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Antimicrobial Agents and Chemotherapy, Ahead of Print. …

Nature Medicine, Published online: 06 October 2022; doi:10.1038/s41591-022-02048-yEmerging evidence shows that boosting with updated mRNA vaccines that target SARS-CoV-2 variants stimulates better neutralizing antibody responses than homologous boosters.

Nature Medicine, Published online: 06 October 2022; doi:10.1038/s41591-022-02031-7A bivalent vaccine encoding the ancestral and Beta variant SARS-CoV-2 spike proteins boosts neutralizing antibody responses against multiple viral variants, suggesting that a bivalent approach is an effective strategy to broadly enhance protection against COVID-19.

Introduction

WHO has generated standardised clinical and epidemiological research protocols to address key public health questions for SARS-CoV-2 (COVID-19) pandemic. We present a standardised protocol with the aim to fill a gap in understanding the needs, attitudes and practices related to sexual and reproductive health in the context of COVID-19 pandemic, focusing on pregnancy, pregnancy prevention and abortion.

Methods and analysis plan

This protocol is a prospective qualitative research, using semi-structured interviews with at least 15 pregnant women at different gestational ages and after delivery, 6 months apart from the first interview. At least 10 partners, 10 non-pregnant women and 5 healthcare professionals will be interviewed once during the course of the research. Higher number of subjects may be needed if a saturation is not achieved with these numbers. Data collection will be performed in a standardised way by skilled trained interviewers using written notes or audio-record of the interview. The data will be explored using the thematic content analysis and the researchers will look for broad patterns, generalisations or theories from these categories.

Ethics and dissemination

The current protocol was first technically assessed and approved by the WHO scientific committee and then approved by its ethics review committee as a guidance document. It is expected that each country/setting implementing such a generic protocol adapted to their conditions also obtain local ethical approval. Comments for the user’s consideration are provided the document, as the user may need to modify methods slightly because of the local context in which this study will be carried out.

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Objective

This study aimed to assess factors associated with poor medication adherence during the COVID-19 pandemic among hypertensive patients visiting public hospitals in Eastern Ethiopia.

Setting

Hospital-based cross-sectional study was conducted in Harari regional state and Dire Dawa Administration from 1 January to 30 February 2022. Both settings are found in Eastern Ethiopia.

Participants

A total of 402 adult hypertensive patients who visited the chronic diseases clinic for follow-up were included in the study.

Main outcome measures

The main outcome measure was poor medication adherence during the COVID-19 pandemic.

Results

The level of poor antihypetensive medication adherence was 63% (95% CI 48.1 to 67.9). Patients who had no formal education (adjusted OR (AOR)=1.56, 95% CI 1.03 to 4.30), existing comorbid conditions (AOR=1.98, 95% CI 1.35 to 4.35), self-funded for medication cost (AOR=2.05, 95% CI 1.34 to 4.73), poor knowledge about hypertension (HTN) and its treatment (AOR=2.67, 95% CI 1.45 to 3.99), poor patient–physician relationship (AOR=1.22, 95% CI 1.02 to 4.34) and unavailability of medication (AOR=5.05, 95% CI 2.78 to 12.04) showed significant association with poor medication adherence during the pandemic of COVID-19.

Conclusion

The level of poor antihypertensive medication adherence was high in this study. No formal education, comorbidity, self-funded medication cost, poor knowledge about HTN and its treatment, poor patient–physician relationship, and unavailability of medication during the COVID-19 pandemic were factors significantly associated with poor adherence to antihypertensive medication. All stakeholders should take into account and create strategies to reduce the impact of the COVID-19 pandemic on medication adherence of chronic diseases.

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Clinical Microbiology Reviews, Ahead of Print. …

Mycobacterium kansasii (M. kansasii) pulmonary disease is frequently misdiagnosed and treated as tuberculosis, especially in countries with high tuberculosis burden. This study aimed to investigate the drug resistance profile of M. kansasii in patients with M. kansasii pulmonary disease in Shanghai, and to determine the variations in drug resistance after the 2-month antimycobacterial treatment.

The objective of this study was to compare the incidence rate for complications to upper respiratory tract infections, including acute bronchitis (URTI) and lower urinary tract infections (UTI) for untreated compared with those treated with antibiotics.

Chlamydia are Gram-negative, obligate intracellular pathogens, which currently comprise 13 species and 3 candidate species (Bommana and Polkinghorne 2019). Most of them have significant impacts on the health of humans or animals. Chlamydia trachomatis, Chlamydia pneumoniae, and Chlamydia psittaci are the major species that infect humans and can cause a variety of diseases (Elwell et al. 2016).

Patients with genetic and acquired humoral immunodeficiency present with an atypical COVID-19 course. Persistent viral shedding with multiple viral relapses continue in these patients for weeks. [1] Lymphopenia, recent anti-CD20 therapy, chimeric antigen receptor T cell therapy (CAR-T), hypogammaglobulinemia and hematopoietic stem cell transplantation are associated with virological persistence. [2] These patients have low seroconversion rates following SARS-CoV-2 vaccination, and are predisposed to SARS-CoV-2 infection and severe disease.

New England Journal of Medicine, Volume 387, Issue 14, October 2022. …

New England Journal of Medicine, Ahead of Print. …

Dendritic cells (DCs) play a key role to modulate anti-cancer immunity in the tumor microenvironment (TME). They link innate to adaptive immunity by processing and presenting tumor antigens to T cells thereby initiating an anti-tumor response. However, subsets of DCs also induce immune-tolerance, leading to tumor immune escape. In this regard, the TME plays a major role in adversely affecting DC function. Better understanding of DC impairment mechanisms in the TME will lead to more efficient DC-targeting immunotherapy. Here, we review the different subtypes and functions of DCs in the TME, including conventional DCs, plasmacytoid DC and the newly proposed subset, mregDC. We further focus on how cancer cells modulate DCs to escape from the host’s immune-surveillance. Immune checkpoint expression, small molecule mediators, metabolites, deprivation of pro-immunogenic and release of pro-tumorigenic cytokine secretion by tumors and tumor-attracted immuno-suppressive cells inhibit DC differentiation and function. Finally, we discuss the impact of established therapies on DCs, such as immune checkpoint blockade. Creative DC-targeted therapeutic strategies will be highlighted, including cancer vaccines and cell-based therapies.…

Proof-of-concept studies demonstrate that antimalarial drugs designed for human treatment can also be applied to mosquitoes to interrupt malaria transmission. Deploying a new control tool is ideally undertaken within a stewardship programme that maximises a drug's lifespan by minimising the risk of resistance evolution and slowing its spread once emerged. We ask: what are the epidemiological and evolutionary consequences of targeting parasites within mosquitoes? Our synthesis argues that targeting parasites inside mosquitoes (i) can be modelled by readily expanding existing epidemiological frameworks; (ii) provides a functionally novel control method that has potential to be more robust to resistance evolution than targeting parasites in humans; and (iii) could extend the lifespan and clinical benefit of antimalarials used exclusively to treat humans.

Science Advances, Volume 8, Issue 40, October 2022. …

Science Advances, Volume 8, Issue 40, October 2022. …

Science Advances, Volume 8, Issue 40, October 2022. …

Science Advances, Volume 8, Issue 40, October 2022. …

Objectives:

Sepsis causes significant mortality. However, most patients who die of sepsis do not present with severe infection, hampering efforts to deliver early, aggressive therapy. It is also known that the host gene expression response to infection precedes clinical illness. This study seeks to develop transcriptomic models to predict progression to sepsis or shock within 72 hours of hospitalization and to validate previously identified transcriptomic signatures in the prediction of 28-day mortality.

Design:

Retrospective differential gene expression analysis and predictive modeling using RNA sequencing data.

Patients:

Two-hundred seventy-seven patients enrolled at four large academic medical centers; all with clinically adjudicated infection were considered for inclusion in this study.

Measurements and Main Results:

Sepsis progression was defined as an increase in Sepsis 3 category within 72 hours. Transcriptomic data were generated using RNAseq of whole blood. Least absolute shrinkage and selection operator modeling was used to identify predictive signatures for various measures of disease progression. Four previously identified gene signatures were tested for their ability to predict 28-day mortality. There were no significant differentially expressed genes in 136 subjects with worsened Sepsis 3 category compared with 141 nonprogressor controls. There were 1,178 differentially expressed genes identified when sepsis progression was defined as ICU admission or 28-day mortality. A model based on these genes predicted progression with an area under the curve of 0.71. Validation of previously identified gene signatures to predict sepsis mortality revealed area under the receiver operating characteristic values of 0.70–0.75 and no significant difference between signatures.

Conclusions:

Host gene expression was unable to predict sepsis progression when defined by an increase in Sepsis-3 category, suggesting this definition is not a useful framework for transcriptomic prediction methods. However, there was a differential response when progression was defined as ICU admission or death. Validation of previously described signatures predicted 28-day mortality with insufficient accuracy to offer meaningful clinical utility.

Objectives:

Bloodstream infections (BSIs) acquired in the ICU represent a detrimental yet potentially preventable condition. We determined the prevalence of BSI acquired in the ICU (ICU-onset BSI), pathogen profile, and associated risk factors.

Design:

Retrospective cohort study.

DATA SOURCES:

Eighty-five U.S. hospitals in the Cerner Healthfacts Database.

PATIENT SELECTION:

Adult hospitalizations between January 2009 and December 2015 including a (≥ 3 d) ICU stay.

DATA EXTRACTION AND DATA SYNTHESIS:

Prevalence of ICU-onset BSI (between ICU Day 3 and ICU discharge) and associated pathogen and antibiotic resistance distributions were compared with BSI present on (ICU) admission (ICU-BSIPOA); and BSI present on ICU admission day or Day 2. Cox models identified risk factors for ICU-onset BSI among host, care setting, and treatment-related factors. Among 150,948 ICU patients, 5,600 (3.7%) had ICU-BSIPOA and 1,306 (0.9%) had ICU-onset BSI. Of those with ICU-BSIPOA, 4,359 (77.8%) were admitted to ICU at hospital admission day. Patients with ICU-onset BSI (vs ICU-BSIPOA) displayed higher crude mortality of 37.9% (vs 20.4%) (p < 0.001) and longer median (interquartile range) length of stay of 13 days (8–23 d) (vs 5 d [3–8 d]) (p < 0.001) (considering all ICU stay). Compared with ICU-BSIPOA, ICU-onset BSI displayed more Pseudomonas, Acinetobacter, Enterococcus, Candida, and Coagulase-negative Staphylococcus species, and more methicillin-resistant staphylococci, vancomycin-resistant enterococci, ceftriaxone-resistant Enterobacter, and carbapenem-resistant Enterobacterales and Acinetobacter species, respectively. Being younger, male, Black, Hispanic, having greater comorbidity burden, sepsis, trauma, acute pulmonary or gastrointestinal presentations, and pre-ICU exposure to antibacterial and antifungal agents was associated with greater ICU-onset BSI risk after adjusted analysis. Mixed ICUs (vs medical or surgical ICUs) and urban and small/medium rural hospitals were also associated with greater ICU-onset BSI risk. The associated risk of acquiring ICU-onset BSI manifested with any duration of mechanical ventilation and 7 days after insertion of central venous or arterial catheters.

Conclusions:

ICU-onset BSI is a serious condition that displays a unique pathogen and resistance profile compared with ICU-BSIPOA. Further scrutiny of modifiable risk factors for ICU-onset BSI may inform control strategies.

Antimicrobial Agents and Chemotherapy, Ahead of Print. …

Antimicrobial Agents and Chemotherapy, Ahead of Print. …

Antimicrobial Agents and Chemotherapy, Ahead of Print. …

by Eirik Amundsen, Åse Haugstvedt, Vegard Skogen, Rigmor C. Berg

Background Chemsex typically involves drugs such as GHB/GBL, crystal meth and mephedrone, and is increasingly common among MSM. The behaviour has been found to be associated with sexually transmitted infections (STIs) and mental health problems. We aimed to assess the extent of chemsex engagement and associations with different aspects of health, among MSM attending a free specialist walk-in clinic for STIs in Oslo, Norway. Methods Anonymous cross-sectional survey data was collected from June to October 2016. Differences in STI health (chlamydia, gonorrhoea, syphilis, HIV diagnoses), mental health (depression/anxiety) and internalised homonegativity between MSM using and not using GHB/GBL, crystal meth, mephedrone, cocaine or ketamine with sex in the last year were assessed descriptively and in a multivariate logistic regression model. The predictors were number of self-reported chlamydia, gonorrhoea or syphilis diagnoses, HIV diagnosis, depression/anxiety, and degree of internalised homonegativity. We adjusted for age, education level and having lived abroad. Results Of the 518 MSM respondents, 17% reported sexualised use of either GHB/GBL, crystal meth, mephedrone, cocaine or ketamine in the last year (chemsex). We found significant positive associations between chemsex and self-reported HIV diagnoses (adjusted odds ratio [aOR] = 3.26, 95%CI = 1.37–7.76), number of reported chlamydia, gonorrhoea or syphilis diagnoses in the last year (aOR = 1.63, 95%CI = 1.18–2.12), having lived more than one year abroad (aOR = 2.10, 95%CI = 1.20–3.65), but no significant association with depression/anxiety (aOR = 1.02, 95%CI = 0.53–1.93), nor internalised homonegativity (aOR = 0.62, 95%CI = 0.33–1.19). Conclusion Chemsex engagement in Norway is relatively low compared to findings from STI clinics in other European countries, and GHB/GBL and cocaine the two most commonly used drugs with sex. Chemsex was more common among MSM having lived more than one year abroad, reporting HIV diagnoses and a higher number of either chlamydia, gonorrhoea or syphilis diagnoses in the last year. Health care providers need to be made aware of chemsex as a behavioural phenomenon among MSM, and special care should be afforded to MSM living with HIV and being diagnosed with STIs.…

by Péter Gyula, Tamás Tóth, Teréz Gorcsa, Tünde Nyikó, Anita Sós-Hegedűs, György Szittya

Arabidopsis thaliana is one of the most studied model organisms of plant biology with hundreds of geographical variants called ecotypes. One might expect that this enormous genetic variety could result in differential response to pathogens. Indeed, we observed previously that the Bur ecotype develops much more severe symptoms (upward curling leaves and wavy leaf margins) upon infection with two positive-strand RNA viruses of different families (turnip vein-clearing virus, TVCV, and turnip mosaic virus, TuMV). To find the genes potentially responsible for the ecotype-specific response, we performed a differential expression analysis of the mRNA and sRNA pools of TVCV and TuMV-infected Bur and Col plants along with the corresponding mock controls. We focused on the genes and sRNAs that showed an induced or reduced expression selectively in the Bur virus samples in both virus series. We found that the two ecotypes respond to the viral infection differently, yet both viruses selectively block the production of the TAS3-derived small RNA specimen called tasiARF only in the virus-infected Bur plants. The tasiARF normally forms a gradient through the adaxial and abaxial parts of the leaf (being more abundant in the adaxial part) and post-transcriptionally regulates ARF4, a major leaf polarity determinant in plants. The lack of tasiARF-mediated silencing could lead to an ectopically expressed ARF4 in the adaxial part of the leaf where the misregulation of auxin-dependent signaling would result in an irregular growth of the leaf blade manifesting as upward curling leaf and wavy leaf margin. QTL mapping using Recombinant Inbred Lines (RILs) suggests that the observed symptoms are the result of a multigenic interaction that allows the symptoms to develop only in the Bur ecotype. The particular nature of genetic differences leading to the ecotype-specific symptoms remains obscure and needs further study.

by Ron Blonder, Yael Feldman-Maggor, Shelley Rap

The experience of graduate degree lecturers in the natural sciences when they switched to online teaching during the Covid-19 pandemic is described. The shift to online teaching throughout the pandemic provided an opportunity to evaluate how lecturers integrate technology into their teaching and what they need to improve their remote teaching. This study used a twofold perspective of TPACK (Technological Pedagogical Content Knowledge) and self-efficacy in online education. Its data were derived from pre-and post-questionnaires, comprising closed and open-ended questions, given at the start and end of the semester. We found that lecturers focused on learning and applying technological and techno-pedagogical knowledge but paid less attention to the integration of three components: technology, pedagogy, and scientific content. Although no statistically significant differences in lecturers’ perceived self-efficacy was found between the start and the end of the semester, at the end of the semester we found a statistically significant correlation between the variables involved in building self-efficacy in online teaching: (1) satisfaction with online teaching and the belief that (2) technology promotes teaching, student interactions, participation, and engagement. Our results enabled us to identify the knowledge aspects that lecturers implemented initiatively and to better understand what aspects required more professional development training. In addition, the results emphasized the importance of developing the lecturers’ self-efficacy for online teaching. These insights can help to improve and enhance online teaching in higher education.

by Sonia Ijaz Haider, Farhatulain Ahmed, Hassan Pasha, Hadia Pasha, Nudrat Farheen, Muhammad Talha Zahid

Purpose Life satisfaction influences well-being. Medical students often experience more stress as compared to their counterparts in other disciplines as they are required to meet the demands of both academic workload and clinical responsibilities. However, during the current pandemic, in addition to academic changes, inability to complete clinical placements, loss of peer interaction and social connectedness and, deployment to areas in times of crisis could exacerbate their stress. This would impact their ability to cope with stress and eventually influence their life satisfaction. Students approach these challenges in various ways, either positively, religiously, or by avoiding. This study aimed to explore the association between resilience, coping mechanisms and life satisfaction in medical students during the pandemic. Methods A cross-sectional web-based survey was conducted from undergraduate medical students from year 1 to year 5. Three instruments were used to measure life satisfaction, resilience, and coping, namely The Brief Resilience Scale, The Satisfaction with Life Scale and the COPE inventory. Mean and standard deviation were calculated for all continuous variables. Robust linear regression model was used for analysis. Hierarchical (forward) stepwise model building technique was used for final model. Alpha cut off was kept at 0.05. Results A total of 351 students (out of 500 students) completed the questionnaires. A moderately negative, slightly linear correlation between life satisfaction and avoidant coping was reported. Life satisfaction showed moderately positive, slightly linear correlation with resilience score. Three variables stayed significant in the final model: Resilience, avoidant coping, and religion coping. Conclusion Life satisfaction can be improved among medical students by focusing on strategies which enhance resilience. Religion is identified as a significant coping strategy among medical students. Students coping mechanism can vary and more research is needed to assess which types of coping strategies could contribute positively to the quality of their personal and professional lives…

by Matteo Guardiani, Philipp Frank, Andrija Kostić, Gordian Edenhofer, Jakob Roth, Berit Uhlmann, Torsten Enßlin

The viral load of patients infected with SARS-CoV-2 varies on logarithmic scales and possibly with age. Controversial claims have been made in the literature regarding whether the viral load distribution actually depends on the age of the patients. Such a dependence would have implications for the COVID-19 spreading mechanism, the age-dependent immune system reaction, and thus for policymaking. We hereby develop a method to analyze viral-load distribution data as a function of the patients’ age within a flexible, non-parametric, hierarchical, Bayesian, and causal model. The causal nature of the developed reconstruction additionally allows to test for bias in the data. This could be due to, e.g., bias in patient-testing and data collection or systematic errors in the measurement of the viral load. We perform these tests by calculating the Bayesian evidence for each implied possible causal direction. The possibility of testing for bias in data collection and identifying causal directions can be very useful in other contexts as well. For this reason we make our model freely available. When applied to publicly available age and SARS-CoV-2 viral load data, we find a statistically significant increase in the viral load with age, but only for one of the two analyzed datasets. If we consider this dataset, and based on the current understanding of viral load’s impact on patients’ infectivity, we expect a non-negligible difference in the infectivity of different age groups. This difference is nonetheless too small to justify considering any age group as noninfectious.

by Viki Bockstal, Georgi Shukarev, Chelsea McLean, Neil Goldstein, Stephan Bart, Auguste Gaddah, Dickson Anumenden, Jeroen N. Stoop, Anne Marit de Groot, Maria G. Pau, Jenny Hendriks, Stephen C. De Rosa, Kristen W. Cohen, M. Juliana McElrath, Benoit Callendret, Kerstin Luhn, Macaya Douoguih, Cynthia Robinson

Background Though clinically similar, Ebola virus disease and Marburg virus disease are caused by different viruses. Of the 30 documented outbreaks of these diseases in sub-Saharan Africa, eight were major outbreaks (≥200 cases; five caused by Zaire ebolavirus [EBOV], two by Sudan ebolavirus [SUDV], and one by Marburg virus [MARV]). Our purpose is to develop a multivalent vaccine regimen protecting against each of these filoviruses. This first-in-human study assessed the safety and immunogenicity of several multivalent two-dose vaccine regimens that contain Ad26.Filo and MVA-BN-Filo. Methods Ad26.Filo combines three vaccines encoding the glycoprotein (GP) of EBOV, SUDV, and MARV. MVA-BN-Filo is a multivalent vector encoding EBOV, SUDV, and MARV GPs, and Taï Forest nucleoprotein. This Phase 1, randomized, double-blind, placebo-controlled study enrolled healthy adults (18–50 years) into four groups, randomized 5:1 (active:placebo), to assess different Ad26.Filo and MVA-BN-Filo vaccine directionality and administration intervals. The primary endpoint was safety; immune responses against EBOV, SUDV, and MARV GPs were also assessed. Results Seventy-two participants were randomized, and 60 (83.3%) completed the study. All regimens were well tolerated with no deaths or vaccine-related serious adverse events (AEs). The most frequently reported solicited local AE was injection site pain/tenderness. Solicited systemic AEs most frequently reported were headache, fatigue, chills, and myalgia; most solicited AEs were Grade 1–2. Solicited/unsolicited AE profiles were similar between regimens. Twenty-one days post-dose 2, 100% of participants on active regimen responded to vaccination and exhibited binding antibodies against EBOV, SUDV, and MARV GPs; neutralizing antibody responses were robust against EBOV (85.7–100%), but lower against SUDV (35.7–100%) and MARV (0–57.1%) GPs. An Ad26.Filo booster induced a rapid further increase in humoral responses. Conclusion This study demonstrates that heterologous two-dose vaccine regimens with Ad26.Filo and MVA-BN-Filo are well tolerated and immunogenic in healthy adults. ClinicalTrials.gov NCT02860650.…

by Randi Jessen, Line Nielsen, Nicolai Balle Larsen, Arieh Sierra Cohen, Vithiagaran Gunalan, Ellinor Marving, Alonzo Alfaro-Núñez, Charlotta Polacek, The Danish COVID-19 Genome Consortium (DCGC) , Anders Fomsgaard, Katja Spiess

Fast surveillance strategies are needed to control the spread of new emerging SARS-CoV-2 variants and gain time for evaluation of their pathogenic potential. This was essential for the Omicron variant (B.1.1.529) that replaced the Delta variant (B.1.617.2) and is currently the dominant SARS-CoV-2 variant circulating worldwide. RT-qPCR strategies complement whole genome sequencing, especially in resource lean countries, but mutations in the targeting primer and probe sequences of new emerging variants can lead to a failure of the existing RT-qPCRs. Here, we introduced an RT-qPCR platform for detecting the Delta- and the Omicron variant simultaneously using a degenerate probe targeting the key ΔH69/V70 mutation in the spike protein. By inclusion of the L452R mutation into the RT-qPCR platform, we could detect not only the Delta and the Omicron variants, but also the Omicron sub-lineages BA.1, BA.2 and BA.4/BA.5. The RT-qPCR platform was validated in small- and large-scale. It can easily be incorporated for continued monitoring of Omicron sub-lineages, and offers a fast adaption strategy of existing RT-qPCRs to detect new emerging SARS-CoV-2 variants using degenerate probes.

Abstract

Background

Quantifying disease costs is critical for policymakers to set priorities, allocate resources, select control and prevention strategies, and evaluate the cost-effectiveness of interventions. Although malaria carries a very large disease burden, the availability of comprehensive and comparable estimates of malaria costs across endemic countries is scarce.

Methods

A literature review to summarize methodologies utilized to estimate malaria treatment costs was conducted to identify gaps in knowledge.

Results

Only 45 publications met the inclusion criteria. They utilize different methods, include distinct cost components, have varied geographical coverage (a country vs a city), include different periods in the analysis, and focus on specific parasite types or population groups (e.g., pregnant women).

Conclusions

Cost estimates currently available are not comparable, hindering broad statements on the costs of malaria, and constraining advocacy efforts towards investment in malaria control and elimination, particularly with the finance and development sectors of the government.

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