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In 2017, an estimated 14 million cases of Plasmodium vivax malaria were reported from Asia, Central and South America, and the Horn of Africa. The clinical burden of vivax malaria is largely driven by its ability to form dormant liver stages (hypnozoites) that can reactivate to cause recurrent episodes of malaria. Elimination of both the blood and liver stages of the parasites (\"radical cure\") is required to achieve a sustained clinical response and prevent ongoing transmission of the parasite. Novel treatment options and point-of-care diagnostics are now available to ensure that radical cure can be administered safely and effectively. We quantified the global economic cost of vivax malaria and estimated the potential cost benefit of a policy of radical cure after testing patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Estimates of the healthcare provider and household costs due to vivax malaria were collated and combined with national case estimates for 44 endemic countries in 2017. These provider and household costs were compared with those that would be incurred under 2 scenarios for radical cure following G6PD screening: (1) complete adherence following daily supervised primaquine therapy and (2) unsupervised treatment with an assumed 40% effectiveness. A probabilistic sensitivity analysis generated credible intervals (CrIs) for the estimates. Globally, the annual cost of vivax malaria was US$359 million (95% CrI: US$222 to 563 million), attributable to 14.2 million cases of vivax malaria in 2017. From a societal perspective, adopting a policy of G6PD deficiency screening and supervision of primaquine to all eligible patients would prevent 6.1 million cases and reduce the global cost of vivax malaria to US$266 million (95% CrI: US$161 to 415 million), although healthcare provider costs would increase by US$39 million. If perfect adherence could be achieved with a single visit, then the global cost would fall further to US$225 million, equivalent to $135 million in cost savings from the baseline global costs. A policy of unsupervised primaquine reduced the cost to US$342 million (95% CrI: US$209 to 532 million) while preventing 2.1 million cases. Limitations of the study include partial availability of country-level cost data and parameter uncertainty for the proportion of patients prescribed primaquine, patient adherence to a full course of primaquine, and effectiveness of primaquine when unsupervised. Our modelling study highlights a substantial global economic burden of vivax malaria that could be reduced through investment in safe and effective radical cure achieved by routine screening for G6PD deficiency and supervision of treatment. Novel, low-cost interventions for improving adherence to primaquine to ensure effective radical cure and widespread access to screening for G6PD deficiency will be critical to achieving the timely global elimination of P. vivax.

Distinct bacterial trophic networks exist in the gut microbiota of individuals in industrialized and non-industrialized countries. In particular, non-industrialized gut microbiomes tend to be enriched with Prevotella species. To study the development of these Prevotella -rich compositions, we investigated the gut microbiota of children aged between 7 and 37 months living in rural Gambia (616 children, 1,389 stool samples, stratified by 3-month age groups). These infants, who typically eat a high-fibre, low-protein diet, were part of a double-blind, randomized iron intervention trial (NCT02941081) and here we report the secondary outcome. We found that child age was the largest discriminating factor between samples and that anthropometric indices (collection time points, season, geographic collection site, and iron supplementation) did not significantly influence the gut microbiome. Prevotella copri , Faecalibacterium prausnitzii and Prevotella stercorea were, on average, the most abundant species in these 1,389 samples (35%, 11% and 7%, respectively). Distinct bacterial trophic network clusters were identified, centred around either P. stercorea or F . prausnitzii and were found to develop steadily with age, whereas P. copri , independently of other species, rapidly became dominant after weaning. This dataset, set within a critical gut microbial developmental time frame, provides insights into the development of Prevotella -rich gut microbiomes, which are typically understudied and are underrepresented in western populations. Analysis of gut microbiomes from Gambian infants reveals bacterial trophic networks based around Prevotella species, which are typically enriched in non-industrialized populations.

The World Health Organization recommends that primaquine should be given once weekly for 8-weeks to patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) deficiency, but data on its antirelapse efficacy and safety are limited. Within the context of a multicentre, randomised clinical trial of two primaquine regimens in P. vivax malaria, patients with G6PD deficiency were excluded and enrolled into a separate 12-month observational study. They were treated with a weekly dose of 0.75 mg/kg primaquine for 8 weeks (PQ8W) plus dihydroartemisinin piperaquine (Indonesia) or chloroquine (Afghanistan, Ethiopia, Vietnam). G6PD status was diagnosed using the fluorescent spot test and confirmed by genotyping for locally prevalent G6PD variants. The risk of P. vivax recurrence following PQ8W and the consequent haematological recovery were characterized in all patients and in patients with genotypically confirmed G6PD variants, and compared with the patients enrolled in the main randomised control trial. Between July 2014 and November 2017, 42 male and 8 female patients were enrolled in Afghanistan (6), Ethiopia (5), Indonesia (19), and Vietnam (20). G6PD deficiency was confirmed by genotyping in 31 patients: Viangchan (14), Mediterranean (4), 357A-G (3), Canton (2), Kaiping (2), and one each for A-, Chatham, Gaohe, Ludhiana, Orissa, and Vanua Lava. Two patients had recurrent P. vivax parasitaemia (days 68 and 207). The overall 12-month cumulative risk of recurrent P. vivax malaria was 5.1% (95% CI: 1.3-18.9) and the incidence rate of recurrence was 46.8 per 1000 person-years (95% CI: 11.7-187.1). The risk of P. vivax recurrence was lower in G6PD deficient patients treated with PQ8W compared to G6PD normal patients in all treatment arms of the randomised controlled trial. Two of the 26 confirmed hemizygous males had a significant fall in haemoglobin (>5g/dl) after the first dose but were able to complete their 8 week regimen. PQ8W was highly effective in preventing P. vivax recurrences. Whilst PQ8W was well tolerated in most patients across a range of different G6PD variants, significant falls in haemoglobin may occur after the first dose and require clinical monitoring. This trial is registered at ClinicalTrials.gov (NCT01814683).

IntroductionLongitudinal studies can provide timely and accurate information to evaluate and inform COVID-19 control and mitigation strategies and future pandemic preparedness. The Optimise Study is a multidisciplinary research platform established in the Australian state of Victoria in September 2020 to collect epidemiological, social, psychological and behavioural data from priority populations. It aims to understand changing public attitudes, behaviours and experiences of COVID-19 and inform epidemic modelling and support responsive government policy.Methods and analysisThis protocol paper describes the data collection procedures for the Optimise Study, an ongoing longitudinal cohort of ~1000 Victorian adults and their social networks. Participants are recruited using snowball sampling with a set of seeds and two waves of snowball recruitment. Seeds are purposively selected from priority groups, including recent COVID-19 cases and close contacts and people at heightened risk of infection and/or adverse outcomes of COVID-19 infection and/or public health measures. Participants complete a schedule of monthly quantitative surveys and daily diaries for up to 24 months, plus additional surveys annually for up to 48 months. Cohort participants are recruited for qualitative interviews at key time points to enable in-depth exploration of people’s lived experiences. Separately, community representatives are invited to participate in community engagement groups, which review and interpret research findings to inform policy and practice recommendations.Ethics and disseminationThe Optimise longitudinal cohort and qualitative interviews are approved by the Alfred Hospital Human Research Ethics Committee (# 333/20). The Optimise Study CEG is approved by the La Trobe University Human Ethics Committee (# HEC20532). All participants provide informed verbal consent to enter the cohort, with additional consent provided prior to any of the sub studies. Study findings will be disseminated through public website (https://optimisecovid.com.au/study-findings/) and through peer-reviewed publications.Trial registration numberNCT05323799.

Background Reducing antibiotic use in Australia, and the subsequent impact on antimicrobial resistance, requires multiple, sustained approaches with appropriate resources and support. Additional strategies to reduce antibiotic prescribing include effective vaccines, against pathogens such as Streptococcus pyogenes , the most common bacterial cause of sore throat. As part of efforts towards assessing the benefits of introducing new strategies to reduce antimicrobial prescribing, we aimed to determine the burden of antimicrobial prescribing for sore throat in general practice. Methods General practice activity data from 2013 – 2017 derived from the first 8 practices participating in the ‘Primary Care Audit, Teaching and Research Open Network’ (Patron) program were analysed according to reason for visit (upper respiratory tract infection, URTI, or sore throat) and antibiotic prescription. The main outcome measures were percentage of sore throat or URTI presentations with antibiotic prescription by age. Results A total of 722,339 visits to general practice were made by 65,449 patients; 5.7% of visits were for URTI with 0.8% meeting the more specific criteria for sore throat. 66.1% of sore throat visits and 36.2% of URTI visits resulted in antibiotic prescription. Penicillin, the recommended antibiotic for sore throat when indicated, was the antibiotic of choice in only 52.9% of sore throat cases prescribed antibiotics. Broader spectrum antibiotics were prescribed more frequently in older age groups. Conclusions Frequency of antibiotic prescribing for sore throat is high and broad, despite Australian Therapeutic guideline recommendations. Multiple, sustained interventions to reduce prescribing, including availability of effective S. pyogenes vaccines that could reduce the incidence of streptococcal pharyngitis, could obviate the need to prescribe antibiotics and support ongoing efforts to promote antimicrobial stewardship.

Abstract Among patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia from a prospective randomized clinical trial, acute kidney injury (AKI) rates increased with increasing vancomycin exposure, even within the therapeutic range. AKI was independently more common for the (flu)cloxacillin group. Day 2 vancomycin AUC ≥470 mg·h/L was significantly associated with AKI, independent of (flu)cloxacillin receipt.

There is a high risk of Plasmodium vivax recurrence in patients treated for Plasmodium falciparum malaria in co-endemic areas. Primaquine radical cure has the potential to reduce P vivax recurrences in patients presenting with P falciparum as well as P vivax malaria but is undermined by poor adherence to the currently recommended 14-day regimen. We aimed to assess the efficacy and safety of supervised versus unsupervised primaquine radical cure in patients presenting with uncomplicated malaria. We did a cluster-randomised, controlled, open-label superiority trial in Papua, Indonesia. 21 clusters of village health posts, matched by annual parasite index, were randomly assigned (1:1) to treat patients (age >12 months and body weight >5 kg) presenting with confirmed uncomplicated P falciparum or P vivax malaria with oral dihydroartemisinin–piperaquine plus either a supervised or unsupervised 14-day course of oral primaquine (0·5 mg/kg per day). Patients in the supervised group were supervised taking their primaquine dose on alternate days. Patients were followed-up for 6 months and those who presented again with malaria were retreated with the same drug regimen. Masking was not possible due to the nature of the study. The primary outcome was the incidence risk of P vivax malaria over 6 months, assessed in the modified intention-to-treat population (all patients who were assigned to a treatment group, excluding patients who were lost to follow-up after their first visit). This trial is now complete, and is registered with ClinicalTrials.gov, NCT02787070. Between Sept 14, 2016, and July 31, 2018, 436 patients were screened for eligibility and 419 were enrolled; 223 (53%) patients in 11 clusters were assigned to supervised primaquine treatment and 196 (47%) in ten clusters to unsupervised primaquine treatment. 161 (72%) of 223 patients in the supervised group and 151 (77%) of 196 in the unsupervised group completed 6 months of follow-up. At 6 months, the incidence risk of P vivax recurrence in the supervised group was 29·7% (95% CI 16·4–49·9) versus 55·8% (32·3–81·8) in the unsupervised group (hazard ratio 0·23 [95% CI 0·07–0·76]; p=0·016). The incidence rate for P vivax recurrence was 539 (95% CI 390–747) infections per 1000 person-years in the supervised group versus 859 (673–1096) in the unsupervised group (incidence rate ratio 0·63 [95% CI 0·42–0·94]; p=0·025). The corresponding rates in the 224 patients who presented with P falciparum malaria were 346 (95% CI 213–563) and 660 (446–977; incidence rate ratio 0·52 [95% CI 0·28–0·98]; p=0·043). Seven serious adverse events were reported (three in the supervised group, four in the unsupervised group), none of which were deemed treatment-related, and there were no deaths. In this area of moderate malaria transmission, supervision of primaquine radical cure treatment reduced the risk of P vivax recurrence. This finding was apparent for patients presenting with either P falciparum or P vivax malaria. Further studies are warranted to investigate the safety and efficacy of radical cure for patients presenting with uncomplicated falciparum malaria in other co-endemic areas. The Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Foreign Affairs and Trade of the Australian Government. For the Indonesian translation of the abstract see Supplementary Materials section.

In 2017, an estimated 14 million cases of Plasmodium vivax malaria were reported from Asia, Central and South America, and the Horn of Africa. The clinical burden of vivax malaria is largely driven by its ability to form dormant liver stages (hypnozoites) that can reactivate to cause recurrent episodes of malaria. Elimination of both the blood and liver stages of the parasites (\"radical cure\") is required to achieve a sustained clinical response and prevent ongoing transmission of the parasite. Novel treatment options and point-of-care diagnostics are now available to ensure that radical cure can be administered safely and effectively. We quantified the global economic cost of vivax malaria and estimated the potential cost benefit of a policy of radical cure after testing patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Estimates of the healthcare provider and household costs due to vivax malaria were collated and combined with national case estimates for 44 endemic countries in 2017. These provider and household costs were compared with those that would be incurred under 2 scenarios for radical cure following G6PD screening: (1) complete adherence following daily supervised primaquine therapy and (2) unsupervised treatment with an assumed 40% effectiveness. A probabilistic sensitivity analysis generated credible intervals (CrIs) for the estimates. Globally, the annual cost of vivax malaria was US $359 million (95% CrI: US$ 222 to 563 million), attributable to 14.2 million cases of vivax malaria in 2017. From a societal perspective, adopting a policy of G6PD deficiency screening and supervision of primaquine to all eligible patients would prevent 6.1 million cases and reduce the global cost of vivax malaria to US $266 million (95% CrI: US$ 161 to 415 million), although healthcare provider costs would increase by US $39 million. If perfect adherence could be achieved with a single visit, then the global cost would fall further to US$ 225 million, equivalent to$135 million in cost savings from the baseline global costs. A policy of unsupervised primaquine reduced the cost to US$ 342 million (95% CrI: US$209 to 532 million) while preventing 2.1 million cases. Limitations of the study include partial availability of country-level cost data and parameter uncertainty for the proportion of patients prescribed primaquine, patient adherence to a full course of primaquine, and effectiveness of primaquine when unsupervised. Our modelling study highlights a substantial global economic burden of vivax malaria that could be reduced through investment in safe and effective radical cure achieved by routine screening for G6PD deficiency and supervision of treatment. Novel, low-cost interventions for improving adherence to primaquine to ensure effective radical cure and widespread access to screening for G6PD deficiency will be critical to achieving the timely global elimination of P. vivax.

Background Clinical risk factors for nephrotoxicity in Staphylococcus aureus bacteraemia remain largely undetermined, despite its common occurrence and clinical significance. In an international, multicentre, prospective clinical trial (CAMERA2), which compared standard therapy (vancomycin monotherapy) to combination therapy (adding an anti-staphylococcal beta-lactam) for methicillin-resistant S. aureus bacteraemia, significantly more people in the combination therapy arm experienced acute kidney injury compared with those in the monotherapy arm (23% vs 6%). Objective The aim of this post hoc analysis was to explore in greater depth the risk factors for acute kidney injury from the CAMERA2 trial. Methods Among participants of the CAMERA2 trial, demographic-related, infection-related and treatment-related risk factors were assessed for their relationship with acute kidney injury by univariable and multivariable logistic regression. Acute kidney injury was defined by a modified-KDIGO (Kidney Disease: Improving Global Outcomes) criteria (not including urinary output). Results Of the 266 participants included, age ( p = 0.04), randomisation to combination therapy ( p = 0.002), vancomycin area under the concentration–time curve ( p = 0.03) and receipt of (flu)cloxacillin as the companion beta-lactam ( p < 0.001) were significantly associated with acute kidney injury. On a multivariable analysis, concurrent use of (flu)cloxacillin increased the risk of acute kidney injury over four times compared with the use of cefazolin or no beta-lactam. The association of vancomycin area under the concentration–time curve with acute kidney injury also persisted in the multivariable model. Conclusions For participants receiving vancomycin for S. aureus bacteraemia, use of (flu)cloxacillin and increased vancomycin area under the concentration–time curve were risk factors for acute kidney injury. These represent potentially modifiable risk factors for nephrotoxicity and highlight the importance of avoiding the use of concurrent nephrotoxins.