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Background: Myotonic dystrophy type 1 (DM1) patients are at risk for metabolic abnormalities and commonly experience overweight and obesity. Possibly, weight issues result from lowered resting energy expenditure (EE) and impaired muscle oxidative metabolism. Objectives: This study aims to assess EE, body composition, and muscle oxidative capacity in patients with DM1 compared to age-, sex- and BMI-matched controls. Methods: A prospective case control study was conducted including 15 DM1 patients and 15 matched controls. Participants underwent state-of-the-art methodologies including 24 h whole room calorimetry, doubly labeled water and accelerometer analysis under 15-days of free-living conditions, muscle biopsy, full body magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DEXA), computed tomography (CT) upper leg, and cardiopulmonary exercise testing. Results: Fat ratio determined by full body MRI was significantly higher in DM1 patients (56 [49–62] %) compared to healthy controls (44 [37–52] % ; p = 0.027). Resting EE did not differ between groups (1948 [1742–2146] vs (2001 [1853–2425>] kcal/24 h, respectively; p = 0.466). In contrast, total EE was 23% lower in DM1 patients (2162 [1794–2494] vs 2814 [2424–3310] kcal/24 h; p = 0.027). Also, DM1 patients had 63% less steps (3090 [2263–5063] vs 8283 [6855–11485] steps/24 h; p = 0.003) and a significantly lower VO2 peak (22 [17–24] vs 33 [26–39] mL/min/kg; p = 0.003) compared to the healthy controls. Muscle biopsy citrate synthase activity did not differ between groups (15.4 [13.3–20.0] vs 20.1 [16.6–25.8] μM/g/min, respectively; p = 0.449). Conclusions: Resting EE does not differ between DM1 patients and healthy, matched controls when assessed under standardized circumstances. However, under free living conditions, total EE is substantially reduced in DM1 patients due to a lower physical activity level. The sedentary lifestyle of DM1 patients seems responsible for the undesirable changes in body composition and aerobic capacity.

BackgroundCognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes.Methods204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up.ResultsThree distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition (n = 76), one moderately impaired cluster (n = 74) and one severely impaired cluster (n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present.ConclusionsCurrent results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes.

Aims To evaluate the clinical effectiveness of routine 24 h Holter monitoring to screen for conduction disturbances and arrhythmias in patients with myotonic dystrophy type 1 (DM1). Methods and results A retrospective two-centre study was conducted including DM1-affected individuals undergoing routine cardiac screening with at least one 24 h Holter monitoring between January 2010 and December 2020. For each individual, the following data were collected: Holter results, results of electrocardiograms (ECGs) performed at the same year as Holter monitoring, presence of cardiac complaints, and neuromuscular status. Holter findings were compared with the results of cardiac screening (ECG + history taking) performed at the same year. Cardiac conduction abnormalities and/or arrhythmias that would have remained undiagnosed based on history taking and ECG alone were considered de novo findings. A total 235 genetically confirmed DM1 patients were included. Abnormal Holter results were discovered in 126 (54%) patients after a mean follow-up of 64 ± 28 months in which an average of 3 ± 1 Holter recordings per patient was performed. Abnormalities upon Holter mainly consisted of conduction disorders (70%) such as atrioventricular (AV) block. Out of 126 patients with abnormal Holter findings, 74 (59%) patients had de novo Holter findings including second-degree AV block, atrial fibrillation/flutter and non-sustained ventricular tachycardia. Patient characteristics were unable to predict the occurrence of de novo Holter findings. In 39 out of 133 (29%) patients with normal ECGs upon yearly cardiac screening, abnormalities were found on Holter monitoring during follow-up. Conclusion Twenty-four hour Holter monitoring is of added value to routine cardiac screening for all DM1 patients.

Psychiatric comorbidity is common in patients with chronic pain. In peripheral neuropathic pain, particularly anxiety and mood disorders are frequently present and associated with a high level of catastrophizing. Small fiber neuropathy (SFN) is a peripheral neuropathy dominated by pain. This study aimed to investigate the prevalence of and factors associated with anxiety and depressive symptoms in SFN. All consecutive patients diagnosed with SFN at Maastricht University Medical Center+, between September 2016 and October 2021, were included (n = 1310). Data on demographics, medical history, diagnostic tests, and questionnaires about pain, SFN-specific symptoms, and mental health were collected once. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety and depression and the Pain Catastrophizing Scale (PCS) to measure the degree of catastrophizing. One-third of the patients had an abnormal HADS score (>= 11) on the subscales anxiety and/or depression (26.5% anxiety and 23.0% depression) indicating clinical relevance. Regression analysis showed that higher pain intensity, catastrophizing, and more SFN-related complaints were significantly associated with an abnormal HADS-score. In conclusion, the prevalence of reported anxiety or depressive symptoms in SFN is 36.3%. A multidisciplinary approach, not only focusing on pain relief, is therefore essential for the treatment of SFN.

PURPOSE OF REVIEW: Several conditions have been associated with the development of small fiber neuropathy (SFN). The list of metabolic, immune-mediated, infectious, toxic, drugs-related, and hereditary conditions is still growing and various hypotheses are made about the underlying pathophysiological mechanisms. Understanding these processes is important to provide new targets for treatment. In addition, the specific SFN phenotype can provide direction for the underlying etiology. This review discusses the latest developments concerning the expanding etiologies in SFN. RECENT FINDINGS: In the past 18 months, special attention has been paid to immunological etiologies, partly due to the coronavirus disease 2019 pandemic, but also new auto-antibodies in SFN have been demonstrated. Identifying patients with immune-mediated SFN can be challenging, since contrary to the classical distal sensory phenotype, a nonlength-dependent pattern is more common.Besides the etiologies of classical SFN, small fiber pathology is increasingly described in diseases without the typical neuropathic pain features of SFN, sometimes called syndromic SFN. However, the clinical relevance is not yet fully understood. SUMMARY: The expansion of the etiologies of SFN continues and brings more insight in possible targets for treatment. The clinical presentation may vary as a result of the underlying condition.

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.

Objective: To examine the genetic architecture of cam morphology using alpha angle (AA) as a proxy measure and conduct an AA genome-wide association study (GWAS) followed by Mendelian randomization (MR) to evaluate its causal relationship with hip osteoarthritis (OA). Methods: Observational analyses examined associations between AA measurements derived from hip dual x-ray absorptiometry (DXA) scans from the UK Biobank study and radiographic hip OA outcomes and subsequent total hip replacement. Following these analyses, an AA GWAS meta-analysis was performed (N = 44,214) using AA measurements previously derived in the Rotterdam Study. Linkage disequilibrium score regression assessed the genetic correlation between AA and hip OA. Genetic associations considered significant (P < 5 × 10−8) were used as AA genetic instrument for 2-sample MR analysis. Results: DXA-derived AA showed expected associations between AA and radiographic hip OA (adjusted odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.58, 1.67]) and between AA and total hip replacement (adjusted hazard ratio 1.45 [95% CI 1.33, 1.59]) in the UK Biobank study cohort. The heritability of AA was 10%, and AA had a moderate genetic correlation with hip OA (rg = 0.26 [95% CI 0.10, 0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on hip OA risk (inverse variance weighted OR 1.84 [95% CI 1.14, 2.96], P = 0.01). In contrast, genetic predisposition for hip OA had stronger evidence of a causal effect on increased AA (inverse variance weighted β = 0.09 [95% CI 0.04, 0.13], P = 4.58 × 10−5). Conclusion: Expected observational associations between AA and related clinical outcomes provided face validity for the DXA-derived AA measurements. Evidence of bidirectional associations between AA and hip OA, particularly for risk of hip OA on AA, suggests that hip shape modeling secondary to a genetic predisposition to hip OA contributes to the well-established relationship between hip OA and cam morphology in older adults.

ObjectiveMinimum joint space width (mJSW) from 2-dimensional images provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and use them to (ii) examine causal effects of mJSW on hip osteoarthritis (HOA) risk.MethodsGWAS meta-analysis of hip mJSW derived from plain X-rays (four cohorts) or DXA (one cohort) was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA.Results50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci (35 novel), were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (βIVW-0.01 [95% CI -0.19, 0.17]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life.ConclusionsGWAS and MR analyses suggested one group of mJSW loci reduces HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to mJSW and HOA risk via a growth-related mechanism.

Maintenance therapy with pemetrexed has shown survival benefit in patients with advanced stage non-small cell lung cancer (NSCLC). The recommended dose schedule is 500 mg/m 2 in 21-day cycles. Prolonged treatment with maintenance pemetrexed can result in cumulative toxicities. We sought to compare treatment outcomes in patients receiving an alternate maintenance schedule in realworld practice.This single-center, retrospective study investigated patients with advanced stage (IIIB and IV) NSCLC receiving at least two doses of maintenance pemetrexed from May 1, 2011 to June 30, 2016. The objective was to compare time on treatment with maintenance pemetrexed therapy initiated at a standard schedule (q3 weeks) versus an alternate schedule (q4 weeks or longer). Also evaluated were progressionfree survival (PFS) and overall survival (OS) differences between the two groups.129 patients were included, of whom 40 started the alternate schedule no later than cycle 3 of treatment (29 of 40 patients initiated maintenance treatment on the alternate schedule). Average time on maintenance treatment for patients appeared to be longer in the patients who received the alternate schedule regimen (195 vs 263 days, p =0.008). OS trended towards better survival among patients receiving the alternate schedule regimen (11.9 vs 18.1 months, p =0.3). Limiting the analysis to ALK wildtype, the patients showed a similar trend, with median PFS (7.6 vs 11.5 months, p =0.46) and OS (11.9 vs 17.6 months, p =0.38), still favoring the alternate schedule.The alternate dosing schedule of maintenance pemetrexed (q4 weeks or longer) is feasible and not detrimental to OS. Future investigations evaluating the optimal administration schedule of maintenance pemetrexed is warranted.

Personalized management of neuropathic pain is an unmet clinical need due to heterogeneity of the underlying aetiologies, incompletely understood pathophysiological mechanisms and limited efficacy of existing treatments. Recent studies on microRNA in pain preclinical models have begun to yield insights into pain-related mechanisms, identifying nociception-related species differences and pinpointing potential drug candidates. With the aim of bridging the translational gap towards the clinic, we generated a human pain-related integrative miRNA and mRNA molecular profile of the epidermis, the tissue hosting small nerve fibres, in a deeply phenotyped cohort of patients with sodium channel-related painful neuropathy not responding to currently available therapies. We identified four miRNAs strongly discriminating patients from healthy individuals, confirming their effect on differentially expressed gene targets driving peripheral sensory transduction, transmission, modulation and post-transcriptional modifications, with strong effects on gene targets including NEDD4. We identified a complex epidermal miRNA-mRNA network based on tissue-specific experimental data suggesting a cross-talk between epidermal cells and axons in neuropathy pain. Using immunofluorescence assay and confocal microscopy, we observed that Nav1.7 signal intensity in keratinocytes strongly inversely correlated with NEDD4 expression that was downregulated by miR-30 family, suggesting post-transcriptional fine tuning of pain-related protein expression. Our targeted molecular profiling advances the understanding of specific neuropathic pain fine signatures and may accelerate process towards personalized medicine in patients with neuropathic pain.Andelic et al. identify miRNA-driven epidermal regulatory mechanisms in SCN9A-related painful neuropathy not responding to currently available therapies. By revealing unique molecular signatures of neuropathic pain in deeply phenotyped patients, these findings could accelerate the development of personalized therapies.

Clonal hematopoiesis (CH) is a risk factor for the development of therapy-related myelodysplastic syndromes (tMDS) and acute myeloid leukemia (tAML). Adoption of targeted-immunotherapeutics since 2011, may alter the risk of CH progression to tMDS/AML. To study this, we evaluated risk of tMDS and tAML in 667 588 ≥ 1-year survivors of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma and multiple-myeloma (MM) diagnosed during: 2000–2005, 2006–2010 and 2011–2016. The risk of tMDS increased significantly after NSCLC across all time periods (Ptrend = 0.002) while tAML risk decreased from 2006–2010 to 2011–2016, coinciding with increasing use of non-chemotherapeutic agents. tAML risk after RCC decreased (Ptrend = 0.007) whereas tMDS risk did not significantly change over time. After melanoma, tMDS and tAML risks were similar to the general population. tMDS and tAML risk after MM increased from the first to second time-period, however, only risk of tMDS decreased during last period. We report diverging trends in the risk of tAML and tMDS after adoption of modern cancer therapies for specific cancers. It is imperative to further explore impact of contemporary treatment strategies on clonal evolution. Modern treatments via their discrete mechanism of actions on pre-existing CH may alter the risk of subsequent tMDS and tAML.

Neuropathic pain is amongst the most common non-communicable disorders and the poor effectiveness of current treatment is an unmet need. Although pain is a universal experience, there are significant inter-individual phenotypic differences. Developing models that can accurately recapitulate the clinical pain features is crucial to better understand underlying pathophysiological mechanisms and find innovative treatments. Current data from heterologous expression systems that investigate properties of specific molecules involved in pain signaling, and from animal models, show limited success with their translation into the development of novel treatments for pain. This is in part because they do not recapitulate the native environment in which a particular molecule functions, and due to species-specific differences in the properties of several key molecules that are involved in pain signaling. The limited availability of post-mortem tissue, in particular dorsal root ganglia (DRG), has hampered research using human cells in pre-clinical studies. Human induced-pluripotent stem cells (iPSCs) have emerged as an exciting alternative platform to study patient-specific diseases. Sensory neurons that are derived from iPSCs (iPSC-SNs) have provided new avenues towards elucidating peripheral pathophysiological mechanisms, the potential for development of personalized treatments, and as a cell-based system for high-throughput screening for discovering novel analgesics. Nevertheless, reprogramming and differentiation protocols to obtain nociceptors have mostly yielded immature homogenous cell populations that do not recapitulate the heterogeneity of native sensory neurons. To close the gap between native human tissue and iPSCs, alternative strategies have been developed. We will review here recent developments in differentiating iPSC-SNs and their use in pre-clinical translational studies. Direct conversion of stem cells into the cells of interest has provided a more cost- and time-saving method to improve reproducibility and diversity of sensory cell types. Furthermore, multi-cellular strategies that mimic in vivo microenvironments for cell maturation, by improving cell contact and communication (co-cultures), reproducing the organ complexity and architecture (three-dimensional organoid), and providing iPSCs with the full spatiotemporal context and nutrients needed for acquiring a mature phenotype (xenotransplantation), have led to functional sensory neuron-like systems. Finally, this review touches on novel prospective strategies, including fluorescent-tracking to select the differentiated neurons of relevance, and dynamic clamp, an electrophysiological method that allows direct manipulation of ionic conductances that are missing in iPSC-SNs.

Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated A delta and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several poreforming voltage-gated sodium channel alpha subunits (Na-v) in a subset of patients with SFN, but the auxiliary sodium channel beta-subunits have been less implicated in the development of the disease. beta subunits modulate Na-v trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the beta 2 subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel beta subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly identified Y69H variant of the beta(2) subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the beta(2)-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of beta(2) subunits in SFN and strengthens the link between sodium channel beta subunits and the development of neuropathic pain in humans.NEW & NOTEWORTHY Small fiber neuropathy (SFN) often has no discernible cause, although mutations in the voltage-gated sodium channel alpha subunits have been implicated in some cases. We identify a patient suffering from SFN with a mutation in the auxiliary beta 2 subunit and no other discernible causes for SFN. Functional assessment confirms this mutation renders dorsal root ganglion neurons hyperexcitable and upregulates tetrodotoxin-sensitive sodium currents. This study strengthens a newly emerging link between sodium channel beta 2 subunit mutations and human pain disorders.

The optimal approach to combine gemtuzumab-ozogamicin (GO) with various chemotherapy backbones and other newer agents safely remains to be determined. We performed a retrospective analysis of the safety and outcomes of newly diagnosed adult AML patients treated with GO in combination with intensified versus standard anthracycline doses (i.e. daunorubicin dose 90 mg/m(2) vs 60 mg/m(2)) ± FLT3 inhibitors. Chi-square test and Mann Whitney U test were used to compare categorical and continuous data. Survival estimates were calculated by Kaplan–Meier method and survival comparisons made using log-rank test. We report an ORR of 97% in newly diagnosed AML patients (n=37) with a median age of 54 (range, 19–75) years treated with GO in combination with standard induction. All eleven patients (100%) receiving GO plus daunorubicin dose 90 mg/m(2) as part of 7+3 induction achieved CR vs 91% (20/22) CR in the standard daunorubicin 60 mg/m(2) dose group (p=NS), No increased toxicity was noted with the higher daunorubicin dose or when GO and 7+3 were combined with FLT3 inhibitors in younger patients (age

Contains fulltext : 290747.pdf (Publisher’s version ) (Open Access) INTRODUCTION/AIMS: Although the extent of muscle weakness and organ complications has not been well studied in patients with late-onset myotonic dystrophy type 1 (DM1), adult-onset DM1 is associated with severe muscle involvement and possible life-threatening cardiac and respiratory complications. In this study we aimed to compare the clinical phenotype of adult-onset vs late-onset DM1, focusing on the prevalence of cardiac, respiratory, and muscular involvement. METHODS: Data were prospectively collected in the Dutch DM1 registry. RESULTS: Two hundred seventy-five adult-onset and 66 late-onset DM1 patients were included. Conduction delay on electrocardiogram was present in 123 of 275 (45%) adult-onset patients, compared with 24 of 66 (36%) late-onset patients (P = .218). DM1 subtype did not predict presence of conduction delay (odds ratio [OR] 0.706; confidence interval [CI] 0.405 to 1.230, P = .219). Subtype did predict indication for noninvasive ventilation (NIV) (late onset vs adult onset: OR, 0.254; CI, 0.104 to 0.617; P = .002) and 17% of late-onset patients required NIV compared with 40% of adult-onset patients. Muscular Impairment Rating Scale (MIRS) scores were significantly different between subtypes (MIRS 1 to 3 in 66% of adult onset vs 100% of late onset [P

Neuropathic pain is a characteristic feature of small fiber neuropathy (SFN), which in 18% of the cases is caused by genetic variants in voltage-gated sodium ion channels. In this study, we assessed the role of fifteen other ion channels in neuropathic pain. Patients with SFN (n = 414) were analyzed for ANO1, ANO3, HCN1, KCNA2, KCNA4, KCNK18, KCNN1, KCNQ3, KCNQ5, KCNS1, TRPA1, TRPM8, TRPV1, TRPV3 and TRPV4 variants by single-molecule molecular inversion probes–next-generation sequencing. These patients did not have genetic variants in SCN3A, SCN7A-SCN11A and SCN1B-SCN4B. In twenty patients (20/414, 4.8%), a potentially pathogenic heterozygous variant was identified in an ion-channel gene (ICG). Variants were present in seven genes, for two patients (0.5%) in ANO3, one (0.2%) in KCNK18, two (0.5%) in KCNQ3, seven (1.7%) in TRPA1, three (0.7%) in TRPM8, three (0.7%) in TRPV1 and two (0.5%) in TRPV3. Variants in the TRP genes were the most frequent (n = 15, 3.6%), partly in patients with high mean maximal pain scores VAS = 9.65 ± 0.7 (n = 4). Patients with ICG variants reported more severe pain compared to patients without such variants (VAS = 9.36 ± 0.72 vs. VAS = 7.47 ± 2.37). This cohort study identified ICG variants in neuropathic pain in SFN, complementing previous findings of ICG variants in diabetic neuropathy. These data show that ICG variants are central in neuropathic pain of different etiologies and provides promising gene candidates for future research.

Introduction: Chronic hypercapnic respiratory failure induces considerable morbidity and mortality in patients with myotonic dystrophy type 1 (DM1). This study systematically reviews the effects of noninvasive home mechanical ventilation (HMV) on gas exchange, quality of life, survival, and compliance in DM1 patients. Methods: A systematic Medline and Embase search was performed (January 1995 to January 2020). Records were screened for eligibility criteria, data were extracted from included studies, and risk of bias was assessed. We present findings mainly using a narrative synthesis. Results: Twenty-eight relevant full-text articles were screened for eligibility criteria. Nine studies were included. Randomized controlled trials were not found. Studies had either an observational (n = 8) or interventional (n = 1) design. In the pooled data analysis, HMV showed to improve mean oxygen saturation with 4.8% and decreased mean carbon dioxide values with 3 mm Hg. Compliance varied widely between studies, from no use to more than 12 h per day. Quality of life was not studied extensively, but some studies reported positive effects of HMV on symptoms of chronic respiratory failure. HMV may improve survival in DM1 patients with chronic hypercapnic respiratory failure. Conclusion: This review shows that HMV can improve gas exchange and relieve symptoms with a possible survival benefit in DM1 patients with chronic hypercapnic respiratory failure. Future studies should focus on developing strategies to optimize the timing of HMV initiation and to promote compliance.

Several conditions have been associated with the development of small fiber neuropathy (SFN). The list of metabolic, immune-mediated, infectious, toxic, drugs-related, and hereditary conditions is still growing and various hypotheses are made about the underlying pathophysiological mechanisms. Understanding these processes is important to provide new targets for treatment. In addition, the specific SFN phenotype can provide direction for the underlying etiology. This review discusses the latest developments concerning the expanding etiologies in SFN.In the past 18 months, special attention has been paid to immunological etiologies, partly due to the coronavirus disease 2019 pandemic, but also new auto-antibodies in SFN have been demonstrated. Identifying patients with immune-mediated SFN can be challenging, since contrary to the classical distal sensory phenotype, a nonlength-dependent pattern is more common.Besides the etiologies of classical SFN, small fiber pathology is increasingly described in diseases without the typical neuropathic pain features of SFN, sometimes called syndromic SFN. However, the clinical relevance is not yet fully understood.The expansion of the etiologies of SFN continues and brings more insight in possible targets for treatment. The clinical presentation may vary as a result of the underlying condition.

Background and objectives Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient‐reported Rasch‐built interval scale on activity and participation for FSHD. Methods A pre‐phase FSHD‐Rasch‐built overall disability scale (pre‐FSHD‐RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease‐related functional consequences was completed by 762 FSHD patients (Netherlands: n = 171; UK: n = 287; United States: n = 221; France: n = 52; Australia: n = 32). A proportion of the patient cohort completed it twice (n = 230; interval 2–4 weeks; reliability studies). The pre‐FSHD‐RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure. Results The pre‐FSHD‐RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38‐inquiry (originating from 32 items; six items split) FSHD‐RODS was constructed achieving Rasch model expectations. Adequate test‐retest reliability and (cross‐cultural and external) validity scores were obtained. Conclusions The FSHD‐RODS is a disease‐specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD., This paper presents the development and validation of a patient‐reported Rasch‐built interval scale on activity and participation for facioscapulohumeral muscular dystrophy (FSHD‐RODS). The final 38‐inquiry scale met Rasch model expectations and showed adequate discriminative power, test‐retest reliability and validity. The use of this scale is recommended in the near future to determine the functional deterioration slope in facioscapulohumeral muscular dystrophy (FSHD) per year as a preparation for the upcoming clinical intervention trials in FSHD.

ObjectiveThis is the first double-blind randomized controlled trial evaluating the efficacy and safety of IV immunoglobulin (IVIG) vs placebo in patients with idiopathic small fiber neuropathy (I-SFN).MethodsBetween July 2016 and November 2018, 60 Dutch patients with skin biopsy–proven I-SFN randomly received a starting dose of IVIG (2 g/kg body weight) or matching placebo (0.9% saline). Subsequently, 3 additional infusions of IVIG (1 g/kg) or placebo were administered at 3-week intervals. The primary outcome was a 1-point change in Pain Intensity Numerical Rating Scale score at 12 weeks compared to baseline.ResultsThirty patients received IVIG, and 30 received placebo. In both groups, 29 patients completed the trial. In 40% of patients receiving IVIG, the mean average pain was decreased by at least 1 point compared to 30% of the patients receiving placebo (p = 0.588, odds ratio 1.56, 95% confidence interval 0.53–4.53). No significant differences were found on any of the other prespecified outcomes, including general well-being, autonomic symptoms, and overall functioning and disability.ConclusionsThis randomized controlled trial showed that IVIG treatment had no significant effect on pain in patients with painful I-SFN.Trial Registration InformationClinicalTrials.gov Identifier: NCT02637700, EudraCT 2015-002624-31.Classification of EvidenceThis study provides Class I evidence that for patients with painful I-SFN, IVIG did not significantly reduce pain compared to placebo.

Voltage-gated sodium channels (NavChs) are pore-forming membrane proteins that regulate the transport of sodium ions through the cell membrane. Understanding the structure and function of NavChs is of major biophysical, as well as clinical, importance given their key role in cellular pathophysiology. In this work, we provide a computational framework for modeling system-size-dependent, i.e., cumulative, atomic properties around a NavCh’s pore. We illustrate our methodologies on the bacterial NavAb channel captured in a closed-pore state where we demonstrate that the atomic environment around its pore exhibits a bi-phasic spatial organization dictated by the structural separation of the pore domains (PDs) from the voltage-sensing domains (VSDs). Accordingly, a mathematical model describing packing of atoms around NavAb’s pore is constructed that allows—under certain conservation conditions—for a power-law approximation of the cumulative hydropathic dipole field effect acting along NavAb’s pore. This verified the non-extensitivity hypothesis for the closed-pore NavAb channel and revealed a long-range hydropathic interactions law regulating atom-packing around the NavAb’s selectivity filter. Our model predicts a PDs-VSDs coupling energy of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sim \!282.1$\end{document}∼282.1 kcal/mol corresponding to a global maximum of the atom-packing energy profile. Crucially, we demonstrate for the first time how critical phenomena can emerge in a single-channel structure as a consequence of the non-extensive character of its atomic porous environment. Supplementary Information The online version contains supplementary material available at 10.1007/s10867-021-09565-w.

Contains fulltext : 241356.pdf (Publisher’s version ) (Open Access) Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype-genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0-80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.