Therapeutic drug monitoring of liposomal amphotericin B in children. Are we there yet? A systematic review.

INTRODUCTION: Therapeutic drug monitoring (TDM) is a tool that supports personalized dosing, but its role for liposomal amphotericin B (L-amb) is unclear. This systematic review assessed the evidence for L-amb TDM in children. OBJECTIVES: To evaluate the concentration-efficacy relationship, concentration-toxicity relationship and pharmacokinetic/pharmacodynamic (PK/PD) variability of L-amb in children. METHODS: We systematically reviewed PubMed and Embase databases following PRISMA guidelines. Eligible studies included L-amb PK/PD studies in children aged 0-18 years. Review articles, case series of 600 mg·h/L for nephrotoxicity. L-amb doses of 2.5-10 mg/kg/day were reported to achieve Cmax/MIC > 25 using an MIC of 1 mg/L. CONCLUSIONS: While significant PK variability was observed in children, evidence to support routine L-amb TDM was limited. Further studies on efficacy and toxicity benefits are required before routine TDM of L-amb can be recommended.

Vitamin D Supplements for Prevention of Tuberculosis Infection and Disease.

BACKGROUND: Vitamin D metabolites support innate immune responses to Mycobacterium tuberculosis. Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis infection are lacking. METHODS: We randomly assigned children who had negative results for M. tuberculosis infection according to the QuantiFERON-TB Gold In-Tube assay (QFT) to receive a weekly oral dose of either 14,000 IU of vitamin D3 or placebo for 3 years. The primary outcome was a positive QFT result at the 3-year follow-up, expressed as a proportion of children. Secondary outcomes included the serum 25-hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of tuberculosis disease, acute respiratory infection, and adverse events. RESULTS: A total of 8851 children underwent randomization: 4418 were assigned to the vitamin D group, and 4433 to the placebo group; 95.6% of children had a baseline serum 25(OH)D level of less than 20 ng per milliliter. Among children with a valid QFT result at the end of the trial, the percentage with a positive result was 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval [CI], 0.87 to 1.38; P = 0.42). The mean 25(OH)D level at the end of the trial was 31.0 ng per milliliter in the vitamin D group and 10.7 ng per milliliter in the placebo group (mean between-group difference, 20.3 ng per milliliter; 95% CI, 19.9 to 20.6). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (adjusted risk ratio, 0.87; 95% CI, 0.49 to 1.55). A total of 29 children in the vitamin D group and 34 in the placebo group were hospitalized for treatment of acute respiratory infection (adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Vitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D-deficient schoolchildren in Mongolia. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02276755.).

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Genomic markers of drug resistance in Mycobacterium tuberculosis populations with minority variants.

Minority variants of Mycobacterium tuberculosis harboring mutations conferring resistance can become dominant populations during tuberculosis (TB) treatment, leading to treatment failure. Our understanding of drug-resistant within-host subpopulations and the frequency of resistance-conferring mutations in minority variants remains limited. M. tuberculosis sequences recovered from liquid cultures of culture-confirmed TB cases notified between January 2017 and December 2021 in New South Wales, Australia were examined. Potential drug resistance-conferring minority variants were identified using LoFreq, and mixed populations of different M. tuberculosis strains (≥100 SNPs apart) were examined using QuantTB. A total of 1831 routinely sequenced M. tuberculosis strains were included in the analysis. Drug resistance-conferring minority variants were detected in 3.5% (65/1831) of sequenced cultures; 84.6% (55/65) had majority strains that were drug susceptible and 15.4% (10/65) had majority strains that were drug resistant. Minority variants with high-confidence drug resistance-conferring mutations were 1.5 times more common when the majority strains were drug resistant. Mixed M. tuberculosis strain populations were documented in 10.0% (183/1831) of specimens. Minority variants with high-confidence drug resistance-conferring mutations were more frequently detected in mixed M. tuberculosis strain populations (2.7%, 5/183) than in single strain populations (0.6%, 10/1648; P = 0.01). Drug-resistant minority variants require monitoring in settings that implement routine M. tuberculosis sequencing. The frequency with which drug-resistant minority variants are detected is likely influenced by pre-culture requirement. Culture-independent sequencing methods should provide a more accurate reflection of drug-resistant subpopulations.

Tuberculosis in older adults: case studies from four countries with rapidly ageing populations in the western pacific region.

BACKGROUND: The Western Pacific Region has one of the fastest-growing populations of older adults (≥ 65 years) globally, among whom tuberculosis (TB) poses a particular concern. This study reports country case studies from China, Japan, the Republic of Korea, and Singapore reflecting on their experiences in managing TB among older adults. FINDINGS: Across all four countries, TB case notification and incidence rates were highest among older adults, but clinical and public health guidance focused on this population was limited. Individual country reports illustrated a range of practices and challenges. Passive case finding remains the norm, with limited active case finding (ACF) programs implemented in China, Japan, and the Republic of Korea. Different approaches have been trialled to assist older adults in securing an early diagnosis, as well as adhering to their TB treatment. All countries emphasised the need for person-centred approaches that include the creative application of new technology and tailored incentive programs, as well as reconceptualisation of how we provide treatment support. The use of traditional medicines was found to be culturally entrenched among older adults, with a need for careful consideration of their complementary use. TB infection testing and the provision of TB preventive treatment (TPT) were underutilised with highly variable practice. CONCLUSION: Older adults require specific consideration in TB response policies, given the burgeoning aging population and their high TB risk. Policymakers, TB programs and funders must invest in and develop locally contextualised practice guidelines to inform evidence-based TB prevention and care practices for older adults.

Evolving role of chest radiographs for diagnosis of pediatric pulmonary tuberculosis.

Chest radiographs (CXR) have played an important and evolving role in diagnosis, classification and management of pediatric pulmonary tuberculosis (TB). During the pre-chemotherapy era, CXR aided in determining infectiousness, mainly to guide isolation practices, by detecting calcified and non-calcified lymphadenopathy. The availability of TB chemotherapy from the mid-1900s increased the urgency to find accurate diagnostic tools for what had become a treatable disease. Chest radiographs provided the mainstay of diagnosis in children, despite high inter-reader variability limiting its accuracy. The development of cross-sectional imaging modalities, such as computed tomography, provided more accurate intra-thoracic lymph node assessment, but these modalities have major availability, cost and radiation exposure disadvantages. As a consequence, CXR remains the most widely used modality for childhood  pulmonary TB diagnosis, given its relatively low cost and accessibility. Publication of the revised 2022 World Health Organization Consolidated TB guidelines added practical value to CXR interpretation in children, by allowing the selection of children for shorter TB treatment using radiological signs of severity of disease, that have high reliability. This article provides a review of the historical journey and evolving role of CXR in pediatric pulmonary TB.

Time to commencement of effective treatment in patients with drug-resistant tuberculosis diagnosed in the Torres Strait-Papua New Guinea cross-border region.

INTRODUCTION: Delays between self-reported symptom onset and commencement of effective treatment contribute to ongoing tuberculosis (TB) transmission, which is a particular concern in patients with drug-resistant (DR)-TB. The study authors assessed improvements in time to commencement of effective treatment in patients diagnosed with DR-TB in the Torres Strait-Papua New Guinea cross-border region. METHODS: All laboratory-confirmed DR-TB cases diagnosed in the Torres Strait between 1 March 2000 and 31 March 2020 were reviewed. Total time from self-reported onset of symptoms to effective treatment commencement in different programmatic time periods was assessed. Pairwise analyses and time to event proportional hazard calculations were used to explore the association between delays in median time to effective treatment, and selected variables. Data were further analysed to examine predictors of excessive treatment delay. RESULTS: The median number of days from self-reported onset of symptoms to effective treatment commencement was 124 days (interquartile range 51-214) over two decades. Between 2006 and 2012, most (57%) cases exceeded this 'grand median' while the median 'time to treat' in the most recent time period (2016-2020) was significantly reduced to 29 days (p<0.001). Although there was a reduction in the median 'time to treat' with the introduction of Xpert MTB/RIF (135 days pre-Xpert v 67 days post-Xpert) this was not statistically significant (p=0.07). Establishment of the Torres and Cape TB Control Unit on Thursday Island (2016-2020) was significantly associated with reduced treatment delay, compared to the previous TB program period (2000-2005, p<0.04; 2006-2012, p<0.001). CONCLUSION: Minimising TB treatment delay in remote settings like the Torres Strait-Papua New Guinea cross-border region requires effective decentralised diagnosis and management structures. The results of this study suggest that the establishment of the Torres and Cape TB Control Unit on Thursday Island significantly improved time to commencement of effective TB treatment. Possible contributing factors include better TB education, cross-border communication and patient-centred care.

Treatment Outcomes of Childhood Tuberculous Meningitis in a Real-World Retrospective Cohort, Bandung, Indonesia.

We retrospectively evaluated clinical features and outcomes in children treated for tuberculous meningitis (TBM) at Hasan Sadikin Hospital, Bandung, Indonesia, during 2011-2020. Among 283 patients, 153 (54.1%) were <5 years of age, and 226 (79.9%) had stage II or III TBM. Predictors of in-hospital death (n = 44 [15.5%]) were stage III TBM, hydrocephalus, male sex, low-income parents, seizures at admission, and lack of bacillus Calmette-Guérin vaccination. Predictors of postdischarge death (n = 18 [6.4%]) were hydrocephalus, tuberculoma, and lack of bacillus Calmette-Guérin vaccination. At treatment completion, 91 (32.1%) patients were documented to have survived, of whom 33 (36.3%) had severe neurologic sequelae and 118 (41.7%) had unknown outcomes. Predictors of severe neurologic sequelae were baseline temperature >38°C, stage III TBM, and baseline motor deficit. Despite treatment, childhood TBM in Indonesia causes substantial neurologic sequelae and death, highlighting the importance of improved early diagnosis, better tuberculosis prevention, and optimized TBM management strategies.

Evolution and spread of a highly drug resistant strain of Mycobacterium tuberculosis in Papua New Guinea.

BACKGROUND: Molecular mechanisms determining the transmission and prevalence of drug resistant tuberculosis (DR-TB) in Papua New Guinea (PNG) are poorly understood. We used genomic and drug susceptibility data to explore the evolutionary history, temporal acquisition of resistance and transmission dynamics of DR-TB across PNG. METHODS: We performed whole genome sequencing on isolates from Central Public Health Laboratory, PNG, collected 2017-2019. Data analysis was done on a composite dataset that also included 100 genomes previously sequenced from Daru, PNG (2012-2015). RESULTS: Sampled isolates represented 14 of the 22 PNG provinces, the majority (66/94; 70%) came from the National Capital District (NCD). In the composite dataset, 91% of strains were Beijing 2.2.1.1, identified in 13 provinces. Phylogenetic tree of Beijing strains revealed two clades, Daru dominant clade (A) and NCD dominant clade (B). Multi-drug resistance (MDR) was repeatedly and independently acquired, with the first MDR cases in both clades noted to have emerged in the early 1990s, while fluoroquinolone resistance emerged in 2009 (95% highest posterior density 2000-2016). We identified the presence of a frameshift mutation within Rv0678 (p.Asp47fs) which has been suggested to confer resistance to bedaquiline, despite no known exposure to the drug. Overall genomic clustering was significantly associated with rpoC compensatory and inhA promoter mutations (p < 0.001), with high percentage of most genomic clusters (12/14) identified in NCD, reflecting its role as a potential national amplifier. CONCLUSIONS: The acquisition and evolution of drug resistance among the major clades of Beijing strain threaten the success of DR-TB treatment in PNG. With continued transmission of this strain in PNG, genotypic drug resistance surveillance using whole genome sequencing is essential for improved public health response to outbreaks. With occurrence of resistance to newer drugs such as bedaquiline, knowledge of full drug resistance profiles will be important for optimal treatment selection.

Exploring Tuberculosis Riskscapes in a Papua New Guinean 'Hotspot'.

This article explores socio-spatial dimensions of risk and how they can enhance understanding of a high burden tuberculosis (TB) context in the South Fly District of Papua New Guinea. We report on select findings from a qualitative study that included 128 semi-structured in-depth interviews and 10 focus group discussions with a wide range of South Fly District community members. Using the conceptual framework of 'riskscapes' to examine emic perspectives on risk, space and practice, we map key elements of TB riskscapes on Daru Island, South Fly District, along with solutions for navigating through these riskscapes. Overcrowding, lack of water, sanitation and hygiene, as well as food insecurity and undernutrition, were identified as common elements within participants' riskscapes, that compounded upon each other to create the perception of an assemblage of risk favourable to TB transmission.

Saliva-based linezolid monitoring on a mobile UV spectrophotometer.

BACKGROUND: In TB, therapeutic drug monitoring (TDM) is recommended for linezolid; however, implementation is challenging in endemic settings. Non-invasive saliva sampling using a mobile assay would increase the feasibility of TDM. OBJECTIVES: To validate a linezolid saliva assay using a mobile UV spectrophotometer. METHODS: The saliva assay was developed using NanoPhotometer NP80® and linezolid concentrations were quantified using second-order derivative spectroscopy. Sample preparation involved liquid-liquid extraction of saliva, using saturated sodium chloride and ethyl acetate at 1:1:3 (v/v/v). The assay was validated for accuracy, precision, selectivity, specificity, carry-over, matrix effect, stability and filters. Acceptance criteria were bias and coefficient of variation (CV) <15% for quality control (QC) samples and <20% for the lower limit of quantification (LLOQ). RESULTS: Linezolid concentrations correlated with the amplitude between 250 and 270 nm on the second-order derivative spectra. The linezolid calibration curve was linear over the range of 3.0 to 25 mg/L (R2 = 0.99) and the LLOQ was 3.0 mg/L. Accuracy and precision were demonstrated with bias of -7.5% to 2.7% and CV ≤5.6%. The assay met the criteria for selectivity, matrix effect, carry-over, stability (tested up to 3 days) and use of filters (0.22 µM Millex®-GV and Millex®-GP). Specificity was tested with potential co-medications. Interferences from pyrazinamide, levofloxacin, moxifloxacin, rifampicin, abacavir, acetaminophen and trimethoprim were noted; however, with minimal clinical implications on linezolid dosing. CONCLUSIONS: We validated a UV spectrophotometric assay using non-invasive saliva sampling for linezolid. The next step is to demonstrate clinical feasibility and value to facilitate programmatic implementation of TDM.

Evaluation of the 2016-2020 regional tuberculosis response framework, WHO Western Pacific Region.

OBJECTIVE: To assess the implementation of the Regional framework for action on implementation of the End TB Strategy in the Western Pacific, 2016-2020 in countries and areas in the World Health Organization Western Pacific Region. METHODS: We used a mixed methods approach to assess the framework's measurable and perceived impact. We conducted an analysis of national tuberculosis strategic plans, a cross-sectional survey of senior staff of tuberculosis programmes, key informant interviews and some country case studies. FINDINGS: Of the 37 countries and areas of the Western Pacific Region, 14 had a national tuberculosis strategic plan, including all countries and areas with a high incidence of tuberculosis. Most senior tuberculosis programme staff who responded to the survey (16/23) found the regional framework useful when developing their national targets and grant applications. Programmatic challenges identified included financing, human resources, public-private mix, active case finding, and paediatric and drug-resistant tuberculosis. Most of the 17 key informants thought that the regional framework's categorization of actions (for all settings, for specific settings and for pre-elimination settings) was useful, but that the added value of the regional framework over other relevant documents was not obvious because of overlap in content. CONCLUSION: The regional framework influenced national level tuberculosis control planning and implementation in a positive way. A future regional framework should provide a longer-term strategic horizon and specifically address emerging trends and persistent problems faced by countries or areas of the region.

Screening tests for active pulmonary tuberculosis in children.

BACKGROUND: Globally, children under 15 years represent approximately 12% of new tuberculosis cases, but 16% of the estimated 1.4 million deaths. This higher share of mortality highlights the urgent need to develop strategies to improve case detection in this age group and identify children without tuberculosis disease who should be considered for tuberculosis preventive treatment. One such strategy is systematic screening for tuberculosis in high-risk groups. OBJECTIVES: To estimate the sensitivity and specificity of the presence of one or more tuberculosis symptoms, or symptom combinations; chest radiography (CXR); Xpert MTB/RIF; Xpert Ultra; and combinations of these as screening tests for detecting active pulmonary childhood tuberculosis in the following groups. - Tuberculosis contacts, including household contacts, school contacts, and other close contacts of a person with infectious tuberculosis. - Children living with HIV. - Children with pneumonia. - Other risk groups (e.g. children with a history of previous tuberculosis, malnourished children). - Children in the general population in high tuberculosis burden settings. SEARCH METHODS: We searched six databases, including the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, on 14 February 2020 without language restrictions and contacted researchers in the field. SELECTION CRITERIA: Cross-sectional and cohort studies where at least 75% of children were aged under 15 years. Studies were eligible if conducted for screening rather than diagnosing tuberculosis. Reference standards were microbiological (MRS) and composite reference standard (CRS), which may incorporate symptoms and CXR. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed study quality using QUADAS-2. We consolidated symptom screens across included studies into groups that used similar combinations of symptoms as follows: one or more of cough, fever, or poor weight gain and one or more of cough, fever, or decreased playfulness. For combination of symptoms, a positive screen was the presence of one or more than one symptom. We used a bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs) and performed analyses separately by reference standard. We assessed certainty of evidence using GRADE. MAIN RESULTS: Nineteen studies assessed the following screens: one symptom (15 studies, 10,097 participants); combinations of symptoms (12 studies, 29,889 participants); CXR (10 studies, 7146 participants); and Xpert MTB/RIF (2 studies, 787 participants). Several studies assessed more than one screening test. No studies assessed Xpert Ultra. For 16 studies (84%), risk of bias for the reference standard domain was unclear owing to concern about incorporation bias. Across other quality domains, risk of bias was generally low. Symptom screen (verified by CRS) One or more of cough, fever, or poor weight gain in tuberculosis contacts (4 studies, tuberculosis prevalence 2% to 13%): pooled sensitivity was 89% (95% CI 52% to 98%; 113 participants; low-certainty evidence) and pooled specificity was 69% (95% CI 51% to 83%; 2582 participants; low-certainty evidence). Of 1000 children where 50 have pulmonary tuberculosis, 339 would be screen-positive, of whom 294 (87%) would not have pulmonary tuberculosis (false positives); 661 would be screen-negative, of whom five (1%) would have pulmonary tuberculosis (false negatives). One or more of cough, fever, or decreased playfulness in children aged under five years, inpatient or outpatient (3 studies, tuberculosis prevalence 3% to 13%): sensitivity ranged from 64% to 76% (106 participants; moderate-certainty evidence) and specificity from 37% to 77% (2339 participants; low-certainty evidence). Of 1000 children where 50 have pulmonary tuberculosis, 251 to 636 would be screen-positive, of whom 219 to 598 (87% to 94%) would not have pulmonary tuberculosis; 364 to 749 would be screen-negative, of whom 12 to 18 (2% to 3%) would have pulmonary tuberculosis. One or more of cough, fever, poor weight gain, or tuberculosis close contact (World Health Organization four-symptom screen) in children living with HIV, outpatient (2 studies, tuberculosis prevalence 3% and 8%): pooled sensitivity was 61% (95% CI 58% to 64%; 1219 screens; moderate-certainty evidence) and pooled specificity was 94% (95% CI 86% to 98%; 201,916 screens; low-certainty evidence). Of 1000 symptom screens where 50 of the screens are on children with pulmonary tuberculosis, 88 would be screen-positive, of which 57 (65%) would be on children who do not have pulmonary tuberculosis; 912 would be screen-negative, of which 19 (2%) would be on children who have pulmonary tuberculosis. CXR (verified by CRS) CXR with any abnormality in tuberculosis contacts (8 studies, tuberculosis prevalence 2% to 25%): pooled sensitivity was 87% (95% CI 75% to 93%; 232 participants; low-certainty evidence) and pooled specificity was 99% (95% CI 68% to 100%; 3281 participants; low-certainty evidence). Of 1000 children, where 50 have pulmonary tuberculosis, 63 would be screen-positive, of whom 19 (30%) would not have pulmonary tuberculosis; 937 would be screen-negative, of whom 6 (1%) would have pulmonary tuberculosis. Xpert MTB/RIF (verified by MRS) Xpert MTB/RIF, inpatient or outpatient (2 studies, tuberculosis prevalence 1% and 4%): sensitivity was 43% and 100% (16 participants; very low-certainty evidence) and specificity was 99% and 100% (771 participants; moderate-certainty evidence). Of 1000 children, where 50 have pulmonary tuberculosis, 31 to 69 would be Xpert MTB/RIF-positive, of whom 9 to 19 (28% to 29%) would not have pulmonary tuberculosis; 969 to 931 would be Xpert MTB/RIF-negative, of whom 0 to 28 (0% to 3%) would have tuberculosis. Studies often assessed more symptoms than those included in the index test and symptom definitions varied. These differences complicated data aggregation and may have influenced accuracy estimates. Both symptoms and CXR formed part of the CRS (incorporation bias), which may have led to overestimation of sensitivity and specificity. AUTHORS' CONCLUSIONS: We found that in children who are tuberculosis contacts or living with HIV, screening tests using symptoms or CXR may be useful, but our review is limited by design issues with the index test and incorporation bias in the reference standard. For Xpert MTB/RIF, we found insufficient evidence regarding screening accuracy. Prospective evaluations of screening tests for tuberculosis in children will help clarify their use. In the meantime, screening strategies need to be pragmatic to address the persistent gaps in prevention and case detection that exist in resource-limited settings.

Ethics of selective restriction of liberty in a pandemic.

Liberty-restricting measures have been implemented for centuries to limit the spread of infectious diseases. This article considers if and when it may be ethically acceptable to impose selective liberty-restricting measures in order to reduce the negative impacts of a pandemic by preventing particularly vulnerable groups of the community from contracting the disease. We argue that the commonly accepted explanation-that liberty restrictions may be justified to prevent harm to others when this is the least restrictive option-fails to adequately accommodate the complexity of the issue or the difficult choices that must be made, as illustrated by the COVID-19 pandemic. We introduce a dualist consequentialist approach, weighing utility at both a population and individual level, which may provide a better framework for considering the justification for liberty restrictions. While liberty-restricting measures may be justified on the basis of significant benefits to the population and small costs for overall utility to individuals, the question of whether it is acceptable to discriminate should be considered separately. This is because the consequentialist approach does not adequately account for the value of equality. This value may be protected through the application of an additional proportionality test. An algorithm for making decisions is proposed. Ultimately whether selective liberty-restricting measures are imposed will depend on a range of factors, including how widespread infection is in the community, the level of risk and harm a society is willing to accept, and the efficacy and cost of other mitigation options.

Under-explored 'third dimension' of medical ethics.

In this paper, we nominally propose three dimensions of medical ethics, using the term medical ethics rather than clinical ethics to focus on the professional obligation of paediatricians in and beyond the ward and clinic. We argue there exists a duty to children along the continuum of all three dimensions. In this taxonomy, the first dimension is the obligation of paediatricians to serve the best interests of their individual patients. The second dimension involves public health aspects and communitarian concerns with a focus on utilitarian principles, such as cost-effectiveness and just resource allocation. The third dimension of medical ethics is the obligation we hold in trust to support and respect the well-being of future generations. As our ecological footprint, characterised by climate change and biodiversity collapse, will adversely affect the health of today's children and those yet unborn, paediatricians have a contemporaneous moral obligation to speak out and act as both advocates and activists.

Ethical considerations regarding the effects of climate change and planetary health on children.

Climate change represents one of the most significant health challenges and global inequities of our generation. As a 'wicked' problem, climate change imposes an involuntary exposure on vulnerable individuals and societies that is regressive in its nature, with those least responsible for destroying planetary health at greatest risk of suffering the direct and indirect health consequences of unabated warming of the planet. The current and future generations of children are the most vulnerable population to suffer the effects of climate change. By 2030, there will be 131 000 additional child deaths each year if climate mitigation strategies are not enacted, driven by the synergy of an increasing burden of infectious diseases, food insecurity and political instability. Over half a billion of the world's children live in areas vulnerable to extreme weather events, and there is a pressing risk that our current lack of action to mitigate and adapt to climate change will result in today's children, and future generations, being the first to have poorer physical and mental health than previous generations - creating a significant intergenerational ethical dilemma. Child health-care professionals need to advocate for policies to address climate change that consider the complex health, planetary and ethical considerations necessary to solve the most significant risk to our children's health today. Without immediate action, the health of the current and future generations of children is perilous.

Impact of climate change and biodiversity collapse on the global emergence and spread of infectious diseases.

The reality of climate change and biodiversity collapse is irrefutable in the 21st century, with urgent action required not only to conserve threatened species but also to protect human life and wellbeing. This existential threat forces us to recognise that our existence is completely dependent upon well-functioning ecosystems that sustain the diversity of life on our planet, including that required for human health. By synthesising data on the ecology, epidemiology and evolutionary biology of various pathogens, we are gaining a better understanding of factors that underlie disease emergence and spread. However, our knowledge remains rudimentary with limited insight into the complex feedback loops that underlie ecological stability, which are at risk of rapidly unravelling once certain tipping points are breached. In this paper, we consider the impact of climate change and biodiversity collapse on the ever-present risk of infectious disease emergence and spread. We review historical and contemporaneous infectious diseases that have been influenced by human environmental manipulation, including zoonoses and vector- and water-borne diseases, alongside an evaluation of the impact of migration, urbanisation and human density on transmissible diseases. The current lack of urgency in political commitment to address climate change warrants enhanced understanding and action from paediatricians - to ensure that we safeguard the health and wellbeing of children in our care today, as well as those of future generations.

Tuberculosis in the Torres Strait: the lady doth test too much.

INTRODUCTION: Smear-positive pulmonary tuberculosis (PTB) requires rapid diagnosis and treatment to prevent ongoing transmission. Collection of two sputum specimens is considered the minimum requirement for the diagnosis of PTB but current guidelines in the Torres Strait Islands, Australia, recommend three sputum specimens; this frequently delays treatment initiation. METHODS: A retrospective study was performed to ascertain the diagnostic yield of sputum specimens collected in the Torres Strait Islands. The study assessed demographics and characteristics of all PTB cases diagnosed between 2000 and 2018, and assessed the diagnostic yield in 143 patients from whom at least three sputum specimens had been collected prior to treatment commencement. Incremental and cumulative yield was calculated for each sputum specimen. Data were further analysed using binary logistic regression to examine the association between selected characteristics and a smear-positive acid-fast bacilli (AFB) result. RESULTS: Overall, AFB was detected from the first or second sputum specimen in 97 of 101 PTB cases that were sputum smear positive. A smear-positive result was more common (odds ratio 2.84, 95% confidence interval 1.08-7.46) for Papua New Guinea nationals compared to Australian born patients. Of the 429 samples collected, 76 (18%) were of poor quality and the association between poor quality specimens and smear-negative results was significant (p<0.01). Among sputum smear-negative cases, 5/42 (12%) had three consecutive poor quality specimens. The most common collection modality in adults was voluntary expectoration; done in 391/429 (91%) of all specimens collected. Alternative specimen collection methods were mainly used in children; induced sputum 1/429 (0.2%), gastric aspirate 26/429 (6%) and nasopharyngeal aspirate 7/429 (1.6%). Errors with labelling, packaging and transportation occurred in 44 specimens from 15 patients. CONCLUSION: Two good quality specimens ensure adequate diagnostic yield for PTB and a third specimen should only be collected from patients with two negative specimens who have persistent symptoms. Ideally, decentralised Xpert Ultra® should be the frontline diagnostic test in remote settings, especially in settings like the Torres Strait Islands with high rates of drug-resistant TB.

Predictors of Unlikely Bacterial Pneumonia and Adverse Pneumonia Outcome in Children Admitted to a Hospital in Central Vietnam.

BACKGROUND: Pneumonia is the leading cause of antibiotic use and hospitalization in Vietnam. There is a need for better prediction of unlikely bacterial pneumonia and adverse pneumonia outcome in order to guide hospital admission and improve rational antibiotic use. METHODS: All children under 5 admitted with pneumonia (per clinician assessment) to the Da Nang Hospital for Women and Children were prospectively enrolled. Children were classified as having likely or unlikely bacterial pneumonia and followed for outcome assessment. A Bayesian model averaging approach was used to identify predictors of unlikely bacterial pneumonia and adverse pneumonia outcome, which guided the development of a pragmatic management algorithm. RESULTS: Of 3817 patients assessed, 2199 (57.6%) met World Health Organization (WHO) pneumonia criteria. In total, 1594 (41.7%) children were classified as having unlikely and 129 (3.4%) as having likely bacterial pneumonia. The remainder (2399; 62.9%) were considered to have disease of uncertain etiology. Factors predictive of unlikely bacterial pneumonia were no fever, no consolidation on chest radiograph, and absolute neutrophil count <5 × 109/L at presentation, which had a negative predictive value (NPV) for likely bacterial pneumonia of 99.0%. Among those who met WHO pneumonia criteria, 8.6% (189/2199) experienced an adverse outcome. Not having any WHO danger sign or consolidation on chest radiograph had an NPV of 96.8% for adverse pneumonia outcome. CONCLUSIONS: An algorithm that screens for predictors of likely bacterial pneumonia and adverse pneumonia outcome could reduce unnecessary antibiotic use and hospital admission, but its clinical utility requires validation in a prospective study.

Tuberculosis in children: screening, diagnosis and management.

PURPOSE OF REVIEW: The present review focuses on recent advances and current challenges in screening, diagnosis and management of tuberculosis (TB) in children, encompassing TB infection and TB disease, and public health priorities for screening and family engagement. RECENT FINDINGS: Although awareness has improved in recent years that children in TB endemic areas suffer a huge disease burden, translation into better prevention and care remains challenging. Recent WHO guidelines have incorporated screening of all household contacts of pulmonary TB cases, but implementation in high incidence settings remains limited. Improved tests using noninvasive samples, such as the lateral flow urinary lipoarabinomannan assay and the new Xpert Ultra assay applied to induced sputum or stool in young children, are showing promise and further assessment is eagerly awaited. From a treatment perspective, child-friendly dispersible fixed dose combination tablets are now widely available with excellent acceptability and tolerance reported in young children. SUMMARY: High-level government commitment to TB control as a public health priority and feasible strategies to achieve this are required to contain the global epidemic, whereas strong engagement of local TB clinics and affected families in TB prevention is essential to limit secondary cases and protect exposed children.