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The sensitivity of animals to sensory input must be regulated to ensure that signals are detected and also discriminable. However, how circuits regulate the dynamic range of sensitivity to sensory stimuli is not well understood. A given odor is represented in the insect mushroom bodies (MBs) by sparse combinatorial coding by Kenyon cells (KCs), forming an odor quality representation. To address how intensity of sensory stimuli is processed at the level of the MB input region, the calyx, we characterized a set of novel mushroom body output neurons that respond preferentially to high odor concentrations. We show that a pair of MB calyx output neurons, MBON-a1/2, are postsynaptic in the MB calyx, where they receive extensive synaptic inputs from KC dendrites, the inhibitory feedback neuron APL, and octopaminergic sVUM1 neurons, but relatively few inputs from projection neurons. This pattern is broadly consistent in the third-instar larva as well as in the first instar connectome. MBON-a1/a2 presynaptic terminals innervate a region immediately surrounding the MB medial lobe output region in the ipsilateral and contralateral brain hemispheres. By monitoring calcium activity using jRCamP1b, we find that MBON-a1/a2 responses are odor-concentration dependent, responding only to ethyl acetate (EA) concentrations higher than a 200-fold dilution, in contrast to MB neurons which are more concentration-invariant and respond to EA dilutions as low as 10–4. Optogenetic activation of the calyx-innervating sVUM1 modulatory neurons originating in the SEZ (Subesophageal zone), did not show a detectable effect on MBON-a1/a2 odor responses. Optogenetic activation of MBON-a1/a2 using CsChrimson impaired odor discrimination learning compared to controls. We propose that MBON-a1/a2 form an output channel of the calyx, summing convergent sensory and modulatory input, firing preferentially to high odor concentration, and might affect the activity of downstream MB targets.

Biomimetic flapping-foil thrusters can operate efficiently while offering desirable levels of thrust required for the propulsion of a small vessel or an Autonomous Underwater Vehicle (AUV). These systems have been studied both as main propulsion devices and for augmenting ship propulsion in waves. In this work, the unsteady hydrofoil loads are used to calculate the source terms of the Ffowcs Williams–Hawkings (FW-H) equation which is applied to model noise propagation in the underwater ocean acoustic environment. The solution provided by a simplified version of the Farassat formulation in free space is extended to account for a bounded domain and an inhomogeneous medium, characterizing the sea acoustic waveguide. Assuming the simplicity azimuthal symmetry of the environmental parameters, a numerical model is developed based on a Finite Difference Time Domain (FDTD) scheme, incorporating free-surface and seabed effects, in the presence of a variable sound speed profile. For the treatment of the outgoing radiating field, a Perfectly Matched Layer (PML) technique is implemented. Numerical results are presented illustrating the applicability of the method.

Flapping-foil thrusters are systems that operate at a substantially lower frequency compared with marine propellers and are characterized by a much smaller power concentration. These biomimetic devices are able to operate very efficiently, offering desirable levels of thrust required for the propulsion of small vessels or autonomous underwater vehicles (AUVs), and can be used for the standalone propulsion of small vessels or for augmenting ship propulsion in waves, alleviating the generation of noise and its adverse effects on sea life, particularly on marine mammals. In this work, we consider the generation of noise by flapping foils arranged in the neighborhood of the above vessels including the scattering effects by the hull, which, in addition to free-surface and seabed effects, significantly contribute to the modification of the characteristics of the acoustic field. A Boundary Element Method (BEM) is developed to treat the 3D scattering problem in the frequency domain forced by monopole and dipole source terms associated with the Ffowcs Williams and Hawkings (FW-H) equation. Numerical results are presented in selected cases illustrating that the hull geometry and acoustic properties, as well as the sea surface and seabed effects, are important for the determination of the directionality of the generated noise and significantly affect the propagation in the underwater ocean environment.

Vortex-induced oscillations offer a potential means to harness hydrokinetic energy even at low current speeds. In this study, we consider a novel converter where a cylinder undergoes angular oscillations with respect to a pivot point, in contrast to most previous configurations, where the cylinder undergoes flow-induced oscillations transversely to the incident free stream. We formulate a theoretical model to deal with the coupling of the hydrodynamics and the structural dynamics, and we numerically solve the resulting nonlinear equation of cylinder motion in order to assess the performance of the energy converter. The hydrodynamical model utilizes a novel approach where the fluid forces acting on the oscillating cylinder are split into components acting along and normal to the instantaneous relative velocity between the moving cylinder and the free stream. Contour plots illustrate the effects of the main design parameters (in dimensionless form) on the angular response of the cylinder and the energy efficiency of the converter. Peak efficiencies of approximately 20% can be attained by optimal selection of the main design parameters. Guidelines on the sizing of actual converters are discussed.

The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease. Their predominant T cell immunodeficiency is characterized by significant T cell lymphopenia, defects in late stages of thymic T cell development, and impaired function of peripheral T cells, including inadequate NF-κB- and NFAT-mediated, proliferative, and metabolic responses to activation. Pathogenicity is not due to haploinsufficiency, rather ITPR3 protein variants interfere with IP3R channel function leading to depletion of ER Ca2+ stores and blunted SOCE in T cells., (© 2024 Blanco et al.)

The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity. We assessed the response of dupilumab in five patients and omalizumab in one patient with CADINS for the treatment of severe atopic symptoms. CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB. Three children and three adults with dominant-negative CARD11 LOF mutations were included. All developed atopic disease in infancy or early childhood. In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria. Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria. All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued. In conclusion, treatment with dupilumab and omalizumab for severe, refractory atopic disease in patients with CADINS appears to be effective and well tolerated in patients with CADINS with severe atopy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Scope: These European Society of Clinical Microbiology and Infectious Diseases guidelines are intended for clinicians involved in diagnosis and treatment of brain abscess in children and adults., Methods: Key questions were developed, and a systematic review was carried out of all studies published since 1 January 1996, using the search terms 'brain abscess' OR 'cerebral abscess' as Mesh terms or text in electronic databases of PubMed, Embase, and the Cochrane registry. The search was updated on 29 September 2022. Exclusion criteria were a sample size <10 patients or publication in non-English language. Extracted data was summarized as narrative reviews and tables. Meta-analysis was carried out using a random effects model and heterogeneity was examined by I 2 tests as well as funnel and Galbraith plots. Risk of bias was assessed using Risk Of Bias in Non-randomised Studies - of Interventions (ROBINS-I) (observational studies) and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) (diagnostic studies). The Grading of Recommendations Assessment, Development and Evaluation approach was applied to classify strength of recommendations (strong or conditional) and quality of evidence (high, moderate, low, or very low)., Questions Addressed by the Guidelines and Recommendations: Magnetic resonance imaging is recommended for diagnosis of brain abscess (strong and high). Antimicrobials may be withheld until aspiration or excision of brain abscess in patients without severe disease if neurosurgery can be carried out within reasonable time, preferably within 24 hours (conditional and low). Molecular-based diagnostics are recommended, if available, in patients with negative cultures (conditional and moderate). Aspiration or excision of brain abscess is recommended whenever feasible, except for cases with toxoplasmosis (strong and low). Recommended empirical antimicrobial treatment for community-acquired brain abscess in immuno-competent individuals is a 3rd-generation cephalosporin and metronidazole (strong and moderate) with the addition of trimethoprim-sulfamethoxazole and voriconazole in patients with severe immuno-compromise (conditional and low). Recommended empirical treatment of post-neurosurgical brain abscess is a carbapenem combined with vancomycin or linezolid (conditional and low). The recommended duration of antimicrobial treatment is 6-8 weeks (conditional and low). No recommendation is offered for early transition to oral antimicrobials because of a lack of data, and oral consolidation treatment after ≥6 weeks of intravenous antimicrobials is not routinely recommended (conditional and very low). Adjunctive glucocorticoid treatment is recommended for treatment of severe symptoms because of perifocal oedema or impending herniation (strong and low). Primary prophylaxis with antiepileptics is not recommended (conditional and very low). Research needs are addressed., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To report on population-based epidemiological trends in central nervous system (CNS) abscesses and empyemas in England over five decades., Methods: Trend analyses of age-sex-specific hospital admission and death rates using routinely collected English national hospital discharge records, mortality records, and annual population denominators from 1968 to 2019., Results: Hospital admission rates for CNS abscesses and empyemas were stable in England until the late 1980s. In the last two decades of the study period (1999-2019), first-time admissions increased from 1.24 per 100,000 population in 1999 (95% confidence interval [CI] 1.14-1.35) to 2.86 in 2019 (95% CI 2.72-3.01). Admission rates were highest among infants and older adults, and were higher for males than females. There were small but significant increases in annual mortality rates for CNS abscesses and empyemas over the last two decades of the study period after accounting for population ageing, but mortality remained low at around 0.1-0.2 per 100,000 population. Mortality increased with advancing age; deaths in childhood were extremely rare. Case fatality rates where a relevant diagnosis was recorded as either the underlying or contributing cause were 4.3% and 9.7% respectively., Conclusions: The increase in CNS abscesses and empyemas in England might reflect improved case ascertainment, but the likelihood of a true rise in incidence should be considered., Competing Interests: Declaration of Competing Interest The authors declare no financial or commercial conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Purpose Regulatory T cells (Tregs) have been implicated in the pathogenesis of several autoimmune disorders and used in adoptive cell transfer therapies. Neither have been explored in patients with autoimmune encephalitis where treated patient outcomes remain suboptimal with frequent relapses. Here, to identify new treatment strategies for autoimmune encephalitis, we sought to evaluate the proportion of circulating Tregs and Treg subpopulations in peripheral blood of patients with N -methyl-ᴅ-aspartate receptor-antibody encephalitis (NMDAR-Ab-E) and compared this with healthy controls., Methods: We compared the phenotype of peripheral blood Tregs in four adult NMDAR-Ab-E patients and four age- and sex-matched healthy controls using an 11-color flow cytometry assay panel for characterization of Tregs (CD4+ CD25+ FoxP3+) cells into naïve (chemokine receptor [CCR] 7+ CD45RA+), central memory (CCR7+ CD45RA-), and effector memory (CCR7- CD45RA-) cells. We also examined and compared the expression of the CCR6 by circulating Tregs and the respective Treg subpopulations between the study groups., Results: The proportion of circulating Tregs was similar between patients with NMDAR-Ab-E and healthy controls but the proportion of naïve Tregs was lower in NMDAR-Ab-E patients (p = 0.0026). Additionally, the frequency of circulating effector memory Tregs was higher, and the proportion of circulating effector memory Tregs expressing CCR6 was lower, in NMDAR-Ab-E patients compared with healthy controls (p = 0.0026)., Conclusion: Altered Treg homeostasis may be a feature of patients with NMDAR-Ab-E. Future studies with larger samples are warranted to validate these findings., Competing Interests: Conflicts of Interest Irani SR is an inventor of ‘Diagnostic Strategy to improve specificity of CASPR2 antibody detection (PCT/G82019/051257)' and receives royalties on a licensed patent application for LGI1/CASPR2 testing as co-applicant (PCT/GB2009/051441) entitled “Neurological Autoimmune Disorders.” Irani SR has received honoraria and/or research support from UCB, Immunovant, MedImmun, Roche, Janssen, Cerebral therapeutics, CSL Behring, and ONO Pharma. Iro MA is funded by Health Education England (HEE) / NIHR for this research project. No other potential conflict of interest relevant to this article was reported., (Copyright © 2023 Korean Encephalitis and Neuroinflammation Society.)

Competing Interests: Competing interests: None declared.

Competing Interests: Competing interests: MAI is a NIHR Academic Clinical Lecturer and SNF a NIHR Senior Investigator.

The deterioration of a previously stable preterm infant is a common scenario on the neonatal unit. The the most common bacterial causes of deterioration are nosocomial infections, such as coagulase-negative Staphylococcus and Staphylococcus aureus Non-infective conditions such as pulmonary haemorrhage, anaemia of prematurity and necrotising enterocolitis may also cause preterm infants to deteriorate. This case chronicles the unusual diagnostic journey of an infant born at 27+1 weeks who deteriorated at 26 days of life and did not respond to antimicrobial therapy as anticipated., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: Studies indicating that non-coding RNAs (ncRNAs) play a regulatory role in sepsis are increasing rapidly. This present review summarizes recent publications on the role of microRNAs and long non-coding RNAs (lncRNAs) in sepsis., Recent Findings: MicroRNAs (miRNAs) and lncRNAs are being identified as potential sepsis biomarkers and therapeutic targets. Experimental studies have examined the biological mechanisms that might underpin the regulatory role of these ncRNAs in sepsis., Summary: Clinical applications of miRNAs and lncRNAs in sepsis are on the horizon. These data could lead to the identification of novel treatments or indeed support the repurposing of existing drugs for sepsis. Validation of the findings from these preliminary studies and crucially integration of multiomics datasets will undoubtedly revolutionize the clinical management of sepsis.

Background: Encephalitis is a serious neurologic condition that can result in admission to intensive care. Yet, there are no studies on pediatric intensive care unit (PICU) admission rates and usage of intensive care resources by children with encephalitis in England and Wales. The objectives of this study were to (1) define the PICU incidence and mortality rates for childhood encephalitis, (2) describe the usage of intensive care resources by children with encephalitis admitted to PICU and (3) explore the associated cost from PICU encephalitis admissions., Methods: Retrospective analysis of anonymized data for 1031 children (0-17 years) with encephalitis admitted (January 2003 to December 2013) to PICU in England and Wales., Results: The PICU encephalitis incidence was 0.79/100,000 population/yr (95% confidence interval [CI]: 0.74-0.84), which gives an annual total of 214 bed days of intensive care occupancy for children admitted with encephalitis and an estimated annual PICU bed cost of £414,230 (interquartile range: 198,111-882,495) for this cohort. PICU encephalitis admissions increased during the study period (annual percentage change = 4.5%, 95% CI: 2.43%-6.50%, P ≤ 0.0001). In total, 808/1024 (78.9%) cases received invasive ventilation while 216/983 (22.0%) and 50/890 (5.6%) cases received vasoactive treatment and renal support, respectively. There were 87 deaths (8.4%), giving a PICU encephalitis mortality rate of 0.07/100,000 population (0-17 years)/yr (95% CI: 0.05-0.08)., Conclusions: These data suggest that encephalitis places a significant burden to the healthcare service. More work is needed to improve outcomes for children with encephalitis.

Background: The World Health Organization (WHO) recommends rapid intravenous rehydration, using fluid volumes of 70-100mls/kg over 3-6 h, with some of the initial volume given rapidly as initial fluid boluses to treat hypovolaemic shock for children with acute gastroenteritis (AGE) and severe dehydration. The evidence supporting the safety and efficacy of rapid versus slower rehydration remains uncertain., Methods: We conducted a systematic review of randomised controlled trials (RCTs) on 11th of May 2017 comparing different rates of intravenous fluid therapy in children with AGE and moderate or severe dehydration, using standard search terms. Two authors independently assessed trial quality and extracted data. Non-RCTs and non-English articles were excluded. The primary endpoint was mortality and secondary endpoints included adverse events (safety) and treatment efficacy., Main Results: Of the 1390 studies initially identified, 18 were assessed for eligibility. Of these, 3 studies (n = 464) fulfilled a priori criteria for inclusion; most studied children with moderate dehydration and none were conducted in resource-poor settings. Volumes and rates of fluid replacement varied from 20 to 60 ml/kg given over 1-2 h (fast) versus 2-4 h (slow). There was substantial heterogeneity in methodology between the studies with only one adjudicated to be of high quality. There were no deaths in any study. Safety endpoints only identified oedema (n = 6) and dysnatraemia (n = 2). Pooled analysis showed no significant difference between the rapid and slow intravenous rehydration groups for the proportion of treatment failures (N = 468): pooled RR 1.30 (95% CI: 0.87, 1.93) and the readmission rates (N = 439): pooled RR 1.39 (95% CI: 0.68, 2.85)., Conclusions: Despite wide implementation of WHO Plan C guideline for severe AGE, we found no clinical evaluation in resource-limited settings, and only limited evaluation of the rate and volume of rehydration in other parts of the world. Recent concerns over aggressive fluid expansion warrants further research to inform guidelines on rates of intravenous rehydration therapy for severe AGE.

Background: One schedule for the capsular group B meningococcal vaccine 4CMenB is 2 doses that are administered 2 months apart for children aged 12-23 months, with a booster dose 12-24 months later. Our objective was to provide data on persistence of human serum bactericidal antibody (hSBA) titres in children up to 4 years of age after initial doses at 12-24 months, and immunogenicity of a booster dose at 48 months of age compared with vaccine-naive children., Methods: Children previously immunized, as part of a randomized controlled trial, with 2 doses of 4CMenB vaccine at 12-24 months of age received a booster at 4 years of age. Vaccine-naive age-matched toddlers received 2 doses of 4CMenB. Human serum bactericidal antibody titres against reference strains H44/76, 5/99, NZ98/254 and M10713 were evaluated before and after innoculation with 4CMenB vaccine in 4-year-old children., Results: Of 332 children in the study, 123 had previously received 4CMenB and 209 were vaccine-naive controls. Before the booster, the proportions of participants (previously vaccinated groups compared with controls) with hSBA titres of 1:5 or more were as follows: 9%-11% v. 1% (H44/76), 84%-100% v. 4% (5/99), 0%-18% v. 0% (NZ98/254) and 59%-60% v. 60% (M10713). After 1 dose of 4CMenB in previously immunized children, the proportions of participants achieving hSBA titres of 1:5 or more were 100% (H44/76 and 5/99), 70%-100% (NZ98/254) and 90%-100% (M10713)., Interpretation: We found that waning of hSBA titres by 4 years of age occurred after 2 doses of 4CMenB vaccine administered at 12-24 months, and doses at 12-24 months have a priming effect on the immune system. A booster may be necessary to maintain hSBA titres of 1:5 or more among those children with increased disease risk. Trial registration : ClinicalTrials.gov, no. NCT01717638., Competing Interests: Competing interests: Manish Sadarangani has received a grant from Novartis during the conduct of this study (Novartis Vaccines Division was subsequently acquired by the GSK group of companies) and a grant for investigator-initiated research studies outside the submitted work from Pfizer. Manish Sadarangani has also received payment as site investigator/co-investigator for multicentre trials from Variation Biotechnologies and Merck. Matthew Snape has received a grant from Novartis during the conduct of this study (Novartis Vaccines Division was subsequently acquired by GSK group of companies) and grants paid to his institution for work as an investigator on clinical trials from Novartis Vaccines and Diagnostics (subsequently acquired by GSK group of companies), GSK group of companies, Pfizer, Janssen, MedImmune, Alios BioPharma and Ablynx. He has also received support for travel and accommodation to attend international conferences from GSK group of companies, and he has received support paid to his institution as a member of the advisory board for Sanofi-Pasteur MSD and as a consultant for MedImmune. Matthew Snape receives salary support from the National Institute for Health Research Oxford Biomedical Research Centre and is a Jenner Investigator. Adam Finn has received grants paid to his institution from Novartis, GSK group of companies, Pfizer and Sanofi-Pasteur MSD for studies outside the submitted work, and a grant from Novartis (Novartis Vaccines Division was subsequently acquired by the GSK group of companies) for the submitted work. Owing to his membership on the Joint Committee on Vaccination and Immunisation for the United Kingdom Department of Health, Adam Finn no longer gives lectures or undertakes advisory work for industry, either paid or unpaid. Paul Heath has received grants paid to his institution from GSK group of companies, Sanofi-Pasteur MSD and Novartis for studies outside the submitted work, and a grant from Novartis for the submitted work. Gianni Bona has received lecture fees and nonfinancial support for clinical trials during the conduct of this study from Novartis Vaccines and Diagnostics, and support from Novartis Vaccines and Diagnostics, GSK group of companies, Sanofi-Pasteur and Pfizer as an investigator for clinical trials outside the submitted work. Susanna Esposito has received a grant paid to her institution from Novartis Vaccines and Diagnostics; grants from Novartis Vaccines and Diagnostics, GSK group of companies, Pfizer, Sanofi-Aventis and Sanofi-Pasteur MSD; and personal fees (in the form of consultant and speaker fees, and reimbursements for travel and accommodation) from Novartis Vaccines and Diagnostics, GSK group of companies, Pfizer and MedImmune. Javier Diez-Domingo has received reimbursement for being a member of the advisory committees for GSK group of companies and Pfizer, as well as travel support from Pfizer. Roman Prymula received a grant for the submitted work from Novartis, and has received grants from Novartis, Sanofi-Pasteur MSD and GSK group of companies outside the submitted work. Mildred Iro has received nonfinancial support for travel to conferences from GSK group of companies. Andrew Pollard has received a grant from Novartis during the conduct of this study, and grants from Pfizer and Okairos in the past 36 months. His department received unrestricted educational grants from Pfizer, GSK group of companies and AstraZeneca in July 2016, and Gilead, MSD, GSK group of companies and AstraZeneca in June 2017 for a course on Infection and immunity in children. Andrew Pollard is the chair of UK Department of Health’s Joint Committee on Vaccination and Immunisation, and the Vaccines Scientific Advisory group of the European Medicines Agency, and is a member of the World Health Organization’s Strategic Advisory Group of Experts (SAGE). Adefowope Odueyungbo was a GSK employee at the time the study was conducted (formerly Novartis Vaccines and Diagnostics). Daniela Toneatto declares that she is employed by and holds shares in the GSK group of companies. Andrew Pollard, Paul Heath, Matthew Snape, Manish Sadarangani and Adam Finn do not receive any personal remuneration from vaccine manufacturers., (© 2017 Canadian Medical Association or its licensors.)

Background: Encephalitis is a syndrome of neurological dysfunction due to inflammation of the brain parenchyma, caused by an infection or an exaggerated host immune response, or both. Attenuation of brain inflammation through modulation of the immune response could improve patient outcomes. Biological agents such as immunoglobulin that have both anti-inflammatory and immunomodulatory properties may therefore be useful as adjunctive therapies for people with encephalitis., Objectives: To assess the efficacy and safety of intravenous immunoglobulin (IVIG) as add-on treatment for children with encephalitis., Search Methods: The Cochrane Multiple Sclerosis and Rare Diseases of the CNS group's Information Specialist searched the following databases up to 30 September 2016: CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, and the WHO ICTRP Search Portal. In addition, two review authors searched Science Citation Index Expanded (SCI-EXPANDED) & Conference Proceedings Citation Index - Science (CPCI-S) (Web of Science Core Collection, Thomson Reuters) (1945 to January 2016), Global Health Library (Virtual Health Library), and Database of Abstracts of Reviews of Effects (DARE)., Selection Criteria: Randomised controlled trials (RCTs) comparing IVIG in addition to standard care versus standard care alone or placebo., Data Collection and Analysis: Two review authors independently selected articles for inclusion, extracted relevant data, and assessed quality of trials. We resolved disagreements by discussion among the review authors. Where possible, we contacted authors of included studies for additional information. We presented results as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI)., Main Results: The search identified three RCTs with 138 participants. All three trials included only children with viral encephalitis, one of these included only children with Japanese encephalitis, a specific form of viral encephalitis. Only the trial of Japanese encephalitis (22 children) contributed to the primary outcome of this review and follow-up in that study was for three to six months after hospital discharge. There was no follow-up of participants in the other two studies. We identified one ongoing trial.For the primary outcomes, the results showed no significant difference between IVIG and placebo when used in the treatment of children with Japanese encephalitis: significant disability (RR 0.75, 95% CI 0.22 to 2.60; P = 0.65) and serious adverse events (RR 1.00, 95% CI 0.07 to 14.05; P = 1.00).For the secondary outcomes, the study of Japanese encephalitis showed no significant difference between IVIG and placebo when assessing significant disability at hospital discharge (RR 1.00, 95% CI 0.60 to 1.67). There was no significant difference (P = 0.53) in Glasgow Coma Score at discharge between IVIG (median score 14; range 3 to 15) and placebo (median 14 score; range 7 to 15) in the Japanese encephalitis study. The median length of hospital stay in the Japanese encephalitis study was similar for IVIG-treated (median 13 days; range 9 to 21) and placebo-treated (median 12 days; range 6 to 18) children (P = 0.59).Pooled analysis of the results of the other two studies resulted in a significantly lower mean length of hospital stay (MD -4.54 days, 95% CI -7.47 to -1.61; P = 0.002), time to resolution of fever (MD -0.97 days, 95% CI -1.25 to -0.69; P < 0.00001), time to stop spasms (MD -1.49 days, 95% CI -1.97 to -1.01; P < 0.00001), time to regain consciousness (MD -1.10 days, 95% CI -1.48 to -0.72; P < 0.00001), and time to resolution of neuropathic symptoms (MD -3.20 days, 95% CI -3.34 to -3.06; P < 0.00001) in favour of IVIG when compared with standard care.None of the included studies reported other outcomes of interest in this review including need for invasive ventilation, duration of invasive ventilation, cognitive impairment, poor adaptive functioning, quality of life, number of seizures, and new diagnosis of epilepsy.The quality of evidence was very low for all outcomes of this review., Authors' Conclusions: The findings suggest a clinical benefit of adjunctive IVIG treatment for children with viral encephalitis for some clinical measures (i.e. mean length of hospital stay, time (days) to stop spasms, time to regain consciousness, and time to resolution of neuropathic symptoms and fever. For children with Japanese encephalitis, IVIG had a similar effect to placebo when assessing significant disability and serious adverse events.Despite these findings, the risk of bias in the included studies and quality of the evidence make it impossible to reach any firm conclusions on the efficacy and safety of IVIG as add-on treatment for children with encephalitis. Furthermore, the included studies involved only children with viral encephalitis, therefore findings of this review cannot be generalised to all forms of encephalitis. Future well-designed RCTs are needed to assess the efficacy and safety of IVIG in the management of children with all forms of encephalitis. There is a need for internationally agreed core outcome measures for clinical trials in childhood encephalitis.

Background: Encephalitis is a serious neurological disorder, yet data on admission rates for all-cause childhood encephalitis in England are scarce. We aimed to estimate admission rates for childhood encephalitis in England over 33 years (1979-2011), to describe trends in admission rates, and to observe how these rates have varied with the introduction of vaccines and improved diagnostics., Methods: We did a retrospective analysis of hospital admission statistics for encephalitis for individuals aged 0-19 years using national data from the Hospital Inpatient Enquiry (HIPE, 1979-85) and Hospital Episode Statistics (HES, 1990-2011). We analysed annual age-specific and age-standardised admission rates in single calendar years and admission rate trends for specified aetiologies in relation to introduction of PCR testing and measles-mumps-rubella (MMR) vaccination. We compared admission rates between the two International Classification of Diseases (ICD) periods, ICD9 (1979-94) and ICD10 (1995-2011)., Findings: We found 16 571 encephalitis hospital admissions in the period 1979-2011, with a mean hospital admission rate of 5·97 per 100 000 per year (95% CI 5·52-6·41). Hospital admission rates declined from 1979 to 1994 (ICD9; annual percentage change [APC] -3·30%; 95% CI -2·88 to -3·66; p<0·0001) and increased between 1995 and 2011 (ICD10; APC 3·30%; 2·75-3·85; p<0·0001). Admissions for measles decreased by 97% (from 0·32 to 0·009) and admissions for mumps encephalitis decreased by 98% (from 0·60 to 0·01) after the introduction of the two-dose MMR vaccine. Hospital admission rates for encephalitis of unknown aetiology have increased by 37% since the introduction of PCR testing., Interpretation: Hospital admission rates for all-cause childhood encephalitis in England are increasing. Admissions for measles and mumps encephalitis have decreased substantially. The numbers of encephalitis admissions without a specific diagnosis are increasing despite availability of PCR testing, indicating the need for strategies to improve aetiological diagnosis in children with encephalitis., Funding: None., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Infectious and immune-mediated encephalitides are important but under-recognised causes of morbidity and mortality in childhood, with a 7% death rate and up to 50% morbidity after prolonged follow-up. There is a theoretical basis for ameliorating the immune response with intravenous immunoglobulin (IVIG), which is supported by empirical evidence of a beneficial response following its use in the treatment of viral and autoimmune encephalitis. In immune-mediated encephalitis, IVIG is often used after a delay (by weeks in some cases), while diagnosis is confirmed. Wider use of IVIG in infectious encephalitis and earlier use in immune-mediated encephalitis could improve outcomes for these conditions. We describe the protocol for the first ever randomised control trial of IVIG treatment for children with all-cause encephalitis., Methods and Analysis: 308 children (6 months to 16 years) with a diagnosis of acute/subacute encephalitis will be recruited in ∼30 UK hospitals and randomised to receive 2 doses (1 g/kg/dose) of either IVIG or matching placebo, in addition to standard treatment. Recruitment will be over a 42-month period and follow-up of each participant will be for 12 months post randomisation. The primary outcome is 'good recovery' (score of 2 or lower on the Glasgow Outcome Score Extended-paediatric version), at 12 months after randomisation. Additional secondary neurological measures will be collected at 4-6 weeks after discharge from acute care and at 6 and 12 months after randomisation. Safety, radiological, other autoimmune and tertiary outcomes will also be assessed., Ethics and Dissemination: This trial has been approved by the UK National Research Ethics committee (South Central-Oxford A; REC 14/SC/1416). Current protocol: V4.0 (10/03/2016). The findings will be presented at national and international meetings and conferences and published in peer-reviewed journals., Trial Registration Numbers: NCT02308982, EudraCT201400299735 and ISRCTN15791925; Pre-results., Competing Interests: CSL Behring have provided the study IMP (IVIG) and funded manufacture of placebo and the supply and distribution of IMP and placebo. AJP reports grants from NIHR EME programme, during the conduct of the study. The University of Oxford and AV hold patents for VGKC-complex antibody tests, licensed to Euroimmun AG, and receive royalties. The neuroimmunology work in the described trial is funded through the MRC/NIHR grant. MA serves on the data safety monitoring board for a study sponsored by Neurim Pharmaceuticals and is on the editorial advisory board for the International Journal of Language and Communication Disorders. MAI and LW report salary from the NIHR EME grant. ML has received consultation fees from CSL Behring, travel grants from Merck Serono and been awarded educational grants to organise meetings by Novartis, Biogen Idec, Merck Serono and Bayer. MS reports grants from Pfizer, outside the submitted work. TS is supported by the National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections at Liverpool. AE, LW, L-MY, MP, MS, RK and WKC have nothing to disclose., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: A substantial reduction in bacterial meningitis has occurred in the UK following successful implementation of immunisation programmes. Most childhood meningitis in developed countries is now caused by viruses. Long-term trends in paediatric viral meningitis in England have not previously been reported. The objective of this study is to report on epidemiological trends over time in childhood viral meningitis in England., Methods: In this population-based observational study, we used routinely collected hospital discharge records from English National Health Service hospitals from 1968-2011 to analyse annual age-specific admission rates for viral meningitis, including specific viral aetiologies, in children younger than 15 years., Findings: We analysed hospital discharge records from Jan 1, 1968, to Dec 31, 2011. Hospital admission rates for viral meningitis from Jan 1, 1968, to Dec 31, 1985, varied annually, with a mean of 13·5 admissions per 100 000 children aged less than 15 years, per year (95% CI 13·0-14·0). Admission rates declined during the late 1980s, and the mean number of admissions from 1989-2011 was 5·2 per 100 000 per year (5·1-5·3). This decrease was entirely in children aged 1-14 years. Admission rates for infants aged less than 1 year increased since 2005, to 70·0 per 100 000 (63·7-76·2) in 2011, which was driven by an increase in admission of infants aged 90 days or less. In 1968-85, the majority of cases in children were in those aged 1-14 years (22 150 [89%] of 24 920 admissions). In 2007-11, 1716 (72%) of 2382 cases were in infants. Admissions for mumps-related meningitis almost disappeared following introduction of the measles-mumps-rubella (MMR) vaccine in 1988. Admissions with a specified viral aetiology have increased since 2000., Interpretation: Trends in viral meningitis admissions have changed substantially over the past 50 years, and probably reflect the impact of the MMR vaccine programme and the use of more sensitive diagnostic techniques., Funding: None., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The use of different limbs for the administration of sequential doses of an intradermal rabies vaccine was shown to result in reduced vaccine immunogenicity. We aimed to assess whether this phenomenon also occurs with routine infant vaccines., Methods: In this open-label, randomised, controlled study, eligible healthy infants 6-12 weeks of age recruited through five clinical trials units (four in the UK and one in Malta) were randomly assigned in a 1:1 ratio to two vaccination groups: consistent limb or alternating limb. Infants in the consistent limb group received the diphtheria-tetanus-acellular pertussis-inactived polio-Haemophilus influenzae type b combined vaccine (DTaP-IPV-Hib) at 2, 3, and 4 months of age, and the pneumococcal conjugate vaccine (PCV13) at 2, 4, and 12 months, all administered to the right leg. Infants in the alternating limb group received DTaP-IPV-Hib in the left leg at 2 months and in the right leg at 3 and 4 months; and PCV13 in the left leg at 2 months, in the right leg at 4 months, and in the left arm at 12 months. All infants in both groups received the combined H influenzae type b and capsular group C Neisseria meningitidis tetanus toxoid conjugate vaccine (Hib-MenC-TT), administered in the left leg at 12 months. Randomisation was achieved by randomly generated codes, with permuted block size of 30, and was stratified by study site. Group allocation was not masked from study staff and parents of participants after enrolment, but group allocation was masked from laboratory staff assessing blood samples. The current study was a prespecified secondary objective of a parent phase 4 trial that assessed the induction of immunity following varying schedules of vaccination with glyco-conjugate capsular group C Neisseria meningitidis (Men C) vaccines in infancy. The objective of the current study was to compare the immunogenicity and reactogenicity of vaccines delivered in either consistent or alternating limbs. Immunogenicity was assessed by comparing serum IgG geometric mean concentrations at 5, 12, 13, and 24 months, analysed per protocol. This study is registered with ClinicalTrials.gov, number NCT01129518., Findings: Between July 5, 2010, and Aug 1, 2013, we enrolled 509 infants and randomly allocated them to the consistent limb group (n=254) or the alternating limb group (n=255). Anti-H influenzae type b anti-polyribosylribitol phosphate IgG geometric mean concentrations were lower in the consistent limb group than in the alternating limb group at 5 months (consistent limb 0·41 μg/mL [95% CI 0·31-0·54] vs alternating limb 0·61 μg/mL [0·45-0·82]; p=0·0268) and at 12 months (0·35 μg/mL [0·28-0·43] vs 0·50 μg/mL [0·40-0·62]; p=0·0136). Anti-tetanus toxoid antibody IgG geometric mean concentrations were lower in the consistent limb group (1·63 IU/mL [95% CI 1·40-1·90]) than in the alternating limb group (2·30 IU/mL [1·97-2·68]) at 13 months (p=0·0008) and at 24 months (0·44 IU/mL [0·37-0·52] vs 0·61 IU/mL [0·51-0·73]; p=0·0074). Anti-pneumococcal IgG geometric mean concentrations were similar between both groups at all timepoints. The proportions of participants who had adverse events did not differ between the two groups., Interpretation: Use of different (alternating) limbs for sequential doses of routine infant vaccines does not reduce, and might enhance, immunogenicity. The underlying mechanism for this finding warrants further research., Funding: NIHR Oxford Biomedical Research Centre and GlaxoSmithKline Biologicals., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A HIV-positive child presented with acute onset of right hemiplegia, facial palsy and dysphasia 4 weeks after commencing highly active antiretroviral therapy. Magnetic resonance imaging confirmed a left-sided cerebral infarct. Cerebrospinal fluid polymerase chain reaction was positive for varicella zoster virus. This is the first reported pediatric case of varicella zoster virus-related immune reconstitution inflammatory syndrome involving the central nervous system.