The Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis cohort population structure and disease etiology.

Background: Previous genetic and epidemiological studies have examined subpopulations from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) patient cohort, but an encompassing analysis of the study population has not yet been carried out. Objective: This study examines patterns of multiple sclerosis (MS) prevalence in 13,663 cohort members, including 4,821 patients with MS or suspected MS and 8,842 family members. Methods: We grouped participants into epidemiologic subgroups based on age of MS onset, clinical stage at diagnosis, symptom type at disease onset, sex, proband status, disability as measured by the EDSS, and ancestry based on reported ethnicity. Results: We observed a 2.7:1 MS prevalence ratio of women to men, though disease severity was greater for male patients. Variation in the age of disease onset between patients was only slightly associated with sex and strongly associated with disease type. Specific types of clinical symptoms at disease onset were associated with the prognosis. Regional residence did not correlate with disease onset, type, or severity. Conclusion: Population trends, as presented here, are not explained by environmental factors alone, highlighting the need for a comprehensive genetic analysis to understand disease variance across families.

The prevalence and topography of spinal cord demyelination in multiple sclerosis: a retrospective study.

Spinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is 'burnt out' and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.

Out with the old, in with the new: Could plasma exchange be used to fill a therapeutic gap in neurology?

The global tally of neurological disorders is exponentially rising and yet effective therapies for most remain evasive. There is a great deal of research into novel small molecules, immunotherapies and gene therapies to fill this therapeutic gap. We believe greater focus on plasma exchange as a research and clinical tool may provide useful insight into pathological mechanisms and effective treatment strategies. Plasma exchange has been traditionally used to treat antibody-mediated neurological diseases, such as myasthenia gravis and neuromyelitis optica, but there could be much wider future potential uses in neurology. Plasma exchange is not antibody specific, as it also removes a variety of other plasma-soluble factors, including age-related and disease-associated neurotoxic proteins, such as fibrinogen and amyloid. As research develops into the role of blood-brain barrier and immunological alterations in diseases not typically regarded as immune-driven, interest in neurotoxic plasma proteins grows. Here, we highlight that plasma exchange may have uses outside of antibody-mediated neurological diseases, by removing neurotoxic proteins from the systemic circulation.

Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease.

We report a pleiotropic disease due to loss-of-function mutations in RHBDF2, the gene encoding iRHOM2, in two kindreds with recurrent infections in different organs. One patient had recurrent pneumonia but no colon involvement, another had recurrent infectious hemorrhagic colitis but no lung involvement and the other two experienced recurrent respiratory infections. Loss of iRHOM2, a rhomboid superfamily member that regulates the ADAM17 metalloproteinase, caused defective ADAM17-dependent cleavage and release of cytokines, including tumor-necrosis factor and amphiregulin. To understand the diverse clinical phenotypes, we challenged Rhbdf2-/- mice with Pseudomonas aeruginosa by nasal gavage and observed more severe pneumonia, whereas infection with Citrobacter rodentium caused worse inflammatory colitis than in wild-type mice. The fecal microbiota in the colitis patient had characteristic oral species that can predispose to colitis. Thus, a human immunodeficiency arising from iRHOM2 deficiency causes divergent disease phenotypes that can involve the local microbial environment.

Gram-Negative Taxa and Antimicrobial Susceptibility after Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection.

Fecal microbiota transplantation (FMT) has promising applications in reducing multidrug-resistant organism (MDRO) colonization and antibiotic resistance (AR) gene abundance. However, data on clinical microbiology results after FMT are limited. We examined the changes in antimicrobial susceptibility profiles in patients with Gram-negative infections in the year before and the year after treatment with FMT for recurrent Clostridioides difficile infection (RCDI). We also examined whether a history of FMT changed health care provider behavior with respect to culture ordering and antibiotic prescription. Medical records for RCDI patients who underwent FMT at Emory University between July 2012 and March 2017 were reviewed retrospectively. FMT-treated patients with Gram-negative culture data in the 1-year period preceding and the 1-year period following FMT were included. Demographic and clinical data were abstracted, including CDI history, frequency of Gram-negative cultures, microbiological results, and antibiotic prescription in response to positive cultures in the period following FMT. Twelve patients were included in this case series. We pooled data from infections at all body sites and found a decrease in the number of total and Gram-negative cultures post-FMT. We compared susceptibility profiles across taxa given the potential for horizontal transmission of AR elements and observed increased susceptibility to nitrofurantoin, trimethoprim-sulfamethoxazole, and the aminoglycosides. FMT did not drastically influence health care provider ordering of bacterial cultures or antibiotic prescribing practices. We observed a reduction in Gram-negative cultures and a trend toward increased antimicrobial susceptibility. This study supports further investigation of FMT as a means of improving antimicrobial susceptibility.IMPORTANCE Fecal microbiota transplantation (FMT), which is highly efficacious in treating recurrent C. difficile infection (RCDI), has a promising application in decolonization of multidrug-resistant organisms, reduction of antibiotic resistance gene abundance, and restoration of healthy intestinal microbiota. However, data representing clinical microbiology results after FMT are limited. We sought to characterize the differences in culture positivity and antimicrobial susceptibility profiles in patients with Gram-negative infections in the year before and the year after FMT for RCDI. Drawing on prior studies that had demonstrated the success of FMT in eradicating extraintestinal infections and the occurrence of patient-level interspecies transfer of resistance elements, we employed an agnostic analytic approach of reviewing the data irrespective of body site or species. In a small RCDI population, we observed an improvement in the antimicrobial susceptibility profile of Gram-negative bacteria following FMT, which supports further study of FMT as a strategy to combat antibiotic resistance.

A guide to cancer immunotherapy: from T cell basic science to clinical practice.

The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.

Outcomes of whole-brain radiation with simultaneous in-field boost (SIB) for the treatment of brain metastases.

PURPOSE: Prospective studies have demonstrated increased local control with the addition of a radiosurgery (SRS) boost to whole-brain irradiation (WBRT) in patients with brain metastases. However, the clinical application of SRS boost can be limited by several factors, including tumor size, numbers of lesions, and high cost of care. Here, we investigate the use of WBRT with a simultaneous integrated boost (SIB) to visible lesions in patients with brain metastases. MATERIALS: From 2011 to 2016, patients were prospectively enrolled and prescribed a dose of 25 or 37.5 Gray (Gy) WBRT with a SIB dose of 45 or 52.5 Gy to the gross lesions in 10 or 15 fractions, respectively. All plans were optimized for dose coverage of the whole brain and lesions using volumetric arc therapy (VMAT). Comprehensive neurocognitive and quality of life assessments were conducted at baseline and at follow-up. RESULTS: Thirteen patients were treated on this protocol. The 1-year local control rates were 92% at the patient level, and 98.6% at the lesion level. The overall 1-year intracranial control was 46%. Patients had no significant declines in Mini-Mental State Examination (MMSE), Hopkins Verbal Learning Test-Revised (HVLT-R), and Medical Outcomes Study (MOS) Cognitive Functional status scores pre- and post-treatment. CONCLUSION: WBRT with SIB to gross lesions using VMAT planning appears to be safe and effective in the treatment of brain metastases without significant cognitive decline. This treatment strategy should be considered in those patients with a high number of metastases or ones not amenable for radiosurgery. CLINICAL TRIAL REGISTRATION CODE: NCT01218542.

Survival and failure trends of cerebrospinal fluid shunts with distal slit valves: comparative study and literature review.

OBJECTIVE: The malfunction rates of and trends in various cerebrospinal fluid (CSF) shunt designs have been widely studied, but one area that has received little attention is the comparison of the peritoneal distal slit valve (DSV) shunt to other conventional valve (CV) type shunts. The literature that does exist comes from older case series that provide only indirect comparisons, and the conclusions are mixed. Here, the authors provide a direct comparison of the overall survival and failure trends of DSV shunts to those of other valve type shunts. METHODS: Three hundred seventy-two new CSF shunts were placed in pediatric patients at the authors' institution between January 2011 and December 2015. Only ventriculoperitoneal (VP) shunts were eligible for study inclusion. Ventriculoatrial, lumboperitoneal, cystoperitoneal, subdural-peritoneal, and spinal shunts were all excluded. Rates and patterns of shunt malfunction were compared, and survival curves were generated. Patterns of failure were categorized as proximal failure, distal failure, simultaneous proximal and distal (proximal+distal) failure, removal for infection, externalization for abdominal pseudocyst, and addition of a ventricular catheter for loculated hydrocephalus. RESULTS: A total of 232 VP shunts were included in the final analysis, 115 DSV shunts and 117 CV shunts. There was no difference in the overall failure rate or time to failure between the two groups, and the follow-up period was statistically similar between the groups. The DSV group had a failure rate of 54% and a mean time to failure of 17.8 months. The CV group had a failure rate of 50% (p = 0.50) and a mean time to failure of 18.5 months (p = 0.56). The overall shunt survival curves for these two groups were similar; however, the location of failure was significantly different between the two groups. Shunts with DSVs had proportionately more distal failures than the CV group (34% vs 14%, respectively, p = 0.009). DSV shunts were also found to have proximal+distal catheter occlusions more frequently than CV shunts (23% vs 5%, respectively, p = 0.005). CV shunts were found to have significantly more proximal failures than the DSV shunts (53% vs 27%, p = 0.028). However, the only failure type that carried a statistically significant adjusted hazard ratio in a multivariate analysis was proximal+distal catheter obstruction (CV vs DSV shunt: HR 0.21, 95% CI 0.05-0.81). CONCLUSIONS: There appears to be a difference in the location of catheter obstruction leading to the malfunction of shunts with DSVs compared to shunts with CVs; however, overall shunt survival is similar between the two. These failure types are also affected by other factors such etiology of hydrocephalus and endoscope use. The implications of these findings are unclear, and this topic warrants further investigation.