Preventing herpes zoster in immunocompromised patients: Current concepts.

Herpes zoster (HZ) incidence is much higher in immunocompromised individuals than in immunocompetent individuals. HZ also occurs at a younger age and is often more severe in immunocompromised persons. Preventive strategies center around the recombinant zoster vaccine (RZV), which is approved for immunocompromised adults age 19 and older. Identifying those at greatest risk is critical. For those considering vaccination, evidence gaps regarding vaccine efficacy, toxicity, length of protection, and potential effects on underlying conditions may complicate shared and informed decision-making. Recent data have filled some of these gaps, with several societies issuing recommendations regarding vaccination. Remaining gaps are currently addressed by expert opinion.

Major vault protein is part of an extracellular cement material in the Atlantic salmon louse (Lepeophtheirus salmonis).

Major vault protein (MVP) is the main component of the vault complex, which is a highly conserved ribonucleoprotein complex found in most eukaryotic organisms. MVP or vaults have previously been found to be overexpressed in multidrug-resistant cancer cells and implicated in various cellular processes such as cell signaling and innate immunity. The precise function of MVP is, however, poorly understood and its expression and probable function in lower eukaryotes are not well characterized. In this study, we report that the Atlantic salmon louse expresses three full-length MVP paralogues (LsMVP1-3). Furthermore, we extended our search and identified MVP orthologues in several other ecdysozoan species. LsMVPs were shown to be expressed in various tissues at both transcript and protein levels. In addition, evidence for LsMVP to assemble into vaults was demonstrated by performing differential centrifugation. LsMVP was found to be highly expressed in cement, an extracellular material produced by a pair of cement glands in the adult female salmon louse. Cement is important for the formation of egg strings that serve as protective coats for developing embryos. Our results imply a possible novel function of LsMVP as a secretory cement protein. LsMVP may play a role in structural or reproductive functions, although this has to be further investigated.

A method for empirically validating FMEA RPN scores in a radiation oncology clinic using physics QC data.

In failure modes and effects analysis (FMEA), the components of the risk priority number (RPN) for a failure mode (FM) are often chosen by consensus. We describe an empirical method for estimating the occurrence (O) and detectability (D) components of a RPN. The method requires for a given FM that its associated quality control measure be performed twice as is the case when a FM is checked for in an initial physics check and again during a weekly physics check. If instances of the FM caught by these checks are recorded, O and D can be computed. Incorporation of the remaining RPN component, Severity, is discussed. This method can be used as part of quality management design ahead of an anticipated FMEA or afterwards to validate consensus values.

Testing psychosocial interventions in context: Commentary on Beidas et al. (2023).

In their recent Viewpoint article, Beidas et al. (2023) argue that researchers should test psychosocial interventions in the contexts in which they are meant to be delivered and that they can accelerate the deployment of these interventions by advancing directly from pilot trials to effectiveness and implementation studies without conducting efficacy trials. In this commentary, we argue that this is a well-intended but problematic approach and that there is a more productive strategy for translational behavioral intervention research. The commentary discusses issues concerning intervention development, refinement, and optimization; pilot and efficacy testing of interventions; the contexts in which interventions are delivered; clinical practice guidelines; and quick versus programmatic answers to significant clinical research questions. Testing psychosocial interventions in the contexts in which they are meant to be delivered is a complex task for interventions that are designed to be used in a wide variety of contexts. Nevertheless, interventions can be tested in the contexts in which they are meant to be delivered without sacrificing programmatic intervention development or safety and efficacy testing. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Thin seams and small mines are associated with higher exposures to respirable crystalline silica in US underground coal mines.

OBJECTIVES: Previous radiologic and histopathologic studies suggest respirable crystalline silica (RCS) overexposure has been driving the resurgence of pneumoconiosis among contemporary US coal miners, with a higher prevalence of severe disease in Central Appalachia. We sought to better understand RCS exposure among US underground coal miners. METHODS: We analysed RCS levels, as measured by respirable quartz, from coal mine dust compliance data from 1982 to 2021. RESULTS: We analysed 322 919 respirable quartz samples from 5064 US underground coal mines. Mean mine-level respirable quartz percentage and mass concentrations were consistently higher for Central Appalachian mines than the rest of the USA. Mean mine-level respirable quartz mass concentrations decreased significantly over time, from 0.116 mg/m3 in 1982 to as low as 0.017 mg/m3 for Central Appalachian mines, and from 0.089 mg/m3 in 1983 to 0.015 mg/m3 in 2020 for the rest of the USA. Smaller mine size, location in Central Appalachia, lack of mine safety committee and thinner coal seams were predictive of higher respirable quartz mass concentrations. CONCLUSIONS: These data substantially support the association between RCS overexposure and the resurgence of coal workers' pneumoconiosis in the USA, particularly in smaller mines in Central Appalachia.

Cultivating Patient Preferences in ALS Clinical Trials: Reliability and Prognostic Value of the Patient-Ranked Order of Function.

BACKGROUND AND OBJECTIVES: The Patient-Ranked Order of Function (PROOF) is a novel approach to account for patient-reported preferences in the evaluation of treatments of amyotrophic lateral sclerosis (ALS). In this study, we assess the reliability and prognostic value of different sets of patient-reported preferences that can be used for the PROOF end point. METHODS: Data were obtained through online surveys over the course of 12 months using the population-based registry of the Netherlands. Patients were asked to score functional domains of the ALS Functional Rating Scale (ALSFRS-R) and rank the order of importance of each domain. Two weeks after the initial invite, the questionnaire was repeated to evaluate test-retest reliability. Vital status was extracted from the municipal population register. RESULTS: In total, 611 patients with ALS were followed up for survival and 382 patients were included in the test-retest reliability study. All versions of PROOF, using different sets of preferences, resulted in excellent reliability (intraclass correlation coefficients ranged from 0.89 [95% CI 0.87-0.91] to 0.97 [95% CI 0.97-0.98], all p < 0.001), without systematic differences between baseline and week 2 (mean rank difference range -1 to -3 [95% CI range -8 to 2], all p > 0.20). Preferences about future events were more variable than preferences about current symptoms. All versions of PROOF strongly predicted overall survival (hazard ratios per 10th rank percentile ranged from 0.80 to 0.83 [95% CI range 0.76-0.87], all p < 0.001) and had a more even separation of survival curves between rank-stratified subgroups compared with the ALSFRS-R total score. DISCUSSION: In a large cohort of patients, we show how patient-reported preferences can be measured and integrated reliably with the ALSFRS-R without leading to systematic bias. Patient preferences may provide unique prognostic information in addition to what is already measured conventionally. This could provide a more comprehensive understanding of how medical interventions effectively address the patient's concerns and improve what matters most to them.

Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.

BACKGROUND AND OBJECTIVES: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival. METHODS: Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate. RESULTS: Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (ß = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (ß = -4.79 [-8.39 to -2.49], p = 0.001, ß = -10.14 [-15.88 to -4.39], p = 0.004, and ß = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (ß = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029). DISCUSSION: We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.

Resting diffusing capacity and severity of radiographic disease predict gas exchange abnormalities with exercise in former US coal miners.

BACKGROUND: The US Department of Labor (DOL) does not fund diffusing capacity (DLCO) or metabolic measurements from cardiopulmonary exercise testing (CPET) for coal miners' disability evaluations. Although exercise arterial blood gas testing is covered, many miners are unable to perform maximal tests, and sampling at peak exercise can be challenging. We explored the relationship between resting DLCO, radiographic disease severity, and CPET abnormalities in former US coal miners. METHODS: We analyzed data from miners evaluated between 2005 and 2015. Multivariable linear and logistic regression analyses were used to examine relationships between percent predicted (pp) forced expiratory volume in 1 s (FEV1pp), DLCOpp, VO2maxpp, A-a oxygen gradient (A-a)pp, dead space fraction (Vd/Vt), disabling oxygen tension (PO2), and radiographic findings of pneumoconiosis. RESULTS: Data from 2015 male coal miners was analyzed. Mean tenure was 28 years (SD 8.6). Thirty-twopercent had an abnormal A-a gradient (>150 pp), 20% had elevated Vd/Vt (>0.33), and 34% a VO2max < 60 pp. DLCOpp strongly predicted a disabling PO2, with an odds ratio (OR) of 2.33 [2.09-2.60], compared to 1.18 [1.08-1.29] for FEV1. Each increase in subcategory of small opacity (simple) pneumoconiosis increased the odds of a disabling PO2 by 42% [1.29-1.57], controlling for age, body mass index, pack-years of tobacco smoke exposure, and years of coal mine employment. CONCLUSIONS: DLCO is the best resting pulmonary function test predictor of CPET abnormalities. Radiographic severity of pneumoconiosis was also associated with CPET abnormalities. These findings support funding DLCO testing for impairment and suggest the term "small opacity" should replace "simple" pneumoconiosis to reflect significant associations with impairment.

Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation. METHODS: We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models. RESULTS: Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001). DISCUSSION: We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results.

Measuring lung diffusing capacity: an opportunity for improved medical surveillance and disability evaluation of coal miners.

OBJECTIVES: Spirometry is the primary lung function test utilised for medical surveillance and disability examination for coal mine dust lung disease. However, spirometry likely underestimates physiologic impairment. We sought to characterise abnormalities of single-breath diffusing capacity for carbon monoxide (DLCO) among a population of former coal miners. METHODS: Data from 3115 former coal miners evaluated at a West Virginia black lung clinic between 2006 and 2015 were retrospectively analysed to study the association between diffusion impairment (abnormally low DLCO), resting spirometry and the presence and severity of coal workers' pneumoconiosis on chest radiography. We developed ordinary least squares linear regression models to evaluate factors associated with per cent predicted DLCO (DLCOpp). RESULTS: Diffusion impairment was identified in 20.2% of subjects. Ten per cent of all miners with normal spirometry had diffusion impairment including 7.4% of never smokers. The prevalence of diffusion impairment increased with worsening radiographic category of pneumoconiosis. Mean DLCOpp decreased with increasing small opacity profusion subcategory in miners without progressive massive fibrosis. Linear regression analysis also showed significant decreases in DLCOpp with increasing small opacity profusion and presence of large opacities. CONCLUSIONS: Diffusion impairment is common among former coal miners, including among never smokers, miners without radiographic pneumoconiosis and miners with normal spirometry. These findings demonstrate the value of including DLCO testing in disability examinations of former coal miners and an important role for its use in medical surveillance of working miners to detect early chronic lung disease.

REVEALS-a longitudinal cohort study of multifaceted respiratory assessment in ALS.

OBJECTIVE: To systematically assess decline in respiratory measures in amyotrophic lateral sclerosis (ALS) and to examine the impact of sex, disease onset type and baseline morbidity on progression. METHODS: The REVEALS study (Registry of Endpoints and Validated Experiences in ALS) was conducted between April 2018 and February 2021 in six European ALS centers. Slow and forced vital capacity (S/FVC), sniff nasal inspiratory pressure (SNIP), peak cough flow, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and respiratory morbidity were collected. Data were analyzed using a Bayesian multiple outcomes random effects model. RESULTS: Two hundred and eighty participants had a median of three assessments (IQR 2.0, 5.0) over a median of 8 months (IQR 2.3, 14.1). There were 974 data collection timepoints. Differences in respiratory measures and rates of decline between disease-onset and sex subgroups were identified. Females had lower scores in all respiratory measures and females with bulbar onset ALS had faster decline compared with other sub-groups. These differences were not detected by the ALSFRS-r respiratory subscale. Dyspnea, orthopnea, and a higher King's stage at baseline were associated with lower respiratory scores throughout follow-up, while having a regular productive cough at baseline was associated with lower peak cough flow scores. CONCLUSION: Respiratory function declines more quickly in females with ALS compared with males when measured by FVC, SVC, SNIP, or PCF, but not the ALSFRS-R respiratory sub-score. Higher baseline King's staging and the presence of clinical respiratory symptoms at baseline were associated with worse respiratory function. The ALSFRS-R respiratory sub-score is poorly correlated with objective respiratory measurements.

qPCR assay optimisation for a clinical study comparing oral health risk in Rett syndrome.

PURPOSE: This study aimed to validate qPCR assays for specific microbiota, for use on dental plaque samples stored on Whatman FTA cards to compare relative oral health risk in Rett syndrome. METHODS: Supragingival dental plaque samples were collected, using a sterile swab, (COPAN FLOQswab™) swabbed onto Whatman FTA™ cards. DNA extraction was performed using a modified Powersoil™ protocol. Where published assays were unsuitable, species-specific qPCR assays for caries-associated, gingivitis-associated and oral-health-associated bacteria were designed using multiple sequence alignment, Primer3Plus and PrimerQuest. Assays were run using absolute quantification. Limit of detection (LOD) and limit of quantification (LOQ) were calculated, and PCR products verified by Sanger sequencing. RESULTS: Most assays allowed detection using real-time qPCR with high specificity on samples collected on FTA cards. Several assays showed low or even single gene copy numbers on the test samples. CONCLUSION: Assays were optimised for detection and evaluation of oral health risk in dental plaque samples stored on FTA cards when cold storage is not feasible, except for F. nucleatum. Several assays showed gene copy numbers less than the LOQ or outside the range of the standard curve, so there is merit in optimising these assays using digital droplet PCR.

International network for ALS research and care (INARC).

The International Network for Amyotrophic Lateral Sclerosis (ALS) Research and Care (INARC) was founded in 2022. INARC's main goals are to offer a platform dedicated to staff members for ALS clinics and research teams who are not physicians. By nurturing experience and expertise exchanges to improve problem solving skills, the ultimate goal is to increase the standard ALS care and research. This brief report aims to describe the formation of INARC, the 2023 INARC meeting, as well as to report topics discussed, lessons learned and challenges raised by INARC members.

Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation.

According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells.

Genomic profiling of pleomorphic rhabdomyosarcoma reveals a genomic signature distinct from that of embryonal rhabdomyosarcoma.

Pleomorphic rhabdomyosarcoma (PRMS) is a rare and highly aggressive sarcoma, occurring mostly in the deep soft tissues of middle-aged adults and showing a variable degree of skeletal muscle differentiation. The diagnosis is challenging as pathologic features overlap with embryonal rhabdomyosarcoma (ERMS), malignant Triton tumor, and other pleomorphic sarcomas. As recurrent genetic alterations underlying PRMS have not been described to date, ancillary molecular diagnostic testing is not useful in subclassification. Herein, we perform genomic profiling of a well-characterized cohort of 14 PRMS, compared to a control group of 23 ERMS and other pleomorphic sarcomas (undifferentiated pleomorphic sarcoma and pleomorphic liposarcoma) using clinically validated DNA-targeted Next generation sequencing (NGS) panels (MSK-IMPACT). The PRMS cohort included eight males and six females, with a median age of 53 years (range 31-76 years). Despite similar tumor mutation burdens, the genomic landscape of PRMS, with a high frequency of TP53 (79%) and RB1 (43%) alterations, stood in stark contrast to ERMS, with 4% and 0%, respectively. CDKN2A deletions were more common in PRMS (43%), compared to ERMS (13%). In contrast, ERMS harbored somatic driver mutations in the RAS pathway and loss of function mutations in BCOR, which were absent in PRMS. Copy number variations in PRMS showed multiple chromosomal arm-level changes, most commonly gains of chr17p and chr22q and loss of chr6q. Notably, gain of chr8, commonly seen in ERMS (61%) was conspicuously absent in PRMS. The genomic profiles of other pleomorphic sarcomas were overall analogous to PRMS, showing shared alterations in TP53, RB1, and CDKN2A. Overall survival and progression-free survival of PRMS were significantly worse (p < 0.0005) than that of ERMS. Our findings revealed that the molecular landscape of PRMS aligns with other adult pleomorphic sarcomas and is distinct from that of ERMS. Thus, NGS assays may be applied in select challenging cases toward a refined classification. Finally, our data corroborate the inclusion of PRMS in the therapeutic bracket of pleomorphic sarcomas, given that their clinical outcomes are comparable.

Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. FUNDING: Orphazyme.

Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS.

OBJECTIVE: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. METHODS: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case-control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data. RESULTS: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13-9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14-1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18-1.77, pMadsen-Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86-4.37, pMadsen-Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricate architecture that requires further investigation. INTERPRETATION: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.

NF1-Driven Rhabdomyosarcoma Phenotypes: A Comparative Clinical and Molecular Study of NF1-Mutant Rhabdomyosarcoma and NF1-Associated Malignant Triton Tumor.

PURPOSE: Alterations of the NF1 tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting molecular events are not well defined. Additionally, NF1 alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor [MTT]). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of NF1-mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis. METHODS: We investigated the clinicopathologic and molecular landscape of a cohort of 22 NF1-mutant RMS and a control group of 13 NF1-associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing. RESULTS: Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was TP53 abnormality (36%), being mutually exclusive from NRAS mutations (14%). MTT showed coexisting CDKN2A/B and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with NF1-mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic NF1-mutant ERMS were associated with TP53 alterations. CONCLUSION: Patients with NF1-mutant ERMS lacking TP53 alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.

IgM anti-GM2 antibodies in patients with multifocal motor neuropathy target Schwann cells and are associated with early onset.

BACKGROUND: Multifocal motor neuropathy (MMN) is a rare, chronic immune-mediated polyneuropathy characterized by asymmetric distal limb weakness. An important feature of MMN is the presence of IgM antibodies against gangliosides, in particular GM1 and less often GM2. Antibodies against GM1 bind to motor neurons (MNs) and cause damage through complement activation. The involvement of Schwann cells (SCs), expressing GM1 and GM2, in the pathogenesis of MMN is unknown. METHODS: Combining the data of our 2007 and 2015 combined cross-sectional and follow-up studies in Dutch patients with MMN, we evaluated the presence of IgM antibodies against GM1 and GM2 in serum from 124 patients with MMN and investigated their binding to SCs and complement-activating properties. We also assessed the relation of IgM binding and complement deposition with clinical characteristics. RESULTS: Thirteen out of 124 patients (10%) had a positive ELISA titer for IgM anti-GM2. Age at onset of symptoms was significantly lower in MMN patients with anti-GM2 IgM. IgM binding to SCs correlated with IgM anti-GM2 titers. We found no correlation between IgM anti-GM2 titers and MN binding or with IgM anti-GM1 titers. IgM binding to SCs decreased upon pre-incubation of serum with soluble GM2, but not with soluble GM1. IgM anti-GM2 binding to SCs correlated with complement activation, as reflected by increased C3 fixation on SCs and C5a formation in the supernatant. CONCLUSION: Circulating IgM anti-GM2 antibodies define a subgroup of patients with MMN that has an earlier onset of disease. These antibodies probably target SCs specifically and activate complement, similarly as IgM anti-GM1 on MNs. Our data indicate that complement activation by IgM antibodies bound to SCs and MNs underlies MMN pathology.