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.

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.

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

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 the initial MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are established standard treatment at first relapse, but their effectiveness as compared to chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes amongst patients at first, late-POD beyond 24 months. Patients treated upfront with BTKi were excluded. The primary objective was progression-free survival from time of second-line therapy (PFS-2) of BTKi versus CIT. After accrual, all patients were prospectively followed-up. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 (range:19-70) years and 77% were males. Median follow-up from time of first relapse was 53 months (range:12-144). Overall, 114 patients had second-line BTKi, while 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-CHOP- or platinum-based, n=100). The two groups were balanced for clinicopathological features, and median time to first relapse (48 months for both). 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-HR, 0.41 for R-B, 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in BTKi-naïve MCL patients.

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.

How European Research Projects Can Support Vaccination Strategies: The Case of the ORCHESTRA Project for SARS-CoV-2.

ORCHESTRA ("Connecting European Cohorts to Increase Common and Effective Response To SARS-CoV-2 Pandemic") is an EU-funded project which aims to help rapidly advance the knowledge related to the prevention of the SARS-CoV-2 infection and the management of COVID-19 and its long-term sequelae. Here, we describe the early results of this project, focusing on the strengths of multiple, international, historical and prospective cohort studies and highlighting those results which are of potential relevance for vaccination strategies, such as the necessity of a vaccine booster dose after a primary vaccination course in hematologic cancer patients and in solid organ transplant recipients to elicit a higher antibody titer, and the protective effect of vaccination on severe COVID-19 clinical manifestation and on the emergence of post-COVID-19 conditions. Valuable data regarding epidemiological variations, risk factors of SARS-CoV-2 infection and its sequelae, and vaccination efficacy in different subpopulations can support further defining public health vaccination policies.

Risk factors for colonization with multidrug-resistant Gram-negative bacteria and Clostridioides difficile in Long Term Care Facilities (LTCFs) residents: the evidence from 27 facilities in a high endemic setting.

Introduction: Residency in LTCFs increases the likelihood of colonization with multidrug resistant Gram-negative bacteria (MDR-GNB). We assessed the prevalence and risk factors for enteric colonization by III-generation cephalosporins-resistant and carbapenem-resistant (CR) GNB in a large group of LTCFs in a high endemic setting. We also assessed the prevalence and risk factors for C. difficile colonization. Methods: A point prevalence survey with rectal screening (RS) was conducted in 27 LTCFs in north Italy. Epidemiological and clinical variables on the survey day, history of hospitalization and surgery within one year, and antibiotics within three months, were collected. The presence of III-generation cephalosporin resistant and CR GNB was assessed using a selective culture on chromogenic medium and PCR for carbapenemase detection. The presence of C. difficile was assessed using ELISA for GDH and RT-PCR to identify toxigenic strains. Multi-variable analyses were performed using two-level logistic regression models. Results: In the study period 1947 RSs were performed. The prevalence of colonization by at least one GNB resistant to III-generation cephalosporin was 51% (E. coli 65%, K. pneumoniae 14% of isolates). The prevalence of colonization by CR GNB was 6%. 6% of all isolates (1150 strains) resulted in a carbapenem-resistant K. pneumoniae, and 3% in a carbapenem-resistant E. coli. KPC was the most frequent carbapenemase (73%) identified by PCR, followed by VIM (23%). The prevalence of colonization by C. difficile was 11.7%. The presence of a medical device (OR 2.67) and previous antibiotic use (OR 1.48) were significantly associated with III-generation cephalosporin resistant GNB colonization. The presence of a medical device (OR 2.67) and previous hospitalization (OR 1.80) were significantly associated with CR GNB. The presence of a medical device (OR 2.30) was significantly associated with C. difficile colonization. Main previously used antibiotic classes were fluoroquinolones (32% of previously treated subjects), III-generation cephalosporins (21%), and penicillins (19%). Conclusion: Antimicrobial stewardship in LTCFs is a critical issue, being previous antibiotic treatment a risk factor for colonization by MDR-GNB. The prevalence of colonization by III-generation cephalosporin and CR GNB among LTCF residents also underlines the importance to adhere to hand hygiene indications, infection prevention and control measures, and environmental hygiene protocols, more achievable than rigorous contact precautions in this type of social setting.

Colonisation with Extended-Spectrum Cephalosporin-Resistant Enterobacterales and Infection Risk in Surgical Patients: A Systematic Review and Meta-analysis.

INTRODUCTION: Limited evidence has been reported for surgical site infections (SSIs) in patients undergoing surgery who are carriers of extended-spectrum cephalosporin-resistant Enterobacterales (ESCR-E). A systematic review and meta-analysis were conducted to evaluate the risk of postoperative infections in adult inpatients colonised with ESCR-E before surgery. METHODS: The Medline, Embase and Cochrane databases were searched between January 2011 and April 2022, following PRISMA indications. Random effects meta-analysis was used to quantify the association between ESCR-E colonisation and infection. RESULTS: Among the 467 articles reviewed, 9 observational studies encompassing 7219 adult patients undergoing surgery were included. The ESCR-E colonisation rate was 13.7% (95% CI 7.7-19.7). The most commonly reported surgeries included abdominal surgery (44%) and liver transplantation (LT; 33%). The SSI rate was 23.2% (95% CI 13.2-33.1). Pooled incidence risk was 0.36 (95% CI 0.22-0.50) vs 0.13 (95% CI 0.02-0.24) for any postoperative infection and 0.28 (95% CI 0.18-0.38) vs 0.17 (95% CI 0.07-0.26) for SSIs in ESCR-E carriers vs noncarriers, respectively. In ESCR-E carriers, the ESCR-E infection ratio was 7 times higher than noncarriers. Postoperative infection risk was higher in carriers versus noncarriers following LT. Sources of detected heterogeneity between studies included ESCR-E colonisation and the geographic region of origin. CONCLUSIONS: Patients colonised with ESCR-E before surgery had increased incidence rates of post-surgical infections and SSIs compared to noncarriers. Our results suggest considering the implementation of pre-surgical screening for detecting ESCR-E colonisation status according to the type of surgery and the local epidemiology.

Mediterranean diet and physical activity in Down syndrome pediatric subjects: the DONUT STUDY.

INTRODUCTION: Children with Down syndrome (DS) are characterised by peculiar dietary choices and approach to physical activity. The aim of this study is to quantify their adherence to the Mediterranean diet, their level of physical activity and lipid profile. METHODS: Cross-sectional study, involving 61 children affected by DS. Parents of the patients were requested to complete two questionnaires, Mediterranean Diet Quality Index in children and adolescents (KIDMED) and Godin Leisure-Time Physical Activity Questionnaire (Godin). In addition, children underwent a venous sampling to check their lipid profile. RESULTS: High scores on KIDMED and Godin were found and were associated with a reduced likelihood of being overweight or obese (0.001< p < 0.077; 0.001< p < 0.248). The level of physical activity and the probability of finding pathological HDL values in plasma were inversely related (0.001< p < 0.263). CONCLUSIONS: The DONUT study proves that KIDMED and Godin questionnaires can identify children affected by DS that can lead to develop inadequate anthropometric variables and low levels of HDL cholesterol. Moreover, the results of this study show that, despite potential difficulties in the pursuit of a correct diet and an adequate approach to physical activity, children with DS could achieve results that are substantially like those of non-DS children.

Hepatitis B Virus Reactivation upon Immunosuppression: Is There a Role for Hepatitis B Core-Related Antigen in Patients with Immune-Escape Mutants? A Case Report.

The reactivation of hepatitis B virus (HBVr) in patients undergoing pharmacological immunosuppression is a potentially fatal clinical event that may occur in patients with overt or occult HBV infection. The risk of HBVr is mainly determined by the type of immunosuppressive therapy and the HBV serologic profile, with a higher risk in patients positive for the hepatitis B surface antigen (HBsAg), and a lower risk in HBsAg-negative/antibodies to core antigen-positive subjects. Notably, a considerable proportion of patients experiencing HBVr showed a high degree of variability of the HBV S gene, possibly leading to immune escape mutants. These mutations, usually in the "a-determinant" of the HBsAg, can cause diagnostic problems and consequently hamper the appropriate management strategy of patients at risk of HBVr. Here, we describe a case of HBVr in a patient with a diagnosis of chronic myeloid leukemia and a previous history of kidney transplant, providing evidence of the potential usefulness of hepatitis B core-related antigen measurement in patients with HBV immune-escape mutants at risk of viral reactivation.

Long-Term Patient-Centred Follow-up in a Prospective Cohort of Patients with COVID-19.

INTRODUCTION: To better define COVID-19 long-term impact we prospectively analysed patient-centred outcomes, including general health and symptom duration. METHODS: Barthel index (BI), St. George's Respiratory Questionnaire adapted to patients with COVID-19 (aSGRQ) and WHO Clinical Progression Scale (CPS) were measured at enrolment and at 6 weeks from the onset of symptoms. Persistence of most frequently reported symptoms was assessed at 6 weeks and, among symptomatic patients, at 12 weeks from the onset of symptoms. Predictors of impaired general health over time were identified using an ordinal multilevel multivariate model. RESULTS: A total of 448 patients (55% men, median age 56 years) were enrolled. WHO-CPS showed mild, moderate and severe disease in 48%, 42% and 10% of patients at admission and mild disease in all patients at follow-up, respectively. BI and aSGRQ were normal in 96% and 93% patients before COVID-19 but only in 47% and 16% at COVID-19 diagnosis and in 87% and 65% at 6-week follow-up. Male gender was identified by all three assessments as a predictor of impaired general health (BI, OR 2.14, p < 0.0001; aSGRQ, OR 0.53, p = 0.003; WHO-CPS, OR 1.56, p = 0.01). Other predictors included age, ICU admission and comorbidities (e.g. cardiovascular disease and cancer) for BI, hospital admission for aSGRQ, age and presence of comorbidities for WHO-CPS. At 6- and 12-week follow-up, 39% and 20% of patients, respectively, were still reporting symptoms. Fatigue and breathlessness were the most frequently reported symptoms. CONCLUSIONS: Long-term follow-up facilitates the monitoring of health impairment and symptom persistence and can contribute to plan tailored interventions.

Changes in the prevalence of self-reported sexually transmitted bacterial infections from 2010 and 2017 in two large European samples of men having sex with men-is it time to re-evaluate STI-screening as a control strategy?

BACKGROUND/OBJECTIVES: Many European countries reported increased numbers of syphilis, gonorrhoea and chlamydia diagnoses among men who have sex with men (MSM) in recent years. Behaviour changes and increased testing are thought to drive these increases. METHODS: In 2010 and 2017, two large online surveys for MSM in Europe (EMIS-2010, EMIS-2017) collected self-reported data on STI diagnoses in the previous 12 months, diagnostic procedures, STI symptoms when testing, number of sexual partners, and sexual behaviours such as condom use during the last intercourse with a non-steady partner in 46 European countries. Multivariate regression models were used to analyse factors associated with diagnoses of syphilis, gonorrhoea/chlamydia, and respective diagnoses classified as symptomatic and asymptomatic. If applicable, they included country-level screening rates. RESULTS: Questions on STI diagnoses and sexual behaviours were answered by 156,018 (2010) and 125,837 (2017) participants. Between 2010 and 2017, overall diagnoses with gonorrhoea/chlamydia and syphilis increased by 76% and 83% across countries. Increases were more pronounced for asymptomatic compared to symptomatic infections. The proportion of respondents screened and the frequency of screening grew considerably. Condomless anal intercourse with the last non-steady partner rose by 62%; self-reported partner numbers grew. Increased syphilis diagnoses were largely explained by behavioural changes (including more frequent screening). Gonorrhoea/chlamydia increases were mainly explained by more screening and a change in testing performance. A country variable representing the proportion of men screened for asymptomatic infection was positively associated with reporting symptomatic gonorrhoea/chlamydia, but not syphilis. DISCUSSION/CONCLUSION: The positive association of country-level screening rates with the proportion of symptomatic infections with gonorrhoea/chlamydia may indicate a paradoxical effect of screening on incidence of symptomatic infections. Treatment of asymptomatic men might render them more susceptible to new infections, while spontaneous clearance may result in reduced susceptibility. Before expanding screening programmes, evidence of the effects of screening and treatment is warranted.

Socio-demographic Characteristics, Sexual and Test-Seeking Behaviours Amongst Men Who have Sex with Both Men and Women: Results from a Bio-behavioural Survey in 13 European Cities.

Within the MSM population, men who have sex with both men and women (MSMW) are identified as a high-risk group both worldwide and in Europe. In a multi-centred bio-behavioural cross-sectional study, we aimed to assess the relationship(s) between socio-demographic factors, stigma, sexual behavioural patterns, test seeking behaviour and sero-status amongst MSMW. A multi-level analysis was conducted to identify factors associated with being MSMW versus Men who have Sex with Men Only (MSMO). A total of 4901 MSM were enrolled across the 13 study sites. Participants were categorised as MSMW in the 12.64% of the cases. Factors such as educational status, perceived homonegativity, testing facilities knowledge and HIV testing lifetime seem to be relevant factors when characterising the MSMW group. The results highlight the vulnerability of MSMW and the wide spectrum of risky behavioural and psycho-social patterns, particularly in terms of HIV testing, 'outness', and perceived stigma.

Undiagnosed HIV infection in a population of MSM from six European cities: results from the Sialon project.

OBJECTIVES: The purpose of this article is to assess the distribution of undiagnosed HIV infection in men who have sex with men (MSM) in Southern and Eastern European countries, to describe the differences in epidemiology and behaviour between undiagnosed, diagnosed HIV-positive and HIV-negative MSM and to identify factors associated with undiagnosed HIV infection in the study population. METHODS: A multi-centre biological and behavioural cross-sectional study was conducted in 2008. Time-location sampling was used to recruit men attending different venues. A self-administered questionnaire was completed and oral fluid samples were collected to estimate HIV prevalence. RESULTS: HIV prevalence was 17% in Barcelona, 12% in Verona, 6% in Bratislava, 5% in Ljubljana, 5% in Bucharest and 3% in Prague while undiagnosed HIV infection was 47, 62, 67, 83, 85 and 57%, respectively. Diagnosed HIV-positive men reported more casual partners than HIV-negative MSM (mean: 19 and 9, respectively) (P < 0.001), and they were more likely to self-reported condyloma in the last year than undiagnosed HIV-positive and HIV-negative men (15, 1 and 3%, respectively) (P < 0.001). Factors associated with undiagnosed HIV infection included attending sex-focused venues (OR = 2.49), reporting syphilis in the previous 12 months (OR = 2.56), using poppers at last sexual intercourse (OR = 3.36) and having had an HIV test in the previous year (OR = 2.00). CONCLUSIONS: Many HIV infections remain undiagnosed, and there is evidence of the persistence of frequent risk behaviours and sexually transmitted infections (STI) despite knowledge of HIV-positive status, emphasising the need for a multidimensional approach to HIV/STI prevention. Access to HIV testing should be considered a priority in prevention programs targeted at MSM, especially in Eastern Europe.