Multiple sclerosis and the risk of infection: Association of British Neurologists consensus guideline.

Infection in people with multiple sclerosis (MS) is of major concern, particularly for those receiving disease-modifying therapies. This article explores the risk of infection in people with MS and provides guidance-developed by Delphi consensus by specialists involved in their management-on how to screen for, prevent and manage infection in this population.

If it ain't broke don't fix it: Lack of review of antimicrobials in 'well' patients - time for a CRP change.

INTRODUCTION: The rising prevalence of multi-resistant organisms threatens the efficacy of current antimicrobial treatments. Antibiotic stewardship is a key factor in slowing the development of resistance and must become part of a clinician's regular practice. National guidance unanimously emphasises the importance of a 48-hour review of antimicrobial prescriptions. We assessed the compliance of antibiotic reviews across two sites in Wales. METHOD: Two cycles of data were retrospectively collected across two teaching hospitals in Wales prior and following introduction of an antimicrobial alert sticker. A univariate odds ratio for 48-hour referral stratified by C-reactive protein (CRP) was calculated in a logistic regression model for the cycle one data. RESULTS: One-hundred and thirty-nine patients were included in the cycle 1 data across both sites. We identified that patients with a CRP ≤100 mg/L (a marker of less severe infection) were less likely to have their antibiotic prescription reviewed by 48 hours. DISCUSSION: Patients with CRP ≤100 mg/L were less likely to receive a 48-hour review of their antimicrobial prescription. Compliance with review improved following introduction of a simple alert measure.

Means restriction for the prevention of suicide on roads.

BACKGROUND: Road traffic suicides are common. However, due to the difficulty in distinguishing between motor vehicle crash fatalities and actual suicides, no official figures exist for this method of suicide. Restricting access to means is an important universal or population-based approach to suicide prevention with clear evidence of its effectiveness. However, the evidence with respect to means restriction for the prevention of suicide on roads is not well established. We conducted a systematic review to assess the impact of restrictions on the availability of, or access to, means of suicide on roads. OBJECTIVES: To evaluate the effectiveness of interventions to restrict the availability of, or access to, means of suicide on roads. SEARCH METHODS: We searched the Cochrane Library, MEDLINE, Embase, PsycINFO, and the Transport Research International Documentation (TRID) Database from the date of database inception to March 2020. We conducted searches of the World Health Organization International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov to identify unpublished and ongoing studies. We applied no date, language, or publication status restrictions to these searches. SELECTION CRITERIA: Eligible studies were randomised or quasi-randomised controlled trials, controlled intervention studies without randomisation, before-after studies, or studies using interrupted time series designs, which evaluated interventions to restrict the availability of, or access to, means of suicide on roads. DATA COLLECTION AND ANALYSIS: Two review authors screened abstracts and full-text publications against the inclusion criteria. Two review authors planned to independently extract data and assess risk of bias of included studies. However, we identified no studies eligible for inclusion. MAIN RESULTS: We identified no studies that met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: This systematic review highlights the paucity of research around road traffic suicides and the need for future robust studies that aim to investigate the effectiveness of interventions to prevent suicide on roads. Suicide ascertainment is a key issue; therefore, clear objective criteria are necessary in order to scale up and study this method more accurately. In the absence of any substantial evidence, we advocate for more awareness on road traffic suicides and its inclusion in future government suicide prevention policies. Further research exploring effective measures, particularly those that do not require driver compliance, are also needed.

A Case of Multiple Sclerosis-Like Relapsing Remitting Encephalomyelitis Following Allogeneic Hematopoietic Stem Cell Transplantation and a Review of the Published Literature.

Complications involving the central nervous system (CNS) occur in 9-14% of patients following allogeneic hematopoietic stem cell transplantation (HSCT), including stroke-like episodes, demyelination, encephalitis, and nonspecific neurological symptoms. Here we report a case of multiple sclerosis (MS) like relapsing remitting encephalomyelitis following allogeneic HSCT, which did not respond to disease modifying therapies (DMTs) and "domino" autologous HSCT. A 53-year-old male was treated with allogeneic HSCT for lymphoid blast transformation of chronic myeloid leukemia. Ten months later he presented with confusion, slurred speech, left sided facial weakness and ataxia. A magnetic resonance imaging brain scan showed multiple enhancing tumefactive lesions. Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibodies were negative. After extensive investigations for infections, autoimmune disorders and recurrence of malignancy, he underwent brain biopsy, which showed a macrophage rich lesion with severe myelin loss but axonal preservation indicating a demyelinating pathology. Although his symptoms improved with corticosteroids, he relapsed five months later. In the absence of any systemic features suggesting graft versus host disease (GvHD), his presentation was thought to be compatible with MS. The illness followed an aggressive course that did not respond to glatiramer acetate and natalizumab. He was therefore treated with "domino" autologous HSCT, which also failed to induce long-term remission. Despite further treatment with ocrelizumab, he died of progressive disease. An autopsy limited to the examination of brain revealed multifocal destructive leukoencephalopathy with severe myelin and axonal loss. Immunohistochemistry showed macrophage located in the perivascular area, with no T or B lymphocytes. The appearance was unusual and not typical for chronic MS plaques. Reported cases of CNS demyelination following allogeneic HSCT are very limited in the literature, especially in relation to histopathological examination. Although the clinical disease course of our patient following allogeneic HSCT resembled an "MS-like" relapsing remitting encephalomyelitis, the autopsy examination did not show any evidence of active inflammation. The impact of DMTs and HSCT on the histological appearance of "MS-like" CNS pathologies is unknown. Therefore, reporting this and similar cases will improve our awareness and understanding of underlying disease mechanisms.

Means restriction for the prevention of suicide by jumping.

BACKGROUND: Jumping from a height is an uncommon but lethal means of suicide. Restricting access to means is an important universal or population-based approach to suicide prevention with clear evidence of its effectiveness. However, the evidence with respect to means restriction for the prevention of suicide by jumping is not well established. OBJECTIVES: To evaluate the effectiveness of interventions to restrict the availability of, or access to, means of suicide by jumping. These include the use of physical barriers, fencing or safety nets at frequently-used jumping sites, or restriction of access to these sites, such as by way of road closures. SEARCH METHODS: We searched the Cochrane Library, Embase, MEDLINE, PsycINFO, and Web of Science to May 2019. We conducted additional searches of the international trial registries including the World Health Organization International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov, to identify relevant unpublished and ongoing studies. We searched the reference lists of all included studies and relevant systematic reviews to identify additional studies and contacted authors and subject experts for information on unpublished or ongoing studies. We applied no restrictions on date, language or publication status to the searches. Two review authors independently assessed all citations from the searches and identified relevant titles and abstracts. Our main outcomes of interest were suicide, attempted suicide or self-harm, and cost-effectiveness of interventions. SELECTION CRITERIA: Eligible studies were randomised or quasi-randomised controlled trials, controlled intervention studies without randomisation, before-and-after studies, or studies using interrupted time series designs, which evaluated interventions to restrict the availability of, or access to, means of suicide by jumping. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and three review authors extracted study data. We pooled studies that evaluated similar interventions and outcomes using a random-effects meta-analysis, and we synthesised data from other studies in a narrative summary. We summarised the quality of the evidence included in this review using the GRADE approach. MAIN RESULTS: We included 14 studies in this review. Thirteen were before-and-after studies and one was a cost-effectiveness analysis. Three studies each took place in Switzerland and the USA, while two studies each were from the UK, Canada, New Zealand, and Australia respectively. The majority of studies (10/14) assessed jumping means restriction interventions delivered in isolation, half of which were at bridges. Due to the observational nature of included studies, none compared comparator interventions or control conditions. During the pre- and postintervention period among the 13 before-and-after studies, a total of 742.3 suicides (5.5 suicides per year) occurred during the pre-intervention period (134.5 study years), while 70.6 suicides (0.8 suicides per year) occurred during the postintervention period (92.4 study years) - a 91% reduction in suicides. A meta-analysis of all studies assessing jumping means restriction interventions (delivered in isolation or in combination with other interventions) showed a directionality of effect in favour of the interventions, as evidenced by a reduction in the number of suicides at intervention sites (12 studies; incidence rate ratio (IRR) = 0.09, 95% confidence interval (CI) 0.03 to 0.27; P < 0.001; I2 = 88.40%). Similar findings were demonstrated for studies assessing jumping means restriction interventions delivered in isolation (9 studies; IRR = 0.05, 95% CI 0.01 to 0.16; P < 0.001; I2 = 73.67%), studies assessing jumping means restriction interventions delivered in combination with other interventions (3 studies; IRR = 0.54, 95% CI 0.31 to 0.93; P = 0.03; I2 = 40.8%), studies assessing the effectiveness of physical barriers (7 studies; IRR = 0.07, 95% CI 0.02 to 0.24; P < 0.001; I2 = 84.07%), and studies assessing the effectiveness of safety nets (2 studies; IRR = 0.09, 95% CI 0.01 to 1.30; P = 0.07; I2 = 29.3%). Data on suicide attempts were limited and none of the studies used self-harm as an outcome. There was considerable heterogeneity between studies for the primary outcome (suicide) in the majority of the analyses except those relating to jumping means restriction delivered in combination with other interventions, and safety nets. Nevertheless, every study included in the forest plots showed the same directional effects in favour of jumping means restriction. Due to methodological limitations of the included studies, we rated the quality of the evidence from these studies as low. A cost-effectiveness analysis suggested that the construction of a physical barrier on a bridge would be a highly cost-effective project in the long term as a result of overall reduced suicide mortality. AUTHORS' CONCLUSIONS: The findings from this review suggest that jumping means restriction interventions are capable of reducing the frequency of suicides by jumping. However, due to methodological limitations of included studies, this finding is based on low-quality evidence. Therefore, further well-designed high-quality studies are required to further evaluate the effectiveness of these interventions, as well as other measures at jumping sites. In addition, further research is required to investigate the potential for suicide method substitution and displacement effects in populations exposed to interventions to prevent suicide by jumping.

Effect of remote ischaemic preconditioning on walking in people with multiple sclerosis: double-blind randomised controlled trial.

BACKGROUND: Remote ischaemic preconditioning (RIPC) is the exposure of body parts to brief periods of circulatory occlusion and reperfusion. Recent studies have also shown that RIPC can improve exercise performance in healthy individuals. OBJECTIVE: This study aimed to assess the effect of RIPC on walking in people with multiple sclerosis (MS). METHODS: This was a double-blind randomised controlled clinical trial. We used three cycles of RIPC delivered by occluding the upper arm with a blood pressure (BP) cuff inflated to a pressure of 30 mm Hg above the systolic BP. In patients in the sham intervention group, the BP cuff was inflated only to 30 mm Hg below diastolic BP. Outcome measures included the Six-Minute Walk Test (6MWT), gait speed, the Borg rate of perceived exertion (RPE) scale, the tolerability of the RIPC using a Numerical Rating Scale for discomfort from 0 to 10, and adverse events. We identified responders meeting the minimal clinically important difference (MCID) established in the literature in each group. RESULTS: Seventy-five participants completed the study (RIPC: 38 and Sham: 37). The distance walked during the 6MWT improved by 1.9% in the sham group and 5.7% in the RIPC group (p=0.012). The number of responders meeting MCID criteria in the RIPC group was significantly greater compared with the sham intervention group. No serious adverse events occurred. CONCLUSION: Single cycle of RIPC resulted in immediate improvement in walking distances during 6MWT in people with MS. TRIAL REGISTRATION NUMBERS: NCT03153553.

Newspaper Reporting on a Cluster of Suicides in the UK.

BACKGROUND: Media reporting may influence suicide clusters through imitation or contagion. In 2008 there was extensive national and international newspaper coverage of a cluster of suicides in young people in the Bridgend area of South Wales, UK. AIMS: To explore the quantity and quality of newspaper reporting during the identified cluster. METHOD: Searches were conducted for articles on suicide in Bridgend for 6 months before and after the defined cluster (June 26, 2007, to September 16, 2008). Frequency, quality (using the PRINTQUAL instrument), and sensationalism were examined. RESULTS: In all, 577 newspaper articles were identified. One in seven articles included the suicide method in the headline, 47.3% referred to earlier suicides, and 44% used phrases that guidelines suggest should be avoided. Only 13% included sources of information or advice. CONCLUSION: A high level of poor-quality and sensationalist reporting was found during an ongoing suicide cluster at the very time when good-quality reporting could be considered important. A broad awareness of media guidelines and expansion and adherence to press codes of practice are required by journalists to ensure ethical reporting.

Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of C9ORF72.

BACKGROUND: Crossover in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) has been described but is poorly understood. A GGGGCC hexanucleotide repeat expansion of C9ORF72 has recently been identified in a significant proportion of patients with ALS. METHODS: In approximately 650 patients diagnosed with ALS from the North of England we identified seven patients who initially presented with MS. DNA obtained from five patients with MS-ALS and 215 patients with MS alone was screened for the C9ORF72 expansion. Post-mortem material was examined from two patients with MS-ALS. Gene expression profiling was performed on lymphoblastoid cells and levels of CXCL10 were measured in cerebrospinal fluid (CSF) from patients with ALS with and without the C9ORF72 expansion and controls. RESULTS: Concurrence of MS and ALS is higher than expected in our population. The C9ORF72 expansion was identified in 80% of patients with MS-ALS but not in those with MS alone. In the presence of preceding MS, C9ORF72-ALS was more rapidly progressive. MetaCore analysis identified alteration of the NF-кB pathway in C9ORF72-ALS and non-C9ORF72-ALS. NF-кB activation is associated with increased expression of the neuroprotective cytokine CXCL10 but, in C9ORF72-ALS, CXCL10 is downregulated and CSF levels are reduced. CONCLUSIONS: We propose that MS-associated neuroinflammation may affect penetrance and progression of the C9ORF72 expansion. In particular, the NF-кB pathway is activated in MS and appears to be dysfunctional in C9ORF72-ALS. Aberrant downregulation of CXCL10 may explain the predisposition of C9ORF72 expansion carriers to develop ALS in the context of MS and NF-кB activation, and offers a potential therapeutic target.

Adversarial growth in patients with multiple sclerosis and their partners: relationships with illness perceptions, disability and distress.

The purpose of this study was to investigate whether patients with multiple sclerosis (MS) and their partners show adversarial growth and to examine which psychological and disability variables contribute to this in patients and their partners. The study also investigated the relationship between growth and distress. Seventy-two patients with MS and their partners provided demographic information and completed measures of posttraumatic growth, illness perceptions, depression, cognitive function and disability. Both patients and partners showed adversarial growth, with patients reporting significantly higher growth than partners. The only significant predictor for patient growth was partner growth, and vice versa. Dissimilarity in illness representations between patients and their partners on the consequences of MS dimension, patient mood and patient growth accounted for significant variance in partner growth. The findings support the idea of a 'communal search for meaning' where patients and their partners experience the trauma of having a chronic illness and subsequently find positive aspects together.

The chemokine IL8 is up-regulated in bovine endometrial stromal cells by the BoHV-4 IE2 gene product, ORF50/Rta: a step ahead toward a mechanism for BoHV-4 induced endometritis.

Postpartum infections of the endometrium and metritis are common causes of delayed conception and infertility in cattle. These infections are characterized by inflammation of the endometrium and secretion of the chemokine interleukin 8 (IL8), which attracts granulocytes to the endometrium. Bovine herpesvirus 4 (BoHV-4) is tropic for the endometrium and the only virus consistently associated with postpartum metritis. The BoHV-4 Immediate Early 2 (IE2) gene is the first viral gene transcribed by host cells after infection, and the IE2 gene product, ORF50/Rta, transactivates host cell genes. The present study tested the hypothesis that ORF50/Rta transactivates the IL8 gene promoter during BoHV-4 infection of bovine endometrial stromal cells (BESCs). Infection of primary BESCs with BoHV-4 stimulated IL8 gene promoter activity and IL8 protein secretion. However, IL8 production was dependent on the transcription of viral genes, because psoralen/ultraviolet cross-linking of the viral DNA abrogated the response to BoHV-4 infection. Furthermore, IL8 promoter serial deletion analysis revealed a specific region responsive to ORF50/Rta. These observations may represent an endometrial defense mechanism against viral infection or a virulence mechanism by which viral replication stimulates chemokine secretion to attract more susceptible host cells to the endometrium.

Specific strains of Escherichia coli are pathogenic for the endometrium of cattle and cause pelvic inflammatory disease in cattle and mice.

BACKGROUND: Escherichia coli are widespread in the environment and pathogenic strains cause diseases of mucosal surfaces including the female genital tract. Pelvic inflammatory disease (PID; metritis) or endometritis affects approximately 40% of cattle after parturition. We tested the expectation that multiple genetically diverse E. coli from the environment opportunistically contaminate the uterine lumen after parturition to establish PID. METHODOLOGY/PRINCIPAL FINDINGS: Distinct clonal groups of E. coli were identified by Random Amplification of Polymorphic DNA (RAPD) and Multilocus sequence typing (MLST) from animals with uterine disease and these differed from known diarrhoeic or extra-intestinal pathogenic E. coli. The endometrial pathogenic E. coli (EnPEC) were more adherent and invasive for endometrial epithelial and stromal cells, compared with E. coli isolated from the uterus of clinically unaffected animals. The endometrial epithelial and stromal cells produced more prostaglandin E(2) and interleukin-8 in response to lipopolysaccharide (LPS) purified from EnPEC compared with non-pathogenic E. coli. The EnPEC or their LPS also caused PID when infused into the uterus of mice with accumulation of neutrophils and macrophages in the endometrium. Infusion of EnPEC was only associated with bacterial invasion of the endometrium and myometrium. Despite their ability to invade cultured cells, elicit host cell responses and establish PID, EnPEC lacked sixteen genes commonly associated with adhesion and invasion by enteric or extraintestinal pathogenic E. coli, though the ferric yersiniabactin uptake gene (fyuA) was present in PID-associated EnPEC. Endometrial epithelial or stromal cells from wild type but not Toll-like receptor 4 (TLR4) null mice secreted prostaglandin E(2) and chemokine (C-X-C motif) ligand 1 (CXCL1) in response to LPS from EnPEC, highlighting the key role of LPS in PID. CONCLUSIONS/SIGNIFICANCE: The implication arising from the discovery of EnPEC is that development of treatments or vaccines for PID should focus specifically on EnPEC and not other strains of E. coli.

Measurement of radiotherapy superficial X-ray dose under eye shields with radiochromic film.

Accurate measurement and knowledge of dose delivered under eye shield during superficial X-ray radiotherapy is required for patient peripheral dose assessment. Critical structures can include the cornea, lens and retina. Measurement of dose under eye shields has been historically performed with Thermoluminescent Dosimeters (TLD's) due to their small size and design. Restrictions include the energy dependence and the fact that they only provide a point dose assessment. This note investigates the use of a low energy dependence radiochromic thin film for measurement of dose under eye shields in a phantom and compares results to theoretical calculation of dose. Results have shown a good match between predicted and experimentally measured results at the centre of an eye shield irradiated with 50kVp and 150kVp beams. The added advantage of radiochromic film compared to TLD measurements is the two dimensional dose map which is recorded for the assessment of dose providing not only an assessment at the site of the cornea, lens and retina in a phantom but in other areas as well. Radiochromic film has been found to accurately measure dose under eye shield in phantom treatments.