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AbstractEbola virus disease is marked by the rapid virus replication and spread. Ebola virus (EBOV) enters the cell by macropinocytosis, replicates in the cytoplasm, and nascent virions egress from the cell surface to infect neighboring cells. Here, we show that EBOV uses an alternate route to disseminate: tunneling nanotubes (TNTs). TNTs, an actin-based long-range intercellular communication system, allows for direct exchange of cytosolic constituents between cells. Using live, scanning electron and high-resolution quantitative 3D-microscopy, we show that EBOV infection of primary human cells results in the enhanced formation of TNTs, containing viral nucleocapsids. TNTs promoted the intercellular transfer of nucleocapsids in the absence of live virus, and virus could replicate in cells devoid of entry factors after initial stall. Our studies suggest an alternate model of EBOV dissemination within its host, laying the groundwork for further investigations into the pathogenesis of filoviruses and, importantly, stimulating new areas of antiviral design.

AbstractTo gain insight into interactions among respiratory viruses, we modeled influenza A virus (IAV) - SARS-CoV-2 coinfections using differentiated human airway epithelial cultures. Replicating IAV induced a more robust interferon response than SARS-CoV-2 and suppressed SARS-CoV-2 replication in both sequential and simultaneous infections, whereas SARS-CoV-2 did not enhance host cell defense during influenza infection or suppress IAV replication. Oseltamivir, an antiviral targeting influenza, reduced IAV replication during coinfection but also reduced the host antiviral response and restored SARS-CoV-2 replication. These results demonstrate how perturbations in one viral infection can impact its effect on a coinfecting virus.

AbstractBacterial vaginosis (BV) is a dysbiotic condition of the vaginal microbiome associated with higher risk of infection by Neisseria gonorrhoeae - the cause of gonorrhea. Here we test if one known facet of BV - the presence of bacterial cytolysins – leads to mobilization of intracellular contents that enhance gonococcal virulence. We cloned and expressed recombinant vaginolysin (VLY), a cytolysin produced by the BV-associated bacterium Gardnerella, verifying that it liberates contents of cervical epithelial (HeLa) cells, while vector control preparations did not. We tested if VLY mediates a well-known gonococcal virulence mechanism – the molecular mimicry of host glycans. To evade host immunity, N. gonorrhoeae caps its lipooligosaccharide (LOS) with α2-3-linked sialic acid. For this, gonococci must scavenge a metabolite made inside host cells. Flow-cytometry based lectin-binding assays showed that gonococci exposed to vaginolysin-liberated contents of HeLa cells displayed greater sialic acid capping of their LOS. This higher level of bacterial sialylation was accompanied by increased binding of the complement regulatory protein Factor H, and greater resistance to complement attack. Together these results suggest that cytolytic activities present during BV may enhance the ability of N. gonorrhoeae to capture intracellular metabolites and evade host immunity via glycan molecular mimicry.

IntroductionOlder surgical candidates are at increased risk of a phenomenon known as postoperative cognitive dysfunction (POCD). Several studies have looked at the incidence of POCD at different time points following surgery, using different study methods. Fewer have assessed whether changes in cognition after surgery are attributable to surgery and how they impact patient function and quality of life. The aim of this systematic review is to summarise and appraise studies addressing any of the following research questions (RQs): (RQ1) what is the frequency of POCD after non-cardiac surgery?; (RQ2) is non-cardiac surgery associated with an increased risk of cognitive decline?; (RQ3) is POCD after non-cardiac surgery associated with patient-important outcomes? Methods and analysisThis protocol adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. Three electronic databases (MEDLINE, PsycINFO and EMBASE) will be systematically searched from their inception date. Identified studies will be screened by two reviewers for eligibility using Covidence, and data will be extracted into a standardised electronic form. We will evaluate methodological quality of included studies using the Quality In Prognosis Studies and its adaptation to the overall prognosis question, and the CLARITY risk of bias for cohort and case–control studies. For RQ1, we will estimate an average POCD frequency at different time points by performing a meta-analysis of included studies when appropriate. For RQ2 and RQ3, we will extract and meta-analyse the effect measures for the association of surgery with cognitive decline when compared with the non-surgical comparator, and association of cognitive changes with functional changes, quality of life and other patient-important outcomes based on available evidence. We will narratively summarise and discuss the different methods implemented in the existing studies to answer the three RQs, and when meta-analysis is deemed infeasible, we will qualitatively report the results of the included studies. Ethics and disseminationThis project involves the collection and analysis of data from previously published studies and therefore does not require ethics approval. We plan to present the findings of this research project at peer-reviewed conferences and publish the results in peer-reviewed journals. PROSPERO registration numberCRD42022370674. …

ObjectiveThis survey investigated the relationship between social isolation, depression, nutritional status and quality of life among community-dwelling older adults during COVID-19. DesignThis was a cross-sectional survey study. SettingCommunities in Pudong New Area, Shanghai, China that have contracted with Renji Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. ParticipantsFrom May to July 2022, 406 community-dwelling older adults were selected by convenience sampling in Shanghai, China. Primary and secondary outcome measuresThe Lubben Social Network Scale, Geriatric Depression Scale, 36-item Short Form Health Survey Scale and risk assessment of malnutrition were used in older adults. Mediation models were constructed to determine the mediating role of depression and nutritional status on social isolation and quality of life among older adults. ResultsThe prevalence of social isolation among older adults in the community was 44.3%. The total social isolation score in community-dwelling older adults was positively associated with the total malnutrition risk and quality of life scores, and negatively associated with depression (p

ObjectivesTargeted testing policy for HIV/syphilis at Dutch sexual health centres (SHCs) was evaluated for its efficiency in younger heterosexuals but not for heterosexuals ≥25 years. Currently, all older heterosexuals are tested for HIV/syphilis at SHCs. To explore possibilities for increased efficiency of testing in heterosexuals aged >25 years, this study aimed to identify determinants of HIV and syphilis diagnoses that could be used in targeted testing strategies. DesignAn observational study using surveillance data from all Dutch SHC. ParticipantsWomen and heterosexual men aged >25 years visiting SHC between 2015 and 2021. Primary and secondary outcome measuresThe primary outcome was HIV/syphilis diagnosis, determinants of a diagnosis were analysed. Based on these determinants and their applicability in SHC practice, different targeted testing scenarios were evaluated. For each scenario, the percentage of consultations involving HIV and syphilis testing and the total amount of missed HIV and syphilis diagnoses were calculated. Results109 122 consultations were included among 75 718 individuals. The strongest determinants of HIV/syphilis diagnosis were HIV/syphilis-specific symptoms (adjusted OR (aOR) 34.9 (24.1–50.2)) and receiving partner notification (aOR 18.3 (13.2–25.2)), followed by low/middle education level (aOR 2.8 (2.0–4.0)), male sex (aOR 2.2 (1.6–3.0)) and age ≥30 years (aOR 1.8 (1.3–2.5)). When applying feasible determinants to targeted testing scenarios, HIV/syphilis testing would have been conducted in 54.5% of all consultations, missing 2 HIV and 3 syphilis diagnoses annually (13.4% and 11.4% of all diagnoses, respectively). In the scenario with the lowest number of missed HIV/syphilis diagnoses (0.3 HIV and 2 syphilis diagnoses annually), HIV/syphilis testing would have been conducted in 74.2% of all consultations. ConclusionsIn any targeted testing scenario studied, HIV and/or syphilis diagnoses would have been missed. This raises the question whether it is acceptable to put any of these scenarios into practice. This study contributes to a discussion about the impact of targeted testing policy. …

IntroductionCoronary heart disease (CHD) is one of the common cardiovascular diseases that seriously jeopardise human health, and endothelial inflammation and dyslipidaemia are the initiating links leading to its occurrence. Percutaneous coronary intervention (PCI) is one of the most effective surgical treatments for CHD with narrowed or blocked blood vessels, which can quickly unblock the blocked vessels and restore coronary blood supply. However, most patients may experience coronary microcirculation disorders (CMDs) and decreased cardiac function after PCI treatment, which directly affects the efficacy of PCI and the prognosis of patients. Preprotein converting enzyme subtilisin/Kexin 9 (PCSK9) inhibitors are novel pleiotropy lipid-lowering drug with dual anti-inflammation and lipid-lowering effects, and represent a new clinical pathway for rapid correction of dyslipidaemia. Therefore, we designed this protocol to systematically evaluate the effects of PCSK9 inhibitors on coronary microcirculation and cardiac function in patients with CHD after PCI, and to provide high-quality evidence-based evidence for the clinical application of PCSK9 inhibitors. Methods and analysisThis protocol is reported strictly in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols Guidelines. We will search PubMed, EMBASE, Web of Science and three Chinese databases (CNKI, Wanfang and VIP database) according to preset search strategies, without language and publication data restrictions. We will work with manual retrieval to screen references that have been included in the literature. Google Scholar will be used to search for grey literature. The final included literature must meet the established inclusion criteria. Titles, abstracts and full text will be extracted independently by two reviewers, and disagreements will be resolved through discussion or the involvement of a third reviewer. Extracted data will be analysed using Review Manager V.5.3. The Cochrane Risk of Bias Tool will be used to evaluate the risk of bias. Publication bias will be assessed by funnel plots. Heterogeneity will be assessed by I2 test and subgroup analyses will be used to further investigate potential sources of heterogeneity. The quality of the literature will be assessed by GRADE score. This protocol will start in January 2026 and end in December 2030. Ethics and disseminationThis study is a systematic review of published literature data and no special ethical approval was required. PROSPERO registration numberCRD42022346189. …

IntroductionPrompt detection of hepatocellular carcinoma (HCC) in patients with chronic liver diseases is critical for enhancing prognosis. Existing imaging techniques and serum markers fall short of clinical needs. This study aims to establish a non-invasive diagnostic model for early HCC detection in the Chinese population. Methods and analysisThis prospective, multicentre, observational study will enrol 2000 participants, including HCC patients, those with chronic liver diseases (hepatitis, cirrhosis and benign liver space-occupying lesions), and healthy individuals. The study will collect demographic data and blood samples, which will be used to test α-fetoprotein (AFP), des--carboxy-prothrombin (DCP) and circulating tumour DNA (ctDNA) methylation. The GAMAD (Gender+Age+Methylation+AFP+DCP) model involving gender, age, ctDNA methylation signature, AFP and DCP will be developed and blindly validated in training and validation sets (1400 and 600 cases, respectively). Primary endpoints include sensitivity, specificity and accuracy (receiver operating characteristic curves; area under the curve value) of GAMAD for HCC and/or high-risk HCC groups. Secondary endpoints involve comparing GAMAD with the established GALAD (Gender+Age+AFP-L3+AFP+DCP) model and each blood index (AFP, DCP and methylation signature) to evaluate: (1) GAMAD’s clinical utility for HCC patients in all stages according to different staging systems; (2) GAMAD’s discrimination ability for patients in various subgroups, including liver cirrhosis (LC) related HCC and LC, hepatitis B virus (HBV) related HCC and HBV, hepatitis C virus (HCV) related HCC and HCV, and non-alcoholic fatty liver disease (NAFLD) related HCC and NAFLD. Ethics and disseminationThis trial has been approved by the Medical Ethics Committees of the First Hospital of Jilin University (#22K073-001), the Eastern Hepatobiliary Surgery Hospital, Naval Medical University (#EHBHKY2023-H0003-P001) and Tianjin Third Central Hospital (#IRB2023-007-01). All participants in the trial will provide written informed consent. Results of this study will be disseminated in peer-reviewed scientific journals and at conferences nationally and internationally. Trial registration numberNCT05626985. …

Strategic use of Plasmodium falciparum genetic variation has great potential to inform public health actions for malaria control and elimination. Malaria molecular surveillance (MMS) begins with a strategy to identify and collect parasite samples, guided by public-health priorities. In this review we discuss sampling design practices for MMS and point out epidemiological, biological, and statistical factors that need to be considered. We present examples for different use cases, including detecting emergence and spread of rare variants, establishing transmission sources and inferring in malaria transmission intensity. This review will potentially guide the collection of samples and data, serve as a starting point for further methodological innovation, and enhance utilization of MMS to support malaria elimination.

Tuberculosis (TB) is the leading infectious killer of adults worldwide and responsible for almost 2 million deaths each year. The fact that the disease is entirely preventable and curable makes these statistics especially bleak, and they speak to the gross inequalities that drive TB morbidity and mortality today. While in wealthier countries and populations, TB is considered a “disease of the past”, it was only in the mid-1950s that modern chemotherapeutic approaches to TB were developed. Prior to this time, “rest cures”, isolation in sanitoria, and painful surgeries were the norm, virtually guaranteeing death for most.

by Zanetta Gant, André Dailey, Xiaohong Hu, Wei Song, Linda Beer, Shacara Johnson Lyons, Damian J. Denson, Anna Satcher Johnson Objective(s) To examine associations between Index of Concentration at the Extremes (ICE) measures for economic and racial segregation and HIV outcomes in the United States (U.S.) and Puerto Rico. Methods County-level HIV testing data from CDC’s National HIV Prevention Program Monitoring and Evaluation and census tract-level HIV diagnoses, linkage to HIV medical care, and viral suppression data from the National HIV Surveillance System were used. Three ICE measures of spatial polarization were obtained from the U.S. Census Bureau’s American Community Survey: ICEincome (income segregation), ICErace (Black-White racial segregation), and ICEincome+race (Black-White racialized economic segregation). Rate ratios (RRs) for HIV diagnoses and prevalence ratios (PRs) for HIV testing, linkage to care within 1 month of diagnosis, and viral suppression within 6 months of diagnosis were estimated with 95% confidence intervals (CIs) to examine changes across ICE quintiles using the most privileged communities (Quintile 5, Q5) as the reference group. Results PRs and RRs showed a higher likelihood of testing and adverse HIV outcomes among persons residing in Q1 (least privileged) communities compared with Q5 (most privileged) across ICE measures. For HIV testing percentages and diagnosis rates, across quintiles, PRs and RRs were consistently greatest for ICErace. For linkage to care and viral suppression, PRs were consistently lower for ICEincome+race. Conclusions We found that poor HIV outcomes and disparities were associated with income, racial, and economic segregation as measured by ICE. These ICE measures contribute to poor HIV outcomes and disparities by unfairly concentrating certain groups (i.e., Black persons) in highly segregated and deprived communities that experience a lack of access to quality, affordable health care. Expanded efforts are needed to address the social/economic barriers that impede access to HIV care among Black persons. Increased partnerships between government agencies and the private sector are needed to change policies that promote and sustain racial and income segregation. …

The SARS-CoV-2 (“Covid-19”) pandemic altered human life throughout the world and led to devastating illness and many deaths [1]. This infection has been associated with a wide array of complications. Risk factors for adverse Covid-19 outcomes include older age and metabolic syndrome associated factors (diabetes, hypertension, obesity), which are also risk factors for one Covid-19 complication that merits attention: rhabdomyolysis [1, 2].

Abstract Background While anaemia following liver transplant is common, anaemia in the context of BK viraemia is not a commonly recognised phenomenon. Case presentation We present the case of 59-year old gentleman with severe anaemia in the context of BK viraemia and nephropathy following ABO incompatible liver transplant. Severity of anaemia appeared to correlate with high titres of BK virus in the serum. Bone marrow biopsy revealed hypocellular marrow with normal cytogenetics. Anaemia improved with treatment with cidofovir, intravenous immunoglobulin, reduction in immunosuppression and erythropoietin stimulating agent. Conclusion To our knowledge, this is the first case of anaemia post liver transplant contributed to by BK viraemia. …

Abstract Background The course of monkeypox can be severe. Our aim was to retrospectively compare the risk of hospital admission, the need for ventilation, sepsis, pneumonitis and death between the recent outbreak and historical outbreaks. Materials and Methods Cases of monkeypox were retrieved from the TriNetX database and assigned to either cohort I (recent outbreak between May 1st and September 16th, 2022) and cohort II (historical outbreaks before May 1st, 2022). After matching for age distribution, statistical analysis was performed. Results Of 640 patients with monkeypox 81 subjects per cohort remained after matching (mean age±standard deviation = 36.1±18.3 years). Within 56 days after diagnosis 10 patients per cohort were hospitalized (12.4%) and/or developed sepsis (12.4%). The risk of ventilation and pneumonitis were significantly lower among cohort I compared with cohort II (0 vs. 10 cases; risk difference = 12.4%; p = 0.001; Log-Rank test). No cases of death were recorded. Conclusion Even though monkeypox provides a risk of severe courses, the infection is self-limiting in most cases. Unlike past outbreaks, the risk of ventilation and pneumonitis may be relatively low among recent outbreaks. …

Abstract Background Severe community-acquired pneumonia (SCAP) is commonly treated with an empiric combination therapy, including a macrolide, or a quinolone and a β-lactam. However, the risk of Legionella pneumonia may lead to a prolonged combination therapy even after negative urinary antigen tests (UAT). Methods We conducted a retrospective cohort study in a French intensive care unit (ICU) over 6 years and included all the patients admitted with documented SCAP. All patients received an empirical combination therapy with a β-lactam plus a macrolide or quinolone, and a Legionella UAT was performed. Macrolide or quinolone were discontinued when the UAT was confirmed negative. We examined the clinical and epidemiological features of SCAP and analysed the independent factors associated with ICU mortality. Results Among the 856 patients with documented SCAP, 26 patients had atypical pneumonia: 18 Legionella pneumophila (LP) serogroup 1, 3 Mycoplasma pneumonia (MP), and 5 Chlamydia psittaci (CP). UAT diagnosed 16 (89%) Legionella pneumonia and PCR confirmed the diagnosis for the other atypical pneumonia. No atypical pneumonia was found by culture only. Type of pathogen was not associated with a higher ICU mortality in the multivariate analysis. Conclusion Legionella pneumophila UAT proved to be highly effective in detecting the majority of cases, with only a negligible percentage of patients being missed, but is not sufficient to diagnose atypical pneumonia, and culture did not provide any supplementary information. These results suggest that the discontinuation of macrolides or quinolones may be a safe option when Legionella UAT is negative in countries with a low incidence of Legionella pneumonia. …

Abstract Background Malaria cases in non-endemic zero-indigenous case areas are most likely to have been imported whatever of the route of importation. In countries recently declared malaria-free and now without local transmission, imported cases remain a threat to re-introduction of the disease and a burden on the health system. Case presentation Three days after returning from a long trip to malaria- endemic countries; Abyei-Sudan, Chad and Uganda, a 41-year-old male resident from Jericho, Palestine, suffered paroxysms of fever, general fatigue, myalgia, arthralgia, headache, and a strong desire to vomit. Thin and thick Giemsa-stained blood smears were prepared and examined microscopically using oil immersion. Immature trophozoites (ring forms) were seen to parasitize approximately 10% of the erythrocytes revealing hyperparasitemia equivalent to > 100,000 parasites/ µl indicating severe malaria [1, 2]. The double chromatin configuration (headphones) and accolé (applique) position are both indicative of Plasmodium falciparum infection. The 18S rRNA- PCR targeting the rPLU6-rPLU5 region was used to confirm the diagnosis. The next-generation sequencing (NGS) method was carried out according to the manufacturer’s instructions (Illumina® DNA Prep, (M) Tagmentation kit (20060060), Illumina) to identify Plasmodium spp. Furthermore, NGS produced a whole-genome sequence of 22.8Mbp of the 14 chromosomes and 25Kbp of the apicoplast. A BLAST search of the apicoplast DNA and selected chromosomal DNA revealed that P. falciparum was the causative agent. The merozoite surface protein-1 (msp-1) was used to construct a phylogenetic tree of 26 P. falciparum, including the one isolated from the patient from Jericho, which clustered with the Sudanese isolate indicating genetic relatedness between the two. Conclusion The travel history together with signs and symptoms of malaria, followed by prompt diagnosis using conventional microscopic inspection of Giemsa-stained films together with molecular DNA tracking tools like msp-1 were key means in tracking the place of origin of infection in the case of travel to multiple destination. …

Abstract Introduction Acute uncomplicated urinary tract infections are common in outpatient settings but are not treated optimally. Few studies of the outpatient use of antibiotics for specific diagnoses have been done in sub-Saharan Africa, so little is known about the prescribing patterns of medical officers in the region. Methods Aga Khan University has 16 outpatient clinics throughout the Nairobi metro area with a medical officer specifically assigned to that clinic. A baseline assessment of evaluation and treatment of suspected UTI was performed from medical records in these clinics. Then the medical officer from each of the 16 clinics was recruited from each clinic was recruited with eight each randomized to control vs. feedback groups. Both groups were given a multimodal educational session including locally adapted UTI guidelines and emphasis on problems identified in the baseline assessment Each record was scored using a scoring system that was developed for the study according to adequacy of history, physical examination, clinical diagnosis matching recorded data, diagnostic workup and treatment. Three audits were done for both groups; baseline (audit 1), post-CME (audit 2), and a final audit, which was after feedback for the feedback group (audit 3). The primary analysis assessed overall guideline adherence in the feedback group versus the CME only group. Results The overall scores in both groups showed significant improvement after the CME in comparison to baseline and for each group, the scores in most domains also improved. However, audit 3 showed persistence of the gains attained after the CME but no additional benefit from the feedback. Some deficiencies that persisted throughout the study included lack of workup of possible STI and excess use of non-UTI laboratory tests such as CBC, stool culture and H. pylori Ag. After the CME, the use of nitrofurantoin rose from only 4% to 8% and cephalosporin use increased from 49 to 67%, accompanied by a drop in quinolone use. Conclusion The CME led to modest improvements in patient care in the categories of history taking, treatment and investigations, but feedback had no additional effect. Future studies should consider an enforcement element or a more intensive feedback approach. …

Abstract Background Public health depends largely on people’s knowledge, beliefs, or behaviors regarding their health and medical treatments. Although works based on the health belief model have shown that public beliefs about medical treatments affect willingness to take the treatments, little is known about the effects of changes in beliefs on attitudes toward treatment. How one’s past experiences relate to one’s beliefs about a given medical treatment is worth considering. Methods We implemented an online panel survey in February 2021 and March 2022 in Japan before and after COVID-19 vaccines were administered to the public within the country. We exploited delayed localized hypersensitivity reactions to COVID-19 vaccines, namely, “COVID arm”, as an exogenous shock to investigate the relationship between past negative experiences and current beliefs about medical treatments or science. “COVID arm” was an unexpected side effect and thus likely caused updated beliefs about the vaccine. Out of the nonprobability sample of 15,000 respondents in the first wave in February 2021, 9,668 respondents also responded to the second wave conducted in March 2022. Outcome variables were whether experiencing “COVID arm” affected the respondents’ 1) confidence in vaccine safety, 2) willingness to take the next dose of COVID-19 vaccines, 3) acknowledgment of the importance of vaccination, and 4) confidence in science. We measured the impact of experience with “COVID arm” on changes in the probability that survey respondents would respond affirmatively to questions posed about the issues listed above. Results Experiencing “COVID arm” significantly lowered confidence in the safety of vaccination by 4.3 percentage points, which was approximately 6% of the sample mean for the first wave, and lowered the probability of taking a second dose of the COVID-19 vaccine by 1.5 percentage points. These adverse impacts were observed after conditioning background characteristics and prior confidence in vaccination. Experiencing “COVID arm” affected neither the acknowledged importance of vaccination nor confidence in science in a statistically significant way. Conclusions An unexpected and uncomfortable shock regarding beliefs about a treatment decreases willingness to take the treatment. An appropriate public health policy should account for this effect. Trial registration The survey was preregistered with the American Economic Association’s RCT Registry (Fukai et al., 2022). …

AbstractBackgroundNative vertebral osteomyelitis (NVO) caused by Staphylococcus aureus is associated with high risk of treatment failure and increased morbidity. The role of rifampin-based therapy for the treatment of this condition is controversial. The goal of this systematic review and meta-analysis is to explore the efficacy and safety of rifampin-based therapy for the treatment of S. aureus NVO.MethodsWe searched Cochrane, Embase, Medline, Scopus, and Web of Science databases for studies published up to May 2023, focusing on adults with NVO treated with or without rifampin containing regimens. A random-effects model meta-analysis estimated relative risks (RR) and risk difference (RD) with 95% confidence intervals (CI).ResultsThirteen studies (two RCTs and 11 comparative cohort studies), comprising 244 patients with S. aureus NVO who received rifampin and 435 who did not were analyzed. Meta-analysis showed that rifampin-based regimens were associated with lower risk of clinical failure (RD -14%; 95% CI: -19%, -8%; P 

AbstractBackgroundCurrent Tuberculosis treatment regimens could be improved by adjunct host-directed-therapies (HDT) targeting host responses. We investigated the anti-mycobacterial capacity of macrophages from tuberculosis patients in a phase 1/2 randomized clinical trial (TBCOX2) of the Cyclooxygenase-2 inhibitor etoricoxib.MethodsPBMC from 15 tuberculosis patients treated with adjunctive COX-2i and 18 controls (standard therapy) were collected on day 56 after treatment initiation. The ex vivo capacity of macrophages to control mycobacterial infection was assessed by challenge with Mycobacterium avium, using an in vitro culture model. Macrophage inflammatory responses were analyzed by gene expression signatures, and concentrations of cytokines were analyzed in supernatants by multiplex.ResultsMacrophages from patients receiving adjunctive COX-2i treatment had higher Mav loads than controls after 6 days, suggesting an impaired capacity to control mycobacterial infection compared to macrophages from the control group. Macrophages from the COX-2i group had lower gene expression of TNF, IL-1B, CCL4, CXCL9, and CXCL10 and lowered production of cytokines IFN-β and S100A8/A9 than controls.ConclusionsOur data suggest potential unfavorable effects with impaired macrophage capacity to control mycobacterial growth in tuberculosis patients receiving COX-2i treatment. Larger clinical trials are required to analyze the safety of COX-2i as HDT in patients with tuberculosis.

AbstractBackgroundPeople with suspected malaria may harbor Plasmodium falciparum undetected by rapid diagnostic test (RDT). The impact is not fully understood of these sub-patent infections on the risk of developing clinical malaria.MethodsWe analyzed sub-patent P. falciparum infections using a longitudinal cohort in a high transmission site in Kenya. Weighted Kaplan-Meier models estimated the risk difference (RD) for clinical malaria during the 60 days following a symptomatic sub-patent infection. Stratum-specific estimates by age and transmission season assessed modification.ResultsOver 54 months, we observed 1,128 symptomatic RDT-negative suspected malaria episodes, of which 400 (35.5%) harbored sub-patent P. falciparum. Overall 60-day risk of developing clinical malaria was low following all episodes (8.6%,95% Confidence Interval: 6.7%, 10.4%). In the low transmission season, the risk of clinical malaria was slightly higher in those with sub-patent infection, whereas the opposite was true in the high transmission season (RD low season: 2.3%, CI: 0.4%, 4.2%; RD high season: -4.8%, CI: -9.5%, -0.05%).ConclusionsThe risk of developing clinical malaria among people with undetected sub-patent infections is low. A slightly elevated risk in the low season may merit alternate management, but RDTs diagnose clinically-relevant infections in the high transmission season.

Acute HIV infection (AHI) refers to the period immediately after acquiring HIV, when the virus spreads first through the mucosa and the local lymphoid tissue at the exposure site, and then disseminates systemically [1,2]. This initial phase of HIV infection can be divided into stages based on the sequential appearance of viral markers and antibodies in the blood [3]. It is during AHI when the latent HIV reservoir is established [4], although reseeding of the reservoir will continue in untreated chronic infection [5].

Journal of Medical Virology, Volume 95, Issue 9, September 2023.

With growing human populations living along freshwater shores and marine coastlines, aquatic ecosystems are experiencing rising levels of light pollution. Through its effects on hosts and parasites, anthropogenic light at night can disrupt host–parasite interactions evolved under a normal photoperiod. Yet its impact on aquatic parasites has been ignored to date. Here, I discuss the direct effects of light on the physiology and behaviour of parasite infective stages and their hosts. I argue that night-time lights can change the spatiotemporal dynamics of infection risk and drive the rapid evolution of parasites. I then highlight knowledge gaps and how impacts on parasitic diseases should be incorporated into the design of measures aimed at mitigating the impact of anthropogenic light on wildlife.

The unicellular picocyanobacterium Prochlorococcus is the most abundant photoautotroph and contributes substantially to global CO2 fixation. In the vast euphotic zones of the open ocean, Prochlorococcus converts CO2 into organic compounds and supports diverse organisms, forming an intricate network of interactions that regulate the magnitude of carbon cycling and storage in the ocean. An understanding of the biological interactions with Prochlorococcus is critical for accurately estimating the contributions of Prochlorococcus and interacting organisms to the marine carbon cycle. This review synthesizes the primary production contributed by Prochlorococcus in the global ocean. We outline recent progress on the interactions of Prochlorococcus with heterotrophic bacteria, phages, and grazers that multifacetedly determine Prochlorococcus carbon production and fate. We discuss that climate change might affect the biological interactions with Prochlorococcus and thus the marine carbon cycle.

Abstract Background In 2021, Brazil was responsible for more than 25% of malaria cases in the Americas. Although the country has shown a reduction of cases in the last decades, in 2021 it reported over 139,000 malaria cases. One major malaria control strategy implemented in Brazil is the “Malaria Supporters Project”, which has been active since 2012 and is directed to municipalities responsible for most Brazil’s cases. The objective of this study is to analyse the intervention effect on the selected municipalities. Methods An ecological time-series analysis was conducted to assess the “Malaria Supporters Project” effect. The study used data on Annual Parasitic Incidence (API) spanning the period from 2003 to 2020 across 48 intervention municipalities and 88 control municipalities. To evaluate the intervention effect a Prais–Winsten segmented regression model was fitted to the difference in malaria Annual Parasitic Incidence (API) between control and intervention areas. Results The intervention group registered 1,104,430 cases between 2012 and 2020, a 50.6% reduction compared to total cases between 2003 and 2011. In 2020 there were 95,621 cases, 50.4% fewer than in 2011. The number of high-risk municipalities (API > 50 cases/1000) reduced from 31 to 2011 to 17 in 2020. The segmented regression showed a significant 42.0 cases/1000 residents annual decrease in API compared to control group. Conclusions The intervention is not a silver bullet to control malaria, but it has reduced API in locations with high malaria endemicity. Furthermore, the model has the potential to be replicated in other countries with similar epidemiological scenarios. …

Abstract Background Centers for Disease Control and Prevention (CDC) light traps are widely used for sampling mosquitoes. However, this trap, manufactured in the USA, poses challenges for use in sub-Saharan Africa due to procurement costs and shipping time. Traps that are equally efficient than the CDC light trap, but which are amenable for use in remote African settings and made in Africa, are desirable to improve local vector surveillance. This study evaluated a novel solar-powered light trap made in South Africa (Silver Bullet trap; SB), for its efficiency in malaria vector sampling in western Kenya. Methods Large cage (173.7 m3) experiments and field evaluations were conducted to compare the CDC-incandescent light trap (CDC-iLT), CDC-UV fluorescent tube light trap (CDC-UV), SB with white diodes (SB-White) and SB with UV diodes (SB-UV) for sampling Anopheles mosquitoes. Field assessments were done indoors and outdoors following a Latin square design. The wavelengths and absolute spectral irradiance of traps were compared using spectrometry. Results The odds of catching a released Anopheles in the large cage experiments with the SB-UV under ambient conditions in the presence of a CDC-iLT in the same system was three times higher than what would have been expected when the two traps were equally attractive (odds ratio (OR) 3.2, 95% confidence interval CI 2.8–3.7, P 

Abstract Background Following the World Health Organization (WHO) endorsement of dual active ingredient (AI) nets, an increased uptake of pyrethroid-chlorfenapyr and pyrethroid-pyriproxyfen nets is expected. Studies evaluating their physical and insecticidal durability are essential for making programmatic and procurement decisions. This paper describes the methodology for a prospective study to evaluate the attrition, fabric integrity, insecticidal durability of Interceptor® G2 (alpha-cypermethrin-chlorfenapyr) and Royal Guard® (alpha-cypermethrin-pyriproxyfen), compared to Interceptor® (alpha-cypermethrin), embedded in a 3-arm cluster randomized controlled trial (cRCT) in the Zou Department of Benin. Methods Ten clusters randomly selected from each arm of the cRCT will be used for the study. A total of 750 ITNs per type will be followed in 5 study clusters per arm to assess ITN attrition and fabric integrity at 6-, 12-, 24- and 36-months post distribution, using standard WHO procedures. A second cohort of 1800 nets per type will be withdrawn every 6 months from all 10 clusters per arm and assessed for chemical content and biological activity in laboratory bioassays at each time point. Alpha-cypermethrin bioefficacy in Interceptor® and Royal Guard® will be monitored in WHO cone bioassays and tunnel tests using the susceptible Anopheles gambiae Kisumu strain. The bioefficacy of the non-pyrethroid insecticides (chlorfenapyr in Interceptor® G2 and pyriproxyfen in Royal Guard®) will be monitored using the pyrethroid-resistant Anopheles coluzzii Akron strain. Chlorfenapyr activity will be assessed in tunnel tests while pyriproxyfen activity will be assessed in cone bioassays in terms of the reduction in fertility of blood-fed survivors observed by dissecting mosquito ovaries. Nets withdrawn at 12, 24 and 36 months will be tested in experimental hut trials within the cRCT study area against wild free-flying pyrethroid resistant An. gambiae sensu lato to investigate their superiority to Interceptor® and to compare them to ITNs washed 20 times for experimental hut evaluation studies. Mechanistic models will also be used to investigate whether entomological outcomes with each dual ITN type in experimental hut trials can predict their epidemiological performance in the cRCT. Conclusion This study will provide information on the durability of two dual AI nets (Interceptor® G2 and Royal Guard®) in Benin and will help identify suitable methods for monitoring the durability of their insecticidal activity under operational conditions. The modelling component will determine the capacity of experimental hut trials to predict the epidemiological performance of dual AI nets across their lifespan. …

AbstractObjectiveTo determine the association of Nirmatlevir/ritonavir (NMV/r) with hospitalization or death within 30 days compared with untreated controls in previously uninfected non-hospitalized persons.MethodsWe used a matched cohort design using inverse probability of treatment weights (IPTW). Individuals prescribed NMV/r within 3 days of COVID-19 diagnosis were compared with IPT-weighted untreated controls. Variables for IPTW included age, race, sex, body mass index, geographical location, vaccination status and multiple comorbidities. Additional analysis were conducted on NMV/r treated and propensity-score matched untreated controls.ResultsAmong 7,615 individuals prescribed NMV/r and 62,077 controls identified between January 1, 2022 and February 25, 2023, the risk of hospitalization/death was lower among NMV/r treated vs. untreated controls (243 vs. 3,468 events; Absolute risk difference, ARD [95% CI] -2.36[-2.57, -2.14]) The difference was significant for those >60 and

AbstractBackgroundThere is no consensus on how to best quantify disease severity in infants with respiratory syncytial virus (RSV) and/or bronchiolitis; this lack of a sufficiently validated score complicates the provision of clinical care and, the evaluation of trials of therapeutics and vaccines. The ReSVinet score appears to be one of the most promising; however it is too time-consuming to be incorporated into routine clinical care. We aimed to develop and externally validate simplified versions of this score.MethodsData were used from a multinational (Netherlands, Spain & United Kingdom) multicentre case-control observational study of infants with RSV to develop simplified versions of the ReSVinet by conducting a grid search to determine the best combination of equally weighted parameters to maximise for the discriminative ability of the scores across a range of outcomes (hospitalisation, intensive care unit admission, ventilation requirement). Subsequently discriminative validity of the score for a range of secondary care outcomes was externally validated by conducting a secondary analysis of data collected in infants with respiratory infection from tertiary hospitals in Rwanda and Colombia.ResultsThree candidate simplified scores were identified using the development dataset; they were excellent (area under the receiver-operator characteristic curve [AUROC] >0.9) in the development dataset at discriminating for a range of outcomes, and their performance was not statistically significantly different to the original ReSVinet score despite having fewer parameters. In the external validation datasets, the simplified scores were moderate-excellent (AUROC 0.7-1) across a range of outcomes. In all outcomes, except for in a single dataset at predicting admission to the high dependency unit, they performed at least as well as the original ReSVinet score.ConclusionsThree promising candidate simplified scores were developed; however further external validation work in larger datasets, ideally from resource-limited settings needs to be conducted before any recommendation regarding their use.

AbstractDeveloping new adjuvants that can effectively induce both humoral and cellular immune responses while broadening the immune response is of great value. In this study, we aimed to develop GM-CSF- or IL-18-expressing single-stranded RNA (ssRNA) adjuvants based on the encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) and tested their efficacy in combination with ovalbumin (OVA) or inactivated influenza vaccines. Notably, cytokine-expressing RNA adjuvants increased the expression of antigen-presenting cell activation markers. Specifically, GM-CSF-expressing RNA adjuvants increased CD4+T cell responses, while IL-18-expressing RNA adjuvants increased CD8+T cell responses in mice when combined with OVA. In addition, cytokine-expressing RNA adjuvants increased the frequency of polyclonal T cells in combination with the influenza vaccine and reduced the clinical illness scores and weight loss of mice after viral challenge. Collectively, our results suggest that cytokine-expressing RNA adjuvants can be applied to protein-based or inactivated vaccines to increase their efficacy.

AbstractIn 2018 there was a large yellow fever outbreak in São Paulo, Brazil, with a high fatality rate. Yellow fever virus can cause, among other symptoms, haemorrhage and disseminated intravascular coagulation, indicating a role for endothelial cells in the disease pathogenesis. Here, we conducted a case-control study and measured markers related to endothelial damage in plasma and its association with mortality. We found that angiopoietin-2 is strongly associated with a fatal outcome and could serve as a predictive marker for mortality. This could be used to monitor severe patients and provide care to improve disease outcome.

AbstractKaposi Sarcoma (KS) continues to cause substantial morbidity and mortality in populations at risk in the southern US. Utilizing biospecimens from the Houston site of the Young Men’s Affiliate Project, 351 men who have sex with men had blood tested for Kaposi Sarcoma-associated herpesvirus (KSHV) IgG. Measuring seroprevalence, seroconversion between timepoints, and demographic and clinical correlates, KSHV prevalence was 36.7% and incidence was 8.9 per 100 person-years, prevalence and incidence were higher among Black individuals, people living with HIV, and those with a history of syphilis. Further research on KSHV risk may improve health disparities in KS diagnosis and outcomes.

Early identification of extended spectrum ß-lactamase (ESBL) and carbapenemase producing Enterobacterales (CP-CRE) is critical for timely therapy. Rapid phenotypic tests identifying these resistance mechanisms from pure bacterial colonies have been developed.

Abstract Background Omicron variant of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global threat to public health. Numerous asymptomatic and mild cases had been admitted in shelter hospitals to quickly win the fight against Omicron pandemic in Shanghai. However, little is known about influencing factors for deterioration and length of stay (LOS) in hospitals among these non-severe cases. Methods This study included 12,555 non-severe cases with COVID-19 in largest shelter hospital of Shanghai, aiming to explore prognostic factors and build effective models for prediction of LOS. Results Data showed that 75.0% of participants were initially asymptomatic. In addition, 94.6% were discharged within 10 days, only 0.3% with deterioration in hospitals. The multivariate analysis indicated that less comorbidities (OR = 1.792, P = 0.012) and booster vaccination (OR = 0.255, P = 0.015) was associated with the decreased risk of deterioration. Moreover, age (HR = 0.991, P 

Abstract Background The development of scoring systems to predict the short-term mortality and the length of hospital stay (LOS) in patients with bacteraemia is essential to improve the quality of care and reduce the occupancy variance in the hospital bed. Methods Adults hospitalised with community-onset bacteraemia in the coronavirus disease 2019 (COVID-19) and pre-COVID-19 eras were captured as the validation and derivation cohorts in the multicentre study, respectively. Model I incorporated all variables available on day 0, Model II incorporated all variables available on day 3, and Models III, IV, and V incorporated the variables that changed from day 0 to day 3. This study adopted the statistical and machine learning (ML) methods to jointly determine the prediction performance of these models in two study cohorts. Results A total of 3,639 (81.4%) and 834 (18.6%) patients were included in the derivation and validation cohorts, respectively. Model IV achieved the best performance in predicting 30-day mortality in both cohorts. The most frequently identified variables incorporated into Model IV were deteriorated consciousness from day 0 to day 3 and deteriorated respiration from day 0 to day 3. Model V achieved the best performance in predicting LOS in both cohorts. The most frequently identified variables in Model V were deteriorated consciousness from day 0 to day 3, a body temperature ≤ 36.0 °C or ≥ 39.0 °C on day 3, and a diagnosis of complicated bacteraemia. Conclusions For hospitalised adults with community-onset bacteraemia, clinical variables that dynamically changed from day 0 to day 3 were crucial in predicting the short-term mortality and LOS. …

Journal of Medical Virology, Volume 95, Issue 9, September 2023.

There have been several reports of persistent infection and evolution of SARS-CoV-2 in immunocompromised hosts [1] [2] [3] [4]. Previous authors studied the correlations between clinical course and evolution of SARS-CoV-2 in immunocompromised hosts, reporting that while most immunocompromised persons effectively clear SARS-CoV-2 infection, some patients develop persistent infection and accelerated viral evolution. Although there is no consensus on the mechanisms underlying the emergence of new viral variants, accelerated viral evolution in immunocompromised patients seems to be involved in the genesis of variants of concern.

Bacterial meningitis is defined clinically by a triad that includes fever, neck stiffness and altered mental status and represents a medical emergency with a high mortality rate. Its worldwide incidence in high-income countries is estimated at 80/100,000 individuals per year. Delayed antimicrobial therapy increases mortality and neurological sequelae for survivors. Rapid diagnostic methods were developed to identify the most common pathogens responsible for community-acquired bacterial meningitis.

Ittiprasert and colleagues identified genomic safe harbour (GSH) sites in Schistosoma mansoni using computational methods and inserted a transgene into one of the sites through clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-assisted homology-directed repair. This study outlines a promising strategy for functional genomics to study this parasite that causes a debilitating and neglected tropical disease.

There have been significant advances in the prevention and management of Ebola virus disease (EVD) caused by Zaire Ebola virus (ZEBOV), including the development of two effective vaccines, rVSV-ZEBOV and Ad26.ZEBOV/MVA-BN-Filo. In addition, ZEBOV monoclonal antibodies have become first-line therapy for EVD. However, the 2022–23 outbreak of Sudan Ebola virus (SUDV) in Uganda has highlighted the gap in current therapies and vaccines, whose efficacy is uncertain against non-ZEBOV species. Health-care and laboratory staff working in EVD treatment centres or Ebola virus diagnostic and research laboratories face unique risks relating to potential occupational exposure to Ebola viruses.

Candida albicans, a significant commensal fungus in the human gut, causes a wide spectrum of opportunistic infections. In a recent study, Yang et al. revealed the importance of a host-associated gut signal, GlcNAc, in C. albicans and described its significant role towards achieving a successful commensal–virulence trade-off program in the human body.

AbstractToxin-antitoxin (TA) systems are entities found in the prokaryotic genomes, with eight reported types. Type II, the best characterised, is comprised of two genes organised as an operon. Whereas toxins impair growth, the cognate antitoxin neutralises its activity. TAs appeared to be involved in plasmid maintenance, persistence, virulence, and defence against bacteriophages. Most Type II toxins target the bacterial translational machinery. They seem to be antecessors of Higher Eukaryotes and Prokaryotes Nucleotide-binding (HEPN) RNases, minimal nucleotidyltransferase domains, or CRISPR-Cas systems. Four TAs encoded by Streptococcus pneumoniae, RelBE, YefMYoeB, Phd-Doc, and HicAB, belong to HEPN-RNases. The fifth is represented by PezAT/Epsilon-Zeta. PezT/Zeta toxins phosphorylate the peptidoglycan precursors, thereby blocking cell wall synthesis. We explore the body of knowledge (facts) and hypotheses procured for Type II TAs and analyse the data accumulated on the PezAT family. Bioinformatics analyses showed that homologues of PezT/Zeta toxin are abundantly distributed among 14 bacterial phyla mostly in Proteobacteria (48%), Firmicutes (27%), and Actinobacteria (18%), showing the widespread distribution of this TA. The pezAT locus was found to be mainly chromosomally encoded whereas its homologue, the tripartite omega-epsilon-zeta locus, was found mostly on plasmids. We found several orphan pezT/zeta toxins, unaccompanied by a cognate antitoxin.