI], -21.1 to +57.4), and in patients aged >= 65 years, it was 47.3% (95% CI, -76.0 to +86.0). This indicates that the influenza vaccination offered continued protection during the 2019/2020 influenza season, but a detailed analysis of more cases with a careful consideration of methodology is necessary to estimate VE more precisely.

Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferator-activated receptor α (PPARα) agonist, has protective effects against diabetic retinopathy. However, the underlying mechanism has not been clarified. We performed genome-wide analyses of gene expression and PPARα binding sites in vascular endothelial cells treated with the selective PPARα modulator pemafibrate and identified 221 target genes of PPARα including THBD, which encodes thrombomodulin (TM). ChIP-qPCR and luciferase reporter analyses showed that PPARα directly regulated THBD expression via binding to the promoter. In the rat diabetic retina, treatment with pemafibrate inhibited the expression of inflammatory molecules such as VCAM-1 and MCP1, and these effects were attenuated by intravitreal injection of small interfering RNA targeted to THBD. Furthermore, pemafibrate treatment inhibited diabetes-induced vascular leukostasis and leakage through the upregulation of THBD. Our results indicate that PPARα activation inhibits inflammatory and vasopermeable responses in the diabetic retina through the upregulation of TM.

Following a lot of reports of coronavirus disease 2019 (COVID-19) CT images, the feature of FDG-PET/ CT imaging of COVID-19 was reported in several articles. Since FDG accumulates in activated inflammatory cells, FDG-PET/CT has huge potential for diagnosing and monitoring of inflammatory disease. However, FDG-PET/CT cannot be routinely used in an emergency setting and is not generally recommended as a first choice for diagnosis of infectious diseases. In this review, we demonstrate FDG-PET/CT imaging features of COVID-19, including our experience and current knowledge, and discuss the value of FDG-PET/CT in terms of estimating the pathologic mechanism.

Objectives Following the massive earthquake that struck eastern Japan on March 11, 2011, a large amount of radioactive material was released into the environment from the damaged reactor of the Fukushima Daiichi Nuclear Power Plant (FDNPP). After the FDNPP accident, radiocaesium was first detected in muscle samples from wild Japanese monkeys exposed to radioactive materials, and haematologic effects, changes in head size, and delayed body weight gain were also reported, but little is known about the distribution of 137Cs in the organs and tissues of wild Japanese monkeys. Results We detected the 137Cs in various organ and tissue samples of 10 wild Japanese monkeys inhabiting the forested areas of Fukushima City that were captured between July and August 2012. Among muscle, brain, heart, kidney, liver, lung, and spleen, muscle exhibited the highest and the brain the lowest 137Cs concentration. The concentration (mean ± SD) of 137Cs in muscle, brain, heart, kidney, liver, lung, and spleen was 77 ± 66, 26 ± 22, 41 ± 35, 49 ± 41, 41 ± 38, 53 ± 41, and 53 ± 51 Bq/kg, respectively. These results can help us understand the biological effects of long-term internal radiation exposure in non-human primates.

Objectives Following the massive earthquake that struck eastern Japan on March 11, 2011, a large amount of radioactive material was released into the environment from the damaged reactor of the Fukushima Daiichi Nuclear Power Plant (FDNPP). After the FDNPP accident, radiocaesium was first detected in muscle samples from wild Japanese monkeys exposed to radioactive materials, and haematologic effects, changes in head size, and delayed body weight gain were also reported, but little is known about the distribution of 137Cs in the organs and tissues of wild Japanese monkeys. Results We detected the 137Cs in various organ and tissue samples of 10 wild Japanese monkeys inhabiting the forested areas of Fukushima City that were captured between July and August 2012. Among muscle, brain, heart, kidney, liver, lung, and spleen, muscle exhibited the highest and the brain the lowest 137Cs concentration. The concentration (mean ± SD) of 137Cs in muscle, brain, heart, kidney, liver, lung, and spleen was 77 ± 66, 26 ± 22, 41 ± 35, 49 ± 41, 41 ± 38, 53 ± 41, and 53 ± 51 Bq/kg, respectively. These results can help us understand the biological effects of long-term internal radiation exposure in non-human primates.

BACKGROUND The short-term efficacy of pulmonary rehabilitation (PR) in patients with chronic obstructive pulmonary disease (COPD) has been established. Although continuous follow-up and sustained exercise training is important to maintain the effects, the long-term efficacy of PR without frequent supervised training remains unclear. The aim of this meta-analysis was to investigate the long-term efficacy of PR with home-based or low frequent maintenance program on exercise capacity and health related quality of life (HRQOL) in patients with COPD. METHODS We identified randomized controlled trials (RCTs) comparing long-term efficacy of PR with home-based or low frequent maintenance and no maintenance program from PubMed and the Cochrane Library. Primary outcomes were exercise capacity [6-minute walking distance (6MWD), incremental shuttle walking test (ISWT)] and HRQOL [St. George's Respiratory Questionnaire (SGRQ)]. Outcomes were combined using a random-effects model. This study is registered with PROSPERO, number CRD42019109718. RESULTS Seven RCTs with a total of 492 patients with COPD met the inclusion criteria. PR with maintenance significantly improved 6MWD [mean difference (MD) 27.00; 95% CI: 1.04-52.96; P=0.01] and ISWT (MD 44.48; 95% CI: 30.70-58.25; P