bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long‐term favorable prognosis in late onset dominant distal titinopathy: Tibial muscular dystrophy
Authors: Lillback Victoria , Savarese Marco , Sandholm Niina , Hackman Peter , Udd Bjarne 
Published: January 2023

AbstractBackground and purposeTibial muscular dystrophy (TMD) is a dominant late onset distal titinopathy. It was first described in Finnish patients 3 decades ago. TMD patients with several other TTN mutations occur in many European populations. In this retrospective study, we were able to obtain longitudinal follow‐up data of the disease progression over 15 years in 137 TMD patients.MethodsWe retrieved clinical data retrospectively from three examinations spanning a period of 15 years. The data were analyzed in R. Frequencies, percentages, and median values were used to describe data. Probability values were determined with the chi‐squared test.ResultsIn the cohort, the first symptoms were walking difficulties (97.8%) and weakness in distal lower limbs (98.5%). The progression of the weakness in distal lower limbs was moderate, and in the proximal lower limbs and proximal upper limbs it was mild. The distal upper limbs were not affected. Magnetic resonance imaging results indicated fatty degeneration preferentially in lower leg anterior muscles, gluteus minimus, and hamstring muscles. Serum creatine kinase values in the cohort were mostly normal (40.7%) or mildly elevated (53.7%). The data suggest that 50% of patients need walking aids by the age of 88 years.ConclusionsDespite individual variability of severity, the overall disability due to walking difficulties and upper limb weakness remained moderate even at very advanced ages, and cardiomyopathy did not develop due to the titin defect alone. The acquired results promote the correct identification of TMD, and the obtained trajectories of disease evolution can be used as natural history data for any therapeutic intervention.
Interplay between the catecholaminergic enzymatic axis and neurodegeneration/neuroinflammation processes in the Alzheimer's disease continuum
Authors: Motta Caterina , Assogna Martina , Bonomi Chiara Giuseppina , Di Lorenzo Francesco , Nuccetelli Marzia , Mercuri Nicola Biagio , Koch Giacomo , Martorana Alessandro 
Published: January 2023

AbstractBackground and PurposeThe locus coeruleus (LC) provides dopamine/noradrenaline (DA/NA) innervation throughout the brain and undergoes early degeneration in Alzheimer's disease (AD). We evaluated catecholaminergic enzyme levels in the cerebrospinal fluid (CSF) of a group of patients biologically defined as within the AD continuum (ADc) and explored their relationship with AD biomarkers and cytokine/growth factor levels to investigate their interplay with neurodegenerative and neuroinflammatory processes.MethodsThe CSF concentration of DA transporter (DAT), tyrosine‐hydroxylase (TH), DOPA‐decarboxylase (DDC), and dopamine‐β‐hydroxylase (DβH), as well as cytokine/growth factor levels, were analyzed in 41 ADc patients stratified according to CSF beta‐amyloid (Aβ)1‐42 (A) and p‐tau (T) in AD pathological changes (A+ T‐) and AD (A+ T+) subgroups, as well as in 15 control subjects (A‐ T‐).ResultsThe ADc group had lower CSF levels of DAT and TH but increased DβH levels to compensate for NA synthesis. DDC levels were higher in the A+ T+ subgroup but comparable with controls in the A+ T– subgroup, probably because the DA system is resilient to the degeneration of LC neurons in the absence of tau pathology. Adjusting for age, sex, APOE genotype, and cognitive status, a significant association was found between TH and Aβ1‐42 (R2 = 0.25) and between DDC and p‐tau (R2 = 0.33). Finally, TH correlated with interleukin (IL)‐10 levels (p = 0.0008) and DβH with IL‐1β (p = 0.03), IL‐4 (p = 0.02), granulocyte colony‐stimulating factor (p = 0.007), and IL‐17 (p = 0.01).ConclusionsTaken together, these findings suggest that catecholaminergic enzymes, functional markers of the catecholaminergic system, are closely linked to the neurodegenerative and neuroinflammatory processes in AD pathology.
Chronic inflammatory demyelinating polyradiculoneuropathy‐associated tremor: Phenotype and pathogenesis
Authors: Silsby Matthew , Fois Alessandro F. , Yiannikas Con , Ng Karl , Kiernan Matthew C. , Fung Victor S. C. , Vucic Steve 
Published: January 2023

AbstractBackground and purposeTremor in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is underrecognized, and the pathophysiology remains incompletely understood. This study evaluated tremor in CIDP and tested the hypothesis, established in other demyelinating neuropathies, that tremor occurs due to mistimed peripheral inputs affecting central motor processing. Additionally, the tremor stability index (TSI) was calculated with the hypothesis that CIDP‐related tremor is more variable than other tremor disorders.MethodsConsecutive patients with typical CIDP were prospectively recruited from neuromuscular clinics. Alternative causes of neuropathy and tremor were excluded. Cross‐sectional clinical assessment and extensive tremor study recordings were undertaken. Pearson correlation coefficient was used to compare nerve conduction studies and tremor characteristics, and t‐test was used for comparisons between groups.ResultsTwenty‐four patients with CIDP were included. Upper limb postural and action tremor was present in 66% and was mild according to the Essential Tremor Rating Assessment Scale. Tremor did not significantly impact disability. Surface electromyography (EMG) found high‐frequency spectral peaks in deltoid (13.73 ± 0.66 Hz), biceps brachii (11.82 ± 0.91 Hz), and extensor carpi radialis (11.87 ± 0.91 Hz) muscles, with lower peaks in abductor pollicis brevis EMG (6.07 ± 0.45 Hz) and index finger accelerometry (6.53 ± 0.42 Hz). Tremor was unchanged by weight loading but correlated with ulnar nerve F‐wave latency and median nerve sensory amplitude. TSI (2.3 ± 0.1) was significantly higher than essential tremor.ConclusionsPostural tremor is a common feature in CIDP. Tremor was unaffected by weight loading, typical of centrally generated tremors, although there was a correlation with peripheral nerve abnormalities. The high beat‐to‐beat variability on TSI and gradation of peak frequencies further suggest a complex pathophysiology. These findings may assist clinicians with the diagnosis of neuropathic tremor.
Endovascular thrombectomy for basilar artery occlusion stroke: Analysis of the German Stroke Registry‐Endovascular Treatment
Authors: Feil Katharina , Berndt Maria Teresa , Wunderlich Silke , Maegerlein Christian , Bernkopf Kathleen , Zimmermann Hanna , Herzberg Moriz , Tiedt Steffen , Küpper Clemens , Wischmann Johannes , Schönecker Sonja , Dimitriadis Konstantin , Liebig Thomas , Dieterich Marianne , Zimmer Claus , Kellert Lars , Boeckh‐Behrens Tobias ,   for the GSR Investigators
Published: January 2023

AbstractBackground and purposeAcute ischemic stroke due to basilar artery occlusion (BAO) causes the most severe strokes and has a poor prognosis. Data regarding efficacy of endovascular thrombectomy in BAO are sparse. Therefore, in this study, we performed an analysis of the therapy of patients with BAO in routine clinical practice.MethodsPatients enrolled between June 2015 and December 2019 in the German Stroke Registry‐Endovascular Treatment (GSR‐ET) were analyzed. Primary outcomes were successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] score of 2b‐3), substantial neurological improvement (≥8‐point National Institute of Health Stroke Scale [NIHSS] score reduction from admission to discharge or NIHSS score at discharge ≤1), and good functional outcome at 3 months (modified Rankin Scale [mRS] score of 0–2).ResultsOut of 6635 GSR‐ET patients, 640 (9.6%) patients (age 72.2 ± 13.3, 43.3% female) experienced BAO (median [interquartile range] NIHSS score 17 [8, 27]). Successful reperfusion was achieved in 88.4%. Substantial neurological improvement at discharge was reached by 45.5%. At 3‐month follow‐up, good clinical outcome was observed in 31.1% of patients and the mortality rate was 39.2%. Analysis of mTICI3 versus mTICI2b groups showed considerable better outcome in those with mTICI3 (38.9% vs. 24.4%; p = 0.005). The strongest predictors of good functional outcome were intravenous thrombolysis (IVT) treatment (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.76–5.23) and successful reperfusion (OR 4.92, 95% CI 1.15–21.11), while the effect of time between symptom onset and reperfusion seemed to be small.ConclusionsAcute reperfusion strategies in BAO are common in daily practice and can achieve good rates of successful reperfusion, neurological improvement and good functional outcome. Our data suggest that, in addition to IVT treatment, successful and, in particular, complete reperfusion (mTICI3) strongly predicts good outcome, while time from symptom onset seemed to have a lower impact.
Risk of poststroke epilepsy after reperfusion therapies: A national cohort study
Authors: Eriksson Hanna , Nordanstig Annika , Rentzos Alexandros , Zelano Johan , Redfors Petra 
Published: January 2023

AbstractBackground and purposeThe risk of poststroke epilepsy (PSE) after endovascular treatment (EVT) is not well characterized. In this nationwide study, we assessed the risk of PSE after EVT and identified associated predictors.MethodsWe included all individuals (n = 3319) treated with EVT (±intravenous thrombolysis [IVT]) between 2015 and 2019 in the Swedish National Quality Register for EVT. Two control groups were identified from the Swedish Stroke Register: the first treated with IVT alone (n = 3132) and the second with no treatment (n = 3184), both matched for age, sex, stroke severity, and time of stroke.ResultsPSE developed in 7.9% (n = 410). The survival‐adjusted 2‐year risk was 6.5% (95% confidence interval [CI] = 5.28–7.70) after EVT, 10.0% (95% CI = 8.25–11.75) after IVT, and 12.3% after no revascularization (95% CI = 10.33–14.25). The hazard ratio (HR) of PSE after EVT was almost half compared to no treatment (HR = 0.51, 95% CI = 0.41–0.64). The risk of PSE after EVT was lower compared to no treatment in a multivariable Cox model that adjusted for age, sex, hemicraniectomy, and stroke severity (HR = 0.76, 95% CI = 0.60–0.96). Multivariable predictors of PSE after EVT were large infarction on computed tomography Day 1, high posttreatment National Institutes of Health Stroke Scale score, and need of assistance 3 months after stroke. IVT before EVT was associated with a lower risk of PSE (HR = 0.66, 95% CI = 0.46–0.94).ConclusionsThis nationwide study identified a reduced risk of PSE after EVT. Markers of severe infarction after EVT were associated with PSE, whereas IVT given before EVT was protective.
Cortical lesions at diagnosis predict long‐term cognitive impairment in multiple sclerosis: A 20‐year study
Authors: Ziccardi Stefano , Pisani Anna Isabella , Schiavi Gian Marco , Guandalini Maddalena , Crescenzo Francesco , Colombi Annalisa , Peloso Angela , Tamanti Agnese , Bertolazzo Maddalena , Marastoni Damiano , Calabrese Massimiliano 
Published: January 2023

AbstractBackground and purposeAlthough cognitive impairment (CI) is frequent in multiple sclerosis (MS) patients, few studies (and with conflicting results) have evaluated early predictors of CI in the long term. We aimed at determining associations between early clinical/neuroradiological variables with reference to CI after 20 years of MS.MethodsWe investigated in 170 MS patients the relationship between clinical/magnetic resonance imaging (MRI) data at diagnosis and cognitive status almost 20 years after MS onset. Among others, number and volume of both white matter lesions (WMLs) and cortical lesions (CLs) were evaluated at diagnosis and after 2 years. All MS patients were followed over time and underwent a comprehensive neuropsychological assessment at the end of study. Advanced statistical methods (unsupervised cluster analysis and random forest model) were conducted.ResultsCI patients showed higher focal cortical pathology at diagnosis compared to cognitively normal subjects (p < 0.001). Volumes of both WMLs and CLs emerged as the MRI metrics most associated with long‐term CI. Moreover, number of CLs (especially ≥3) was also strongly associated with long‐term CI (≥3 CLs: odds ratio [OR] = 3.7, 95% confidence interval = 1.8–7.5, p < 0.001), more than number of WMLs; the optimal cutoff of three CLs (area under the curve = 0.67, specificity = 75%, sensitivity = 55%) was estimated according to the risk of developing CI.ConclusionsThese results highlight the impact of considering both white and gray matter focal damage from early MS stages. Given the low predictive value of WML number and the poor clinical applicability of lesion volume estimation in the daily clinical context, the evaluation of number of CLs could represent a reliable prognostic marker of CI.
Genotype–phenotype characteristics and baseline natural history of Chinese myelin protein zero gene related neuropathy patients
Authors: Lei Liu , Xiaobo Li , Zhiqiang Lin , Yongzhi Xie , Shunxiang Huang , Huadong Zhao , Beisha Tang , Ruxu Zhang 
Published: January 2023

AbstractBackground and purposeThe aim was to characterize the phenotypic and genotypic features of myelin protein zero (MPZ) related neuropathy and provide baseline data for longitudinal natural history studies or drug clinical trials.MethodClinical, neurophysiological and genetic data of 37 neuropathy patients with MPZ mutations were retrospectively collected.ResultsNineteen different MPZ mutations in 23 unrelated neuropathy families were detected, and the frequency of MPZ mutations was 5.84% in total. Mutations c.103_104InsTGGTTTACACCG, c.513dupG, c.521_557del and c.696_699delCAGT had not been reported previously. Hot spot mutation p.Thr124Met was detected in four unrelated families, and seven patients carried de novo mutations. The onset age indicated a bimodal distribution: prominent clustering in the first and fourth decades. The infantile‐onset group included 12 families, the childhood‐onset group consisted of two families and the adult‐onset group included nine families. The Charcot–Marie–Tooth Disease Neuropathy Score ranged from 3 to 25 with a mean value of 15.85 ± 5.88. Mutations that changed the cysteine residue (p.Arg98Cys, p.Cys127Trp, p.Ser140Cys and p.Cys127Arg) in the extracellular region were more likely to cause severe early‐onset Charcot–Marie–Tooth disease type 1B (CMT1B) or Dejerine–Sottas syndrome. Nonsense‐mediated mRNA decay mutations p.Asp35delInsVVYTD, p.Leu174Argfs*66 and p.Leu172Alafs*63 were related to severe infantile‐onset CMT1B or Dejerine–Sottas syndrome; however, mutation p.Val232Valfs*19 was associated with a relatively milder childhood‐onset CMT1 phenotype.ConclusionFour novel MPZ mutations are reported that expand the genetic spectrum. De novo mutations accounted for 30.4% and were most related to a severe infantile‐onset phenotype. Genetic and clinical data from this cohort will provide the baseline data necessary for clinical trials and natural history studies.
Performance validity tests in nonlitigant patients with functional motor disorder
Authors: Di Vico Ilaria A. , Stone Jon , Mcwhirter Laura , Riello Marianna , Zanolin Maria Elisabetta , Colombari Michela , Fiorio Mirta , Tinazzi Michele 
Published: January 2023

AbstractBackground and purposePerformance validity tests (PVTs) are used in neuropsychological assessments to detect patterns of performance suggesting that the broader evaluation may be an invalid reflection of an individual's abilities. Data on functional motor disorder (FMD) are currently poor and conflicting. We aimed to examine the rate of failure on three different PVTs of nonlitigant, non‐compensation‐seeking FMD patients, and we compared their performance to that of healthy controls and controls asked to simulate malingering (healthy simulators).MethodsWe enrolled 29 nonlitigant, non‐compensation‐seeking patients with a clinical diagnosis of FMD, 29 healthy controls, and 29 healthy simulators. Three PVTs, the Coin in the Hand Test (CIH), the Rey 15‐Item Test (REY), and the Finger Tapping Test (FTT), were employed.ResultsFunctional motor disorder patients showed low rates of failure on the CIH and REY (7% and 10%, respectively) and slightly higher rates on the FTT (15%, n = 26), which implies a motor task. Their performance was statistically comparable to that of healthy controls but statistically different from that of healthy simulators (p < 0.001). Ninety‐three percent of FMD patients, 7% of healthy simulators, and 100% of healthy controls passed at least two of the three tests.ConclusionsPerformance validity test performance of nonlitigant, non‐compensation‐seeking patients with FMD ranged from 7% to 15%. Patients' performance was comparable to that of controls and significantly differed from that of simulators. This simple battery of three PVTs could be of practical utility and routinely used in clinical practice.
Virulence evolution of Toxoplasma gondii within a multi‐host system
Authors: Wang Mengyue , Jiang Wen 
Published: January 2023

AbstractCurrent research on the virulence evolution of Toxoplasma gondii is mainly conducted via experiments, and studies using mathematical models are still limited. Here, we constructed a complex cycle model of T. gondii in a multi‐host system considering multiple transmission routes and cat‐mouse interaction. Based on this model, we studied how the virulence of T. gondii evolves with the factors related to transmission routes and the regulation of infection on host behavior under an adaptive dynamics framework. The study shows that all factors that enhance the role of mice favored decreased virulence of T. gondii, except the decay rate of oocysts that led to different evolutionary trajectories under different vertical transmission. The same was true of the environmental infection rate of cats, whose effect was different under different vertical transmission. The effect of the regulation factor on the virulence evolution of T. gondii was the same as that of the inherent predation rate depending on its net effect on direct and vertical transmissions. The global sensitivity analysis on the evolutionary outcome suggests that changing the vertical infection rate and decay rate was most effective in regulating the virulence of T. gondii. Furthermore, the presence of coinfection would favor virulent T. gondii and make evolutionary bifurcation easy to occur. The results reveal that the virulence evolution of T. gondii had a compromise between adapting to different transmission routes and maintaining the cat‐mouse interaction thereby leading to different evolutionary scenarios. This highlights the significance of evolutionary ecological feedback to evolution. In addition, the qualitative verification of T. gondii virulence evolution in different areas by the present framework will provide a new perspective for the study of evolution.
Efficacy and safety of topical JAK inhibitors in the treatment of atopic dermatitis in paediatrics and adults: A systematic review
Authors: Sadeghi Sara , Mohandesi Nessa Aghazadeh 
Published: January 2023

AbstractAtopic dermatitis (AD) is the most common skin inflammatory disease. Dysregulation of innate and adaptive immune systems plays a major role in the pathophysiology of AD. JAKi (Janus Kinase Inhibitors) reduce the production of pro‐inflammatory cytokines and represent a promising novel treatment for AD. To assess and summarize the overall efficacy and safety of topial JAKi in the treatment of AD in adults and pediatrics, a broad search was performed on Ovid Medline, Ovid Embase, Cochrane Library, Web of Sciences, Scopus, CINAHL and Google Scholar until 14 June 2022. After screening, 19 studies remained for the final review. The current systematic review was conducted according to PRISMA, and the protocol was registered in PROSPERO (ID #CRD42022303321). Topical delgocitinib, tofacitinib, ruxolitinib, cerdulatinib and ifidancitinib are effective in treating AD and significantly improve EASI, IGA, pruritus‐NRS score and some other indexes in adults. Moreover, topical delgocitinib was observed to have a great efficacy in the treatment of AD in paediatrics. All topical JAKi showed minimal risk of mild‐to‐moderate adverse effects. Available topical JAKi are effective and safe modalities in treating AD. Nevertheless, further studies with longer duration and head‐to‐head comparative trials are necessary to find the best option with the least adverse effects.
Inhibition of eukaryotic initiation factor 4E by tomivosertib suppresses angiogenesis, growth, and survival of glioblastoma and enhances chemotherapy's efficacy
Authors: Zhang Qi , Zhao Juan , Xu Tingwei 
Published: January 2023

AbstractGlioblastoma is characterized by extensive vascularization and is highly resistant to current therapy. Identification of drugs that target tumor directly and angiogenesis processes present an effective therapeutic strategy for glioblastoma. Mnk kinase is required for the activation of eukaryotic initiation factor 4E (eIF4E), which mediates translation of oncogenic proteins. We investigated the effects of tomivosertib, a novel MAPK‐interacting kinase (MNK) inhibitor, on glioblastoma angiogenesis, growth, and survival. We found that tomivosertib inhibited growth and induced caspase‐dependent apoptosis in various glioblastoma cell lines. Tomivosertib disrupted glioblastoma endothelial cell capillary network formation, growth, and survival. Mechanistically, tomivosertib acted on glioblastoma via suppressing MNK‐dependent eIF4E phosphorylation and activation in tumor and endothelial cells. We further found that temozolomide activated eIF4E and this was reversed by tomivosertib. Using glioblastoma xenograft mouse model, we demonstrated that temozolomide and tomivosertib combination had higher efficacy than tomivosertib alone. Of note, tomivosertib inhibited glioblastoma angiogenesis and decreased p‐eIF4E level in mice. We finally showed that p‐eIF4E activation was a common molecular feature in glioblastoma patients. Our pre‐clinical findings suggest that tomivosertib is a useful addition to the treatment armamentarium for glioblastoma and that targeting MNK‐eIF4E pathway represents a therapeutic strategy to overcome glioblastoma chemoresistance.