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We have investigated the effect of methylprednisolone on the intracellular activity of erythromycin and clindamycin in vitro. An assay system was developed for the determination of intracellular activity of antibiotics against Legionella pneumophila using guinea pig resident alveolar macrophages. Erythromycin at a concentration of 0.625 mg/L (5 x MIC) and clindamycin at a concentration of 8 mg/L (MIC) inhibited the growth of a single strain of L. pneumophila in macrophages, whilst ceftizoxime at a concentration of 0.625 mg/L (5 x MIC) did not. Methylprednisolone at therapeutic concentrations did not affect the intracellular antibacterial activity of either erythromycin or clindamycin against L. pneumophila. We found no direct effect of methylprednisolone on the intracellular antibacterial activity of either erythromycin or clindamycin. [ABSTRACT FROM AUTHOR]

Abstract Article Retracted

Abstract Background Hepatocyte growth factor (HGF) is known to be involved in the resolution of pulmonary inflammation and repair of acute lung injury. Legionella pneumonia is sometimes complicated by acute lung injury. Our study aimed to determine the role of serum HGF levels in Legionella pneumonia. Methods Sera from patients with Legionella pneumonia (42 cases), other bacterial pneumonia (33 cases), pulmonary tuberculosis (19 cases), and normal controls (29 cases) were collected. The serum HGF levels for each serum sample were determined by sandwich ELISA. Clinical and laboratory data were collected by reviewing the medical charts. Results Serum HGF levels were higher in patients with Legionella pneumonia than in those with other bacterial pneumonia, pulmonary tuberculosis, and controls. The HGF levels were compared with white blood cell counts, C-reactive protein, Alanine amino- transferase, and lactate dehydrogenase (LDH). The HGF levels were correlated to serum LDH levels. Moreover, serum HGF levels were significantly higher in non-survivors than in survivors. Conclusions HGF levels increased in severer pneumonia caused by Legionella, suggesting that HGF might play a significant role in the Legionella pneumonia.

Abstract Background Legionella pneumophila is the causative agent of human Legionnaire's disease. During infection, the bacterium invades macrophages and lung epithelial cells, and replicates intracellularly. However, little is known about its interaction with T cells. We investigated the ability of L. pneumophila to infect and stimulate the production of interleukin-8 (IL-8) in T cells. The objective of this study was to assess whether L. pneumophila interferes with the immune system by interacting and infecting T cells. Results Wild-type L. pneumophila and flagellin-deficient Legionella, but not L. pneumophila lacking a functional type IV secretion system Dot/Icm, replicated in T cells. On the other hand, wild-type L. pneumophila and Dot/Icm-deficient Legionella, but not flagellin-deficient Legionella or heat-killed Legionella induced IL-8 expression. L. pneumophila activated an IL-8 promoter through the NF-κB and AP-1 binding regions. Wild-type L. pneumophila but not flagellin-deficient Legionella activated NF-κB, p38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinase (JNK), and transforming growth factor β-associated kinase 1 (TAK1). Transfection of dominant negative mutants of IκBα, IκB kinase, NF-κB-inducing kinase, TAK1, MyD88, and p38 MAPK inhibited L. pneumophila-induced IL-8 activation. Inhibitors of NF-κB, p38 MAPK, and JNK blocked L. pneumophila-induced IL-8 expression. In addition, c-Jun, JunD, cyclic AMP response element binding protein, and activating transcription factor 1, which are substrates of p38 MAPK and JNK, bound to the AP-1 site of the IL-8 promoter. Conclusions Taken together, L. pneumophila induced a flagellin-dependent activation of TAK1, p38 MAPK, and JNK, as well as NF-κB and AP-1, which resulted in IL-8 production in human T cells, presumably contributing to the immune response in Legionnaire's disease.

Abstract Background Legionella pneumophila pneumonia often exacerbates acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Apoptosis of alveolar epithelial cells is considered to play an important role in the pathogenesis of ALI and ARDS. In this study, we investigated the precise mechanism by which A549 alveolar epithelial cells induced by L. pneumophila undergo apoptosis. We also studied the effect of methyl prednisolone on apoptosis in these cells. Methods Nuclear deoxyribonucleic acid (DNA) fragmentation and caspase activation in L. pneumophila-infected A549 alveolar epithelial cells were assessed using the terminal deoxyribonucleotidyl transferase-mediated triphosphate (dUTP)-biotin nick end labeling method (TUNEL method) and colorimetric caspase activity assays. The virulent L. pneumophila strain AA100jm and the avirulent dotO mutant were used and compared in this study. In addition, we investigated whether methyl prednisolone has any influence on nuclear DNA fragmentation and caspase activation in A549 alveolar epithelial cells infected with L. pneumophila. Results The virulent strain of L. pneumophila grew within A549 alveolar epithelial cells and induced subsequent cell death in a dose-dependent manner. The avirulent strain dotO mutant showed no such effect. The virulent strains of L. pneumophila induced DNA fragmentation (shown by TUNEL staining) and activation of caspases 3, 8, 9, and 1 in A549 cells, while the avirulent strain did not. High-mobility group box 1 (HMGB1) protein was released from A549 cells infected with virulent Legionella. Methyl prednisolone (53.4 μM) did not influence the intracellular growth of L. pneumophila within alveolar epithelial cells, but affected DNA fragmentation and caspase activation of infected A549 cells. Conclusion Infection of A549 alveolar epithelial cells with L. pneumophila caused programmed cell death, activation of various caspases, and release of HMGB1. The dot/icm system, a major virulence factor of L. pneumophila, is involved in the effects we measured in alveolar epithelial cells. Methyl prednisolone may modulate the interaction of Legionella and these cells.

Abstract Background Legionella pneumophila is a facultative intracellular bacterium, capable of replicating within the phagosomes of macrophages and monocytes, but little is known about its interaction with human lung epithelial cells. We investigated the effect of L. pneumophila on the expression of interleukin-8 (IL-8) in human A549 alveolar and NCI-H292 tracheal epithelial cell lines. Results Infection of L. pneumophila strain, but not heat-killed strain, resulted in upregulation of IL-8. IL-8 mRNA expression was induced immediately after the infection and its signal became gradually stronger until 24 h after infection. On the other hand, IL-8 expression in A549 cells infected with L. pneumophila lacking a functional type IV secretion system was transient. The IL-8 expression was slightly induced at 16 h and increased at 24 h after infection with flagellin-deficient Legionella. Activation of the IL-8 promoter by L. pneumophila infection occurred through the action of nuclear factor-κB (NF-κB). Transfection of dominant negative mutants of NF-κB-inducing kinase, IκB kinase and IκB inhibited L. pneumophila-mediated activation of IL-8 promoter. Treatment with hsp90 inhibitor suppressed L. pneumophila-induced IL-8 mRNA due to deactivation of NF-κB. Conclusion Collectively, these results suggest that L. pneumophila induces activation of NF-κB through an intracellular signaling pathway that involves NF-κB-inducing kinase and IκB kinase, leading to IL-8 gene transcription, and that hsp90 acts as a crucial regulator in L. pneumophila-induced IL-8 expression, presumably contributing to immune response in L. pneumophila. The presence of flagellin and a type IV secretion system are critical for Legionella to induce IL-8 expression in lung epithelial cells.

Background: Legionella pneumophila pneumonia often exacerbates acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Apoptosis of alveolar epithelial cells is considered to play an important role in the pathogenesis of ALI and ARDS. In this study, we investigated the precise mechanism by which A549 alveolar epithelial cells induced by L. pneumophila undergo apoptosis. We also studied the effect of methyl prednisolone on apoptosis in these cells.Methods: Nuclear deoxyribonucleic acid (DNA) fragmentation and caspase activation in L. pneumophila-infected A549 alveolar epithelial cells were assessed using the terminal deoxyribonucleotidyl transferase-mediated triphosphate (dUTP)-biotin nick end labeling method (TUNEL method) and colorimetric caspase activity assays. The virulent L. pneumophila strain AA100jm and the avirulent dotO mutant were used and compared in this study. In addition, we investigated whether methyl prednisolone has any influence on nuclear DNA fragmentation and caspase activation in A549 alveolar epithelial cells infected with L. pneumophila.Results: The virulent strain of L. pneumophila grew within A549 alveolar epithelial cells and induced subsequent cell death in a dose-dependent manner. The avirulent strain dotO mutant showed no such effect. The virulent strains of L. pneumophila induced DNA fragmentation (shown by TUNEL staining) and activation of caspases 3, 8, 9, and 1 in A549 cells, while the avirulent strain did not. High-mobility group box 1 (HMGB1) protein was released from A549 cells infected with virulent Legionella. Methyl prednisolone (53.4 muM) did not influence the intracellular growth of L. pneumophila within alveolar epithelial cells, but affected DNA fragmentation and caspase activation of infected A549 cells.Conclusion: Infection of A549 alveolar epithelial cells with L. pneumophila caused programmed cell death, activation of various caspases, and release of HMGB1. The dot/icm system, a major virulence factor of L. pneumophila, is involved in the effects we measured in alveolar epithelial cells. Methyl prednisolone may modulate the interaction of Legionella and these cells. [ABSTRACT FROM AUTHOR]

Legionella pneumonia is an important cause of community-acquired pneumonia (CAP). The Japanese Respiratory Society (JRS) pneumonia guideline 2024 proposed use of the Legionella Diagnostic Prediction Score for the management of CAP in adults. The committee for the JRS pneumonia guideline is required to verify the validity of the Legionella Diagnostic Prediction Score for the next revision. In addition, it is necessary to determine appropriate cutoff scores by examining all pneumonia cases. In the present study, we validated the usefulness of the Legionella Diagnostic Prediction Score using SARS-CoV-2 Omicron CAP. We analyzed 116 patients with L. pneumophila CAP and 947 patients with SARS-CoV-2 Omicron CAP. Among Omicron cases, the median Legionella Diagnostic Prediction Score was identical among BA.1, BA.2, BA.5, XBB lineage, BA.2.86 and JN.1 subvariants. The median Legionella Diagnostic Prediction Score was significantly higher in the L. pneumophila CAP group than the SARS-CoV-2 Omicron CAP group (4 vs 1, p<0.0001). When targeting all 947 patients with Omicron subvariants, the diagnostic sensitivity and specificity for the presumptive diagnosis of L. pneumophila CAP were 90.5% and 90.8%, respectively, when a total score ≥ 3 points was set as the cutoff level. When the cutoff score was ≥ 4 points, the diagnostic sensitivity and specificity for presumptive diagnosis of L. pneumophila CAP were 76.7% and 99.6%, respectively. Our results demonstrated that the Legionella Diagnostic Prediction Score had good diagnostic ability during the SARS-CoV-2 Omicron variant epidemic period. To set optimal indicators and cutoff values for the Legionella Diagnostic Prediction Score, the policy of the committee for the JRS pneumonia guideline is to continue testing for all pneumonia types., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background and Objective: Since 2023, COVID-19 induced by SARS-CoV-2 XBB variants have been a global epidemic. The XBB variant-induced epidemic was largest in the Okinawa Prefecture among areas in Japan, and healthcare institutions have been burdened by increased COVID-19 hospitalizations. This study aimed to evaluate the clinical features of XBB variant-induced COVID-19 and risk factors for severe COVID-19., Methods: This retrospective study included adult patients hospitalized for COVID-19 between May and July 2023 at four tertiary medical institutions in Okinawa, Japan. Patients with bacterial infection-related complications were excluded. According to oxygen supplementation and intensive care unit admission, patients were divided into two groups, mild and severe. Patient backgrounds, symptoms, and outcomes were compared between both groups, and the risk factors for severe COVID-19 were analyzed using a multivariate logistic regression model., Results: In total of 367 patients included, the median age was 75 years, with 18.5% classified into the severe group. The all-cause mortality rate was 4.9%. Patients in the severe group were more older, had more underlying diseases, and had a higher mortality rate (13.2%) than those in the mild group (3.0%). Multivariate logistic regression analysis showed that diabetes mellitus was an independent risk factor for severe COVID-19 (95% confidence interval [CI], 1.002-3.772), whereas bivalent omicron booster vaccination was an independent factor for less severe COVID-19 (95% CI, 0.203-0.862)., Conclusion: This study implies that assessing risk factors in older adults is particularly important in the era of omicron variants., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ideguchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: In this priority-setting exercise, we sought to identify leading research priorities needed for strengthening future pandemic preparedness and response across countries., Methods: The International Society of Global Health (ISoGH) used the Child Health and Nutrition Research Initiative (CHNRI) method to identify research priorities for future pandemic preparedness. Eighty experts in global health, translational and clinical research identified 163 research ideas, of which 42 experts then scored based on five pre-defined criteria. We calculated intermediate criterion-specific scores and overall research priority scores from the mean of individual scores for each research idea. We used a bootstrap (n = 1000) to compute the 95% confidence intervals., Results: Key priorities included strengthening health systems, rapid vaccine and treatment production, improving international cooperation, and enhancing surveillance efficiency. Other priorities included learning from the coronavirus disease 2019 (COVID-19) pandemic, managing supply chains, identifying planning gaps, and promoting equitable interventions. We compared this CHNRI-based outcome with the 14 research priorities generated and ranked by ChatGPT, encountering both striking similarities and clear differences., Conclusions: Priority setting processes based on human crowdsourcing - such as the CHNRI method - and the output provided by ChatGPT are both valuable, as they complement and strengthen each other. The priorities identified by ChatGPT were more grounded in theory, while those identified by CHNRI were guided by recent practical experiences. Addressing these priorities, along with improvements in health planning, equitable community-based interventions, and the capacity of primary health care, is vital for better pandemic preparedness and response in many settings., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and declare the following activities and/or relationships: IR is the Co-Editor in Chief, PS is the China Regional Editor, and DA is an Editorial Board Member of the Journal of Global Health. To ensure that any possible conflict of interest relevant to the journal has been addressed, this article was reviewed according to best practice guidelines of international editorial organisations., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Objective: Epidemiological information is essential in providing appropriate empiric antimicrobial therapy for pneumonia. This study aimed to clarify the epidemiology of community-acquired pneumonia (CAP) by conducting a systematic review of published studies in Japan., Design: Systematic review., Data Source: PubMed and Ichushi web database (January 1970 to October 2022)., Eligibility Criteria: Clinical studies describing pathogenic micro-organisms in CAP written in English or Japanese, excluding studies on pneumonia other than adult CAP, investigations limited to specific pathogens and case reports., Data Extraction and Synthesis: Patient setting (inpatient vs outpatient), number of patients, concordance with the CAP guidelines, diagnostic criteria and methods for diagnosing pneumonia pathogens as well as the numbers of each isolate. A meta-analysis of various situations was performed to measure the frequency of each aetiological agent., Results: Fifty-six studies were included and 17 095 cases of CAP were identified. Pathogens were undetectable in 44.1% (95% CI 39.7% to 48.5%). Streptococcus pneumoniae was the most common cause of CAP requiring hospitalisation or outpatient care (20.0% (95% CI 17.2% to 22.8%)), followed by Haemophilus influenzae (10.8% (95% CI 7.3% to 14.3%)) and Mycoplasma pneumoniae (7.5% (95% CI 4.6% to 10.4%)). However, when limited to CAP requiring hospitalisation, Staphylococcus aureus was the third most common at 4.9% (95% CI 3.9% to 5.8%). Pseudomonas aeruginosa was more frequent in hospitalised cases, while atypical pathogens were less common. Methicillin-resistant S. aureus accounted for 40.7% (95% CI 29.0% to 52.4%) of S. aureus cases. In studies that used PCR testing for pan-respiratory viral pathogens, human enterovirus/human rhinovirus (9.4% (95% CI 0% to 20.5%)) and several other respiratory pathogenic viruses were detected. The epidemiology varied depending on the methodology and situation., Conclusion: The epidemiology of CAP varies depending on the situation, such as in the hospital versus outpatient setting. Viruses are more frequently detected by exhaustive genetic searches, resulting in a significant variation in epidemiology., Competing Interests: Competing interests: YF: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (Kyorin Pharmaceutical). HM: Grants or contracts (Taiho Pharmaceutical, Meiji Seika Pharma, Kyorin Pharmaceutical, Nippon Boehringer Ingelheim, Taisho Pharma, SHIONOGI, OTSUKA Pharmaceutical), Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (Eli Lilly Japan K.K., Taiho Pharmaceutical, Teijin Healthcare, Bristol-Myers Squibb, Chugai Pharmaceutical, Janssen Pharmaceutical K.K., Meiji Seika Pharma, Asahi Kasei Pharma, Sumitomo Pharma, Kyorin Pharmaceutical, Taisho Pharma, AstraZeneca K.K., Astellas Pharma, SHIONOGI, Daiichi Sankyo, Pfizer, MSD, Nippon Boehringer Ingelheim, FUJIFILM Toyama Chemical, Miyarisan Pharmaceutical, Novartis Pharma K.K, GlaxoSmithKline K.K., Fisher & Paykel Healthcare., Insmed Incorporated, Sanofi K.K., Gilead Sciences., Kyokuto Pharmaceutical Industrial, TAUNS Laboratories, Takeda Pharmaceutical, bioMérieux Japan, Merck Biopharma, Tosoh Corporation, Nippon Kayaku), Payment for expert testimony (Kyorin Pharmaceutical, SHIONOGI, MSD, Gilead Sciences, Janssen Pharmaceutical K.K., Meiji Seika Pharma, Taiho Pharmaceutical, Insmed Incorporated)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Invasive meningococcal disease (IMD) is a major health problem. Given the post-COVID-19 pandemic scenario with the loosening of the non-pharmacological measures to control the virus transmission and considering the observed global reduction of meningococcal vaccination coverage, an increase in IMD cases can be expected., Methodology: Using whole-genome sequencing, we characterized six Neisseria meningitidis serogroup X (MenX) isolates recovered from IMD cases in Brazil in the last 30 years., Results: The predominance (66.6%, 4/6) of ST2888 presenting fHbp 160, NHBA 129, NadA 21, and PorA 19,15 was found on isolates. Two novel STs, 15458 and 15477, were described., Conclusion: This study describes the circulation of MenX lineage ST2888 in Brazil, previously reported only in Europe. Continuous universal surveillance is crucial to implement prompt public health measures aiming to prevent and control non-vaccine preventable serogroup X IMD cases., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Aspiration pneumonia is increasingly recognised as a common condition. While antibiotics covering anaerobes are thought to be necessary based on old studies reporting anaerobes as causative organisms, recent studies suggest that it may not necessarily benefit prognosis, or even be harmful. Clinical practice should be based on current data reflecting the shift in causative bacteria. The aim of this review was to investigate whether anaerobic coverage is recommended in the treatment of aspiration pneumonia., Methods: A systematic review and meta-analysis of studies comparing antibiotics with and without anaerobic coverage in the treatment of aspiration pneumonia was performed. The main outcome studied was mortality. Additional outcomes were resolution of pneumonia, development of resistant bacteria, length of stay, recurrence, and adverse effects. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed., Results: From an initial 2523 publications, one randomised control trial and two observational studies were selected. The studies did not show a clear benefit of anaerobic coverage. Upon meta-analysis, there was no benefit of anaerobic coverage in improving mortality (Odds ratio 1.23, 95% CI 0.67-2.25). Studies reporting resolution of pneumonia, length of hospital stay, recurrence of pneumonia, and adverse effects showed no benefit of anaerobic coverage. The development of resistant bacteria was not discussed in these studies., Conclusion: In the current review, there are insufficient data to assess the necessity of anaerobic coverage in the antibiotic treatment of aspiration pneumonia. Further studies are needed to determine which cases require anaerobic coverage, if any.

Legionella pneumophila is a major causative pathogen of community-acquired pneumonia (CAP), but recently the novel coronavirus disease 2019 (COVID-19) became the most common causative pathogen of CAP. Because L. pneumophila CAP is clinically distinct from bacterial CAPs, the Japan Society for Chemotherapy (JSC) developed a simple scoring system, the Legionella Score, using six parameters for the presumptive diagnosis of L. pneumophila pneumonia. We investigated the clinical and laboratory differences of L. pneumophila CAP and COVID-19 CAP and validated the Legionella Score in both CAP groups. We analyzed 102 patients with L. pneumophila CAP and 956 patients with COVID-19 CAP. Dyspnea and psychiatric symptoms were more frequently observed and cough was less frequently observed in patients with L. pneumophila CAP than those with COVID-19 CAP. Loss of taste and anosmia were observed in patients with COVID-19 CAP but not observed in those with L. pneumophila CAP. C-reactive protein and lactate dehydrogenase levels in L. pneumophila CAP group were significantly higher than in the COVID-19 CAP group. In contrast, sodium level in the L. pneumophila CAP group was significantly lower than in the COVID-19 CAP group. The median Legionella Score was significantly higher in the L. pneumophila CAP group than the COVID-19 CAP group (score 4 vs 2, p < 0.001). Our results demonstrated that the JSC Legionella Score had good diagnostic ability during the COVID-19 pandemic. However, physicians should consider COVID-19 CAP when loss of taste and/or anosmia are observed regardless of the Legionella Score., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: We examine the impact of financial distress caused by the COVID-19 pandemic on mental health and psychological well-being. Methods: We analyze cross-sectional survey data ( n = 2,545) from the Life during Pandemic study in Chile. We estimate linear probability models to analyze the relationship between economic fragility, financial distress, and psychological well-being. Results: Our findings show unemployment and income loss are highly predictive of experiencing a range of financial problems, such as a lack of savings, as well as difficulties paying bills, consumer debt, and mortgage loans. In turn, financial distress leads to a higher prevalence of poor well-being and mental health deterioration, and sleep problems. Conclusion: Expansion of mental health assistance services are needed, as new diagnosis of mental health conditions has increased, but treatment has not, pointing to a barrier in the access to some mental health care services during the pandemic. Policies designed with the objective of improving financial education are necessary to increase precautionary savings and financial resilience, and alleviate the psychological burden of debt in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Borrescio-Higa, Droller and Valenzuela.)

Background: The COVID-19 pandemic has caused disruptions to the functioning of societies and their health systems. Prior to the pandemic, health systems in low- and middle-income countries (LMIC) were particularly stretched and vulnerable. The International Society of Global Health (ISoGH) sought to systematically identify priorities for health research that would have the potential to reduce the impact of the COVID-19 pandemic in LMICs., Methods: The Child Health and Nutrition Research Initiative (CHNRI) method was used to identify COVID-19-related research priorities. All ISoGH members were invited to participate. Seventy-nine experts in clinical, translational, and population research contributed 192 research questions for consideration. Fifty-two experts then scored those questions based on five pre-defined criteria that were selected for this exercise: 1) feasibility and answerability; 2) potential for burden reduction; 3) potential for a paradigm shift; 4) potential for translation and implementation; and 5) impact on equity., Results: Among the top 10 research priorities, research questions related to vaccination were prominent: health care system access barriers to equitable uptake of COVID-19 vaccination (ranked 1st), determinants of vaccine hesitancy (4th), development and evaluation of effective interventions to decrease vaccine hesitancy (5th), and vaccination impacts on vulnerable population/s (6th). Health care delivery questions also ranked highly, including: effective strategies to manage COVID-19 globally and in LMICs (2nd) and integrating health care for COVID-19 with other essential health services in LMICs (3rd). Additionally, the assessment of COVID-19 patients' needs in rural areas of LMICs was ranked 7th, and studying the leading socioeconomic determinants and consequences of the COVID-19 pandemic in LMICs using multi-faceted approaches was ranked 8th. The remaining questions in the top 10 were: clarifying paediatric case-fatality rates (CFR) in LMICs and identifying effective strategies for community engagement against COVID-19 in different LMIC contexts., Interpretation: Health policy and systems research to inform COVID-19 vaccine uptake and equitable access to care are urgently needed, especially for rural, vulnerable, and/or marginalised populations. This research should occur in parallel with studies that will identify approaches to minimise vaccine hesitancy and effectively integrate care for COVID-19 with other essential health services in LMICs. ISoGH calls on the funders of health research in LMICs to consider the urgency and priority of this research during the COVID-19 pandemic and support studies that could make a positive difference for the populations of LMICs., Competing Interests: Competing interests: Ana Marušić, Harry Campbell and Igor Rudan are the Co-Editors in Chief of the Journal of Global Health. To ensure that any possible conflict of interest relevant to the journal has been addressed, this article was reviewed according to best practice guidelines of international editorial organisations. The authors completed the ICMJE Unified Competing Interests Form (available upon request from the corresponding author) and declare no further conflicts of interest., (Copyright © 2022 by the Journal of Global Health. All rights reserved.)

Cancer is the second leading cause of death for children, and leukemias are the most common pediatric cancer diagnoses in Chile. Childhood cancer is a traumatic experience and is associated with distress, pain, and other negative experiences for patients and their families. Thus, psychosocial costs represent a large part of the overall burden of cancer. This study examines psychosocial experiences in a sample of 90 families of children with blood-related cancer in Chile. We provide a global overview of the family experience, focusing on patients, caregivers, and siblings. We find that most families report a negative impact upon diagnosis; disruptions in family dynamics; a range of negative feelings of the patient, such as depression, discouragement, and irritability; and difficulty with social lives. Additionally, they report negative effects in the relationship between the siblings of the patient and their parents, and within their caregivers' spouse/partner relationship, as well as a worsening of the economic condition of the primary caregiver. Furthermore, over half of the families in the sample had to move due to diagnosis and/or treatment. Promoting interventions that can help patients, siblings, and parents cope with distress and promote resilience and well-being are important.

Objective: We explore gender differences in mental health deterioration and psychological well-being due to the COVID-19 pandemic, as well as the mechanisms through which these differences may operate. Methods: Using data from the Life during Pandemic survey in Chile, which covers 2,545 adult respondents, we estimate econometric models to explore gender differences in psychological well-being and mental health as well as economic fragility and household workload during the COVID-19 pandemic. Results: We find women are more likely to report overall bad mental health and deterioration of well-being. They are also more likely to have a new diagnosis of a mental health problem, to be pursuing treatment and taking prescription medication. Moreover, women report an increase in household chores and in childcare, and are more likely to have lost their employment or experienced a loss of income due to the pandemic. Conclusion: Our results offer a general picture of gender differences in the psychological impact of COVID-19. We argue that policies that mitigate economic stress and address the needs of women specifically may ease mental health deterioration due to the pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Borrescio-Higa and Valenzuela.)

Objective: To examine whether the effect of population aging on healthcare expenditures as a share of Gross Domestic Product (GDP) is attenuated in more educated countries. Method: The analysis is based on a dataset of 22 Latin American countries between 1995 and 2013. We estimate panel data models with country and time fixed effects, and control for potential nonlinear effects of population aging on health expenditure. Results: We find population aging increases health expenditure as a share of GDP in economies characterized by low levels of education, but this effect is mitigated in economies with higher levels of education. Results are driven by private health expenditures. Discussion: Results suggest population aging and education have a stronger influence on healthcare expenditures in less developed countries. This finding is important in a context in which the rapid growth of the aging population is likely to lead to significant costs in terms of health expenditures, but less so in more educated societies.

Medical care for children with cancer is complex and expensive, and represents a large financial burden for families around the world. We estimated the medical cost of cancer care for children under the age of 18, using administrative records of the universe of children with private insurance in Chile in the period 2007-2018, based on a sample of 3853 observations. We analyzed total cost and out-of-pocket spending by patients' characteristics, type of cancer, and by service. Children with cancer had high annual medical costs, USD 32,287 on average for 2018. Costs were higher for the younger children in the sample. The vast majority of the cost was driven by inpatient hospital care for all types of cancer. The average total cost increased 20% in real terms over the period of study, while out-of-pocket expenses increased almost 29%. Private insurance beneficiaries faced a significant economic burden associated with medical treatment of a child with cancer. Interventions that reduce hospitalizations, as well as systemwide reforms that incorporate maximum out-of-pocket payments and prevent catastrophic expenditures, can contribute to alleviating the financial burden of childhood cancer.

Objectives: The aim of this study was to evaluate the diagnostic utility of a novel test kit that could theoretically detect all serogroups of Legionella pneumophila for diagnosing Legionella pneumonia, in comparison with existing kits., Methods: This study was conducted in 16 hospitals in Japan from April 2016 to December 2018. Three urinary antigen test kits were used: the novel kit (LAC-116), BinaxNOW Legionella (Binax), and Q-line Kyokutou Legionella (Q-line). In addition, sputum culture and nucleic acid detection tests and serum antibody tests were performed where possible. The diagnostic accuracy and correlations of the novel kit with the two existing kits were analyzed., Results: In total, 56 patients were diagnosed with Legionella pneumonia. The sensitivities of LAC-116, Binax, and Q-line were 79%, 84%, and 71%, respectively. The overall match rate between LAC-116 and Binax was 96.8% and between LAC-116 and Q-line was 96.4%. One patient had L. pneumophila serogroup 2, and only LAC-116 showed a positive result, whereas Binax and Q-line did not., Conclusions: The novel Legionella urinary antigen test kit was useful for diagnosing Legionella pneumonia. In addition, it could detect Legionella pneumonia caused by non-L. pneumophila serogroup 1., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Individuals with tuberculosis (TB) who are being treated with anti-tumor necrosis factor α (anti-TNFα) for coexisting conditions may experience unexpected exacerbations of TB after the initiation of antituberculous therapy, so-called anti-TNFα-induced TB-immune reconstitution inflammatory syndrome (anti-TNFα-induced TB-IRIS). Anti-TNFα-induced TB-IRIS is often treated empirically with corticosteroids; however, the evidence of the effectiveness of corticosteroids is lacking and the management can be a challenge., Patient Concerns: A 32-year-old man on long-term infliximab therapy for Crohn disease visited a clinic complaining of persistent fever and cough that had started 1 week previously. His most recent infliximab injection had been administered 14 days before the visit. A chest X-ray revealed a left pleural effusion, and he was admitted to a local hospital., Diagnosis: A chest computed tomography (CT) scan revealed miliary pulmonary nodules; acid-fast bacilli were found in a sputum smear and a urine sediment sample; and polymerase chain reaction confirmed the presence of Mycobacterium tuberculosis in both his sputum and the pleural effusion. He was diagnosed with miliary TB., Interventions: Antituberculous therapy was started and he was transferred to our hospital for further management. His symptoms initially improved after the initiation of antituberculous therapy, but 2 weeks later, his symptoms recurred and shadows on chest X-ray worsened. A repeat chest CT scan revealed enlarged miliary pulmonary nodules, extensive ground-glass opacities, and an increased volume of his pleural effusion. This paradoxical exacerbation was diagnosed as TB-IRIS associated with infliximab. A moderate-dose of systemic corticosteroid was initiated [prednisolone 25 mg/day (0.5 mg/kg/day)]., Outcomes: After starting corticosteroid treatment, his radiological findings improved immediately, and his fever and cough disappeared within a few days. After discharge, prednisolone was tapered off over the course of 10 weeks, and he completed a 9-month course of antituberculous therapy uneventfully. He had not restarted infliximab at his most recent follow-up 14 months later., Conclusion: We successfully managed a patient with anti-TNFα-induced TB-IRIS using moderate-dose corticosteroids. Due to the limited evidence currently available, physicians should consider the necessity, dosage, and duration of corticosteroids for each case of anti-TNFα-induced TB-IRIS on an individual patient-by-patient basis.

Objective: To measure poverty-based disparities in inpatient length of stay for paediatric hospitalisations. In particular, this paper examines the relationship between municipality level poverty rates and length of stay, accounting for individual level characteristics., Design: We use patient discharge data to conduct a repeated cross-sectional study of the totality of paediatric hospitalisations in 15 regions of Chile, in the years 2011, 2013, 2015 and 2017., Setting: All hospital discharges in 15 regions of Chile., Participants: 1 033 222 discharges for children under the age of 15, between 2011 and 2017., Outcome Measures: Length of stay (LOS); LOS by type of insurance and type of hospital; hospitalisation rates; municipality-level average LOS., Results: We find that municipality level poverty rates are a significant predictor of LOS, even after controlling for individual and area level characteristics, including type of insurance. Children from municipalities in the poorest quintile have a LOS that is 14% shorter as compared with children from municipalities in the richest quintile. This relationship is stronger for publicly insured children: the decrease in LOS associated with the same poverty change is of 22%., Conclusions: This paper shows that there is an association between municipality-level poverty rates and length of stay for paediatric hospitalisations in Chile. For the vast majority of the sample, and after controlling for individual level characteristics, an increase in the municipality level poverty rate is associated with a decrease in the length of stay. Further, there is a non-linearity in the relationship, where at the highest poverty rates, poverty and LOS are positively associated. These findings are robust after controlling for type of hospital (public vs private), type of insurance (public vs private), type of diagnosis, as well as year and region fixed effects., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Legionella species are consistently identified as some of the most common causative agents of severe community-acquired pneumonia (CAP) or nosocomial pneumonia. Although the number of reported Legionella infection cases is gradually increasing in Japan, most cases are diagnosed by a urinary antigen test, which identifies only L. pneumophila serogroup 1. Therefore, assessment of pneumonia-causing Legionella species and serogroups would be important. The Japan Society for Chemotherapy Legionella committee has collected the isolates and clinical information on cases of sporadic community-acquired Legionella pneumonia throughout Japan. Between December 2006 and March 2019, totally 140 sporadic cases were identified, in which L. pneumophila was the most frequently isolated species (90.7%) followed by L. bozemanae (3.6%), L. dumofii (3.6%), L. micdadei (1.4%), and L. longbeachae (0.7%). Among 127 isolates of L. pneumophila, 111 isolates were of serogroup 1, two of serogroup 2, four of serogroup 3, one of serogroup 4, one of serogroup 5, seven of serogroup 6, and one was of serogroup 10. We also assessed in vitro activity of antibiotics against these isolates and showed that quinolones and macrolides have potent anti-Legionella activity. Our study showed that pneumonia-causing Legionella species and serogroup distribution was comparable to that reported in former surveillances. L. pneumophila was the most common etiologic agent in patients with community-acquired Legionella pneumonia, and L. pneumophila serogroup 1 was the predominant serogroup., Competing Interests: Declaration of Competing Interest Naoyuki Miyashita has received speaker honoraria from Daiichi Sankyo Co., Ltd., Astellas Pharma Inc., Pfizer Japan Inc., and Taisho Toyama Pharmaceutical Co., Ltd. Yosuke Aoki has received speaker honoraria from MSD K.K., Shionogi & Co., Ltd. and Pfizer Japan Inc.; and grant support from Shionogi & Co., Ltd. Toshiaki Kikuchi has received grant support from Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Inc., Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., and Astellas Pharma Inc. Masafumi Seki has received speaker honoraria from MSD K.K., Pfizer Japan Inc., Taisho Toyama Pharmaceutical Co., Ltd., and Shionogi & Co., Ltd. Kazuhiro Tateda has received speaker honoraria from Pfizer Japan Inc., MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., Meiji Seika Pharma Co., Ltd. and Taisho Toyama Pharmaceutical Co., Ltd.; research funding from Otsuka Pharmaceutical Co., Ltd., grant support from Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Japan Blood Products Organization, Asahi Kasei Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Shionogi & Co., Ltd., Meiji Seika Pharma Co., Ltd., and Toyama Pharmaceutical Co., Ltd.; and donations from Kyorin Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Astellas Pharma Inc., Meiji Seika Pharma Co., Ltd., Daiichi Sankyo Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., and MSD K.K. Nobuko Maki is an employee of Taisho Toyama Pharmaceutical Co., Ltd. Kazuhiko Uchino is an employee of Daiichi Sankyo Co., Ltd. Hiroshi Kiyota has received grant support from Taisho Toyama Pharmaceutical Co., Ltd., Toyama Chemical Co., Ltd., Daiichi Sankyo Co., Ltd., Astellas Pharma Inc., and Taiho Pharmaceutical Co., Ltd. Akira Watanabe has received speaker honoraria from MSD K.K., Kobayashi Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Daiichi Sankyo Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Pfizer Japan Inc., UCB Japan Co. Ltd., AbbVie GK and GlaxoSmithKline K.K.; donations from Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., and Sumitomo Dainippon Pharma Co., Ltd.; payments for manuscript drafting and editing from Iyaku (Medicine and Drug) Journal Co., Ltd.; and grant support from Kyorin Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Daiichi Sankyo Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Toyama Chemical Co., Ltd., Fujifilm Pharma Co., Ltd., and Meiji Seika Pharma Co., Ltd., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Serum markers that differentiate between tuberculous and non-tuberculous pneumonia would be clinically useful. However, few serum markers have been investigated for their association with either disease. In this study, serum levels of interferon gamma (IFN-γ), matrix metalloproteinases 1 and 9 (MMP-1 and MMP-9, respectively), and periostin were compared between 40 pulmonary tuberculosis (PTB) and 28 non-tuberculous pneumonia (non-PTB) patients. Diagnostic performance was assessed by analysis of receiver-operating characteristic (ROC) curves and classification trees. Serum IFN-γ and MMP-1 levels were significantly higher and serum MMP-9 levels significantly lower in PTB than in non-PTB patients (p < 0.001, p = 0.002, p < 0.001, respectively). No significant difference was observed in serum periostin levels between groups. ROC curve analysis could not determine the appropriate cut-off value with high sensitivity and specificity; therefore, a classification tree method was applied. This method identified patients with limited infiltration into three groups with statistical significance (p = 0.01), and those with MMP-1 levels < 0.01 ng/mL and periostin levels ≥ 118.8 ng/mL included only non-PTB patients (95% confidence interval 0.0-41.0). Patients with extensive infiltration were also divided into three groups with statistical significance (p < 0.001), and those with MMP-9 levels < 3.009 ng/mL included only PTB patients (95% confidence interval 76.8-100.0). In conclusion, the novel classification tree developed using MMP-1, MMP-9, and periostin data distinguished PTB from non-PTB patients. Further studies are needed to validate our cut-off values and the overall clinical usefulness of these markers., Competing Interests: The authors have declared that no competing interests exist.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2014. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between January 2014 and April 2015 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standards Institute. Susceptibility testing was evaluated in 1534 strains (335 Staphylococcus aureus, 264 Streptococcus pneumoniae, 29 Streptococcus pyogenes, 281 Haemophilus influenzae, 164 Moraxella catarrhalis, 207 Klebsiella pneumoniae, and 254 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 43.6%, and those of penicillin-susceptible S. pneumoniae was 100%. Among H. influenzae, 8.2% of them were found to be β-lactamase-producing ampicillin-resistant strains, and 49.1% to be β-lactamase-non-producing ampicillin-resistant strains. Extended spectrum β-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo β-lactamase were 9.2% and 0.4%, respectively., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Community-acquired pneumonia (CAP) due to Legionella has a high mortality rate in patients who do not receive adequate antibiotic therapy. In a previous study, we developed a simple Legionella Score to distinguish patients with Legionella and non-Legionella pneumonia based on clinical information at diagnosis. In the present study, we validated this Legionella Score for the presumptive diagnosis of Legionella CAP., Methods: This validation cohort included 109 patients with Legionella CAP and 683 patients with non-Legionella CAP. The Legionella Score includes six parameters by assigning one point for each of the following items: being male, absence of cough, dyspnea, C-reactive protein (CRP) ≥ 18 mg/dL, lactate dehydrogenase (LDH) ≥ 260 U/L, and sodium < 134 mmol/L., Results: When the Legionella CAP and non-Legionella CAP were compared by univariate analysis, most of the evaluated symptoms and laboratory test results differed substantially. The six parameters that were used for the Legionella Score also indicated clear differences between the Legionella and non-Legionella CAP. All Legionella patients had a score of 2 points or higher. The median Legionella Scores were 4 in the Legionella CAP cases and 2 in the non-Legionella CAP cases. A receiver operating characteristics curve showed that the area under the curve was 0.93. The proposed best cutoff, total score ≥3, had sensitivity of 93% and specificity of 75%., Conclusion: Our Legionella Score was shown to have good diagnostic ability with a positive likelihood of 3.7 and a negative likelihood of 0.10., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)