Korean Guidelines for the Management and Antibiotic Therapy in Adult Patients with Hospital-Acquired Pneumonia.

BACKGROUND: Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are correlated with high morbidity and mortality rates. Guidelines that consider local epidemiologic data are fundamental for identifying optimal treatment strategies. However, Korea has no HAP/VAP guidelines. METHODS: This study was conducted by a committee of nine experts from the Korean Academy of Tuberculosis and Respiratory Diseases Respiratory Infection Study Group using the results of Korean HAP/VAP epidemiologic studies. Eleven key questions for HAP/VAP diagnosis and treatment were addressed. The Convergence of Opinion on Suggestions and Evidence (CORE) process was used to derive suggestions, and evidence levels and recommendation grades were in accordance with the Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology. RESULTS: Suggestions were made for the 11 key questions pertinent to diagnosis, biomarkers, antibiotics, and treatment strategies for adult patients with HAP/VAP. CONCLUSION: Using the CORE process and GRADE methodology, the committee generated a series of recommendations for HAP/VAP diagnosis and treatment in the Korean context.

Disease severity and activity in bronchiectasis: A paradigm shift in bronchiectasis management.

Bronchiectasis has an increasing prevalence and substantial clinical and economic burden. Therefore, physicians should identify patients with bronchiectasis at high risk of disease progression to ensure optimal management in advance. The heterogeneity of bronchiectasis means it is unlikely that any single parameter could identify high-risk patients, therefore disease severity is usually assessed using validated composite tools, such as the Bronchiectasis Severity Index, FACED, and Bronchiectasis Aetiology Comorbidity Index, to predict long-term outcomes in bronchiectasis. Disease severity, however, implies an advanced process with lung destruction. Earlier intervention may prevent disease progression and improve outcomes. To identify patients at risk, rather than patients with established advanced disease, we need to shift our focus from disease severity to disease activity. Disease activity denotes the activation level of underlying pathophysiological processes and can be measured using clinical presentations and biomarkers. This review discusses a paradigm shift in bronchiectasis management, focusing on disease activity rather than severity, to prevent disease progression.

Bronchiectasis in Asia: a review of current status and challenges.

Recent bronchiectasis studies from large-scale multinational, multicentre registries have demonstrated that the characteristics of the disease vary according to geographic region. However, most perspectives on bronchiectasis are dominated by data from Western countries. This review intends to provide an Asian perspective on the disease, focusing on the established registries in India, Korea and China. Asian patients with bronchiectasis are less likely to show female predominance and experience exacerbations, are more likely to be younger, have milder disease, and have fewer options for guideline-recommended treatment than those living in other global regions. Furthermore, Asian bronchiectasis patients demonstrate different comorbidities, microbiological profiles and unique endophenotypes, including post-tuberculosis and dry bronchiectasis. Notably, each Asian region reveals further geographic variations and inter-patient differences. Future studies are warranted to better characterise Asian patients with bronchiectasis.

The impact of pulmonary tuberculosis on SARS-CoV-2 infection: a nationwide cohort study.

Background: The interaction between COVID-19 and tuberculosis (TB) is not yet fully understood, and large-scale research on the mortality outcome of such dual infection has been limited. This study aimed to investigate the impact of PTB on mortality among patients with COVID-19 within a Korean population by conducting an extensive analysis of a nationwide large dataset. Method: We investigated the mortality and disease severity among COVID-19 patients who had PTB in South Korea. This study analyzed 462,444 out of 566,494 COVID-19 patients identified between January 2020 and December 2021. Result: A total of 203 COVID-19 with PTB patients and 812 matched COVID-19 without PTB were analyzed using 1:4 propensity score matching. COVID-19 patients with PTB exhibited higher in-hospital mortality (odds ratio (OR) 3.02, 95% confidence interval (CI) 1.45-6.27, p-value = 0.003) and were at increased risk of requiring conventional oxygen therapy (OR 1.57, 95% CI 1.10-2.25, p-value = 0.013) as well as high flow nasal cannula (HFNC) or noninvasive ventilation (NIV) oxygen therapy (OR 1.91, 95 CI 1.10-3.32, p-value = 0.022) compared to those without PTB. Compared to matched COVID-19 without PTB, co-infected patients showed increased mortality rates across various timeframes, including during hospitalization, and at 30 day and 90 day intervals. In-hospital mortality rates were particularly elevated among women, individuals with malignancy, and those with lower incomes. Furthermore, the increased in-hospital mortality among PTB patients persisted irrespective of the timing of TB diagnosis or vaccination status against COVID-19. Conclusion: We suggest that physicians be aware of the risk of mortality and severity among COVID-19 patients with PTB; coinfection with COVID-19 is a critical situation that remains to be further explored and needs more attention in countries with an intermediate to high PTB burden.

Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2.

Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta-amyloid (Aß) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2-mediated phagocytosis of beta-amyloid (Aß) plaques remains unknown. Here, using advanced 2D/3D/4D co-culture systems with loss-of-function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aß via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aß plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR-Cas9-based APOE4 lines) and familial (APPNL-G-F/MAPT double knock-in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer-positive Aß plaques. Herein new insight is provided into TREM2-dependent microglial phagocytosis of Aß plaques in the context of the presence of ePtdSer during AD progression.

Tyrosol blocks E. coli anaerobic biofilm formation via YbfA and FNR to increase antibiotic susceptibility.

Bacteria within mature biofilms are highly resistant to antibiotics than planktonic cells. Oxygen limitation contributes to antibiotic resistance in mature biofilms. Nitric oxide (NO) induces biofilm dispersal; however, low NO levels stimulate biofilm formation, an underexplored process. Here, we introduce a mechanism of anaerobic biofilm formation by investigating the antibiofilm activity of tyrosol, a component in wine. Tyrosol inhibits E. coli and Pseudomonas aeruginosa biofilm formation by enhancing NO production. YbfA is identified as a target of tyrosol and its downstream targets are sequentially determined. YbfA activates YfeR, which then suppresses the anaerobic regulator FNR. This suppression leads to decreased NO production, elevated bis-(3'-5')-cyclic dimeric GMP levels, and finally stimulates anaerobic biofilm formation in the mature stage. Blocking YbfA with tyrosol treatment renders biofilm cells as susceptible to antibiotics as planktonic cells. Thus, this study presents YbfA as a promising antibiofilm target to address antibiotic resistance posed by biofilm-forming bacteria, with tyrosol acting as an inhibitor.

Effects of work environments on satisfaction of nurses working for integrated care system in South Korea: a multisite cross-sectional investigation.

BACKGROUND: Nurses' satisfaction has an impact on organizational and patient outcomes. Integrated care system in South Korea was established in 2015 to improve care quality and decrease caregiving burden. Since then, nurses' satisfaction has increased due to an increase in nursing staffing. However, besides nurse staffing, various work environments still affect nurse satisfaction. METHODS: Individual online surveys were conducted with participants to determine their personal characteristics, work environments, and hospital characteristics. We used mixed-effects linear regression equation contained both fixed and random effects. RESULTS: This study included 2,913 nurses from 119 hospitals. Their average job satisfaction was less than 6 points out of 10 points. Age, shift type, perceived workload, and delegation criteria were significant factors influencing nurses' satisfaction. There was no significant factor among hospital characteristics. The satisfaction level of nurses was high for no-night rotating shift, low perceived workload, and clear delegation criteria. CONCLUSIONS: Nurses' satisfaction is affected by several work environmental factors. Low nurse satisfaction has a substantial impact on both patients and nurses. Therefore, nurse managers and hospitals should determine factors influencing their satisfaction and develop strategies to improve their satisfaction.

Increased bronchiectasis risk and related risk factors in inflammatory bowel disease: a 10-year Korean national cohort study.

Background: The association between inflammatory bowel disease (IBD) and an increased risk of bronchiectasis, as well as contributing factors, remains unclear. Additionally, whether bronchiectasis increases disease burden in IBD remains unknown. Therefore, this study aimed to: 1) assess whether IBD increases the risk of incident bronchiectasis; 2) compare the risk of bronchiectasis between individuals with Crohn's disease (CD) and those with ulcerative colitis (UC); 3) identify risk factors for bronchiectasis in individuals with IBD; and 4) examine the disease burden in individuals with IBD and bronchiectasis versus those without. Methods: We conducted a population-based matched cohort study involving adults aged ≥20 years with IBD, using data acquired from the Korean National Health Insurance Service-National Sample Cohort database between 2002 and 2012. Results: During the mean follow-up of 9.6 years, the incidence rate of bronchiectasis was 419.63 out of 100 000 person-years (PY) and 309.65 out of 100 000 PY in the IBD and matched cohorts (adjusted hazard ratio (aHR) 1.21, 95% CI 1.05-1.39), respectively. UC was associated with increased bronchiectasis risk (aHR 1.42, 95% CI 1.19-1.69), but CD was not. Multivariate Cox regression analyses showed that age, male sex, medical aid, underweight status, COPD and diabetes mellitus were associated with an increased risk of bronchiectasis in the IBD cohort (p<0.05). The mortality, emergency department visit and hospitalisation rates were significantly higher for individuals with IBD and bronchiectasis compared with those without bronchiectasis (p<0.05). Conclusion: IBD is associated with increased risk of bronchiectasis, which results in a greater disease burden in individuals with IBD.

Uncovering COVID-19 transmission tree: identifying traced and untraced infections in an infection network.

Introduction: This paper presents a comprehensive analysis of COVID-19 transmission dynamics using an infection network derived from epidemiological data in South Korea, covering the period from January 3, 2020, to July 11, 2021. The network illustrates infector-infectee relationships and provides invaluable insights for managing and mitigating the spread of the disease. However, significant missing data hinder conventional analysis of such networks from epidemiological surveillance. Methods: To address this challenge, this article suggests a novel approach for categorizing individuals into four distinct groups, based on the classification of their infector or infectee status as either traced or untraced cases among all confirmed cases. The study analyzes the changes in the infection networks among untraced and traced cases across five distinct periods. Results: The four types of cases emphasize the impact of various factors, such as the implementation of public health strategies and the emergence of novel COVID-19 variants, which contribute to the propagation of COVID-19 transmission. One of the key findings is the identification of notable transmission patterns in specific age groups, particularly in those aged 20-29, 40-69, and 0-9, based on the four type classifications. Furthermore, we develop a novel real-time indicator to assess the potential for infectious disease transmission more effectively. By analyzing the lengths of connected components, this indicator facilitates improved predictions and enables policymakers to proactively respond, thereby helping to mitigate the effects of the pandemic on global communities. Conclusion: This study offers a novel approach to categorizing COVID-19 cases, provides insights into transmission patterns, and introduces a real-time indicator for better assessment and management of the disease transmission, thereby supporting more effective public health interventions.

Eosinophilia Is a Favorable Marker for Pneumonia in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) expressing eosinophilia experience slightly fewer episodes of community-acquired pneumonia (CAP), than those without eosinophilia. However, the severity and burden of hospitalized pneumonia patients with COPD involving eosinophilia have not been assessed. METHODS: We evaluated the differences in clinical characteristics between patients with CAP and COPD with or without eosinophilia by a post hoc analysis of a prospective, multi-center, cohort study data. RESULTS: Of 349 CAP patients with COPD, 45 (12.9%) had eosinophilia (blood eosinophil ≥300 cells/µL). Patients with eosinophilia had a lower sputum culture percentile (8.1% vs. 23.4%, p<0.05), a lower percentile of neutrophils (70.3% vs. 80.2%, p<0.05), reduced C-reactive protein levels (30.6 mg/L vs. 86.6 mg/L, p<0.05), and a lower pneumonia severity index score (82.5 vs. 90.0, p<0.05), than those without eosinophilia. The duration of antibiotic treatment (8.0 days vs. 10.0 days, p<0.05) and hospitalization (7.0 days vs. 9.0 days, p<0.05) were shorter in eosinophilic patients. The cost of medical care per day (256.4 US$ vs. 291.0 US$, p<0.05), cost for the medication (276.4 US$ vs. 349.9 US$, p<0.05), and cost for examination (685.5 US$ vs. 958.1 US$, p<0.05) were lower in patients with eosinophilia than those without eosinophilia. CONCLUSION: Eosinophilia serves as a favorable marker for the severity of pneumonia, health-care consumption, and cost of medical care in patients with CAP and COPD.

Endotypes of Exacerbation in Bronchiectasis: An Observational Cohort Study.

Rationale: Bronchiectasis is characterized by acute exacerbations, but the biological mechanisms underlying these events are poorly characterized. Objectives: To investigate the inflammatory and microbial characteristics of exacerbations of bronchiectasis. Methods: A total of 120 patients with bronchiectasis were enrolled and presented with acute exacerbations within 12 months. Spontaneous sputum samples were obtained during a period of clinical stability and again at exacerbation before receipt of antibiotic treatment. A validated rapid PCR assay for bacteria and viruses was used to classify exacerbations as bacterial, viral, or both. Sputum inflammatory assessments included label-free liquid chromatography-tandem mass spectrometry and measurement of sputum cytokines and neutrophil elastase activity. 16 s rRNA sequencing was used to characterize the microbiome. Measurements and Main Results: Bronchiectasis exacerbations showed profound molecular heterogeneity. At least one bacterium was identified in 103 samples (86%), and a high bacterial load (total bacterial load > 107 copies/g) was observed in 81 patients (68%). Respiratory viruses were identified in 55 (46%) patients, with rhinovirus being the most common virus (31%). PCR testing was more sensitive than culture. No consistent change in the microbiome was observed at exacerbation. Exacerbations were associated with increased neutrophil elastase, proteinase-3, IL-1ß, and CXCL8. These markers were particularly associated with bacterial and bacterial plus viral exacerbations. Distinct inflammatory and microbiome profiles were seen between different exacerbation subtypes, including bacterial, viral, and eosinophilic events in both hypothesis-led and hypothesis-free analysis using integrated microbiome and proteomics, demonstrating four subtypes of exacerbation. Conclusions: Bronchiectasis exacerbations are heterogeneous events with contributions from bacteria, viruses, and inflammatory dysregulation.

Respiratory pathogen and clinical features of hospitalized patients in acute exacerbation of chronic obstructive pulmonary disease after COVID 19 pandemic.

Respiratory infections are common causes of acute exacerbation of chronic obstructive lung disease (AECOPD). We explored whether the pathogens causing AECOPD and clinical features changed from before to after the coronavirus disease 2019 (COVID-19) outbreak. We reviewed the medical records of patients hospitalized with AECOPD at four university hospitals between January 2017 and December 2018 and between January 2021 and December. We evaluated 1180 patients with AECOPD for whom medication histories were available. After the outbreak, the number of patients hospitalized with AECOPD was almost 44% lower compared with before the outbreak. Patients hospitalized with AECOPD after the outbreak were younger (75 vs. 77 years, p = 0.003) and more often stayed at home (96.6% vs. 88.6%, p < 0.001) than patients of AECOPD before the outbreak. Hospital stay was longer after the outbreak than before the outbreak (10 vs. 8 days. p < 0.001). After the COVID-19 outbreak, the identification rates of S. pneumoniae (15.3 vs. 6.2%, p < 0.001) and Hemophilus influenzae (6.4 vs. 2.4%, p = 0.002) decreased, whereas the identification rates of P. aeruginosa (9.4 vs. 13.7%, p = 0.023), Klebsiella pneumoniae (5.3 vs. 9.8%, p = 0.004), and methicillin-resistant Staphylococcus aureus (1.0 vs. 2.8%, p = 0.023) increased. After the outbreak, the identification rate of influenza A decreased (10.4 vs. 1.0%, p = 0.023). After the outbreak, the number of patients hospitalized with AECOPD was lower and the identification rates of community-transmitted pathogens tended to decrease, whereas the rates of pathogens capable of chronic colonization tended to increase. During the period of large-scale viral outbreaks that require quarantine, patients with AECOPD might be given more consideration for treatment against strains that can colonize chronic respiratory disease rather than community acquired pathogens.

Bronchiectasis management in adults: state of the art and future directions.

Formerly regarded as a rare disease, bronchiectasis is increasingly recognised. A renewed interest in this disease has led to significant progress in bronchiectasis research. Randomised clinical trials (RCTs) have demonstrated the benefits of airway clearance techniques, inhaled antibiotics and long-term macrolide therapy in bronchiectasis patients. However, the heterogeneity of bronchiectasis remains one of the most challenging aspects of management. Phenotypes and endotypes of bronchiectasis have been identified to help find "treatable traits" and partially overcome disease complexity. The goals of therapy for bronchiectasis are to reduce the symptom burden, improve quality of life, reduce exacerbations and prevent disease progression. We review the pharmacological and non-pharmacological treatments that can improve mucociliary clearance, reduce airway inflammation and tackle airway infection, the key pathophysiological features of bronchiectasis. There are also promising treatments in development for the management of bronchiectasis, including novel anti-inflammatory therapies. This review provides a critical update on the management of bronchiectasis focusing on treatable traits and recent RCTs.

Tuberculosis and osteoporotic fracture risk: development of individualized fracture risk estimation prediction model using a nationwide cohort study.

Purpose: Tuberculosis (TB) is linked to sustained inflammation even after treatment, and fracture risk is higher in TB survivors than in the general population. However, no individualized fracture risk prediction model exists for TB survivors. We aimed to estimate fracture risk, identify fracture-related factors, and develop an individualized risk prediction model for TB survivors. Methods: TB survivors (n = 44,453) between 2010 and 2017 and 1:1 age- and sex-matched controls were enrolled. One year after TB diagnosis, the participants were followed-up until the date of fracture, death, or end of the study period (December 2018). Cox proportional hazard regression analyses were performed to compare the fracture risk between TB survivors and controls and to identify fracture-related factors among TB survivors. Results: During median 3.4 (interquartile range, 1.6-5.3) follow-up years, the incident fracture rate was significantly higher in TB survivors than in the matched controls (19.3 vs. 14.6 per 1,000 person-years, p < 0.001). Even after adjusting for potential confounders, TB survivors had a higher risk for all fractures (adjusted hazard ratio 1.27 [95% confidence interval 1.20-1.34]), including hip (1.65 [1.39-1.96]) and vertebral (1.35 [1.25-1.46]) fractures, than matched controls. Fracture-related factors included pulmonary TB, female sex, older age, heavy alcohol consumption, reduced exercise, and a higher Charlson Comorbidity Index (p < 0.05). The individualized fracture risk model showed good discrimination (concordance statistic = 0.678). Conclusion: TB survivors have a higher fracture risk than matched controls. An individualized prediction model may help prevent fractures in TB survivors, especially in high-risk groups.

Improved weight initialization for deep and narrow feedforward neural network.

Appropriate weight initialization settings, along with the ReLU activation function, have become cornerstones of modern deep learning, enabling the training and deployment of highly effective and efficient neural network models across diverse areas of artificial intelligence. The problem of "dying ReLU," where ReLU neurons become inactive and yield zero output, presents a significant challenge in the training of deep neural networks with ReLU activation function. Theoretical research and various methods have been introduced to address the problem. However, even with these methods and research, training remains challenging for extremely deep and narrow feedforward networks with ReLU activation function. In this paper, we propose a novel weight initialization method to address this issue. We establish several properties of our initial weight matrix and demonstrate how these properties enable the effective propagation of signal vectors. Through a series of experiments and comparisons with existing methods, we demonstrate the effectiveness of the novel initialization method.

Genetic characterization of a locus responsible for low pungency using EMS-induced mutants in Capsicum annuum L.

KEY MESSAGE: The pepper mutants ('221-2-1a' and '1559-1-2h') with very low pungency were genetically characterized. The Pun4 locus, responsible for the reduced pungency of the mutant fruits, was localized to a 208 Mb region on chromosome 6. DEMF06G16460, encoding 3-ketoacyl-CoA synthase, was proposed as a strong candidate gene based on the genetic analyses of bulked segregants, DEG, and expression analyses. Capsaicinoids are unique alkaloids present in pepper (Capsicum spp.), synthesized through the condensation of by-products from the phenylpropanoid and branched-chain fatty acid pathways, and accumulating in the placenta. In this study, we characterized two allelic ethyl methanesulfonate-induced mutant lines with extremely low pungency ('221-2-1a' and '1559-1-2h'). These mutants, derived from the pungent Korean landrace 'Yuwolcho,' exhibited lower capsaicinoid content than Yuwolcho but still contained a small amount of capsaicinoid with functional capsaicinoid biosynthetic genes. Genetic crosses between the mutants and Yuwolcho or pungent lines indicated that a single recessive mutation was responsible for the low-pungency phenotype of mutant 221-2-1a; we named the causal locus Pungency 4 (Pun4). To identify Pun4, we combined genome-wide polymorphism analysis and transcriptome analysis with bulked-segregant analysis. We narrowed down the location of Pun4 to a 208-Mb region on chromosome 6 containing five candidate genes, of which DEMF06G16460, encoding a 3-ketoacyl-CoA synthase associated with branched-chain fatty acid biosynthesis, is the most likely candidate for Pun4. The expression of capsaicinoid biosynthetic genes in placental tissues in Yuwolcho and the mutant was consistent with the branched-chain fatty acid pathway playing a pivotal role in the lower pungency observed in the mutant. We also obtained a list of differentially expressed genes in placental tissues between the mutant and Yuwolcho, from which we selected candidate genes using gene co-expression analysis. In summary, we characterized the capsaicinoid biosynthesis-related locus Pun4 through integrated of genetic, genomic, and transcriptome analyses. These findings will contribute to our understanding of capsaicinoid biosynthesis in pepper.

Increased Risk of Incident Chronic Obstructive Pulmonary Disease and Related Hospitalizations in Tuberculosis Survivors: A Population-Based Matched Cohort Study.

BACKGROUND: Tuberculosis (TB) survivors have an increased risk of developing chronic obstructive pulmonary disease (COPD). This study assessed the risk of COPD development and COPD-related hospitalization in TB survivors compared to controls. METHODS: We conducted a population-based cohort study of TB survivors and 1:1 age- and sex-matched controls using data from the Korean National Health Insurance Service database collected from 2010 to 2017. We compared the risk of COPD development and COPD-related hospitalization between TB survivors and controls. RESULTS: Of the subjects, 9.6% developed COPD, and 2.8% experienced COPD-related hospitalization. TB survivors had significantly higher COPD incidence rates (36.7/1,000 vs. 18.8/1,000 person-years, P < 0.001) and COPD-related hospitalization (10.7/1,000 vs. 4.3/1,000 person-years, P < 0.001) than controls. Multivariable Cox regression analyses revealed higher risks of COPD development (adjusted hazard ratio [aHR], 1.63; 95% confidence interval [CI], 1.54-1.73) and COPD-related hospitalization (aHR, 2.03; 95% CI, 1.81-2.27) in TB survivors. Among those who developed COPD, the hospitalization rate was higher in individuals with post-TB COPD compared to those with non-TB COPD (10.7/1,000 vs. 4.9/1,000 person-years, P < 0.001), showing an increased risk of COPD-related hospitalization (aHR, 1.84; 95% CI, 1.17-2.92). CONCLUSION: TB survivors had higher risks of incident COPD and COPD-related hospitalization compared to controls. These results suggest that previous TB is an important COPD etiology associated with COPD-related hospitalization.

Brain hypothyroidism silences the immune response of microglia in Alzheimer's disease animal model.

Thyroid hormone (TH) imbalance is linked to the pathophysiology of reversible dementia and Alzheimer's disease (AD). It is unclear whether tissue hypothyroidism occurs in the AD brain and how it affects on AD pathology. We find that decreased iodothyronine deiodinase 2 is correlated with hippocampal hypothyroidism in early AD model mice before TH alterations in the blood. TH deficiency leads to spontaneous activation of microglia in wild-type mice under nonstimulated conditions, resulting in lowered innate immune responses of microglia in response to inflammatory stimuli or amyloid-ß. In AD model mice, TH deficiency aggravates AD pathology by reducing the disease-associated microglia population and microglial phagocytosis. We find that TH deficiency reduces microglial ecto-5'-nucleotidase (CD73) and inhibition of CD73 leads to impaired innate immune responses in microglia. Our findings reveal that TH shapes microglial responses to inflammatory stimuli including amyloid-ß, and brain hypothyroidism in early AD model mice aggravates AD pathology by microglial dysfunction.

The Efficacy and Safety of Inhaled Antibiotics for the Treatment of Bronchiectasis in Adults: Updated Systematic Review and Meta-Analysis.

BACKGROUND: Inhaled antibiotics are recommended conditionally by international bronchiectasis guidelines for the treatment of patients with bronchiectasis, but results of individual studies are inconsistent. A previous meta-analysis demonstrated promising results regarding the efficacy and safety of inhaled antibiotics in bronchiectasis. Subsequent publications have supplemented the existing body of evidence further in this area. RESEARCH QUESTION: To what extent do inhaled antibiotics demonstrate both efficacy and safety as a treatment option for adults with bronchiectasis? STUDY DESIGN AND METHODS: Systematic review and meta-analysis of randomized controlled trials of inhaled antibiotics in adult patients with bronchiectasis. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for eligible studies. Studies were included if they enrolled adults with bronchiectasis diagnosed by CT imaging and had a treatment duration of at least 4 weeks. The primary end point was exacerbation frequency, with additional key efficacy end points including severe exacerbations, bacterial load, symptoms, quality of life, and FEV1. Data were pooled through random-effects meta-analysis. RESULTS: Twenty studies involving 3,468 patients were included. Inhaled antibiotics were associated with reduced number of patients with exacerbations (risk ratio, 0.85; 95% CI, 0.75-0.96), a slight reduction in exacerbation frequency (rate ratio [RR], 0.78; 95% CI, 0.68-0.91), a probable reduction in the frequency of severe exacerbations (RR, 0.48; 95% CI, 0.31-0.74), and a likely slight increase in time to first exacerbation (hazard ratio, 0.80; 95% CI, 0.68-0.94). Inhaled antibiotics likely lead to a slight increase in the Quality of Life Questionnaire-Bronchiectasis respiratory symptom score (mean difference, 2.51; 95% CI, 0.44-4.31) and may reduce scores on the St. George Respiratory Questionnaire (mean difference, -3.13; 95% CI, -5.93 to -0.32). Bacterial load consistently was reduced, but FEV1 was not changed with treatment. Evidence suggests little to no difference in adverse effects between groups (OR, 0.99; 95% CI, 0.75-1.30). Antibiotic-resistant organisms likely were increased by treatment. INTERPRETATION: In this systematic review and meta-analysis, inhaled antibiotics resulted in a slight reduction in exacerbations, a probable reduction in severe exacerbations, and a likely slight improvement in symptoms and quality of life in adults with bronchiectasis. TRIAL REGISTRY: International Prospective Register of Systematic Reviews; No.: CRD42023384694; URL: https://www.crd.york.ac.uk/prospero/.