Infectious Diseases Ethics: A Worldwide Survey.

OBJECTIVES: COVID-19 unravelled new ethical issues in the neglected field of infectious diseases ethics (IDE). We investigated IDE involvement among ID professionals. METHODS: A global survey was disseminated during 2021-2022. Responses were stratified by demographics, WHO region, income, and ethics training. A confirmatory factor analysis (CFA) was used to identify two themes representing IDE relevant areas (Theme 1, including stigma, inequity, vulnerability, public health, and global impact) and emerging topics (Theme 2, including inequity and research integrity in COVID-19, increased ethics interest, and gaps in IDE). Quantile and logistic regression analyses investigated determinants of ethics themes and responders' ethics attitude. RESULTS: We included 477 participants from 71 countries. Most were females (282/460, 61%) and clinicians (327/457, 72%). Participants advocated further personal (289/443, 65%) or societies' (374/450, 83%) involvement in bioethics. Only 5% (22/477) of respondents claimed to have received enough bioethics training and 28% (114/412) were dissatisfied with it. Dedicated courses or expert case discussion were the preferred ways for receiving education in bioethics. Theme 1 and 2 median values were above 7 (on a 1-10 scale), showing high interest in IDE. CFA showed optimal and acceptable fit, respectively. Being from the region of Americas was associated with Theme 1, while having received bioethics training was associated with both themes. Females, respondents trained in bioethics, and those from the Americas and Europe regions reported lower involvement in bioethics activities, while those aged between 44-54 years and trained in bioethics were more involved. Age above 55 years and non-clinical role were negatively associated with aspiration for further bioethics involvement. CONCLUSIONS: We identified IDE themes that can inform on gaps in bioethics. Ethics training was associated with interest in IDE and bioethics activities and should be offered to integrate this discipline into daily clinical practice across age, gender, and different areas worldwide.

Chemosensory assessment and impact on quality of life in neurosensorial cluster of the post COVID 19 syndrome.

COVID-19 pandemic brought chemosensory impairment to the forefront of medicine, revealing gaps in the knowledge of pathophysiological mechanisms, true prevalence and preventive/therapeutic alternatives. This is a sub-study of the ORCHESTRA cohort focusing on post-COVID-19 chemosensory symptoms. Risk factors for neurosensorial cluster of post-COVID-19 syndrome (NSc-PCS) were assessed through multivariable analysis. Psychophysical validated tests were applied on a sub-population of 50 patients. Qualitative chemosensory symptoms as well as nasal and oral chemesthesis were evaluated through anamnestic interview and the quality of life through the SF-36 questionnaire. Chemosensory symptoms evolution and olfactory training's outcome were assessed through phone-call interviews. Out of 1187 patients (female, N = 630), 550 (47%) presented NSc-PCS, with a lower risk for older age and monoclonal antibodies treatment, and a higher risk in females (p < 0.001). Out of the 50 patients evaluated with psychophysical tests, 66% showed smell reduction with a qualitative alteration in 50% of hyposmic and 35% of normosmic patients. Hypogeusia was present in 14 (28%) of the patients assessed, with 56% showing a qualitative alteration; 53% of normogeusic patients presented qualitative disorders. NSc-PCS has a complex, fluctuating, multifaceted presentation. Quantifying and characterizing COVID-19-related chemosensory impairment is key to understand underlying mechanisms and to develop preventive and therapeutic treatment.

Pooled analysis of the MANTICO2 and MONET randomized controlled trials comparing drug efficacy for early treatment of COVID-19 during Omicron waves.

BACKGROUND: The clinical effectiveness of early therapies for mild-to-moderate COVID-19, comparing antivirals and monoclonal antibodies (mAbs) during the Omicron era, has not been conclusively assessed through a post-approval comparative trial. We present a pooled analysis of two randomized clinical trials conducted during Omicron waves. METHODS: The MANTICO2/MONET trial is a pooled analysis of two multicentric, independent, phase-4, three-arm, superiority, randomized, open-label trials. Nonhospitalized patients with early mild-to-moderate COVID-19 (≤5 days after symptoms' onset) and at least one risk factor for disease progression were randomized 1:1:1 to receive 500 mg of intravenous sotrovimab (SOT) or 600 mg of intramuscular tixagevimab/cilgavimab (TGM/CGM) or oral 5-days course of nirmatrelvir/ritonavir (NMV/r) 300/100 mg BID. Primary outcome was COVID-19-related hospitalization or death within 29 days after randomization. Fisher's exact test for pooled data and incidence of failure was reported as overall and by arm with respective 95% CI. Pairwise comparisons across the arms were conducted using unadjusted exact logistic regression. An analysis by means of a doubly robust marginal model using augmented inverse probability weighting (AIPW) was also conducted to estimate the potential outcomes (Pom) in each treatment group and their difference by the average treatment effect (ATE). Analysis of symptom persistence within 30 days after randomization was performed using a 2-level hierarchical mixed-effects logistic model with a random intercept at the patient's level. Point estimates and 95% confidence intervals were adjusted for age and sex and calculated using ANOVA-like methods for the mixed effects logistic model. These trials are registered with the European Clinical Trials Database, EudraCT2021-002612-31 (MANTICO2) and EudraCT2021-004188-28 (MONET) and ClinicalTrials.gov, NCT05321394 (MANTICO2). FINDINGS: Between March 2022 and February 2023, 991 patients (SOT = 332, TGM/CGM = 327, NMV/r = 332) were enrolled in 15 Italian centers. The overall mean age was 66 years; 482 participants (48.80%) were male, and 856 were vaccinated with at least a primary course (86%). Among the 8/991 hospitalizations observed, one resulted in death. The overall estimate of failure was 0.81% (95%CI; 0.35-1.58%). The odds ratio (OR) for the primary outcome in the NMV/r arm compared to the TGM/CGM and SOT arms was 8.41 (95% CI 1.21 to infinity; p = 0.015) and 2.42 (95% CI 0.19 to infinity; p = 0.499), respectively. No significant difference was observed between SOT and TGM/CGM (OR 0.32; 95% CI 0.032-1.83; p = 0.174). Results were similar when we applied the marginal weighted model accounting for potential residual confounding bias. There was no evidence for a difference in the prevalence of symptoms between treatment groups, except for cough, which was higher in the SOT group compared to the other two groups at the 21-day follow-up (P = 0.039) and a higher prevalence of nausea at the 7-day follow-up in the NMV/r group compared to the mAbs group (p = 0.036). INTERPRETATION: NMV/r was superior to TGM/CGM in reducing hospital admission or death in clinically vulnerable patients with SARS-CoV-2 infection treated within 5 days of symptoms' onset. No significant difference in symptom prevalence over time across the arms was found.

The gut microbiota as an early predictor of COVID-19 severity.

Several studies reported alterations of the human gut microbiota (GM) during COVID-19. To evaluate the potential role of the GM as an early predictor of COVID-19 at disease onset, we analyzed gut microbial samples of 315 COVID-19 patients that differed in disease severity. We observed significant variations in microbial diversity and composition associated with increasing disease severity, as the reduction of short-chain fatty acid producers such as Faecalibacterium and Ruminococcus, and the growth of pathobionts as Anaerococcus and Campylobacter. Notably, we developed a multi-class machine-learning classifier, specifically a convolutional neural network, which achieved an 81.5% accuracy rate in predicting COVID-19 severity based on GM composition at disease onset. This achievement highlights its potential as a valuable early biomarker during the first week of infection. These findings offer promising insights into the intricate relationship between GM and COVID-19, providing a potential tool for optimizing patient triage and streamlining healthcare during the pandemic.IMPORTANCEEfficient patient triage for COVID-19 is vital to manage healthcare resources effectively. This study underscores the potential of gut microbiota (GM) composition as an early biomarker for COVID-19 severity. By analyzing GM samples from 315 patients, significant correlations between microbial diversity and disease severity were observed. Notably, a convolutional neural network classifier was developed, achieving an 81.5% accuracy in predicting disease severity based on GM composition at disease onset. These findings suggest that GM profiling could enhance early triage processes, offering a novel approach to optimizing patient management during the pandemic.

A Digital Approach to Improve Infection Screening Among Solid Organ Transplant Candidates.

BACKGROUND: Pretransplant infection screening (IS) of potential organ recipients is essential to optimal outcome of solid organ transplantation (SOT). METHODS: A pre-post study was performed during 2020-2023 to investigate the impact of the STREAM (Solid organ TRansplant stEwArdship and Multidisciplinary approach) intervention to improve IS in SOT. The intervention, performed in 2022, included the implementation of IS through educational meetings, local guidelines, and the availability of a digital screening tool. The objective of the study was the assessment of IS completion, including a list of 17 laboratory tests and the investigation of vaccination status. The reduction of unnecessary tests was also analyzed. The test of proportions and a multilevel multivariate Poisson regression model were used to compare IS completion before and after STREAM. infectious diseases (ID) consultation and urgent evaluation were investigated as predictors of IS completion. RESULTS: A total of 171 patients were enrolled, including liver (44%), heart (32%), and kidney (24%) transplant candidates. Mean age was 56 ± 11 years, and most patients (77%) were males. Ninety-five (56%) patients were included before the intervention and 76 (44%) after STREAM. IS completion increased after STREAM (IRR 1.41, p < 0.001) with significant improvement recorded for seven (39%) IS items. Unnecessary tests decreased by 43% after the intervention. ID consultation (IRR 1.13, p = 0.02) and urgent evaluation (p = 0.68, p < 0.001) were predictors of IS improvement. CONCLUSIONS: STREAM was successful in improving IS completion. Further research is needed to investigate the impact of this intervention on posttransplant infections.

Interleukin-2-mediated CD4 T-cell activation correlates highly with effective serological and T-cell responses to SARS-CoV-2 vaccination in people living with HIV.

People living with HIV (PLWH) despite having an appreciable depletion of CD4+ T-cells show a good severe acute respiratory syndrome coronavirus 2 vaccination response. The underlying mechanism(s) are currently not understood. We studied serological and polyfunctional T-cell responses in PLWH receiving anti-retroviral therapy stratified on CD4+ counts as PLWH-high (CD4 ≥ 500 cells/mm3) and PLWH-low (<500 cells/mm3). Responses were assessed longitudinally before the first vaccination (T0), 1-month after the first dose (T1), 3-months (T2), and 6-months (T3) after the second dose. Expectedly, both PLWH-high and -low groups developed similar serological responses after T2, which were also non-significantly different from age and vaccination-matched HIV-negative controls at T3. The immunoglobulin G titers were also protective showing a good correlation with angiotensin-converting enzyme 2-neutralizations (R = 0.628, p = 0.005). While surface and intracellular activation analysis showed no significant difference at T3 between PLWH and controls in activated CD4+CD154+ and CD4+ memory T-cells, spike-specific CD4+ polyfunctional cytokine expression analysis showed that PLWH preferentially express interleukin (IL)-2 (p < 0.001) and controls, interferon-γ (p = 0.017). CD4+ T-cell counts negatively correlated with IL-2-expressing CD4+ T-cells including CD4+ memory T-cells (Spearman ρ: -0.85 and -0.80, respectively; p < 0.001). Our results suggest that the durable serological and CD4+ T-cell responses developing in vaccinated PLWH are associated with IL-2-mediated CD4+ T-cell activation that likely compensates for CD4+ T-cell depletion in PLWH.

Clinic-based evaluation of point-of-care dual HIV/syphilis rapid diagnostic tests at primary healthcare antenatal facilities in South Africa and Zambia.

BACKGROUND: Southern African countries have the largest global burden of HIV and syphilis, with a high prevalence among women of reproductive age. Although antenatal screening is standard of care, syphilis screening has generally lagged behind HIV screening. We aimed to evaluate the performance and operational characteristics of two commercial dual HIV/syphilis point-of-care tests (POCTs) for simultaneous maternal HIV/syphilis screening. METHODS: A clinic-based evaluation of dual HIV/syphilis POCTs (SD Bioline and Chembio) was conducted at five primary healthcare centres (PHCs) in South Africa and Zambia. POCT results using capillary fingerprick blood were compared to reference laboratory syphilis and HIV serological assays. RESULTS: Three thousand four hundred twelve consenting pregnant women aged ≥ 18 years were enrolled. The prevalence of treponemal antibody seropositivity and HIV infection ranged from 3.7 to 9.9% (n = 253) and 17.8 to 21.3% (n = 643), respectively. Pooled sensitivity for syphilis compared to the reference assay was 66.0% (95%CI 57.7-73.4) with SD Bioline and 67.9% (95%CI 58.2-76.3) with Chembio. Pooled specificity for syphilis was above 98% with both POCTs. The sensitivities of SD Bioline and Chembio assays were 78.0% (95%CI 68.6-85.7) and 81.0% (95%CI 71.9-88.2), respectively compared to an active syphilis case definition of treponemal test positive with a rapid plasma reagin titre of ≥ 8. The negative predictive values (NPVs) based on various prevalence estimates for syphilis with both assays ranged from 97 to 99%. The pooled sensitivity for HIV was 92.1% (95%CI 89.4-94.2) with SD Bioline; and 91.5% (95%CI 88.2-93.9) with Chembio. The pooled specificities for HIV were 97.2% (95%CI 94.8-98.5) with SD Bioline and 96.7% (95%CI 95.1-97.8) with Chembio. The NPV based on various prevalence estimates for HIV with both assays was approximately 98%. Most participating women (91%) preferred dual POCTs over two single POCTs for HIV and syphilis, and healthcare providers gave favourable feedback on the utility of both assays at PHC level. CONCLUSIONS: Based on the need to improve antenatal screening coverage for syphilis, dual HIV/syphilis POCTs could be effectively incorporated into antenatal testing algorithms to enhance efforts towards elimination of mother-to-child transmission of these infections.

Standardised protocol for a prospective international multicentre clinical-based evaluation of point-of-care tests for the screening of genital and extragenital chlamydial and gonococcal infections in men who have sex with men and for the screening of genital chlamydial, gonococcal and Trichomonas vaginalis infections in at risk women.

INTRODUCTION: In 2016, WHO estimated there were roughly 374 million new infections among adults of the following four curable sexually transmitted infections (STIs): chlamydia (caused by Chlamydia trachomatis (CT)), gonorrhoea (Neisseria gonorrhoeae (NG)), syphilis (Treponema pallidum) and trichomoniasis (Trichomonas vaginalis (TV)). Accurate point-of-care tests (POCTs) for screening of genital and extragenital CT, NG and TV infections are of great value and have been developed during recent decade. Several tests are commercially available and have shown encouraging performance compared with 'gold-standard' reference tests in laboratory-based studies. However, there is limited data on their clinical performance, including at the POC. Key populations, such as men who have sex with men (MSM), are at higher risk of these STIs at genital and extragenital sites and these STIs are often asymptomatic, especially in extragenital sites and in women. We will conduct a clinical-based evaluation to assess the performance characteristics and acceptability to end-users of molecular-based diagnostic technology for POC/near patient use of the Xpert CT/NG (Cepheid, Sunnyvale, California, USA) test for screening of genital, anorectal and pharyngeal CT and NG infections in MSM and the Xpert CT/NG and Xpert TV (Cepheid, Sunnyvale, California, USA) for screening of genital CT, NG and TV among women at risk for these STIs compared with gold-standard reference nucleic acid amplification tests. This master protocol outlines the overall research approach that will be used in seven countries. METHOD AND ANALYSES: Consecutive MSM and women at risk presenting at the clinical sites in high, and low- and middle-income countries will be enrolled. The POCTs to be evaluated are Xpert CT/NG and Xpert TV. All procedures will be carried out by trained healthcare staff and tests performed in strict accordance with the manufacturer's instructions. The sensitivity, specificity, positive and negative predictive values for each POCT will be calculated. The study is ongoing with recruitment expected to be completed in all countries by mid-2022 to late-2022. ETHICS AND DISSEMINATION: Prior to enrolment, this core protocol was independently peer-reviewed and approved by the research project review panel (RP2) of the WHO Department of Sexual and Reproductive Health and Research and by the WHO Ethics Review Committee (ERC). The core protocol has been slightly adapted accordingly to individual countries and adaptations approved by both RP2 and ERC, as well as all relevant institutional review boards at each participating site. Results will be disseminated through peer-reviewed journals and presented at relevant national/international conferences.

Sexual satisfaction, an indicator of sexual health and well-being? Insights from STI/HIV prevention research in European men who have sex with men.

INTRODUCTION: Although sexual health has been holistically defined to include sexual satisfaction, it has been largely absent in health services and sexual and reproductive health and rights programmes in many parts of the world. We propose sexual satisfaction as a useful indicator, as one of the proxy measures for sexual health and well-being and as a component of well-being in general. METHODS: The Sialon II project is a multicentre biological and behavioural cross-sectional community-based survey implemented across 13 European cities during 2013-2014 among men who have sex with men. Sexual satisfaction was explored using one single item: 'How satisfied are you with your sex life?' A multivariable multilevel logistic random-intercept model was estimated to identify factors associated with reporting positive sexual satisfaction versus negative sexual satisfaction. RESULTS: Age, the number of partners and self-reported HIV status were not significantly associated with sexual satisfaction in the multivariate model. Participants reporting an insertive role or reported both an insertive and receptive role during the last anal intercourse were more likely to be sexually satisfied, compared with a receptive role. Participants reporting anal intercourse with a condom were more likely to be satisfied than those declaring no anal intercourse in the last 6 months, but no significant association was found compared with anal intercourse without condom. Knowledge of HIV-serostatus concordance with the last sexual partner was positively correlated with sexual satisfaction. Having had sexual intercourse with non-steady partners only in the last 6 months was negatively correlated. The more positive participants perceived their work/school, parents and friends/acquaintances' attitudes towards gay or bisexual persons, the higher the odds they were satisfied with their sexual life. CONCLUSION: Using a single item on sexual satisfaction in a bio-behavioural study, our analysis has shown that it is associated with individual, interpersonal and social/structural factors and has proven its usefulness as a sexual health indicator among men who have sex with men.

Outcomes of younger patients with mantle cell lymphoma experiencing late relapse (>24 months): the LATE-POD study.

ABSTRACT: Patients with mantle cell lymphoma (MCL) who experience first relapse/refractoriness can be categorized into early or late progression-of-disease (POD) groups, with a threshold of 24 months from MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are the established standard treatment at first relapse, but their effectiveness compared with chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes among patients at first, late POD beyond 24 months. The primary objective was progression-free survival from the time of second-line therapy (PFS-2) of BTKi vs CIT. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 years (range, 19-70), and 77% were male. Median follow-up from the time of second-line therapy was 53 months (range, 12-144). Overall, 114 patients had second-line BTKi, whereas 271 had CIT, consisting of rituximab-bendamustine (R-B; n = 101), R-B and cytarabine (R-BAC; n = 70), or other regimens (mostly cyclophosphamide-hydroxydaunorubicin-vincristine-prednisone]- or platinum-based; n = 100). The 2 groups were balanced in clinicopathological features and median time to first relapse. Overall, BTKi was associated with significantly prolonged median PFS-2 than CIT (not reached [NR] vs 26 months, respectively; P = .0003) and overall survival (NR and 56 months, respectively; P = .03). Multivariate analyses showed that BTKi was associated with lower risk of death than R-B and other regimens (hazard ratio, 0.41 for R-B and 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in patients with BTKi-naïve MCL.

A Scalable Pseudonymization Tool for Rapid Deployment in Large Biomedical Research Networks: Development and Evaluation Study.

Background: The SARS-CoV-2 pandemic has demonstrated once again that rapid collaborative research is essential for the future of biomedicine. Large research networks are needed to collect, share, and reuse data and biosamples to generate collaborative evidence. However, setting up such networks is often complex and time-consuming, as common tools and policies are needed to ensure interoperability and the required flows of data and samples, especially for handling personal data and the associated data protection issues. In biomedical research, pseudonymization detaches directly identifying details from biomedical data and biosamples and connects them using secure identifiers, the so-called pseudonyms. This protects privacy by design but allows the necessary linkage and reidentification. Objective: Although pseudonymization is used in almost every biomedical study, there are currently no pseudonymization tools that can be rapidly deployed across many institutions. Moreover, using centralized services is often not possible, for example, when data are reused and consent for this type of data processing is lacking. We present the ORCHESTRA Pseudonymization Tool (OPT), developed under the umbrella of the ORCHESTRA consortium, which faced exactly these challenges when it came to rapidly establishing a large-scale research network in the context of the rapid pandemic response in Europe. Methods: To overcome challenges caused by the heterogeneity of IT infrastructures across institutions, the OPT was developed based on programmable runtime environments available at practically every institution: office suites. The software is highly configurable and provides many features, from subject and biosample registration to record linkage and the printing of machine-readable codes for labeling biosample tubes. Special care has been taken to ensure that the algorithms implemented are efficient so that the OPT can be used to pseudonymize large data sets, which we demonstrate through a comprehensive evaluation. Results: The OPT is available for Microsoft Office and LibreOffice, so it can be deployed on Windows, Linux, and MacOS. It provides multiuser support and is configurable to meet the needs of different types of research projects. Within the ORCHESTRA research network, the OPT has been successfully deployed at 13 institutions in 11 countries in Europe and beyond. As of June 2023, the software manages data about more than 30,000 subjects and 15,000 biosamples. Over 10,000 labels have been printed. The results of our experimental evaluation show that the OPT offers practical response times for all major functionalities, pseudonymizing 100,000 subjects in 10 seconds using Microsoft Excel and in 54 seconds using LibreOffice. Conclusions: Innovative solutions are needed to make the process of establishing large research networks more efficient. The OPT, which leverages the runtime environment of common office suites, can be used to rapidly deploy pseudonymization and biosample management capabilities across research networks. The tool is highly configurable and available as open-source software.

Independent clinic-based evaluation of point-of-care testing for the screening of Chlamydia trachomatis, Neisseria gonorrhoea and Trichomonas vaginalis in women-at-risk in Australia, Guatemala, Morocco, and South Africa.

BACKGROUND: In 2018, the World Health Organization commenced a multi-country validation study of the Cepheid GeneXpert for a range of molecular-based point-of-care (POC) tests in primary care settings. One study arm focused on the evaluation of POC tests for screening 'women at risk' for chlamydia (CT), gonorrhoea (NG) and trichomonas (TV) in four countries - Australia, Guatemala, Morocco and South Africa. METHODS: Study participants completed a pre-test questionnaire which included demographics, clinical information and general questions on POC testing (POCT). Two vaginal swab samples (either self-collected or clinician collected) from each patient were tested on the GeneXpert at the POC and at a reference laboratory using quality-assured nucleic acid amplification tests (NAATs). RESULTS: One thousand three hundred and eighty-three women were enrolled: 58.6% from South Africa, 29.2% from Morocco, 6.2% from Guatemala, and 6.0% from Australia. 1296 samples for CT/NG and 1380 samples for TV were tested by the GeneXpert and the reference NAAT. The rate of unsuccessful tests on the GeneXpert was 1.9% for CT, 1.5% for NG and 0.96% for TV. The prevalence of CT, NG and TV was 31%, 13% and 23%, respectively. 1.5% of samples were positive for all three infections; 7.8% were positive for CT and NG; 2.4% were positive for NG and TV; and 7.3% were positive for CT and TV. Compared to reference NAATs, pooled estimates of sensitivity for the GeneXpert tests were 83.7% (95% confidence intervals 69.2-92.1) for CT, 90.5% (85.1-94.1) for NG and 64.7% (58.1-70.7) for TV (although estimates varied considerably between countries). Estimates for specificity were ≥96% for all three tests both within- and between-countries. Pooled positive and negative likelihood ratios were: 32.7 ([CI] 21.2-50.5) and 0.17 (0.08-0.33) for CT; 95.3 (36.9-245.7) and 0.10 (0.06-0.15) for NG; and 56.5 (31.6-101.1) and 0.35 (0.27-0.47) for TV. CONCLUSION: This multi-country evaluation is the first of its kind world-wide. Positive likelihood ratios, as well as specificity estimates, indicate the GeneXpert POC test results for CT, NG and TV were clinically acceptable for ruling in the presence of disease. However, negative likelihood ratios and variable sensitivity estimates from this study were poorer than expected for ruling out these infections, particularly for TV. TRIAL REGISTRATION: Ethics approval to conduct the ProSPeRo study was granted by the WHO Ethics Review Committee, as well as local ethics committees from all participating countries.

A multi-country comparative study of two treponemal tests for the serodiagnosis of syphilis amongst men who have sex with men (MSM): Chemo-luminescent assay vs Treponema pallidum particle agglutination assay.

INTRODUCTION: International guidelines recommend routine screening for syphilis (aetiological agent: Treponema pallidum subspecies pallidum) amongst key populations and vulnerable populations using tests detecting treponemal and non-treponemal antibodies. Whilst treponemal tests have high sensitivities and specificities, they differ regarding subjective or objective interpretation, throughput and workload. Chemiluminescence immunoassays (CLIAs) are cost- and time-effective automated methods for detecting treponemal antibodies. The Treponema pallidum particle agglutination assay (TPPA) has been considered the "gold standard" treponemal assay, however, this includes a highly manual procedure, low throughput and subjective interpretation. The present multi-country study evaluated the ADVIA Centaur® Syphilis CLIA (Siemens Healthcare) assay compared to the reference SERODIA-TP·PA® (Fujirebio Diagnostics) for the serodiagnosis of syphilis amongst men who have sex with men (MSM). METHOD: 1,485 MSM were enrolled in Brighton (UK), Malta, and Verona (Italy) as part of a larger WHO multi-country and multi-site ProSPeRo study. Ethical approval was obtained. Serum was tested with the ADVIA Centaur® Syphilis CLIA assay and SERODIA-TP·PA®, in accordance with the manufacturers' instructions, for a first round of validation. A second round of validation was carried out for discrepant results that were additionally tested with both Western Blot (Westernblot EUROIMMUN®) and an Immunoblot (INNO-LIA, Fujirebio Diagnostics). Sensitivity, specificity, positive and negative predictive value (PPV and NPV), likelihood ratios (positive/negative), and the Diagnostic Odds Ratio (DOR)/pre-post-test probability (Fagan's nomogram) were calculated. RESULTS: Out of 1,485 eligible samples analysed in the first phase, the SERODIA-TP·PA® identified 360 positive and 1,125 negative cases. The ADVIA Centaur® Syphilis CLIA assay (Siemens) identified 366 positives, missclassifying one TPPA-positive sample. In the second phase, the ADVIA Centaur® Syphilis CLIA resulted in 1 false negative and 4 false positive results. Considering the syphilis study prevalence of 24% (95% CI: 22-26.7), The sensitivity of the ADVIA Centaur® Syphilis CLIA assay was 99.7% (95% CI: 98.5-100), and the specificity was 99.4% (95% CI: 98.7-99.7). The ROC area values were 0.996 (95% CI: 0.992-0.999), and both the PPV and NPV values were above 98% (PPV 98.1%, 95% CI: 96.1-99.2; NPV 99.9%, 95% CI: 99.5-100). CONCLUSIONS: The ADVIA Centaur® Syphilis CLIA assay showed similar performance compared to the SERODIA-TP·PA®. Considering the study is based on QUADAS principles and with a homogeneous population, results are also likely to be generalisable to MSM population but potentially not applicable to lower prevalence populations routinely screened for syphilis. The automated CLIA treponemal assay confirmed to be accurate and appropriate for routine initial syphilis screening, i.e. when the reverse testing algorithm is applied.

A clinical utility evaluation of dual HIV/Syphilis point-of-care tests in non-clinical settings for screening for HIV and syphilis in men who have sex with men.

BACKGROUND: Dual point-of-care tests (POCTs) for the simultaneous detection of antibodies to HIV and syphilis have been developed. Since community-based organisations (CBO) are effective providers of HIV and syphilis testing among men who have sex with men (MSM), evaluation of the utility of these dual tests at CBO testing services is a high priority. The aim of this study is to determine the feasibility of performing dual HIV-syphilis POCT testing among both users and providers at these non-clinical sites. METHODS: This evaluation assessed the utility of two lateral flow immunochromatographic antibody technologies for dual screening for HIV/syphilis among MSM seeking testing in four CBO testing services in Spain, Slovenia, Latvia, and Ukraine. The study's conceptual framework divides the concept of feasibility into two inter-related domains, acceptability, and usability and further breaks it down into six subdomains: learnability, willingness, suitability, satisfaction, efficacy, and effectiveness. The feasibility analysis was performed by calculating the median score in 3 stages (for individual questions, subdomains, and domains), using a summated scores method. RESULTS: The final sample included 844 participants, 60 of which were found to be HIV test positive (7.1%) and 61 (7.2%) positive on testing for syphilis. There was a small difference (1.1%) when comparing the results of the two dual POCTs under evaluation to the tests routinely used at each site. The inter-rater agreement showed a high concordance between two independent readings. The analysis of the feasibility for the users of the services indicated good satisfaction, suitability, and willingness. In addition, among 18 providers the total mean score showed good acceptability and usability, good willingness, easy learnability, high suitability, and good efficacy, but lower satisfaction and effectiveness. The operational characteristics of both dual study POCTs were well evaluated by providers. CONCLUSIONS: The introduction of dual HIV and syphilis  POCTs in CBO testing services for screening of MSM is feasible, with a high acceptability and usability both for users and providers. Implementation of dual POCTs for HIV and syphilis in CBO testing services is an opportunity for scaling up integrated HIV/syphilis testing for MSM.

Clinic-based evaluation of the dual Xpert CT/NG assay on the GeneXpert System for screening for extragenital chlamydial and gonococcal infections amongst men who have sex with men.

BACKGROUND: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections have increased globally. Asymptomatic infections represent a significant risk of long-term complications. Men who have sex with men (MSM) are disproportionally affected, underscoring the need to offer screening programmes to this population. CT/NG Point of Care Testing (POCT) constitutes a strategic tool to improve the continuum of STI care, however extensive real-life evaluations amongst at risk populations are lacking. The aim of this study is to estimate the GeneXpert CT/NG assay performance and usability for CT and NG at genital and extragenital sites for screening amongst MSM. METHODS: This study was a multi-site sexual health clinic-based evaluation (Italy, Malta and Peru) with consecutive enrolment. A first void urine sample (divided in two aliquots), two oropharyngeal and two anorectal swabs were collected for each study participant. One specimen set (one for each anatomical site) was tested with the dual index test (Cepheid) at the clinics by the healthcare staff, the other set with FDA/CE approved Nucleic Acid Amplification Tests (NAATs) at the laboratory. Clinical sites and reference laboratories participated in an internal and external quality control programme. Sensitivity, specificity, positive and negative likelihood ratios, positive and negative predictive values for each anatomical site were estimated using a meta-analytic approach. RESULTS: One thousand seven hundred two MSM were recruited across all clinical sites for a total of 5049 biological specimens. NG and CT were respectively detected in 274 and 287 of samples. Overall, the NG POCT sensitivity and specificity was 91.43% and 99.75% in urine (LR + 372.80, LR- 0.09), 89.68% and 99.55% in rectal specimens (LR + 197.30, LR- 0.10) and 75.87% and 98.77% at the pharynx respectively (LR + 61.94, LR- 0.24). The CT component of the POCT sensitivity was 84.82% and specificity 99.63% in urine (LR + 228.68, LR- 0.15), 78.07% and 99.19% respectively on rectal site (LR + 96.23, LR-0.22), 67.79% and 99.88% respectively at pharyngeal site (LR + 554.89, LR- 0.32). 95.95% of MSM reported to be willing to wait for POCT results and no provider reported difficulties in terms of performance or interpretation of the results of the Xpert CT/NG. CONCLUSION: Rapid turnaround time, ease of use and high acceptability make the Xpert CT/NG testing system a strategic tool for increasing testing frequency, reaching those not yet tested and offering the possibility of immediate treatment if needed. The assay showed good negative likelihood ratios and confirms its use to rule out CT/NG infections. Sensitivity varied across sites and pathogens. Periodic staff training at the testing sites should be mandatory.

Independent clinic-based evaluation of dual POCTs for screening for HIV and syphilis in men who have sex with men in Italy, Malta, Peru, and the United Kingdom.

INTRODUCTION: Globally, the incidence of HIV and syphilis can be reduced by the use of validated point of care tests (POCTs). As part of the WHO PRoSPeRo Network, we aimed to evaluate the performance, acceptability, and operational characteristics of two dual HIV/syphilis POCTs (Bioline HIV/Syphilis Duo (Abbott) and DPP® HIV-Syphilis assay (Chembio) for the screening of HIV and syphilis amongst men who have sex with men (MSM). METHOD AND ANALYSES: A cross sectional study of 2,577 MSM in Italy, Malta, Peru, and the United Kingdom (UK) presenting to seven clinic sites, were enrolled. Finger prick blood was collected to perform POCTs and results compared with standard laboratory investigations on venepuncture blood. Acceptability and operational characteristics were assessed using questionnaires. Diagnostic meta-analysis was used to combine data from the evaluation sites. RESULTS: Based on laboratory tests, 23.46% (n = 598/2549) of participants were confirmed HIV positive, and 35.88% of participants (n = 901/2511) were positive on treponemal reference testing. Of all participants showing evidence of antibodies to Treponema pallidum, 50.56% (n = 455/900) were Rapid Plasma Reagin (RPR) test reactive. Of HIV positive individuals, 60.62% (n = 354/584) had evidence of antibodies to T. pallidum, and of these 60.45% (n = 214/354) exhibited reactive RPR tests indicating probable (co)infection. For Bioline POCT, pooled sensitivities and specificities for HIV were 98.95% and 99.89% respectively, and for syphilis were 73.79% and 99.57%. For Chembio pooled sensitivities and specificities for HIV were 98.66% and 99.55%, and for syphilis were 78.60% and 99.48%. Both tests can detect greater than 90% of probable active syphilis cases, as defined by reactive RPR and treponemal test results. These dual POCTs were preferred by 74.77% (n = 1,926) of participants, due to their convenience, and the operational characteristics made them acceptable to health care providers (HCPs). CONCLUSIONS: Both the Bioline and the Chembio dual POCT for syphilis and HIV had acceptable performance, acceptability and operational characteristics amongst MSM in the PRoSPeRo network. These dual POCTs could serve as a strategic, more cost effective, patient and healthcare provider (HCP) friendly alternative to conventional testing; in clinical and other field settings, especially those in resource-limited settings.

Gut Microbiome Disruption Following SARS-CoV-2: A Review.

COVID-19 has been associated with having a negative impact on patients' gut microbiome during both active disease and in the post-acute phase. In acute COVID-19, rapid alteration of the gut microbiome composition was observed, showing on one side a reduction in beneficial symbionts (e.g., Roseburia, Lachnospiraceae) and on the other side an increase in opportunistic pathogens such as Enterococcus and Proteobacteria. Alpha diversity tends to decrease, especially initially with symptom onset and hospital admission. Although clinical recovery appears to align with improved gut homeostasis, this process could take several weeks, even in mild infections. Moreover, patients with COVID-19 post-acute syndrome showed changes in gut microbiome composition, with specific signatures associated with decreased respiratory function up to 12 months following acute disease. Potential treatments, especially probiotic-based therapy, are under investigation. Open questions remain on the possibility to use gut microbiome data to predict disease progression and on potential confounders that may impair result interpretation (e.g., concomitant therapies in the acute phase; reinfection, vaccines, and occurrence of novel conditions or diseases in the post-acute syndrome). Understanding the relationships between gut microbiome dynamics and disease progression may contribute to better understanding post-COVID syndrome pathogenesis or inform personalized treatment that can affect specific targets or microbiome markers.

Microaggression toward LGBTIQ people and implications for mental health: A systematic review.

BACKGROUND: Research suggests that microaggressions detrimentally impact the mental health of members of marginalized social groups. AIMS: The aim of this systematic review was to assess the exposure to microaggressions and related implications on mental health of Lesbian, Gay, Bisexual, Transgender, Intersex, and Queer (LGBTIQ) people. METHOD: Medline, Scopus, PsycINFO, CINAHL, and EMBASE were searched until January 2023. Studies reporting data on the exposure to microaggressions toward LGBTIQ people were identified. Meta-analyses of rates of exposure to microaggression and of the association between microaggressions and mental health outcomes were based on odds ratio (OR) and standardized mean difference (SMD) with 95% confidence intervals (95% CI), estimated through inverse variance models with random effects. RESULTS: The review process led to the selection of 17 studies, involving a total of 9036 LGBTIQ people, of which 6827 identifying as cisgenders, and 492 as heterosexuals, were included in the quantitative synthesis. Overall, LGBTIQ people showed an increased risk of microaggression (SMD: 0.89; 95% CI [0.28, 1.50]), with Transgender people having the highest risk (OR: 10.0; 95% CI [3.08, 32.4]). Microaggression resulted associated with risk of depression (SMD: 0.21; 95% CI [0.05, 0.37]), anxiety (SMD: 0.29; 95% CI [0.17, 0.40]), suicide attempts (OR: 1.13; 95% CI [1.08, 1.18]), alcohol abuse (OR: 1.32; 95% CI [1.13, 1.54]), but not to suicidal ideation (OR: 1.56; 95% CI [0.64, 3.81]) and cannabis abuse (OR: 1.44; 95% CI [0.82, 2.55]). The quality of the evidence was limited by the small number of studies. CONCLUSIONS: LGBTIQ people are at higher risk of microaggressions compared with their cisgender/heterosexual peers, which may lead to mental health consequences. This evidence may contribute to public awareness of LGBTIQ mental health needs and suggest supportive strategies as well as preventive interventions (e.g., supportive programs and destigmatizing efforts) as parts of tailored health-care planning aimed to reduce psychiatric morbidity in this population.

Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort.

Background: Lack of specific definitions of clinical characteristics, disease severity, and risk and preventive factors of post-COVID-19 syndrome (PCS) severely impacts research and discovery of new preventive and therapeutics drugs. Methods: This prospective multicenter cohort study was conducted from February 2020 to June 2022 in 5 countries, enrolling SARS-CoV-2 out- and in-patients followed at 3-, 6-, and 12-month from diagnosis, with assessment of clinical and biochemical features, antibody (Ab) response, Variant of Concern (VoC), and physical and mental quality of life (QoL). Outcome of interest was identification of risk and protective factors of PCS by clinical phenotype, setting, severity of disease, treatment, and vaccination status. We used SF-36 questionnaire to assess evolution in QoL index during follow-up and unsupervised machine learning algorithms (principal component analysis, PCA) to explore symptom clusters. Severity of PCS was defined by clinical phenotype and QoL. We also used generalized linear models to analyse the impact of PCS on QoL and associated risk and preventive factors. CT registration number: NCT05097677. Findings: Among 1796 patients enrolled, 1030 (57%) suffered from at least one symptom at 12-month. PCA identified 4 clinical phenotypes: chronic fatigue-like syndrome (CFs: fatigue, headache and memory loss, 757 patients, 42%), respiratory syndrome (REs: cough and dyspnoea, 502, 23%); chronic pain syndrome (CPs: arthralgia and myalgia, 399, 22%); and neurosensorial syndrome (NSs: alteration in taste and smell, 197, 11%). Determinants of clinical phenotypes were different (all comparisons p < 0.05): being female increased risk of CPs, NSs, and CFs; chronic pulmonary diseases of REs; neurological symptoms at SARS-CoV-2 diagnosis of REs, NSs, and CFs; oxygen therapy of CFs and REs; and gastrointestinal symptoms at SARS-CoV-2 diagnosis of CFs. Early treatment of SARS-CoV-2 infection with monoclonal Ab (all clinical phenotypes), corticosteroids therapy for mild/severe cases (NSs), and SARS-CoV-2 vaccination (CPs) were less likely to be associated to PCS (all comparisons p < 0.05). Highest reduction in QoL was detected in REs and CPs (43.57 and 43.86 vs 57.32 in PCS-negative controls, p < 0.001). Female sex (p < 0.001), gastrointestinal symptoms (p = 0.034) and renal complications (p = 0.002) during the acute infection were likely to increase risk of severe PCS (QoL <50). Vaccination and early treatment with monoclonal Ab reduced the risk of severe PCS (p = 0.01 and p = 0.03, respectively). Interpretation: Our study provides new evidence suggesting that PCS can be classified by clinical phenotypes with different impact on QoL, underlying possible different pathogenic mechanisms. We identified factors associated to each clinical phenotype and to severe PCS. These results might help in designing pathogenesis studies and in selecting high-risk patients for inclusion in therapeutic and management clinical trials. Funding: The study received funding from the Horizon 2020 ORCHESTRA project, grant 101016167; from the Netherlands Organisation for Health Research and Development (ZonMw), grant 10430012010023; from Inserm, REACTing (REsearch & ACtion emergING infectious diseases) consortium and the French Ministry of Health, grant PHRC 20-0424.

Body composition and laboratory parameters in children with down syndrome: The DONUT study.

BACKGROUND & AIMS: Children affected by Down syndrome (DS) have a higher prevalence of obesity, dyslipidemia, and altered liver enzymes. This study investigates a small sample of pediatric patients with DS and possible associations among their anthropometric and laboratory data. METHODS: Cross-sectional study involving 33 children (5-17 years old) affected by DS. Children underwent the measurement of anthropometric parameters through bioelectrical impedance analysis and a venous sampling to check their hepatic and lipid profiles. RESULTS: 54.6% of subjects were overweight or obese according to WHO (BMI z-score ≥1) and 42% of subjects were overweight or obese according to McCarthy et al. with a percentage of body fat (PBF) ≥ 85° centiles. 28% of subjects were dyslipidemic, showing an alteration of total, LDL, HDL cholesterol or triglycerides according to our laboratory reference values, and a low HDL value (under the normal range for gender and age) was the most frequent lipidic alteration (12.5%). An association was found between some values: lower HDL value was associated with higher PBF (p = 0.025); higher ALT value was associated with higher BMI z-score (p = 0.01) and higher PBF (p = 0.01); higher GGT value was associated with higher BMI z-score (p = 0.002) and higher PBF (p = 0.002). CONCLUSIONS: Children with DS are at high risk for obesity and its complications. Our results show dyslipidemia and altered liver enzymes in obese subjects. Pediatricians should monitor children with DS for obesity and consider liver function testing and lipid profiles on children with DS and obesity.