Nyt fra tidsskrifterne

Science Advances, <a href='https://www.science.org/toc/sciadv/8/3'>Volume 8, Issue 3</a>, January 2022. …

by Harumasa Yokota, Hiroki Hayashi, Junya Hanaguri, Satoru Yamagami, Akifumi Kushiyama, Hironori Nakagami, Taiji Nagaoka

Prorenin is viewed as an ideal target molecule in the prevention of diabetic retinopathy. However, no drugs are available for inhibiting activation of prorenin. Here, we tested the effect of a prorenin peptide vaccine (VP) in the retina of a murine model of type 2 diabetes (T2D). To choose the optimal vaccine, we selected three different epitopes of the prorenin prosegment (E1, E2, and E3) and conjugated them to keyhole limpet hemocyanin (KLH). We injected C57BL/6J mice twice with KLH only (as a control vaccine), E1 conjugated with KLH (E1-KLH), E2-KLH, or E3-KLH and compared antibody titers. E2-KLH showed the highest antibody titer and specific immunoreactivity of anti-sera against prorenin, so we used E2-KLH as VP. Then, we administered injections to the non-diabetic db/m and diabetic db/db mice, as follows: db/m + KLH, db/db + KLH, and db/db + VP. Retinal blood flow measurement with laser speckle flowgraphy showed that the impaired retinal circulation response to both flicker light and systemic hyperoxia in db/db mice improved with VP. Furthermore, the prolonged implicit time of b-wave and oscillatory potentials in electroretinography was prevented, and immunohistochemical analysis showed reduced microglial activation, gliosis, and vascular leakage. The enzyme-linked immunosorbent spot assay confirmed vaccinated mice had no auto-immune response against prorenin itself. The present data suggest that vaccination against prorenin is an effective and safe measure against the early pathological changes of diabetic retinopathy in T2D.

Abstract:

Background:

Antiretroviral post-exposure prophylaxis (PEP) is recommended to prevent HIV infection after a high risk exposure, but current regimens have presented challenges in tolerability, regimen completion, and potential drug-drug interactions. Because co-formulatedbictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) is effective for HIV treatment, it was evaluated for use for PEP.

Setting:

Boston community health center.

Methods:

Individuals accessing PEP were enrolled in an open label study of co-formulated BIC/FTC/TAF, taken as one pill daily for 28 days. Pearson's chi-squared and Fisher's exact tests were used to assess if BIC/FTC/TAF differed with respect to side effects and regimen completion rates compared to historical PEP regimens.

Results:

Between August, 2018 and March, 2020, 52 individuals enrolled in the study. Most identified as cisgender gay (67.3%) or bisexual (11.5%) men, but 7.7% identified as cisgender heterosexual men and 3.8% cisgender heterosexual women. The most common regimen side effects were nausea or vomiting (15.4%), fatigue (9.6%), and diarrhea/loose stools (7.7%), which were less common than historical controls using other PEP regimens, including those containing other integrase strand transfer inhibitors. Only 1 participant discontinued the regimen because of fatigue, and all other side effects were self-limited. Almost all participants (90.4%) completed the indicated regimen, which was a higher completion rate compared to earlier PEP regimens, and none became HIV-positive.

Conclusions:

BIC/FTC/TAF co-formulated as a single daily pill was found to be safe, well-tolerated, and highly acceptable when used for PEP, and compared more favorably than historical PEP regimens used at an urban health center.

Corresponding Author: Kenneth H. Mayer, MD, The Fenway Institute, Fenway Health, 1340 Boylston St, 10th Floor, Boston, MA 02215, USA, Office: (617) 927-6087, Fax: (617) 267-0764 kmayer@fenwayhealth.org

The authors report no conflicts of interest related to this work.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

AbstractBackgroundWaning of IgG antibodies against SARS-CoV-2 complicates diagnosis of past infection. Durability of T cell memory against SARS-CoV-2 remains unclear, and most current T cell protocols are unsuited for large-scale automation.MethodsWhole blood samples from 31 patients with verified past COVID-19 and 46 controls, out of which 40 received SARS-CoV-2 vaccine were stimulated with peptides spanning the nucleocapsid (NC) or spike 1 (S1) regions of SARS-CoV-2 and analyzed for interferon-γ (IFN-γ) in supernatant plasma. Diagnostic accuracy of these assays was evaluated against serum anti-NC and anti-receptor-binding domain S1 IgG.ResultsInduction of IFN-γ in whole blood by NC or S1 peptides diagnosed past COVID-19 with high accuracy (AUC=0.93, AUC=0.95, respectively). In accordance with previous studies, NC-IgG levels rapidly waned with only 5/17 patients (29%) remaining seropositive >180 days after infection. By contrast, NC-peptide-induced T cell memory responses remained in 13/17 (76%) subjects >180 days after infection (P=0.012 vs. NC-IgG, McNemar test). After two vaccine doses, 18/18 donors exhibited S1-specific T cell memory.ConclusionsCytokine release assays for the monitoring of T cell memory in whole blood may be useful for evaluation of complications following unverified past COVID-19 and for long-term assessment of vaccine-induced T cell immunity.

Investigators reported the first clinical trial results for CoVac-1, a COVID-19 vaccine candidate designed to induce T-cell immunity, in Nature. The multipeptide-based vaccine had a favorable safety profile and induced a broad and potent T-cell response.

by Ashley Winfred Nakawuki, Rebecca Nekaka, Lydia V. N. Ssenyonga, George Masifa, Dorreck Nuwasiima, Julius Nteziyaremye, Jacob Stanley Iramiot

Background Postpartum urinary Catheter-Related Infections (CRIs) are a significant cause of maternal sepsis. Several studies done have reported the presence of mixed populations of bacteria with a significant increase in Extended-Spectrum Beta-Lactamase (ESBL) Enterobacteriaceae spps, Methicillin-Resistant Staphylococcus aureus (MRSA), Multi-Drug Resistant (MDR) bacteria in urine and blood cultures of catheterized patients despite the use of prophylactic antibiotics. This study aimed at determining the bacterial species diversity and susceptibility patterns of indwelling urinary catheters from postpartum mothers attending Mbale Regional Referral Hospital (MRRH). Methods A cross-sectional study employing quantitative and qualitative was carried out in MRRH among postpartum mothers with urinary catheters and their care-takers. The purposive non-random sampling strategy was used to collect data using an interviewer-administered questionnaire for the quantitative data collection and in-depth interviews for qualitative data collection. All the data collection tools used were developed, pretested and validated. At the point of de-catheterization, Catheter tips from enrolled participants were cut about 2-3cm below the balloon aseptically into test-tube containing peptone water, sonication technique employed, and incubation done 24hours then cultured to ensure phenotypic identification. An antibiotic sensitivity test was performed using the disc diffusion method following Clinical and Laboratory Standards Institute (CLSI) guidelines. Quantitative data collected was entered in Microsoft Excel and then exported to STATA14 for statistical analysis. Thematic analysis was used to analyse and organise qualitative data by an inductive coding method using Nvivo 12 software. Results In this study, 208 postpartum mothers participated, the majority of whom were caesarean section mothers of age range 20–24 years and 17 care-takers with a median age of 32 years. The prevalence of catheter tips bacterial colonisation was 98% despite 88.5% of the participants being on broad-spectrum antibiotics. The average duration of catheterisation was 2 days. All bacteria isolates were potential uro-pathogens with a mean occurrence of 2 bacteria species in each urinary catheter tip. The rates of MDR to commonly used antibiotics were high. The urinary catheter size of greater than F14 and duration of catheterization greater than 2 days were significantly associated with the number of bacterial species isolated from each sample. The maintenance care and knowledge of care-urinary catheter care among the care-takers was found sub-optimal. Conclusion There was a high prevalence of catheter colonisation with bacterial spps diversity averaging 2 spps per sample despite use of broad spectrum antibiotics. The MDR rates were high, which calls for routine culture and sensitivity. Health workers practicing obstetric medicine need to pay attention to catheter sizes during catheterisation and its duration. Health education should be part of antenatal and postnatal care education.…

Cytolytic T cell responses are predicted to be biased towards membrane proteins. The peptide-binding grooves of most alleles of histocompatibility complex class I (MHC-I) are relatively hydrophobic, therefore peptide fragments derived from human transmembrane helices (TMHs) are predicted to be presented more often as would be expected based on their abundance in the proteome. However, the physiological reason of why membrane proteins might be over-presented is unclear. In this study, we show that the predicted over-presentation of TMH-derived peptides is general, as it is predicted for bacteria and viruses and for both MHC-I and MHC-II, and confirmed by re-analysis of epitope databases. Moreover, we show that TMHs are evolutionarily more conserved, because single nucleotide polymorphisms (SNPs) are present relatively less frequently in TMH-coding chromosomal regions compared to regions coding for extracellular and cytoplasmic protein regions. Thus, our findings suggest that both cytolytic and helper T cells are more tuned to respond to membrane proteins, because these are evolutionary more conserved. We speculate that TMHs are less prone to mutations that enable pathogens to evade T cell responses.…

Objectives

We assessed the relationship between the Patient Health Questionnaire-9 (PHQ-9) at intake and other measurements intended to assess biological factors, markers of disease and health status.

Design, setting and participants

We performed a cross-sectional analysis of 2365 participants from the Baseline Health Study, a prospective cohort of adults selected to represent major demographic groups in the USA. Participants underwent deep phenotyping on demographic, clinical, laboratory, functional and imaging findings.

Importance

Despite extensive research on the clinical implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and other measures of health and disease; we sought to better understand this relationship.

Interventions

None.

Main outcomes and measures

Cross-sectional measures of medical illnesses, gait, balance strength, activities of daily living, imaging and laboratory tests.

Results

Compared with lower PHQ-9 scores, higher scores were associated with female sex (46.9%–66.7%), younger participants (53.6–42.4 years) and compromised physical status (higher resting heart rates (65 vs 75 bpm), larger body mass index (26.5–30 kg/m2), greater waist circumference (91–96.5 cm)) and chronic conditions, including gastro-oesophageal reflux disease (13.2%–24.7%) and asthma (9.5%–20.4%) (p<0.0001). Increasing PHQ-9 score was associated with a higher frequency of comorbidities (migraines (6%–20.4%)) and active symptoms (leg cramps (6.4%–24.7%), mood change (1.2%–47.3%), lack of energy (1.2%–57%)) (p<0.0001). After adjustment for relevant demographic, socioeconomic, behavioural and medical characteristics, we found that memory change, tension, shortness of breath and indicators of musculoskeletal symptoms (backache and neck pain) are related to higher PHQ-9 scores (p<0.0001).

Conclusions

Our study highlights how: (1) even subthreshold depressive symptoms (measured by PHQ-9) may be indicative of several individual- and population-level concerns that demand more attention; and (2) depression should be considered a comorbidity in common disease.

Trial registration number

NCT03154346.

…

Nature Medicine, Published online: 23 December 2021; doi:10.1038/s41591-021-01557-6An antisense oligonucleotide targets mutant transcripts of the ALS gene C9orf72, suppressing the poly(GP) dipeptide in tissues in mice and in the spinal fluid of a single patient harboring the C9orf72 gene mutation…

American Journal of Respiratory and Critical Care Medicine, Volume 204, Issue 10, Page 1227-1231, November 15, 2021.

Introduction

Bidirectional associations have been reported between sleep disturbance and both cognitive impairment, including Alzheimer’s disease and amyloid beta-peptide (Aβ) accumulation. These relationships can be explained by the glymphatic system, which acts as a garbage drainage system in the brain. As interstitial fluid dynamics are suggested to increase during sleep, clearance of Aβ can be influenced by sleep disturbance or deprivation. We hypothesised that using lemborexant, an orexin receptor antagonist, to improve sleep quality would also improve the function of the glymphatic system. We plan to examine the effect of lemborexant on sleep quality and the glymphatic system among patients with insomnia disorder.

Methods and analysis

This pilot study is designed as an open-label, single-arm, single-centre trial. Thirty patients aged 50 years and over with insomnia will be recruited. The participants will take lemborexant (5 mg) at bedtime for 12 weeks and undergo a home-based sleep study at baseline and weeks 4 and 12, as well as MRI examinations to evaluate the glymphatic system at baseline and week 12. The primary outcome will be changes in objective sleep parameters as evaluated using a sleep monitoring system. The secondary outcomes will be changes in subjective sleep parameters. The relationships between changes in sleep parameters and the glymphatic system will be evaluated using diffusion tensor image analysis along the perivascular space, which is called the ALPS-index. Sleep parameters and the ALPS-index will be analysed using a paired t-test or Pearson’s correlation coefficient.

Ethics and dissemination

The study protocol was approved by Nagoya University Certified Review Board. The findings from this research will be published in peer-reviewed journals and be presented at local, national and international conferences.

Trial registration number

jRCTs041210024.

Introduction

Evidence suggests that diabetes burden can be reduced by implementing early lifestyle intervention programmes in population with pre-diabetes in high-income countries. However, little is known in developing nations like Nepal. This study aims to assess effectiveness of community-based Diabetes Prevention Education Program (DiPEP) on haemoglobin A1c (HbA1c) level, proportion of pre-diabetes reverting to normoglycaemia, diet, physical activity, weight reduction, diabetes knowledge and health literacy after 6 months of follow-up. Furthermore, we will also conduct qualitative studies to explore experiences of participants of intervention sessions and perception of healthcare workers/volunteers about DiPEP.

Methods and analyses

This is a community-based two-arm, open-label, cluster randomised controlled trial. We will randomise 14 clusters into intervention arm and control arm. Estimated total sample size is 448. We will screen individuals without diabetes, aged 18–64 years, and permanent residents of study sites. HbA1c test will be only performed if both Indian Diabetes Risk Score and random blood sugar value are ≥60 and 140–250 mg/dL, respectively. At baseline, participants in intervention arm will receive DiPEP package (including intensive intervention classes, diabetes prevention brochure, exercise calendar and food record booklet), and participants in control arm will be provided only with diabetes prevention brochure. The change in outcome measures will be compared between intervention to control arm after 6 months of follow-up by linear mixed models. Also, we will conduct individual interviews among participants and healthcare workers as part of a qualitative study. We will use thematic analysis to analyse qualitative data.

Ethics and dissemination

Regional Committee for Medical and Health Research Ethics, Norway; Nepal Health Research Council, Nepal and Institutional Review Committee, Kathmandu University School of Medical Sciences have approved the study. The DiPEP package can be implemented in other communities of Nepal if it is effective in preventing diabetes.

Trial registration number

NCT04074148, 2019/783.

Introduction

Coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) are associated with risk of death, as well as brain, heart and kidney injury. Glucagon-like peptide-1 (GLP-1) analogues are approved for treatment of type 2 diabetes, and GLP-1 analogues have been suggested to have potential organ-protective and anti-inflammatory effects. During cardiopulmonary bypass (CPB), consensus on the optimal fraction of oxygen is lacking. The objective of this study is to determine the efficacy of the GLP-1-analogue exenatide versus placebo and restrictive oxygenation (50% fractional inspired oxygen, FiO2) versus liberal oxygenation (100% FiO2) in patients undergoing open heart surgery.

Methods and analysis

A randomised, placebo-controlled, double blind (for the exenatide intervention)/single blind (for the oxygenation strategy), 2x2 factorial designed single-centre trial on adult patients undergoing elective or subacute CABG and/or surgical AVR. Patients will be randomised in a 1:1 and 1:1 ratio to a 6-hour and 15 min infusion of 17.4 µg of exenatide or placebo during CPB and to a FiO2 of 50% or 100% during and after weaning from CPB. Patients will be followed until 12 months after inclusion of the last participant. The primary composite endpoint consists of time to first event of death, renal failure requiring renal replacement therapy, hospitalisation for stroke or heart failure. In addition, the trial will include predefined sub-studies applying more advanced measures of cardiac- and pulmonary dysfunction, renal dysfunction and cerebral dysfunction. The trial is event driven and aims at 323 primary endpoints with a projected inclusion of 1400 patients.

Ethics and dissemination

Eligible patients will provide informed, written consent prior to randomisation. The trial is approved by the local ethics committee and is conducted in accordance with Danish legislation and the Declaration of Helsinki. The results will be presented in peer-reviewed journals.

Trial registration number

NCT02673931.

Antimicrobial Agents and Chemotherapy, <a href="https://journals.asm.org/toc/aac/0/ja">Volume 0, Issue ja</a>, -Not available-.

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

“Our core aim is to build laboratory systems to address the health agenda as defined by Africa”, says Pascale Ondoa, who for the past 5 years has been Director of Science and New Initiatives at the African Society for Laboratory Medicine (ASLM). Part of this role is to direct technical advice and provide leadership to help shape health strategy and laboratory medicine improvement at the country level. “A lot of our work involves the coordination of partners and experts, so that investments from agencies like PEPFAR, the Global Fund to Fight AIDS, Tuberculosis and Malaria, the Fleming Fund, and others generate substantial and sustainable impact.

>In late September, 2021, US President Joe Biden tapped John Nkengasong to lead the US President's Emergency Plan for AIDS Relief (PEPFAR). If approved for the role as Ambassador-at-Large and Coordinator of US Government Activities to Combat HIV/AIDS Globally, Nkengasong will inherit a programme at a point of inflection. PEPFAR has been leaderless since Deborah Birx decamped in February, 2020, to coordinate the White House's COVID-19 response under the administration of Donald Trump. She left PEPFAR ahead of the findings from UNAIDS in July, 2020, that highlighted uneven progress towards 2020 milestones in the global bid to end the AIDS epidemic by 2030.

Tumor-infiltrating dendritic cells (DCs) are central to the anti-tumor immune response. Duong et al. reveal an activation state of CD11b+ conventional DCs (DC2) characterized by expression of interferon (IFN)-stimulated genes (ISG+ DCs) and capable of acquiring and presenting intact tumor-derived peptide-MHC class I complexes. ISG+ DCs can activate CD8+ T cells and promote protective anti-tumor immunity in the absence of DC1.

Objective:

To assess the central nervous system (CNS) impact of a kick&kill HIV cure strategy using therapeutic vaccine MVA.HIVconsv and the histone deacetylase inhibitor (HDACi) romidepsin (RMD) as latency-reversing agent.

Design:

Neurological observational substudy of the BCN02 trial (NCT02616874), a proof-of-concept, open-label, single-arm, phase I clinical trial testing the safety and immunogenicity of the MVA.HIVconsv vaccine and RMD in early-treated HIV-1-infected individuals. A monitored antiretroviral pause (MAP) was performed, with cART resumption after 2 pVL >2,000 copies/ml. Reinitiated participants were followed for 24 weeks.

Methods:

Substudy participation was offered to all BCN02 participants (N = 15). Evaluations covered cognitive, functional, and brain imaging outcomes, performed before RMD administration (Pre-RMD), after 3 RMD infusions (Post-RMD), and at the end of the study (EoS). A group of early-treated HIV-1-infected individuals with matched clinical characteristics was additionally recruited (n = 10). Primary endpoint was change in a global cognitive score (NPZ-6).

Results:

Eleven participants from BCN02 trial were enrolled. No significant changes were observed in cognitive, functional, or brain imaging outcomes from Pre-RMD to Post-RMD. No relevant alterations were detected from Pre-RMD to EoS either. Scores at EoS were similar in participants off cART for 32 weeks (n = 3) and those who resumed therapy for 24 weeks (n = 7). Controls showed comparable punctuations in NPZ-6 across all timepoints.

Conclusions:

No detrimental effects on cognitive status, functional outcomes, or brain imaging parameters were observed after using the HDACi RMD as latency-reversing agent with the MVA.HIVconsv vaccine in early-treated HIV-1-infected individuals. CNS safety was also confirmed after completion of the MAP.

Correspondence to Jose A. Muñoz-Moreno, Fundació Lluita contra la SIDA (FLS) - Hospital Universitari Germans Trias i Pujol, Ctra. del Canyet, SN - CP: 08916 - Badalona, Catalonia, Spain; e-mail: jmunoz@flsida.org

Received 15 July, 2021

Revised 28 October, 2021

Accepted 30 October, 2021

Copyright © 2021 Wolters Kluwer Health, Inc.

Antimicrobial Agents and Chemotherapy, <a href="https://journals.asm.org/toc/aac/0/ja">Volume 0, Issue ja</a>, -Not available-.

Bacteria deploy the type VI secretion system (T6SS) to inject effectors into bacterial rivals. Contrary to the prevailing model, a recent study (Le et al.) expands the target range of the T6SS by demonstrating that it delivers and potentializes a peptidoglycan-targeting bifunctional toxin into Gram-positive bacteria.

Background:

Estimating cause-related mortality among the dead is not common, yet for clinical and public health purposes, a lot can be learnt from the dead. HIV/AIDS accounted for the third most frequent cause of deaths in Kenya; 39.7 deaths per 100,000 population in 2019. OraQuick® has previously been validated on oral fluid and implemented as a screening assay for HIV self-testing in Kenya among living subjects. We assessed the feasibility and diagnostic accuracy of OraQuick® for HIV screening among decedents.

Methods:

Trained morticians collected oral fluid from 132 pre- and post-embalmed decedents aged >18 months at Jaramogi Oginga Odinga Teaching and Referral Hospital mortuary in western Kenya and tested for HIV using OraQuick®. Test results were compared with those obtained using the national HIV Testing Services algorithm on matched pre-embalming whole blood specimens as a gold standard (Determine® HIV and First Response® HIV 1-2-O). We calculated positive predictive values (PPV), negative predictive values (NPV), Area Under Curve (AUC), sensitivity and specificity of OraQuick® compared to the national HTS algorithm.

Results:

OraQuick® had similar sensitivity of 92.6%, (95.0% confidence interval (CI):75.7- 99.1) on pre- and post-embalmed samples compared to the gold standard. Specificity was 97.1% (95.0% CI:91.9-99.4) and 95.2%, (95.0% CI:89.2-98.4) pre and post embalming respectively. Pre and post embalming PPV was 89.3% (95.0% CI:71.8-97.7) and 83.3% (95.0% CI:65.3-94.4) respectively. The AUC pre-and post embalming was 94.9% (95% CI: 89.6 - 100) and 93.9% (95% CI, 88.5 - 99.4) respectively.

Conclusions:

The study showed a relatively high performance sensitivity and specificity of OraQuick® HIV-1/2 test among decedents, similar to those observed among living subjects. OraQuick® HIV-1/2 presents a convenient and less invasive screening test for surveillance of HIV among decedents within a mortuary setting.

Corresponding author: Valarie Opollo, Kenya Medical Research Institute, Tel: +254723903176, Email: vopollo@kemricdc.org

The authors report no conflicts of interest related to this work.

Funding: This study has been supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Centers for Disease Control and Prevention (CDC) under the terms of 6NU2GGH001520.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding agencies.

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

AbstractBackgroundTo evaluate the impact of vitamin D and calcium supplementation (VitD/Ca) on lumbar spine bone mineral density (LSBMD) and bone metabolism among Thai adolescents with perinatally acquired HIV (PHIVA).MethodsA multicenter, randomized, active-control, open-labeled trial was conducted. PHIVA (aged 10–20 years) who were on stable cART were enrolled. Baseline LSBMD status was defined as low (z-score ≤ −2) and normal (> −2). Eligible PHIVA were randomly assigned to receive standard-dose (400 IU/1200 mg/day) or high-dose (400 IU/1200 mg/day plus ergocalciferol 20 000 IU/week) VitD/Ca supplementation for 48 weeks (ratio 1:1, stratified by baseline LSBMD). Study outcomes were changes in LSBMD, LSBMD z-scores, and bone metabolism–related biomarkers (25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone [iPTH], C-terminal telopeptide [CTX], procollagen type I amino-terminal propeptide [PINP]) from baseline to week 48.ResultsAmong 200 enrolled PHIVA, median age was 16 (IQR:14–18) years; 61% were on NNRTI-based cART. Median 25(OH)D level was 25.5 (IQR: 20.8–33.0) ng/mL. After 48-week VitD/Ca supplementation, LSBMD significantly increased in both treatment groups (high-dose: median: +0.07 [IQR: +0.04 to +0.11] g/cm2; P < .001; standard-dose: +0.09 [+0.03 to +0.13] g/cm2; P < .001). Notably, the change in LSBMD z-scores was significantly greater in high-dose versus standard-dose groups (median: +0.4 [IQR: −0.1 to +0.9] vs +0.1 [−0.4 to +0.7]; P = .02). Levels of 25(OH)D increased, whereas iPTH, CTX, and PINP declined significantly in both groups (P < .05), but no between-group differences were demonstrated.ConclusionsOver 48-week VitD/Ca supplementation, significant increases in LSBMD, and significant decreases in bone metabolism–related markers were observed among our Thai PHIVA in both treatment groups. The improvement in LSBMD z-score was more enhanced with high-dose VitD/Ca supplementation than standard-dose. High-dose VitD/Ca supplementation might be considered to promote bone health in this population.Clinical Trials RegistrationNCT02426840.

by Raianna F. Fantin, Vanessa G. Fraga, Camila A. Lopes, Isabella C. de Azevedo, João L. Reis-Cunha, Dhelio B. Pereira, Francisco P. Lobo, Marcela M. de Oliveira, Anderson C. dos Santos, Daniela C. Bartholomeu, Ricardo T. Fujiwara, Lilian L. Bueno

Peptide-based vaccines have demonstrated to be an important way to induce long-lived immune responses and, therefore, a promising strategy in the rational of vaccine development. As to malaria, among the classic vaccine targets, the Apical membrane antigen (AMA-1) was proven to have important B cell epitopes that can induce specific immune response and, hence, became key players for a vaccine approach. The peptides selection was carried out using a bioinformatic approach based on Hidden Markov Models profiles of known antigens and propensity scale methods based on hydrophilicity and secondary structure prediction. The antigenicity of the selected B-cell peptides was assessed by multiple serological assays using sera from acute P.vivax infected subjects. The synthetic peptides were recognized by 45.5%, 48.7% and 32.2% of infected subjects for peptides I, II and III respectively. Moreover, when synthetized together (tripeptide), the reactivity increases up to 62%, which is comparable to the reactivity found against the whole protein PvAMA-1 (57%). Furthermore, IgG reactivity against the tripeptide after depletion was reduced by 42%, indicating that these epitopes may be responsible for a considerable part of the protein immunogenicity. These results represent an excellent perspective regarding future chimeric vaccine constructions that may come to contemplate several targets with the potential to generate the robust and protective immune response that a vivax malaria vaccine needs to succeed.

American Journal of Respiratory and Critical Care Medicine, Volume 204, Issue 9, Page 1103-1106, November 1, 2021.

Author Summary. We utilized a virome-wide protein array to better understand whether (1) different segments of a given Epstein-Barr virus (EBV) protein and/or (2) different variants of select EBV protein sequences (i.e., amino acid changes in a protein segment) elicited differential IgG antibody reactivity in health adults. We posited that this approach would help identify EBV protein regionss containing immunodominant epitopes for eliciting antibody mediated B-cell immunity. Using this approach, we identified eight EBV proteins with at least one sequence associated with differential IgG antibody response, including three proteins with segments that were differentially reactive (BALF5, LMP1, LMP2A), and five proteins with specific amino acid changes that altered IgG antibody response (BLF4, EBNA3A, EBNA3B, EBNA-LP, LF1) in two independent populations.

Objectives

Recently studies demonstrated that adipose tissue can produce and release complement C3 and serum complement C3 levels were associated with diabetes mellitus, metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Thus, we plan to investigate the association of complement C3 levels and the presence of metabolic-associated fatty liver disease (MAFLD).

Design

Observational study with a cross-sectional sample.

Setting

This study surveyed 4729 participants in Zhejiang province, China.

Participants

55 participants were excluded for acute infection and 1001 participants were excluded for lack of ultrasonography diagnoses and complete or partial absence of laboratory tests. The final sample size was 3673 participants.

Outcome measures

Spearman correlation analysis was used to examine the correlations between complement C3 levels and variables. Binary logistic regression was carried out to evaluate the association between complement C3 levels and the presence of MAFLD after adjustment for demographic and biochemical variables. Mediation effects were used to explore whether insulin resistance (IR), hyperlipidaemia and obesity mediated the association between complement C3 and MAFLD.

Results

Participants with MAFLD had higher complement C3 levels and complement C3 levels were closely associated with body mass index, waist circumference, alanine aminotransferase, aspartate aminotransferase, -glutamyl transpeptidase and homoeostasis model assessment (HOMA)-IR. The presence of MAFLD increased with the increase of complement C3 levels and the presence of MAFLD were highest in the HOMA-IR ≥2.5 participants. We found the OR and Cl of standardised C3 for MAFLD was 1.333 (1.185–1.500), each 1 SD increase in C3 would increase the presence of MAFLD by 33.3%, and obesity partly mediated the effect of complement C3 on the presence of MAFLD.

Conclusions

The present results suggest that complement C3 can be used as a risk factor for the presence of MAFLD after adjustment for confounding variables and obesity may partly mediate the effect of complement C3 on the presence of MAFLD.

New England Journal of Medicine, Ahead of Print.

Journalist Emily Bass has all the reasons to write a book about AIDS, To End a Plague: America's Fight to Defeat AIDS in Africa. For over two decades, she has been an AIDS activist. She watched all the events relevant to the disease since the unravelling of the AIDS pandemic in the USA. She was even arrested for protesting. No surprise then that Bass started to write about what began as the US President George W. Bush's landmark announcement on Jan 28, 2003. Later touted as the US's greatest ever bipartisan foreign aid success since its World War II Marshall Plan to revive Europe, Bush's announcement changed millions of lives for good in the following decades.

Objective

Age and alarm features are commonly used as indicators for endoscopy in dyspeptic patients; however, the age cut-off and the predictive value of these parameters for identifying upper gastrointestinal (UGI) malignancies are uncertain.

Design

Cross-sectional study.

Setting

Data were extracted from the Gastrointestinal Endoscopy Centre of Siriraj Hospital, Thailand, during 2005–2011.

Participants

Consecutive patients underwent a first-time upper endoscopy for dyspepsia. Patients with previous surgery, suspected UGI malignancy by imaging, or indefinite biopsy results on prior examination were excluded.

Main outcome measures

Alarm features included dysphagia, unintentional weight loss, GI bleeding/anaemia, and persistent vomiting. The diagnostic performance of each alarm feature and different age cut-off values were evaluated.

Results

A total of 4664 patients (mean age: 52.0±14.4 years, 66% female) were included. Alarm symptoms were presented in 21.6%. The prevalence of active Helicobacter pylori infection was 26.3%. Fifty-eight (1.2%) patients had UGI malignancy. The prevalence of malignancy significantly increased with increasing age (0.6% in patients aged <50 years, and 1.8% in patients aged >60 years (p<0.001)). Cancer was found in two patients aged <50 years who did not have alarm features. Patients with alarm features had a higher prevalence of malignancy (OR 22.3, 95% CI 10.5 to 47.4; p<0.001) than those without. The pooled sensitivity, specificity, positive predictive value and negative predictive value of alarm features for UGI malignancy were 87.0%, 79.1%, 4.7% and 99.8%, respectively. Among all age groups, persistent vomiting had a positive likelihood ratio (PLR) >10, while dysphagia and GI bleeding/anaemia had a PLR >10 in patients <50 years old.

Conclusion

Despite the overall limited value of age and alarm features, persistent vomiting, dysphagia, and GI bleeding/anaemia are strong predictors for malignancy in patients aged <50 years. Without these symptoms, cancer prevalence is negligible; thus, they are worthy guidance for endoscopic evaluation in this age group.

Classical dendritic cells (cDCs) in mice have been divided into 2 major subsets based on the expression of nuclear transcription factors: a CD8+Irf8+Batf3 dependent (DC1) subset, and a CD8-Irf4+ (DC2) subset. We found that the CD8+DC1 subset can be further divided into CD8+DC1a and CD8+DC1b subsets by differences in surface receptors, gene expression, and function. Whereas all 3 DC subsets can act alone to induce potent Th1 cytokine responses to class I and II MHC restricted peptides derived from ovalbumin (OVA) by OT-I and OT-II transgenic T cells, only the DC1b subset could effectively present glycolipid antigens to natural killer T (NKT) cells. Vaccination with OVA protein pulsed DC1b and DC2 cells were more effective in reducing the growth of the B16-OVA melanoma as compared to pulsed DC1a cells in wild type mice. In conclusion, the Batf3-/- dependent DC1 cells can be further divided into two subsets with different immune functional profiles in vitro and in vivo.

Objectives

The steroid hormone vitamin D has roles in immunomodulation and bone health. Insufficiency is associated with susceptibility to respiratory infections. We report 25-hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors.

Design

Cross-sectional study.

Setting and participants

Plasma was obtained from 295 hospitalised people with COVID-19 (International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)/WHO Clinical Characterization Protocol for Severe Emerging Infections UK study), 93 with influenza A (Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study, during the 2009–2010 H1N1 pandemic) and 139 survivors of non-selected critical illness (prior to the COVID-19 pandemic). Total 25(OH)D was measured by liquid chromatography-tandem mass spectrometry. Free 25(OH)D was measured by ELISA in COVID-19 samples.

Outcome measures

Receipt of invasive mechanical ventilation (IMV) and in-hospital mortality.

Results

Vitamin D insufficiency (total 25(OH)D 25–50 nmol/L) and deficiency (<25 nmol/L) were prevalent in COVID-19 (29.3% and 44.4%, respectively), influenza A (47.3% and 37.6%) and critical illness survivors (30.2% and 56.8%). In COVID-19 and influenza A, total 25(OH)D measured early in illness was lower in patients who received IMV (19.6 vs 31.9 nmol/L (p<0.0001) and 22.9 vs 31.1 nmol/L (p=0.0009), respectively). In COVID-19, biologically active free 25(OH)D correlated with total 25(OH)D and was lower in patients who received IMV, but was not associated with selected circulating inflammatory mediators.

Conclusions

Vitamin D deficiency/insufficiency was present in majority of hospitalised patients with COVID-19 or influenza A and correlated with severity and persisted in critical illness survivors at concentrations expected to disrupt bone metabolism. These findings support early supplementation trials to determine if insufficiency is causal in progression to severe disease, and investigation of longer-term bone health outcomes.

Science Translational Medicine, Ahead of Print.

Objectives

To investigate the association between baseline use of glucose-lowering drugs and serious clinical outcome among patients with type 2 diabetes.

Design

Territory-wide retrospective cohort of confirmed cases of COVID-19 between January 2020 and February 2021.

Setting

All public health facilities in Hong Kong.

Participants

1220 patients with diabetes who were admitted for confirmed COVID-19.

Primary and secondary outcome measures

Composite clinical endpoint of intensive care unit admission, requirement of invasive mechanical ventilation and/or in-hospital death.

Results

In this cohort (median age 65.3 years, 54.3% men), 737 (60.4%) patients were treated with metformin, 385 (31.6%) with sulphonylureas, 199 (16.3%) with dipeptidyl peptidase-4 (DPP-4) inhibitors and 273 (22.4%) with insulin prior to admission. In multivariate Cox regression, use of metformin and DPP-4 inhibitors was associated with reduced incidence of the composite endpoint relative to non-use, with respective HRs of 0.51 (95% CI 0.34 to 0.77, p=0.001) and 0.46 (95% CI 0.29 to 0.71, p<0.001), adjusted for age, sex, diabetes duration, glycated haemoglobin (HbA1c), smoking, comorbidities and drugs. Use of sulphonylureas (HR 1.55, 95% CI 1.07 to 2.24, p=0.022) and insulin (HR 6.34, 95% CI 3.72 to 10.78, p<0.001) were both associated with increased hazards of the composite endpoint.

Conclusions

Users of metformin and DPP-4 inhibitors had fewer adverse outcomes from COVID-19 compared with non-users, whereas insulin and sulphonylurea might predict a worse prognosis.

AbstractMycobacterium abscessus subsp. abscessus is one of the most difficult pathogens to treat and its incidence in disease is increasing. Dual β-lactam combinations act synergistically in vitro but are not widely employed in practice. A recent study shows that a combination of imipenem and ceftaroline significantly lowers the minimum inhibitory concentration of clinical isolates, despite both drugs targeting the same peptidoglycan synthesis enzymes. The underlying mechanism of this effect provides a basis for further investigations of dual β-lactam combinations in the treatment of M. abscessus subsp. abscessus, eventually leading to a clinical trial. Furthermore, dual β-lactam strategies may be explored for other difficult mycobacterial infections.

AbstractBackgroundQuantiFERON enzyme-linked immunosorbent assay (ELISA; Qiagen) with Borrelia burgdorferi peptide antigens was previously shown to reliably detect interferon-γ (IFN-γ) in blood samples from adult patients with early Lyme disease and the response disappeared rapidly after treatment. We evaluated the response before and after appropriate antibiotic therapy in adolescent and adult subjects with more diverse stages of the illness.MethodsBlood was obtained from patients with clinician-identified Lyme disease with constitutional complaints, erythema migrans, nerve palsy, cardiac abnormality, or arthritis before (n = 68) and 6 weeks (n = 46) and 6 months (n = 45) after therapy. The sera were tested for Lyme disease by standard 2-tiered testing (STTT) and anti–C6 antibodies by ELISA and the levels of IFN-γ in the blood samples were detected by QuantiFERON ELISA.ResultsA positive STTT result supported the clinical diagnosis of 37 (54%) subjects and anti-C6 antibodies were detected in 45 (66%) subjects, including 36 (97%) STTT-positive subjects, and the responses often persisted or expanded after antibiotic therapy. IFN-γ was detected in 49 (72%) subjects prior to treatment and the response most often significantly decreased 6 weeks (P = .007) or 6 months (P = .001) after treatment.ConclusionsThe QuantiFERON ELISA reliably detected IFN-γ in blood samples from adult and adolescent patients with varying stages of Lyme disease and the response disappeared rapidly after treatment. Additional studies to more critically evaluate clinical utility as a laboratory test for diagnosis and confirmation of effective therapy are warranted.

Science Translational Medicine, Ahead of Print.

Objectives:

Factors common to socioeconomically disadvantaged neighborhoods, such as low availability of transportation, may limit access to restorative care services for critical illness survivors. Our primary objective was to evaluate whether neighborhood socioeconomic disadvantage was associated with an increased disability burden after critical illness. Our secondary objective was to determine if the effect differed for those discharged to the community compared with those discharged to a facility.

Design:

Longitudinal cohort study with linked Medicare claims data.

Setting:

United States.

Patients:

One hundred ninety-nine older adults, contributing to 239 ICU admissions, who underwent monthly assessments of disability for 12 months following hospital discharge in 13 different functional tasks from 1998 to 2017.

Measurements and Main Results:

Neighborhood disadvantage was assessed using the area deprivation index, a 1–100 ranking evaluating poverty, housing, and employment metrics. Those living in disadvantaged neighborhoods (top quartile of scores) were less likely to self-identify as non-Hispanic White compared with those in more advantaged neighborhoods. In adjusted models, older adults living in disadvantaged neighborhoods had a 9% higher disability burden over the 12 months following ICU discharge compared with those in more advantaged areas (rate ratio, 1.09; 95% Bayesian credible interval, 1.02–1.16). In the secondary analysis adjusting for discharge destination, neighborhood disadvantage was associated with a 14% increase in disability burden over 12 months of follow-up (rate ratio, 1.14; 95% credible interval, 1.07–1.21). Disability burden was 10% higher for those living in disadvantaged neighborhoods and discharged home as compared with those discharged to a facility, but this difference was not statistically significant (interaction rate ratio, 1.10; 95% credible interval, 0.98–1.25).

Conclusions:

Neighborhood socioeconomic disadvantage is associated with a higher disability burden in the 12 months after a critical illness. Future studies should evaluate barriers to functional recovery for ICU survivors living in disadvantaged neighborhoods.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Drs. Falvey and Ferrante made substantial contributions to the conception or design of the work, and drafted the work. All authors contributed to acquisition, analysis, or interpretation of data for the work; critical revision for important intellectual content; final approval of version to be published; and agreement to be accountable for all aspects of the work.

Supported, in part, by a grant from the National Institute on Aging (R01AG17560).

Dr. Falvey received grant support from a Foundation for Physical Therapy Research Pipeline to Health Services Research Grant, a National Institute on Aging (NIA) training grant T32AG019134, and from the University of Maryland Claude D. Pepper Older Americans Independence Center (P30AG028747). Dr. Murphy is supported by the Yale Claude D. Pepper Older Americans Independence Center (P30AG021342). Dr. Ferrante is supported by a Paul B. Beeson Emerging Leaders Career Development Award in Aging from the NIA (K76AG057023) and the Yale Claude D. Pepper Older Americans Independence Center (P30AG021342). Each author certifies that he or she has no commercial associations (e.g., consultancies, stock ownership, equity interest, and patent/licensing arrangements) that might pose a conflict of interest in connection with the submitted article. Dr. Falvey’s institution received support for article research from the Foundation for Physical Therapy Research. Drs. Falvey’s, Murphy’s, Gill’s, and Ferrante’s institutions received funding from the National Institutes on Aging (NIA). Drs. Falvey, Murphy, Gill, and Ferrante received support for article research from the National Institutes of Health. Dr. Leo-Summers received support for article research from the NIA.

This work was completed at Yale School of Medicine, New Haven, CT.

For information regarding this article, E-mail: jfalvey@som.umaryland.edu

Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract

Background

Transgender and gender diverse individuals often face structural barriers to health care because of their gender minority status. The aim of this study was to examine the association between gender minority stress and access to specific health care services among transgender women and transfeminine people in China.

Methods

This multicenter cross-sectional study recruited participants between January 1st and June 30th 2020. Eligible participants were 18 years or older, assigned male at birth, not currently identifying as male, and living in China. Gender minority stress was measured using 45 items adapted from validated subscales. We examined access to health care services and interventions relevant to transgender and gender diverse people, including gender affirming interventions (hormones, surgeries), human immunodeficiency virus (HIV) and sexually transmitted infections (STIs) testing, pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP). Multivariable regression was used to measure correlations between gender minority stress and access to health care service.

Results

Three hundred and twenty-four people completed a survey and data from 277 (85.5%) people were analyzed. The mean age was 29 years old (standard deviation [SD] = 8). Participants used hormones (118/277, 42.6%), gender affirming surgery (26/277, 9.4%), HIV testing (220/277, 79.4%), STI testing (132/277, 47.7%), PrEP (24/276, 8.7%), and PEP (29/267, 10.9%). Using gender affirming hormones was associated with higher levels of discrimination (adjusted odds ratio [aOR] 1.41, 95% confidence interval [CI] 1.17–1.70) and internalized transphobia (aOR 1.06, 95%CI 1.00–1.12). STI testing was associated with lower levels of internalized transphobia (aOR 0.91, 95%CI 0.84–0.98).

Conclusions

Our data suggest that gender minority stress is closely related to using health services. Stigma reduction interventions and gender-affirming medical support are needed to improve transgender health.

Abstract

Background

Transgender and gender diverse individuals often face structural barriers to health care because of their gender minority status. The aim of this study was to examine the association between gender minority stress and access to specific health care services among transgender women and transfeminine people in China.

Methods

This multicenter cross-sectional study recruited participants between January 1st and June 30th 2020. Eligible participants were 18 years or older, assigned male at birth, not currently identifying as male, and living in China. Gender minority stress was measured using 45 items adapted from validated subscales. We examined access to health care services and interventions relevant to transgender and gender diverse people, including gender affirming interventions (hormones, surgeries), human immunodeficiency virus (HIV) and sexually transmitted infections (STIs) testing, pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP). Multivariable regression was used to measure correlations between gender minority stress and access to health care service.

Results

Three hundred and twenty-four people completed a survey and data from 277 (85.5%) people were analyzed. The mean age was 29 years old (standard deviation [SD] = 8). Participants used hormones (118/277, 42.6%), gender affirming surgery (26/277, 9.4%), HIV testing (220/277, 79.4%), STI testing (132/277, 47.7%), PrEP (24/276, 8.7%), and PEP (29/267, 10.9%). Using gender affirming hormones was associated with higher levels of discrimination (adjusted odds ratio [aOR] 1.41, 95% confidence interval [CI] 1.17–1.70) and internalized transphobia (aOR 1.06, 95%CI 1.00–1.12). STI testing was associated with lower levels of internalized transphobia (aOR 0.91, 95%CI 0.84–0.98).

Conclusions

Our data suggest that gender minority stress is closely related to using health services. Stigma reduction interventions and gender-affirming medical support are needed to improve transgender health.

Antimicrobial Agents and Chemotherapy, <a href="https://journals.asm.org/toc/aac/0/ja">Volume 0, Issue ja</a>, -Not available-.

by Tuvshinzaya Zorigt, Yoshikazu Furuta, Manyando Simbotwe, Akihiro Ochi, Mai Tsujinouchi, Misheck Shawa, Tomoko Shimizu, Norikazu Isoda, Jargalsaikhan Enkhtuya, Hideaki Higashi

Anthrax is a zoonotic disease caused by the gram-positive spore-forming bacterium Bacillus anthracis. Detecting naturally acquired antibodies against anthrax sublethal exposure in animals is essential for anthrax surveillance and effective control measures. Serological assays based on protective antigen (PA) of B. anthracis are mainly used for anthrax surveillance and vaccine evaluation. Although the assay is reliable, it is challenging to distinguish the naturally acquired antibodies from vaccine-induced immunity in animals because PA is cross-reactive to both antibodies. Although additional data on the vaccination history of animals could bypass this problem, such data are not readily accessible in many cases. In this study, we established a new enzyme-linked immunosorbent assay (ELISA) specific to antibodies against capsule biosynthesis protein CapA antigen of B. anthracis, which is non-cross-reactive to vaccine-induced antibodies in horses. Using in silico analyses, we screened coding sequences encoded on pXO2 plasmid, which is absent in the veterinary vaccine strain Sterne 34F2 but present in virulent strains of B. anthracis. Among the 8 selected antigen candidates, capsule biosynthesis protein CapA (GBAA_RS28240) and peptide ABC transporter substrate-binding protein (GBAA_RS28340) were detected by antibodies in infected horse sera. Of these, CapA has not yet been identified as immunoreactive in other studies to the best of our knowledge. Considering the protein solubility and specificity of B. anthracis, we prepared the C-terminus region of CapA, named CapA322, and developed CapA322-ELISA based on a horse model. Comparative analysis of the CapA322-ELISA and PAD1-ELISA (ELISA uses domain one of the PA) showed that CapA322-ELISA could detect anti-CapA antibodies in sera from infected horses but was non-reactive to sera from vaccinated horses. The CapA322-ELISA could contribute to the anthrax surveillance in endemic areas, and two immunoreactive proteins identified in this study could be additives to the improvement of current or future vaccine development.

Plant pathogens and parasites use multiple virulence factors to successfully infect plants. While most plant–pathogen interaction studies focus on pathogen effectors and their functions in suppressing plant immunity or interfering with normal cellular processes, other virulence factors likely also contribute. Here we highlight another important strategy used by pathogens to promote virulence: secretion of mimics of host molecules, including peptides, phytohormones, and small RNAs, which play diverse roles in plant development and stress responses.

AbstractTests for visceral leishmaniasis (VL) are not uniformly effective for all endemic regions. In a serological assay, a novel antigen, otubain cysteine peptidase, compared with rK39, showed comparable sensitivity with Indian VL serum samples and prominently increased sensitivity with Brazilian samples, as well as improved monitoring of the treatment response.

AbstractBackgroundThe efficacy of voluntary male medical circumcision (VMMC) for human immunodeficiency virus (HIV) prevention in men was demonstrated in 3 randomized trials. This led to the adoption of VMMC as an integral component of the United States President’s Emergency Plan for AIDS Relief (PEPFAR) combination HIV prevention program in sub-Saharan Africa. However, evidence on the individual-level effectiveness of VMMC programs in real-world, programmatic settings is limited.MethodsA cohort of initially uncircumcised, non-Muslim, HIV-uninfected men in the Rakai Community Cohort Study in Uganda was followed between 2009 and 2016 during VMMC scale-up. Self-reported VMMC status was collected and HIV tests performed at surveys conducted every 18 months. Multivariable Poisson regression was used to estimate the incidence rate ratio (IRR) of HIV acquisition in newly circumcised vs uncircumcised men.ResultsA total of 3916 non-Muslim men were followed for 17 088 person-years (PY). There were 1338 newly reported VMMCs (9.8/100 PY). Over the study period, the median age of men adopting VMMC declined from 28 years (interquartile range [IQR], 21–35 years) to 22 years (IQR, 18–29 years) (P for trend < .001). HIV incidence was 0.40/100 PY (20/4992.8 PY) among newly circumcised men and 0.98/100 PY (118/12 095.1 PY) among uncircumcised men with an adjusted IRR of 0.47 (95% confidence interval, .28–.78). The effectiveness of VMMC was sustained with increasing time from surgery and was similar across age groups and calendar time.ConclusionsVMMC programs are highly effective in preventing HIV acquisition in men. The observed effectiveness is consistent with efficacy in clinical trials and supports current recommendations that VMMC is a key component of programs to reduce HIV incidence.

Abstract

Background

Cytomegalovirus (CMV) reactivation is associated with adverse prognoses of critically ill patients. However, the epidemiology and predictors of CMV reactivation in immunocompetent patients receiving mechanical ventilation (MV) are not clear. The aim of this study was to investigate the epidemiology and predictors of CMV reactivation in immunocompetent patients requiring MV.

Methods

A single-center, prospective observational study (conducted from June 30, 2017 to July 01, 2018) with a follow-up of 90 days (September 29, 2018) that included 71 CMV-seropositive immunocompetent patients with MV at a 37-bed university hospital general intensive care unit (ICU) in China. Routine detection of CMV DNAemia was performed once a week for 28 days (Days 1, 7, 14, 21, and 28). CMV serology, laboratory findings, and clinical data were obtained during hospitalization.

Results

Among 71 patients, 13 (18.3%) showed CMV reactivation within 28 days in the ICU. The median time to reactivation was 7 days. CMV reactivation was related to various factors, including body mass index (BMI), sepsis, N-terminal pro-b-type natriuretic peptide (NT-proBNP), blood urea nitrogen (BUN), and hemoglobin (Hb) levels (P < 0.05). In the multivariate regression model, BMI, Hb level, and sepsis were independently associated with CMV reactivation patients (P < 0.05). Moreover, the area under the receiver operating characteristic (AUROC) of BMI, Hb, and BMI combined with Hb was 0.69, 0.70, and 0.76, respectively. The duration of MV, hospitalization expense, length of ICU stay, and 90 day all-cause mortality rate in patients with CMV reactivation was significantly higher than in those without CMV reactivation (P < 0.05).

Conclusions

Among immunocompetent patients with MV, the incidence of CMV reactivation was 18.3%. CMV reactivation was associated with several adverse prognoses. BMI, Hb, and sepsis were independent risk factors for CMV reactivation. BMI and Hb may predict CMV reactivation.

Abstract

Background

Cytomegalovirus (CMV) reactivation is associated with adverse prognoses of critically ill patients. However, the epidemiology and predictors of CMV reactivation in immunocompetent patients receiving mechanical ventilation (MV) are not clear. The aim of this study was to investigate the epidemiology and predictors of CMV reactivation in immunocompetent patients requiring MV.

Methods

A single-center, prospective observational study (conducted from June 30, 2017 to July 01, 2018) with a follow-up of 90 days (September 29, 2018) that included 71 CMV-seropositive immunocompetent patients with MV at a 37-bed university hospital general intensive care unit (ICU) in China. Routine detection of CMV DNAemia was performed once a week for 28 days (Days 1, 7, 14, 21, and 28). CMV serology, laboratory findings, and clinical data were obtained during hospitalization.

Results

Among 71 patients, 13 (18.3%) showed CMV reactivation within 28 days in the ICU. The median time to reactivation was 7 days. CMV reactivation was related to various factors, including body mass index (BMI), sepsis, N-terminal pro-b-type natriuretic peptide (NT-proBNP), blood urea nitrogen (BUN), and hemoglobin (Hb) levels (P < 0.05). In the multivariate regression model, BMI, Hb level, and sepsis were independently associated with CMV reactivation patients (P < 0.05). Moreover, the area under the receiver operating characteristic (AUROC) of BMI, Hb, and BMI combined with Hb was 0.69, 0.70, and 0.76, respectively. The duration of MV, hospitalization expense, length of ICU stay, and 90 day all-cause mortality rate in patients with CMV reactivation was significantly higher than in those without CMV reactivation (P < 0.05).

Conclusions

Among immunocompetent patients with MV, the incidence of CMV reactivation was 18.3%. CMV reactivation was associated with several adverse prognoses. BMI, Hb, and sepsis were independent risk factors for CMV reactivation. BMI and Hb may predict CMV reactivation.

John Nkengasong, head of Africa CDC, is to be nominated to head PEPFAR, the US Government's global HIV/AIDS response programme. Paul Adepoju reports.

by Sara M. Mangsbo, Sebastian Havervall, Ida Laurén, Robin Lindsay, August Jernbom Falk, Ulrika Marking, Martin Lord, Marcus Buggert, Pierre Dönnes, Gustaf Christoffersson, Peter Nilsson, Sophia Hober, Mia Phillipson, Jonas Klingström, Charlotte Thålin

Numerous assays evaluating serological and cellular responses have been developed to characterize immune responses against SARS-CoV-2. Serological assays are both cost- and time-effective compared to cellular assays, but cellular immune responses may provide a diagnostic value to determine previous SARS-CoV-2 infection in seronegative individuals. However, potential cross-reactive T cell responses stemming from prior encounters with human coronaviruses (HCoVs) may affect assay specificity. In this study, we evaluated the specificity and sensitivity of a SARS-CoV-2 IFN-γ Release Assay (IGRA) based on the FluoroSpot method employing commercially available SARS-CoV-2-specific peptide pools, as well as an in-house designed SARS-CoV-2 peptide pool restricted to 5 amino acid stretches or less aligning with endemic HCoVs. Blood samples were obtained from healthcare workers (HCW) 5–6 months post SARS-CoV-2 spike (S) IgG and nucleocapsid (N) IgG dual seroconversion (n = 187) and HCW who had been S IgG and N IgG dual seronegative at repeated occasions, including the current sampling time point (n = 102). In addition, samples were obtained 4 to 5 months post infection from 55 polymerase chain reaction (PCR)-confirmed COVID-19 patients. Assay specificity and sensitivity were calculated with serology as a reference standard for HCW. The in-house generated peptide pool displayed a specificity of 96.1%, while the commercially available peptide pools displayed specificities of 80.4% and 85.3%, respectively. Sensitivity was higher in a cohort of previously hospitalized COVID-19 patients (96.4% and 84.0% for the commercially available peptide pools and 92.7% for the in-house generated peptide pool) compared to the HCW cohort (92.0% and 66.8% for the commercially available peptide pools and 76.0% for the in-house generated peptide pool). Based on these findings, the individual diagnostic value of T cell immune responses against SARS-CoV-2 currently appears to be limited but remain an important research tool ahead.

Science, Ahead of Print.