Estimating the impact of alternative programmatic cotrimoxazole strategies on mortality among children born to mothers with HIV: A modelling study.

BACKGROUND: World Health Organization (WHO) guidelines recommend cotrimoxazole prophylaxis for children who are HIV-exposed until infection is excluded and vertical transmission risk has ended. While cotrimoxazole has benefits for children with HIV, there is no mortality benefit for children who are HIV-exposed but uninfected, prompting a review of global guidelines. Here, we model the potential impact of alternative cotrimoxazole strategies on mortality in children who are HIV-exposed. METHODS AND FINDINGS: Using a deterministic compartmental model, we estimated mortality in children who are HIV-exposed from 6 weeks to 2 years of age in 4 high-burden countries: Côte d'Ivoire, Mozambique, Uganda, and Zimbabwe. Vertical transmission rates, testing rates, and antiretroviral therapy (ART) uptake were derived from UNAIDS data, trial evidence, and meta-analyses. We explored 6 programmatic strategies: maintaining current recommendations; shorter cotrimoxazole provision for 3, 6, 9, or 12 months; and starting cotrimoxazole only for children diagnosed with HIV. Modelled alternatives to the current strategy increased mortality to varying degrees; countries with high vertical transmission had the greatest mortality. Compared to current recommendations, starting cotrimoxazole only after a positive HIV test had the greatest predicted increase in mortality: Mozambique (961 excess annual deaths; excess mortality 339 per 100,000 HIV-exposed children; risk ratio (RR) 1.06), Uganda (491; 221; RR 1.04), Zimbabwe (352; 260; RR 1.05), and Côte d'Ivoire (125; 322; RR 1.06). Similar effects were observed for 3-, 6-, 9-, and 12-month strategies. Increased mortality persisted but was attenuated when modelling lower cotrimoxazole uptake, smaller mortality benefits, higher testing coverage, and lower vertical transmission rates. The study is limited by uncertain estimates of cotrimoxazole coverage in programmatic settings; an inability to model increases in mortality arising from antimicrobial resistance due to limited surveillance data in sub-Saharan Africa; and lack of a formal health economic analysis. CONCLUSIONS: Changing current guidelines from universal cotrimoxazole provision for children who are HIV-exposed increased predicted mortality across the 4 modelled high-burden countries, depending on test-to-treat cascade coverage and vertical transmission rates. These findings can help inform policymaker deliberations on cotrimoxazole strategies, recognising that the risks and benefits differ across settings.

How a thrombectomy service can reduce hospital deficit: a cost-effectiveness study.

BACKGROUND: There is level 1 evidence for cerebral thrombectomy with thrombolysis in acute large vessel occlusion. Many hospitals are now contemplating setting up this life-saving service. For the hospital, however, the first treatment is associated with an initial high cost to cover the procedure. Whilst the health economic benefit of treating stroke is documented, this is the only study to date performing matched-pair, patient-level costing to determine treatment cost within the first hospital episode and up to 90 days post-event. METHODS: We conducted a retrospective coarsened exact matched-pair analysis of 50 acute stroke patients eligible for thrombectomy. RESULTS: Thrombectomy resulted in significantly more good outcomes (mRS 0-2) compared to matched controls (56% vs 8%, p = 0.001). More patients in the thrombectomy group could be discharged home (60% vs 28%), fewer were discharged to nursing homes (4% vs 16%), residential homes (0% vs 12%) or rehabilitation centres (8% vs 20%). Thrombectomy patients had fewer serious adverse events (n = 30 vs 86) and were, on average, discharged 36 days earlier. They required significantly fewer physiotherapy sessions (18.72 vs 46.49, p = 0.0009) resulting in a median reduction in total rehabilitation cost of £4982 (p = 0.0002) per patient. The total cost of additional investigations was £227 lower (p = 0.0369). Overall, the median cost without thrombectomy was £39,664 per case vs £22,444, resulting in median savings of £17,221 (p = 0.0489). CONCLUSIONS: Mechanical thrombectomy improved patient outcome, reduced length of hospitalisation and, even without procedural reimbursement, significantly reduced cost to the thrombectomy providing hospital.

A comparison of five paediatric dosing guidelines for antibiotics.

OBJECTIVE: To compare dosing guidance in the paediatric formularies of high- and middle-income countries for 32 commonly prescribed antibiotics on the World Health Organization's (WHO's) 2017 Model list of essential medicines for children. METHODS: We identified paediatric antibiotic guidelines that were either widely used internationally or originated from countries in which antibiotic use has increased markedly in recent years (i.e. Brazil, China, India, the Russian Federation and South Africa). FINDINGS: The study analysis considered five leading antibiotic guidelines: (i) the Manual of childhood infections: the blue book; (ii) the BNF (British national formulary) for children; (iii) the Red book®: 2018-2021 report of the committee on infectious diseases; (iv) WHO's Pocket book of hospital care for children; and (v) Indian National treatment guidelines for antimicrobial use in infectious diseases. There was marked heterogeneity in the recommended dosing (i.e. daily dose, age dosing bands and dose frequency) for most commonly used antibiotics. The rationale for dosing recommendations was generally unclear. CONCLUSION: The pharmacokinetic, pharmacodynamic and clinical evidence supporting paediatric antibiotic dosing, particularly on total doses and on age or weight dosing bands, needs to be improved. Future research should consider whether the variations in guidance identified stem from different clinical disease patterns, varying levels of antibiotic resistance or drug availability rather than historical preferences. Interested global parties could collaborate with WHO's Model list of essential medicines antibiotic working group to develop an evidence-based consensus and identify research priorities.

Mobile Stroke Unit in the UK Healthcare System: Avoidance of Unnecessary Accident and Emergency Admissions.

BACKGROUND: Acute stroke patients are usually transported to the nearest hospital regardless of their required level of care. This can lead to increased pressure on emergency departments and treatment delay. OBJECTIVE: The aim of the study was to explore the benefit of a mobile stroke unit (MSU) in the UK National Health Service (NHS) for reduction of hospital admissions. METHODS: Prospective cohort audit observation with dispatch of the MSU in the East of England Ambulance Service area in Southend-on-Sea was conducted. Emergency patients categorized as code stroke and headache were included from June 5, 2018, to December 18, 2018. Rate of avoided admission to the accident and emergency (A&E) department, rate of admission directly to target ward, and stroke management metrics were assessed. RESULTS: In 116 MSU-treated patients, the following diagnoses were made: acute stroke, n = 33 (28.4%); transient ischaemic attacks, n = 13 (11.2%); stroke mimics, n = 32 (27.6%); and other conditions, n = 38 (32.8%). Pre-hospital thrombolysis was administered to 8 of 28 (28.6%) ischaemic stroke patients. Pre-hospital diagnosis avoided hospital admission for 29 (25.0%) patients. As hospital treatment was indicated, 35 (30.2%) patients were directly triaged to the stroke unit, 1 patient (0.9%) even directly to the catheter laboratory. Thus, only 50 (43.1%) patients required transfer to the A&E department. Moreover, the MSU enabled thrombolysis with a median dispatch-to-needle time of 42 min (interquartile range, 40-60). CONCLUSION: This first deployment of an MSU in the UK NHS demonstrated improved triage decision-making for or against hospital admission and admission to the appropriate target ward, thereby reducing pressure on strained A&E departments.

Collateral Automation for Triage in Stroke: Evaluating Automated Scoring of Collaterals in Acute Stroke on Computed Tomography Scans.

Computed tomography angiography (CTA) collateral scoring can identify patients most likely to benefit from mechanical thrombectomy and those more likely to have good outcomes and ranges from 0 (no collaterals) to 3 (complete collaterals). In this study, we used a machine learning approach to categorise the degree of collateral flow in 98 patients who were eligible for mechanical thrombectomy and generate an e-CTA collateral score (CTA-CS) for each patient (e-STROKE SUITE, Brainomix Ltd., Oxford, UK). Three experienced neuroradiologists (NRs) independently estimated the CTA-CS, first without and then with knowledge of the e-CTA output, before finally agreeing on a consensus score. Addition of the e-CTA improved the intraclass correlation coefficient (ICC) between NRs from 0.58 (0.46-0.67) to 0.77 (0.66-0.85, p = 0.003). Automated e-CTA, without NR input, agreed with the consensus score in 90% of scans with the remaining 10% within 1 point of the consensus (ICC 0.93, 0.90-0.95). Sensitivity and specificity for identifying favourable collateral flow (collateral score 2-3) were 0.99 (0.93-1.00) and 0.94 (0.70-1.00), respectively. e-CTA correlated with the Alberta Stroke Programme Early CT Score (Spearman correlation 0.46, p < 0.001) highlighting the value of good collateral flow in maintaining tissue viability prior to reperfusion. In conclusion, -e-CTA provides a real-time and fully automated approach to collateral scoring with the potential to improve consistency of image interpretation and to independently quantify collateral scores even without expert rater input.

Optic nerve sheath diameter: present and future perspectives for neurologists and critical care physicians.

BACKGROUND: Estimation of intracranial pressure (ICP) may be helpful in the management of neurological critically ill patients. It has been shown that ultrasonography of the optic nerve sheath diameter (ONSD) is a reliable tool for non-invasive estimation of increased intracranial pressure (ICP) at hospital admission or in intensive care. Less is known about the estimation of increased ICP and usefulness of ONSD in the prehospital setting. The aim of this review was to elucidate both prevailing and novel applications of ONSD for neurologists and critical care physicians. METHODS: In this review, we discuss the technique and the novel approach of ONSD measurement, the clinical applications of ONSD in neurology and critical care patients. RESULTS: ONSD measurement is simple, easy to learn, and has diverse applications. ONSD has utility for ICP measurement in intracranial hemorrhage and ischemic stroke, meningitis and encephalitis, and idiopathic intracranial hypertension (IIH). It is also valuable for lesser known syndromes, where an increase of ICP is postulated, such as acute mountain sickness and posterior reversible encephalopathy syndrome. ONSD changes develop in inflammatory or ischemic optic neuropathies. Some papers demonstrate the usefulness of ONSD studies in symptomatic intracranial hypotension. CONCLUSIONS: ONSD is a safe and low-cost bedside tool with the potential of screening patients who need other neuroimaging and those who may need an invasive measurement of ICP.

Patient portal use: Persistent disparities from pre- to post-onset of the COVID-19 pandemic.

INTRODUCTION: The primary objective of this study was to examine patient portal usage from pre- to post-onset of the COVID-19 pandemic to determine what impact the pandemic had on portal usage by patient sub-populations. The second study objective was to assess differences in portal usage by chronic disorders from pre- to post-onset of the pandemic. METHODS: Patient portal data were extracted and analyzed from a non-profit healthcare system in the Mid-Atlantic region. A total of 153,628 unique patients with patient portal account were included in this study. We assessed patient portal usage from pre-onset (March 2019-February 2020) to post-onset of the COVID-19 pandemic (March 2020-February 2021). We examined usage by patient sub-populations (age, sex, race, ethnicity), comorbid conditions, and health insurance type. RESULTS: Differences were seen in specific patient portal actions. Increases were seen in immunization views (0.43, 95% CI: 0.39, 0.46) and health record views (0.43, 95% CI: 0.40, 0.46) from post-onset compared to pre-onset. A decrease was noted in prescription renewal (medication) views (-0.07, 95% CI -0.09, -0.05) from pre- to post-onset There was a decrease in both immunization views and health record views among Black patients (-0.07, 95% CI: -0.11, -0.03) in comparison to White patients, but an increase in prescription renewal (medication) views (0.07, 95%CI 0.04, 0.09) amongst Black patients compared to White patients. CONCLUSIONS: Patient portals are integral to patient care, allowing patients to actively engage in their care and communicate with their healthcare team about ongoing health needs. However, prior disparities in patient portal access have been exacerbated by the COVID-19 pandemic and solutions to address these disparities are urgently needed.

Prehospital stroke management in the thrombectomy era.

Acute stroke management has been revolutionised by evidence of the effectiveness of thrombectomy. Because time is brain in stroke care, the speed with which a patient with large vessel occlusion is transferred to a thrombectomy-capable centre determines outcome. Therefore, each link in the stroke rescue chain, starting with symptom onset and ending with recanalisation, should be streamlined. However, in contrast to inhospital delays, prehospital delays are unchanged despite substantial efforts in quality improvement. Furthermore, thrombectomy is offered by only a few, usually distant, specialised centres and not by the many other, usually nearer, hospitals. To take maximum advantage of the first so-called golden hours after stroke, and because of the difficulty of on-scene triage decision making with respect to the target hospital offering the required level of care, the focus of stroke research has shifted to the prehospital setting. Current research focuses on the effects of public education, implementation of protocols for emergency medical services for streamlining clinical investigations and accurate triage, use of preclinical scales for stroke recognition, and deployment of novel technical solutions such as smartphone applications, telemedicine, and mobile stroke units.

Improving Prehospital Stroke Services in Rural and Underserved Settings With Mobile Stroke Units.

In acute stroke management, time is brain, as narrow therapeutic windows for both intravenous thrombolysis and mechanical thrombectomy depend on expedient and specialized treatment. In rural settings, patients are often far from specialized treatment centers. Concurrently, financial constraints, cutting of services and understaffing of specialists for many rural hospitals have resulted in many patients being underserved. Mobile Stroke Units (MSU) provide a valuable prehospital resource to rural and remote settings where patients may not have easy access to in-hospital stroke care. In addition to standard ambulance equipment, the MSU is equipped with the necessary tools for diagnosis and treatment of acute stroke or similar emergencies at the emergency site. The MSU strategy has proven to be effective at facilitating time-saving stroke triage decisions. The additional on-board imaging helps to determine whether a patient should be taken to a primary stroke center (PSC) for standard treatment or to a comprehensive stroke center (CSC) for advanced stroke treatment (such as intra-arterial therapy) instead. Diagnosis at the emergency site may prevent additional in-hospital delays in workup, handover and secondary (inter-hospital) transport. MSUs may be adapted to local needs-especially in rural and remote settings-with adjustments in staffing, ambulance configuration, and transport models. Further, with advanced imaging and further diagnostic capabilities, MSUs provide a valuable platform for telemedicine (teleradiology and telestroke) in these underserved areas. As MSU programmes continue to be implemented across the world, optimal and adaptable configurations could be explored.

GAPPS (Grading and Assessment of Pharmacokinetic-Pharmacodynamic Studies) a critical appraisal system for antimicrobial PKPD studies - development and application in pediatric antibiotic studies.

Introduction: There are limited data on optimal dosing of antibiotics in different age groups for neonates and children. Clinicians usually consult pediatric formularies or online databases for dose selection, but these have variable recommendations, are usually based on expert opinion and are not graded based on the existing pharmacokinetic-pharmacodynamic (PKPD) studies. We describe here a potential new tool that could be used to grade the strength of evidence emanating from PKPD studies.Areas covered: A scoring system was developed (GAPPS tool) to quantify the strength of each PK assessment and rate the studies quality in already published articles. GAPPS was evaluated by applying it to pediatric PKPD studies of antibiotics from the 2019 Essential Medicines List for children (EMLC), identified through a search of PubMed.Expert opinion: Evidence for most antibiotic dose selection decisions was generally weak, coming from individual PK studies and lacked PKPD modeling and simulations. However, the quality of evidence appears to have improved over the last two decades.Incorporating a formal grading system, such as GAPPS, into formulary development will provide a transparent tool to support decision-making in clinical practice and guideline development, and guide PKPD authors on study designs most likely to influence guidelines.

Prehospital Stroke Management Optimized by Use of Clinical Scoring vs Mobile Stroke Unit for Triage of Patients With Stroke: A Randomized Clinical Trial.

Importance: Transferring patients with large-vessel occlusion (LVO) or intracranial hemorrhage (ICH) to hospitals not providing interventional treatment options is an unresolved medical problem. Objective: To determine how optimized prehospital management (OPM) based on use of the Los Angeles Motor Scale (LAMS) compares with management in a Mobile Stroke Unit (MSU) in accurately triaging patients to the appropriate hospital with (comprehensive stroke center [CSC]) or without (primary stroke center [PSC]) interventional treatment. Design, Setting, and Participants: In this randomized multicenter trial with 3-month follow-up, patients were assigned week-wise to one of the pathways between June 15, 2015, and November 15, 2017, in 2 regions of Saarland, Germany; 708 of 824 suspected stroke patients did not meet inclusion criteria, resulting in a study population of 116 adult patients. Interventions: Patients received either OPM based on a standard operating procedure that included the use of the LAMS (cut point ≥4) or management in an MSU (an ambulance with vascular imaging, point-of-care laboratory, and telecommunication capabilities). Main Outcomes and Measures: The primary end point was the proportion of patients accurately triaged to either CSCs (LVO, ICH) or PSCs (others). Results: A predefined interim analysis was performed after 116 patients of the planned 232 patients had been enrolled. Of these, 53 were included in the OPM group (67.9% women; mean [SD] age, 74 [11] years) and 63 in the MSU group (57.1% women; mean [SD] age, 75 [11] years). The primary end point, an accurate triage decision, was reached for 37 of 53 patients (69.8%) in the OPM group and for 63 of 63 patients (100%) in the MSU group (difference, 30.2%; 95% CI, 17.8%-42.5%; P < .001). Whereas 7 of 17 OPM patients (41.2%) with LVO or ICH required secondary transfers from a PSC to a CSC, none of the 11 MSU patients (0%) required such transfers (difference, 41.2%; 95% CI, 17.8%-64.6%; P = .02). The LAMS at a cut point of 4 or higher led to an accurate diagnosis of LVO or ICH for 13 of 17 patients (76.5%; 6 triaged to a CSC) and of LVO selectively for 7 of 9 patients (77.8%; 2 triaged to a CSC). Stroke management metrics were better in the MSU group, although patient outcomes were not significantly different. Conclusions and Relevance: Whereas prehospital management optimized by LAMS allows accurate triage decisions for approximately 70% of patients, MSU-based management enables accurate triage decisions for 100%. Depending on the specific health care environment considered, both approaches are potentially valuable in triaging stroke patients. Trial Registration: ClinicalTrials.gov identifier: NCT02465346.

Reviewing the WHO guidelines for antibiotic use for sepsis in neonates and children.

Background Guidelines from 2005 for treating suspected sepsis in low- and middle-income countries (LMIC) recommended hospitalisation and prophylactic intramuscular (IM) or intravenous (IV) ampicillin and gentamicin. In 2015, recommendations when referral to hospital is not possible suggest the administration of IM gentamicin and oral amoxicillin. In an era of increasing antimicrobial resistance, an updated review of the appropriate empirical therapy for treating sepsis (taking into account susceptibility patterns, cost and risk of adverse events) in neonates and children is necessary. Methods Systematic literature review and international guidelines were used to identify published evidence regarding the treatment of (suspected) sepsis. Results Five adequately designed and powered studies comparing antibiotic treatments in a low-risk community in neonates and young infants in LMIC were identified. These addressed potential simplifications of the current WHO treatment of reference, for infants for whom admission to inpatient care was not possible. Research is lacking regarding the treatment of suspected sepsis in neonates and children with hospital-acquired sepsis, despite rising antimicrobial resistance rates worldwide. Conclusions Current WHO guidelines supporting the use of gentamicin and penicillin for hospital-based patients or gentamicin (IM) and amoxicillin (oral) when referral to a hospital is not possible are in accordance with currently available evidence and other international guidelines, and there is no strong evidence to change this. The benefit of a cephalosporin alone or in combination as a second-line therapy in regions with known high rates of non-susceptibility is not well established. Further research into hospital-acquired sepsis in neonates and children is required.

Antibiotic use for community-acquired pneumonia in neonates and children: WHO evidence review.

Background Pneumonia is the most common cause of death in children worldwide, accounting for 15% of all deaths of children under 5 years of age. This review summarises the evidence for the empirical antibiotic treatment of community-acquired pneumonia in neonates and children and puts emphasis on publications since the release of the previous WHO Evidence Summary report published in 2014. Methods A systematic search for systematic reviews and meta-analyses of antibiotic therapy for community-acquired pneumonia was conducted between 1 January 2013 and 10 November 2016. Results The optimal dosing recommendation for amoxicillin remains unclear with limited pharmacological and clinical evidence. There is limited evidence from surveillance to indicate whether amoxicillin or broader spectrum antibiotics (e.g. third-generation cephalosporins) are being used most commonly for paediatric CAP in different WHO regions. Data are lacking on clinical efficacy in the context of pneumococcal, staphylococcal and mycoplasma disease and the relative contributions of varying first-line and step-down options to the selection of such resistance. Conclusion Further pragmatic trials are required to optimise management of hospitalised children with severe and very severe pneumonia.

ECEL1 gene related contractural syndrome: Long-term follow-up and update on clinical and pathological aspects.

Autosomal recessive mutations in the ECEL1 gene have recently been associated with a wide phenotypic spectrum including severe congenital contractural syndromes and distal arthrogryposis type 5D (DA5D). Here, we describe four novel families with ECEL1 gene mutations, reporting 15 years of follow-up for four patients and detailed muscle pathological description for three individuals. In particular, we observed mild myopathic features, prominent core-like areas in one individual, and presence of nCAM positive fibres in three patients from 2 unrelated families suggesting a possible problem with innervation. Our findings expand current knowledge concerning the phenotypic and pathological spectrum associated with ECEL1 gene mutations and may suggest novel insights regarding the underlying pathomechanism of the disease.

An International Survey of Health Care Providers Involved in the Management of Cancer Patients Exposed to Cardiotoxic Therapy.

Cardiotoxicity is the second leading cause of morbidity and mortality in cancer survivors. The objective of this international cardiac oncology survey was to gain a better understanding of current knowledge and practice patterns among HCPs involved in the management of cancer patients exposed to potentially cardiotoxic drugs. Between 2012 and 2013, we conducted an email-based survey of HCPs involved in the management of cardiac disease in cancer patients. 393 survey responses were received, of which 77 were from Canadian respondents. The majority of respondents were cardiologists (47%), followed closely by medical oncologists. The majority of respondents agreed that cardiac issues are important to cancer patients (97%). However, only 36% of total respondents agreed with an accepted definition of cardiotoxicity. While 78% of respondents felt that cardiac medications are protective during active cancer treatment, only 51% would consider prescribing these medications up-front in cancer patients. Although results confirm a high level of concern for cardiac safety, there continues to be a lack of consensus on the definition of cardiotoxicity and a discrepancy in clinical practice between cardiologists and oncologists. These differences in opinion require resolution through more effective research collaboration and formulation of evidence-based guidelines.

Clinical Experience of Patients Referred to a Multidisciplinary Cardiac Oncology Clinic: An Observational Study.

Cardiotoxicity is the second leading cause of long-term morbidity and mortality among cancer survivors. The purpose of this retrospective observational study is to report on the clinical and cardiac outcomes in patients with early stage and advanced cancer who were referred to our multidisciplinary cardiac oncology clinic (COC). A total of 428 patients were referred to the COC between October 2008 and January 2013. The median age of patients at time of cancer diagnosis was 60. Almost half of patients who received cancer therapy received first-line chemotherapy alone (169, 41.7%), of which 84 (49.7%) were exposed to anthracyclines. The most common reasons for referral to the cardiac oncology clinic were decreased LVEF (34.6%), prechemotherapy assessment (11.9%), and arrhythmia (8.4%). A total of 175 (40.9%) patients referred to the COC were treated with cardiac medications. The majority (331, 77.3%) of patients were alive as of January 2013, and 93 (21.7%) patients were deceased. Through regular review of cardiac oncology clinic referral patterns, management plans, and patient outcomes, we aim to continuously improve delivery of cardiac care to our patient population and optimize cardiac health.