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Introduction The autoimmune encephalitides (AE) are a heterogeneous group of neurological disorders with significant morbidity and healthcare costs. Despite advancements in understanding their pathophysiology, uncertainties persist regarding long-term prognosis and optimal management. This study aims to address these gaps, focusing on immunotherapeutic strategies, neoplastic associations and functional outcomes.Methods and analysis The Retrospective Linkage Study of Autoimmune Encephalitis project will use data linkage techniques to establish a retrospective 10-year population cohort of Australian patients with AE. Two cohorts will be analysed, the Reference Cohort (clinically confirmed AE cases obtained from hospital medical records, n=145) and the Operationally Defined Cohort (AE cases identified through administrative coding data, n≈5000). Univariate statistical methods will identify candidate coding elements for use in the operational case definition and multivariate models and evaluation methods used to identify and internally validate the optimal coding algorithms. The two study cohorts will be analysed separately due to the high likelihood of overlap. Primary outcomes include relapse rate, prevalence and control of epilepsy, cognitive disability, poor educational attainment, delayed tumour diagnosis and mortality. Statistical analyses, including random mixed-effects regression models, will assess treatment effects, covariates and outcomes.Ethics and dissemination This project has been approved by the leading investigators’ institutional Human Research Ethics Committee (HREC), the St Vincent’s Hospital Melbourne HREC, as well as the Australian Institute of Health and Welfare HREC and relevant jurisdictional HRECs where required. The dissemination of findings through peer-reviewed publications and patient advocacy channels will maximise the impact of this research.

Abstract Introduction Respiratory distress syndrome in preterm infants is an important cause of morbidity and mortality. Less invasive methods of surfactant administration, along with the use of continuous positive airway pressure (CPAP), have improved outcomes of preterm infants. Aerosolized surfactant can be given without the need for airway instrumentation and may be employed in areas where these skills are scarce. Recent trials from high-resourced countries utilising aerosolized surfactant have had a low quality of evidence and varying outcomes. Methods and analysis The Neo-INSPIRe trial is an unblinded, multicentre, randomised trial of a novel aerosolized surfactant drug/device combination. Inclusion criteria include preterm infants of 27–34+6 weeks’ gestational age who weigh 900-1999g and who require CPAP with a fraction of inspired oxygen (FiO2) of 0.25–0.35 in the first 2–24 h of age. Infants are randomised 1:1 to control (CPAP alone) or intervention (CPAP with aerosolized surfactant). The primary outcome is the need for intratracheal bolus surfactant instillation within 72 h of age. Secondary outcomes include the incidence of reaching failure criteria (persistent FiO2 of > 0.40, severe apnoea or severe work of breathing), the need for and duration of ventilation and respiratory support, bronchopulmonary dysplasia and selected co-morbidities of prematurity. Assuming a 40% relative risk reduction to reduce the proportion of infants requiring intratracheal bolus surfactant from 45 to 27%, the study will aim to enrol 232 infants for the study to have a power of 80% to detect a significant difference with a type 1 error of 0.05. Ethics and dissemination Ethical approval has been granted by the relevant human research ethics committees at University of Cape Town (HREC 681/2022), University of the Witwatersrand HREC (221112) and Stellenbosch University (M23/02/004). Trial registration PACTR202307490670785

Serial femtosecond crystallography has opened up many new opportunities in structural biology. In recent years, several approaches employing light-inducible systems have emerged to enable time-resolved experiments that reveal protein dynamics at high atomic and temporal resolutions. However, very few enzymes are light-dependent, whereas macromolecules requiring ligand diffusion into an active site are ubiquitous. In this work we present a drop-on-drop sample delivery system that enables the study of enzyme-catalyzed reactions in microcrystal slurries. The system delivers ligand solutions in bursts of multiple picoliter-sized drops on top of a larger crystal-containing drop inducing turbulent mixing and transports the mixture to the X-ray interaction region with temporal resolution. We demonstrate mixing using fluorescent dyes, numerical simulations and time-resolved serial femtosecond crystallography, which show rapid ligand diffusion through microdroplets. The drop-on-drop method has the potential to be widely applicable to serial crystallography studies, particularly of enzyme reactions with small molecule substrates.

Objectives The Bronchiolitis Endotracheal Surfactant Study (BESS) is a randomised controlled trial to determine the efficacy of endo-tracheal surfactant therapy for critically ill infants with bronchiolitis. To explore acceptability of BESS, including approach to consent within a limited time frame, we explored parent and staff experiences of trial involvement in the first two bronchiolitis seasons to inform subsequent trial conduct.Design A mixed-method embedded study involving a site staff survey, questionnaires and interviews with parents approached about BESS.Setting Fourteen UK paediatric intensive care units.Participants Of the 179 parents of children approached to take part in BESS, 75 parents (of 69 children) took part in the embedded study. Of these, 55/69 (78%) completed a questionnaire, and 15/69 (21%) were interviewed. Thirty-eight staff completed a questionnaire.Results Parents and staff found the trial acceptable. All constructs of the Adapted Theoretical Framework of Acceptability were met. Parents viewed surfactant as being low risk and hoped their child’s participation would help others in the future. Although parents supported research without prior consent in studies of time critical interventions, they believed there was sufficient time to consider this trial. Parents recommended that prospective informed consent should continue to be sought for BESS. Many felt that the time between the consent process and intervention being administered took too long and should be ‘streamlined’ to avoid delays in administration of trial interventions. Staff described how the training and trial processes worked well, yet patients were missed due to lack of staff to deliver the intervention, particularly at weekends.Conclusion Parents and staff supported BESS trial and highlighted aspects of the protocol, which should be refined, including a streamlined informed consent process. Findings will be useful to inform proportionate approaches to consent in future paediatric trials where there is a short timeframe for consent discussions.Trial registration number ISRCTN11746266.

BackgroundSyphilis during pregnancy remains an important global health concern causing miscarriage, stillbirth, preterm birth and neonatal death. As part of the fetal infection, placental changes occur which may include a heavier placenta than expected.MethodsA cohort of 50 neonates with symptomatic congenital syphilis has previously been described. This cohort was admitted to Groote Schuur neonatal unit in Cape Town South Africa from 2011 to 2013. For this study, the placental weights of the neonates were analyzed and compared to population based placental centiles.ResultsThere was data for 37 placentae. Heavy placentae (>90th centile) occurred in 76% of placentae in the study. All 6 infants with birth weights ≥2,500 g had heavy placentae. There was no correlation between placental centile and death.ConclusionHeavy placenta are an important and frequent finding with symptomatic congenital syphilis, especially in the larger neonates.

Abstract We presented the case of an adult patient with hyper‐IgE syndrome (HIES) who was admitted acutely with a large hydropneumothorax from lung consolidation, a bronchopleural fistula and pleural infection. He has had recurrent pulmonary and skin infections since childhood and longstanding pneumatoceles. He was treated with systemic antibiotics and chest tube drainage. Administration of two doses of low‐dose intrapleural therapy (1 mg tissue plasminogen activator and 5 mg deoxyribonuclease) allowed complete evacuation of his residual loculated pleural fluid, aided resolution of his infection without provoking a significant air leak and avoided the need for surgery.

Background: Neonatal sepsis is a leading cause of death in low- and middle- income countries (LMIC). Increasing antibiotic resistance in early onset (< 72 h of life) bloodstream infection (EO-BSI) pathogens in LMIC has reduced the effectiveness of the recommended empiric antibiotic regimen (ampicillin plus gentamicin). Methods: We retrospectively analysed blood culture-confirmed EO-BSI episodes at nine neonatal units from three central and six peripheral hospitals in the Western Cape Province, South Africa between 1 January 2017 and 31 December 2018. Clinical and electronic laboratory records were reviewed to determine pathogen profile, empiric antibiotic coverage rates and factors associated with EO-BSI attributable mortality, stratified by hospital type. Results: Of the 8252 blood culture specimens submitted for the investigation of suspected EO-BSI, 136 EO-BSI episodes yielding 141 pathogens were identified with an EO-BSI rate of 1.3 and 0.5 episodes/1000 live births at central and peripheral hospitals respectively. Preterm (93/136; 68.3%) and low birth weight (84/136; 61.8%) neonates were most affected. The predominant pathogens were Streptococcus agalactiae (46/136; 34%), Klebsiella pneumoniae (17/136; 13%), Listeria monocytogenes (11/136; 8%), Acinetobacter baumannii (11/136; 8%) and Escherichia coli (11/136; 8%). The empiric antibiotic (ampicillin plus gentamicin) coverage rate was 64% (95% CI 51–74) at central hospitals and 84% (95% CI 74–94) at peripheral hospitals. Neonates with Gram-negative EO-BSI and discordant empiric antibiotic therapy had almost four-fold and three-fold higher odds of death respectively. Conclusion: Preterm and low birth weight neonates are most vulnerable to EO-BSI and have higher odds of death with Gram-negative pathogens and discordant empiric antibiotic therapy. [ABSTRACT FROM AUTHOR]

Introduction: The Care Act (2014) requires local authorities to provide reablement services but does not standardise how to do this, leading to different services utilising different outcome measures. This article investigates the Morriston Occupational Therapy Outcome Measure, which has been under researched in community reablement settings. Method: A questionnaire was distributed to the staff working within one local authority to seek their experience of using the Morriston Occupational Therapy Outcome Measure. The questionnaire consisted of closed and open-ended questions to gain insights into their understanding and experience of the Morriston Occupational Therapy Outcome Measure. Findings: Quantitative findings showed that staff felt they understood the Morriston Occupational Therapy Outcome Measure, and most respondents agreed that the Morriston Occupational Therapy Outcome Measure was an effective tool for reablement services. However, staff provided contradictory responses as to whether the Morriston Occupational Therapy Outcome Measure was applied consistently or that service users understand the assessment. Qualitative: Findings showed the Morriston Occupational Therapy Outcome Measure is a service user tool, service provider tool, and it provides quality assurance. However, the Morriston Occupational Therapy Outcome Measure can have restricted applicability and within this local authority, more training was needed to improve the consistency of goal-scoring. Conclusion: The Morriston Occupational Therapy Outcome Measure does have strengths within reablement services; however, to ensure it is an effective tool, this research highlights the need for a high level of training. [ABSTRACT FROM AUTHOR]

ObjectiveTo evaluate the impact of small for gestational age (SGA) on outcomes of very preterm infants at Groote Schuur Hospital (GSH), Cape Town, South Africa.Study designData were obtained from the Vermont Oxford Network (VON) GSH database from 2012 to 2018. The study is a secondary analysis of prospectively collected observational data. Fenton growth charts were used to define SGA as birth weight < 10th centile for gestational age.ResultsMortality [28.9% vs. 18.5%, adjusted risk ratio (aRR) 2.1, 95% confidence interval (CI) 1.6–2.7], bronchopulmonary dysplasia (BPD; 14% vs. 4.5%, aRR 3.7, 95% CI 2.3–6.1), and late-onset sepsis (LOS; 16.7% vs. 9.6%, aRR 2.3, 95% CI 1.6–3.3) were higher in the SGA than in the non-SGA group.ConclusionSmall for gestational age infants have a higher risk of mortality and morbidity among very preterm infants at GSH. This may be useful for counseling and perinatal management.

Currently many of the time resolved serial femtosecond (SFX) crystallography experiments are done with light driven protein systems, whereas the reaction initiation for non-light triggered enzymes remains a major bottle neck. Here, the authors present an expanded Drop-on-Tape system, where picoliter-sized droplets of a substrate or inhibitor are turbulently mixed with nanoliter sized droplets of microcrystal slurries, and they use it for time-resolved SFX measurements of inhibitor binding to lysozyme and secondly, binding of a β-lactam antibiotic to a bacterial serine β-lactamase.

Background. Invasive group B streptococcal disease (iGBS) is an important cause of morbidity and mortality in newborns globally and is more common in Sub-Saharan Africa and South Africa. Few studies describe newborn iGBS cases in the Western Cape, leaving limited data to guide local prevention and treatment strategies. Objective. To describe all cases of newborn iGBS at Groote Schuur Hospital (GSH), Western Cape, between January 2015 and December 2020. Methods. A retrospective review was conducted of all blood or cerebrospinal fluid-positive cases of newborn iGBS between January 2015 and December 2020. Results. Thirty-five cases of iGBS were included in the study, 51% with early-onset disease (EoD) and 49% with late-onset disease (LoD). The median gestational age at birth was 27 and 31.5 weeks in the LoD and EoD groups, respectively. The median birth weight was 900 g and 1 812 g in the LoD and EoD groups, respectively. Meningitis was more common in the LoD group and pneumonia was more common in the EoD group. The overall mortality rate was 23%, with similar mortality rates in the EoD and LoD groups (22% and 24%, respectively). Invasive GBS disease accounted for a cumulative 274 intensive care unit days during the study period. Conclusion. Invasive GBS disease in newborns at GSH is associated with a high mortality rate, with this study showing similar mortality rates between the EoD and LoD groups. [ABSTRACT FROM AUTHOR]

Aim: There is limited literature available about necrotising enterocolitis (NEC) in low‐ and middle‐income countries. This study sought to determine the proportion, pattern and risk factors for mortality among very low birth weight (VLBW) neonates with NEC in a middle‐income setting. Methods: A retrospective observational cohort study was conducted on all infants with birth weights less than 1501 g admitted from 2018 to 2020 at Groote Schuur Hospital, Cape Town, South Africa. Data were obtained from the Vermont Oxford Network and hospital folders. Results: A total of 104/1582 (6.6%) neonates were diagnosed with NEC with a median onset of 8 days of life. The mortality rate was 39.0%, compared to the all‐cause mortality rate of 18.7% for VLBW neonates. Thirty‐two (32.0%) neonates with NEC were transferred for surgery of whom 10 (31.3%) died. Small for gestational age (p = 0.13), NEC stage 2B or above (p = 0,002), a positive blood culture (p = 0.018), a raised C‐reactive protein (p = 0.013), hyponatraemia (p = 0.004), anaemia requiring blood transfusion (p = 0.003) and thrombocytopenia requiring platelet transfusion (p = 0.033) were associated with mortality. A positive blood culture was found in 37.0% with a predominance of Klebsiella pneumoniae isolates. Conclusion: NEC has an early onset and a high mortality rate in our setting. [ABSTRACT FROM AUTHOR]

ABSTRACT β-Lactamases hydrolyze β-lactam antibiotics and are major determinants of antibiotic resistance in Gram-negative pathogens. Enmetazobactam (formerly AAI101) and tazobactam are penicillanic acid sulfone (PAS) β-lactamase inhibitors that differ by an additional methyl group on the triazole ring of enmetazobactam, rendering it zwitterionic. In this study, ultrahigh-resolution X-ray crystal structures and mass spectrometry revealed the mechanism of PAS inhibition of CTX-M-15, an extended-spectrum β-lactamase (ESBL) globally disseminated among Enterobacterales. CTX-M-15 crystals grown in the presence of enmetazobactam or tazobactam revealed loss of the Ser70 hydroxyl group and formation of a lysinoalanine cross-link between Lys73 and Ser70, two residues critical for catalysis. Moreover, the residue at position 70 undergoes epimerization, resulting in formation of a d-amino acid. Cocrystallization of enmetazobactam or tazobactam with CTX-M-15 with a Glu166Gln mutant revealed the same cross-link, indicating that this modification is not dependent on Glu166-catalyzed deacylation of the PAS-acylenzyme. A cocrystal structure of enmetazobactam with CTX-M-15 with a Lys73Ala mutation indicates that epimerization can occur without cross-link formation and positions the Ser70 Cβ closer to Lys73, likely facilitating formation of the Ser70-Lys73 cross-link. A crystal structure of a tazobactam-derived imine intermediate covalently linked to Ser70, obtained after 30 min of exposure of CTX-M-15 crystals to tazobactam, supports formation of an initial acylenzyme by PAS inhibitors on reaction with CTX-M-15. These data rationalize earlier results showing CTX-M-15 deactivation by PAS inhibitors to involve loss of protein mass, and they identify a distinct mechanism of β-lactamase inhibition by these agents. IMPORTANCE β-Lactams are the most prescribed antibiotic class for treating bacterial diseases, but their continued efficacy is threatened by bacterial strains producing β-lactamase enzymes that catalyze their inactivation. The CTX-M family of ESBLs are major contributors to β-lactam resistance in Enterobacterales, preventing effective treatment with most penicillins and cephalosporins. Combining β-lactams with β-lactamase inhibitors (BLIs) is a validated route to overcome such resistance. Here, we describe how exposure to enmetazobactam and tazobactam, BLIs based on a penicillanic acid sulfone (PAS) scaffold, leads to a protein modification in CTX-M-15, resulting in irremediable inactivation of this most commonly encountered member of the CTX-M family. High-resolution X-ray crystal structures showed that PAS exposure induces formation of a cross-link between Ser70 and Lys73, two residues critical to β-lactamase function. This previously undescribed mechanism of inhibition furthers our understanding of β-lactamase inhibition by classical PAS inhibitors and provides a basis for further, rational inhibitor development.