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INTRODUCTION/AIMS Progressive axonal loss in multifocal motor neuropathy (MMN) is often assessed with nerve conduction studies (NCS), by recording maximum compound muscle action potentials (CMAPs). However, reinnervation maintains the CMAP amplitude until a significant portion of the motor unit (MU) pool is lost. We therefore performed more informative CMAP scans to study MU characteristics in a large cohort of patients with MMN. METHODS We derived the maximum CMAP amplitude (CMAPmax ), a MU number estimate (MUNE) and the largest MU amplitude, stimulus current required to elicit 5%-50%-95% of CMAPmax (S5, S50, S95) and relative ranges ([S95-S5]x100/S50) from the scans. These metrics were compared with clinical, laboratory and NCS results. RESULTS 40 MMN patients and 24 healthy controls were included. CMAPmax and MUNE were reduced in MMN patients (both p

Background Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent, paralleling the obesity epidemic. Ketone bodies are produced in the liver, but it is currently uncertain whether circulating ketone bodies are increased in the context of NAFLD. We investigated the association between NAFLD and circulating ketone bodies and determined the extent to which NAFLD and circulating ketone bodies are associated with all-cause mortality.Methods Plasma ketone bodies were measured by nuclear magnetic resonance spectroscopy in participants of the general population-based PREVEND study. A fatty liver index (FLI) >= 60 was regarded as a proxy of NAFLD. Associations of an elevated FLI and ketone bodies with all-cause mortality were investigated using Cox regression analyses.Results The study included 6,297 participants aged 54 +/- 12 years, of whom 1,970 (31%) had elevated FLI. Participants with elevated FLI had higher total ketone bodies (194 [153-259] vs 170 [133-243] mu mol/L; P < .001) than participants without elevated FLI. During 7.9 [7.8-8.9] years of follow-up, 387 (6%) participants died. An elevated FLI was independently associated with an increased risk of mortality (HR: 1.34 [1.06-1.70]; P = .02). Higher total ketone bodies were also associated with an increased mortality risk (HR per doubling: 1.29 [1.12-1.49]; P < .001). Mediation analysis suggested that the association of elevated FLI with all-cause mortality was in part mediated by ketone bodies (proportion mediated: 10%, P < .001).Conclusion Circulating ketone bodies were increased in participants with suspected NAFLD. Both suspected NAFLD and higher circulating ketone bodies are associated with an increased risk of all-cause mortality.

Objective To determine which compound muscle action potential (CMAP) scan-derived electrophysiological markers are most sensitive for monitoring disease progression in amyotrophic lateral sclerosis (ALS), and whether they hold value for clinical trials. Methods We used four independent patient cohorts to assess longitudinal patterns of a comprehensive set of electrophysiological markers including their association with the ALS functional rating scale (ALSFRS-R). Results were translated to trial sample size requirements. Results In 65 patients, 225 thenar CMAP scan recordings were obtained. Electrophysiological markers showed extensive variation in their longitudinal trajectories. Expressed as standard deviations per month, motor unit number estimation (MUNE) values declined by 0.09 (CI 0.07–0.12), D50, a measure that quantifies CMAP scan discontinuities, declined by 0.09 (CI 0.06–0.13) and maximum CMAP by 0.05 (CI 0.03–0.08). ALSFRS-R declined fastest (0.12, CI 0.08 – 0.15), however the between-patient variability was larger compared to electrophysiological markers, resulting in larger sample sizes. MUNE reduced the sample size by 19.1% (n = 388 vs n = 314) for a 6-month study compared to the ALSFRS-R. Conclusions CMAP scan-derived markers show promise in monitoring disease progression in ALS patients, where MUNE may be its most suitable derivate. Significance MUNE may increase clinical trial efficiency compared to clinical endpoints.

Amyotrophic lateral sclerosis is a devastating disease characterized primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. Amyotrophic lateral sclerosis is both clinically and biologically heterogeneous. Subgrouping is currently undertaken using clinical parameters, such as site of symptom onset (bulbar or spinal), burden of disease (based on the modified El Escorial Research Criteria) and genomics in those with familial disease. However, with the exception of genomics, these subcategories do not take into account underlying disease pathobiology, and are not fully predictive of disease course or prognosis. Recently, we have shown that resting-state EEG can reliably and quantitatively capture abnormal patterns of motor and cognitive network disruption in amyotrophic lateral sclerosis. These network disruptions have been identified across multiple frequency bands, and using measures of neural activity (spectral power) and connectivity (comodulation of activity by amplitude envelope correlation and synchrony by imaginary coherence) on source-localized brain oscillations from high-density EEG. Using data-driven methods (similarity network fusion and spectral clustering), we have now undertaken a clustering analysis to identify disease subphenotypes and to determine whether different patterns of disruption are predictive of disease outcome. We show that amyotrophic lateral sclerosis patients (n = 95) can be subgrouped into four phenotypes with distinct neurophysiological profiles. These clusters are characterized by varying degrees of disruption in the somatomotor (α-band synchrony), frontotemporal (β-band neural activity and γl-band synchrony) and frontoparietal (γl-band comodulation) networks, which reliably correlate with distinct clinical profiles and different disease trajectories. Using an in-depth stability analysis, we show that these clusters are statistically reproducible and robust, remain stable after reassessment using a follow-up EEG session, and continue to predict the clinical trajectory and disease outcome. Our data demonstrate that novel phenotyping using neuroelectric signal analysis can distinguish disease subtypes based exclusively on different patterns of network disturbances. These patterns may reflect underlying disease neurobiology. The identification of amyotrophic lateral sclerosis subtypes based on profiles of differential impairment in neuronal networks has clear potential in future stratification for clinical trials. Advanced network profiling in amyotrophic lateral sclerosis can also underpin new therapeutic strategies that are based on principles of neurobiology and designed to modulate network disruption.

ObjectivesTo investigate sensitivity of brain MRI and neurological examination for detection of upper motor neuron (UMN) degeneration in patients with amyotrophic lateral sclerosis (ALS).MethodsWe studied 192 patients with ALS and 314 controls longitudinally. All patients visited our centre twice and underwent full neurological examination and brain MRI. At each visit, we assessed UMN degeneration by measuring motor cortex thickness (CT) and pyramidal tract fibre density (FD) corresponding to five body regions (bulbar region and limbs). For each body region, we measured degree of clinical UMN and lower motor neuron (LMN) symptom burden using a validated scoring system.ResultsWe found deterioration over time of CT of motor regions (p≤0.0081) and progression of UMN signs of bulbar region and left arm (p≤0.04). FD was discriminative between controls and patients with moderate/severe UMN signs (all regions, p≤0.034), but did not change longitudinally. Higher clinical UMN burden correlated with reduced CT, but not lower FD, for the bulbar region (p=2.2×10−10) and legs (p≤0.025). In the arms, we found that severe LMN signs may reduce the detectability of UMN signs (p≤0.043). With MRI, UMN degeneration was detectable before UMN signs became clinically evident (CT: p=1.1×10−10, FD: p=6.3×10−4). Motor CT, but not FD, deteriorated more than UMN signs during the study period.ConclusionsMotor CT is a more sensitive measure of UMN degeneration than UMN signs. Motor CT and pyramidal tract FD are discriminative between patients and controls. Brain MRI can monitor UMN degeneration before signs become clinically evident. These findings promote MRI as a potential biomarker for UMN progression in clinical trials in ALS.

Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

Hostile political actors frequently engage in malign information influence, projecting antagonistic strategic narratives in targeted societies to manipulate the information environment and distort the perceptions of the citizens. Research examining malign information influence is growing, but more attention could be given to its psychological effects. Information operations are commonly assumed to affect the levels of trust and the emotional experiences of citizens who are targeted by them, but these notions are currently supported by limited evidence. We propose that experimental psychological research is a promising avenue to more clearly demonstrate these effects and individual differences of the target audience that may exacerbate these effects. This article discusses the knowledge gap regarding the psychological effects of malign information influence and suggests relevant psychological research that can be built upon when devising experimental studies that might address it. Finally, the article outlines key benefits that insights gleaned from this experimental research would offer to those seeking to counter malign information influence.

To gain further insight in the immunopathology underlying multifocal motor neuropathy (MMN) by exploring the association between MMN and the human leukocyte antigen (HLA) class II DRB1, DQB1, and DQA loci in depth and by correlating associated haplotypes to detailed clinical and anti-ganglioside antibody data.We performed high-resolution HLA-class II typing for the DRB1, DQB1, and DQA1 loci in 126 well-characterized MMN patients and assessed disease associations with haplotypes. We used a cohort of 1305 random individuals as a reference for haplotype distribution in the Dutch population.The DRB1*15:01-DQB1*06:02 haplotype (OR 1.6 [95% CI 1.1-2.2], p0.05) and the DRB1*12:01-DQB1*03:01 haplotype (OR 2.7 [95% CI 1.2-5.5], p0.05) were more frequent in patients with MMN than in controls. These haplotypes were not associated with disease course, response to treatment or anti-ganglioside antibodies.MMN is associated with the DRB1*15:01-DQB1*06:02 and DRB1*12:01-DQB1*03:01 haplotypes. These HLA molecules or gene variants in their immediate vicinity may promote the specific inflammatory processes underlying MMN.

Introduction In multifocal motor neuropathy (MMN), knowledge about the pattern of treatment response in a wide spectrum of muscle groups, distal as well as proximal, after intravenous immunoglobulin (IVIg) initiation is lacking. Methods Hand‐held dynamometry data of 11 upper and lower limb muscles, from 47 patients with MMN was reviewed. Linear mixed models were used to determine the treatment response after IVIg initiation and its relationship with initial muscle weakness. Results All muscle groups showed a positive treatment response after IVIg initiation. Changes in SD scores ranged from +0.1 to +0.95. A strong association between weakness at baseline and the magnitude of the treatment response was found. Discussion Improved muscle strength in response to IVIg appears not only in distal, but to a similar degree also in proximal muscle groups in MMN, with the largest response in muscle groups that show the greatest initial weakness.

BACKGROUND: Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5?*?5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete. FINDINGS: Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). INTERPRETATION: The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. FUNDING: Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.

Background We aimed to determine (1) the test–retest reliability of a newly developed portable fixed dynamometer (PFD) as compared to the hand-held dynamometer (HHD) in patients with motor neuron disease (MND) and (2) the PFD’s ability to reduce possible examiner-induced ceiling effects. Methods Test–retest reliability of isometric muscle strength of the quadriceps was measured in patients with MND and non-neurological controls using the HHD and PFD. Reliability was estimated by the intraclass correlation coefficient (ICC) and standard error of measurement (SEM) using linear mixed effects models, and the Bland–Altman method of agreement. Results In total, 45 patients with MND and 43 healthy controls were enrolled in this study. The ICC of the PFD was excellent and similar in both patients and controls (ICC Patients 99.5% vs. ICC Controls 98.6%) with a SEM of 6.2%. A strong examiner-induced ceiling effect in HHD was found when the participant’s strength exceeded that of examiner. Employing the PFD increased the range of muscle strength measurements across individuals nearly twofold from 414 to 783 N. Conclusions Portable fixed dynamometry may significantly reduce examiner-induced ceiling effects, optimize the standardization of muscle strength testing, and maximize reliability. Ultimately, PFD may improve the delivery of care due to its potential for unsupervised, home-based assessments and reduce the burden to the patient of participating in clinical trials for MND or other neuromuscular diseases.

Objective To assess excitability differences between motor and sensory axons of affected nerves in patients with multifocal motor neuropathy (MMN). Methods We performed motor and sensory excitability tests in affected median nerves of 20 MMN patients and in 20 age-matched normal subjects. CMAPs were recorded from the thenar and SNAPs from the 3rd digit. Clinical tests included assessment of muscle strength, two-point discrimination and joint position. Results All MMN patients had weakness of the thenar muscle and normal sensory tests. Motor excitability testing in MMN showed an increased threshold for a 50% CMAP, increased rheobase, decreased stimulus-response slope, fanning-out of threshold electrotonus, decreased resting I/V slope, shortened refractory period, and more pronounced superexcitability. Sensory excitability testing in MMN revealed decreased accommodation half-time and S2-accommodation and less pronounced subexcitability. Mathematical modeling indicated increased Barrett-Barrett conductance for motor fibers and increase in internodal fast potassium conductance for sensory fibers. Conclusions Excitability findings in MMN suggest myelin sheath or paranodal seal involvement in motor fibers and, possibly, paranodal detachment in sensory fibers. Significance Excitability properties of affected nerves in MMN differ between motor and sensory nerve fibers.

In a New Zealand population-based case-control study we assessed associations with occupational exposure to electric shocks, extremely low-frequency magnetic fields (ELF-MF) and motor neurone disease using job-exposure matrices to assess exposure. Participants were recruited between 2013 and 2016. Associations with ever/never, duration, and cumulative exposure were assessed using logistic regression adjusted for age, sex, ethnicity, socioeconomic status, education, smoking, alcohol consumption, sports, head or spine injury, and solvents, and was mutually adjusted for the other exposure. All analyses were repeated stratified by sex. An elevated risk was observed for having ever worked in a job with potential for electric shocks (odds ratio (OR) = 1.35, 95% confidence interval (CI): 0.98, 1.86), with the strongest association for the highest level of exposure (OR = 2.01, 95% CI: 1.31, 3.09). Analysis by duration suggested a nonlinear association: Risk was increased for both short duration (24 years; OR = 1.88; 95% CI: 1.05, 3.36) in a job with high level of electric shock exposure, with less pronounced associations for intermediate durations. No association with ELF-MF was found. Our findings provide support for an association between occupational exposure to electric shocks and motor neurone disease but did not show associations with exposure to work-related ELF-MF.

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow...

Objective This study aimed at developing a quantitative approach to assess abnormalities on MRI of the brachial plexus and the cervical roots in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) and to evaluate interrater reliability and its diagnostic value. Methods We performed a cross-sectional study in 50 patients with CIDP, 31 with MMN and 42 disease controls. We systematically measured cervical nerve root sizes on MRI bilaterally (C5, C6, C7) in the coronal [diameter (mm)] and sagittal planes [area (mm2)], next to the ganglion (G0) and 1 cm distal from the ganglion (G1). We determined their diagnostic value using a multivariate binary logistic model and ROC analysis. In addition, we evaluated intra- and interrater reliability. Results Nerve root size was larger in patients with CIDP and MMN compared to controls at all predetermined anatomical sites. We found that nerve root diameters in the coronal plane had optimal reliability (intrarater ICC 0.55–0.87; interrater ICC 0.65–0.90). AUC was 0.78 (95% CI 0.69–0.87) for measurements at G0 and 0.81 (95% CI 0.72–0.91) for measurements at G1. Importantly, our quantitative assessment of brachial plexus MRI identified an additional 10% of patients that showed response to treatment, but were missed by nerve conduction (NCS) and nerve ultrasound studies. Conclusion Our study showed that a quantitative assessment of brachial plexus MRI is reliable. MRI can serve as an important additional diagnostic tool to identify treatment-responsive patients, complementary to NCS and nerve ultrasound.

Purpose of review To review the current developments in the design and conduct of clinical trials for amyotrophic lateral sclerosis (ALS), illustrated by a critical appraisal of ClinicalTrials.gov. Recent findings In total, 63 clinical trials were included in the analysis, of which 13 phase 1, 35 phase 2 and 15 phase 3. Virtually all phase 3 clinical trials can be classified as randomized, placebo controlled, whereas this is only true for 57% of the phase 2 clinical trials. There are promising developments in the routes of drug administration, eligibility criteria, efficacy endpoints and overall trial design. Some of these innovative approaches may, however, not fulfil clinical trial guidelines or regulatory requirements. This could delay the development of effective therapy or hamper our ability to determine whether a treatment is truly (in)effective. The initiation of trial consortia comprising patient organizations, academia, industry and funding bodies may significantly strengthen the future clinical trial landscape for ALS. Summary The ALS clinical trial landscape is currently highly active with several promising innovative developments and therapeutic options. By further refinement of evidence-based guidelines, and alignment of our current endeavours, we may soon be able to positively impact the lives of people living with ALS.

Contains fulltext : 225882.pdf (Publisher’s version ) (Closed access) Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged

OBJECTIVE The rs12608932 single nucleotide polymorphism in UNC13A is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype of UNC13A in patients with ALS. METHODS We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. A subcohort of 428 patients with ALS was used to study cognitive and behavioral profiles, and 375 patients to study neuroimaging characteristics. Associations were analyzed under an additive genetic model. RESULTS Genotyping rs12608932 resulted in 854 A/A, 988 A/C, and 374 C/C genotypes. The C allele was associated with a higher age at symptom onset (median years A/A 63.5, A/C 65.6, and C/C 65.5; p

ObjectiveTo determine the prevalence and prognostic value of weight loss (WL) prior to diagnosis in patients with amyotrophic lateral sclerosis (ALS).MethodsWe enrolled patients diagnosed with ALS between 2010 and 2018 in a population-based setting. At diagnosis, detailed information was obtained regarding the patient’s disease characteristics, anthropological changes, ALS-related genotypes and cognitive functioning. Complete survival data were obtained. Cox proportional hazard models were used to assess the association between WL and the risk of death during follow-up.ResultsThe data set comprised 2420 patients of whom 67.5% reported WL at diagnosis. WL occurred in 71.8% of the bulbar-onset and in 64.2% of the spinal-onset patients; the mean loss of body weight was 6.9% (95% CI 6.8 to 6.9) and 5.5% (95% CI 5.5 to 5.6), respectively (pConclusionsThis population-based study shows that two-thirds of the patients with ALS have WL at diagnosis, which also occurs independent of dysphagia, and is related to survival. Our results suggest that WL is a multifactorial process that may differ from patient to patient. Gaining further insight in its underlying factors could prove essential for future therapeutic measures.

Objective To assess motor unit (MU) changes in patients with spinal muscular atrophy (SMA) using compound muscle action potential (CMAP) scans. Methods We performed CMAP scan recordings in median nerves of 24 treatment-naive patients (median age 39; range 12-75 years) with SMA types 2-4. From each scan, we determined maximum CMAP amplitude (CMAPmax), a motor unit number estimate (MUNE), and D50 which quantifies the largest discontinuities within CMAP scans. Results Median CMAPmax was 8.1 mV (range 0.9-14.6 mV), MUNE was 29 (range 6-131), and D50 was 25 (range 2-57). We found a reduced D50 ( Conclusions The CMAP scan is an easily applicable technique that is superior to routine assessment of CMAPmax in SMA. Significance The detection of pathological MU changes across the spectrum of SMA may provide important biomarkers for evaluating disease course and monitoring treatment efficacy.

Purpose of ReviewTo improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN).Recent FindingsWe identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases.SummaryFOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis–FTD spectrum.

Background Respiratory muscle weakness is an important feature of spinal muscular atrophy (SMA). Progressive lung function decline is the most important cause of mortality and morbidity in patients. The natural history of lung function in SMA has, however, not been studied in much detail. Results We analysed 2098 measurements of lung function from 170 treatment-naïve patients with SMA types 1c–4, aged 4–74 years. All patients are participating in an ongoing population-based prevalence cohort study. We measured Forced Expiratory Volume in 1 s (FEV1), Forced Vital Capacity (FVC), and Vital Capacity (VC). Longitudinal patterns of lung function were analysed using linear mixed-effects and non-linear models. Additionally, we also assessed postural effects on results of FEV1 and FVC tests. In early-onset SMA types (1c–3a), we observed a progressive decline of lung function at younger ages with relative stabilisation during adulthood. Estimated baseline values were significantly lower in more severely affected patients: %FEV1 ranged from 42% in SMA type 1c to 100% in type 3b, %FVC 50 to 109%, and %VC 44 to 96%. Average annual decline rates also differed significantly between SMA types, ranging from − 0.1% to − 1.4% for FEV1, − 0.2% to − 1.4% for FVC, and + 0.2% to − 1.7% for VC. In contrast to SMA types 1c–3a, we found normal values for all outcomes in later-onset SMA types 3b and 4 throughout life, although with some exceptions and based on limited available data. Finally, we found no important differences in FVC or FEV1 values measured in either sitting or supine position. Conclusions Our data illustrate the longitudinal course of lung function in patients with SMA, which is characterised by a progressive decline in childhood and stabilisation in early adulthood. The data do not support an additional benefit of measuring FEV1 or FVC in both sitting and supine position. These data may serve as a reference to assess longer-term outcomes in clinical trials.

ObjectiveTo investigate probabilities of survival and its surrogate, that is, mechanical ventilation, in patients with spinal muscular atrophy (SMA).MethodsWe studied survival in a population-based cohort on clinical prevalence of genetically confirmed, treatment-naive patients with SMA, stratified for best acquired motor milestone (i.e., none: type 1a/b; head control in supine position or rolling: type 1c; sitting independently: type 2a; standing: type 2b; walking: type 3a/b; adult onset: type 4). We also assessed the need for mechanical ventilation as a surrogate endpoint for survival.ResultsWe included 307 patients with a total follow-up of 7,141 person-years. Median survival was 9 days in SMA type 1a, 7.7 months in type 1b, and 17.0 years in type 1c. Patients with type 2a had endpoint-free survival probabilities of 74.2% and 61.5% at ages 40 and 60 years, respectively. Endpoint-free survival of SMA types 2b, 3, and 4 was relatively normal, at least within the first 60 years of life. Patients with SMA types 1c and 2a required mechanical ventilation more frequently and from younger ages compared to patients with milder SMA types. In our cohort, patients ventilated up to 12 h/d progressed not gradually, but abruptly, to ≥16 h/d.ConclusionsShortened endpoint-free survival is an important characteristic of SMA types 1 and 2a, but not types 2b, 3, and 4. For SMA types 1c and 2a, the age at which initiation of mechanical ventilation is necessary may be a more suitable endpoint than the arbitrarily set 16 h/d.

Objective: To evaluate the use of telehealth as part of specialized care for patients with amyotrophic lateral sclerosis (ALS) and the user experiences of patients and healthcare professionals. Methods: Fifty patients with ALS were recruited from a single specialist center and used telehealth, consisting of an ALS-app for self-monitoring and messaging, alerts for symptom-worsening, and nurse practitioner follow-up. Patients self-monitored their well-being (daily report), body weight (weekly) and functional status (monthly). The use of the telehealth service was evaluated through adoption rate, dropout rate and adherence to self-monitoring. User-experiences were collected through online surveys among 23 patients and nine healthcare professionals, and interviews with 12 patients. Results: The adoption rate was 80%, dropout rate 4% and median follow-up was 11 months. Good adherence was seen in 49% of patients for well-being, 83% for body weight and 87% for functional assessment. For patients who discontinued using telehealth due to the end-of-life phase, median time between last measurement and death was 19 days. The majority of patients experienced using telehealth as easy, helpful, not burdensome, and reported satisfaction with flexible clinic visits and the continuity of care. Healthcare professionals reported that telehealth was of added value in ALS-care. Conclusions: ALS-care supplemented by home-monitoring and nurse practitioner follow-up was shown to be suitable and widely accepted by patients and healthcare professionals in our ALS clinic. Success factors were low self-monitoring burden, a user-friendly platform and the provision of personalized feedback. Further research is needed to replicate these findings in other ALS clinics.

The chemical industry is currently facing the challenge of developing biobased production processes suitable for a more sustainable chemical industry. Acrylic acid produced from monopropylene glycol is a good candidate to become a cost-competitive and sustainable platform chemical. The propylene glycol price is expected to drop due to the expected abundance of propylene glycol as a sugar hydrogenolysis byproduct, which is required to make the conversion to acrylic acid cost-competitive. Two different processes for the conversion of propylene glycol to acrylic acid are evaluated in this work, either by (1) low temperature oxidation of propylene glycol to lactic acid and high temperature dehydration to acrylic acid or by (2) high temperature dehydration of propylene glycol to allyl alcohol and further high temperature oxidation to acrylic acid. Liquid-liquid extraction was found to be a key operation in both production processes. At similar overall yields, the allyl alcohol route appears inherently favored, as a result of the opportunity to integrate the reaction heat available at high temperature. To conclude, the price of propylene glycol has to drop by 45-55% to make the biobased production of acrylic acid from propylene glycol economically feasible.

Purposes Studies investigating self-reported long-term morbidity in childhood cancer survivors (CCS) are using heterogeneous outcome definitions, which compromises comparability and include (un)treated asymptomatic and symptomatic outcomes. We generated a Dutch LATER core set of clinically relevant physical outcomes, based on self-reported data. Clinically relevant outcomes were defined as outcomes associated with clinical symptoms or requiring medical treatment. Methods First, we generated a draft outcome set based on existing questionnaires embedded in the Childhood Cancer Survivor Study, British Childhood Cancer Survivor Study, and Dutch LATER study. We added specific outcomes reported by survivors in the Dutch LATER questionnaire. Second, we selected a list of clinical relevant outcomes by agreement among a Dutch LATER experts team. Third, we compared the proposed clinically relevant outcomes to the severity grading of the Common Terminology Criteria for Adverse Events (CTCAE). Results A core set of 74 self-reported long-term clinically relevant physical morbidity outcomes was established. Comparison to the CTCAE showed that 36% of these clinically relevant outcomes were missing in the CTCAE. Implications for Cancer Survivors This proposed core outcome set of clinical relevant outcomes for self-reported data will be used to investigate the self-reported morbidity in the Dutch LATER study. Furthermore, this Dutch LATER outcome set can be used as a starting point for international harmonization for long-term outcomes in survivors of childhood cancer.

ObjectiveTo assess the clinical course of multifocal motor neuropathy (MMN) in a large cohort of patients and to identify predictive factors of a progressive disease course.MethodsBetween May 2015 and February 2016, we collected clinical data from 100 patients with MMN, of whom 60 had participated in a nationwide cross-sectional cohort study in 2007. We documented clinical characteristics using standardized questionnaires and performed a standardized neurologic examination. We used multiple linear regression analysis to identify factors that correlated with worse outcome.ResultsWe found that age at diagnosis (45.2 vs 48.6 years, p < 0.02) was significantly increased between 2007 and 2015–2016, whereas diagnostic delay decreased by 15 months. Seven out of 10 outcome measures deteriorated over time (all p < 0.01). Patients who had a lower Medical Research Council (MRC) sumscore and absence of 1 or more reflexes at the baseline visit showed a greater functional loss at follow-up (p = 0.007 and p = 0.016).ConclusionsOur study shows that MMN is a progressive disease. Although 87% of patients received maintenance treatment, muscle strength, reflexes, vibration sense, and the Self-Evaluation Scale score significantly deteriorated over time. Lower MRC sumscore and absence of reflexes predicted a more progressive disease course.Classification of evidenceThis study provides Class II evidence that lower MRC sumscore and the absence of reflexes predict a more progressive disease course in patients with MMN.

Background Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol consumption from blood was reported with high accuracy, but these results were based on employing the same dataset for model training and testing, which can lead to accuracy overestimation. Moreover, only subsets of alcohol consumption categories were used, which makes it impossible to extrapolate such models to the general population. By using data from eight population-based European cohorts (N = 4677), we internally and externally validated the previously reported biomarkers and models for epigenetic inference of alcohol consumption from blood and developed new models comprising all data from all categories. Results By employing data from six European cohorts (N = 2883), we empirically tested the reproducibility of the previously suggested biomarkers and prediction models via ten-fold internal cross-validation. In contrast to previous findings, all seven models based on 144-CpGs yielded lower mean AUCs compared to the models with less CpGs. For instance, the 144-CpG heavy versus non-drinkers model gave an AUC of 0.78 ± 0.06, while the 5 and 23 CpG models achieved 0.83 ± 0.05, respectively. The transportability of the models was empirically tested via external validation in three independent European cohorts (N = 1794), revealing high AUC variance between datasets within models. For instance, the 144-CpG heavy versus non-drinkers model yielded AUCs ranging from 0.60 to 0.84 between datasets. The newly developed models that considered data from all categories showed low AUCs but gave low AUC variation in the external validation. For instance, the 144-CpG heavy and at-risk versus light and non-drinkers model achieved AUCs of 0.67 ± 0.02 in the internal cross-validation and 0.61–0.66 in the external validation datasets. Conclusions The outcomes of our internal and external validation demonstrate that the previously reported prediction models suffer from both overfitting and accuracy overestimation. Our results show that the previously proposed biomarkers are not yet sufficient for accurate and robust inference of alcohol consumption from blood. Overall, our findings imply that DNA methylation prediction biomarkers and models need to be improved considerably before epigenetic inference of alcohol consumption from blood can be considered for practical applications.

Purpose Vincristine (VCR) is a chemotherapeutic agent used in the treatment of pediatric oncology patients, but its main toxicity is VCR‐induced peripheral neuropathy (VIPN). However, whether VIPN has an effect on health‐related quality of life (HR‐QoL) in children during treatment is unknown. Therefore, the aim of our study was to investigate the association between VIPN and HR‐QoL in children starting treatment for cancer. Methods Measurements of VIPN were performed using two tools: Common Terminology Criteria for Adverse Events (CTCAE) and pediatric‐modified Total Neuropathy Score (ped‐mTNS). Assessment of HR‐QoL was done with self‐ and proxy assessment of the Cancer and Generic module of the Pediatric Cancer Quality of Life Inventory™ (PedsQL). Results In total, N = 86 children were included. HR‐QoL of children with VIPN (n = 67%, 76%) was significantly lower in comparison with children without VIPN: estimated Total score of PedsQL Generic (proxy) 84.57; β = −8.96 and 95% confidence interval (CI) −14.48 to −3.43; p = 0.002, estimated PedsQL Generic Total score (self‐reported): 85.16, β = −8.38 (95% CI: −13.76 to −3.00); p = 0.003. Similar results were found in the Pain and Hurt domain of the PedsQL Cancer (pain: estimated score [proxy]: 85.28, β = −9.94 [95%CI: −16.44 to −3.45], p = 0.003; hurt: estimated score [self‐report] 97.57, β = −19.15 [95%CI: −26.82 to −11.48], p, This article reports on the association between vincristine‐induced peripheral neuropathy and health‐related quality of life in pediatric oncology patients. Our data show that health‐related quality of life is significantly lower in children who experience vincristine‐induced peripheral neuropathy compared to pediatric oncology patients without vincristine‐induced peripheral neuropathy.

Background and ObjectivesTo determine the role of complement in the disease pathology of multifocal motor neuropathy (MMN), we investigated complement activation, and inhibition, on binding of MMN patient-derived immunoglobulin M (IgM) antibodies in an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model for MMN.MethodsiPSC-derived MNs were characterized for the expression of complement receptors and membrane-bound regulators, for the binding of circulating IgM anti-GM1 from patients with MMN, and for subsequent fixation of C4 and C3 on incubation with fresh serum. The potency of ARGX-117, a novel inhibitory monoclonal antibody targeting C2, to inhibit fixation of complement was assessed.ResultsiPSC-derived MNs moderately express the complement regulatory proteins CD46 and CD55 and strongly expressed CD59. Furthermore, MNs express C3aR, C5aR, and complement receptor 1. IgM anti-GM1 antibodies in serum from patients with MMN bind to MNs and induce C3 and C4 fixation on incubation with fresh serum. ARGX-117 inhibits complement activation downstream of C4 induced by patient-derived anti-GM1 antibodies bound to MNs.DiscussionBinding of IgM antibodies from patients with MMN to iPSC-derived MNs induces complement activation. By expressing complement regulatory proteins, particularly CD59, MNs are protected against complement-mediated lysis. Yet, because of expressing C3aR, the function of these cells may be affected by complement activation upstream of membrane attack complex formation. ARGX-117 inhibits complement activation upstream of C3 in this disease model for MMN and therefore represents an intervention strategy to prevent harmful effects of complement in MMN.

The ENCALS survival prediction model offers patients with amyotrophic lateral sclerosis (ALS) the opportunity to receive a personalized prognosis of survival at the time of diagnosis. We explored experiences of patients with ALS, caregivers, and physicians with discussing personalized prognosis through interviews with patients and their caregivers, and in a focus group of physicians. Thematic analysis revealed four themes with seven subthemes; these were recognized by the focus group. First, tailored communication: physician’s communication style and information provision mediated emotional impact and increased satisfaction with communication. Second, personal factors: coping style, illness experiences, and information needs affected patient and caregiver coping with the prognosis. Third, emotional impact ranged from happy and reassuring to regret. Fourth, regaining control over the future: participants found it helpful in looking towards the future, and emphasized the importance of quality over quantity of life. Personalized prognosis can be discussed with minimal adverse emotional impact. How it is communicated—i.e., tailored to individual needs—is as important as what is communicated—i.e., a good or poor prognosis. Discussing personalized prognosis may help patients with ALS and their caregivers regain control over the future and facilitate planning of the future (care). For many patients, quality of life matters more than quantity of time remaining.

Determine vitamin B12 threshold levels below which additional testing of methylmalonic acid (MMA) and/or homocysteine (Hcy) is useful to diagnose metabolic vitamin B12 deficiency in patients with polyneuropathy, and how vitamin B12, MMA and Hcy levels relate to the effect of supplementation therapy.In a retrospective cohort study of 331 patients with polyneuropathy, vitamin B12, MMA and Hcy were measured. Linear regression models with vitamin B12 as dependent and Hcy or MMA as covariate were compared, to assess which was best related to vitamin B12. Threshold vitamin B12 levels for metabolic deficiency (defined as elevatede metabolites) were determined using logistic regression with elevated metabolites as dependent and vitamin B12 as covariate. A structured interview was conducted in 42 patients to evaluate response to vitamin B12 supplementation.MMA was best related to vitamin B12. Using elevated MMA for metabolic deficiency, we found 90% sensitivity at a vitamin B12 threshold level264 pmol/L (358 pg/mL) and 95% sensitivity at304 pmol/L (412 pg/mL). Improvement after supplementation was reported by 19% patients and stabilization by 24%. 88% of patients with improvement and 90% with stabilization either had absolute deficiency (Vitamin B12 148 pmol/L) or metabolic deficiency (elevated MMA and vitamin B12 ≥ 148 pmol/L). There were no additional patients with improvement or stabilization with isolated elevated Hcy.Testing of MMA has additional value in identifying patients with clinically relevant metabolic deficiency when vitamin B12 is below 304 pmol/L (412 pg/mL). Supplementation can be effective in patients with absolute and metabolic deficiency.

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral blood. If the activation of circulating, tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses toward 71 melanoma-associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the circulating melanoma-reactive CD8 T cell response was unaltered upon PD-1 blockade. In contrast, a broadening of the circulating melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. Based on these results, we conclude that PD-1 and CTLA-4 blockade have distinct mechanisms of action. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site.

Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS-(1) patient selection and (2) analytical strategy-and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population. ispartof: NEUROLOGY vol:97 issue:11 pages:528-536 ispartof: location:United States status: published

OBJECTIVE To describe current practices and barriers and support needs in gastrostomy indication and decision-making amongst rehabilitation physicians of ALS care teams in the Netherlands. Methods: Cross-sectional online survey of rehabilitation physicians of ALS care teams in the Netherlands. Survey items covered current practices in timing of indication (i.e. indicators and criteria), goals, initiating discussion about gastrostomy, and criteria for preferred method of placement; and barriers and support needs in indication and decision-making. Descriptive analysis was used for quantitative responses, thematic, and content analysis for qualitative data. Results: Twenty-nine physicians (41%) of 27 ALS care teams (71%) responded. Timing of indication: physicians agreed on important indicators but not cutoff values/criteria. Goals: optimizing nutritional status (100%), ensuring safe food-intake (72%), and reducing effort of meals (59%). Initiating discussion about gastrostomy: 52% introduces the topic early after diagnosis, 48% at indication. Criteria for method of placement included physician preference (69%), availability of service (21%), lower complication risk (17%), contraindication (59%), and patient preference (24%). Reported barriers (69% of respondents) were: patient readiness (52%), timing of indication (31%), and organizational barriers (18%). Support needs (62%): evidence-based timing of indication (35%) and tailored patient education (31%). Conclusions: There is practice variation in the timing of first introduction of gastrostomy and preferred method of placement, but agreement on goals and indicators . More evidence on optimal timing of gastrostomy placement is needed. However, until then early and regular discussion of the topic of gastrostomy and better patient information may promote patient readiness and support patient choice.

BackgroundUsual vulvar intraepithelial neoplasia (uVIN) is a premalignancy caused by persistent infection with high-risk types of human papillomavirus (HPV), mainly type 16. Even though different treatment modalities are available (eg, surgical excision, laser evaporation or topical application of imiquimod), these treatments can be mutilating, patients often have recurrences and 2%–8% of patients develop vulvar carcinoma. Therefore, immunotherapeutic strategies targeting the pivotal oncogenic HPV proteins E6 and E7 are being explored to repress carcinogenesis.MethodIn this phase I/II clinical trial, 14 patients with HPV16+ uVIN were treated with a genetically enhanced DNA vaccine targeting E6 and E7. Safety, clinical responses and immunogenicity were assessed. Patients received four intradermal HPV-16 E6/E7 DNA tattoo vaccinations, with a 2-week interval, alternating between both upper legs. Biopsies of the uVIN lesions were taken at screening and +3 months after last vaccination. Digital photography of the vulva was performed at every check-up until 12 months of follow-up for measurement of the lesions. HPV16-specific T-cell responses were measured in blood over time in ex vivo reactivity assays.ResultsVaccinations were well tolerated, although one grade 3 suspected unexpected serious adverse reaction was observed. Clinical responses were observed in 6/14 (43%) patients, with 2 complete responses and 4 partial responses (PR). 5/14 patients showed HPV-specific T-cell responses in blood, measured in ex vivo reactivity assays. Notably, all five patients with HPV-specific T-cell responses had a clinical response.ConclusionsOur results indicate that HPV-16 E6/E7 DNA tattoo vaccination is a biologically active and safe treatment strategy in patients with uVIN, and suggest that T-cell reactivity against the HPV oncogenes is associated with clinical benefit.Trial registration numberNTR4607.

Caregivers of Amyotrophic Lateral Sclerosis (ALS) and Progressive Muscular Atrophy (PMA) patients often experience psychological distress. Yet, it is unclear which factors explain the variance in psychological distress. This study seeks to evaluate how care demands and perceived control over caregiving influence psychological distress using moderation and mediation analysis. Data were collected as part of a RCT and 148 partners of patients with ALS or PMA were included. Psychological distress was assessed using the Hospital Anxiety and Depression Scale. Care demands were operationalized as physical functioning (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised) and behavioural changes of the patient (Amyotrophic Lateral Sclerosis-Frontotemporal Dementia-Questionnaire). Perceived control over caregiving was assessed using items adapted from the Job Content Questionnaire. Results showed that more behavioural changes and lower perceived control over caregiving were associated with higher levels of psychological distress in caregivers. Patients' physical functioning was not significantly related to caregivers' psychological distress. No moderation or mediation effects were found of perceived control over caregiving on the relationship between demand and psychological distress. Monitoring, psychoeducation and caregiver support with regard to behavioural changes in patients, seem to be important for the wellbeing of caregivers. Caregivers' perceived control might be a target for future interventions.

ObjectiveTo define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies.MethodsWe prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non–amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS.ResultsThe mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was −1.8 ± 1.7 for ALS Functional Rating Scale–Revised and −1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G4C2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives.ConclusionsWe present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data.

Introduction We present a case series of six treatment‐naive patients with clinical phenotypes compatible with chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy without electrodiagnostic features of demyelination but with abnormal peripheral ultrasound findings who responded to treatment. Methods All six patients underwent a complete set of ancillary investigations, including extensive nerve conduction studies. We also performed standardized nerve ultrasound of median nerves and brachial plexus as part of a larger effort to evaluate diagnostic value of sonography. Results Nerve conduction studies did not show conduction block or other signs of demyelination in any of the six patients. Sonographic nerve enlargement was present in all patients and was most prominent in proximal segments of the median nerve and brachial plexus. Treatment with intravenous immunoglobulin resulted in objective clinical improvement. Discussion Our study provides evidence that nerve ultrasound represents a useful complementary diagnostic tool for the identification of treatment‐responsive inflammatory neuropathies.

Objective The primary aim was to determine the safety of treatment with human immune globulin 10% with recombinant human hyaluronidase (fSCIg) compared to intravenous immunoglobulin (IVIg) in a prospective open-label study in patients with multifocal motor neuropathy (MMN). Methods Our study consisted of two phases: the IVIg phase (visits 1–3; 12 weeks), in which patients remained on IVIg treatment, and the fSCIg phase (visits 4–7; 36 weeks), in which patients received fSCIg treatment. After visit 3, IVIg was switched to an equivalent dose and frequency of fSCIg. Outcome measures were safety, muscle strength, disability and treatment satisfaction. Results Eighteen patients were enrolled in this study. Switching to fSCIg reduced the number of systemic adverse events (IVIg 11.6 vs. fSCIg 5.0 adverse events/per person-year, p

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing, with concomitant high incidence of lipoprotein abnormalities. Cardiovascular disease (CVD) is the main cause of death in subjects with NAFLD and management of dyslipidemia is pivotal for prevention. We aimed to determine cardiovascular risk and indication for statin therapy in subjects with NAFLD.METHODS: Cross sectional analysis of the population-based Lifelines Cohort Study of 34,240 adult individuals. Subjects with reported use of lipid-lowering drugs were excluded. Suspected NAFLD was defined as Fatty Liver Index (FLI) ≥60 and advanced hepatic fibrosis as NAFLD fibrosis score (NFS) >0.676. Cardiovascular risk and indication for statin therapy were defined according to the European Society of Cardiology and European Atherosclerosis Society Guideline for the Management of Dyslipidemias.RESULTS: FLI≥60 was present in 7,067 (20.6%) participants and coincided with increased prevalence of type 2 diabetes mellitus, metabolic syndrome, CVD and impaired renal function (all P0.676 (73.2% vs. 30.6%, P0.676 (OR 5.03, 95%CI: 2.76-9.17%, PCONCLUSIONS: Because of increased cardiovascular risk, substantial proportions of subjects with suspected NAFLD and/or fibrosis have an indication for lipid-lowering treatment and could benefit from statin therapy. This article is protected by copyright. All rights reserved.

Background: The extensive heterogeneity between patients with amyotrophic lateral sclerosis (ALS) complicates the quantification of disease progression. In this study, we determine the value of remote, accelerometer-based monitoring of physical activity in patients with ALS. Methods: This longitudinal cohort study was conducted in a home-based setting; all study materials were sent by mail. Patients wore the ActiGraph during waking hours for 7 days every 2–3 months and provided information regarding their daily functioning (ALSFRS-R). We defined four accelerometer-based endpoints that either reflect the average daily activity or quantify the patient’s physical capacity. Results: A total of 42 patients participated; the total valid monitoring period was 9288 h with a 93.0% adherence rate. At baseline, patients were active 27.9% (range 11.6–52.4%) of their time; this declined by 0.64% (95% 0.43–0.86, p < 0.001) per month. Accelerometer-based endpoints were strongly associated with the ALSFRS-R (r 0.78, 95% CI 0.63–0.92, p < 0.001), but showed less variability over time than the ALSFRS-R (coefficient of variation 0.64–0.81 vs. 1.06, respectively). Accelerometer-based endpoints could reduce sample size by 30.3% for 12-month trials and 44.6% for 18-month trials; for trials lasting less than 9 months, the ALSFRS-R resulted in smaller sample sizes. Conclusion: Accelerometry is an objective method for quantifying disease progression, which could obtain real-world insights in the patient’s physical functioning and may personalize the delivery of care. In addition, remote monitoring provides patients with the opportunity to participate in clinical trials from home, paving the way to a patient-centric clinical trial model.

ObjectiveTo investigate the natural course of scoliosis and to estimate lifetime probability of scoliosis surgery in spinal muscular atrophy (SMA).MethodsWe analyzed cross-sectional data from 283 patients from our population-based cohort study. Additional longitudinal data on scoliosis progression and spinal surgery were collected from 36 consecutive patients who received scoliosis surgery at our center.ResultsThe lifetime probability of receiving scoliosis surgery was ≈80% in SMA types 1c and 2. Patients with type 2 who only learned to sit (type 2a) were significantly younger at time of surgery than those who learned to sit and stand (type 2b). The lifetime risk of surgery was lower in type 3a (40%) and strongly associated with age at loss of ambulation: 71% in patients losing ambulation before 10 years of age vs 22% losing ambulation after the age of 10 years (p = 0.005). In type 3a, preserving the ability to walk 1 year longer corresponded to a 15% decrease in lifetime risk of scoliosis surgery (hazard ratio 0.852, p = 0.017). Scoliosis development was characterized by initial slow progression, followed by acceleration in the 1.5- to 2-year period before surgery.ConclusionThe lifetime probability of scoliosis surgery is high in SMA types 1c and 2 and depends on age at loss of ambulation in type 3. Motor milestones such as standing that are not part of the standard classification system are of additional predictive value. Our data may act as a reference to assess long-term effects of new SMA-specific therapies.

Background: Weakness caused by motor neuron degeneration in amyotrophic lateral sclerosis (ALS) may result in avoidance of physical activity, resulting in deconditioning and reduced health-related quality of life (HRQoL). Objective: To study the effectiveness of aerobic exercise therapy (AET) on disease-specific and generic HRQoL in ambulatory patients with ALS. Methods: We conducted a multicenter, assessor-blinded, randomized controlled trial. Using a biphasic randomization model, ambulatory ALS patients were assigned (1:1) to AET+usual care (UC), or UC. AET consisted of a 16-week aerobic cycling exercise program. Primary outcome measures were the 40-item ALS assessment questionnaire (ALSAQ-40), and the mental component summary (MCS) and physical component summary (PCS) scores of the short-form survey (SF-36), using linear mixed effects models. Per-protocol (PP) analysis was performed for those patients who attended ≥75% of the training sessions; controls were matched (1:1) by propensity score matching. Results: Of 325 screened patients, 57 were randomized: 27 to AET+UC and 30 to UC. No significant mean slope differences between groups were observed for ALSAQ-40 (-1.07; 95% confidence interval [CI] -2.6 to 0.5, P=0.172) nor for SF-36 MCS (0.24; -0.7 to 1.1, P=0.576) or PCS (-0.51; -1.4 to 0.38, P=0.263). There were no adverse events related to the AET. PP-analyses showed significantly less deterioration in ALSAQ-40 (-1.88, -3.8 to 0.0, P=0.046) in AET+UC compared to UC. Conclusions: AET+UC was not superior to UC alone in preserving HRQoL in ambulatory ALS patient. However, the study was unfortunately underpowered, because only 10 patients completed the protocol. AET+UC may preserve disease-specific HRQoL in slow progressors. Clinical trial registration number: Netherlands National Trial Register (NTR): 1616.

Introduction Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM-PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated glycoprotein (MAG) and gangliosides. Methods To test whether B-cell-stimulating cytokines are increased in IgM-PNP, we measured serum concentrations of 11 cytokines in 81 patients with IgM-PNP and 113 controls. Results Median interleukin (IL)-6 concentrations were higher in patients with IgM-PNP, and median IL-10 concentrations were higher in the subgroup with anti-MAG IgM antibodies. These serum concentrations were not increased in 110 patients with multifocal motor neuropathy. Discussion Median IL-6 and IL-10 serum concentrations differ between patients with anti-MAG neuropathy and other patients with IgM-PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune-mediated disease mechanisms. Muscle Nerve 59:694-698, 2019.

Macroscale white matter pathways form the infrastructure for large-scale communication in the human brain, a prerequisite for healthy brain function. Conversely, disruptions in the brain’s connectivity architecture are thought to play an important role in a wide range of psychiatric and neurological brain disorders. Here we show that especially connections important for global communication and network integration are involved in a wide range of brain disorders. We report on a meta-analytic connectome study comprising in total 895 patients and 1,016 controls across twelve neurological and psychiatric disorders. We extracted disorder connectome fingerprints for each of these twelve disorders, which were then combined into a cross-disorder disconnectivity involvement map, representing the involvement of each brain pathway across brain disorders. Our findings show connections central to the brain’s infrastructure are disproportionally involved across a wide range of disorders. Connections critical for global network communication and integration display high disturbance across disorders, suggesting a general cross-disorder involvement and importance of these pathways in normal function. Taken together, our cross-disorder study suggests a convergence of disconnectivity across disorders to a partially shared disconnectivity substrate of central connections.

To establish the utility of venous creatinine as a biomarker to monitor loss of fat-free mass in patients with amyotrophic lateral sclerosis (ALS).In this multicenter natural history study, body composition and venous creatinine were assessed in 107 patients with ALS and 52 healthy controls. Longitudinal patterns of venous creatinine and its association with the risk of death during follow-up were determined in a cohort of patients with ALS from Australia (n = 69) and the Netherlands (n = 38).The mean levels of venous creatinine were 75.78 ± 11.15 μmol/L for controls, 70.25 ± 12.81 μmol/L for Australian patients, and 59.95 ± 14.62 μmol/L for Dutch patients with ALS. The relationship between measures of venous creatinine and fat-free mass was similar between all groups (r = 0.36, p 0.001). Within patients, fat-free mass declined by 0.31 (95% confidence interval [CI]: 0.22-0.40) kg/month, and venous creatinine declined by 0.52 (95% CI: 0.38-0.66) μmol/L/month, with a longitudinal correlation of 0.57 (95% CI: 0.35-0.76, p 0.001). Lower levels of venous creatinine were associated with increased risk for earlier death in patients with ALS (hazard ratio = 0.94, 95% CI: 0.90-0.98, p = 0.007).Venous creatinine is decreased in ALS and declines alongside a decline in fat-free mass over the course of the disease, and may serve as a practical marker to monitor the change of fat-free mass in patients with ALS. This could inform clinical care and provide an alternative endpoint for the evaluation of therapeutic interventions that focus on slowing the loss of fat-free mass and disease progression in ALS.

ObjectiveTo assess the association between copy number (CN) variation in the survival motor neuron (SMN) locus and multifocal motor neuropathy (MMN), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS) susceptibility and to determine the association of SMN1 and SMN2 CN with MMN, PMA, and PLS disease course.MethodsIn this monocenter study, we used multiplex ligation-dependent probe amplification to determine SMN1 and SMN2 CN in Dutch patients with MMN, PMA, and PLS and controls. We stratified clinical parameters for SMN1 and SMN2 CN. We analyzed SMN1 and SMN2 exons 1–6, intron 6, and exon 8 CN to study the genetic architecture of SMN1 duplications.ResultsSMN1 and SMN2 CN were determined in 132 patients with MMN, 150 patients with PMA, 104 patients with PLS, and 956 control subjects. MMN and PLS were not associated with CN variation in SMN1 or SMN2. By contrast, patients with PMA more often than controls carried SMN1 duplications (≥3 SMN1 copies, 12.0% vs 5.0%, odds ratio 2.69 (1.43–4.91), p 0.0020). SMN1 and SMN2 CN status was not associated with MMN, PLS, or PMA disease course. In case of SMN1 exon 7 duplications, exons 1–6, exon 8, and introns 6 and 7 were also duplicated, suggesting full SMN1 duplications.ConclusionsSMN1 duplications are associated with PMA, but not with PLS and MMN. SMN1 duplications in PMA are balanced duplications. The results of this study highlight the primary effect of altered SMN CN on lower motor neurons.

Latent infection with cytomegalovirus (CMV) is assumed to contribute to the age-associated decline of the immune system. CMV induces large changes in the T-cell pool and may thereby affect other immune responses. CMV is expected to impact especially older adults, who are already at higher risk of severe disease and hospitalization upon infections such as influenza virus (IAV) infection. Here, we investigated the impact of CMV infection on IAV-specific CD8+ T-cell frequencies in healthy individuals (n=96) and the response to IAV infection in older adults (n=72). IAV-specific memory T-cell frequencies were lower in healthy CMV+ older individuals compared to healthy CMV- older individuals. Upon acute IAV infection, CMV serostatus or CMV-specific antibody levels were not negatively associated with IAV-specific T-cell frequencies, function, phenotype or T-cell receptor repertoire diversity. This suggests that specific T-cell responses upon acute IAV infection are not negatively affected by CMV. In addition, we found neither an association between CMV infection and inflammatory cytokine levels in serum during acute IAV infection nor between cytokine levels and the height of the IAV-specific T-cell response upon infection. Finally, CMV infection was not associated with increased severity of influenza-related symptoms. In fact, CMV infection was even associated with increased IAV-specific T-cell responses early upon acute IAV infection. In conclusion, although associated with lower frequencies of memory IAV-specific T cells in healthy individuals, CMV infection does not seem to hamper the induction of a proper T-cell response during acute IAV infection in older adults.

Background and objective Nerve ultrasound is a promising new tool in chronic inflammatory neuropathies. The aim of this study was to determine its prognostic value in a prospective multicenter cohort study including incident and prevalent patients with CIDP and MMN. Methods We enrolled 126 patients with CIDP, and 72 with MMN; 71 were treatment-naive. Patients with chronic idiopathic axonal polyneuropathy (CIAP; n = 35) were considered as disease controls. Standardized neurological examination, questionnaires, and nerve ultrasonography were obtained at time of inclusion and 1-year follow-up. Nerve size development over time and correlation between nerve size and clinical outcome measures were determined using linear mixed effects models. Results Nerve size development over time was heterogeneous. Only in MMN was there a correlation between C5 nerve root size and deterioration of grip strength (-1.3 kPa/mm2 (95% confidence interval [CI] -2.3 to -0.2). No other significant correlations between nerve size and clinical outcome measures were found. In MMN, presence of nerve enlargement at inclusion predicted deterioration of grip strength, and MMN patients with enlargement confined to the brachial plexus seemed to have more favorable outcomes. No other predictive effects of sonographic nerve size were found. Conclusions The present study indicates that the natural course of nerve size development in CIDP and MMN is heterogeneous, and that the prognostic value of sonographic nerve enlargement is limited. It had some predictive effect in patients with MMN. Further research in specific subgroups of chronic inflammatory neuropathy is necessary to determine the usefulness of nerve ultrasonography after the diagnostic phase.