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BACKGROUND. Weakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-[gamma] autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs. METHODS. This study analyzed the detection and neutralization of anti-IFN-[gamma] autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM. RESULTS. We found that anti-IFN-[gamma] auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs. CONCLUSION. These findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease. FUNDING. The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983 and U19AIN1625568), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62IBEID), ANR-GENMSMD (ANR-16-CE17-0005-01), ANR-MAFMACRO (ANR-22-CE92-0008), ANRSECTZ170784, the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the ANR-RHU program (ANR-21-RHUS-08-COVIFERON), the European Union's Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir--Fonds de solidarity pour I'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, William E. Ford, General Atlantic's Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic's Co-President, Managing Director, and Head of business in EMEA, and the General Atlantic Foundation, Institut National de la Sante et de la Recherche Medicale (INSERM) and of Paris Cite University. JR was supported by the INSERM PhD program for doctors of pharmacy (poste d'accueil INSERM). JR and TLV were supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. MO was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the New York Hideyo Noguchi Memorial Society (HNMS)., Introduction Mendelian susceptibility to mycobacterial disease (MSMD) is a rare inherited condition characterized by susceptibility to infection by weakly virulent mycobacteria, including BCG vaccines and environmental mycobacteria (EM) (1-4). The [...]

Background The neutrophil percentage-to-albumin ratio (NPAR) is a novel measure of systemic inflammation and infection. Low albumin levels increase the risk of infection, while high neutrophil counts indicate the presence of infection. Spontaneous bacterial peritonitis (SBP) is a serious infection in cirrhotic ascites, and the potential of NPAR in diagnosing SBP is not yet established. Objective The objective of this study is to determine the diagnostic value of NPAR in identifying SBP. Patients This prospective multicenter study included 465 patients diagnosed with cirrhotic ascites and SBP according to international guidelines. Demographic, clinical, and laboratory data were collected. The sensitivity and specificity of NPAR values for diagnosing SBP were assessed using the receiver operating characteristic curve. Results For SBP diagnosis in the total cohort, NPAR of > 17 had a sensitivity of 85.71%, specificity of 66.67%, and 95% CI (42.1-99.6). In culture-positive SBP, the NPAR at a cut-off > 5.2 had a sensitivity of 85.71%, specificity of 83.33%, and 95% CI (0.709 to 0.979), while in culture-negative SBP, the NPAR at a cut-off > 2.1 had a sensitivity of 92.86%, specificity of 33.33% and CI (0.367 to 0.764). The multivariate analysis revealed that albumin (OR = 2.78, [1.11;3.98], INR (OR = 0.198, [0.066;0.596], creatinine (OR = 0.292, [0.1; 0.81], CRP (OR = 3.18, [1.239;4.52] total leukocytic count (TLC) (OR = 1.97, [1.878; 2.07], platelets (OR = 2.09, [0.99; 2.31] and neutrophil (OR = 3.43, [1.04;3.89] were significantly associated with higher prediction rates for culture positive SBP. Conclusions NPAR could be a new, affordable, noninvasive test for diagnosing SBP. Keywords: The neutrophil percentage-to-albumin ratio, Liver cirrhosis and spontaneous bacterial peritonitis, Author(s): Nasser Mousa[sup.1], Mohamed salah[sup.1], Sherif Elbaz[sup.2], Alaa Elmetwalli[sup.3], Amr Elhammady[sup.4], Eman Abdelkader[sup.5], Mostafa Abdelsalam[sup.5], Niveen El-wakeel[sup.6,7], Marwa Mansour[sup.5], Manal Hashem[sup.8], Ola El-Emam[sup.9], Wesam Elderiny[sup.9], Mohammed Abdelaziz[sup.1], Ayman Elgamal[sup.10] and [...]

Dengue fever, caused by four distinct serotypes of the dengue virus (DENV1-4), poses a public health concern for much of the world. The NIH's Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases (NIAID) has developed a series of single-dose, live-attenuated tetravalent DENV vaccines, including TV005. However, phase III trials require a lengthy three-to-five year follow-up. In contrast, controlled human infection models (CHIMs) offer a faster means to assess vaccine efficacy for any of the four serotypes. In this issue of the JCI, Pierce, Durbin, and colleagues conducted a CHIM study with attenuated DENV2 and DENV3 challenge viruses in individuals six months after vaccination with TV005. The TV005 vaccine was well tolerated and effectively protected all vaccinated individuals from viremia and rash during challenges with DENV2 or DENV3. Notably, vaccine recipients also showed serotype-specific efficacy. While long-term studies are still needed, these findings represent an important step in providing protection against dengue virus., Vaccines against dengue virus Dengue fever, a widespread arboviral infection caused by four distinct serotypes of the dengue virus (DENV1-4), continues to be a substantial public health concern in numerous [...]

Purpose In the critically ill, hospital-acquired bloodstream infections (HA-BSI) are associated with significant mortality. Granular data are required for optimizing management, and developing guidelines and clinical trials. Methods We carried out a prospective international cohort study of adult patients ([greater than or equal to] 18 years of age) with HA-BSI treated in intensive care units (ICUs) between June 2019 and February 2021. Results 2600 patients from 333 ICUs in 52 countries were included. 78% HA-BSI were ICU-acquired. Median Sequential Organ Failure Assessment (SOFA) score was 8 [IQR 5; 11] at HA-BSI diagnosis. Most frequent sources of infection included pneumonia (26.7%) and intravascular catheters (26.4%). Most frequent pathogens were Gram-negative bacteria (59.0%), predominantly Klebsiella spp. (27.9%), Acinetobacter spp. (20.3%), Escherichia coli (15.8%), and Pseudomonas spp. (14.3%). Carbapenem resistance was present in 37.8%, 84.6%, 7.4%, and 33.2%, respectively. Difficult-to-treat resistance (DTR) was present in 23.5% and pan-drug resistance in 1.5%. Antimicrobial therapy was deemed adequate within 24 h for 51.5%. Antimicrobial resistance was associated with longer delays to adequate antimicrobial therapy. Source control was needed in 52.5% but not achieved in 18.2%. Mortality was 37.1%, and only 16.1% had been discharged alive from hospital by day-28. Conclusions HA-BSI was frequently caused by Gram-negative, carbapenem-resistant and DTR pathogens. Antimicrobial resistance led to delays in adequate antimicrobial therapy. Mortality was high, and at day-28 only a minority of the patients were discharged alive from the hospital. Prevention of antimicrobial resistance and focusing on adequate antimicrobial therapy and source control are important to optimize patient management and outcomes., Author(s): Alexis Tabah [sup.1] [sup.2] [sup.3] [sup.4], Niccolò Buetti [sup.5] [sup.6], Quentin Staiquly [sup.7], Stéphane Ruckly [sup.6] [sup.7], Murat Akova [sup.8], Abdullah Tarik Aslan [sup.9], Marc Leone [sup.10], Andrew Conway [...]

Purpose Carbapenem-resistant Klebsiella pneumoniae (CRKP) is one of the leading causes of healthcare-associated infections (HAIs) and is particularly pervasive in intensive care units (ICUs). This study takes ICU layout as the research object, and integrates clinical data and bacterial genome analysis to clarify the role of separate, small wards within the ICU in controlling the transmission of CRKP. Methods This study prospectively observed the carriage and spread of CRKP from a long-term in-hospital patient (hereafter called the Patient) colonized with CRKP in the gut and located in a separate, small ward within the ICU. The study also retrospectively investigated CRKP-HAIs in the same ICU. The relationship and transmission between CRKP isolates from the Patient and HAI events in the ICU were explored with comparative genomics. Results In this study, 65 CRKP-HAI cases occurred during the investigation period. Seven CRKP-HAI outbreaks were also observed. A total of 95 nonrepetitive CRKP isolates were collected, including 32 strains from the Patient in the separate small ward. Phylogenetic analysis based on core genome single-nucleotide polymorphism (cgSNP) showed that there were five possible CRKP clonal transmission events and two clonal outbreaks (A1, A2) during the study. CRKP strains from the Patient did not cause CRKP between-patient transmission or outbreaks in the ICU during the 5-year study period. Conclusion The presence of a long-term hospitalized patient carrying CRKP and positioned in a separate, small ward did not lead to CRKP transmission or infection outbreaks in the ICU. Combining a small-ward ICU layout with normative HAI control measures for multidrug-resistant pathogen infection was effective in reducing CRKP transmission., Author(s): Xiaohui Chi [sup.1], Xiaohua Meng [sup.1], Luying Xiong [sup.1], Tao Chen [sup.1], Yanzi Zhou [sup.1], Jinru Ji [sup.1], Beiwen Zheng [sup.1] [sup.2] [sup.3], Yonghong Xiao [sup.1] [sup.2] [sup.3] Author [...]

Background: Psoriasis (PS), vitiligo (VT), and Pityriasis rosea (PR) are chronic skin diseases often occurring as a consequence of exaggerated immune responses. These skin manifestations can be triggered as a result of the molecular mimicry between viral protein (s) and host protein (s), which could generate auto-antibodies. In addition, it can be hypothesised that skin diseases are manifestations of the reduced immunity that is observed in chronic hepatitis B virus (HBV)-infected individuals. Aims and Objective: To investigate the presence of HBV in PS, VT, and PR cases and Human Herpes Virus (HHV) 6 and 7 in PR cases. Materials and Methods: DNA extracted from healthy controls (n = 20), PS (n = 10), VT (n = 11), and PR (n = 12) were subjected to HBV-S gene-specific polymerase chain reactions (PCRs) and HHV 6-UL57 and HHV7-UL10 gene-specific PCRs. PCR products of positive samples (HBV and HHV 6 and 7 DNA) of expected length were bi-directionally sequenced using overlapping primers. Sequence identification was performed by NCBI BLAST and analysed by multiple sequence alignment. HBV DNA copy number was determined through quantitative real-time PCR. The blood samples were also tested for HBV serological markers and Interferon gamma (IFN-γ) by enzyme immunoassays. Results: The PCR data and Immunoassay study revealed that seven out of 12 PR, six out of 10 PS, and six out of 11 VT cases had signs of HBV infection. HHV 6 DNA was detected in four, whereas HHV 7 DNA was found in two of the 12 PR blood samples. PR6 presented the evidence of both HHV 6 and 7 co-infections. Conclusion: Observing the correlation of HBV with skin diseases, albeit at the pilot level, a larger study is warranted to identify HBV infection in skin disease patients. The evidence of HHV 6 and HHV 7 DNA in PR cases supports the HHV infection linkage with PR. Keywords: Co-infection, Pityriasis rosea, psoriasis, vitiligo, KEY MESSAGES: Underlying viral infections may be linked to chronic skin disease manifestations. Evidence of high frequency of HBV infection in PS, VT, and PR cases and the presence of HHV 6 and/or 7 infections in PR draw a diagnostic perspective for screening these subjects for these viruses as well., Author(s): Ruchi Supekar [1,2]; Subrata Roy [2]; Abhishek De [3]; Subhajit Biswas (corresponding author) [1,2] Introduction Psoriasis (PS), vitiligo (VT), and Pityriasis rosea (PR) are chronic skin diseases that often [...]

Background Patients with mental disorders have a high risk of intestinal parasitic infection due to poor hygiene practices. Hence, to better clarify this overlooked phenomenon, the current study is conducted to determine the global prevalence of protozoan parasite infections in patients with mental disorders and investigate the associated risk factors. Methods Several databases (PubMed, Scopus, Web of Science, ProQuest, and Google Scholar) were searched for papers published until December 2022. The fixed effect meta-analysis was used to estimate the overall odds ratio (OR) and pooled prevalence was estimated using a random-effects model with a 95% confidence interval (CI). Results Totally, 131 articles (91 case-control and 40 cross-sectional studies) met the eligibility criteria. Patients with mental disorders were significantly at higher risk for protozoan parasites than healthy controls (OR: 2.059, 1.830-2.317). The highest pooled OR (2.485, 1.413-4.368) was related to patients with neurodevelopmental disorders, and the highest pooled prevalence was detected in patients with neurodevelopmental disorders (0.341, 0.244-0.446), followed by bipolar and related disorders (0.321, 0.000-0.995). Toxoplasma gondii was the most prevalent protozoan parasite (0.343, 0.228-0.467) in cross-sectional studies and the highest pooled OR was related to Cyclospora cayetanensis (4.719, 1.352-16.474) followed by Cryptosporidium parvum (4.618, 2.877-7.412). Conclusion Our findings demonstrated that individuals afflicted with mental disorders are significantly more susceptible to acquiring protozoan parasites in comparison to healthy individuals. Preventive interventions, regular screening, and treatment approaches for parasitic diseases should be considered for patients with mental disorders. Keywords: Protozoan parasites, Mental disorders, Prevalence, Meta-analysis, Worldwide, Author(s): Amir Abdoli[sup.1,2], Meysam Olfatifar[sup.3], Aida Vafae Eslahi[sup.4], Zeinab Moghadamizad[sup.5], Rasoul Samimi[sup.4], Mohammad Amin Habibi[sup.6,7], Amir Sam Kianimoghadam[sup.8], Milad Badri[sup.4] and Panagiotis Karanis[sup.9,10] Background Over the past few decades, protozoan [...]

Background Myanmar has a large majority of all malaria in the Greater Mekong Subregion. In the past decade, substantial progress was made in malaria control. The residual burden of malaria is in remote areas where currently recommended malaria elimination approaches are generally not feasible. In such hard-to-reach communities in Mon state, East Myanmar, Medical Action Myanmar introduced community health workers (CHWs) to deliver early diagnosis and treatment for malaria. We conducted a retrospective analysis to assess the impact of this intervention. Methods and findings This retrospective analysis involved data collected routinely from a CHW programme in Mon state conducted between 2011 and 2018. A network of 172 CHWs serving a population of 236,340 was deployed. These CHWs carried out 260,201 malaria rapid diagnostic tests (RDTs) to investigate patients with acute febrile illness. The median blood examination rate was 1.33%; interquartile range (IQR) (0.38 to 3.48%); 95% CI [1.28%, 1.36%] per month. The changes in malaria incidence and prevalence in patients presenting with fever were assessed using negative binomial regression mixed effects models fitted to the observed data. The incidence of Plasmodium falciparum malaria (including mixed infections) declined by 70%; 95% CI [65%, 75%]; p < 0.001 for each year of CHW operation. The incidence of P. vivax malaria declined by 56%; 95% CI [50%, 62%]; p < 0.001 per year. Malaria RDT positivity rates for P. falciparum and P. vivax declined by 69%; 95% CI [62%, 75%]; p < 0.001 and 53%; 95% CI [47%, 59%]; p < 0.001 per year, respectively. Between 2017 and 2018, only 1 imported P. falciparum case was detected in 54,961 RDTs. The main limitations of the study are use of retrospective data with possible unidentified confounders and uncharacterised population movement. Conclusions The introduction of CHWs providing community-based malaria diagnosis and treatment and basic health care services in remote communities in Mon state was associated with a substantial reduction in malaria. Within 6 years, P. falciparum was eliminated and the incidence of P. vivax fell markedly., Author(s): Aye Sandar Zaw 1,2, Ei Shwe Sin Win 1, Soe Wai Yan 1, Kyaw Sithu Thein 1, Vasundhara Verma 2, Alistair R. D. McLean 1,2, Thar Tun Kyaw 1,2,3, [...]

Background Rapid and accurate detection of pathogens is needed in community-acquired pneumonia (CAP) to enable appropriate antibiotics and to slow the development of antibiotic resistance. We aimed to compare the effect of point-of-care (POC) polymerase chain reaction (PCR) detection of respiratory pathogens added to standard care with standard care only (SCO) on antibiotic prescriptions after acute hospital admission. Methods and findings We performed a superiority, parallel-group, open-label, multicentre, randomised controlled trial (RCT) in 3 Danish medical emergency departments (EDs) from March 2021 to February 2022. Adults acutely admitted with suspected CAP during the daytime on weekdays were included and randomly assigned (1:1) to POC-PCR (The Biofire FilmArray Pneumonia Panel plus added to standard care) or SCO (routine culture and, if requested by the attending physician, target-specific PCR) analysis of respiratory samples. We randomly assigned 294 patients with successfully collected samples (tracheal secretion 78.4% or expectorated sputum 21.6%) to POC-PCR (n = 148, 50.4%) or SCO (146, 49.6%). Patients and investigators owning the data were blinded to the allocation and test results. Outcome adjudicators and clinical staff at the ED were not blinded to allocation and test results but were together with the statistician, blinded to data management and analysis. Laboratory staff performing standard care analyses was blinded to allocation. The study coordinator was not blinded. Intention-to-treat and per protocol analysis were performed using logistic regression with Huber-White clustered standard errors for the prescription of antibiotic treatment. Loss to follow-up comprises 3 patients in the POC-PCR (2%) and none in the SCO group. Intention-to-treat analysis showed no difference in the primary outcome of prescriptions of no or narrow-spectrum antibiotics at 4 h after admission for the POC-PCR (n = 91, 62.8%) odds ratio (OR) 1.13; (95% confidence interval (CI) [0.96, 1.34] p = 0.134) and SCO (n = 87, 59.6%). Secondary outcomes showed that prescriptions were significantly more targeted at 4-h OR 5.68; (95% CI [2.49, 12.94] p < 0.001) and 48-h OR 4.20; (95% CI [1.87, 9.40] p < 0.001) and more adequate at 48-h OR 2.11; (95% CI [1.23, 3.61] p = 0.006) and on day 5 in the POC-PCR group OR 1.40; (95% CI [1.18, 1.66] p < 0.001). There was no difference between the groups in relation to intensive care unit (ICU) admissions OR 0.54; (95% CI [0.10, 2.91] p = 0.475), readmission within 30 days OR 0.90; (95% CI [0.43, 1.86] p = 0.787), length of stay (LOS) IRR 0.82; (95% CI [0.63, 1.07] p = 0.164), 30 days mortality OR 1.24; (95% CI [0.32, 4.82] p = 0.749), and in-hospital mortality OR 0.98; (95% CI [0.19, 5.06] p = 0.986). Conclusions In a setting with an already restrictive use of antibiotics, adding POC-PCR to the diagnostic setup did not increase the number of patients treated with narrow-spectrum or without antibiotics. POC-PCR may result in a more targeted and adequate use of antibiotics. A significant study limitation was the concurrent Coronavirus Disease 2019 (COVID-19) pandemic resulting in an unusually low transmission of respiratory virus. Trial registration ClinicalTrials.gov (NCT04651712)., Author(s): Mariana Bichuette Cartuliares 1,2,*, Flemming Schønning Rosenvinge 3,4, Christian Backer Mogensen 1,2, Thor Aage Skovsted 5, Steen Lomborg Andersen 6, Claus Østergaard 7, Andreas Kristian Pedersen 8, Helene Skjøt-arkil [...]