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Daniel Hsiang-Te Tsai,1,2 J Simon Bell,3 Shahab Abtahi,4 Brenda N Baak,5 Marloes T Bazelier,4 Ruth Brauer,6 Adrienne YL Chan,6– 9 Esther W Chan,9– 12 Haoqian Chen,13 Celine SL Chui,9,14,15 Sharon Cook,16 Stephen Crystal,16 Poonam Gandhi,13 Sirpa Hartikainen,17 Frederick K Ho,18 Shao-Ti Hsu,1 Jenni Ilomäki,3 Ju Hwan Kim,19 Olaf H Klungel,4 Marjaana Koponen,17 Wallis CY Lau,6,8,9 Kui Kai Lau,20,21 Terry YS Lum,22 Hao Luo,22 Kenneth KC Man,6,8,9 Jill P Pell,18 Soko Setoguchi,13,23 Shih-Chieh Shao,1,24 Chin-Yao Shen,1 Ju-Young Shin,19,25,26 Patrick C Souverein,4 Anna-Maija Tolppanen,17 Li Wei,6,9 Ian CK Wong,6,8,9,27 Edward Chia-Cheng Lai1 1School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Centre for Neonatal and Paediatric Infection, St George’s University of London, London, UK; 3Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia; 4Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; 5PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 6Research Department of Practice and Policy, UCL School of Pharmacy, London, UK; 7Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, ‐Epidemiology and ‐Economics, University of Groningen, Groningen, the Netherlands; 8Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 9Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Hong Kong, Special Administrative Region, People’s Republic of China; 10Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 11Department of Pharmacy, the University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China; 12The University of Hong Kong Shenzhen Institute of Research and Innovation, Shenzhen, People’s Republic of China; 13Center for Pharmacoepidemiology and Treatment Science (PETS), Institute for Health, Rutgers University, New Brunswick, NJ, USA; 14School of Nursing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 15School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 16Center for Health Services Research, Rutgers University, New Brunswick, NJ, USA; 17Kuopio Research Centre of Geriatric Care and School of Pharmacy, University of Eastern Finland, Kuopio, Finland; 18School of Health and Wellbeing, University of Glasgow, Glasgow, UK; 19School of Pharmacy, Sungkyunkwan University, Suwon, South Korea; 20Division of Neurology, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 21State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 22Department of Social Work and Social Administration, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 23Department of Medicine, Rutgers Robert Wood Johnson Medical School and Pharmacoepidemiology and Treatments Science, Institute for Health, Rutgers University, New Brunswick, NJ, USA; 24Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; 25Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea; 26Department of Biohealth Regulatory Science, Sungkyunkwan University, Seoul, South Korea; 27Aston Pharmacy School, Aston University, Birmingham, UKCorrespondence: Edward Chia-Cheng Lai, School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Email edward_lai@mail.ncku.edu.twPurpose: To describe and categorize detailed components of databases in the Neurological and Mental Health Global Epidemiology Network (NeuroGEN).Methods: An online 132-item questionnaire was sent to key researchers and data custodians of NeuroGEN in North America, Europe, Asia and Oceania. From the responses, we assessed data characteristics including population coverage, data follow-up, clinical information, validity of diagnoses, medication use and data latency. We also evaluated the possibility of conversion into a common data model (CDM) to implement a federated network approach. Moreover, we used radar charts to visualize the data capacity assessments, based on different perspectives.Results: The results indicated that the 15 databases covered approximately 320 million individuals, included in 7 nationwide claims databases from Australia, Finland, South Korea, Taiwan and the US, 6 population-based electronic health record databases from Hong Kong, Scotland, Taiwan, the Netherlands and the UK, and 2 biomedical databases from Taiwan and the UK.Conclusion: The 15 databases showed good potential for a federated network approach using a common data model. Our study provided publicly accessible information on these databases for those seeking to employ real-world data to facilitate current assessment and future development of treatments for neurological and mental disorders.Keywords: meta-data, data repository, Neurological and Mental Health Global Epidemiology Network, NeuroGEN

Ling-bin Shu,1,* Qun Lu,2,* Ren-hua Sun,3 Le-qing Lin,4 Qiao-ling Sun,1 Jie Hu,1 Hong-wei Zhou,1 Edward Wai-Chi Chan,5,6 Sheng Chen,5,6 Rong Zhang11Department of Clinical Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; 2Department of Hospital Infection Management, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; 3Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China; 4Department of Intensive Care Unit, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China; 5Shenzhen Key Lab for Food Biological Safety Control, Food Safety and Technology Research Center, Hong Kong PolyU Shen Zhen Research Institute, Shenzhen, China; 6State Key Lab of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong *These authors contributed equally to this work Objective: To understand the prevalence and transmission of carbapenem-resistant Klebsiella pneumoniae (CRKP) in ICU patients in Zhejiang Province, China, and determined the genetic and phenotypic characteristics of these CRKP strains. Materials and Methods: A total of 202 ICU patients from eight tertiary hospitals were recruited and 55 non-duplicate CRKP strains were collected during July and August in 2017. These strains were subjected to determination of MICs, carriage of carbapenemase genes and tet(A) variants, PFGE, MLST and virulence potential using G. mellonella larvae infection model. Results: A total of 55 CRKP strains were recovered from 42 patients, representing a carriage rate of 20.8%. CRKP strains were recovered from both the intestinal and respiratory tract of 13 patients. Importantly, strains isolated from sputum and fecal samples often displayed identical PFGE profiles, suggesting that CRKP may also colonize the respiratory tract. The most dominant ST type of these CRKP strains was ST11, accounting for 78% (43/55) of the test strains. The majority of CRKP strains were resistant to multiple antibiotics, with the exception of tigecycline and ceftazidime/avibactam. Interestingly, 32 strains were found to harbor the tet(A) variant, which is known to confer reduced tigecycline susceptibility. Assessment of the virulence potential of these CRKP strains by string test showed that results were negative for 53 of the 55 test strains. However, further assessment of virulence potential using a G. mellonella larvae infection model showed that CRKP isolated from sputum consistently exhibited a higher virulence level than strains recovered from fecal samples. Conclusion: CRKP is highly prevalent in ICU patients in Zhejiang Province with strains isolated from respiratory exhibiting higher virulence potential than those from GI tract. These data provide essential insight into development of new infection control measures to halt the transmission of CRKP in clinical settings. Keywords: carbapenem-resistant Klebsiella pneumoniae, surveillance, sputum, feces, ICU, resistance, virulence

Ahmed Nasr,1,2 Katrina J Sullivan,1 Emily W Chan,1 Coralie A Wong,3 Eric I Benchimol2–5 1Department of Pediatric Surgery, Children’s Hospital of Eastern Ontario, 2Faculty of Medicine, University of Ottawa, 3Institute for Clinical Evaluative Science (ICES University of Ottawa), 4CHEO Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Eastern Ontario, 5School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada Objective: Incidence rates of Hirschsprung disease (HD) vary by geographical region, yet no recent population-based estimate exists for Canada. The objective of our study was to validate and use health administrative data from Ontario, Canada to describe trends in incidence of HD between 1991 and 2013.Study design: To identify children with HD we tested algorithms consisting of a combination of diagnostic, procedural, and intervention codes against the reference standard of abstracted clinical charts from a tertiary pediatric hospital. The algorithm with the highest positive predictive value (PPV) that could maintain high sensitivity was applied to health administrative data from April 31, 1991 to March 31, 2014 (fiscal years 1991–2013) to determine annual incidence. Temporal trends were evaluated using Poisson regression, controlling for sex as a covariate.Results: The selected algorithm was highly sensitive (93.5%) and specific (>99.9%) with excellent predictive abilities (PPV 89.6% and negative predictive value >99.9%). Using the algorithm, a total of 679 patients diagnosed with HD were identified in Ontario between 1991 and 2013. The overall incidence during this time was 2.05 per 10,000 live births (or 1 in 4,868 live births). The incidence did not change significantly over time (odds ratio 0.998, 95% confidence interval 0.983–1.013, p = 0.80).Conclusion: Ontario health administrative data can be used to accurately identify cases of HD and describe trends in incidence. There has not been a significant change in HD incidence over time in Ontario between 1991 and 2013. Keywords: Hirschsprung disease, algorithm validation, incidence, health administrative data

Errol W Chan,1 Tina T Wong,2,3 Hla M Htoon,3 Ching L Ho,2 Donald T Tan,1,2,3 Jodhbir S Mehta2,3,4 1Department of Ophthalmology, National University Health System, Singapore; 2Singapore National Eye Centre, Singapore; 3Singapore Eye Research Institute, Singapore; 4Department of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore Objective: To compare the 3-year incidence of de novo ocular hypertension (OHT) after Descemet stripping automated endothelial keratoplasty (DSAEK) and penetrating keratoplasty (PK). For DSAEK, to evaluate predictors for OHT and 2-year outcomes after OHT development. Methods: This was a review of the prospective Singapore Corneal Transplant Study at a single tertiary referral center. Consecutive DSAEKs and PKs for Fuchs’ endothelial dystrophy (FED) and pseudophakic bullous keratopathy (PBK) in eyes without pre-existing glaucoma were analyzed. OHT incidence after DSAEK and PK were compared using Kaplan–Meier survival analysis, and OHT risk factors identified using Cox proportional regression. OHT was defined: intraocular pressure (IOP) ≥ 24 mmHg or ≥ 10 mmHg from baseline. Secondary outcomes 2 years after OHT development in DSAEK were rates of glaucoma medical therapy failure, IOP success, graft failure and rejection, and best-spectacle corrected visual acuity (BSCVA). Results: There were 108 (96.4%) DSAEKs and 216 (96%) PKs. The 1-, 2- and 3-year de novo OHT incidence was not significantly different between DSAEK (36.1%, 47.2%, 47.2%, respectively) and PK (35.7%, 44.9%, 45.8%, respectively; P = 0.914). OHT incidence did not differ in subgroup analyses of multiple clinical variables (P > 0.1). OHT predictors after DSAEK were: fellow eye glaucoma (hazard ratio [HR] 3.20, P = 0.004), age

Wang Chun Kwok,1 Terence Chi Chun Tam,1 Chor Wing Sing,2 Esther Wai Yin Chan,2 Ching-Lung Cheung2 1Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People’s Republic of China; 2Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People’s Republic of ChinaCorrespondence: Ching-Lung Cheung, Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region, People’s Republic of China, Tel +852 3917 9024, Fax +852 2817 0859, Email lung1212@hku.hkBackground: Electronic health record (EHR) databases can facilitate epidemiology research into various diseases including asthma. Given the diagnostic challenges of asthma, the validity of the coding in EHR requires clarification. We aimed to assess the validity of International Classification of Diseases, 9th Revision (ICD-9) code algorithms for identifying asthma in the territory-wide electronic medical health record system of the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong.Methods: Adult patients who had the diagnosis of asthma input from all public hospitals in Hong Kong and those from Queen Mary Hospital in 2011– 2020 were identified using the ICD-9 code of 493 (493.0, 493.1, 493.2, and 493.9) by CDARS. Patients’ clinical record and spirometry were reviewed by two respiratory specialists to confirm the presence of asthma in the randomly selected cases.Results: There were 43,454 patients who had the diagnostic code of asthma among all public hospitals in Hong Kong and 1852 in Queen Mary Hospital in the same period. A total of 200 cases were randomly selected and validated using medical record and spirometry review by a respiratory specialist. The overall positive predictive value (PPV) was 85.0% (95% CI 80.1− 89.9%).Conclusion: This was the first ICD-9 code validation for CDARS (EHR) in Hong Kong on asthma. Our study demonstrated that using ICD-9 code (493.0, 493.1, 493.2 and 493.9) to identify asthma can result in a PPV that was reliable to support the utility of the CDARS database for further research on asthma among the Hong Kong population.Keywords: asthma, algorithms, EHR, electronic health record, validation

Introduction: Infections stemming from multidrug-resistant bacteria present a substantial threat to public health today. Discovering or synthesizing novel compounds is crucial to alleviate this pressing situation., Objective: The main purpose of this study is to verify the antibacterial activity of LTX-315 and explore its primary action mode., Methods: Through antibacterial phenotype assay screening, we obtained a potent compound named LTX-315 from diverse drug libraries, 10,926 compounds in total. Then, the bactericidal effect and its action mode were explored through biochemical and chemistry methods such as atime-killing curve, scanning electronic microscopy, isothermal titration calorimetry analysis, and nuclear magnetic resonance. Finally, the efficacy in vivo of LTX-315 against drug-resistant bacteria was proved through amice infection model., Results: In this study, LTX-315, an oncolytic peptide, was discovered to effectively eliminate gram-positive and gram-negative pathogens, even for those multidrug-resistant strains. Through strong electrostatic interactions, LTX-315 can bind to the membrane component phosphatidylglycerol (PG) with extremely high affinity (nanomolar level). Strikingly, in contrast to the typical electrostatic interactions of antibacterial peptides, the indole group of LTX-315, situated near the alkyl chain, exhibits significantly enhanced recognition and interaction with PG due to the hydrophobic effect of the alkyl chain. Furthermore, it exerts various impacts on cell membranes, including damaging integrity, increasing permeability, and decreasing membrane fluidity. Additionally, microscopy revealed significant cell disintegration. The influence, in turn, disrupts several physiological activities inside cells, such as increasing the reactive oxygen species level, ultimately leading to cell death. Finally, the efficacy of LTX-315 in vivo against multidrug-resistant and hypervirulent Klebsiella pneumoniae was demonstrated., Conclusion: The unique mechanism of LTX-315 involves high-affinity binding to PG and subsequent membrane disruption, providing a novel approach against multidrug-resistant bacteria compared to conventional antibiotics. As a potential candidate, it shows promise in effectively treating bacterial infections, particularly those caused by drug-resistant bacteria, thereby addressing the escalating challenge of antibiotic resistance worldwide., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Since animal growth promoters (AGPs) are used in large quantities and commonly released to the environment from animal farms, it is necessary to determine whether such agents should be regarded as an environmental toxin that poses a threat to the ecosystem and health risk to wildlife. In this study, a multi-omics approach was employed to explore the effects of a representative AGP, lincomycin, on key metabolic and physiological functions of animals, using a mouse model. The results indicated that exposure to lincomycin resulted in a significant increase in growth rate of mice (50.11 %) over an 8 weeks period, during which significant decrease (61.94 %) and increase (68.64 %) in the relative abundance of Firmicutes and Escherichia coli, respectively, was observed in the gut microbiota, indicating that the gut microbiota structure has been altered. Moreover, the mice exhibited altered lipid profiles and liver damage suggestive of early-stage non-alcoholic fatty liver disease (NAFLD). Disruptions in blood glucose and insulin levels associated with type 2 diabetes mellitus (T2DM) were also observed. Furthermore, lincomycin was found to cause suppression in inflammatory responses, as evidenced by the downregulation of related genes and elevated inflammatory mediators, potentially resulting in increased susceptibility to microbial infection. Our findings underscore the detrimental effects of lincomycin on animal health and highlight the necessity for comprehensive toxicological assessments of lincomycin and other AGPs before their environmental release., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The Army Medical Corps comprises the physicians of the U.S. Army. In recent years, the Medical Corps' rate of recruitment has not been able to keep up with the pace of separations. Retention is down. A larger-than-expected proportion of Army physicians who have fulfilled their active-duty service obligation are separating rather than extending their careers and, possibly, serving until they are eligible for military retirement. This trend results in positions at military treatment facilities and other units being unfilled, compromising the Medical Corps' ability to fulfill its missions, whether in deployed operations or in caring for service members and other beneficiaries at home. In this study, the authors examine alternative strategies for the Army Medical Corps to ensure that it has access to the personnel it needs to support operational requirements. The authors consulted with subject-matter experts and gathered and analyzed data to help identify five courses of action (COAs) that could increase retention, increase accessions, or reduce the requirement for uniformed physicians., (Copyright © 2024 RAND Corporation.)

Background: Non-adherence to lipid-lowering agents poses significant risks to patients and diminishes treatment effectiveness. Current understanding of patients' preferences regarding the characteristics of these agents is limited. This study aims to qualitatively identify the barriers to lipid-lowering medication adherence and the factors considered by patients with hypercholesterolemia when choosing lipid-lowering agents, and to inform the design of a medication preference study., Methods: Face-to-face focus group interviews were conducted with Cantonese-speaking patients diagnosed with hypercholesterolemia in Hong Kong. Patients were recruited by cardiologists at a university-affiliated hospital using convenience sampling. The interviews consisted of three parts: gathering patients' perceptions of disease and medication, identifying important factors in selecting lipid-lowering agents, and completing the medication preference tasks designed using the Discrete Choice Experiment (DCE) method. Thematic analysis was used to categorise the codes derived from the transcripts into higher-order themes., Results: Twenty patients completed the focus group interviews on the university campus between January and March 2023. Four main themes emerged: medication management issues, patients' medication preferences, structure, and comprehension of preference tasks. Barriers to medication adherence included lack of knowledge, a high pill burden, poor communication with healthcare providers, minimal treatment decision involvement, limited access to medication information, side effects, and forgetfulness. Factors influencing medication choice were treatment regimen (i.e. the route and frequency of administration), effectiveness, side effects, doctors' opinions, drug interactions, and out-of-pocket costs. Despite suggestions for modifying attributes and levels, the medication preference tasks effectively reflected patients' trade-offs., Conclusions: The identified barriers to medication adherence and the factors influencing medication choice highlight the importance of considering patients' perspectives. These insights could assist decision-makers in selecting medications that align with patient preferences, thereby promoting medication adherence. A large-scale DCE preference study will be conducted in Hong Kong to quantify the relative importance of the attributes of lipid-lowering agents., Competing Interests: HHEY reported receiving research grants from the Health Bureau of the Government of the Hong Kong SAR (HMRF), outside the submitted work. XL reported receiving research grants from the Health Bureau of the Government of the Hong Kong SAR (HMRF, HMRF Fellowship Scheme); research grants from the Research Grants Council (RGC/ECS, RGC/RIF); research and educational grants from Janssen and Pfizer; internal funding from the University of Hong Kong; and consultancy fees from Merck Sharp & Dohme, all unrelated to this work. CKHW reported receiving research grants from the Research Grant Council (General Research Fund); from the EuroQol Research Foundation; and from AstraZeneca and Boehringer Ingelheim, all outside the submitted work. EWC reported receiving grants from the National Natural Science Foundation of China during the conduct of the study; nonfinancial support from Wellcome Trust; grants from Research Grants Council (RGC), Health Bureau of the Government of the Hong Kong SAR (HMRF), National Health and Medical Research Council (Australia), Narcotics Division of the Security Bureau of Hong Kong SAR, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Pfizer, Takeda, and Novartis; and personal fees from Pfizer, Novartis, and the Hong Kong SAR Hospital Authority, all outside the submitted work., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The emergence and rapid dissemination of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) pose a serious threat to public health. Antibiotic treatment failure of K. pneumoniae infections has been largely attributed to acquisition of antibiotic resistance and bacterial biofilm caused by the presence of antibiotic persisters. There is an urgent need for novel antimicrobial agents or therapy strategies to manage infections caused by these notorious pathogens. In this study, we screened a collection of compounds that can dissipate bacterial proton motive force (PMF) and intermediate metabolites that can suppress antibiotic tolerance, and identified an antifungal drug sulconazole which can act in combination with glucose or trehalose to exert strong antibacterial effect against starvation-induced CR-hvKP persisters. Investigation of underlying mechanisms showed that sulconazole alone caused dissipation of transmembrane PMF, and sulconazole used in combination with glucose or trehalose could significantly inhibit the efflux activity, reduce NADH and ATP levels, and cause intracellular accumulation of reactive oxygen species (ROS) in CR-hvKP persisters, eventually resulting in bacterial cell death. These findings suggest that the sulconazole and glucose/trehalose combination is highly effective in eradicating multidrug-resistant and hypervirulent K. pneumoniae persisters, and may be used in development of a feasible strategy for treatment of chronic and recurrent K. pneumoniae infections., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Klebsiella pneumoniae (Kp) is increasingly recognized as a reservoir for a range of antibiotic resistance genes and a pathogen that frequently causes severe infections in both hospital and community settings. In this study, we have identified a novel mechanism of conjugative transfer of a non-conjugative virulence plasmid through the formation of a fusion plasmid between the virulence plasmid and a novel 59,162 bp IncN- plasmid. This plasmid was found to be a multidrug-resistance (MDR) plasmid and carried a T4SS cluster, which greatly facilitated the efficient horizontal transfer of the fusion plasmid between Kp strains. The fused virulence plasmid conferred the resistance of serum killing and macrophage phagocytosis to the transconjugants. Importantly, this plasmid was shown to be essential for Kp virulence in a mouse model. Mechanistic analysis revealed that the virulence factors encoded by this virulence plasmid contributed to resistance to in vivo clearance and induced a high level of proinflammatory cytokine IL-1β, which acts as an inducer for more neutrophil recruitment. The transmission of the fusion plasmid in Kp has the potential to convert it into both MDR and hypervirulent Kp, accelerating its evolution, and posing a serious threat to human health. The findings of this study provide new insights into the rapid evolution of MDR and hypervirulent Kp in recent years., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) poses grave threats to human health. These strains increased dramatically in clinical settings in China in the past few years but not in other parts of the world. Four isogenic K. pneumoniae strains, including classical K. pneumoniae , carbapenem-resistant K. pneumoniae (CRKP), hypervirulent K. pneumoniae (hvKP) and CR-hvKP, were created and subjected to phenotypic characterization, competition assays, mouse sepsis model and rat colonization tests to investigate the mechanisms underlying the widespread nature of CR-hvKP in China. Acquisition of virulence plasmid led to reduced fitness and abolishment of colonization in the gastrointestinal tract, which may explain why hvKP is not clinically prevalent after its emergence for a long time. However, tigecycline treatment facilitated the colonization of hvKP and CR-hvKP and reduced the population of Lactobacillus spp. in animal gut microbiome. Feeding with Lactobacillus spp. could significantly reduce the colonization of hvKP and CR-hvKP in the animal gastrointestinal tract. Our data implied that the clinical use of tigecycline to treat carbapenem-resistant K. pneumoniae infections facilitated the high spread of CR-hvKP in clinical settings in China and demonstrated that Lactobacillus spp . was a potential candidate for anticolonization strategy against CR-hvKP.

Background: Misdiagnosed vaccine-related "allergies" lead to unnecessary vaccine deferrals and incomplete vaccinations, leaving patients unprotected against COVID-19. To overcome limitations and queues for Allergist assessment, the "VAS-Track" pathway was developed to evaluate patients via a multi-disciplinary triage model including nurses, non-specialists, and Allergists., Objective: We assessed the effectiveness and safety of VAS-Track and evaluate its real-world impact in terms of vaccination rates and COVID-19 protection., Methods: Patients referred to VAS-Track between September 2021 and March 2022 were recruited. Subgroup analysis was performed with prospective pre- and post-clinic antibody levels., Results: Nurse-assisted screening identified 10,412 (76%) referrals as inappropriate. 369 patients were assessed by VAS-Track. Overall, 100% of patients were recommended to complete vaccination and 332 (90%) completed their primary series. No patients reported any significant allergic reactions following subsequent vaccination. Vaccination completion rates between patients seen by non-specialists and additional Allergist review were similar (90% vs. 89%, p = 0.617). Vaccination rates were higher among patients with prior history of immediate-type reactions (odds ratio: 2.43, p = 0.025). Subgroup analysis revealed that only 20% (56/284) of patients had seropositive COVID-19 neutralizing antibody levels (≥ 15 AU/mL) prior to VAS-Track, which increased to 92% after vaccine completion (pre-clinic antibody level 6.0 ± 13.5 AU/mL vs. post-clinic antibody level 778.8 ± 337.4 AU/mL, p > 0.001)., Conclusions: A multi-disciplinary allergy team was able to streamline our COVID-19 VAS services, enabling almost all patients to complete their primary series, significantly boosting antibody levels and real-world COVID-19 protection. We propose similar multidisciplinary models to be further utilized, especially in the settings with limited allergy services.

Vibrio spp., known as significant marine pathogens, have become more prevalent due to global warming. Antibiotics released into the environment drive Vibrio resistance. The increasing consumption of seafood leads to more interactions between Vibrio and humans. Despite this concerning trend, there remains a lack of large-scale surveillance for Vibrio contamination across various types of food. This study isolated 4027 Vibrio strains, primarily comprising V. parahaemolyticus and V. alginolyticus, in 3581 fresh shrimp and meat products from 2013 to 2022. The Vibrio strains showed increased resistance to important antibiotics, especially β-lactams used to treat foodborne bacterial infections. Whole genome sequencing of 591 randomly chosen strains showed a strong correlation between antibiotic resistance and genotypes in Vibrio. Notably, various ESBL genes have evolved over the past 8 years, with bla VEBs being the most dominant. Additionally, carbapenemase genes, such as bla NDM-1 , have become increasingly prevalent in recent years. Various mobile genetic elements, including IncQ and IncA/C plasmids, recoverable in Vibrio, facilitate the transmission of crucial β-lactamase genes. These data provide insights into the evolutionary traits of antimicrobial resistance in foodborne Vibrio strains over a decade. Policymakers should consider these findings when devising appropriate strategies to combat bacterial antimicrobial resistance and safeguard human health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Bacterial antibiotic tolerance is a decades-old phenomenon in which a bacterial sub-population, commonly known as persisters, does not respond to antibiotics and remains viable upon prolonged antimicrobial treatment. Persisters are detectable in populations of bacterial strains that are not antibiotic-resistant and are known to be responsible for treatment failure and the occurrence of chronic and recurrent infection. The clinical significance of antibiotic tolerance is increasingly being recognized and comparable to antibiotic resistance. To eradicate persisters, it is necessary to understand the cellular mechanisms underlying tolerance development. Previous works showed that bacterial antibiotic tolerance was attributed to the reduction in metabolic activities and activation of the stringent response, SOS response and the toxin-antitoxin system which down-regulates transcription functions. The latest research findings, however, showed that decreased metabolic activities alone do not confer a long-lasting tolerance phenotype in persisters, and that active defence mechanisms such as efflux and DNA repair are required for the long-term maintenance of phenotypic tolerance. As such active tolerance-maintenance mechanisms are energy-demanding, persisters need to generate and maintain the transmembrane proton motive force (PMF) for oxidative phosphorylation. This minireview summarizes the current understanding of cellular mechanisms essential for prolonged expression of phenotypic antibiotic tolerance in bacteria, with an emphasis on the importance of generation and maintenance of PMF in enabling proper functioning of the active tolerance mechanisms in persisters. How such mechanisms can be utilized as targets for the development of anti-persister strategies will be discussed., (© 2024 The Author(s). Microbial Biotechnology published by John Wiley & Sons Ltd.)

Acinetobacter baumannii (AB) infections have become a global public health concern due to the continued increase in the incidence of infection and the rate of resistance to carbapenems. This study aimed to investigate the genomic features of AB strains recovered from a tertiary hospital and assess the clinical implications of the findings. A total of 217 AB strains were collected between 2016 and 2018 at a tertiary hospital in Guangzhou, with 183 (84.33%) being carbapenem-resistant AB (CRAB), with the main mechanism being the carriage of the bla OXA-23 gene. The overall mortality rate of patients caused by such strains was 15.21% (n = 33). Artificial lung ventilation and the use of meropenem were mortality risk factors in AB-infected patients, while KL2 AB infection was negatively associated. Core genome multilocus sequence typing and clustering analysis were performed on the integrated AB genome collection from the NCBI database and this study to illustrate the population structure among China. The results revealed diverse core genome profiles (n = 17) among AB strains from China, and strains from this single hospital exhibited most of the core genome profiles (n = 13), suggesting genetic variability within the hospital and transmission across the country. These findings show that the high transmission potential of the CRAB strains and meropenem usage that confers a selective advantage of CRAB clinically are two major factors that pose significant challenges to the effective clinical management of AB infections. Understanding the genetic features and transmission patterns of clinical AB strains is crucial for the effective control of infections caused by this pathogen., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Masson SAS.)

Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chen Sheng reports financial support was provided by the Research Grant Council of the Government of Hong Kong SAR. YANG Xuemei reports financial support was provided by the Research Grant Council of the Government of Hong Kong SAR. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

Purpose: The evidence of the neuropsychiatric effects associated with fluoroquinolones is mainly supported by case reports. Population-based evidence remains largely limited. We aimed to investigate the association between the use of fluoroquinolones and hospitalization or Accident & Emergency department visits for acute neuropsychiatric events using a self-controlled case series (SCCS) and active comparator to reduce confounding., Methods: We conducted a SCCS with a recently described active comparator design using all public outpatient clinics, hospitalization, and Accident and Emergency department records from the Clinical Data Analysis and Reporting System, Hong Kong from 2001 to 2013. Among 166 325 people with an oral fluoroquinolone prescription, 4287 people who had an incident neuropsychiatric event were included. We then estimated the incidence rate ratio (IRR) of acute neuropsychiatric events during periods before and after fluoroquinolone prescription, versus baseline. We repeated the analysis for amoxicillin/clavulanic acid users as an active comparator. We then estimated the comparator-adjusted estimates by dividing the IRR for fluoroquinolone by the IRR for amoxicillin/clavulanic acid. The primary outcome was neuropsychiatric events. Secondary outcomes were psychotic events and cognitive impairment., Results: An increased risk of neuropsychiatric events was observed in the current use of fluoroquinolone [IRR: 2.11 (95% confidence interval (CI): 1.58-2.83)] and 1-7 days after the end of fluoroquinolone prescription [IRR: 1.90 (95% CI: 1.30-2.75)] versus baseline. No increased risk was observed in other risk periods versus baseline. Similar patterns were observed in the current use of amoxicillin/clavulanic acid [IRR: 1.92 (95% CI: 1.19-3.11)] and 1-7 days after the end of fluoroquinolone prescription [IRR: 1.81 (95% CI: 1.11-2.97)] versus baseline. Similar results were found for secondary outcomes. Using the active comparator design, comparator-adjusted estimates were 1.10 (95% CI: 0.63-1.93) in current use of fluoroquinolones and 1.05 (95% CI: 0.57-1.95) in 1-7 days postexposure to fluoroquinolones versus baseline., Conclusions: Although our study showed a higher incidence of neuropsychiatric events in the current use of fluoroquinolones and 7 days after the end of fluoroquinolones prescriptions compared with baseline, a similar temporal pattern was also found for amoxicillin/clavulanic acid users. Using amoxicillin/clavulanic acid as the active comparator, we found no difference in the risk of neuropsychiatric events associated with fluoroquinolone compared with baseline. Therefore, the risk of neuropsychiatric events may not need to influence the decision to prescribe either fluoroquinolones or amoxicillin/clavulanic acid based on the evidence in this study., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: The continuous emergence of multidrug-resistant (MDR) Acinetobacter baumannii (Ab) strains poses further challenges in its control and clinical management. It is necessary to decipher the mechanisms underlying the high mortality of Ab infections to explore unconventional strategies for controlling outbreaks of drug-resistant infections., Methods: The immune responses of Ab sepsis infection were investigated using flow cytometry, RNA-seq, qRT-PCR, and ELISA and scRNA-seq. The detailed pathways mediating Ab immune responses were also depicted and a specific therapy was developed based on the understanding of the mechanisms underlying Ab-induced cytokine storms., Findings: The results highlighted the critical role of alveolar and interstitial macrophages as targets of Ab during the infection process. These cells were found to undergo polarization towards the M1 phenotype, triggering a cytokine storm that eventually caused the death of the host. The polarization and excessive inflammatory response mediated by macrophages were mainly regulated by the TLR2/Myd88/NF-κB signaling pathway. Suppression of Ab-triggered inflammatory responses and M1 polarization by the drug naproxen (NPXS) was shown to confer full protection of mice from lethal infections., Interpretation: The findings in this work depict the major mechanisms underlying the high mortality rate of Ab infections and highlight the clinical potential application of anti-inflammatory drugs or immunosuppressants in reducing the mortality of such infections, including those caused by MDR strains., Funding: Funding sources are described in the acknowledgments section., Competing Interests: Declaration of interests Authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: We investigated whether empagliflozin reduces hepatic steatosis in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus., Approach and Results: This was an investigator-initiated, double-blind, randomized, placebo-controlled trial recruiting adult subjects from the community. Eligible subjects without diabetes mellitus (fasting plasma glucose < 7 mmol/L and HbA1c < 6.5%) who had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 5% were randomly allocated to receive empagliflozin 10 mg daily or placebo (1:1 ratio) for 52 weeks (end of treatment, EOT). MRI-PDFF was conducted at baseline and EOT. The primary outcome was the difference in change of MRI-PDFF between the 2 groups at EOT. Secondary outcomes were hepatic steatosis resolution (MRI-PDFF < 5%), alanine aminotransferase drop ≥ 17 U/L, MRI-PDFF decline ≥ 30%, a combination of both, and changes of anthropometric and laboratory parameters at EOT. All outcomes were based on intention-to-treat analysis. Of 98 recruited subjects (median age: 55.7 y [IQR:49.5-63.4]; male:54 [55.1%]), 97 (empagliflozin:49, placebo:48; median MRI-PDFF:9.7% vs 9.0%) had MRI-PDFF repeated at EOT. The Empagliflozin group had a greater reduction in median MRI-PDFF compared to the placebo group (-2.49% vs. -1.43%; p = 0.025), with a nonsignificant trend of resolution of hepatic steatosis (44.9% vs. 28.6%; p = 0.094). There was no significant difference in alanine aminotransferase drop ≥ 17 U/L (16.3% vs. 12.2%; p = 0.564), MRI-PDFF drop ≥ 30% (49.0% vs. 40.8%; p = 0.417), and composite outcome (8.2% vs. 8.2%; p = 1.000). Empagliflozin group had a greater drop in body weight (-2.7 vs. -0.2 kg), waist circumference (-2.0 vs. 0 cm), fasting glucose (-0.3 vs. 0 mmol/L), and ferritin (-126 vs. -22 pmol/L) (all p < 0.05)., Conclusions: Empagliflozin for 52 weeks reduces hepatic fat content in subjects with nondiabetic metabolic dysfunction-associated steatotic liver disease. (ClinicalTrials.gov Identifier: NCT04642261)., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background and Aim: Proton pump inhibitors (PPIs) may increase the risk of COVID-19 among non-vaccinated subjects via various mechanisms, including gut dysbiosis. We aimed to investigate whether PPIs also affect the clinical outcomes of COVID-19 among vaccine recipients., Methods: This was a territory-wide cohort study of 3 272 286 vaccine recipients (aged ≥ 18 years) of ≥ 2 doses of either BNT162b2 or CoronaVac. Exclusion criteria included prior gastrointestinal surgery, immunocompromised status, and prior COVID-19. The primary outcome was COVID-19, and secondary outcomes included COVID-19-related hospitalization and severe infection (composite of intensive care unit admission, ventilatory support, and/or death). Covariates include age, sex, the Charlson Comorbidity Index, comorbidities, and concomitant medication use. Subjects were followed from index date (first dose of vaccination) until outcome occurrence, death, additional dose of vaccination, or March 31, 2022. Exposure was pre-vaccination PPI use (any prescription within 90 days before the index date). Propensity score (PS) matching and a Poisson regression model were used to estimate the adjusted incidence rate ratio (aIRR) of outcomes with PPI use., Results: Among 439 154 PS-matched two-dose vaccine recipients (mean age: 65.3 years; male: 45.7%) with a median follow-up of 6.8 months (interquartile range: 2.6-7.9), PPI exposure was associated with a higher risk of COVID-19 (aIRR: 1.08; 95% confidence interval [95% CI]: 1.05-1.10), hospitalization (aIRR: 1.20; 95% CI: 1.08-1.33), and severe infection (aIRR: 1.57; 95% CI: 1.24-1.98). Among 188 360 PS-matched three-dose vaccine recipients (mean age: 62.5 years; male: 49.0%; median follow-up: 9.1 months [interquartile range: 8.0-10.9]), PPIs were associated with higher infection risk (aIRR: 1.11; 95% CI: 1.08-1.15) but not other outcomes., Conclusions: Although PPI use was associated with a higher COVID-19 risk, severe infection was limited to two-dose but not three-dose vaccine recipients., (© 2024 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Lithium is considered to be the most effective mood stabilizer for bipolar disorder. Evolving evidence suggested lithium can also regulate bone metabolism which may reduce the risk of fractures. While there are concerns about fractures for antipsychotics and mood stabilizing antiepileptics, very little is known about the overall risk of fractures associated with specific treatments. This study aimed to compare the risk of fractures in patients with bipolar disorder prescribed lithium, antipsychotics or mood stabilizing antiepileptics (valproate, lamotrigine, carbamazepine). Among 40,697 patients with bipolar disorder from 1993 to 2019 identified from a primary care electronic health record database in the UK, 13,385 were new users of mood stabilizing agents (lithium:2339; non-lithium: 11,046). Lithium was associated with a lower risk of fractures compared with non-lithium treatments (HR 0.66, 95 % CI 0.44-0.98). The results were similar when comparing lithium with prolactin raising and sparing antipsychotics, and individual antiepileptics. Lithium use may lower fracture risk, a benefit that is particularly relevant for patients with serious mental illness who are more prone to falls due to their behaviors. Our findings could help inform better treatment decisions for bipolar disorder, and lithium's potential to prevent fractures should be considered for patients at high risk of fractures., Competing Interests: Declaration of competing interest Esther W. Chan has received grants from Research Grants Council (RGC, Hong Kong), Research Fund Secretariat of the Food and Health Bureau, National Natural Science Fund of China, Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Novartis, Amgen, AstraZeneca, Takeda, the RGA Reinsurance Company, Narcotics Division of the Security Bureau of the Hong Kong Special Administrative Region, the National Health and Medical Research Council Australia; consulting fees from AstraZeneca, Pfizer and Novartis; and honorarium from the Hospital Authority Hong Kong, outside the submitted work. Joseph F. Hayes has received consultancy fees from Wellcome Trust and juli Health. Kenneth K.C. Man received the CW Maplethorpe Fellowship, grants from the National Institute for Health Research (United Kingdom), the European Union Horizon 2020 Framework, Innovation and Technology Commission of the Hong Kong Special Administration Region Government, and Hong Kong Research Grant Council and personal fees from IQVIA Holdings, Inc., unrelated to this work. Ian C.K.Wong received research grants from Amgen, Janssen, GSK, Novartis, Pfizer, Bayer and Bristol-Myers Squibb and Takeda, Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia, The European Union's Seventh Framework Programme for research, technological development, Research Grants Council Hong Kong and Health and Medical Research Fund Hong Kong; consulting fee from IQVIA and WHO; payment for expert testimony for Appeal Court in Hong Kong; serves on advisory committees for Member of Pharmacy and Poisons Board; Member of the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization; Member of the Advisory Panel on COVID-19 Vaccines of the Hong Kong Government; is the non-executive director of Jacobson Medical in Hong Kong; is the Founder and Director of Therakind Limited (UK), Advance Data Analytics for Medical Science (ADAMS) Limited (HK), Asia Medicine Regulatory Affairs (AMERA) Services Limited and OCUS Innovation Limited (HK, Ireland and UK). Ching-Lung Cheung received research grants and the honorarium from Amgen, research grant support from HMRF, and the honorarium from Abbott. Wallis C.Y. Lau reports grant from Diabetes UK, AIR@InnoHK administered by Innovation and Technology Commission, outside the submitted work. Vanessa W.S. Ng, Miriam T.Y. Leung, and David P.J. Osborn declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The global public health threat of antibiotic resistance continues to escalate, and necessitates the implementation of urgent measures to expand the arsenal of antimicrobial drugs. This study identified a benzoxaborane compound, namely 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2178), which can inhibit the catalytic activity of the Klebsiella pneumoniae carbapenemase (KPC-2) enzyme effectively. The efficacy of AN2718 as an inhibitor for the KPC-2 enzyme was verified through various assays, including enzyme activity assays and isothermal titration calorimetry. Results of multiple biochemical assays, minimum inhibitory concentration assays and time-killing assays also showed that binding of AN2718 to KPC-2 enabled restoration of the bactericidal effect of meropenem. The survival rate of mice infected with carbapenem-resistant, high-virulence strains increased significantly upon treatment with AN2718. Most importantly, the meropenem and AN2718 combination was effective on KPC-2 mutations such as KPC-33, which evolved clinically and exhibited resistance to ceftazidime-avibactam after clinical use for a couple of years. Comprehensive safety tests both in vitro and in vivo, such as cytotoxicity, haemolytic activity and cytochrome P450 inhibition assays, demonstrated that AN2718 was safe for clinical use. These promising data indicate that AN2718 has high potential for approval for the treatment of drug resistant-bacterial infections, including those caused by ceftazidime-avibactam-resistant strains. AN2718 can be regarded as a valuable addition to the current antimicrobial armamentarium, and a promising tool to combat antimicrobial resistance., (Copyright © 2024. Published by Elsevier Ltd.)

Microeukaryotes are key contributors to marine carbon cycling. Their physiology, ecology, and interactions with the chemical environment are poorly understood in offshore ecosystems, and especially in the deep ocean. Using the Autonomous Underwater Vehicle Clio, microbial communities along a 1050 km transect in the western North Atlantic Ocean were surveyed at 10-200 m vertical depth increments to capture metabolic signatures spanning oligotrophic, continental margin, and productive coastal ecosystems. Microeukaryotes were examined using a paired metatranscriptomic and metaproteomic approach. Here we show a diverse surface assemblage consisting of stramenopiles, dinoflagellates and ciliates represented in both the transcript and protein fractions, with foraminifera, radiolaria, picozoa, and discoba proteins enriched at >200 m, and fungal proteins emerging in waters >3000 m. In the broad microeukaryote community, nitrogen stress biomarkers were found at coastal sites, with phosphorus stress biomarkers offshore. This multi-omics dataset broadens our understanding of how microeukaryotic taxa and their functional processes are structured along environmental gradients of temperature, light, and nutrients., (© 2024. The Author(s).)

The tigecycline resistance gene tet(X4) has been widely reported in animals and animal products in some Asian countries including China in recent years but only sporadically detected in human. In this study, we investigated the prevalence and genetic features of tet(X4)-positive clinical E. coli strains. A total of 462 fecal samples were collected from patients in four hospitals located in four provinces in China in 2023. Nine tet(X4)-positive E. coli strains were isolated and subjected to characterization of their genetic and phenotypic features by performing antimicrobial susceptibility test, whole-genome sequencing, bioinformatic and phylogenetic analysis. The majority of the test strains were found to exhibit resistance to multiple antimicrobial agents including tigecycline but remained susceptible to colistin and meropenem. A total of seven different sequence types (STs) and an unknown ST type were identified among the nine tet(X4)-positive strains. Notably, the tet(X4) gene in six out of these nine tet(X4)-positive E. coli strains was located in a IncFIA-HI1A-HI1B hybrid plasmid, which was an tet(X4)-bearing epidemic plasmid responsible for dissemination of the tet(X4) gene in China. Furthermore, the tet(X4) gene in four out of nine tet(X4)-positive E. coli isolates could be successfully transferred to E. coli EC600 through conjugation. In conclusion, this study characterized the epidemic tet(X4)-bearing plasmids and tet(X4)-associated genetic environment in clinical E. coli strains, suggested the importance of continuous surveillance of such tet(X4)-bearing plasmids to control the increasingly widespread dissemination of tigecycline-resistant pathogens in clinical settings in China., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a global threat due to its high mortality in clinical patients. However, the specific mechanisms underlying this increased mortality remain unclear. The objective of this study is to investigate how the development of a resistance phenotype contributes to the significantly higher mortality associated with this pathogen. To achieve this, a collection of isogeneic strains was generated. The clinical carbapenem-susceptible K. pneumoniae (CSKP) strain HKU3 served as the control isolate, while HKU3-KPC was created through conjugation with a bla KPC-2 -bearing plasmid and served as clinical CRKP strain. Using a sepsis model, it was demonstrated that both HKU3 and HKU3-KPC exhibited similar levels of virulence. Flow cytometry, RNA-seq, and ELISA analysis were employed to assess immune cell response, M1 macrophage polarization, and cytokine storm induction, revealing that both strains elicited comparable types and levels of these immune responses. Subsequently, meropenem was utilized to treat K. pneumoniae infection, and it was found that meropenem effectively reduced bacterial load, inhibited M1 macrophage polarization, and suppressed serum cytokine production during HKU3 (CSKP) infection. However, these effects were not observed in the case of HKU3-KPC (CRKP) infection. These findings provide evidence that the high mortality associated with CRKP is attributed to its enhanced survival within the host during antibiotic treatment, resulting in a cytokine storm and subsequent host death. The development of an effective therapy for CRKP infections could significantly reduce the mortality caused by this pathogen., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier GmbH.)

Gut damage during carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-HvKP) infection is associated with a death risk. Understanding the mechanisms by which CR-HvKP causes intestinal damage and gut microbiota alteration, and the impact on immunity, is crucial for developing therapeutic strategies. This study investigated if gastrointestinal tract damage and disruption of gut microbiota induced by CR-HvKP infection undermined host immunity and facilitated multi-organ invasion of CR-HvKP; whether the therapeutic value of the rifampicin (RIF) and zidovudine (ZDV) combination was attributed to their ability to repair damages and restore host immunity was determined. A sepsis model was utilized to assess the intestinal pathological changes. Metagenomic analysis was performed to characterize the alteration of gut microbiota. The effects of the RIF and ZDV on suppressing inflammatory responses and improving immune functions and gut microbiota were evaluated by immunopathological and transcriptomic analyses. Rapid colonic damage occurred upon activation of the inflammation signaling pathways during lethal infections. Gut inflammation compromised host innate immunity and led to a significant decrease in probiotics abundance, including Bifidobacterium and Lactobacillus. Treatment with combination drugs significantly attenuated the inflammatory response, up-regulated immune cell differentiation signaling pathways, and promoted the abundance of Bifidobacterium (33.40 %). Consistently, supplementation of Bifidobacterium alone delayed the death in sepsis model. Gut inflammation and disrupted microbiota are key disease features of CR-HvKP infection but can be reversed by the RIF and ZDV drug combination. The finding that these drugs can restore host immunity through multiple mechanisms is novel and deserves further investigation of their clinical application potential., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)