CRISPR activation to characterize splice-altering variants in easily accessible cells.

Genetic variants that affect mRNA splicing are a major cause of hereditary disorders, but the spliceogenicity of variants is challenging to predict. RNA diagnostics of clinically accessible tissues enable rapid functional characterization of splice-altering variants within their natural genetic context. However, this analysis cannot be offered to all individuals as one in five human disease genes are not expressed in easily accessible cell types. To overcome this problem, we have used CRISPR activation (CRISPRa) based on a dCas9-VPR mRNA-based delivery platform to induce expression of the gene of interest in skin fibroblasts from individuals with suspected monogenic disorders. Using this ex vivo splicing assay, we characterized the splicing patterns associated with germline variants in the myelin protein zero gene (MPZ), which is exclusively expressed in Schwann cells of the peripheral nerves, and the spastin gene (SPAST), which is predominantly expressed in the central nervous system. After overnight incubation, CRISPRa strongly upregulated MPZ and SPAST transcription in skin fibroblasts, which enabled splice variant profiling using reverse transcription polymerase chain reaction, next-generation sequencing, and long-read sequencing. Our investigations show proof of principle of a promising genetic diagnostic tool that involves CRISPRa to activate gene expression in easily accessible cells to study the functional impact of genetic variants. The procedure is easy to perform in a diagnostic laboratory with equipment and reagents all readily available.

Generalized myasthenia gravis with acetylcholine receptor antibodies: A guidance for treatment.

BACKGROUND: Generalized myasthenia gravis (MG) with antibodies against the acetylcholine receptor is a chronic disease causing muscle weakness. Access to novel treatments warrants authoritative treatment recommendations. The Nordic countries have similar, comprehensive health systems, mandatory health registers, and extensive MG research. METHODS: MG experts and patient representatives from the five Nordic countries formed a working group to prepare treatment guidance for MG based on a systematic literature search and consensus meetings. RESULTS: Pyridostigmine represents the first-line symptomatic treatment, while ambenonium and beta adrenergic agonists are second-line options. Early thymectomy should be undertaken if a thymoma, and in non-thymoma patients up to the age of 50-65 years if not obtaining remission on symptomatic treatment. Most patients need immunosuppressive drug treatment. Combining corticosteroids at the lowest possible dose with azathioprine is recommended, rituximab being an alternative first-line option. Mycophenolate, methotrexate, and tacrolimus represent second-line immunosuppression. Plasma exchange and intravenous immunoglobulin are used for myasthenic crises and acute exacerbations. Novel complement inhibitors and FcRn blockers are effective and fast-acting treatments with promising safety profiles. Their use depends on local availability, refunding policies, and cost-benefit analyses. Adapted physical training is recommended. Planning of pregnancies with optimal treatment, information, and awareness of neonatal MG is necessary. Social support and adaptation of work and daily life activities are recommended. CONCLUSIONS: Successful treatment of MG rests on timely combination of different interventions. Due to spontaneous disease fluctuations, comorbidities, and changes in life conditions, regular long-term specialized follow-up is needed. Most patients do reasonably well but there is room for further improvement. Novel treatments are promising, though subject to restricted access due to costs.

Increased risk of depression after Guillain-Barré syndrome.

INTRODUCTION/AIMS: Guillain-Barré syndrome (GBS) is a potentially life-threatening disorder, and some patients may develop subsequent depression related to traumatic stress or permanent loss of motor function. We determined the short-term (0 to 2 years) and long-term (>2 years) risk of depression after GBS. METHODS: Individual-level data from nationwide registries were linked in this population-based cohort study of all first-time hospital-diagnosed GBS patients in Denmark between 2005 and 2016 and individuals from the general population. After exclusion of individuals with previous depression, we computed cumulative rates of depression, defined as either antidepressant drug prescription or depression hospital diagnosis. We used Cox regression analyses to calculate adjusted depression hazard ratios (HRs) after GBS. RESULTS: We identified 853 incident GBS patients and recruited 8639 individuals from the general population. Depression within 2 years was observed in 21.3% (95% confidence interval [CI], 18.2% to 25.0%) of GBS patients and in 3.3% (95% CI, 2.9% to 3.7%) of those in the general population, resulting in a HR of 7.6 (95% CI, 6.2 to 9.3). The highest depression HR was observed within the first 3 months after GBS (HR, 20.5; 95% CI, 13.6 to 30.9). After the first 2 years, GBS patients and the general population members had similar long-term depression risks with an HR of 0.8 (95% CI, 0.6 to 1.2). DISCUSSION: During the first 2 years after GBS hospital admission, patients with GBS had a 7.6-fold increased hazard of depression compared with individuals in the general population. Two years after GBS, the risk of depression was similar to that of the background population.

Hospital-diagnosed morbidities and recent surgery as risk factors for developing Guillain-Barré syndrome.

BACKGROUND AND PURPOSE: This study was undertaken to determine the association of hospital-diagnosed morbidity and recent surgery with risk of subsequent Guillain-Barré syndrome (GBS) development. METHODS: We conducted a nationwide population-based case-control study of all patients with first-time hospital-diagnosed GBS in Denmark between 2004 and 2016 and 10 age-, sex-, and index date-matched population controls per case. Hospital-diagnosed morbidities included in the Charlson Comorbidity Index were assessed as GBS risk factors up to 10 years prior to the GBS index date. Incident major surgery was assessed within 5 months prior. RESULTS: In the 13-year study period, there were 1086 incident GBS cases, whom we compared with 10,747 matched controls. Any pre-existing hospital-diagnosed morbidity was observed in 27.5% of GBS cases and 20.0% of matched controls, yielding an overall matched odds ratio (OR) of 1.6 (95% confidence interval [CI] = 1.4-1.9). The strongest associations were found for leukemia, lymphoma, diabetes, liver disease, myocardial infarction, congestive heart failure, and cerebrovascular disease, with 1.6- to 4.6-fold increased risks of subsequent GBS. GBS risk was strongest for morbidities newly diagnosed during the past 5 months (OR = 4.1, 95% CI = 3.0-5.6). Surgical procedures within 5 months prior were observed in 10.6% of cases and 5.1% of controls, resulting in a GBS OR of 2.2 (95% CI = 1.8-2.7). Risk of developing GBS was highest during the first month following surgery (OR = 3.7, 95% CI = 2.6-5.2). CONCLUSIONS: In this large nationwide study, individuals with hospital-diagnosed morbidity and recent surgery had a considerably increased risk of GBS.

Changes in axonal and clinical function during intravenous and subcutaneous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND AIMS: Intravenous immunoglobulin (IVIg) has a rapid clinical effect which cannot be explained by remyelination during each treatment cycle in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). This study aimed to investigate axonal membrane properties during the IVIg treatment cycle and their potential correlation with clinically relevant functional measurements. METHODS: Motor nerve excitability testing (NET) of the median nerve was performed before and 4 and 18 days after initiation of an IVIg treatment cycle in 13 treatment-naïve (early) CIDP patients and 24 CIDP patients with long term (late) IVIg treatment, 12 CIDP patients treated with subcutaneous immunoglobulin (SCIg) and 55 healthy controls. Clinical function was measured extensively using the Six Spot Step test, 10-Meter Walk test, 9-Hole Peg test, grip strength, MRC sum score, Overall Neuropathy Limitations Score and Patient Global Impression of Change. RESULTS: Superexcitability and S2 accommodation decreased significantly in the early treatment group from baseline to day 4 and returned to baseline levels at day 18, suggesting temporary depolarization of the axonal membrane. A similar trend was observed for the late IVIg group. Substantial clinical improvement was observed in both early and late IVIg groups during the entire treatment cycle. No statistically significant correlation was found between clinical and NET changes. No change was found in NET or clinical function in the SCIg group or controls. INTERPRETATION: NET suggested temporary depolarization of the axonal membrane during IVIg treatment in treatment naïve CIDP patients. The relation to clinical improvement, however, remains speculative.

Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial.

BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.

Reduced 3-year risk of hospital admission and mortality after 12-week resistance training of cirrhosis patients: A follow-up of a randomized clinical trial.

BACKGROUND AND AIM: Physical activity confers health benefits in many diseases but remains almost unstudied for cirrhosis. We investigated whether a period of resistance training affects the subsequent long-term risk of hospitalization or mortality among patients with cirrhosis. METHODS: The study includes 39 participants with cirrhosis Child-Pugh class A/B who participated in a prior clinical trial randomized to either resistance training three times per week for 12 weeks or a control group. We gathered data through medical records from trial entry and the following 3 years. The outcomes were time to first hospitalization and all-cause mortality. We used regression models to examine the associations between trial groups and outcomes, adjusting for Child-Pugh class, age, gender, and comorbidity. RESULTS: Nine patients who trained and 15 controls were hospitalized, resulting in a lower risk of first hospitalization in the training group (adjusted subdistribution hazard ratio of 0.40, 95% confidence interval [CI] [0.17, 0.92]; P = 0.03). One patient who trained and six controls died, resulting in a lower all-cause mortality in the training group (adjusted hazard ratio of 0.06, 95% CI [0.01, 0.66]; P = 0.02). CONCLUSION: Twelve weeks of resistance training was associated with a reduced risk of first hospitalization and mortality among patients with cirrhosis Child-Pugh class A/B 3 years after trial entry. The mechanisms of this effect are not identified, and larger studies are warranted.

Effects of progressive resistance training in individuals with type 2 diabetic polyneuropathy: a randomised assessor-blinded controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the effects of progressive resistance training (PRT) on muscle strength, intraepidermal nerve fibre density (IENFD) and motor function in individuals with type 2 diabetic polyneuropathy (DPN) and to compare potential adaptations to those of individuals with type 2 diabetes without DPN and healthy controls. METHODS: This was an assessor-blinded trial conducted at the Neurology department, Aarhus University Hospital. Adults with type 2 diabetes, with and without DPN and healthy control participants were randomised to either supervised PRT or non-PRT for 12 weeks. Allocation was concealed by a central office unrelated to the study. The co-primary outcomes were muscle strength in terms of the peak torque of the knee and ankle extensors and flexors, and IENFD. Secondary outcome measures included the 6 min walk test (6MWT), five-time sit-to-stand test (FTSST) and postural stability index obtained by static posturography. RESULTS: A total of 109 individuals were enrolled in three groups (type 2 diabetes with DPN [n = 42], type 2 diabetes without DPN [n = 32] and healthy control [n = 35]). PRT resulted in muscle strength gains of the knee extensors and flexors in all three groups using comparative analysis (DPN group, PRT 10.3 ± 9.6 Nm vs non-PRT -0.4 ± 8.2 Nm; non-DPN group, PRT 7.5 ± 5.8 Nm vs non-PRT 0.6 ± 8.8 Nm; healthy control group, PRT 6.3 ± 9.0 Nm vs non-PRT -0.4 ± 8.4 Nm; p<0.05, respectively). Following PRT the DPN group improved the 6MWT (PRT 34.6 ± 40.9 m vs non-PRT 2.7 ± 19.6 m; p=0.001) and the FTSST (PRT -1.5 ± 2.2 s vs non-PRT 1.5 ± 4.6 s; p=0.02). There was no change in IENFD following PRT in any of the groups. CONCLUSIONS/INTERPRETATION: PRT improved muscle strength of the knee extensors and flexors and motor function in individuals with type 2 diabetic polyneuropathy at levels comparable with those seen in individuals with diabetes without DPN and healthy control individuals, while no effects were observed in IENFD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03252132 FUNDING: Research reported in this paper is part of the International Diabetic Neuropathy Consortium (IDNC) research programme, supported by a Novo Nordisk Foundation Challenge Program grant (grant no. NNF14OC0011633) and Aarhus University.

Increased mortality following Guillain-Barré syndrome: A population-based cohort study.

BACKGROUND AND PURPOSE: Guillain-Barré syndrome (GBS) may be fatal in the acute phase but also affect long-term prognosis due to irreversible sequelae and secondary medical complications. We determined the short-term, intermediate, and long-term mortality of GBS compared to the general population. METHODS: Individual-level data from nationwide registries were linked in this matched cohort study of all first-time hospital-diagnosed GBS patients in Denmark between 1987 and 2016 and 10 individuals from the general population, matched on age, sex, and index date. We used Cox regression analysis to calculate matched mortality hazard ratios (HRs) following GBS, assessing short-term (0-6 months), intermediate (>6 months-4 years), and long-term (>4 years) mortality. RESULTS: We identified 2414 patients with GBS and 23,909 matched individuals from the general population. Short-term mortality was 4.8% (95% confidence interval [CI] = 4.0-5.8) and 0.8% (95% CI = 0.7-0.9) for GBS patients and general population members, respectively, resulting in an HR of 6.6 (95% CI = 4.0-5.8). Intermediate mortality was 7.6% (95% CI = 6.5-8.9), compared with 5.8% (95% CI = 5.5-6.1) for general population members, corresponding to an HR of 1.5 (95% CI = 1.3-1.8). After the first 4 years, long-term mortality showed similar results for GBS patients and general population members (HR = 1.1, 95% CI = 0.9-1.2). CONCLUSIONS: During the first 6 months after GBS hospital admission, GBS was associated with a 6.6-fold increased mortality as compared with the background population of the same age. Mortality remained increased for approximately 4 years following GBS, and then leveled off to a similar long-term mortality rate.

Guillain-Barré syndrome following influenza vaccination: A 15-year nationwide population-based case-control study.

BACKGROUND AND PURPOSE: Influenza vaccination may increase the risk of developing Guillain-Barré syndrome (GBS) due to an elicited immune response, but the exact magnitude and duration of risk is unclear and hence the aim of this study. METHODS: We conducted a retrospective nationwide population-based case-control study of prospectively collected data on all patients with first-time hospital-diagnosed GBS in Denmark between 2002 and 2016 and 10 age-, sex- and index date-matched population controls per case. The primary exposure was incident influenza vaccination 1 month prior to admission with GBS. We used medical registries to ascertain a complete hospital contact history of pre-existing morbidities. To examine duration of GBS risk, we repeated the analysis for five consecutive 1-month risk periods following vaccination. RESULTS: Of the 1295 GBS cases and 12,814 controls, 20 cases (1.5%) and 119 controls (0.9%) had received an influenza vaccination within the last month, yielding a comorbidity-adjusted odds ratio of 1.9 (95% confidence interval 1.1-3.2) for GBS. Stratified analyses by calendar time, gender and age showed similar results. The increased risk of GBS was largely confined to 1 month following influenza vaccination. The population-attributable fraction of GBS from influenza vaccination in Denmark was 0.4%. CONCLUSIONS: Influenza vaccination was associated with a slightly elevated risk of GBS occurrence within 1 month after vaccination. However, only 1.5% of GBS cases in Denmark are associated with recent influenza vaccination. Thus, the benefit of influenza vaccines in preventing influenza infections and associated morbidity and mortality needs to be weighed against the small absolute risk of GBS.

Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology.

BACKGROUND AND PURPOSE: Among post-COVID-19 symptoms, fatigue is reported as one of the most common, even after mild acute infection, and as the cause of fatigue, myopathy diagnosed by electromyography has been proposed in previous reports. This study aimed to explore the histopathological changes in patients with post-COVID-19 fatigue. METHODS: Sixteen patients (mean age = 46 years) with post-COVID-19 complaints of fatigue, myalgia, or weakness persisting for up to 14 months were included. In all patients, quantitative electromyography and muscle biopsies analyzed with light and electron microscopy were taken. RESULTS: Muscle weakness was present in 50% and myopathic electromyography in 75%, and in all patients there were histological changes. Muscle fiber atrophy was found in 38%, and 56% showed indications of fiber regeneration. Mitochondrial changes, comprising loss of cytochrome c oxidase activity, subsarcollemmal accumulation, and/or abnormal cristae, were present in 62%. Inflammation was found in 62%, seen as T lymphocytes and/or muscle fiber human leukocyte antigen ABC expression. In 75%, capillaries were affected, involving basal lamina and cells. In two patients, uncommon amounts of basal lamina were found, not only surrounding muscle fibers but also around nerves and capillaries. CONCLUSIONS: The wide variety of histological changes in this study suggests that skeletal muscles may be a major target of SARS-CoV-2, causing muscular post-COVID-19 symptoms. The mitochondrial changes, inflammation, and capillary injury in muscle biopsies can cause fatigue in part due to reduced energy supply. Because most patients had mild-moderate acute affection, the new variants that might cause less severe acute disease could still have the ability to cause long-term myopathy.

Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management.

Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30-40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycaemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc., which lead to the best therapeutic outcomes.

Falls in individuals with type 2 diabetes; a cross-sectional study on the impact of motor dysfunction, postural instability and diabetic polyneuropathy.

AIM: To estimate the incidence of falls in individuals with type 2 diabetes compared to healthy controls and to describe the characteristics of fallers with type 2 diabetes in relation to motor dysfunction, postural instability and diabetic polyneuropathy (DPN). METHODS: This is a cross-sectional study of individuals with type 2 diabetes with DPN (n = 54), without DPN (n = 38) and healthy controls (n = 39). Falls were recorded within the preceding year. DPN was defined by clinical scores and nerve conduction studies. Motor function was assessed by a 6-min walk test (6 MWT), five-time sit-to-stand test (FTSST) and isokinetic dynamometry at the non-dominant ankle and knee. An instability index (ST) was measured using static posturography. Univariate and bivariate descriptive statistics were used for group comparisons. RESULTS: Compared with healthy controls, individuals with diabetes had a higher incidence of falls 36%, (n = 33) versus 15%, (n = 6), p = 0.02. There were no differences in falls when comparing individuals with and without DPN. Fallers had an impaired 6 MWT versus non-fallers (450 ± 153 m vs. 523 ± 97 m respectively), a slower FTSST (11.9 ± 4.2 s vs. 10.3 ± 2.9 s respectively) and a higher ST (53 ± 29 vs. 41 ± 17 respectively), p < 0.02 for all. CONCLUSION: Individuals with type 2 diabetes reported a higher number of falls within the preceding year compared to healthy controls, irrespective of the presence of DPN. The main factors associated with falls were increased postural instability, lower walking capacity and slower sit-to-stand movements. The 6 MWT, FTSST and posturography should be considered in future screening programs in identification of individuals at risk for falls.

Gender differences in clinical outcomes in myasthenia gravis: A prospective cohort study.

INTRODUCTION/AIMS: It is uncertain whether clinical outcomes differ between male and female patients with myasthenia gravis (MG) while receiving standard clinical care. METHODS: In a prospective cohort study of 107 patients with MG receiving standard of care from 2012 to 2019, the Quantitative MG (QMG), the MG Composite (MGC), the MG Activities of Daily Living (MG-ADL), and the MG Quality of Life 15-Items (QOL15) were determined. Clinical outcomes were analyzed in relation to gender. RESULTS: Mean follow-up time was 4.8 (±0.4) y, and 70 patients completed all follow-up assessments. Patients improved on all clinical scores: QMG -1.8 (P < .001), MGC -1.5 (P < .001), MG-ADL -1.3 (P < .001), and QOL15 -3.0 (P < .001). Females improved less than males on the QMG (P = .01), MGC (P < .001), MG-ADL (P = .006), and QOL15 (P < .001) independent of potential confounders. Males had moderate to strong correlations between changes in all clinical scales (r range 0.52 to 0.73), whereas females had weak correlations between changes in the QMG and MG-ADL (r = 0.13), the QMG and QOL15 (r = 0.27), the MGC and MG-ADL (r = 0.21), the MGC and QOL15 (r = 0.00), and the MG-ADL and QOL15 (r = 0.31). DISCUSSION: Females improved less compared to males on objective and patient-reported outcomes. Moreover, females improved more on objective measures than on patient-reported outcomes. These gender differences should receive attention in clinical care and in the design of future trials.

Small and large fiber sensory polyneuropathy in type 2 diabetes: Influence of diagnostic criteria on neuropathy subtypes.

Diabetic polyneuropathy (DPN) can be classified based on fiber diameter into three subtypes: small fiber neuropathy (SFN), large fiber neuropathy (LFN), and mixed fiber neuropathy (MFN). We examined the effect of different diagnostic models on the frequency of polyneuropathy subtypes in type 2 diabetes patients with DPN. This study was based on patients from the Danish Center for Strategic Research in Type 2 Diabetes cohort. We defined DPN as probable or definite DPN according to the Toronto Consensus Criteria. DPN was then subtyped according to four distinct diagnostic models. A total of 277 diabetes patients (214 with DPN and 63 with no DPN) were included in the study. We found a considerable variation in polyneuropathy subtypes by applying different diagnostic models independent of the degree of certainty of DPN diagnosis. For probable and definite DPN, the frequency of subtypes across diagnostic models varied from: 1.4% to 13.1% for SFN, 9.3% to 21.5% for LFN, 51.4% to 83.2% for MFN, and 0.5% to 14.5% for non-classifiable neuropathy (NCN). For the definite DPN group, the frequency of subtypes varied from: 1.6% to 13.5% for SFN, 5.6% to 20.6% for LFN, 61.9% to 89.7% for MFN, and 0.0% to 6.3% for NCN. The frequency of polyneuropathy subtypes depends on the type and number of criteria applied in a diagnostic model. Future consensus criteria should clearly define sensory functions to be tested, methods of testing, and how findings should be interpreted for both clinical practice and research purpose.

Overactive bladder in patients with myasthenia gravis-A cross-sectional population-based study.

BACKGROUND: In myasthenia gravis (MG), first-line treatment for MG is acetylcholinesterase inhibitors which alleviates symptoms, but concomitantly may cause autonomic adverse effects. AIMS OF THE STUDY: In this study, we evaluated if symptoms of overactive bladder (OAB) are more frequent among MG patients than healthy controls. METHODS: Eighty-three MG patients and 50 healthy sex- and age-matched controls were included and answered the questionnaire "International Consultation on Incontinence Questionnaire Overactive Bladder Module" (ICIQ-OAB), including questions about polyuria, nocturia, urgency, and stress incontinence. Clinical severity of MG was determined based on three standardized clinical evaluations. RESULTS: Compared to control subjects, MG patients had a higher total OAB score (median 5 [range 0-12] versus 3 [0; 7]) (p < 0.005) with higher scores concerning all four items. Also, MG patients had a higher bother score (10 [0-40] versus 5 [0-40]) (p < 0.05). Patients receiving a daily dose of pyridostigmine of more than 300 mg had a higher OAB score than other patients. CONCLUSIONS: Myasthenia gravis patients have more bothering symptoms of OAB than healthy controls, related to the daily dose of pyridostigmine. To minimize adverse effects in patients with symptoms of OAB, the pyridostigmine dose should be as low as possible.

Supervised Training Compared With No Training or Self-training in Patients With Subacromial Pain Syndrome: A Systematic Review and Meta-analysis.

OBJECTIVE: To study the effects of supervised training in adults with subacromial pain syndrome. DATA SOURCES: Embase, MEDLINE, Cochrane Library, Cumulative Index to Nursing and Allied Health, and Physiotherapy Evidence Database were searched from inception to March 2020. STUDY SELECTION: Independent reviewers selected randomized controlled trials comparing supervised training with (1) no training or (2) self-training in adults with subacromial pain syndrome lasting for at least 1 month. Critical outcomes were shoulder pain, function, and patient-perceived effect. Important outcomes included other potential benefits and adverse events at 3-month follow-up. DATA EXTRACTION: Two independent reviewers extracted data for the meta-analysis. Risk of bias was assessed using the Cochrane Risk of Bias tool 1, and certainty of evidence was evaluated using the Grades of Recommendation Assessment, Development, and Evaluation (GRADE). DATA SYNTHESIS: Ten studies (n=597, 43% female) were included. Supervised training resulted in larger improvements than no training on pain (at rest: n=286; mean difference [MD], 1.68; 95% confidence interval [CI], 0.31-3.06 on 0-10 scale; during movement: n=353; MD, 1.84; 95% CI,0.91-2.76), function (n=396; standardized MD, 0.30; 95% CI, 0.07-0.52), and patient-perceived effect (n=118; risk ratio, 1.43; 95% CI, 0.87-2.34). Supervised training had potential benefits regarding quality of life, return to work, dropout, and training adherence, albeit more patients reported mild, transient pain after training. Supervised training and self-training showed equal improvements on pain (n=44) and function (n=76), with no data describing patient-perceived effect. Certainty of evidence was low for critical outcomes and low-moderate for other outcomes. CONCLUSIONS: Supervised training might be superior to no training and equally effective as self-training on critical and important outcomes. Based on low-moderate certainty of evidence, these findings support a weak recommendation for supervised training in adults with subacromial pain syndrome.

16-year follow-up of the Danish Acute Myocardial Infarction 2 (DANAMI-2) trial: primary percutaneous coronary intervention vs. fibrinolysis in ST-segment elevation myocardial infarction.

AIMS: The DANish Acute Myocardial Infarction 2 (DANAMI-2) trial found that interhospital transport to primary percutaneous coronary intervention (pPCI) was superior to fibrinolysis at the local hospital in patients with ST-segment elevation myocardial infarction (STEMI) at 30 days. The present study investigates the 16-year cardiovascular outcomes. METHODS AND RESULTS: We randomized 1572 STEMI patients to pPCI or fibrinolysis at 24 referral hospitals and 5 invasive centres in Denmark. Patients randomized to pPCI at referral hospitals were immediately transported to the nearest invasive centre. The main endpoint of the current study was a composite of death or rehospitalization for myocardial infarction (MI). Outcome information beyond 3 years was obtained through Danish health registries. After 16 years, pPCI-treated patients had a sustained lower rate of composite endpoint compared to patients treated with fibrinolysis in the overall cohort [58.7% vs. 62.3%; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76-0.98], and among patients transported for pPCI (58.7% vs. 64.1%; HR 0.82, 95% CI 0.71-0.96). No difference in all-cause mortality was found, but cardiac mortality was reduced by an absolute of 4.4% in favour of pPCI (18.3% vs. 22.7%; HR 0.78, 95% CI 0.63-0.98). pPCI postponed a main event with 12.3 months in average compared to fibrinolysis (95% CI 5.0-19.5). CONCLUSION: The benefit of pPCI over fibrinolysis was maintained at 16-year follow-up. pPCI reduced the composite endpoint of death or rehospitalization for MI, reduced cardiac mortality, and delayed average time to a main event by approximately 1 year.

Concurrent Validity Between Electronically Administered Physical Activity Questionnaires and Objectively Measured Physical Activity in Danish Community-Dwelling Older Adults.

AIM: To investigate the concurrent validity of the International Physical Activity Questionnaire-short form (IPAQ-SF) and the Nordic Physical Activity Questionnaire-short (NPAQ-short) when compared with objectively measured daily steps among older adults. METHODS: Spearman's ρ between IPAQ-SF and NPAQ-short and objectively measured steps using Garmin Vivofit 3 physical activity monitors. RESULTS: A total of 54 participants were included. The IPAQ-SF subscales' moderate physical activity (PA), moderate to vigorous PA (MVPA), and sedentary time showed little or no correlation with daily steps. The NPAQ-short subscales' vigorous PA, moderate PA, and MVPA showed little or no correlation. The IPAQ-SF subscales' vigorous PA and walking showed fair correlation. Only the IPAQ-SF metabolic equivalent of task minutes showed moderate to good correlation with daily steps. The IPAQ-SF categories and NPAQ-short categorization of World Health Organization compliance were significantly different, but the magnitudes were small and distributions indicated problems with the categorization. CONCLUSION: The concurrent validity is low, as the scores did not reflect objectively measured daily steps.

Resistance Training Increases Muscle Strength and Muscle Size in Patients With Liver Cirrhosis.

BACKGROUND & AIMS: Cirrhosis is often complicated by reduced muscle mass and strength, which limits the ability to perform daily activities and affects quality of life. Resistance training can increase muscle strength and mass in elderly and chronically ill patients. We performed a randomized controlled trial to investigate whether resistance training increases muscle strength and size in patients with compensated cirrhosis. METHODS: We performed a prospective study of 39 patients with cirrhosis (Child-Pugh class A or B) seen at an outpatient clinic in Denmark from January 2015 through March 2017. Participants protein intake and activity levels were registered daily. Participants were randomly assigned (1:1) to a group that performed 36 1-hour sessions of physical exercise (supervised progressive resistance training for 1 hour, 3 times weekly for 12 weeks) or a control group (no change in daily activity level). Maximal muscle strength was measured as the peak torque in isokinetic knee extension and muscle size was measured as the cross-sectional area of the quadriceps muscle, assessed by magnetic resonance imaging of the thigh. RESULTS: The exercise group increased their muscle strength by 13% (from a mean 119 Nm to 134 Nm)-an 11 Nm greater gain in mean strength than that of the control group (P = .05). The exercise group increased their quadriceps cross-sectional area by 10% (from a mean 58.5 cm2 to 64.6 cm2)-a 4.4 cm2 greater gain than that of the control group (P < .01). The exercise group had significant increases in whole-body lean mass and body cell mass, and significant increases in 6-minute walking distance and the mental component summary of the short form-36 questionnaire. Adverse events were minor and equal between groups. CONCLUSIONS: In a randomized trial of patients with compensated cirrhosis, we found that 12 weeks of supervised progressive resistance training increased muscle strength and size and had beneficial effects on general performance measures, compared with patients who did not change their daily activity routine (control subjects). ClinicalTrials.gov no: NCT02343653.