IntroductionHuman papillomavirus (HPV) is necessary but not sufficient for cervical cancer development. During cervical carcinogenesis, methylation levels increase across host and HPV DNA. DNA methylation has been proposed as a test to diagnose cervical intraepithelial neoplasia (CIN); we present a protocol to evaluate the accuracy of methylation markers to detect high-grade CIN and cervical cancer. Methods and analysisWe will search electronic databases (Medline, Embase and Cochrane Library), from inception, to identify studies examining DNA methylation as a diagnostic marker for CIN or cervical cancer, in a cervical screening population. The primary outcome will be to assess the diagnostic test accuracy of host and HPV DNA methylation for high-grade CIN; the secondary outcomes will be to examine the accuracy of different methylation cut-off thresholds, and accuracy in high-risk HPV positive women. Our reference standard will be histology. We will perform meta-analyses using Cochrane guidelines for diagnostic test accuracy. We will use the number of true positives, false negatives, true negatives and false positives from individual studies. We will use the bivariate mixed effect model to estimate sensitivity and specificity with 95% CIs; we will employ different bivariate models to estimate sensitivity and specificity at different thresholds if sufficient data per threshold. For insufficient data, the hierarchical summary receiver operating curve model will be used to calculate a summary curve across thresholds. If there is interstudy and intrastudy variation in thresholds, we will use a linear mixed effects model to calculate the optimum threshold. If few studies are available, we will simplify models by assuming no correlation between sensitivity and specificity and perform univariate, random-effects meta-analysis. We will assess the quality of studies using QUADAS-2 and QUADAS-C. Ethics and disseminationEthical approval is not required. Results will be disseminated to academic beneficiaries, medical practitioners, patients and the public. PROSPERO registration numberCRD42022299760. …

Volume 12, Issue 1, December 2023 .

Publication date: Available online 4 June 2023 Source: Infectious Disease Modelling Author(s): Teerachat Sae-heng, Kesara Na-Bangchang …

Publication date: Available online 4 June 2023 Source: Infectious Disease Modelling Author(s): Yawen Wang, Shi Zhao, Yuchen Wei, Kehang Li, Xiaoting Jiang, Conglu Li, Chao Ren, Shi Yin, Janice Ho, Jinjun Ran, Lefei Han, Benny Chung-ying Zee, Ka Chun Chong …

Volume 14, Issue 1, December 2023 .

AbstractBackgroundCamostat inhibits SARS-CoV-2 infection in vitro. We studied the safety and efficacy of camostat in ACTIV-2/A5401, a phase 2/3 platform trial of therapeutics for COVID-19 in non-hospitalized adults.MethodsWe conducted a phase 2 study in adults with mild-to-moderate COVID-19 randomized to oral camostat for 7 days or a pooled placebo arm. Primary outcomes were time to improvement in COVID-19 symptoms through day 28, proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal (NP) swabs through day 14, and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28.ResultsOf 216 participants (109 randomized to camostat, 107 to placebo) who initiated study intervention, 45% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Median age was 37 years. Median time to symptom improvement was 9 days in both arms (p=0.99). There were no significant differences in the proportion of participants with SARS-CoV-2 RNA

AbstractBackgroundPaenibacillus thiaminolyticus may be an underdiagnosed cause of neonatal sepsis.MethodsWe prospectively enrolled a cohort of 800 full-term neonates presenting with a clinical diagnosis of sepsis at two Ugandan hospitals. Quantitative polymerase chain reaction specific to P. thiaminolyticus and to the Paenibacillus genus were performed on the blood and cerebrospinal fluid (CSF) of 631 neonates who had both specimen types available. Neonates with Paenibacillus genus or species detected in either specimen type were considered to potentially have paenibacilliosis, (37/631, 6%). We described antenatal, perinatal, and neonatal characteristics, presenting signs, and 12-month developmental outcomes for neonates with paenibacillosis vs. clinical sepsis.ResultsMedian age at presentation was 3 days (interquartile range 1, 7). Fever (92%), irritability (84%) and clinical signs of seizures (51%) were common. Eleven (30%) had an adverse outcome: 5 (14%) neonates died during the first year of life; 5 of 32 (16%) survivors developed postinfectious hydrocephalus (PIH) and one (3%) additional survivor had neurodevelopmental impairment without hydrocephalus.ConclusionPaenibacillus species was identified in 6% of neonates with signs of sepsis who presented to two Ugandan referral hospitals; 70% were P. thiaminolyticus. Improved diagnostics for neonatal sepsis are urgently needed. Optimal antibiotic treatment for this infection is unknown but ampicillin and vancomycin will be ineffective in many cases. These results highlight the need to consider local pathogen prevalence and the possibility of unusual pathogens when determining antibiotic choice for neonatal sepsis.

AbstractBackgroundEbola virus disease (EVD) is one of the most severe and fatal viral hemorrhagic fevers and appears to mimic many clinical and laboratory manifestations of hemophagocytic lymphohistiocytosis syndrome (HLS), also known as macrophage activation syndrome (MAS). However, a clear association is yet to be firmly established for effective host-targeted, immunomodulatory therapeutic approaches to improve outcomes in patients with severe EVD.MethodsTwenty-four rhesus monkeys were exposed intramuscularly to the Ebola virus (EBOV) Kikwit and euthanized at prescheduled time points or when they reached the end-stage disease criteria. Three additional monkeys were mock-exposed and used as uninfected controls.ResultsEBOV-exposed monkeys presented with clinicopathologic features of HLS, including fever, multi-organomegaly, pancytopenia, hemophagocytosis, hyperfibrinogenemia with disseminated intravascular coagulation, hypertriglyceridemia, hypercytokinemia, increased concentrations of soluble CD163 and CD25 in serum, and the loss of activated natural killer cells.ConclusionsOur data suggest that EVD in the rhesus macaque model mimics pathophysiologic features of HLS/MAS. Hence, regulating inflammation and immune function might provide an effective treatment for controlling acute EVD pathogenesis.

AbstractBackgroundAnticoagulation (AC) utilization patterns and their predictors among hospitalized coronavirus disease 2019 (COVID-19) patients have not been well-described.MethodsUsing the National COVID Cohort Collaborative, we conducted a retrospective cohort study (2020-2022) to assess AC use patterns and identify factors associated with therapeutic AC employing modified Poisson regression.ResultsAmong 162,842 hospitalized COVID-19 patients, 64% received AC and 24% received therapeutic AC. Therapeutic AC use declined from 32% in 2020 to 12% in 2022, especially after December 2021. Therapeutic AC predictors included age (relative risk (RR), 1.02 [95% confidence interval (CI), 1.02-1.02] per year), male (RR, 1.29 [1.27-1.32]), Non-Hispanic Black (RR, 1.16 [1.13-1.18]), obesity (RR, 1.48 [1.43-1.52]), increased length of stay (RR, 1.01; [1.01-1.01] per day), and invasive ventilation (RR, 1.64 [1.59-1.69]). Vaccination (RR, 0.88 [0.84-0.92]) and higher Charlson Comorbidity Index (CCI) (RR, 0.98 [0.97-0.98]) were associated with lower therapeutic AC.ConclusionsOverall, two thirds of hospitalized COVID-19 patients received any AC and a quarter received therapeutic dosing. Therapeutic AC declined after the introduction of the Omicron variant. Predictors of therapeutic AC included demographics, obesity, LOS, invasive ventilation, CCI, and vaccination, suggesting AC decisions driven by clinical factors including COVID-19 severity, bleeding risks, and comorbidities.

Fusarium species are filamentous fungi ubiquitously found in nature, including soil, water, and plants [1]. The genus can cause a broad spectrum of infections in humans, depending mainly on the host\'s immune status. It manifests in immunocompetent patients primarily as local Fusarium infections, often with ocular and skin involvements such as keratitis and onychomycosis [2]. However, fusariosis may present as a disseminated disease, especially in immunocompromised, hematological malignancies and bone marrow transplant patients.

Abstract Background Individuals in close contact with active pulmonary tuberculosis (TB) patients showed a high risk of recent infection and, once infected, higher risk of developing active TB in the following years post-exposure. But the peak time of active disease onset is unclear. This study aims to estimate post exposure TB incidence risk among close contacts to provide reference for clinical and public health strategies. Methods We searched PubMed, Web of Science, and EMBASE for articles published until December 1, 2022. The incidence rates were quantitatively summarized by means of meta-analysis using the random-effect model. Results Of the 5616 studies, 31 studies included in our analysis. For baseline close contacts results, the summarized prevalence of Mycobacterium tuberculosis (MTB) infection and active TB was found to be 46.30% (95% CI: 37.18%-55.41%) and 2.68% (95% CI: 2.02%-3.35%), respectively. During the follow-up, the 1-year, 2-year and 5-year cumulative incidence of TB in close contacts were 2.15% (95% CI: 1.51%-2.80%), 1.21% (95% CI: 0.93%-1.49%) and 1.11% (95% CI: 0.64%-1.58%), respectively. Individuals with a positive result of MTB infection testing at baseline showed significantly higher cumulative TB incidence as compared to those negatives (3.80% vs. 0.82%, p 

AbstractBackgroundAntibiotic resistance (AMR) is undermining modern medicine, a problem compounded by bacterial adaptation to antibiotic pressures. Phages are viruses that infect bacteria. Their diversity and evolvability offer the prospect of their use as a therapeutic solution. Reported are outcomes of customized phage therapy for patients with difficult-to-treat AMR infections.MethodsWe retrospectively assessed 12 cases of customized phage therapy from a phage production center. Phages were screened, purified, sequenced, characterized, and FDA-approved via the IND compassionate care route. Outcomes were assessed as favorable or unfavorable by microbiologic and clinical standards. Infections were device-related or systemic. Other experiences such as time to treatment, antibiotic synergy and immune responses were recorded.ResultsFifty requests for phage therapy were received. Customized phages were generated for twelve patients. After treatment, 42% (5/12) of cases showed bacterial eradication and 58% (7/12) showed clinical improvement, with two-thirds of all cases (66%) showing favorable responses. No major adverse reactions were observed. Antibiotic-phage synergy in vitro was observed in most cases. Immunological neutralization of phage was reported in five cases. Several cases were complicated by secondary infections. Complete characterization of the phages (morphology, genomics, and activity) and their production (methods, sterility, and endotoxin tests) are reported.ConclusionsCustomized phage production and therapy was safe and yielded favorable clinical or microbiological outcomes in two-thirds of cases. A center or pipeline dedicated to tailoring the phages against a patient’s specific AMR bacterial infection may be a viable option where standard treatment has failed.

Abstract Background Many geographical areas of sub-Saharan Africa, especially in rural settings, lack complete and up-to-date demographic data, posing a challenge for implementation and evaluation of public health interventions and carrying out large-scale health research. A demographic survey was completed in Mopeia district, located in the Zambezia province in Mozambique, to inform the Broad One Health Endectocide-based Malaria Intervention in Africa (BOHEMIA) cluster randomized clinical trial, which tested ivermectin mass drug administration to humans and/or livestock as a potential novel strategy to decrease malaria transmission. Methods The demographic survey was a prospective descriptive study, which collected data of all the households in the district that accepted to participate. Households were mapped through geolocation and identified with a unique identification number. Basic demographic data of the household members was collected and each person received a permanent identification number for the study. Results 25,550 households were mapped and underwent the demographic survey, and 131,818 individuals were registered in the district. The average household size was 5 members and 76.9% of households identified a male household head. Housing conditions are often substandard with low access to improved water systems and electricity. The reported coverage of malaria interventions was 71.1% for indoor residual spraying and 54.1% for universal coverage of long-lasting insecticidal nets. The median age of the population was 15 years old. There were 910 deaths in the previous 12 months reported, and 43.9% were of children less than 5 years of age. Conclusions The study showed that the district had good coverage of vector control tools against malaria but sub-optimal living conditions and poor access to basic services. The majority of households are led by males and Mopeia Sede/Cuacua is the most populated locality in the district. The population of Mopeia is young (

Tropical Medicine &International Health, EarlyView.

New England Journal of Medicine, Ahead of Print.

New England Journal of Medicine, Ahead of Print.

AbstractEndogenous DNA is released into the bloodstream as cell-free DNA (cfDNA) following cell death and is associated with various pathological conditions. However, their association with therapeutic drugs against rheumatoid arthritis (RA) remains unknown. Therefore, we investigated the significance of cfDNA in RA treated with tocilizumab and tumor necrosis factor inhibitor (TNF-I). Biological DMARDs (bDMARDs), including tocilizumab and TNF-I, were administered to 77 and 59 RA patients, respectively. Plasma cfDNA levels were measured at weeks 0, 4, and 12 by quantitative polymerase chain reaction. Disease activity was evaluated at the same time point using DAS28ESR. cfDNA levels from RA synovial cells treated with tocilizumab or etanercept for 24 h were measured. Human toll-like receptor 9 (hTLR9)-expressing HEK293 cells, which release secreted embryonic alkaline phosphatase (SEAP) upon NF-κB activation, were stimulated by cfDNA from RA patients, and subsequently, SEAP levels were determined. NF-κB translocation was evaluated by immunofluorescence staining with or without tocilizumab. The DAS28ESR significantly improved in both bDMARD groups at week 12. However, plasma cfDNA levels significantly decreased in the tocilizumab group at week 12 compared to that in week 0. cfDNA levels correlated with DAS28ESR in biological treatment-naïve patients administered tocilizumab. cfDNA levels in synovial cells were significantly suppressed by tocilizumab treatment and unaltered with etanercept. HEK293 cells released SEAP upon cfDNA stimulation, and the observed NF-κB nuclear translocation was suppressed by tocilizumab. Tocilizumab suppressed inflammation via the TLR9 pathway by decreasing cfDNA levels. Regulation of cfDNA may be a therapeutic target for RA.

Since the 1993 outbreak of hantavirus cardiopulmonary syndrome (HPS or HCPS) in the Four Corners region of the United States, at least 21 rodent-borne orthohantaviruses have been discovered throughout North and South America (conventionally referred to as New World orthohantaviruses) [1]. Specifically, Sin Nombre virus (SNV; North America) and Andes virus (ANDV; South America) have become prominent model systems for orthohantavirus research due to their severe impacts on human health [2,3]. As of May 2023, the Centers for Disease Control and Prevention (CDC) continues to classify all hantaviruses equally in terms of health risks, based largely on SNV (https://www.cdc.gov/hantavirus/index.html), despite many orthohantaviruses being associated with much milder or no human disease [1].

Abstract Background Pfcrt gene has been associated with chloroquine resistance and the pfmdr1 gene can alter malaria parasite susceptibility to lumefantrine, mefloquine, and chloroquine. In the absence of chloroquine (CQ) and extensive use of artemether–lumefantrine (AL) from 2004 to 2020 to treat uncomplicated falciparum malaria, pfcrt haplotype, and pfmdr1 single nucleotide polymorphisms (SNPs) were determined in two sites of West Ethiopia with a gradient of malaria transmission. Methods 230 microscopically confirmed P. falciparum isolates were collected from Assosa (high transmission area) and Gida Ayana (low transmission area) sites, of which 225 of them tested positive by PCR. High-Resolution Melting Assay (HRM) was used to determine the prevalence of pfcrt haplotypes and pfmdr1 SNPs. Furthermore, the pfmdr1 gene copy number (CNV) was determined using real-time PCR. A P-value of less or equal to 0.05 was considered significant. Results Of the 225 samples, 95.5%, 94.4%, 86.7%, 91.1%, and 94.2% were successfully genotyped with HRM for pfcrt haplotype, pfmdr1-86, pfmdr1-184, pfmdr1-1042 and pfmdr1-1246, respectively. The mutant pfcrt haplotypes were detected among 33.5% (52/155) and 80% (48/60) of isolates collected from the Assosa and Gida Ayana sites, respectively. Plasmodium falciparum with chloroquine-resistant haplotypes was more prevalent in the Gida Ayana area compared with the Assosa area (COR = 8.4, P = 0.00). Pfmdr1-N86Y wild type and 184F mutations were found in 79.8% (166/208) and 73.4% (146/199) samples, respectively. No single mutation was observed at the pfmdr1-1042 locus; however, 89.6% (190/212) of parasites in West Ethiopia carry the wild-type D1246Y variants. Eight pfmdr1 haplotypes at codons N86Y–Y184F–D1246Y were identified with the dominant NFD 61% (122/200). There was no difference in the distribution of pfmdr1 SNPs, haplotypes, and CNV between the two study sites (P > 0.05). Conclusion Plasmodium falciparum with the pfcrt wild-type haplotype was prevalent in high malaria transmission site than in low transmission area. The NFD haplotype was the predominant haplotype of the N86Y–Y184F–D1246Y. A continuous investigation is needed to closely monitor the changes in the pfmdr1 SNPs, which are associated with the selection of parasite populations by ACT. …

Staphylococcus aureus bloodstream infection (SAB) is a common and severe infection. This study aims to describe temporal trends in numbers, epidemiological characteristics, clinical manifestations, and outcomes of SAB.

SummaryMucosa-associated invariant T (MAIT) cells are evolutionarily conserved, innate-like T lymphocytes with enormous immunomodulatory potentials. Due to their strategic localization, their invariant T cell receptor (iTCR) specificity for major histocompatibility complex-related protein 1 (MR1) ligands of commensal and pathogenic bacterial origin, and their sensitivity to infection-elicited cytokines, MAIT cells are best known for their antimicrobial characteristics. However, they are thought to also play important parts in the contexts of cancer, autoimmunity, vaccine-induced immunity, and tissue repair. While cognate MR1 ligands and cytokine cues govern MAIT cell maturation, polarization and peripheral activation, other signal transduction pathways, including those mediated by costimulatory interactions, regulate MAIT cell responses. Activated MAIT cells exhibit cytolytic activities and secrete potent inflammatory cytokines of their own, thus transregulating the biological behaviours of several other cell types, including dendritic cells, macrophages, natural killer cells, conventional T cells and B cells, with significant implications in health and disease. Therefore, an in-depth understanding of how costimulatory pathways control MAIT cell responses may introduce new targets for optimized MR1/MAIT cell-based interventions. Herein, we compare and contrast MAIT cells and mainstream T cells for their expression of classic costimulatory molecules belonging to the immunoglobulin superfamily and the tumour necrosis factor (TNF)/TNF receptor superfamily, based not only on the available literature but also on our transcriptomic analyses. We discuss how these molecules participate in MAIT cells’ development and activities. Finally, we introduce several pressing questions vis-à-vis MAIT cell costimulation and offer new directions for future research in this area.

Tropical Medicine &International Health, EarlyView.

AbstractBacillus thuringiensis (Bt) proteins are an environmentally safe and effective alternative to chemical pesticides and have been used as biopesticides, with great commercial success, for over 50 years. Global agricultural production is predicted to require a 70% increase until 2050 to provide for an increasing population. In addition to agriculture, Bt proteins are utilised to control human vectors of disease – namely mosquitoes – which account for >700,000 deaths annually. The evolution of resistance to Bt pesticial toxins threatens the progression of sustainable agriculture. Whilst Bt protein toxins are heavily utilised, the exact mechanisms behind receptor binding and toxicity are unknown. It is critical to gain a better understanding of these mechanisms in order to engineer novel toxin variants and to predict, and prevent, future resistance evolution. This review focuses on the role of carbohydrate binding in the toxicity of the most utilised group of Bt pesticidal proteins – three domain Cry (3D-Cry) toxins.

Invasive infections caused by extensively drug-resistant (XDR) Acinetobacter baumannii (AB), in particular carbapenem-resistant strains (CRAB), are associated with high mortality rates above 50% [1]. The potent in vitro synergy of colistin, often the only active agent, and carbapenems, as stemmed from pre-clinical data [2], has led to the conduct of randomized controlled trials (RCTs), the latest recently published [3]. These trials, showed that there was no difference between colistin-meropenem combination treatment versus colistin monotherapy for various patients’ outcomes, including mortality.

ObjectivesThis study sought first to empirically define dietary patterns and to apply the novel Dietary Inflammation Score (DIS) in data from rural and metropolitan populations in Australia, and second to investigate associations with cardiovascular disease (CVD) risk factors. DesignCross-sectional study. SettingRural and metropolitan Australia. ParticipantsAdults over the age of 18 years living in rural or metropolitan Australia who participated in the Australian Health survey. Primary outcomesA posteriori dietary patterns for participants separated into rural and metropolitan populations using principal component analysis. Secondary outcomes: association of each dietary pattern and DIS with CVD risk factors was explored using logistic regression. ResultsThe sample included 713 rural and 1185 metropolitan participants. The rural sample was significantly older (mean age 52.7 compared with 48.6 years) and had a higher prevalence of CVD risk factors. Two primary dietary patterns were derived from each population (four in total), and dietary patterns were different between the rural and metropolitan areas. None of the identified patterns were associated with CVD risk factors in metropolitan or rural areas, aside diet pattern 2 being strongly associated with from self-reported ischaemic heart disease (OR 13.90 95% CI 2.29 to 84.3) in rural areas. There were no significant differences between the DIS and CVD risk factors across the two populations, except for a higher DIS being associated with overweight/obesity in rural areas. ConclusionExploration of dietary patterns between rural and metropolitan Australia shows differences between the two populations, possibly reflective of distinct cultures, socioeconomic factors, geography, food access and/or food environments in the different areas. Our study provides evidence that action targeting healthier dietary intakes needs to be tailored to rurality in the Australian context. …

IntroductionLong COVID is a prevalent condition with many multisystemic symptoms, such as fatigue, dyspnoea, muscle weakness, anxiety, depression and sleep difficulties, impacting daily life and (social and physical) functioning. Pulmonary rehabilitation (PR) may improve physical status and symptoms of patients with long COVID, yet the evidence is limited. Therefore, this trial aims to study the effect of primary care PR on exercise capacity, symptoms, physical activity and sleep in patients with long COVID. Methods and analysisPuRe-COVID is a prospective, pragmatic, open-label, randomised controlled trial. A sample of 134 adult patients with long COVID will be randomised to a 12 week PR programme in primary care, supervised by a physiotherapist or to a control group, following no PR. A 3 month and 6 month follow-up period is foreseen. The primary endpoint will be the change in exercise capacity measured by 6-minute walk distance (6MWD) at 12 weeks, hypothesising a more significant improvement in the PR group. Other parameters, such as pulmonary function tests (including maximal inspiratory pressure/maximal expiratory pressure), patient-reported outcomes (COPD Assessment Test, modified Medical Research Council Dyspnoea Scale, Checklist Individual Strength, post-COVID-19 Functional Status, Nijmegen questionnaire, Hospital Anxiety and Depression Scale, Work Productivity and Activity Impairment Questionnaire and EuroQol-5D-5L), physical activity measured by an activity tracker, hand grip strength and sleep efficiency, are secondary and exploratory outcomes. The recruitment started on 19 April 2022, and 52 patients were included as of 14 December 2022. Ethics and disseminationEthical approval was obtained in Belgium from the relevant institutional review boards on 21 February 2022 (Antwerp University Hospital, approval number 2022-3067) and on 1 April 2022 (Ziekenhuis Oost-Limburg in Genk, approval number Z-2022-01). Findings from this randomised controlled trial will be disseminated in peer-reviewed publications and presentations at international scientific meetings. Trial registration numberNCT05244044. …

Bovine Leukemia Virus (BLV) is the etiological agent of enzootic bovine leukosis, a disease characterized by the neoplastic proliferation of B cells in cattle. While most European countries have introduced eff...

Piroplasmids are parasitic protozoa of the order Piroplasmida (see Glossary) within the phylum Apicomplexa and are currently divided into three main genera: Babesia, Cytauxzoon, and Theileria. Like their malaria-causing relatives of the genus Plasmodium, piroplasmids are transmitted by an arthropod vector to their vertebrate hosts where they undergo asexual growth. However, in this case the blood-feeding arthropod is an ixodid tick (Box 1). The name piroplasmid derives from the pear shape (piro = pear; from the Latin pirum) that the parasites acquire in the vertebrate host.

Monocytes are myeloid cells that are produced throughout life and play key roles in host defense against pathogens, immune regulation, tissue repair, tumor progression, and cancer [1]. Following their generation in the bone marrow (BM), monocytes enter the bloodstream where they constitute 4% of peripheral leukocytes in mice and 10% in humans [1]. Under physiological conditions, monocytes survey the vasculature or enter tissues to replenish tissue-resident macrophages [1], whereas during inflammation they are rapidly recruited to injured organs regulating the local immune responses [2] by molecular signals that are largely unknown.

Science Advances, Volume 9, Issue 22, June 2023.

Science Advances, Volume 9, Issue 22, June 2023.

by Zul Aizat Mohamad Fisal, Rosliza Abdul Manaf, Ahmad Zaid Fattah Azman, Gurpreet Kaur Karpal Singh Background Depression is the most common psychiatric disorder reported among patients living with Human Immunodeficiency Virus (HIV), resulting from the intricate combination of biological, psychological, and social factors. Biopsychosocial factors can significantly impact the psychological well-being of men who have sex with men (MSM) living with HIV through social stigma, access and compliance to care, economic insecurity, relationship difficulties, and risky behavior. Compared to MSM without HIV, MSM living with HIV were more likely to be depressed. Despite specific vulnerabilities and health needs, MSM living with HIV remain understudied and underserved in Malaysia owing to legal, ethical, and social challenges. Objective This is merely a published protocol, not the findings of a future study. This study aims to determine and explain the predictors of depressive symptoms among MSM living with HIV. Specifically, this study wants to determine the association between depressive symptoms among MSM living with HIV and biological, psychosocial, and social factors. Finally, the mixed methods will answer to what extent the qualitative results confirm the quantitative results of the predictors of depressive symptoms among MSM living with HIV. Methods The study has ethical approval from the Medical Research Ethics Committee (MREC) of the Ministry of Health (MOH) NMRR ID-21-02210-MIT. This study will apply an explanatory sequential mixed methods study design. It comprised two distinct phases: quantitative and qualitative study design for answering the research questions and hypothesis. This study will randomly recruit 941 MSM living with HIV in the quantitative phase, and at least 20 MSM living with HIV purposively will be selected in the qualitative phase. The study will be conducted in ten public Primary Care Clinics in Selangor, Malaysia. A self-administered questionnaire will gather the MSM’s background and social, psychological, and biological factors that could be associated with depressive symptoms. For the quantitative study, descriptive analysis and simple logistic regression will be used for data analysis. Then, variables with a P value < 0.25 will be included in multiple logistic regression to measure the predictors of depressive symptoms. In the qualitative data collection, in-depth interviews will be conducted among those with moderate to severe depressive symptoms from the quantitative phase. The thematic analysis will be used for data analysis in the qualitative phase. Integration occurs at study design, method level, and later during interpretation and report writing. Result The quantitative phase was conducted between March 2022 to February 2023, while qualitative data collection is from March 2023 to April 2023, with baseline results anticipated in June 2023. Conclusion In combination, qualitative and quantitative research provides a better understanding of depressive symptoms among MSM living with HIV. The result could guide us to provide a comprehensive mental healthcare program toward Ending the AIDS epidemic by 2030. …

by Maryke S. Steffens, Bianca Bullivant, Jessica Kaufman, Catherine King, Margie Danchin, Monsurul Hoq, Mathew D. Marques Introduction Achieving high COVID-19 vaccine booster coverage is an ongoing global challenge. Health authorities need evidence about effective communication interventions to improve acceptance and uptake. This study aimed to test effects of persuasive messages about COVID-19 vaccine booster doses on intention to vaccinate amongst eligible adults in Australia. Methods In this online randomised controlled trial, adult participants received one of four intervention messages or a control message. The control message provided information about booster dose eligibility. Intervention messages added to the control message, each using a different persuasive strategy, including: emphasising personal health benefits of booster doses, community health benefits, non-health benefits, and personal agency in choosing vaccination. After the intervention, participants answered items about COVID-19 booster vaccine intention and beliefs. Intervention groups were compared to the control using tests of two proportions; differences of ≥5 percentage points were deemed clinically significant. A sub-group analysis was conducted among hesitant participants. Results Of the 487 consenting and randomised participants, 442 (90.8%) completed the experiment and were included in the analysis. Participants viewing messages emphasising non-health benefits had the highest intention compared to those who viewed the control message (percentage point diff: 9.0, 95% CI -0.8, 18.8, p = 0.071). Intention was even higher among hesitant individuals in this intervention group compared to the control group (percentage point diff: 15.6, 95% CI -6.0, 37.3, p = 0.150). Conversely, intention was lower among hesitant individuals who viewed messages emphasising personal agency compared to the control group (percentage point diff: -10.8, 95% CI -33.0, 11.4, p = 0.330), although evidence in support of these findings is weak. Conclusion Health authorities should highlight non-health benefits to encourage COVID-19 vaccine booster uptake but use messages emphasising personal agency with caution. These findings can inform communication message development and strategies to improve COVID-19 vaccine booster uptake.Clinical trial registration: Registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622001404718); trial webpage: https://www.anzctr.org.au/ACTRN12622001404718.aspx …

by Joan B. Soriano, Adrián Peláez, Xavier Busquets, María Rodrigo-García, Elena Ávalos Pérez-Urría, Tamara Alonso, Rosa Girón, Claudia Valenzuela, Celeste Marcos, Elena García-Castillo, Julio Ancochea Background An association of ABO blood group and COVID-19 remains controversial. Methods Following STROBE guidance for observational research, we explored the distribution of ABO blood group in patients hospitalized for acute COVID-19 and in those with Long COVID. Contingency tables were made and risk factors were explored using crude and adjusted Mantle-Haentzel odds ratios (OR and 95% CI). Results Up to September 2022, there were a total of 5,832 acute COVID-19 hospitalizations in our hospital, corresponding to 5,503 individual patients, of whom blood group determination was available for 1,513 (27.5%). Their distribution by ABO was: 653 (43.2%) group 0, 690 (45.6%) A, 113 (7.5%) B, and 57 (3.8%) AB, which corresponds to the expected frequencies in the general population. In parallel, of 676 patients with Long COVID, blood group determination was available for 135 (20.0%). Their distribution was: 60 (44.4%) from group 0, 61 (45.2%) A, 9 (6.7%) B, and 5 (3.7%) AB. The distribution of the ABO system of Long COVID patients did not show significant differences with respect to that of the total group (p ≥ 0.843). In a multivariate analysis adjusting for age, sex, ethnicity, and severity of acute COVID-19 infection, subgroups A, AB, and B were not significantly associated with developing Long COVID with an OR of 1.015 [0.669–1.541], 1.327 [0.490–3.594] and 0.965 [0.453–2.058], respectively. The effect of the Rh+ factor was also not significant 1,423 [0.772–2,622] regarding Long COVID. Conclusions No association of any ABO blood subgroup with COVID-19 or developing Long COVID was identified. …

by Iyacoob Khunsri, Pinidphon Prombutara, Htut Htut Htoo, Supitcha Wanvimonsuk, Thanadon Samernate, Chindanai Pornsing, Sirinit Tharntada, Phattarunda Jaree, Vorrapon Chaikeeratisak, Kunlaya Somboonwiwat, Poochit Nonejuie Propelled by global climate changes, the shrimp industry has been facing tremendous losses in production due to various disease outbreaks, particularly early mortality syndrome (EMS), a disease caused by Vibrio parahaemolyticus AHPND. Not only is the use of antibiotics as EMS control agents not yet been proven successful, but the overuse and misuse of antibiotics could also worsen one of the most challenging global health issues—antimicrobial resistance. To circumvent antibiotic usage, anti-lipopolysaccharide factor isoform 3 (ALFPm3), an antimicrobial peptide (AMP) derived from the shrimp innate immune system, was proposed as an antibiotic alternative for EMS control. However, prolonged use of AMPs could also lead to bacterial cross resistance with life-saving antibiotics used in human diseases. Here, we showed that ALFPm3-resistant strains of E. coli could be induced in vitro. Genome analysis of the resistant mutants revealed multiple mutations, with the most interesting being a qseC(L299R). A study of antibiotic susceptibility profile showed that the resistant strains harboring the qseC(L299R) not only exhibited higher degree of resistance towards polymyxin antibiotics, but also produced higher biofilm under ALFPm3 stress. Lastly, a single cell death analysis revealed that, at early-log phase when biofilm is scarce, the resistant strains were less affected by ALFPm3 treatment, suggesting additional mechanisms by which qseC orchestrates to protect the bacteria from ALFPm3. Altogether, this study uncovers involvement of qseC mutation in mechanism of resistance of the bacteria against ALFPm3 paving a way for future studies on sustainable use of ALFPm3 as an EMS control agent.

by Regina Billones-Baaijens, Meifang Liu, Mark R. Sosnowski, Matthew R. Ayres, Sandra Savocchia The grapevine trunk disease, Eutypa dieback (ED), causes significant vine decline and yield reduction. For many years, the fungus Eutypa lata was considered the main pathogen causing ED of grapevines in Australia. Recent studies showed other Diatrypaceous fungi were also associated with vines exhibiting dieback symptoms but there is limited information on how these fungal pathogens spread in vineyards. Thus, information on the spore dispersal patterns of Diatrypaceous fungi in different wine regions will assist in identifying high-risk infection periods in vineyards. Using more than 6800 DNA samples from airborne spores collected from eight wine regions in south-eastern Australia over 8 years using a Burkard spore trap, this study investigated the diversity and abundance of Diatrypaceous species, using multi-faceted molecular tools. A multi-target quantitative PCR (qPCR) assay successfully detected and quantified Diatrypaceous spores from 30% of the total samples with spore numbers and frequency of detection varying between regions and years. The high-resolution melting analysis (HRMA) coupled with DNA sequencing identified seven species, with E. lata being present in seven regions and the most prevalent species in the Adelaide Hills, Barossa Valley and McLaren Vale. Cryptovalsa ampelina and Diatrype stigma were the predominant species in the Clare Valley and Coonawarra, respectively while Eutypella citricola and Eu. microtheca dominated in the Hunter Valley and the Riverina regions. This study represents the first report of D. stigma and Cryptosphaeria multicontinentalis in Australian vineyards. This study further showed rainfall as a primary factor that triggers spore release, however, other weather factors that may influence the spore release in different climatic regions of Australia still requires further investigation.

by Dalton S. Graham, Gang Liu, Ailar Arasteh, Xiao-Ming Yin, Shengmin Yan Increased uptake of fat, such as through the ingestion of high fat diet (HFD), can lead to fatty liver diseases and metabolic syndrome. It is not clear whether certain fatty acids may be more pathogenic than others to the liver. Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in the Western diet and its excessive consumption can lead to increased lipid peroxidation. We hypothesized that a high level of LA in HFD will contribute significantly to the hepatic steatosis and injury, whereas vitamin E (VIT-E) may reverse the effects from LA by inhibiting lipid peroxidation. To test this hypothesis, we fed mice with the following diets for 20 weeks: a standard low-fat diet (CHOW), HFD with a low level of LA (LOW-LA, 1% of energy from LA), HFD with a high level of LA (HI-LA, 8% of energy from LA), or HI-LA diet with VIT-E supplement (HI-LA + VIT-E). We found that the HI-LA diet resulted in more body weight gain, larger adipocyte area, and higher serum levels of triglycerides (TG) and free fatty acids (FFA) relative to the CHOW and LOW-LA diets. In mice fed with the HI-LA diet, severer hepatic steatosis was seen with higher levels of hepatic TG and FFA. Expression of genes related to lipid metabolism was altered in the liver by HI-LA diet, including fibroblast growth factor 21 (Fgf21), cluster of differentiation 36 (Cd36), stearoyl-CoA desaturase 1 (Scd1), and acyl-CoA oxidase 1 (Acox1). Liver injury, inflammation and fibrotic response were all enhanced in mice fed with the HI-LA diet when compared with the LOW-LA diet. Notably, addition of VIT-E supplement, which restores the proper VIT-E/PUFA ratio, significantly reduced the detrimental effects of the high level of LA. Taken together, our results suggest that a high level of LA and a low ratio of VIT-E/PUFA in HFD can contribute significantly to metabolic abnormalities and hepatic injury.

by Zainab Ali, Houda Harastani, Moza Hammadi, Lina Reslan, Soha Ghanem, Farah Hajar, Ahmad Sabra, Amjad Haidar, Adlette Inati, Mariam Rajab, Hassan Fakhouri, Bassam Ghanem, Ghassan Baasiri, Bernard Gerbaka, Hassan Zaraket, Ghassan M. Matar, Ghassan Dbaibo …

by Ryota Yamano, Juanwen Yu, Alfabetian Harjuno Condro Haditomo, Chunqi Jiang, Sayaka Mino, Jesús L. Romalde, Kyuhee Kang, Yuichi Sakai, Tomoo Sawabe The genus Thalassotalea is ubiquitous in marine environments, and up to 20 species have been described so far. A Gram-staining-negative, aerobic bacterium, designated strain PTE2T was isolated from laboratory-reared larvae of the Japanese sea cucumber Apostichopus japonicus. Phylogenetic analysis based on the 16S rRNA gene nucleotide sequences revealed that PTE2T was closely related to Thalassotalea sediminis N211T (= KCTC 42588T = MCCC 1H00116T) with 97.9% sequence similarity. ANI and in silico DDH values against Thalassotalea species were 68.5–77.0% and 19.7–24.6%, respectively, indicating the novelty of PTE2T. Based on genome-based taxonomic approaches, strain PTE2T (= JCM 34608T = KCTC 82592T) is proposed as a new species, Thalassotalea hakodatensis sp. nov.

by Yanyu Zhuang, Hua Wei In order to improve the laws and regulations of the financial system, in the construction of laws and regulations, the traditional financial risk Early Warning (EW) model is optimized. The financial prevention and control measures with legal protection are implemented to warn the financial risks, which plays an important role in the construction of the rule of law in the Financial Market (FM) and the establishment of financial risk prevention and control laws and regulations. This paper combines the deep learning model and the Markov regime Switching Vector Auto Regression (MS-VAR) model and constructs a regional financial risk EW model from the following aspects: macroeconomic operation EW indicators, regional economic risk EW indicators, regional financial institution risk EW indicators. The model is empirically researched and analyzed. The results show that the fluctuation trend of the macroeconomic pressure index in the time series is relatively large, and the overall fluctuation of the regional economic pressure index is small, and fluctuates around 0 in most periods. After the financial crisis, local governments stepped up their supervision of non-performing corporate and household loans. From 2011 to 2018, the non-performing loan ratio began to decline, and the overall fluctuation of the regional financial comprehensive stress index was small, fluctuating around 0. Due to the lack of legal regulation, from the perspective of the regional economy, the risk level is more likely to change from low risk to moderate risk, while the risk status is less likely to change from high risk to moderate risk. From the perspective of regional financial institutions, the probabilities of maintaining low risk and moderate risk are 0.98 and 0.97, respectively, which is stronger than maintaining the stability of high risk. From the perspective of the state transition of the regional financial risk composite index, the probability of maintaining low risk and high risk is 0.97 and 0.93, which is higher than maintaining the stability of medium risk. The Deep Learning (DL) regional financial risk EW MS-VAR model has strong risk prediction ability. The model can better analyze the conversion probability of regional financial risk EW index and has better risk EW ability. This paper enhances the role of legal systems in financial risk prevention and control. The regional financial risk EW model incorporating financial legal indicators can better describe the regional financial risk level, and the EW results are basically consistent with the actual situation. In order to effectively prevent financial risks and ensure the safety of the financial system, it is recommended that the government improve local debt management, improve financial regulations and systems, and improve the legislative level of financial legal supervision.

by Afnan I. Shahin, Sumera Zaib, Seyed-Omar Zaraei, Reena A. Kedia, Hanan S. Anbar, Muhammad Tayyab Younas, Taleb H. Al-Tel, Ghalia Khoder, Mohammed I. El-Gamal Urease enzyme is a known therapeutic drug target for treatment of Helicobacter pylori infection due to its role in settlement and growth in gastric mucosa. In this study, we designed a new series of sulfonates and sulfamates bearing imidazo[2,1-b]thiazole scaffold that exhibit a potent inhibitory activity of urease enzyme. The most potent compound 2c inhibited urease with an IC50 value of 2.94 ± 0.05 μM, which is 8-fold more potent than the thiourea positive control (IC50 = 22.3 ± 0.031 μM). Enzyme kinetics study showed that compound 2c is a competitive inhibitor of urease. Molecular modeling studies of the most potent inhibitors in the urease active site suggested multiple binding interactions with different amino acid residues. Phenotypic screening of the developed compounds against H. pylori delivered molecules of that possess high potency (1a, 1d, 1h, 2d, and 2f) in comparison to the positive control, acetohydroxamic acid. Additional studies to investigate the selectivity of these compounds against AGS gastric cell line and E. coli were performed. Permeability of the most promising derivatives (1a, 1d, 1h, 2d, and 2f) in Caco-2 cell line, was investigated. As a result, compound 1d presented itself as a lead drug candidate since it exhibited a promising inhibition against urease with an IC50 of 3.09 ± 0.07 μM, MIC value against H. pylori of 0.031 ± 0.011 mM, and SI against AGS of 6.05. Interestingly, compound 1d did not show activity against urease-negative E. coli and exhibited a low permeability in Caco-2 cells which supports the potential use of this compound for GIT infection without systemic effect.

Abstract Background Plasmodium species of non-human primates (NHP) are of great interest because they can naturally infect humans. Plasmodium simium, a parasite restricted to the Brazilian Atlantic Forest, was recently shown to cause a zoonotic outbreak in the state of Rio de Janeiro. The potential of NHP to act as reservoirs of Plasmodium infection presents a challenge for malaria elimination, as NHP will contribute to the persistence of the parasite. The aim of the current study was to identify and quantify gametocytes in NHP naturally-infected by P. simium. Methods Whole blood samples from 35 NHP were used in quantitative reverse transcription PCR (RT-qPCR) assays targeting 18S rRNA, Pss25 and Pss48/45 malaria parasite transcripts. Absolute quantification was performed in positive samples for 18S rRNA and Pss25 targets. Linear regression was used to compare the quantification cycle (Cq) and the Spearman\'s rank correlation coefficient was used to assess the correlation between the copy numbers of 18S rRNA and Pss25 transcripts. The number of gametocytes/µL was calculated by applying a conversion factor of 4.17 Pss25 transcript copies per gametocyte. Results Overall, 87.5% of the 26 samples, previously diagnosed as P. simium, were positive for 18S rRNA transcript amplification, of which 13 samples (62%) were positive for Pss25 transcript amplification and 7 samples (54%) were also positive for Pss48/45 transcript. A strong positive correlation was identified between the Cq of the 18S rRNA and Pss25 and between the Pss25 and Pss48/45 transcripts. The 18S rRNA and Pss25 transcripts had an average of 1665.88 and 3.07 copies/µL, respectively. A positive correlation was observed between the copy number of Pss25 and 18S rRNA transcripts. Almost all gametocyte carriers exhibited low numbers of gametocytes (

Within a few months, two young people were hospitalized in the infectious diseases department of Bordeaux University Hospital, France, for severe infectious mononucleosis tonsillitis. Both had fever, dysphonia, hypersialorrhea, halitosis, aphagia and activated circulating lymphocytes. Pharyngeal examination revealed a bilateral pseudomembranous and necrotic tonsillitis. Both had a good oral health and did not smoke nor reported alcohol use disorder. The diagnosis of infectious mononucleosis was confirmed by Epstein-Barr Virus serology and plasmatic PCR in both cases.

To evaluate the diagnostic performance and clinical impact of metagenomic next-generation sequencing (mNGS) of plasma microbial cell-free DNA (mcfDNA) in febrile neutropenia (FN).

American Journal of Respiratory and Critical Care Medicine, Volume 207, Issue 11, Page 1486-1497, June 1, 2023.

American Journal of Respiratory and Critical Care Medicine, Volume 207, Issue 11, Page 1525-1532, June 1, 2023.