Symptomatic treatment of children with anti-NMDAR encephalitis.

Abstract AIM: We performed the first study on the perceived benefit and adverse effects of symptomatic management in children with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. METHOD: A retrospective chart review was undertaken at two tertiary paediatric hospitals in Australia and New Zealand. We included 27 children (12 males, 15 females; mean age at admission 7y 1mo) with anti-NMDAR antibodies in serum or cerebrospinal fluid with a typical clinical syndrome. RESULTS: Only two out of 27 patients were white, whereas 16 out of 27 patients were from the Pacific Islands/New Zealand Maori. The mean duration of admission was 69 days (10-224d) and 48% of patients (13/27) needed treatment in an intensive care setting. A mean of eight medications per patient was used for symptomatic management. Symptoms treated were agitation (n=25), seizures (n=24), movement disorders (n=23), sleep disruption (n=17), psychiatric symptoms (n=10), and dysautonomia (n=four). The medications used included five different benzodiazepines (n=25), seven anticonvulsants (n=25), eight sedatives and sleep medications (n=23), five antipsychotics (n=12), and five medications for movement disorders (n=10). Sedative and sleep medications other than benzodiazepines were the most effective, with a mean benefit of 67.4% per medication and a mean adverse effect-benefit ratio of 0.04 per medication. Antipsychotic drugs were used for a short duration (median 9d), and had the poorest mean benefit per medication of 35.4% and an adverse effect-benefit ratio of 2.0 per medication. INTERPRETATION: Long-acting benzodiazepines, anticonvulsants, and clonidine can treat multiple symptoms. Patients with anti-NMDAR encephalitis appear vulnerable to antipsychotic-related adverse effects. Pacific Islanders appear to have a vulnerability to anti-NMDAR encephalitis in our region

Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

Several vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies

Protocol for the PACE trial: A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy

<p>Abstract</p> <p>Background</p> <p>Chronic fatigue syndrome (CFS, also called myalgic encephalomyelitis/encephalopathy or ME) is a debilitating condition with no known cause or cure. Improvement may occur with medical care and additional therapies of pacing, cognitive behavioural therapy and graded exercise therapy. The latter two therapies have been found to be efficacious in small trials, but patient organisations' surveys have reported adverse effects. Although pacing has been advocated by patient organisations, it lacks empirical support. Specialist medical care is commonly provided but its efficacy when given alone is not established. This trial compares the efficacy of the additional therapies when added to specialist medical care against specialist medical care alone.</p> <p>Methods/Design</p> <p>600 patients, who meet operationalised diagnostic criteria for CFS, will be recruited from secondary care into a randomised trial of four treatments, stratified by current comorbid depressive episode and different CFS/ME criteria. The four treatments are standardised specialist medical care either given alone, or with adaptive pacing therapy or cognitive behaviour therapy or graded exercise therapy. Supplementary therapies will involve fourteen sessions over 23 weeks and a 'booster session' at 36 weeks. Outcome will be assessed at 12, 24, and 52 weeks after randomisation. Two primary outcomes of self-rated fatigue and physical function will assess differential effects of each treatment on these measures. Secondary outcomes include adverse events and reactions, subjective measures of symptoms, mood, sleep and function and objective measures of physical activity, fitness, cost-effectiveness and cost-utility. The primary analysis will be based on intention to treat and will use logistic regression models to compare treatments. Secondary outcomes will be analysed by repeated measures analysis of variance with a linear mixed model. All analyses will allow for stratification factors. Mediators and moderators will be explored using multiple linear and logistic regression techniques with interactive terms, with the sample split into two to allow validation of the initial models. Economic analyses will incorporate sensitivity measures.</p> <p>Discussion</p> <p>The results of the trial will provide information about the benefits and adverse effects of these treatments, their cost-effectiveness and cost-utility, the process of clinical improvement and the predictors of efficacy.</p

Estimating the NIH Efficient Frontier

Background: The National Institutes of Health (NIH) is among the world’s largest investors in biomedical research, with a mandate to: “…lengthen life, and reduce the burdens of illness and disability.” Its funding decisions have been criticized as insufficiently focused on disease burden. We hypothesize that modern portfolio theory can create a closer link between basic research and outcome, and offer insight into basic-science related improvements in public health. We propose portfolio theory as a systematic framework for making biomedical funding allocation decisions–one that is directly tied to the risk/reward trade-off of burden-of-disease outcomes. Methods and Findings: Using data from 1965 to 2007, we provide estimates of the NIH “efficient frontier”, the set of funding allocations across 7 groups of disease-oriented NIH institutes that yield the greatest expected return on investment for a given level of risk, where return on investment is measured by subsequent impact on U.S. years of life lost (YLL). The results suggest that NIH may be actively managing its research risk, given that the volatility of its current allocation is 17% less than that of an equal-allocation portfolio with similar expected returns. The estimated efficient frontier suggests that further improvements in expected return (89% to 119% vs. current) or reduction in risk (22% to 35% vs. current) are available holding risk or expected return, respectively, constant, and that 28% to 89% greater decrease in average years-of-life-lost per unit risk may be achievable. However, these results also reflect the imprecision of YLL as a measure of disease burden, the noisy statistical link between basic research and YLL, and other known limitations of portfolio theory itself. Conclusions: Our analysis is intended to serve as a proof-of-concept and starting point for applying quantitative methods to allocating biomedical research funding that are objective, systematic, transparent, repeatable, and expressly designed to reduce the burden of disease. By approaching funding decisions in a more analytical fashion, it may be possible to improve their ultimate outcomes while reducing unintended consequences

Six weeks of home enteral nutrition versus standard care after esophagectomy or total gastrectomy for cancer: study protocol for a randomized controlled trial

Background: Each year approximately 3000 patients in the United Kingdom undergo surgery for esophagogastric cancer. Jejunostomy feeding tubes, placed at the time of surgery for early postoperative nutrition, have been shown to have a positive impact on clinical outcomes in the short term. Whether feeding out of hospital is of benefit is unknown. Local experience has identified that between 15 and 20% of patients required ‘rescue’ jejunostomy feeding for nutritional problems and weight loss while at home. This weight loss and poor nutrition may contribute to the detrimental effect on the overall quality of life (QoL) reported in these patients. Methods/Design: This randomized pilot and feasibility study will provide preliminary information on the routine use of jejunostomy feeding after hospital discharge in terms of clinical benefits and QoL. Sixty participants undergoing esophagectomy or total gastrectomy will be randomized to receive either a planned program of six weeks of home jejunostomy feeding after discharge from hospital (intervention) or treatment-as-usual (control). The intention of this study is to inform a multi-centre randomized controlled trial. The primary outcome measures will be recruitment and retention rates at six weeks and six months. Secondary outcome measures will include disease specific and general QoL measures, nutritional parameters, total and oral nutritional intake, hospital readmission rates, and estimates of healthcare costs. Up to 20 participants will also be enrolled in a qualitative sub-study that will explore participants’ and carers’ experiences of home tube feeding. The results will be disseminated by presentation at surgical, gastroenterological and dietetic meetings and publication in appropriate peer review journals. A patient-friendly lay summary will be made available on the University of Leicester and the University Hospitals of Leicester NHS Trust websites. The study has full ethical and institutional approval and started recruitment in July 2012. Trial registration: UKClinical Research Network ID #12447 (Main study); UKCRN ID#13361 (Qualitative sub study); ClinicalTrials.gov #NCT01870817 (First registered 28 May 2013

Entamoeba Shows Reversible Variation in Ploidy under Different Growth Conditions and between Life Cycle Phases

Under axenic growth conditions, trophozoites of Entamoeba histolytica contain heterogenous amounts of DNA due to the presence of both multiple nuclei and different amounts of DNA in individual nuclei. In order to establish if the DNA content and the observed heterogeneity is maintained during different growth conditions, we have compared E. histolytica cells growing in xenic and axenic cultures. Our results show that the nuclear DNA content of E. histolytica trophozoites growing in axenic cultures is at least 10 fold higher than in xenic cultures. Re-association of axenic cultures with their bacterial flora led to a reduction of DNA content to the original xenic values. Thus switching between xenic and axenic growth conditions was accompanied by significant changes in the nuclear DNA content of this parasite. Changes in DNA content during encystation-excystation were studied in the related reptilian parasite E. invadens. During excystation of E. invadens cysts, it was observed that the nuclear DNA content increased approximately 40 fold following emergence of trophozoites in axenic cultures. Based on the observed large changes in nuclear size and DNA content, and the minor differences in relative abundance of representative protein coding sequences, rDNA and tRNA sequences, it appears that gain or loss of whole genome copies may be occurring during changes in the growth conditions. Our studies demonstrate the inherent plasticity and dynamic nature of the Entamoeba genome in at least two species

Identification of Human Fibroblast Cell Lines as a Feeder Layer for Human Corneal Epithelial Regeneration

There is a great interest in using epithelium generated in vitro for tissue bioengineering. Mouse 3T3 fibroblasts have been used as a feeder layer to cultivate human epithelia including corneal epithelial cells for more than 3 decades. To avoid the use of xeno-components, we evaluated human fibroblasts as an alternative feeder supporting human corneal epithelial regeneration. Five human fibroblast cell lines were used for evaluation with mouse 3T3 fibroblasts as a control. Human epithelial cells isolated from fresh corneal limbal tissue were seeded on these feeders. Colony forming efficiency (CFE) and cell growth capacity were evaluated on days 5–14. The phenotype of the regenerated epithelia was evaluated by morphology and immunostaining with epithelial markers. cDNA microarray was used to analyze the gene expression profile of the supportive human fibroblasts. Among 5 strains of human fibroblasts evaluated, two newborn foreskin fibroblast cell lines, Hs68 and CCD1112Sk, were identified to strongly support human corneal epithelial growth. Tested for 10 passages, these fibroblasts continually showed a comparative efficiency to the 3T3 feeder layer for CFE and growth capacity of human corneal epithelial cells. Limbal epithelial cells seeded at 1×104 in a 35-mm dish (9.6 cm2) grew to confluence (about 1.87–2.41×106 cells) in 12–14 days, representing 187–241 fold expansion with over 7–8 doublings on these human feeders. The regenerated epithelia expressed K3, K12, connexin 43, p63, EGFR and integrin β1, resembling the phenotype of human corneal epithelium. DNA microarray revealed 3 up-regulated and 10 down-regulated genes, which may be involved in the functions of human fibroblast feeders. These findings demonstrate that commercial human fibroblast cell lines support human corneal epithelial regeneration, and have potential use in tissue bioengineering for corneal reconstruction

Investigation into the Presence of and Serological Response to XMRV in CFS Patients

The novel human gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV), originally described in prostate cancer, has also been implicated in chronic fatigue syndrome (CFS). When later reports failed to confirm the link to CFS, they were often criticised for not using the conditions described in the original study. Here, we revisit our patient cohort to investigate the XMRV status in those patients by means of the original PCR protocol which linked the virus to CFS. In addition, sera from our CFS patients were assayed for the presence of xenotropic virus envelope protein, as well as a serological response to it. The results further strengthen our contention that there is no evidence for an association of XMRV with CFS, at least in the UK