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Background Streptococcus pneumoniae is a global cause of community-acquired pneumonia (CAP) and invasive disease in children that requires antibiotic treatment. As part of the CAP-IT trial (grant No. 13/88/11; https://www.capitstudy.org.uk/), we analyzed nasopharyngeal swabs from children with clinically diagnosed CAP, and found no differences in pneumococcal susceptibility between patients receiving oral amoxicillin treatment for shorter or longer durations and at higher or lower antibiotic doses. Here, we perform high-resolution genomics to understand pneumococcal diversity and to unravel potential mechanisms underlying persistence of pneumococcal (vaccine) serotypes.Methods Three-hundred and ninety pneumococci cultured from 1132 nasopharyngeal swabs from 718 children were whole-genome sequenced (Illumina) and tested for susceptibility to penicillin and amoxicillin. Recombination analysis was performed using long-read sequenced isolates (PacBio) and publicly available sequences.Results In 390 unique pneumococcal isolates, non-susceptibility to penicillin (n = 61, 15.6%) and amoxicillin (n = 10, 2.6%) was low and independent of the amoxicillin treatment dosage and duration. Serotypes 15B/C, 11A, 15A and 23B1 were most prevalent. PCV13 serotypes 3, 19A, and 19F were also identified (n = 25, 6.4%), and recombination analysis and genome-wide comparisons with historical isolates dating from 1995 identified several potential capsule switch events in these highly recombinant vaccine serotypes 19A and 19F, in contrast to serotype 3 genomes (n = 13, 3.3%) that showed high genomic stability over the last 20 years. All 23B1 isolates (n = 27, 6.9%) were penicillin non-susceptible, and one was the result of a potential capsule-switch in 19F.Conclusions Our data suggest that vaccination strategies, but not amoxicillin use, are more likely to drive pneumococcal serotype prevalence among children in the UK and prompts consideration of PCVs with additional serotype coverage that are likely to further decrease invasive disease in this target population. Emergence of 23B1, a non-vaccine genotype with penicillin non-susceptibility, might provide a persistence strategy for vaccine serotypes, highlighting the need for continued genomic surveillance.

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole-resistant Candida spp. isolates in low- and middle-income countries (LMICs) compared to high-income countries (HICs). We describe the epidemiology, Candida spp. distribution, treatment, and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalized infants

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Background: HIV prevention for men who have sex with men (MSM) hastypically focused on behaviour change at the individual-level, rather than aspart of a couple. However, recent research has highlighted the role of primarysexual partners in the transmission of HIV among young MSM in the US,estimating that as many as 84% of new transmissions were from men’s mainpartner. This suggests that work with couples could contribute to preventionefforts.Methods: We conducted qualitative in-depth interviews with 30 young MSM(aged 18-29) in Scotland, recruited via a number of strategies; onlineadvertisements, through voluntary sector organisations working with MSM,and snowballing. Thematic data analysis focused on identifying how menunderstand HIV risk management strategies in the context of relationships,specifically the role of ‘safer sex’ practices, HIV testing, and expectationsaround monogamy and/or sexual exclusivity.Results: At the time of interview, nine men reported being in a relationship,and the majority (n=28) discussed their aspirations for sex in long-termrelationships. Participants’ demonstrated varying levels of HIV literacy (i.e.HIV-related knowledge and an individual’s capacity to apply this), andalthough all discussed condom use as part of ‘safer sex’ and their individualmanagement of HIV risk, a recurring theme was desire to discontinue condomuse in the context of a committed relationship. Over a third of the men (n=22)discussed discontinuing condom use in this context. Of those in relationships,six had discontinued condom use, but not all tested for HIV prior to this, norexplicitly discussed expectations for monogamy and/or sexual exclusivity withtheir partners. Agreeing to testing and discussing expectations of fidelity werecomplicated by issues of trust and intimacy.Conclusion: How MSM understand and manage HIV risk in relationships hasimplications for future HIV prevention. Knowledge of their own (and partner’s)HIV status - particularly where serodiscordant relationships are identified -could enable men to make decisions around prevention, and whereappropriate, open up the possibility of accessing biomedical prevention. Ourresearch suggests young MSM in relationships continue to base safer sexdecisions on perceptions of fidelity and trust in their partners. Young MSMaccessing testing in clinical settings could be targeted for interventions toencourage HIV status disclosure and informed safer sex negotiation.

OBJECTIVES The pharmacokinetic and pharmacodynamic effects of antiretroviral therapy may differ in older compared with younger subjects with HIV infection. We aimed to assess factors associated with plasma antiretroviral drug exposure, including age, within a large HIV-infected cohort undergoing therapeutic drug monitoring (TDM). METHODS Data from the Liverpool TDM Registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. All TDM of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) was included and in order to account for different antiretroviral drugs the plasma concentrations were standardized by group measurements according to drug, dosing and timing of TDM. Regression modelling was used to evaluate associations of drug exposure with age and clinical parameters, including hepatic transaminase results and time to antiretroviral treatment modification. RESULTS Data from 3589 TDM samples were available from 2447 subjects. The greatest numbers of plasma concentrations were assessed for lopinavir (22.4%), efavirenz (18.5%), atazanavir (17.0%) and saquinavir (11.6%). As age increased, median standardized NNRTI concentrations remained constant, whereas PI concentrations increased (correlation coefficient 0.04, P = 0.033). In a regression analysis stratified by antiretroviral drug class, standardized plasma concentrations were significantly associated with age for PIs (0.05 increase in standard deviation of drug concentration with each 10 year increase in age, P = 0.044), but not for NNRTIs or other clinical parameters, including hepatic transaminase results or time to antiretroviral treatment modification. CONCLUSIONS With increasing age, statistically significant rises in plasma PI exposure, but not NNRTI exposure, were observed. The clinical relevance of this observation merits further investigation.