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Volume 12, Issue 1, December 2023 .

Volume 12, Issue 1, December 2023 .

Several mechanisms including reduced CCR5 expression, protective HLA, viral restriction factors, broadly neutralizing antibodies, and more efficient T-cell responses, have been reported to account for HIV cont...

Tropical Medicine &International Health, EarlyView.

Tropical Medicine &International Health, EarlyView.

Journal of Medical Virology, Volume 95, Issue 5, May 2023.

Journal of Medical Virology, Volume 95, Issue 5, May 2023.

Journal of Medical Virology, Volume 95, Issue 5, May 2023.

Journal of Medical Virology, Volume 95, Issue 5, May 2023.

AbstractBackgroundThis study examined the effects of HIV on resting state functional connectivity (RSFC) in a large cohort of people living with HIV (PWH) and healthy controls without HIV (PWoH). Within PWH analyses focused on the effects of viral suppression and cognitive impairment on RSFC.MethodsA total of 316 PWH on stable combination antiretroviral therapy and 209 demographically matched PWoH were scanned at a single institution. Effects of the virus were examined by grouping PWH by detectable (viral load > 20 copies/ml; VLD) and undetectable (VLU) viral loads and as being cognitively impaired (CI) (Global Deficit Score ≥ 0.5) or cognitively normal (CN). Regression analysis, Object Oriented Data Analysis, and spring embedded graph models were applied to RSFC measures from 298 established brain ROIs comprising 13 brain networks to examine group differences.ResultsNo significant RSFC differences were observed between PWH and PWoH. Within PWH, there were no significant differences in RSFC between VLD and VLU subgroups and CI and CN subgroups.ConclusionThere were no significant effects of HIV on RSFC in our relatively large cohort of PWH and PWoH. Future studies could increase the sample size and combine with other imaging modalities.

AbstractBackgroundBone mineral density (BMD) loss may be accelerated in people with HIV (PLWH). It is unknown whether an individual polygenic risk score (PRS) is associated with low BMD in PLWH.MethodsWe included Swiss HIV Cohort Study participants of self-reported European descent, each with >2 per-protocol Dual X-ray Absorptiometry (DXA) measurements >2 years apart (2011-2020). We obtained uni-/multivariable odds ratios (OR) for DXA-defined osteoporosis based on traditional and HIV-related osteoporosis risk factors and a genome-wide PRS built from 9413 single nucleotide polymorphisms associated with low BMD in the general population. Controls were free from osteoporosis/osteopenia on all DXA measurements.ResultsWe included 438 participants (149 with osteoporosis, 289 controls; median age, 53 years, 82% male, 95% with suppressed HIV RNA). Participants with unfavorable osteoporosis-PRS (top vs. bottom PRS quintile) had univariable and multivariable-adjusted osteoporosis OR=4.76 (95% confidence interval [CI], 2.34-9.67) and 4.13 (1.86-9.18), respectively. For comparison, hepatitis C seropositivity, 5-year tenofovir disoproxil fumarate exposure, and parent history of hip fracture had univariable osteoporosis-OR=2.26 (1.37-3.74), 1.84 (1.40-2.43), and 1.54 (0.82-2.9), respectively.ConclusionsIn PLWH in Switzerland, osteoporosis was independently associated with a BMD-associated PRS, after adjustment for established osteoporosis risk factors including exposure to tenofovir DF.

AbstractBackgroundOn May 6, 2022, a powerful outbreak of monkeypox virus (MPXV) had been reported outside of Africa, with many continuing new cases being reported around the world. Analysis of mutations among the two different lineages present in the 2021 and 2022 outbreaks revealed the presence of G->A mutations occurring in the 5’GpA context, indicative of APOBEC3 cytidine deaminase activity.MethodsBy using a sensitive PCR (3D-PCR) method allowing differential amplification of AT-rich DNA, we analyzed the level of APOBEC3-induced MPXV editing in infected cells and in patients.ResultsWe demonstrate that G->A hypermutated MPXV genomes can be recovered experimentally from APOBEC3 transfection followed by MPXV infection. Here, among the 7 human APOBEC3 cytidine deaminases (A3A-A3C, A3DE, A3F-A3H), only APOBEC3F was capable of extensively deaminating cytidine residues in MPXV genomes. Hyperedited genomes were also recovered in ∼42% of analyzed patients. Moreover, we demonstrate that substantial repair of these mutations occurs. Upon selection, corrected G->A mutations escaping drift loss contribute to the MPXV evolution observed in the current epidemic.ConclusionsStochastic or transient overexpression of APOBEC3F gene exposes the MPXV genome to a broad spectrum of mutations that may be modeling the mutational landscape after multiple cycles of viral replication.

Publication date: Available online 25 May 2023 Source: Immunity Author(s): Helen L. Wu, Kathleen Busman-Sahay, Whitney C. Weber, Courtney M. Waytashek, Carla D. Boyle, Katherine B. Bateman, Jason S. Reed, Joseph M. Hwang, Christine Shriver-Munsch, Tonya Swanson, Mina Northrup, Kimberly Armantrout, Heidi Price, Mitch Robertson-LeVay, Samantha Uttke, Mithra R. Kumar, Emily J. Fray, Sol Taylor-Brill, Stephen Bondoc, Rebecca Agnor …

We aimed to describe the infectious risk during the dwell-time for different catheter types. Further, we wanted to identify risk factors for infections from catheters in place for >10 days.

AbstractBackgroundLyme disease is the most prevalent vector-borne disease in the United States, yet its host factors are poorly understood and diagnostic tests are limited. We evaluated patients in a large health system to uncover the role of cholesterol in the susceptibility, severity, and machine learning-based diagnosis of Lyme disease.MethodsA longitudinal health system cohort comprised 1,019,175 individuals with electronic health record data and 50,329 with linked genetic data. Associations of blood cholesterol level, a cholesterol genetic score comprising common genetic variants, and burden of rare loss-of-function (LoF) variants in cholesterol metabolism genes with Lyme disease were investigated. A portable machine learning model was constructed and tested to predict Lyme disease using routine lipid and clinical measurements.ResultsThere were 3,832 cases of Lyme disease. Increasing cholesterol was associated with greater risk of Lyme disease and hypercholesterolemia was more prevalent in Lyme disease cases than controls. Cholesterol genetic scores and rare LoF variants in CD36 and LDLR were associated with elevated Lyme disease risk. Serological profiling of cases revealed parallel trajectories of rising cholesterol and immunoglobulin levels over the disease course, including marked increases in individuals with LoF variants and high cholesterol genetic scores. The machine learning model predicted Lyme disease solely using routine lipid panel, blood count, and metabolic measurements.ConclusionsThese results demonstrate the value of large-scale genetic and clinical data to reveal host factors underlying infectious disease biology, risk, and prognosis, and the potential for their clinical translation to machine learning diagnostics that do not need specialized assays.

AbstractBackgroundTuberculosis infection (TBI) and tuberculosis disease (TBD) incidence remains poorly described following household contact (HHC) rifampin-/multidrug-resistant tuberculosis exposure. We sought to characterize TBI and TBD incidence at one-year in HHCs and to evaluate tuberculosis preventive therapy (TPT) use in high-risk groups.MethodsWe previously conducted a cross-sectional study of HHCs of rifampin-/multidrug-resistant tuberculosis in 8 high-burden countries and re-assessed TBI (interferon-gamma release assay, HHCs ≥5 years) and TBD (HHCs all ages) at one-year. Incidence was estimated across age and risk groups (age

Science, Volume 380, Issue 6647, Page 830-835, May 2023.

Science, Volume 380, Issue 6647, Page 784-784, May 2023.

Science, Volume 380, Issue 6647, Page 779-780, May 2023.

Trichodesmium is a globally abundant, marine N2-fixing cyanobacterium (see Glossary). Recordings of the vast surface blooms formed by this organism date back to the late 1700s, including the famous expeditions led by James Cook [1] and Charles Darwin [2]. In the last decade, high-throughput genetic surveys targeting the abundance and/or transcription of nifH genes (encoding a subunit of the N2-fixing protein nitrogenase) and data-driven modeling confirmed the wide spatiotemporal distribution of Trichodesmium [3–7], (Figure 1A).

A court case was dismissed for lack of jurisdiction, but the judge said that The Global Fund had intentionally smeared IRD, which supports tuberculosis care in Pakistan. Talha Burki reports.

Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH.

A 60-year-old woman presented to our emergency department with a 4-day history of mild, diffuse abdominal pain and discomfort in her abdomen. The patient\'s medical history was unremarkable apart from a cholelithiasis-related cholecystectomy which had been done 12 years earlier.

Mpox (formerly known as monkeypox) is a zoonotic viral disease endemic in parts of Africa. In May, 2022, the world was alerted to circulation of monkeypox virus in many high-income countries outside of Africa. Continued spread resulted in a WHO declaration of a Public Health Emergency of International Concern. Although there has been much attention on the global outbreak, most of the focus has been on high-income countries outside of Africa, despite the fact that monkeypox virus has been causing disease in parts of Africa for at least 50 years.

by Pranav Maddali, Anthony Ambesi, Paula J. McKeown-Longo Changes in the organization and structure of the fibronectin matrix are believed to contribute to dysregulated wound healing and subsequent tissue inflammation and tissue fibrosis. These changes include an increase in the EDA isoform of fibronectin as well as the mechanical unfolding of fibronectin type III domains. In previous studies using embryonic foreskin fibroblasts, we have shown that fibronectin’s EDA domain (FnEDA) and the partially unfolded first Type III domain (FnIII-1c) function as Damage Associated Molecular Pattern (DAMP) molecules to stimulate the induction of inflammatory cytokines by serving as agonists for Toll-Like Receptor-4 (TLR4). However, the role of signaling molecules downstream of TLR-4 such as TGF-β Activated Kinase 1 (TAK1) and Mitogen activated protein kinases (MAPK) in regulating the expression of fibronectin DAMP induced inflammatory genes in specific cell types is not known. In the current study, we evaluate the molecular steps regulating the fibronectin driven induction of inflammatory genes in three human fibroblast cell lines: embryonic foreskin, adult dermal, and adult kidney. The fibronectin derived DAMPs each induce the phosphorylation and activation of TAK1 which results in the activation of two downstream signaling arms, IKK/NF-κB and MAPK. Using the specific inhibitor 5Z-(7)-Oxozeanol as well as siRNA, we show TAK1 to be a crucial signaling mediator in the release of cytokines in response to fibronectin DAMPs in all three cell types. Finally, we show that FnEDA and FnIII-1c induce several pro-inflammatory cytokines whose expression is dependent on both TAK1 and JNK MAPK and highlight cell-type specific differences in the gene-expression profiles of the fibroblast cell-lines.

by Benjamin D. Young, Stephanie M. Rosales, Ian C. Enochs, Graham Kolodziej, Nathan Formel, Amelia Moura, Gabrielle L. D’Alonso, Nikki Traylor-Knowles Reef-building corals contain a complex consortium of organisms, a holobiont, which responds dynamically to disease, making pathogen identification difficult. While coral transcriptomics and microbiome communities have previously been characterized, similarities and differences in their responses to different pathogenic sources has not yet been assessed. In this study, we inoculated four genets of the Caribbean branching coral Acropora palmata with a known coral pathogen (Serratia marcescens) and white band disease. We then characterized the coral’s transcriptomic and prokaryotic microbiomes’ (prokaryiome) responses to the disease inoculations, as well as how these responses were affected by a short-term heat stress prior to disease inoculation. We found strong commonality in both the transcriptomic and prokaryiomes responses, regardless of disease inoculation. Differences, however, were observed between inoculated corals that either remained healthy or developed active disease signs. Transcriptomic co-expression analysis identified that corals inoculated with disease increased gene expression of immune, wound healing, and fatty acid metabolic processes. Co-abundance analysis of the prokaryiome identified sets of both healthy-and-disease-state bacteria, while co-expression analysis of the prokaryiomes’ inferred metagenomic function revealed infected corals’ prokaryiomes shifted from free-living to biofilm states, as well as increasing metabolic processes. The short-term heat stress did not increase disease susceptibility for any of the four genets with any of the disease inoculations, and there was only a weak effect captured in the coral hosts’ transcriptomic and prokaryiomes response. Genet identity, however, was a major driver of the transcriptomic variance, primarily due to differences in baseline immune gene expression. Despite genotypic differences in baseline gene expression, we have identified a common response for components of the coral holobiont to different disease inoculations. This work has identified genes and prokaryiome members that can be focused on for future coral disease work, specifically, putative disease diagnostic tools.

by Xuecheng Li, Yi Lu, Xiaoshuang Liang, Xiaofei Zhou, Dirui Li, Zan Zhang, Yunchao Niu, Shuaishuai Liu, Ling Ye, Rufeng Zhang Non-alcoholic fatty liver disease (NAFLD) has a high prevalence worldwide, with a significant proportion of patients progressing into non-alcoholic steatohepatitis (NASH) and further into cirrhosis and hepatocellular carcinoma (HCC). Most of the current animal models of NASH have limitations, such as incompatibility with human pathogenesis characteristics or long induction periods, which severely limit the development of new drugs and preclinical studies for NASH. We investigated the progression of NASH and fibrosis, as well as metabolic indicators, at different time points in aged mice induced by the Gubra Amylin NASH (GAN) diet, a high-fat, high-sugar, high-cholesterol diet, and attempted to establish a rapid and useful mouse model of NASH. Young and aged C57BL/6 mice were induced on a normal chow or GAN diet for 12 and 21 weeks, respectively. After 12 weeks of induction, aged mice developed NASH, including hepatic steatosis, lobular inflammation and hepatic ballooning, and the phenotype was more severe compared with young mice. After 21 weeks of induction, aged mice developed hepatic fibrosis, which greatly shortened the induction time compared with young mice. Furthermore, analysis of immune cell infiltration in the liver by flow cytometry elucidated the changes of multiple immune cells during the pathogenesis of NASH. These findings suggest that aged mice may develop NASH and fibrosis more rapidly under GAN diet induction, which may significantly shorten the period for preclinical studies of NASH.

by Margit Eero, Keith Brander, Tatjana Baranova, Uwe Krumme, Krzysztof Radtke, Jane W. Behrens The Eastern Baltic cod (Gadus morhua) stock is currently in a very poor state, with low biomass and adverse trends in several life history and demographic parameters. This raises concern over whether and to what level recovery is possible. Here, we look for new insights from a historical perspective, extending the time series of various stock health indicators back to the 1940s, i.e. to the beginning of intensive exploitation of the Eastern Baltic cod. The historical data confirm that the stock deterioration in recent years is unprecedented, as all indicators are presently in their worst states on record. Cod body condition and energy reserves were equally low in the 1940s–1950s, accompanied by high parasitic liver worm infection, comparable to that measured in recent years. However, other stock parameters (size structure, size at maturity, stock distribution) are currently in their worst states over the past 80 years. In contrast, the state of cod in the 1970s to early 1990s that is often perceived as a desirable target, was exceptional, with the most favorable indicator levels in the time series. Long-term observation data reveal concurrent or asynchronous trends in different indicators of stock health and to what extent these have coincided with changes in possible external drivers. In this way, the extended time series contribute to ongoing research on understanding the collapse of the cod and its recovery potential.

by Xuechun Mao, Ying Chen, Cong Deng, Xiaqing Zhou Most existing secure biometric authentication schemes are server-centric, and users must fully trust the server to store, process, and manage their biometric data. As a result, users’ biometric data could be leaked by outside attackers or the service provider itself. This paper first constructs the EDZKP protocol based on the inner product, which proves whether the secret value is the Euclidean distance of the secret vectors. Then, combined with the Cuproof protocol, we propose a novel user-centric biometric authentication scheme called BAZKP. In this scheme, all the biometric data remain encrypted during authentication phase, so the server will never see them directly. Meanwhile, the server can determine whether the Euclidean distance of two secret vectors is within a pre-defined threshold by calculation. Security analysis shows BAZKP satisfies completeness, soundness, and zero-knowledge. Based on BAZKP, we propose a privacy-preserving biometric authentication system, and its evaluation demonstrates that it provides reliable and secure authentication.

by Joyce Gyamfi, Juliet Iwelunmor, Shivani Patel, Vilma Irazola, Angela Aifah, Ashlin Rakhra, Mark Butler, Rajesh Vedanthan, Giang Nguyen Hoang, Monicah Nyambura, Hoa Nguyen, Cuc Nguyen, Kwaku Poku Asante, Solomon Nyame, Kwame Adjei, John Amoah, Kingsley Apusiga, Kezia Gladys Amaning Adjei, Manuel Ramierz-Zea, Diego Hernandez, Meredith Fort, Hanspria Sharma, Prashant Jarhyan, Emmanuel Peprah, Gbenga Ogedegbe Guidance on contextually tailored implementation strategies for the prevention, treatment, and control of hypertension is limited in lower-middle income countries (Lower-MIC). To address this limitation, we compiled implementation strategies and accompanying outcomes of evidence-based hypertension interventions currently being implemented in five Lower-MIC. The Global Research on Implementation and Translation Science (GRIT) Coordinating Center (CC) (GRIT-CC) engaged its global network sites at Ghana, Guatemala, India, Kenya, and Vietnam. Purposively sampled implementation science experts completed an electronic survey assessing implementation outcomes, in addition to implementation strategies used in their ongoing hypertension interventions from among 73 strategies within the Expert Recommendations for Implementing Change (ERIC). Experts rated the strategies based on highest priority to their interventions. We analyzed the data by sorting implementation strategies utilized by sites into one of the nine domains in ERIC and summarized the data using frequencies, proportions, and means. Seventeen implementation experts (52.9% men) participated in the exercise. Of Proctor’s implementation outcomes identified across sites, all outcomes except for appropriateness were broadly assessed by three or more countries. Overall, 59 out of 73 (81%) strategies were being utilized in the five countries. The highest priority implementation strategies utilized across all five countries focused on evaluative and iterative strategies (e.g., identification of context specific barriers and facilitators) to delivery of patient- and community-level interventions, while the lowest priority was use of financial and infrastructure change strategies. More capacity building strategies (developing stakeholder interrelationships, training and educating stakeholders, and supporting clinicians) were incorporated into interventions implemented in India and Vietnam than Ghana, Kenya, and Guatemala. Although robust implementation strategies are being used in Lower -MICs, there is minimum use of financial and infrastructure change strategies. Our study contributes to the growing literature that demonstrates the use of Expert Recommendations for Implementing Change (ERIC) implementation strategies to deliver evidence-based hypertension interventions in Lower-MICs and will inform future cross-country data harmonization activities in resource-constrained settings.

by Valerian Mwenda, Joan-Paula Bor, Mary Nyangasi, James Njeru, Sharon Olwande, Patricia Njiri, Marc Arbyn, Steven Weyers, Philippe Tummers, Marleen Temmerman Background Globally, cervical cancer is a major public health problem, with about 604,000 new cases and over 340,000 deaths in 2020. In Kenya, it is the leading cause of cancer deaths, with over 3,000 women dying in 2020 alone. Both the Kenyan cancer screening guidelines and the World Health Organization’s Global Cervical Cancer Elimination Strategy recommend human papillomavirus (HPV) testing as the primary screening test. However, HPV testing is not widely available in the public healthcare system in Kenya. We conducted a pilot study using a point of care (POC) HPV test to inform national roll-out. Methods The pilot was implemented from October 2019 to December 2020, in nine health facilities across six counties. We utilized the GeneXpert platform (Cepheid, Sunnyvale, CA, USA), currently used for TB, Viral load testing and early infant diagnosis for HIV, for HPV screening. Visual inspection with acetic acid (VIA) was used for triage of HPV-positive women, as recommended in national guidelines. Quality assurance (QA) was performed by the National Oncology Reference Laboratory (NORL), using the COBAS 4800 platform (Roche Molecular System, Pleasanton, CF, USA). HPV testing was done using either self or clinician-collected samples. We assessed the following screening performance indicators: screening coverage, screen test positivity, triage compliance, triage positivity and treatment compliance. Test agreement between local GeneXpert and central comparator high-risk HPV (hrHPV) testing for a random set of specimens was calculated as overall concordance and kappa value. We conducted a final evaluation and applied the Nominal Group Technique (NGT) to identify implementation challenges and opportunities. Key findings The screening coverage of target population was 27.0% (4500/16,666); 52.8% (2376/4500) were between 30–49 years of age. HPV positivity rate was 22.8% (1027/4500). Only 10% (105/1027) of HPV positive cases were triaged with VIA/VILI; 21% (22/105) tested VIA/VILI positive, and 73% (16/22) received treatment (15 received cryotherapy, 1 was referred for biopsy). The median HPV testing turnaround time (TAT) was 24 hours (IQR 2–48 hours). Invalid sample rate was 2.0% (91/4500). Concordance between the Cepheid and COBAS was 86.2% (kappa value = 0.71). Of 1042 healthcare workers, only 5.6% (58/1042) were trained in cervical cancer screening and treatment, and only 69% (40/58) of those trained were stationed at service provision areas. Testing capacity was identifed as the main challenge, while the community strategy was the main opportunity. Conclusion HPV testing can be performed on GeneXpert as a near point of care platform. However, triage compliance and testing TAT were major concerns. We recommend strengthening of the screening-triage-treatment cascade and expansion of testing capacity, before adoption of a GeneXpert-based HPV screening among other near point of care platforms in Kenya. …

by Kristina Vingrys, Helen McCarthy, Ricardo Segurado, James R. Hébert, Catherine M. Phillips Introduction Diet-related inflammation is associated with adiposity. Obesity and inflammation in early life may have adverse health outcomes in later life; however, the socio-ecological predictors of a pro-inflammatory diet in childhood and adolescence are not well understood. This rapid scoping review aims to summarise the current state of research from observational studies investigating socio-ecological predictors (childhood, parental, familial, demographic and chronobiological risk factors) and their association with diet-associated inflammation and adiposity in children and adolescents. Methods This scoping review will be conducted using the frameworks based on the Joanna Briggs Institute and Arksey and O’Malley and the Population, Concept and Context (PCC) mnemonic. Searches were conducted in OVID Medline, Cinahl and Embase, with adaptations as required. The piloted study selection process will utilise two reviewers for study selection, with reference lists checked for included studies. A third reviewer will moderate disagreements. Data will be extracted by one reviewer and calibrated by a second reviewer. Results The results will be reported using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist and PRISMA-ScR flow diagram. The main findings will be synthesised into themes and concepts narratively. Tables and graphs will present frequencies, study details and categorical descriptions. Discussion This scoping review will provide an overview of the research conducted to date regarding predictors of diet-related inflammation in childhood and their associations with adiposity. Better understanding of the factors associated with a more inflammatory diet in childhood may be useful for clinicians and policy makers when designing and implementing health interventions. …

Chronic Q fever includes mainly endocarditis and other endovascular infections and more rarely osteoarticular infections. Treatment for the various manifestations of chronic Q fever has been standardized in the last 20 years to doxycycline and hydroxychloroquine given for a minimum of 18 to 24 months. 1,2 Recommendations on duration of treatment beyond the minimal period are based mostly on levels of Q fever IgG phase 1 titers. Monitoring of drug levels is recommended by some experts.

The successful application of metagenomic next-generation sequencing (mNGS; or clinical metagenomics) for the diagnosis of infectious diseases directly from a clinical specimen generated significant interest from a high-profile report nearly a decade ago [1]. Several case series have since emerged, generating further interest, and building momentum for clinical use. Metagenomic NGS holds promise to improve and streamline the diagnosis of infectious diseases due to its untargeted nature, facilitating organism detection without a priori knowledge of the differential diagnosis.

β-haemolytic group A Streptococcus (GAS) and groups C/G Streptococcus (GCGS) are closely related. GCGS of human origin are mostly caused by Streptococcus dysgalactiae subspecies equisimilis (SDSE), which shares an ecological niche and disease spectrum with GAS, including the ability to cause streptococcal toxic shock syndrome (TSS) and necrotising fasciitis[1,2].

Abstract Background Little evidence exists regarding the prevalence of pathogens in bloodstream infections (BSIs), the mortality risk, and the benefit of combination therapy over monotherapy. This study aims to describe patterns of empiric antimicrobial therapy, and the epidemiology of Gram-negative pathogens, and to investigate the effect of appropriate therapy and appropriate combination therapy on the mortality of patients with BSIs. Methods This was a retrospective cohort study including all patients with BSIs of Gram-negative pathogens from January 2017 to December 2022 in a Chinese general hospital. The in-hospital mortality was compared between appropriate and inappropriate therapy, and between monotherapy and combination therapy for patients receiving appropriate therapy. We used Cox regression analysis to identify factors independently associated with in-hospital mortality. Results We included 205 patients in the study, of whom 147 (71.71%) patients received appropriate therapy compared with 58 (28.29%) who received inappropriate therapy. The most common Gram-negative pathogen was Escherichia coli (37.56%). 131 (63.90%) patients received monotherapy and 74 (36.10%) patients received combination therapy. The in-hospital mortality was significantly lower in patients administered appropriate therapy than inappropriate therapy (16.33% vs. 48.28%, p = 0.004); adjusted hazard ratio [HR] 0.55 [95% CI 0.35–0.84], p = 0.006). In-hospital mortality was also not different in combination therapy and monotherapy in the multivariate Cox regression analyses (adjusted HR 0.42 [95% CI 0.15–1.17], p = 0.096). However, combination therapy was associated with lower mortality than monotherapy in patients with sepsis or septic shock (adjusted HR 0.94 [95% CI 0.86–1.02], p = 0.047). Conclusions Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to Gram-negative pathogens. Combination therapy was associated with improved survival in patients with sepsis or septic shock. Clinicians need to choose optical empirical antimicrobials to improve survival outcomes in patients with BSIs. …

Abstract Background The four co-circulating and immunologically interactive dengue virus serotypes (DENV1-4) pose a unique challenge to vaccine design because sub-protective immunity can increase the risk of severe dengue disease. Existing dengue vaccines have lower efficacy in DENV seronegative individuals but higher efficacy in DENV exposed individuals. There is an urgent need to identify immunological measures that are strongly associated with protection against viral replication and disease following sequential exposure to distinct serotypes. Methods/Design This is a phase 1 trial wherein healthy adults with neutralizing antibodies to zero (seronegative), one non-DENV3 (heterotypic), or more than one (polytypic) DENV serotype will be vaccinated with the live attenuated DENV3 monovalent vaccine rDEN3Δ30/31-7164. We will examine how pre-vaccine host immunity influences the safety and immunogenicity of DENV3 vaccination in a non-endemic population. We hypothesize that the vaccine will be safe and well tolerated, and all groups will have a significant increase in the DENV1-4 neutralizing antibody geometric mean titer between days 0 and 28. Compared to the seronegative group, the polytypic group will have lower mean peak vaccine viremia, due to protection conferred by prior DENV exposure, while the heterotypic group will have higher mean peak viremia, due to mild enhancement. Secondary and exploratory endpoints include characterizing serological, innate, and adaptive cell responses; evaluating proviral or antiviral contributions of DENV-infected cells; and immunologically profiling the transcriptome, surface proteins, and B and T cell receptor sequences and affinities of single cells in both peripheral blood and draining lymph nodes sampled via serial image-guided fine needle aspiration. Discussion This trial will compare the immune responses after primary, secondary, and tertiary DENV exposure in naturally infected humans living in non-endemic areas. By evaluating dengue vaccines in a new population and modeling the induction of cross-serotypic immunity, this work may inform vaccine evaluation and broaden potential target populations. Trial Registration NCT05691530 registered on January 20, 2023. …

Abstract Background The World Health Organization (WHO) recommends the diagnosis of tuberculosis (TB) using molecular tests, such as Xpert MTB/RIF (MTB/RIF) or Xpert Ultra (Ultra). These tests are expensive and resource-consuming, and cost-effective approaches are needed for greater coverage. Methods We evaluated the cost-effectiveness of pooling sputum samples for TB testing by using a fixed amount of 1,000 MTB/RIF or Ultra cartridges. We used the number of people with TB detected as the indicator for cost-effectiveness. Cost-minimization analysis was conducted from the healthcare system perspective and included the costs to the healthcare system using pooled and individual testing. Results There was no significant difference in the overall performance of the pooled testing using MTB/RIF or Ultra (sensitivity, 93.9% vs. 97.6%, specificity 98% vs. 97%, p-value > 0.1 for both). The mean unit cost across all studies to test one person was 34.10 international dollars for the individual testing and 21.95 international dollars for the pooled testing, resulting in a savings of 12.15 international dollars per test performed (35.6% decrease). The mean unit cost per bacteriologically confirmed TB case was 249.64 international dollars for the individual testing and 162.44 international dollars for the pooled testing (34.9% decrease). Cost-minimization analysis indicates savings are directly associated with the proportion of samples that are positive. If the TB prevalence is ≥ 30%, pooled testing is not cost-effective. Conclusion Pooled sputum testing can be a cost-effective strategy for diagnosis of TB, resulting in significant resource savings. This approach could increase testing capacity and affordability in resource-limited settings and support increased testing towards achievement of WHO End TB strategy. …

Abstract Background Besides impaired respiratory function and immune system, COVID-19 can affect renal function from elevated blood urea nitrogen (BUN) or serum creatinine (sCr) levels to acute kidney injury (AKI) and renal failure. This study aims to investigate the relationship between Cystatin C and other inflammatory factors with the consequences of COVID-19. Methods A total of 125 patients with confirmed Covid-19 pneumonia were recruited in this cross-sectional study from March 2021 to May 2022 at Firoozgar educational hospital in Tehran, Iran. Lymphopenia was an absolute lymphocyte count of less than 1.5 × 109/L. AKI was identified as elevated serum Cr concentration or reduced urine output. Pulmonary consequences were evaluated. Mortality was recorded in the hospital one and three months after discharge. The effect of baseline biochemical and inflammatory factors on odds of death was examined. SPSS, version 26, was used for all analyses. P-vale less than 0.05 was considered significant. Results The highest amount of co-morbidities was attributed to COPD (31%; n = 39), dyslipidemia and hypertension (27%; n = 34 for each) and diabetes (25%; n = 31). The mean baseline cystatin C level was 1.42 ± 0.93 mg/L, baseline creatinine was 1.38 ± 0.86 mg/L, and baseline NLR was 6.17 ± 4.50. Baseline cystatin C level had a direct and highly significant linear relationship with baseline creatinine level of patients (P 

Abstract Background Healthcare-Acquired Infections are a major problem in the world and within the healthcare delivery system. An estimated 5–10% and around 25% of hospitalized patients have healthcare-acquired infections in developed and developing countries, respectively. Infection prevention and control programs have proven to be successful in lowering the incidence and spread of infections. Thus, this evaluation aims to evaluate the implementation fidelity of infection prevention practices at Debre Tabor comprehensive specialized hospital in Northwest Ethiopia. Methods A facility-based cross-sectional design with a concurrent mixed method was used to evaluate the implementation fidelity of infection prevention practices. A total of 36 indicators were used to measure adherence, participant responsiveness, and facilitation strategy dimensions. A total of 423 clients were administered for an interview, an inventory checklist, a document review, 35 non-participatory observations, and 11 key informant interviews were conducted. A multivariable logistic regression analysis was used to identify factors significantly associated with the satisfaction of clients. The findings were presented using descriptions, tables, and graphs. Result The overall implementation fidelity of the infection prevention practices was 61.8%. The dimensions of adherence to infection prevention and control guidelines were 71.4%, participant responsiveness was 60.6%, and facilitation strategy was 48%. In multivariable analysis, ward admission and educational level had a p-value of below 0.05 and were significantly associated with the satisfaction of clients with infection prevention practices at the hospital. The major themes that emerged in qualitative data analysis were healthcare worker-related factors, management-related factors, and patient- and visitor-related factors. Conclusion The evaluation result of this study concluded that the overall implementation fidelity of infection prevention practice was judged to be medium and needed improvement. It included dimensions of adherence and participant responsiveness that were rated as medium, as well as a facilitation strategy that was rated as low. Enablers and barriers were thematized into factors related to healthcare providers, management, institutions, and patient and visitor relations. …