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Environmental factors including household crowding and inadequate washing facilities underpin recurrent streptococcal infections in childhood that cause acute rheumatic fever (ARF) and subsequent rheumatic heart disease (RHD). No community-based 'primordial'-level interventions to reduce streptococcal infection and ARF rates have been reported from Australia previously. We conducted a study at three Australian Aboriginal communities aiming to reduce infections including skin sores and sore throats, usually caused by Group A Streptococci, and ARF. Data were collected for primary care diagnoses consistent with likely or potential streptococcal infection, relating to ARF or RHD or related to environmental living conditions. Rates of these diagnoses during a one-year Baseline Phase were compared with a three-year Activity Phase. Participants were children or adults receiving penicillin prophylaxis for ARF. Aboriginal community members were trained and employed to share knowledge about ARF prevention, support reporting and repairs of faulty health-hardware including showers and provide healthcare navigation for families focusing on skin sores, sore throat and ARF. We hypothesized that infection-related diagnoses would increase through greater recognition, then decrease. We enrolled 29 participants and their families. Overall infection-related diagnosis rates increased from Baseline (mean rate per-person-year 1.69 [95% CI 1.10-2.28]) to Year One (2.12 [95% CI 1.17-3.07]) then decreased (Year Three: 0.72 [95% CI 0.29-1.15]) but this was not statistically significant ( p = 0.064). Annual numbers of first-known ARF decreased, but numbers were small: there were six cases of first-known ARF during Baseline, then five, 1, 0 over the next three years respectively. There was a relationship between household occupancy and numbers ( p = 0.018), but not rates ( p = 0.447) of infections. This first Australian ARF primordial prevention study provides a feasible model with encouraging findings.

The goals of acute rheumatic fever therapy are to relieve symptoms, mitigate cardiac valve damage and eradicate streptococcal infection. Preventing future recurrences requires long-term secondary antibiotic prophylaxis and ongoing prevention of Streptococcus pyogenes (group A streptococcus) infections The recommended regimen for secondary prophylaxis comprises benzathine benzylpenicillin G intramuscular injections every four weeks. For patients with non-severe or immediate penicillin hypersensitivity, use erythromycin orally twice daily The goals of therapy for rheumatic heart disease are to prevent progression and optimise cardiac function. Secondary antibiotic prophylaxis can reduce the long-term severity of rheumatic heart disease Patients with rheumatic heart disease, including those receiving benzathine benzylpenicillin G prophylaxis, should receive amoxicillin prophylaxis before undergoing high-risk dental or surgical procedures. If they have recently been treated with a course of penicillin or amoxicillin, or have immediate penicillin hypersensitivity, clindamycin is recommended., ((c) NPS MedicineWise.)

Objectives: To establish the priorities of primary care providers to improve assessment and treatment of skin sores and sore throats among Aboriginal and Torres Strait Islander people at risk of acute rheumatic fever (ARF) and rheumatic heart disease (RHD)., Design: Modified eDelphi survey, informed by an expert focus group and literature review., Setting: Primary care services in any one of the five Australian states or territories with a high burden of ARF., Participants: People working in any primary care role within the last 5 years in jurisdiction with a high burden of ARF., Results: Nine people participated in the scoping expert focus group which informed identification of an access framework for subsequent literature review. Fifteen broad concepts, comprising 29 strategies and 63 different actions, were identified on this review. These concepts were presented to participants in a two-round eDelphi survey. Twenty-six participants from five jurisdictions participated, 16/26 (62%) completed both survey rounds. Seven strategies were endorsed as high priorities. Most were demand-side strategies with a focus on engaging communities and individuals in accessible, comprehensive, culturally appropriate primary healthcare. Eight strategies were not endorsed as high priority, all of which were supply-side approaches. Qualitative responses highlighted the importance of a comprehensive primary healthcare approach as standard of care rather than disease-specific strategies related to management of skin sores and sore throat., Conclusion: Primary care staff priorities should inform Australia's commitments to reduce the burden of RHD. In particular, strategies to support comprehensive Aboriginal and Torres Strait Islander primary care services rather than an exclusive focus on discrete, disease-specific initiatives are needed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To explore the acceptability of a novel, outreached-based approach to improve primary and primordial prevention of Strep A skin sores, sore throats and acute rheumatic fever in remote Aboriginal communities., Methods: A comprehensive prevention program delivered by trained Aboriginal Community Workers was evaluated using approximately fortnightly household surveys about health and housing and clinical records., Results: Twenty-seven primary participants from three remote Aboriginal communities in the Northern Territory consented, providing 37.8 years of retrospective baseline data and 18.5 years of prospective data during the study period. Household members were considered to be secondary participants. Five Aboriginal Community Workers were trained and employed, delivering a range of supports to households affected by acute rheumatic fever including environmental health support and education. Clinical record audit and household self-report of Strep A infections were compared. No association between clinical- and self-report was identified., Conclusions: Ongoing participation suggests this outreach-based prevention program was acceptable and associated with improved reporting of household maintenance issues and awareness of prevention opportunities for Strep A infections. Implications for public health: Biomedical, clinic-based approaches to the management of Strep A infections in remote communities can be usefully augmented by outreach-based supports delivered by Aboriginal Community Workers responding to community needs., (© 2021 The Authors.)

Introduction: The absence of a diagnostic test for acute rheumatic fever (ARF) is a major impediment in managing this serious childhood condition. ARF is an autoimmune condition triggered by infection with group A Streptococcus . It is the precursor to rheumatic heart disease (RHD), a leading cause of health inequity and premature mortality for Indigenous peoples of Australia, New Zealand and internationally. METHODS AND ANALYSIS: 'Searching for a Technology-Driven Acute Rheumatic Fever Test' (START) is a biomarker discovery study that aims to detect and test a biomarker signature that distinguishes ARF cases from non-ARF, and use systems biology and serology to better understand ARF pathogenesis. Eligible participants with ARF diagnosed by an expert clinical panel according to the 2015 Revised Jones Criteria, aged 5-30 years, will be recruited from three hospitals in Australia and New Zealand. Age, sex and ethnicity-matched individuals who are healthy or have non-ARF acute diagnoses or RHD, will be recruited as controls. In the discovery cohort, blood samples collected at baseline, and during convalescence in a subset, will be interrogated by comprehensive profiling to generate possible diagnostic biomarker signatures. A biomarker validation cohort will subsequently be used to test promising combinations of biomarkers. By defining the first biomarker signatures able to discriminate between ARF and other clinical conditions, the START study has the potential to transform the approach to ARF diagnosis and RHD prevention., Ethics and Dissemination: The study has approval from the Northern Territory Department of Health and Menzies School of Health Research ethics committee and the New Zealand Health and Disability Ethics Committee. It will be conducted according to ethical standards for research involving Indigenous Australians and New Zealand Māori and Pacific Peoples. Indigenous investigators and governance groups will provide oversight of study processes and advise on cultural matters., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Echocardiographic screening can detect asymptomatic cases of rheumatic heart disease (RHD), facilitating access to treatment. Barriers to implementation of echocardiographic screening include the requirement for expensive equipment and expert practitioners. We aimed to evaluate the diagnostic accuracy of an abbreviated echocardiographic screening protocol (single parasternal-long-axis view with a sweep of the heart) performed by briefly trained, nonexpert practitioners using handheld ultrasound devices., Methods: Participants aged 5 to 20 years in Timor-Leste and the Northern Territory of Australia had 2 echocardiograms: one performed by an expert echocardiographer using a GE Vivid I or Vivid Q portable ultrasound device (reference test), and one performed by a nonexpert practitioner using a GE Vscan handheld ultrasound device (index test). The accuracy of the index test, compared with the reference test, for identifying cases with definite or borderline RHD was determined., Results: There were 3111 enrolled participants; 2573 had both an index test and reference test. Median age was 12 years (interquartile range, 10-15); 58.2% were female. Proportion with definite or borderline RHD was 5.52% (95% CI, 4.70-6.47); proportion with definite RHD was 3.23% (95% CI, 2.61-3.98). Compared with the reference test, sensitivity of the index test for definite or borderline RHD was 70.4% (95% CI, 62.2-77.8), specificity was 78.1% (95% CI, 76.4-79.8)., Conclusions: Nonexpert practitioners can be trained to perform single parasternal-long-axis view with a sweep of the heart echocardiography. However, the specificity and sensitivity are inadequate for echocardiographic screening. Improved training for nonexpert practitioners should be investigated.

Background: The Northern Territory (NT) has the highest tuberculosis (TB) rate of all Australian jurisdictions. We combined TB public health surveillance data with genomic sequencing of Mycobacterium tuberculosis isolates in the tropical 'Top End' of the NT to investigate trends in TB incidence and transmission., Methods: This retrospective observational study included all 741 culture-confirmed cases of TB in the Top End over three decades from 1989-2020. All 497 available M. tuberculosis isolates were sequenced. We used contact tracing data to define a threshold pairwise SNP distance for hierarchical single linkage clustering, and examined putative transmission clusters in the context of epidemiologic information., Findings: There were 359 (48%) cases born overseas, 329 (44%) cases among Australian First Nations peoples, and 52 (7%) cases were Australian-born and non-Indigenous. The annual incidence in First Nations peoples from 1989-2019 fell from average 50.4 to 11.0 per 100,000 (P<0·001). First Nations cases were more likely to die from TB (41/329, 12·5%) than overseas-born cases (11/359, 3·1%; P<0·001). Using a threshold of ≤12 SNPs, 28 clusters of between 2-64 individuals were identified, totalling 250 cases; 214 (86%) were First Nations cases and 189 (76%) were from a remote region. The time between cases and past epidemiologically- and genomically-linked contacts ranged from 4·5 months to 24 years., Interpretation: Our findings support prioritisation of timely case detection, contact tracing augmented by genomic sequencing, and latent TB treatment to break transmission chains in Top End remote hotspot regions., Competing Interests: The authors have no conflicts of interest to declare., (© 2021 The Authors.)

Tuberculosis is a leading public health priority in eastern Malaysia. Knowledge of the genomic epidemiology of tuberculosis can help tailor public health interventions. Our aims were to determine tuberculosis genomic epidemiology and characterize resistance mutations in the ethnically diverse city of Kota Kinabalu, Sabah, located at the nexus of Malaysia, Indonesia, Philippines and Brunei. We used an archive of prospectively collected Mycobacterium tuberculosis samples paired with epidemiological data. We collected sputum and demographic data from consecutive consenting outpatients with pulmonary tuberculosis at the largest tuberculosis clinic from 2012 to 2014, and selected samples from tuberculosis inpatients from the tertiary referral centre during 2012-2014 and 2016-2017. Two hundred and eight M . tuberculosis sequences were available for analysis, representing 8 % of cases notified during the study periods. Whole-genome phylogenetic analysis demonstrated that most strains were lineage 1 (195/208, 93.8 %), with the remainder being lineages 2 (8/208, 3.8 %) or 4 (5/208, 2.4 %). Lineages or sub-lineages were not associated with patient ethnicity. The lineage 1 strains were diverse, with sub-lineage 1.2.1 being dominant (192, 98 %). Lineage 1.2.1.3 isolates were geographically most widely distributed. The greatest diversity occurred in a border town sub-district. The time to the most recent common ancestor for the three major lineage 1.2.1 clades was estimated to be the year 1966 (95 % HPD 1948-1976). An association was found between failure of culture conversion by week 8 of treatment and infection with lineage 2 (4/6, 67 %) compared with lineage 1 strains (4/83, 5 %) ( P <0.001), supporting evidence of greater virulence of lineage 2 strains. Eleven potential transmission clusters (SNP difference ≤12) were identified; at least five included people living in different sub-districts. Some linked cases spanned the whole 4-year study period. One cluster involved a multidrug-resistant tuberculosis strain matching a drug-susceptible strain from 3 years earlier. Drug resistance mutations were uncommon, but revealed one phenotype-genotype mismatch in a genotypically multidrug-resistant isolate, and rare nonsense mutations within the katG gene in two isolates. Consistent with the regionally mobile population, M. tuberculosis strains in Kota Kinabalu were diverse, although several lineage 1 strains dominated and were locally well established. Transmission clusters - uncommonly identified, likely attributable to incomplete sampling - showed clustering occurring across the community, not confined to households or sub-districts. The findings indicate that public health priorities should include active case finding and early institution of tuberculosis management in mobile populations, while there is a need to upscale effective contact investigation beyond households to include other contacts within social networks.

Background: Acute rheumatic fever (ARF) is an abnormal immune reaction following Streptococcus pyogenes (Strep A) infection of the throat, and likely the skin. Primary prevention is the prompt and appropriate antibiotic treatment of Strep A infection, and it can reduce the risk of developing ARF and subsequent rheumatic heart disease., Objective: This article explores current recommendations for primary prevention of ARF in Australia., Discussion: People at increased risk of ARF should be offered empirical antibiotic treatment of Strep A infections to reduce this risk. People at increased ARF risk include young Aboriginal and Torres Strait Islander people in remote Australia as well as those with a personal or family history of ARF and people from migrant communities in urban areas, including Māori and Pacific Island people. Risk-stratified primary prevention can reduce the inequitable burden of ARF and rheumatic heart disease in Australia.

Context: Indigenous children and adolescents in Australia and globally bear the burden of acute rheumatic fever (ARF). It has been virtually eliminated in well-resourced, developed settings. ARF is an autoimmune response to infection with group A Streptococcus. The mainstay of management is long-acting intramuscular penicillin injections to prevent recurrence of ARF and development of rheumatic heart disease (RHD), comprising valvular pathology and attendant complications. In Australia, penicillin injections are currently prescribed every 28 days for 5-10 years after diagnosis of ARF, depending on cardiac involvement. Adherence to this regimen reduces ARF recurrences and RHD progression. 'Days at risk' of ARF recurrence are calculated as the number of days after day 28 that an injection is not received. Adherence to the injection schedule has been reported as difficult in most global locations due to the painful nature of the injections, the long timeframes of the prescription, young age of patients, access problems and costs in some locations. The newly updated Australian guideline on the prevention, diagnosis and management of ARF and RHD has a chapter dedicated to secondary prophylaxis. This chapter takes into account cultural considerations and advises on ways to minimise pain and distress of injections in children such as pain gate strategies, distraction techniques and concurrent injection of local anaesthetic., Issues: Some children continue to find the injection regimen traumatising despite strategies to reduce pain and fear. Clinicians providing the injections to children also find the injecting episodes distressing if pain is not effectively minimised. An Aboriginal Community Controlled Health Service in a remote setting in northern Australia addressed the issue of severe trauma of injection episodes experienced by an Aboriginal boy aged 7 years. Usual strategies were not effective, so advice was sought from an expert anaesthetist at a tertiary hospital. As a result, oral clonidine 3 &micro;g/kg was trialled 45 minutes prior to the penicillin injection. Procedural coaching and monitoring protocols specific to administration of clonidine in children under their care were created by the health service. The initial dose of clonidine was delivered with the child as an inpatient., Lessons Learned: Clonidine was successful in reducing pain related distress and facilitating adherence to the penicillin regimen. Subsequent doses were delivered and monitored in a remote setting by nurses. After 18 months, the boy no longer required clonidine due to his increased coping capacity. A second child was recognised with similar trauma and has been taking clonidine for pre-procedural sedation for 6 months with good effect and no adverse effects. An additional child was similarly prescribed clonidine without success. Failure in that instance was attributed to lack of procedural coaching and receiving the initial dose of clonidine in an emergency department in hurried circumstances. Individualised child-focused and culturally appropriate care in remote settings is feasible: in this instance team planning for use of clonidine and procedural coaching when other measures have failed. However, for children with RHD, or other comorbidities, advice from the child's treating cardiologist is required prior to prescribing clonidine due to possible adverse consequences. These include hypotension and atrioventricular block, which could lead to haemodynamic compromise in the setting of moderate to severe RHD.

Setting: Outpatient clinics, Kota Kinabalu, Malaysia; January-April 2018., Objectives: To identify barriers to full participation in tuberculosis (TB) contact investigation., Methods: Cross-sectional study of knowledge, perceptions, and behaviours among TB contacts. This study was conducted among contacts who attended an initial clinic visit to explore retention in care. During this first visit, contacts were approached for participation in a questionnaire at a follow-up visit. Contacts who consented but did not subsequently attend were interviewed at home. Associations between questionnaire findings and attendance were tested using logistic regression., Results: Of the total 1436 identified contacts, 800 (56%) attended an initial clinic visit. Of 237 consenting TB contacts, 207 (87%) attended their follow-up appointment. In univariable analyses, the odds of attendance were highest for people notified to attend the TB clinic directly by a health inspector; close relatives of TB patients; non-students; people with higher incomes and smaller households; older individuals; males; and people not perceiving TB as stigmatising. In multivariable analysis, mode of notification to attend and having a close relative with TB remained significant., Conclusions: Health inspectors provide an effective role in TB contact investigation through direct personal communication to encourage the completion of the TB screening process, but this requires further integration with clinical processes, and with workplace and school-based investigations.

Background: Aboriginal cultural awareness training aims to build a culturally responsive workforce, however research has found the training has limited impact on the health professional's ability to provide culturally safe care. This study examined cultural awareness training feedback from healthcare professionals working with high Aboriginal patient caseloads in the Top End of the Northern Territory of Australia. The aim of the research was to assess the perception of training and the potential for expansion to better meet workforce needs., Methods: Audit and qualitative thematic analysis of cultural awareness training evaluation forms completed by course participants between March and October 2018. Course participants ranked seven teaching domains using five-point Likert scales (maximum summary score 35 points) and provided free-text feedback. Data were analysed using the Framework Method and assessed against Kirkpatrick's training evaluation model. Cultural safety and decolonising philosophies shaped the approach., Results: 621 participants attended 27 ACAP sessions during the study period. Evaluation forms were completed by 596 (96%). The mean overall assessment score provided was 34/35 points (standard deviation 1.0, range 31-35) indicating high levels of participant satisfaction. Analysis of 683 free text comments found participants wanted more cultural education, designed and delivered by local people, which provides an opportunity to consciously explore both Aboriginal and non-Aboriginal cultures (including self-reflection). Regarding the expansion of cultural education, four major areas requiring specific attention were identified: communication, kinship, history and professional relevance. A strength of this training was the authentic personal stories shared by local Aboriginal cultural educators, reflecting community experiences and attitudes. Criticism of the current model included that too much information was delivered in one day., Conclusions: Healthcare providers found cultural awareness training to be an invaluable entry point. Cultural education which elevates the Aboriginal health user's experience and provides health professionals with an opportunity for critical self-reflection and practical solutions for common cross-cultural clinical encounters may improve the delivery of culturally safe care. We conclude that revised models of cultural education should be developed, tested and evaluated. This requires institutional support, and recognition that cultural education can contribute to addressing systemic racism.

Objectives: We report a cluster of acute rheumatic fever (ARF) cases and the public health response in a high-burden Australian setting., Methods: The public health unit was notified of an increase in ARF cases in a remote Australian Aboriginal community. A multi-disciplinary group coordinated the response. Household contacts were screened for ARF or group A Streptococcus (GAS) infection by questionnaire and swab collection, offered an echocardiogram if aged 5-20 years, and intramuscular benzathine benzylpenicillin if aged over one year or if less than one year with impetigo., Results: Fifteen definite and seven probable ARF cases were diagnosed in the community in July-December 2014 (all-age incidence of definite ARF: 1,473/100,000). The public health response identified two additional cases of ARF. A total of 81 contacts were screened; GAS was detected in 3/76 (4%) throat swabs and 11/24 (46%) skin swabs. Molecular typing revealed high GAS strain diversity., Conclusions: The incidence of ARF during this cluster was very high. Carriage and infection with GAS was observed, but no outbreak strain identified. Implications for public health: A national public health guideline has since been developed that includes advice on the investigation of an ARF outbreak/cluster. Sustained efforts with strong community engagement are required to tackle high ARF rates., (© 2019 The Authors.)

Strategies to date have been ineffective in reducing high rates of rheumatic heart disease (RHD) in Australian Aboriginal people; a disease caused by streptococcal infections. A remote Aboriginal community initiated a collaboration to work towards elimination of RHD. Based in 'both-way learning' (reciprocal knowledge co-creation), the aim of this study was to co-design, implement and evaluate community-based participatory action research (CBPAR) to achieve this vision. Activities related to understanding and addressing RHD social determinants were delivered through an accredited course adapted to meet learner and project needs. Theory-driven evaluation linking CBPAR to empowerment was applied. Data collection comprised focus groups, interviews, observation, and co-development and use of measurement tools such as surveys. Data analysis utilised process indicators from national guidelines for Aboriginal health research, and outcome indicators derived from the Wallerstein framework. Findings include the importance of valuing traditional knowledges and ways of learning such as locally-meaningful metaphors to explore unfamiliar concepts; empowerment through critical thinking and community ownership of knowledge about RHD and research; providing practical guidance in implementing empowering and decolonising principles / theories. Lessons learned are applicable to next stages of the RHD elimination strategy which must include scale-up of community leadership in research agenda-setting and implementation., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Globally, there is wide variation in streptococcal titer upper limits of normal (ULN) for antistreptolysin O (ASO) and anti-deoxyribonuclease B (ADB) used as an evidence of recent group A streptococcal infection to diagnose acute rheumatic fever (ARF)., Methods: We audited ASO and ADB titers among individuals with ARF in New Zealand (NZ) and in Australia's Northern Territory. We summarized streptococcal titers by different ARF clinical manifestations, assessed application of locally recommended serology guidelines where NZ uses high ULN cut-offs and calculated the proportion of cases fulfilling alternative serologic diagnostic criteria., Results: From January 2013 to December 2015, group A streptococcal serology results were available for 350 patients diagnosed with ARF in NZ and 182 patients in Northern Territory. Median peak streptococcal titers were similar in both settings. Among NZ cases, 267/350 (76.3%) met NZ serologic diagnostic criteria, whereas 329/350 (94.0%) met Australian criteria. By applying Australian ULN titer cut-off criteria to NZ cases, excluding chorea, ARF definite cases would increase by 17.6% representing 47 cases., Conclusions: ASO and ADB values were similar in these settings. Use of high ULN cut-offs potentially undercounts definite and probable ARF diagnoses. We recommend NZ and other high-burden settings to use globally accepted, age-specific, lower serologic cut-offs to avoid misclassification of ARF.

Objective: To explore young Aboriginal people's and clinicians' experiences of injection pain for the 10 years of penicillin injections children are prescribed to prevent rheumatic fever recurrences., Methods: Aboriginal children on the penicillin regimen and clinicians were purposively recruited from four remote sites in Australia. Semi-structured interviews and participant observations were conducted. Views were synthesised and thematically analysed., Results: A total of 29 Aboriginal children and 59 clinicians were interviewed. Sixteen participants appeared to become accustomed to the injection pain, eight did not find pain an issue, and five found injection pain difficult. A further five believed the injections made them unwell. Patients expressed varying abilities to negotiate with clinicians about the use of pain reduction measures. Clinicians revealed good knowledge of pain reduction measures, but offered them inconsistently. All clinicians found administering the injections distressing., Conclusion: Repeated painful procedures in children necessitate well-planned and child-focused care. Current practices are not in line with guidance from the Royal Australasian College of Physicians about effects of repeated painful procedures on children. Initiating the long-term injection regimen for rheumatic fever is a special event requiring expert input. A newly reported finding of a subset of young people feeling unwell after receiving the injection requires further investigation. Implications for public health: Improvement of local and jurisdictional guidelines on use of pain reduction measures for children who have been prescribed repeated painful injections for rheumatic fever is needed., (© 2017 The Authors.)

Opinion Statement: Early recognition of group A streptococcal pharyngitis and appropriate management with benzathine penicillin using local clinical prediction rules together with validated rapi-strep testing when available should be incorporated in primary health care. A directed approach to the differential diagnosis of acute rheumatic fever now includes the concept of low-risk versus medium-to-high risk populations. Initiation of secondary prophylaxis and the establishment of early medium to long-term care plans is a key aspect of the management of ARF. It is a requirement to identify high-risk individuals with RHD such as those with heart failure, pregnant women, and those with severe disease and multiple valve involvement. As penicillin is the mainstay of primary and secondary prevention, further research into penicillin supply chains, alternate preparations and modes of delivery is required.

Background: In pulmonary tuberculosis (PTB), morbidity during treatment and residual pulmonary disability can be under-estimated., Methods: Among adults with smear-positive PTB at an outpatient clinic in Papua, Indonesia, we assessed morbidity at baseline and during treatment, and 6-month residual disability, by measuring functional capacity (six-minute walk test [6MWT] and pulmonary function), quality of life (St George's Respiratory Questionnaire [SGRQ]) and Adverse Events ([AE]: new symptoms not present at outset). Results were compared with findings in locally-recruited volunteers., Results: 200 PTB patients and 40 volunteers were enrolled. 6WMT was 497m (interquartile range 460-529) in controls versus 408m (IQR 346-450) in PTB patients at baseline (p<0.0001) and 470m (IQR 418-515) in PTB patients after 6 months (p=0.02 versus controls). SGRQ total score was 0 units (IQR 0-2.9) in controls, versus 36.9 (27.4-52.8) in PTB patients at baseline (p<0.0001) and 4.3 (1.7-8.8) by 6 months (p<0.0001). Mean percentage of predicted FEV1 was 92% (standard deviation 19.9) in controls, versus 63% (19.4) in PTB patients at baseline (p<0.0001) and 71% (17.5) by 6 months (p<0.0001). After 6 months, 27% of TB patients still had at least moderate-severe pulmonary function impairment, and 57% still had respiratory symptoms, despite most achieving 'successful' treatment outcomes, and reporting good quality of life. More-advanced disease at baseline (longer illness duration, worse baseline X-ray) and HIV positivity predicted residual disability. AE at any time during treatment were common: itch 59%, arthralgia 58%, headache 40%, nausea 33%, vomiting 16%., Conclusion: We found high 6-month residual pulmonary disability and high AE rates. Although PTB treatment is highly successful, the extent of morbidity during treatment and residual impairment could be overlooked if not specifically sought. Calculations of PTB-related burden of disease should acknowledge that TB-related morbidity does not stop at 6 months. Early case detection and treatment are key in minimising residual impairment.

Background: Nitric oxide (NO), a key macrophage antimycobacterial mediator that ameliorates immunopathology, is measurable in exhaled breath in individuals with pulmonary tuberculosis. We investigated relationships between fractional exhale NO (FENO) and initial pulmonary tuberculosis severity, change during treatment, and relationship with conversion of sputum culture to negative at 2 months., Methods: In Papua, we measured FENO in patients with pulmonary tuberculosis at baseline and serially over 6 months and once in healthy controls. Treatment outcomes were conversion of sputum culture results at 2 months and time to conversion of sputum microscopy results., Results: Among 200 patients with pulmonary tuberculosis and 88 controls, FENO was lower for patients with pulmonary tuberculosis at diagnosis (geometric mean FENO, 12.7 parts per billion [ppb]; 95% confidence interval [CI], 11.6-13.8) than for controls (geometric mean FENO, 16.6 ppb; 95% CI, 14.2-19.5; P = .002), fell further after treatment initiation (nadir at 1 week), and then recovered by 6 months (P = .03). Lower FENO was associated with more-severe tuberculosis disease, with FENO directly proportional to weight (P < .001) and forced vital-capacity (P = .001) and inversely proportional to radiological score (P = .03). People whose FENO increased or remained unchanged by 2 months were 2.7-fold more likely to achieve conversion of sputum culture than those whose FENO decreased (odds ratio, 2.72; 95% CI, 1.05-7.12; P = .04)., Conclusions: Among patients with pulmonary tuberculosis, impaired pulmonary NO bioavailability is associated with more-severe disease and delayed mycobacterial clearance. Measures to increase pulmonary NO warrant investigation as adjunctive tuberculosis treatments.

Background: Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB)., Methods: In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339., Results: 200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference -3%, 95% CI -19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI -9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes., Conclusion: Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes., Registry: ClinicalTrials.gov. Registry number: NCT00677339.

Group A streptococcus (GAS) or Streptococcus pyogenes has been recognised as an important human pathogen since early days of modern microbiology, and it remains among the top ten causes of mortality from an infectious disease. Clinical manifestations attributable to this organism are perhaps the most diverse of any single human pathogen. These encompass invasive GAS infections, with high mortality rates despite effective antimicrobials, toxin-mediated diseases including scarlet fever and streptococcal toxic shock syndrome, the autoimmune sequelae of rheumatic fever and glomerulonephritis with potential for long-term disability, and nuisance manifestations of superficial skin and pharyngeal infection, which continue to consume a sizable proportion of healthcare resources. Although an historical perspective indicates major overall reductions in GAS infection rates in the modern era, chiefly as a result of widespread improvements in socioeconomic circumstances, this pathogen remains as a leading infectious cause of global morbidity and mortality. More than 18 million people globally are estimated to suffer from serious GAS disease. This burden disproportionally affects least affluent populations, and is a major cause of illness and death among children and young adults, including pregnant women, in low-resource settings. We review GAS transmission characteristics and prevention strategies, historical and geographical trends and report on the estimated global burden disease attributable to GAS. The lack of systematic reporting makes accurate estimation of rates difficult. This highlights the need to support improved surveillance and epidemiological research in low-resource settings, in order to enable better assessment of national and global disease burdens, target control strategies appropriately and assess the success of control interventions.

During the 16 years since the World Health Organization declared tuberculosis (TB) a global emergency, major new challenges have emerged-in particular the spread of extensively drug-resistant (XDR)-TB and its overlap with human immunodeficiency virus infection. However, during this period, we have also witnessed the creation of-and major commitments from-agencies dedicated to TB control, research, and funding, and tangible positive achievements have occurred; these include improvements in both new and existing TB diagnostics, a developmental pipeline of new candidate TB drugs, better treatment outcomes for multidrug-resistant TB and XDR-TB, heightened recognition of the importance of nosocomial transmission, and improved strategies to reduce mortality associated with concurrent human immunodeficiency virus infection and TB. We suggest updates to the 2006 International Standards of Tuberculosis Care to embrace these developments. The incorporation of these recent advances into optimized directly observed treatment, short course (DOTS), programs, in conjunction with more widespread deployment and enhanced political will, all provide grounds for improved control.

Worsening drug resistance and the need for prolonged treatment in tuberculosis (TB) require innovative solutions including investigation of inexpensive, safe adjunctive immunotherapies. L-arginine, the precursor of nitric oxide, and vitamin D recently have elucidated mycobactericidal and immunomodulatory actions against TB and are deficient in people with TB. We review the potential of these agents as adjunctive TB immunotherapies and explore how comparative clinical trials might help clarify their relative importance in the human TB immune response. By enhancing mycobacterial killing in macrophages, L-arginine and vitamin D might have the potential to enable shorter duration of treatment, reduced infectivity and improved response in drug-resistant TB.