Burden of antimicrobial prescribing in primary care attributable to sore throat: a retrospective cohort study of patient record data.

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.

Inter-species gene flow drives ongoing evolution of Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis.

Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging cause of human infection with invasive disease incidence and clinical manifestations comparable to the closely related species, Streptococcus pyogenes. Through systematic genomic analyses of 501 disseminated SDSE strains, we demonstrate extensive overlap between the genomes of SDSE and S. pyogenes. More than 75% of core genes are shared between the two species with one third demonstrating evidence of cross-species recombination. Twenty-five percent of mobile genetic element (MGE) clusters and 16 of 55 SDSE MGE insertion regions were shared across species. Assessing potential cross-protection from leading S. pyogenes vaccine candidates on SDSE, 12/34 preclinical vaccine antigen genes were shown to be present in >99% of isolates of both species. Relevant to possible vaccine evasion, six vaccine candidate genes demonstrated evidence of inter-species recombination. These findings demonstrate previously unappreciated levels of genomic overlap between these closely related pathogens with implications for streptococcal pathobiology, disease surveillance and prevention.

Effectiveness of one and two doses of ivermectin mass drug administration in reducing the prevalence and intensity of soil-transmitted helminth (STH) infections in Western Province, Solomon Islands: a cluster-randomised, before-after analysis.

Background: Ivermectin mass drug administration (MDA) is effective for controlling onchocerciasis and scabies, with evidence supporting its role in some species of soil-transmitted helminth (STH) infections. In the context of RISE, a cluster-randomised trial for scabies, this study evaluated the effectiveness of ivermectin MDA in reducing STH burden in the Western Province of Solomon Islands. Methods: Twenty villages were randomised 1:1 to receive ivermectin MDA as one dose (IVM-1) or two doses (IVM-2) for scabies. The effectiveness of one and two doses in reducing STH prevalence and intensity was evaluated before (May 2019) and 21 months after (February 2021) MDA in May 2019. All residents aged 12 months or older in the study villages were eligible to participate and provide stool specimens. Species-specific STH infection and intensity were assessed using quantitative PCR. We compared prevalence and intensity of infection between baseline and 21 months in each intervention arm individually using cluster-level analysis (adjusted for clustering) and individual-level analysis (adjusted for sex, age, and clustering). The primary outcomes were the prevalence risk difference (RD) from the cluster-level analysis, and the change in adjusted odds of infection from the individual-level analysis. Secondary outcomes included change in incident rates of mean eggs per gram (epg) of stool from baseline to 21 months, relative risk difference in prevalence and relative change in odds of infection between arms at 21 months. Sex data (male/female) were self-reported. Findings: Overall, STH infection was assessed in 830 participants from 18 villages at baseline and 1172 from 20 villages at follow-up. Females represented 58% (n = 478) of the sample at baseline and 59% (n = 690) at follow-up. We observed a reduction in Strongyloides spp. prevalence following two doses of ivermectin MDA in the cluster-level analysis from 7.0% (32/458 participants) to 1.2% (8/674 participants), corresponding to a RD of -0.07 (95% CI -0.14 to -0.01, p = 0.036), and in the individual-level analysis (OR 0.11, 95% CI 0.04-0.33, p < 0.001). T. trichiura prevalence decreased following one dose from 19.4% (74/372 participants) to 11.7% (56/505 participants) (OR 0.44, 95% CI 0.26-0.73, p = 0.0040), while egg count reduced in both arms (IVM-1: IRR 0.28, 95% CI 0.11-0.70, p = 0.0070; IVM-2: IRR 0.18, 95% CI 0.08-0.40, p < 0.001), in the individual-level analysis. We did not detect a significant difference in effect measures between the one- and two-dose arms for any species after 21 months. Interpretation: Our study highlights the long-term benefits of ivermectin MDA in reducing the burden of Strongyloides spp. and T. trichiura. STH control programs should leverage the geographical overlap of NTDs, existing drug distribution channels, and broad-spectrum agents. Funding: The National Health and Medical Research Council of Australia.

Antibiotics to eradicate Streptococcus pyogenes pharyngeal carriage in asymptomatic children and adults: A systematic review.

Streptococcus pyogenes (S. pyogenes) is a Gram-positive bacteria which causes a spectrum of diseases ranging from asymptomatic infection to life-threatening sepsis. Studies report up to 2000 times greater risk of invasive S. pyogenes disease in close contacts of index cases within 30-days of symptom onset. Despite this, there is variability in the management of asymptomatic carriage of S. pyogenes and those at risk of secondary cases of invasive S. pyogenes infection. OBJECTIVE: Our systematic review assessed the efficacy of different antibiotic regimens used for eradication of S. pyogenes from the pharynx in asymptomatic individuals. METHODS: We searched Pubmed, EMBASE (1974-), OVID Medline (1948-) and the Cochrane CENTRAL registry. We included randomised controlled trials (RCTs) with asymptomatic participants with >50% with pharyngeal cultures positive with S. pyogenes at baseline. Only studies with microbiological methods including culture (+/- polymerase chain reaction, PCR) were included. We included studies published in English. Each included study was assessed by two independent reviewers for data extraction and risk of bias. RESULTS: Of 1166 unique records identified, three RCTs were included in the review. Two of the three included RCTs found oral clindamycin for 10-days was the most efficacious regimen, compared to intramuscular benzathine penicillin G followed by 4 days of oral rifampicin, or monotherapy using benzathine penicillin, phenoxymethylpenicillin or erythromycin. Two RCTs were assessed as being at high risk of bias, with the third study demonstrating low/some risk of bias. CONCLUSIONS: Current available evidence for the optimal antibiotic in eradicating pharyngeal S. pyogenes carriage is limited. Future RCTs should include penicillin, first-generation cephalosporins, rifampicin, macrolides (such as azithromycin) and clindamycin.

Global Streptococcus pyogenes strain diversity, disease associations, and implications for vaccine development: a systematic review.

The high strain diversity of Streptococcus pyogenes serves as a major obstacle to vaccine development against this leading global pathogen. We did a systematic review of studies in PubMed, MEDLINE, and Embase that reported the global distribution of S pyogenes emm-types and emm-clusters from Jan 1, 1990, to Feb 23, 2023. 212 datasets were included from 55 countries, encompassing 74 468 bacterial isolates belonging to 211 emm-types. Globally, an inverse correlation was observed between strain diversity and the UNDP Human Development Index (HDI; r=-0·72; p<0·0001), which remained consistent upon subanalysis by global region and site of infection. Greater strain diversity was associated with a lower HDI, suggesting the role of social determinants in diseases caused by S pyogenes. We used a population-weighted analysis to adjust for the disproportionate number of epidemiological studies from high-income countries and identified 15 key representative isolates as vaccine targets. Strong strain type associations were observed between the site of infection (invasive, skin, and throat) and several streptococcal lineages. In conclusion, the development of a truly global vaccine to reduce the immense burden of diseases caused by S pyogenes should consider the multidimensional diversity of the pathogen, including its social and environmental context, and not merely its geographical distribution.

Outcomes of latent rheumatic heart disease: External validation of a simplified score in patients with and without secondary prophylaxis.

BACKGROUND: Secondary antibiotic prophylaxis reduces progression of latent rheumatic heart disease (RHD) but not all children benefit. Improved risk stratification could refine recommendations following positive screening. We aimed to evaluate the performance of a previously developed echocardiographic risk score to predict mid-term outcomes among children with latent RHD. METHODS: We included children who completed the GOAL, a randomized trial of secondary antibiotic prophylaxis among children with latent RHD in Uganda. Outcomes were determined by a 4-member adjudication panel. We applied the point-based score, consisting of 5 variables (mitral valve (MV) anterior leaflet thickening (3 points), MV excessive leaflet tip motion (3 points), MV regurgitation jet length ≥ 2 cm (6 points), aortic valve focal thickening (4 points) and any aortic regurgitation (5 points)), to panel results. Unfavorable outcome was defined as progression of diagnostic category (borderline to definite, mild definite to moderate/severe definite), worsening valve involvement or remaining with mild definite RHD. RESULTS: 799 patients (625 borderline and 174 definite RHD) were included, with median follow-up of 24 months. At total 116 patients (14.5%) had unfavorable outcome per study criteria, 57.8% not under prophylaxis. The score was strongly associated with unfavorable outcome (HR = 1.26, 95% CI 1.16-1.37, p < 0.001). Unfavorable outcome rates in low (≤6 points), intermediate (7-9 points) and high-risk (≥10 points) children at follow-up were 11.8%, 30.4%, and 42.2%, (p < 0.001) respectively (C-statistic = 0.64 (95% CI 0.59-0.69)). CONCLUSIONS: The simple risk score provided an accurate prediction of RHD status at 2-years, showing a good performance in a population with milder RHD phenotypes.

2023 World Heart Federation guidelines for the echocardiographic diagnosis of rheumatic heart disease.

Rheumatic heart disease (RHD) is an important and preventable cause of morbidity and mortality among children and young adults in low-income and middle-income countries, as well as among certain at-risk populations living in high-income countries. The 2012 World Heart Federation echocardiographic criteria provided a standardized approach for the identification of RHD and facilitated an improvement in early case detection. The 2012 criteria were used to define disease burden in numerous epidemiological studies, but researchers and clinicians have since highlighted limitations that have prompted a revision. In this updated version of the guidelines, we incorporate evidence from a scoping review, an expert panel and end-user feedback and present an approach for active case finding for RHD, including the use of screening and confirmatory criteria. These guidelines also introduce a new stage-based classification for RHD to identify the risk of disease progression. They describe the latest evidence and recommendations on population-based echocardiographic active case finding and risk stratification. Secondary antibiotic prophylaxis, echocardiography equipment and task sharing for RHD active case finding are also discussed. These World Heart Federation 2023 guidelines provide a concise and updated resource for clinical and research applications in RHD-endemic regions.

Naturally acquired functional antibody responses to group A Streptococcus differ between major strain types.

Group A Streptococcus (GAS) is a leading human pathogen for which there is no licensed vaccine. Infections are most common in young children and the elderly suggesting immunity accumulates with exposure until immune senescence in older age. Though protection has been postulated to be strain type specific, based on the M-protein (emm-type), the antigenic basis of population-level immunity remains poorly understood. Naturally acquired GAS antibody responses were investigated using intravenous immunoglobulin (IVIG), which contains pooled immunoglobulins from thousands of healthy human donors, as a surrogate for population immunity. Functional opsonophagocytic killing assays were conducted with GAS strains (n = 6) representing the three major emm-pattern types (emm12, A-C pattern; emm53, D-pattern; and emm75, E-pattern). While IVIG induced opsonophagocytic killing of all GAS strains tested, specificity assays showed the profile of protective antibodies differed considerably between emm-types. Antibodies targeting the M-protein were a major component of the functional IVIG antibody response for emm12 and emm53 strains but not for emm75 strains. The striking differences in the contribution of M-protein specific antibodies to killing suggest naturally acquired immunity differs between strains from the major emm-patterns. This challenges the dogma that M-protein is the primary protective antigen across all GAS straintypes. IMPORTANCE Group A Streptococcus (GAS) is a globally important pathogen. With the surge of invasive GAS infections that have occurred in multiple countries, contemporaneous with the relaxation of COVID-19 pandemic restrictions, there is increased interest in the mechanisms underpinning GAS immunity. We utilized intravenous immunoglobulin (IVIG), pooled immunoglobulins from thousands of healthy donors, as a surrogate for population-level immunity to GAS, and explored the contribution of strain-specific (M-type specific) antibodies to GAS immunity using functional killing assays. This revealed striking differences between major strain types as to the contribution of strain specific antibodies to killing. For GAS strains belonging to the E pattern group, M-type specific antibodies do not mediate killing and immunity, which contrasts with strains belonging to pattern A-C and D groups. This challenges the historical dogma, originally proposed by Rebecca Lancefield in the 1950-1960s, that the M-protein is the major protective antigen across all GAS strain types.

Strategic and scientific contributions of human challenge trials for vaccine development: facts versus fantasy.

The unprecedented speed of delivery of SARS-CoV-2 pandemic vaccines has redefined the limits for all vaccine development. Beyond the aspirational 100-day timeline for tomorrow's hypothetical pandemic vaccines, there is a sense of optimism that development of other high priority vaccines can be accelerated. Early in the COVID-19 pandemic, an intense and polarised academic and public discourse arose concerning the role of human challenge trials for vaccine development. A case was made for human challenge trials as a powerful tool to establish early proof-of-concept of vaccine efficacy in humans, inform vaccine down selection, and address crucial knowledge gaps regarding transmission, pathogenesis, and immune protection. We review the track record of human challenge trials contributing to the development of vaccines for 19 different pathogens and discuss relevant limitations, barriers, and pitfalls. This Review also highlights opportunities for efforts to broaden the scope and boost the effects of human challenge trials, to accelerate all vaccine development.

Scabies prevalence after ivermectin-based mass drug administration for lymphatic filariasis, Samoa 2018-2019.

BACKGROUND: Scabies is a common skin infestation caused by the Sarcoptes scabei mite. Ivermectin, one of three drugs used in mass drug administration (MDA) for lymphatic filariasis, is also effective for treating scabies. Ivermectin-based MDA was first conducted in Samoa in August 2018, with ivermectin being offered to those aged ≥5 years. Here, we report scabies prevalence in Samoa after MDA. METHODS: We conducted household surveys 1.5-3.5 months (Survey 1) and 6-8 months (Survey 2) after the 2018 MDA in 35 primary sampling units. We conducted clinical examination for scabies-like rash and used International Alliance for the Control of Scabies classification criteria. We estimated scabies prevalence by age, gender and region. Multivariable logistic regression was used to assess factors associated with prevalence. RESULTS: We surveyed 2868 people (499 households) and 2796 people (544 households) aged 0-75 years in Surveys 1 and 2, respectively. Scabies prevalence increased from 2.4% (95% CI 2.1-2.7%) to 4.4% (95% CI 4.0-4.9%) between surveys. Scabies was associated with younger age (0-4 years: aOR 3.5 [2.9-4.2]; 5-15 years: aOR 1.6 [1.4-1.8] compared to ≥16 years), female gender (aOR 1.2 [95% CI 1.1-1.4]; region (aOR range from 1.4 [1.1-1.7] to 2.5 [2.1-3.1] between regions), large households (aOR 2.6 [2.0-3.4] households ≥13), and not taking MDA in 2018 (aOR 1.3 [95% CI 1.1-1.6]). CONCLUSIONS: We found moderate prevalence of scabies in two population-representative surveys conducted within 8 months of the 2018 MDA for lymphatic filariasis. Prevalence appeared to increase between the surveys, and ongoing surveillance is recommended, particularly in young children.

Safety of Streptococcus pyogenes Vaccines: Anticipating and Overcoming Challenges for Clinical Trials and Post-Marketing Monitoring.

Streptococcus pyogenes (Strep A) infections result in a vastly underestimated burden of acute and chronic disease globally. The Strep A Vaccine Global Consortium's (SAVAC's) mission is to accelerate the development of safe, effective, and affordable S. pyogenes vaccines. The safety of vaccine recipients is of paramount importance. A single S. pyogenes vaccine clinical trial conducted in the 1960s raised important safety concerns. A SAVAC Safety Working Group was established to review the safety assessment methodology and results of more recent early-phase clinical trials and to consider future challenges for vaccine safety assessments across all phases of vaccine development. No clinical or biological safety signals were detected in any of these early-phase trials in the modern era. Improvements in vaccine safety assessments need further consideration, particularly for pediatric clinical trials, large-scale efficacy trials, and preparation for post-marketing pharmacovigilance.

A multicentre, retrospective audit of fosfomycin use for urinary tract infections in Australian children and adolescents.

BACKGROUND: Urinary tract infections (UTIs) due to MDR organisms are increasingly common. The lack of paediatric data on efficacious antibiotics makes UTI treatment particularly challenging. Data on the efficacy of fosfomycin use for UTI in children are variable. METHODS: We conducted a retrospective audit of children aged 0-18 years who were treated with fosfomycin for UTI at seven tertiary paediatric hospitals in Australia over a 7 year period, from 2014 to 2020. RESULTS: Ninety-one children with a median age of 5 years (range 2 months to 18 years) received oral fosfomycin for UTI. The majority (57/91, 63%) had one or more comorbidity, with the most common being renal tract anomalies (24/91, 26%). Fifty-nine (65%) had febrile UTI, 14/91 (15%) had pyelonephritis and 1/91 (1%) was bacteraemic. A majority (80/91, 88%) of urinary cultures had an ESBL-producing Gram-negative pathogen isolated. Fosfomycin susceptibility was evident in all 80 isolates tested. For uncomplicated UTI, the most common dose in children aged <1, 1-12 and >12 years was 1, 2 and 3 g, respectively. For complicated UTI, doses of 2 and 3 g were most common. The median duration of fosfomycin administration was 5 days (range 1-82). Clinical cure was achieved in 84/90 (93%); the six with treatment failure had underlying comorbidities. Overall, 2/91 (2%) children experienced drug-related adverse effects comprising gastrointestinal symptoms in both, which resolved after treatment discontinuation. CONCLUSIONS: Fosfomycin is well tolerated and associated with favourable treatment outcomes in children with UTI. Further research on the optimal dosing strategy is required.

The impact of ivermectin, diethylcarbamazine citrate, and albendazole mass drug administration on the prevalence of scabies and soil-transmitted helminths in school-aged children in three municipalities in Timor-Leste: a before-after assessment.

BACKGROUND: Integrated programmes that use combination mass drug administration (MDA) might improve control of multiple neglected tropical diseases simultaneously. We investigated the impact of Timor-Leste's national ivermectin, diethylcarbamazine citrate, and albendazole MDA, for lymphatic filariasis elimination and soil-transmitted helminth (STH) control, on scabies, impetigo, and STH infections. METHODS: We did a before-after study in six primary schools across three municipalities in Timor-Leste (urban [Dili], semi-urban [Ermera], and rural [Manufahi]) before (April 23 to May 11, 2019) and 18 months after (Nov 9 to Nov 27, 2020) MDA delivery between May 17 and June 1, 2019. Study participants included schoolchildren, as well as infants, children, and adolescents who were incidentally present at school on study days. All schoolchildren whose parents provided consent were eligible to participate in the study. Infants, children, and adolescents younger than 19 years who were not enrolled in the school but were incidentally present at schools on study days were also eligible to participate if their parents consented. Ivermectin, diethylcarbamazine citrate, and albendazole MDA was implemented nationally, with single doses of oral ivermectin (200 µg/kg), diethylcarbamazine citrate (6 mg/kg), and albendazole (400 mg) administered by the Ministry of Health. Scabies and impetigo were assessed by clinical skin examinations, and STHs using quantitative PCR. The primary (cluster-level) analysis adjusted for clustering while the secondary (individual-level) analysis adjusted for sex, age, and clustering. The primary outcomes of the study were prevalence ratios for scabies, impetigo, and STHs (Trichuris trichiura, Ascaris lumbricoides, Necator americanus, and moderate-to-heavy A lumbricoides infections) between baseline and 18 months from the cluster-level analysis. FINDINGS: At baseline, 1043 (87·7%) of 1190 children registered for the study underwent clinical assessment for scabies and impetigo. The mean age of those who completed skin examinations was 9·4 years (SD 2·4) and 514 (53·8%) of 956 were female (87 participants with missing sex data were excluded from this percentage calculation). Stool samples were received for 541 (45·5%) of 1190 children. The mean age of those for whom stool samples were received was 9·8 years (SD 2·2) and 300 (55·5%) were female. At baseline, 348 (33·4%) of 1043 participants had scabies, and 18 months after MDA, 133 (11·1%) of 1196 participants had scabies (prevalence ratio 0·38, 95% CI 0·18-0·88; p=0·020) in the cluster-level analysis. At baseline, 130 (12·5%) of 1043 participants had impetigo, compared with 27 (2·3%) of 1196 participants at follow-up (prevalence ratio 0·14, 95% CI 0·07-0·27; p<0·0001). There was a significant reduction in T trichiura prevalence from baseline (26 [4·8%] of 541 participants) to 18-month follow-up (four [0·6%] of 623 participants; prevalence ratio 0·16, 95% CI 0·04-0·66; p<0·0001). In the individual-level analysis, moderate-to-heavy A lumbricoides infections reduced from 54 (10·0%; 95% CI 0·7-19·6) of 541 participants to 28 (4·5%, 1·2-8·4) of 623 participants (relative reduction 53·6%; 95% CI 9·1-98·1; p=0·018). INTERPRETATION: Ivermectin, diethylcarbamazine citrate, and albendazole MDA was associated with substantial reductions in prevalence of scabies, impetigo, and T trichiura, and of moderate-to-heavy intensity A lumbricoides infections. Combination MDA could be used to support integrated control programmes to target multiple NTDs. FUNDING: National Health and Medical Research Council of Australia and the Department of Foreign Affairs and Trade Indo-Pacific Centre for Health Security. TRANSLATION: For the Tetum translation of the abstract see Supplementary Materials section.

A novel anterior nasal swab to detect respiratory viruses: a prospective study of diagnostic accuracy.

Detection of respiratory viruses requires testing of the upper respiratory tract to obtain specimens for analysis. However, nasal and throat swabs can cause discomfort and procedural anxiety in children. Respiratory sampling methods which are accurate and less invasive are needed. We aim to determine the positive and negative percentage agreement of a novel anterior nasal swab (ANS) compared with the combined throat and anterior nasal swab (CTN), the reference standard, for detection of respiratory viruses. Children 5 - 18 years of age presenting to a tertiary paediatric hospital with respiratory symptoms were tested with both swabs in randomised order. Respiratory samples were tested on a multiplex RT-PCR panel. Viral detections, RT-PCR cycle-threshold values and child/parent/clinician experience of the swab were recorded. There were 157 viral detections from 249 participant CTN swabs. In comparison with the CTN, the overall positive and negative percentage agreement of ANS for detection of respiratory viruses was 96.2% (95% CI, 91.8-98.3%) and 99.8% (95% CI, 99.6-99.9%), respectively. The ANS was "extremely comfortable", or only a "little uncomfortable" for 90% of children compared with 48% for CTN. 202 children (84%) rated the ANS as the preferred swab, and 208 (87%) indicated they would prefer ANS for future testing. The ANS required additional laboratory handling processes compared to the CTN. The ANS has high positive percentage agreement and is comparable to the current standard of care. The high acceptability from the less invasive ANS provides a more comfortable method for respiratory virus testing in children.Trial registrationClinicalTrials.gov ID NCT05043623.

Population-based assessment of cardiovascular complications of rheumatic heart disease in Fiji: a record-linkage analysis.

OBJECTIVE: To determine population-based rates of non-fatal complications of rheumatic heart disease (RHD). DESIGN: Retrospective cohort study based on multiple sources of routine clinical and administrative data amalgamated by probabilistic record-linkage. SETTING: Fiji, an upper-middle-income country, where most of the population has access to government-funded healthcare services. PARTICIPANTS: National cohort of 2116 patients with clinically apparent RHD aged 5-69 years during 2008 and 2012. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was hospitalisation for any of heart failure, atrial fibrillation, ischaemic stroke and infective endocarditis. Secondary outcomes were first hospitalisation for each of the complications individually in the national cohort as well as in hospital (n=1300) and maternity (n=210) subsets. Information on outcomes was obtained from discharge diagnoses coded in the hospital patient information system. Population-based rates were obtained using relative survival methods with census data as the denominator. RESULTS: Among 2116 patients in the national cohort (median age, 23.3 years; 57.7% women), 546 (25.8%) were hospitalised for an RHD complication, a substantial proportion of all cardiovascular admissions in the country during this period in those aged 0-40 years (heart failure, 210/454, 46.3%; ischaemic stroke 31/134, 23.1%). Absolute numbers of RHD complications peaked during the third decade of life with higher population-based rates in women compared with men (incidence rate ratio 1.4, 95% CI 1.3 to 1.6, p<0.001). Hospitalisation for any RHD complication was associated with substantially increased risk of death (HR 5.4, 95% CI 3.4 to 8.8, p<0.001), especially after the onset of heart failure (HR 6.6, 95% CI 4.8 to 9.1, p<0.001). CONCLUSIONS: Our study defines the burden of RHD-attributable morbidity in the general population of Fiji, potentially reflecting the situation in low-income and middle-income countries worldwide. Hospitalisation for an RHD complication is associated with markedly increased risk of death, re-emphasising the importance of effective early prevention.

One versus two doses of ivermectin-based mass drug administration for the control of scabies: A cluster randomised non-inferiority trial.

BACKGROUND: Mass drug administration (MDA) based on two doses of ivermectin, one week apart, substantially reduces prevalence of both scabies and impetigo. The Regimens of Ivermectin for Scabies Elimination (RISE) trial assessed whether one-dose ivermectin-based MDA would be as effective. METHODS: RISE was a cluster-randomised trial in Solomon Islands. We assigned 20 villages in a 1:1 ratio to one- or two-dose ivermectin-based MDA. We planned to test whether the impact of one dose on scabies prevalence at 12 and 24 months was non-inferior to two, at a 5% non-inferiority margin. RESULTS: We deferred endpoint assessment to 21 months due to COVID-19. We enrolled 5239 participants in 20 villages at baseline and 3369 at 21 months from an estimated population of 5500. At baseline scabies prevalence was similar in the two arms (one-dose 17·2%; two-dose 13·2%). At 21 months, there was no reduction in scabies prevalence (one-dose 18·7%; two-dose 13·4%), and the confidence interval around the difference included values substantially greater than 5%. There was however a reduction in prevalence among those who had been present at the baseline assessment (one-dose 15·9%; two-dose 10·8%). Additionally, we found a reduction in both scabies severity and impetigo prevalence in both arms, to a similar degree. CONCLUSIONS: There was no indication of an overall decline in scabies prevalence in either arm. The reduction in scabies prevalence in those present at baseline suggests that the unexpectedly high influx of people into the trial villages, likely related to the COVID-19 pandemic, may have compromised the effectiveness of the MDA. Despite the lack of effect there are important lessons to be learnt from this trial about conducting MDA for scabies in high prevalence settings. TRIAL REGISTRATION: Registered with Australian New Zealand Clinical Trials Registry ACTRN12618001086257.

Paediatric admissions with SARS-CoV-2 during the Delta and Omicron waves: an Australian single-centre retrospective study.

BACKGROUND: The clinical course of Australian children admitted to hospital with COVID-19 infection is not well understood, particularly over the Omicron period. METHODS: This study describes paediatric admissions to a single tertiary paediatric institution through the Delta and Omicron variant waves. All children admitted from 1 June 2021 to 30 September 2022 with a diagnosis of COVID-19 infection were included for analysis. RESULTS: 117 patients were admitted during the Delta wave compared with 737 during the Omicron wave. The median length of stay was 3.3 days (IQR 1.7-6.75.1) during Delta, compared with 2.1 days (IQR 1.1-4.53.4) during Omicron (p<0.01). 83 patients (9.7%) required intensive care unit (ICU) admission, a greater proportion during Delta (20, 17.1%) than Omicron (63, 8.6%, p<0.01). Patients admitted to the ICU were less likely to have received a dose of COVID-19 vaccination prior to admission than patients admitted to the ward (8, 24.2% vs 154, 45.8%, p=0.028). CONCLUSION: The Omicron wave resulted in an absolute increase in the number of children compared with Delta, but cases had lower severity, demonstrated by shorter length of stay and a smaller proportion of patients requiring intensive care. This is consistent with US and UK data describing a similar pattern.

The Streptococcus pyogenes vaccine landscape.

Recent efforts have re-invigorated the Streptococcus pyogenes (Group A Streptococcus) vaccine development field, though scientific, regulatory and commercial barriers persist, and the vaccine pipeline remains sparse. There is an ongoing need to accelerate all aspects of development to address the large global burden of disease caused by the pathogen. Building on over 100 years of S. pyogenes vaccine development, there are currently eight candidates on a product development track, including four M protein-based candidates and four candidates designed around non-M protein antigens. These candidates have demonstrated proof of concept for protection against S. pyogenes in preclinical models, one has demonstrated safety and immunogenicity in a Phase 1 trial and at least four others are poised to soon enter clinical trials. To maintain momentum, the Strep A Vaccine Global Consortium (SAVAC) was established to bring together experts to accelerate global S. pyogenes vaccine development. This article highlights the past, present and future of S. pyogenes vaccine development and emphasizes key priorities, and the role of SAVAC, in advancing the field.