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Infections remain a leading cause of death in neonates. The sparse antibiotic development pipeline and challenges in conducting neonatal research have resulted in few effective antibiotics being adequately studied to treat multidrug-resistant (MDR) infections in neonates, despite the increasing global mortality burden caused by antimicrobial resistance. Of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared with only six trials recruiting neonates. We review the World Health Organization (WHO) priority pathogens list relevant to neonatal sepsis and propose a WHO multiexpert stakeholder meeting to promote the development of a neonatal priority antibiotic development list. The goal is to develop international, interdisciplinary consensus for an accelerated neonatal antibiotic development programme. This programme would enable focused research on identified priority antibiotics for neonates to reduce the excess morbidity and mortality caused by MDR infections in this vulnerable population.

Antimicrobial resistance is an important threat to international health. Therapeutic guidelines for empirical treatment of common life-threatening infections depend on available information regarding microbial aetiology and antimicrobial susceptibility, but sub-Saharan Africa lacks diagnostic capacity and antimicrobial resistance surveillance. We systematically reviewed studies of antimicrobial resistance among children in sub-Saharan Africa since 2005. 18 of 1075 articles reviewed met inclusion criteria, providing data from 67 451 invasive bacterial isolates from inconsistently defined populations in predominantly urban tertiary settings. Among neonates, Gram-negative organisms were the predominant cause of early-onset neonatal sepsis, with a high prevalence of extended-spectrum β-lactamase-producing organisms. Gram-positive bacteria were responsible for a high proportion of infections among children beyond the neon atal period, with high reported prevalence of non-susceptibility to treatment advocated by the WHO therapeutic guidelines. There are few up-to-date or representative studies given the magnitude of the problem of antimicrobial resistance, especially regarding community-acquired infections. Research should focus on differentiating resistance in community-acquired versus hospital-acquired infections, implementation of standardised reporting systems, and pragmatic clinical trials to assess the efficacy of alternative treatment regimens.

Immunocompromised individuals are at high risk of vaccine-preventable diseases, but typically have impaired immune responses to vaccination and require altered vaccination schedules. Serological testing can inform vaccination decisions in this vulnerable population, but is frequently ordered inappropriately. Furthermore, misinterpretion of serological results can misguide clinical decisions. We reviewed existing recommendations and supporting literature to define key criteria for appropriate serological testing in immunocompromised persons. We identified three key criteria: 1) there must be an established immune correlate of protection; 2) there must be a reliable, validated commercial serology test; and 3) test results must inform clinical decisions around vaccination or post-exposure prophylaxis. Serology results can most accurately guide clinical decision-making for hepatitis B, measles, rabies, rubella and yellow fever. In this article, we provide a synthesis of this published evidence to guide clinicians and vaccine providers on the appropriate utilisation of serological testing. •Interpreting the results of serological tests in immunocompromised people is challenging.•Testing is useful when immune correlates of protection and reliable tests are available and results affect clinical decisions.•Testing can inform vaccination for immunocompromised people against hepatitis B, measles, rabies, rubella and yellow fever.

Pneumonia remains a leading cause of hospitalization and death among young children worldwide, and the diagnostic challenge of differentiating bacterial from non-bacterial pneumonia is the main driver of antibiotic use for treating pneumonia in children. Causal Bayesian networks (BNs) serve as powerful tools for this problem as they provide clear maps of probabilistic relationships between variables and produce results in an explainable way by incorporating both domain expert knowledge and numerical data. We used domain expert knowledge and data in combination and iteratively, to construct, parameterise and validate a causal BN to predict causative pathogens for childhood pneumonia. Expert knowledge elicitation occurred through a series of group workshops, surveys and one-on-one meetings involving 6-8 experts from diverse domain areas. The model performance was evaluated based on both quantitative metrics and qualitative expert validation. Sensitivity analyses were conducted to investigate how the target output is influenced by varying key assumptions of a particularly high degree of uncertainty around data or domain expert knowledge. Designed to apply to a cohort of children with X-ray confirmed pneumonia who presented to a tertiary paediatric hospital in Australia, the resulting BN offers explainable and quantitative predictions on a range of variables of interest, including the diagnosis of bacterial pneumonia, detection of respiratory pathogens in the nasopharynx, and the clinical phenotype of a pneumonia episode. Satisfactory numeric performance has been achieved including an area under the receiver operating characteristic curve of 0.8 in predicting clinically-confirmed bacterial pneumonia with sensitivity 88% and specificity 66% given certain input scenarios (i.e., information that is available and entered into the model) and trade-off preferences (i.e., relative weightings of the consequences of false positive versus false negative predictions). We specifically highlight that a desirable model output threshold for practical use is very dependent upon different input scenarios and trade-off preferences. Three commonly encountered scenarios were presented to demonstrate the potential usefulness of the BN outputs in various clinical pictures. To our knowledge, this is the first causal model developed to help determine the causative pathogen for paediatric pneumonia. We have shown how the method works and how it would help decision making on the use of antibiotics, providing insight into how computational model predictions may be translated to actionable decisions in practice. We discussed key next steps including external validation, adaptation and implementation. Our model framework and the methodological approach can be adapted beyond our context to broad respiratory infections and geographical and healthcare settings.

Background Diagnosing urinary tract infections (UTIs) in children in the emergency department (ED) is challenging due to the variable clinical presentations and difficulties in obtaining a urine sample free from contamination. Clinicians need to weigh a range of observations to make timely diagnostic and management decisions, a difficult task to achieve without support due to the complex interactions among relevant factors. Directed acyclic graphs (DAG) and causal Bayesian networks (BN) offer a way to explicitly outline the underlying disease, contamination and diagnostic processes, and to further make quantitative inference on the event of interest thus serving as a tool for decision support. Methods We prospectively collected data on children present to ED with suspected UTIs. Through knowledge elicitation workshops and one-on-one meetings, a DAG was co-developed with clinical domain experts (the Expert DAG) to describe the causal relationships among variables relevant to paediatric UTIs. The Expert DAG was combined with prospective data and further domain knowledge to inform the development of an application-oriented BN (the Applied BN), designed to support the diagnosis of UTI. We assessed the performance of the Applied BN using quantitative and qualitative methods. Results We summarised patient background, clinical and laboratory characteristics of 431 episodes of suspected UTIs enrolled from May 2019 to November 2020. The Expert DAG was presented with a narrative description, elucidating how infection, specimen contamination and management pathways causally interact to form the complex picture of paediatric UTIs. Parameterised using prospective data and expert-elicited parameters, the Applied BN achieved an excellent and stable performance in predicting Escherichia coli culture results, with a mean area under the receiver operating characteristic curve of 0.86 and a mean log loss of 0.48 based on 10-fold cross-validation. The BN predictions were reviewed via a validation workshop, and we illustrate how they can be presented for decision support using three hypothetical clinical scenarios. Conclusion Causal BNs created from both expert knowledge and data can integrate case-specific information to provide individual decision support during the diagnosis of paediatric UTIs in ED. The model aids the interpretation of culture results and the diagnosis of UTIs, promising the prospect of improved patient care and judicious use of antibiotics.

The black line indicates the prior site of extension of skin and soft tissue infection which responded more promptly to antimicrobial therapy, while the nodular lymph node involvement required a more prolonged course of antibiotics for clinical resolution. The patient was commenced on linezolid and cotrimoxazole until imaging of the central nervous system ruled out disseminated infection (a common presentation of Nocardia infection),1 at which point he was changed to amoxicillin-clavulanic acid (following a delayed hypersensitivity reaction to cotrimoxazole). Nocardia spp are Gram-positive, variably acid-fast bacteria present in soil that may inoculate the skin following trauma.1 2 Nocardiosis is typically regarded as an opportunistic infection in the immunocompromised, but approximately one-third of infected patients are immunocompetent.1 3 Nocardia are a rare cause of skin and soft tissue infection with ubiquitous worldwide distribution yet with geographical variation in their prevalence, tending to be more common in tropical climates.4 Nocardiosis should be considered when empirical therapy against usual skin pathogens fails, alongside consideration of other pathogens that may be implicated in nodular lymphangitis (such as Sporothrix schenckii and non-tuberculous mycobacteria).5 Ethics statements Patient consent for publication Parental/guardian consent obtained.

I was relieved to see the despondent situation currently crippling Kenya's health-care system brought to international attention in The Lancet's Editorial (June 17, p 2350).1 The nurses’ strike, which began on June 5, follows closely on the back of a 90-day doctors’ strike that finished mere months ago and is rumoured to soon recur.

Human immunodeficiency virus (HIV) is a neurotropic virus that has a detrimental impact on the developing central nervous system (CNS) of children growing up with perinatal HIV (PHIV) due to a combination of pathophysiological processes related to direct viral cytopathic effects and immune activation. This leads to a spectrum of neurocognitive impairment ranging from severe encephalopathy to subtle domain-specific cognitive impairments, as well as psychological disorders that are compounded by HIV-related stigma and sociodemographic factors that disproportionately affect PHIV children. Early commencement and consistent use of combination antiretroviral therapy (cART) has resulted in a dramatic improvement in neuropsychological outcomes for PHIV children; however, they remain vulnerable to cognitive impairment and psychological disorders, as evidenced by imaging findings, randomised clinical trials and observational studies. An optimal neuroprotective cART regimen remains elusive in children, but systemic viral suppression, regular neurocognitive and psychological screening and ready access to neuropsychological management strategies are key components for optimising neuropsychological outcomes. However, a lack of standardised and validated screening tools, particularly in resource-limited settings, hinders a precise understanding of the nature, prevalence and associations between neuropsychological symptomatology and HIV health. This article reviews the natural history, cellular pathophysiology and structural and functional imaging findings for children growing up with HIV, as well as summarising management strategies related to antiretroviral therapy, screening tools and specific interventions for neurocognitive impairments and psychological disorders.

Abstract Background International consensus definitions for invasive aspergillosis (IA) in research are rigorous, yet clinically significant cases are often excluded from clinical studies for not meeting proven/probable IA case definitions. To better understand reasons for the failure to meet criteria for proven/probable infection, we herein review 47 such cases for their clinical and microbiological characteristics and outcomes. Methods Data on 47 cases that did not meet consensus IA definitions but were deemed significant were derived from a retrospective, observational, multicenter survey of 382 presumed IA cases across Australasia, of which findings of 221 proven/probable infections were recently published. The clinical, microbiological, and radiologic characteristics of these cases were analyzed. Mortality outcomes were compared with those of 221 proven/probable cases. Results Of 47 cases studied, 15 lacked classical host factors; 22 exhibited only a single positive Aspergillus polymerase chain reaction result; 7 lacked typical IA radiologic findings on chest computed tomography; and 3 had borderline galactomannan optical density indices (<1.0 but ≥0.5) in bronchoalveolar lavage fluid. The median age of patients was 61 years (IQR, 52–68); 34 were male (72%). Seven patients (15%) required intensive care admission. All patients had lung as the primary site of infection. Antifungal treatment was initiated in 42 patients (89%). All-cause 90-day mortality was 33%, similar to the 30% mortality in the comparative cohort (n = 221). Conclusions Our findings highlight the limitations of current consensus definitions for IA. Notably, the mortality of patients not meeting these definitions was similar to that of patients with proven/probable IA. Further studies, especially of patients with a single positive Aspergillus polymerase chain reaction result and those without host factors, are needed to determine if future consensus definitions may benefit from modifications. This study examined invasive aspergillosis cases that did not meet international consensus definitions yet were treated as significant to better understand the reasons for their exclusion from consensus case definitions and to raise awareness of their potential clinical significance.