Faster Progression Research Articles

Clinical effectiveness of medical marijuana in patients with amyotrophic lateral sclerosis

Following legalization, Medical Marijuana (MM), has been used to treat the symptoms of Amyotrophic Lateral Sclerosis (ALS), yet data regarding Medical Marijuana's efficacy is lacking. Thus, we conducted a retrospective cohort study to assess Medical Marijuana's impact on ALS symptoms and progression. We reviewed the charts of all ALS patients treated in our clinic over a two-year period to collect data related to the primary outcome measures of symptoms of pain, poor appetite, anxiety, spasticity, insomnia, ALSFRS-R score, BMI, and MM use. Two groups were defined: a control group with target symptoms but no MM prescription, and a test group that filled a MM prescription, including a subgroup on MM for ≥3 visits. Outcomes were correlations between MM usage and symptom prevalence, and between MM usage and BMI and ALSFRS-R decline slope, analyzed using descriptive statistics and qualitative analysis via local regression. Data included 344 ALS patients. We found MM use correlated with alleviation of pain, poor appetite, and anxiety in the short term, but not with spasticity or insomnia. There was no correlation between MM use BMI maintenance. Notably, MM usage correlated with faster ALS progression, although patients using MM exhibited higher symptom burden and progressed faster than controls even pre-MM prescription. In conclusion, MM shows correlation with managing pain, poor appetite, and short-term anxiety in ALS, but is also correlated with faster disease progression based on ALSFRS-R scores. We suggest a multi-center, randomized controlled trial to evaluate both the clinical efficacy and safety of MM in the treatment of ALS.

Framingham Stroke Risk Profile Score and White Matter Disease Progression.

To evaluate the relationship between Framingham Stroke Risk Profile (FSRP) score and rate of white matter hyperintensity (WMH) progression and cognition. Consecutive patients enrolled in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry (2011-2020) with 2 brain-MRI scans at least 1 year apart were included. The primary outcome was annual change in WMH volume (cm 3 /year) stratified as fast versus slow (above vs. below median). Cognition was assessed using a Mini-Mental State Exam (MMSE, 0-30). FSRP score (0 to 8) was calculated by summing the presence of age 65 years or older, smoking, systolic blood pressure greater than 130 mmHg, diabetes, coronary disease, atrial fibrillation, left ventricular hypertrophy, and antihypertensive medication use. Linear and logistic regression analyses were performed to examine the association between FSRP and WMH progression, and cognition. In all, 207 patients were included, with a mean age of 60±16 y and 54.6% female. FSRP scores risk distribution was: 31.9% scored 0 to 1, 36.7% scored 2 to 3, and 31.4% scored ≥4. The baseline WMH volume was 9.6 cm 3 (IQR: 3.3-28.4 cm 3 ), and the annual rate of WMH progression was 0.9 cm3/year (IQR: 0.1 to 3.1 cm 3 /year). A higher FSRP score was associated with fast WMH progression (odds ratio, 1.45; 95% CI: 1.22-1.72; P<0.001) and a lower MMSE score (23.6 vs. 27.1; P<0.001). There was a dose-dependent relationship between higher FSRP score and fast WMH progression (odds ratios, 2.20, 4.64, 7.86, 8.03 for FSRP scores 1, 2, 3, and ≥4, respectively; trend P <0.001). This study demonstrated an association between higher FSRP scores and accelerated WMH progression, as well as lower cognition.

Role of L-carnitine in Cardiovascular Health: Literature Review.

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Secondary preventive measures, like anti-platelet medications, B-blockers, and angiotensin-converting enzyme (ACE) inhibitors, have been found to dramatically lower the risk of cardiovascular disease. However, prolonged usage of these drugs has been linked to multiple adverse impacts. Hence, finding more efficient treatments, especially dietary strategies for long-term use in daily life, is advantageous for primary prevention and treatment. L-carnitine, a naturally occurring amino acid derivative normally synthesized in the liver and kidney, is believed to have a considerable influence on cardiovascular health. L-carnitine can enhance both contractile performance and structural integrity of the cardiac muscle by maintaining efficient energy production and reducing oxidative stress. This literature review aims to address several pressing questions regarding the role of L-carnitine in cardiovascular health: what are the physiological functions of L-carnitine, particularly in relation to cardiovascular health; how effective and safe is L-carnitine supplementation in the management of various cardiovascular diseases, primarily ischemic heart disease, heart failure, and peripheral vascular disease; what are the underlying mechanisms through which L-carnitine exerts its cardioprotective effects; what controversies exist in the current research; and finally, what should be the future directions? Through this comprehensive analysis, the review aims to enrich our understanding of L-carnitine's role in cardiovascular health, providing a robust foundation for future academic and clinical endeavors. PubMed, Embase, and Google Scholar have been used to search the following keywords: L-carnitine, cardiovascular health, mitochondrial function, and L-carnitine side effects. Then, using the existing search engine formats, some keyword combinations were used to find the related articles included and every possibility, including using every first keyword combination with another keyword, using every keyword in every place at each given box, etc. Around 308 articles were reviewed using this process, including systemic reviews, meta-analysis studies, randomized controlled trials, and literature review articles. Inthe end, after leaving the pure articles related to the topic as 35 articles, which are attached below with direct citation, the majority of them were very fresh articles, as recent as 2010, and back words, except just one paper related to the impact of L-carnitine post-myocardial infarction, as its data provided us with a positive and promising impact of L-carnitine in this field. L‑carnitine seems to have a pivotal role in cardiovascular health due to its energy metabolism, anti-oxidative stress, and endothelial role. The safety and effectiveness of L-carnitine administration remain an issue for scientific investigation. One of the major concerns is that the intestinal metabolism of L-carnitine generates trimethylamine-N-oxide (TMAO), a compound that has been linked with faster atherosclerosis progression.

Neuropsychiatric symptoms: Risk factor or disease marker? A study of structural imaging biomarkers of Alzheimer's disease and incident cognitive decline.

Neuropsychiatric symptoms (NPS) are risk factors for Alzheimer's disease (AD) but can also manifest secondary to AD pathology. Mild behavioral impairment (MBI) refers to later-life emergent and persistent NPS that may mark early-stage AD. To distinguish MBI from NPS that are transient or which represent psychiatric conditions (non-MBI NPS), we investigated the effect of applying MBI criteria on NPS associations with AD structural imaging biomarkers and incident cognitive decline. Data for participants (n = 1273) with normal cognition (NC) or mild cognitive impairment (MCI) in the National Alzheimer's Coordinating Center Uniform Data Set were analyzed. NPS status (MBI, non-MBI NPS) was derived from the Neuropsychiatric Inventory Questionnaire and psychiatric history. Normalized measures of bilateral hippocampal (HPC) and entorhinal cortex (EC) volume, and AD meta-region of interest (ROI) mean cortical thickness were acquired from T1-weighted magnetic resonance imaging scans. Multivariable linear and Cox regressions examined NPS associations with imaging biomarkers and incident cognitive decline, respectively. MBI was associated with lower volume and cortical thickness in all ROIs in both NC and MCI, except for EC volume in NC. Non-MBI NPS were only associated with lower HPC volume in NC. Although both of the NPS groups showed higher hazards for MCI/dementia than No NPS, MBI participants showed more rapid decline. Although both types of NPS were linked to HPC atrophy, only NPS that emerged and persisted in later-life, consistent with MBI criteria, were related to AD neurodegenerative patterns beyond the HPC. Moreover, MBI predicted faster progression to dementia than non-MBI NPS.

P051 ASSOCIATION OF BASELINE PLASMA ALDOSTERONE CONCENTRATION WITH ARTERIAL STIFFNESS PROGRESSION IN HYPERTENSIVE PATIENTS

Objective: Limited studies have examined the relationship between plasma aldosterone concentration (PAC) and arterial stiffness progression. The objective of this study was to investigate the longitudinal association between baseline PAC and arterial stiffness progression in hypertensive patients. Methods: A total of 1138 hypertensive patients were enrolled in the study. PAC was measured using standard techniques while in a sitting position. Arterial stiffness was quantified using brachial-ankle pulse wave velocity (baPWV), an indicator of arterial stiffness that is non-invasive in nature. Progression of baPWV was assessed using the baPWV change rate(the absolute difference between baseline and follow-up baPWV, divided by the follow-up time in years. Multivariate linear regression models were employed to idenitify the associations between baseline PAC and the baPWV change rate. Additionally, multivariable restricted cubic splines were utilized to investigate the dose-response relationship between baseline PAC and baPWV change rate. Results: Multivariate linear regression analyses revealed that an increase of one unit in PAC at baseline was associated with a 1.96 cm/s/year increase [95% confidence interval (CI), 0.99, 2.92] in baPWV change rate. Furthermore, RCS demonstrated a significant dose-response relationship between baseline PAC and the baPWV change rate. Conclusion: This study found that higher levels of PAC were associated with a faster progression of arterial stiffness. These findings should be confirmed by further investigations.

Investigations on the machinability performance of Al2O3/TiCN CVD coated carbide tools in sustainable high-speed hard-turning of AISI 4340 alloy steel

Abstract This study investigates the effectiveness of CVD coated carbide inserts in turning hardened AISI 4340 steel at high-machining speed V=300,350m/min under sustainable dry cutting environment. Experiments were executed in accordance to Taguchi L4 orthogonal array and crucial machinability aspects tool life, tool wear progression and mechanism, cutting force, and surface roughness were evaluated in detail. The results of this study revealed that Al2O3/TiCN coating successfully inhibited the faster progression of tool wear at low cutting speed (300m/min), feed rate (0.05mm/rev) and depth of cut (0.1mm), thus delivering the highest tool life of 19.25 min and lowest cutting force of 76.8 N. However, better surface finish of 0.305µm was obtained at high cutting speed (350m/min), low feed rate (0.05mm/rev), and high depth of cut (0.1mm). Nevertheless, at high cutting speed (350 m/min) and feed rate (0.1 mm/rev), involvement of intense thermal-mechanical effects suppressed the effectiveness of coating and tool completed its useful life at 9.24 min. Severe flaking on the cutting edge was observed at high machining parameters. Scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) analysis revealed that adhesion, oxidation, and small scale chipping and abrasion were the primary wear mechanisms attributing in competing the tool life criteria (Vb=300µm) in all cutting conditions. Furthermore, it was established that the cutting force and surface roughness increased with increasing tool flank wear due to coating delamination, material adhesion and tool chipping. This research emphasizes the significant potential of adopting Al2O3/TiCN coated carbide inserts for high-speed industrial hard-turning of AISI 4340 steel.

THE ROLE OF AI IN HEALTHCARE INDUSTRY

This article analyses the present condition of technological applications based on artificial intelligence (AI) and their influence on the healthcare sector. This work conducted a comprehensive literature research and examined certain real-world instances of AI implementations in the healthcare sector. Undoubtedly, the fast progress of artificial intelligence (AI) and associated technologies will enable healthcare providers to provide fresh value for their patients and enhance the effectiveness of their internal operations. However, successful deployment of AI will always pose distinct problems and the adoption of specific approaches to revolutionize the whole care service and operations in order to fully utilize the advantages of future technology. The analysis is derived on an examination of several academic sources, encompassing research from ScienceDirect, MDPI, Elsevier, and the Journal of Consortium. These sources address studies and data published from recent years till 2024.

The Analysis of Influential Factors on the Delay of Dredging Work at Rebaq Rinding River Line in Kutai Kertanegara Regency, Indonesia

Along with fast progress of industrial world, particularly in the building construction project which also increasing rapidly, the difficulty level in managing and implementing construction projects also rising where the higher the difficulty the longer the time required to complete the project. A delay in work implementation is evident from the work package of Dredging Work Project for Rebaq Rinding River at Muara Muntai District of Kutai Kertanegara Regency. Thus, this research was performed to determine factors that influence project delays. The selected data analysis method was a factor analysis and multiple linear regression analysis from the questionnaire answers that distributed to 45 respondents ranging from the service users, contractors, and consultants involved in the Dredging Work Project in Rebaq Rinding River at Muara Muntai District of Kutai Kertanegara Regency which experienced delays. According to the result of this research, factor that has significant influence to project delays is factor of Work Implementation Method with value of tcount = 3.162 &gt; from ttable = 2.028, and based on T test, it was found that the most dominant factor is the factor of Work Implementation Method with ß value = 0.646. The strategy used in dealing with project delays are: prior to the beginning of work implementation, implementation schedule must be prepared in accordance with the rational work stages and the work stages implementation must follow the planned method.

Temporalities of oxytocin for labour augmentation: a mixed-methods study of time factors shaping labour practices in a busy maternity unit in Tanzania

BackgroundHigh rates of labour augmentation with oxytocin have been found in some low- and lower-middle-income countries, causing potential perinatal harm. It is critical to understand the reasons for this overuse. Aim was to explore factors that shape practices around using oxytocin for labour augmentation in a high-volume labour ward in Dar es Salaam, Tanzania.MethodsMixed-methods data collection was conducted from March 2021 to February 2022, including structured observations of 234 births, 220 h of unstructured labour ward observations and 13 individual in-depth interviews with birth attendants. Thematic network analysis and descriptive statistics were used to analyse data. We used a time-lens to understand practices of oxytocin for labour augmentation in time-pressured labour wards.ResultsBirth attendants constantly had to prioritise certain care practices over others in response to time pressure. This led to overuse of oxytocin for augmentation to ensure faster labour progression and decongestion of the, often overburdened, ward. Simultaneously, birth attendants had little time to monitor foetal and maternal condition. Surprisingly, while oxytocin was used in 146 out of 234 (62.4%) structured labour observations, only 9/234 (4.2%) women had active labour lasting more than 12 h. Correspondingly, 21/48 (43.8%) women who were augmented with oxytocin in the first stage of labour had uncomplicated labour progression at the start of augmentation. While the partograph was often not used for decision-making, timing of starting oxytocin often correlated with natural cycles of ward-rounds and shift-turnovers instead of individual women’s labour progression. This resulted in co-existence of ‘too early’ and ‘too late’ use of oxytocin. Liberal use of oxytocin for labour augmentation was facilitated by an underlying fear of prolonged labour and low alertness of oxytocin-related risks.ConclusionsTime scarcity in the labour ward often made birth attendants deviate from clinical guidelines for labour augmentation with oxytocin. Efforts to navigate time pressure resulted in too many women with uncomplicated labour progression receiving oxytocin with little monitoring of labour. Fear of prolonged labour and low alertness to oxytocin-mediated risks were crucial drivers. These findings call for research into safety and benefits of oxytocin in low-resource settings and interventions to address congestion in labour wards to prevent using oxytocin as a time-management tool.

Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis

BackgroundPositive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS). Objective: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation. Study design and settingsA randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial’s last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated. ResultsMean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL − RNS60 group; 3.3 years in low NfL − placebo group; 1.9 years in high NfL − RNS60 group; 1.8 years in high NfL − placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 − RNS60 group; 2.3 years in low MCP-1 − placebo group; 2.8 years in high MCP-1 − RNS60 group; 2.6 years in high MCP-1 − placebo group) levels at baseline. Conclusions and relevanceIn this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug’s effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival. Trial registrationStudy preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.

Tracking the pre-clinical progression of transthyretin amyloid cardiomyopathy using artificial intelligence-enabled electrocardiography and echocardiography.

Diagnosing transthyretin amyloid cardiomyopathy (ATTR-CM) requires advanced imaging, precluding large-scale testing for pre-clinical disease. We examined the application of artificial intelligence (AI) to echocardiography (TTE) and electrocardiography (ECG) as a scalable strategy to quantify pre-clinical trends in ATTR-CM. Across age/sex-matched case-control datasets in the Yale-New Haven Health System (YNHHS) we trained deep learning models to identify ATTR-CM-specific signatures on TTE videos and ECG images (area under the curve of 0.93 and 0.91, respectively). We deployed these across all studies of individuals referred for cardiac nuclear amyloid imaging in an independent population at YNHHS and an external population from the Houston Methodist Hospitals (HMH) to define longitudinal trends in AI-defined probabilities for ATTR-CM using age/sex-adjusted linear mixed models, and describe discrimination metrics during the early pre-clinical stage. Among 984 participants referred for cardiac nuclear amyloid imaging at YNHHS (median age 74 years, 44.3% female) and 806 at HMH (69 years, 34.5% female), 112 (11.4%) and 174 (21.6%) tested positive for ATTR-CM, respectively. Across both cohorts and modalities, AI-defined ATTR-CM probabilities derived from 7,423 TTEs and 32,205 ECGs showed significantly faster progression rates in the years before clinical diagnosis in cases versus controls (p time × group interaction ≤0.004). In the one-to-three-year window before cardiac nuclear amyloid imaging sensitivity/specificity metrics were estimated at 86.2%/44.2% [YNHHS] vs 65.7%/65.5% [HMH] for AI-Echo, and 89.8%/40.6% [YNHHS] vs 88.5%/35.1% [HMH] for AI-ECG. We demonstrate that AI tools for echocardiographic videos and ECG images can enable scalable identification of pre-clinical ATTR-CM, flagging individuals who may benefit from risk-modifying therapies.

Targeting Neurological Aspects of Mucopolysaccharidosis Type II: Enzyme Replacement Therapy and Beyond.

Mucopolysaccharidosis type II (MPS II) is a rare, pediatric, neurometabolic disorder due to the lack of activity of the lysosomal hydrolase iduronate 2-sulfatase (IDS), normally degrading heparansulfate and dermatansulfate within cell lysosomes. The deficit of activity is caused by mutations affecting the IDS gene, leading to the pathological accumulation of both glycosaminoglycans in the lysosomal compartment and in the extracellular matrix of most body districts. Although a continuum of clinical phenotypes is described, two main forms are commonly recognized-attenuated and severe-the latter being characterized by an earlier and faster clinical progression and by a progressive impairment of central nervous system (CNS) functions. However, attenuated forms havealso been recently described as presenting some neurological involvement, although less deep, such as deficits of attention and hearing loss. The main treatment for the disease is represented by enzyme replacement therapy (ERT), applied in several countries since 2006, which, albeit showing partial efficacy on some peripheral organs, exhibited a very poor efficacy on bones and heart, and a total inefficacy on CNS impairment, due to the inability of the recombinant enzyme to cross the blood-brain barrier (BBB). Together with ERT, whose design enhancements, performed in the last few years, allowed a possible brain penetration of the drug through the BBB, other therapeutic approaches aimed at targeting CNS involvement in MPS II were proposed and evaluated in the last decades, such as intrathecal ERT, intracerebroventricular ERT, ex vivo gene therapy, or adeno-associated viral vector (AAV) gene therapy. The aim of this review is to summarize the main clinical aspects of MPS II in addition to current therapeutic options, with particular emphasis on the neurological ones and on the main CNS-targeted therapeutic approaches explored through the years.

Analyzing changes in EU social inclusion using the global Malmquist productivity index

AbstractIn this paper, we use the global and the biennial Malmquist productivity indices for the Inverted Benefit‐of‐the‐Doubt model to analyze changes in EU social inclusion using data for the period 2011–2020. Our empirical results indicate that relatively more progress took place in EU social inclusion during the period 2015–2020, compared to the period 2011–2015. In addition, in the period 2011–2015, these improvements were possible mainly through the effect of efficiency change, while in the period 2015–2020, the main source of progress was the effect of the best‐practice change. In addition, we found that the “older” Member States achieved slightly faster progress rates, compared to the “new” Member States in the period 2011–2015, while the opposite was true for the period 2015–2020.

Storage properties of a quantum perceptron.

Driven by growing computational power and algorithmic developments, machine learning methods have become valuable tools for analyzing vast amounts of data. Simultaneously, the fast technological progress of quantum information processing suggests employing quantum hardware for machine learning purposes. Recent works discuss different architectures of quantum perceptrons, but the abilities of such quantum devices remain debated. Here, we investigate the storage capacity of a particular quantum perceptron architecture by using statistical mechanics techniques and connect our analysis to the theory of classical spin glasses. Specifically, we focus on one concrete quantum perceptron model and explore its storage properties in the limit of a large number of inputs.

Parkinson's Disease and Other Alzheimer's Disease and Related Dementia Pathologies and the Progression of Parkinsonism in Older Adults.

The interrelationship of parkinsonism, Parkinson's disease (PD) and other Alzheimer's disease (AD) and Alzheimer's disease and related dementias (ADRD) pathologies is unclear. We examined the progression of parkinsonian signs in adults with and without parkinsonism, and their underlying brain pathologies. Annual parkinsonian signs were based on a modified Unified Parkinson's Disease Rating Scale. We used linear mixed effects models to compare the progression of parkinsonian signs in 3 groups categorized based on all available clinical evaluations: Group1 (never parkinsonism or clinical PD), Group2 (ever parkinsonism, but never clinical PD), Group3 (ever clinical PD). In decedents, we examined the progression of parkinsonian signs with PD and eight other AD/ADRD pathologies. During average follow-up of 8 years, parkinsonian signs on average increased by 7.3% SD/year (N = 3,807). The progression of parkinsonian signs was slowest in Group1 (never parkinsonism or clinical PD), intermediate in Group2, and fastest in Group3. In decedents (n = 1,717) pathologic PD and cerebrovascular (CVD) pathologies were associated with a faster rate of progressive parkinsonian signs (all p values <0.05). However, pathologic PD was rare in adults without clinical PD (Group1, 5%; Group2, 7% versus Group3, 55%). Yet, 70% of adults in Group2 without pathologic PD showed one or more CVD pathologies. In Group2, adults with pathologic PD showed faster progression of parkinsonian signs compared with those without evidence of pathologic PD and their rate of progression was indistinguishable from adults with clinical PD. Parkinsonism in old age is more commonly related to cerebrovascular pathologies relative to pathologic PD and only a minority manifest prodromal PD.

Prognosticating accelerated deterioration in skeletally mature adolescent idiopathic scoliosis curves of 40-50° using uniplanar radiographic measures of axial rotation.

The management of adolescent idiopathic scoliosis (AIS) curves between 40 and 50° is controversial. Here, we investigated the prognostic significance of simple radiographic rotational parameters to identify curves of this magnitude with accelerated deterioration following skeletal maturity. Seventy-three patients were identified with AIS and Cobb angles of the major curve between 40 and 50° at skeletal maturity. We defined fastprogressive curves as those increasing by ≥ 2° per year after skeletal maturity. From the apical vertebra of the major curve upon presentation and skeletal maturity, we determined the modified Nash-Moe index (×100), and from thoracic major curves, the Rib Index. T tests were performed to compare fast-progressive curves with those that deteriorated by < 2° per year. Receiver operator characteristic (ROC) curves were plotted to establish optimal cutoffs, sensitivity, and specificity measures for rotational parameters. The average duration of follow-up post was 11.8 ± 7.3years. Thirteen out of seventy-three patients were fast progressors. The modified Nash-Moe index was similar between groups at presentation (p = 0.477) but significantly higher in fast progressors than non-fast progressors at maturity for major thoracic curves (25.40 ± 6.60 vs. 19.20 ± 4.40, p < 0.001). Rib Index values were also higher among fast progressors at skeletal maturity (2.50 ± 0.90 vs. 1.80 ± 0.60, p = 0.026). An ROC curve for a modified Nash-Moe index of 0.235 for thoracic curves achieved an area under the curve (AUC) of 0.76 for discriminating fast progressors. A threshold of 1.915 for Rib Index at maturity achieved an AUC of 0.72 for discriminating fast progressors. In combining both rotational parameters, an AUC of 0.81 was achieved. These simple rotational parameters may be useful to predict fast progression in 40-50° AIS curves following skeletal maturity indicated for early fusion, but further validationupon larger cohorts and non-thoracic majorcurves is required.

Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.

Pathogenic variants in the Cu/Zn superoxide dismutase (SOD1) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1-ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0months compared to 198.0months in D91A and 87.0months in L145F patients (HR 7.71, 95% CI 2.89-20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55-11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07-0.20) points lost per month. Median diagnostic delay was 10.0months (IQR 5.5-11.5) and therefore shorter compared to 57.5months (IQR 14.0-83.0) in D91A (p < 0.001) and 21.5months (IQR 5.8-38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1-ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.

Risk for progression to type 1 diabetes in first-degree relatives under 50 years of age.

The detection of pancreatic autoantibodies in first-degree relatives of patients with type 1 diabetes (T1D) is considered a risk factor for disease. Novel available immunotherapies to delay T1D progression highlight the importance of identifying individuals at risk who might benefit from emerging treatments. The objective was to assess the autoimmunity in first-degree relatives of patients with T1D, estimate the time from autoimmunity detection to the onset of clinical diabetes, and identify the associated risk factors. Retrospective multicenter study of 3,015 first-degree relatives of patients with T1D recruited between 1992 and 2018. Pancreatic autoantibodies (IAA, GADA, IA2A, and ZnT8A) were determined by radioimmunoassay, starting the analyses at diagnosis of the proband. All those with positive autoimmunity and normal fasting blood glucose without clinical symptoms of diabetes were followed up in the study. The progression rate to T1D was assessed according to sex, relationship with the proband, age at autoimmunity detection, type/number of autoantibodies, and HLA-DRB1 genotype. Cox proportional-hazard models and Kaplan-Meier survival plots were used for statistical analyses. Among the relatives, 21 progenitors [43.7 years (IQR: 38.1-47.7)] and 27 siblings [7.6 years (IQR: 5.8-16.1)] had positive autoantibodies. Of these, 54.2% (95% CI: 39.2%-68.6%) developed T1D (age at autoimmunity detection 11 months to 39 years) in a median of 5 years (IQR: 3.6-8.7; ranged from 0.9 to 22.6 years). Risk factors associated with faster progression to T1D were multiple autoimmunity and <20 years at autoimmunity detection. Younger relatives (<20 years) with multiple autoantibodies had a 5-year cumulative risk of developing diabetes of 52.9% (95% CI: 22.1%-71.6%) and a 20-year risk of 91.2% (95% CI: 50.5%-98.4%). The 20-year risk decreased to 59.9% (95% CI: 21.9%-79.5%) if only one risk factor was met and to 35.7% (95% CI: 0.0%-66.2%) if the relative was older than 20 years with one autoantibody. In first-degree relatives with autoimmunity, the time to progression to T1D is faster in children and adolescents with multiple autoantibodies. Young adults are also at risk, which supports their consideration in screening strategies for people at risk of developing T1D.

The frequency and clinical impact of synonymous HTT loss-of-interruption and duplication-of-interruption variants in a diverse HD cohort

PurposeTo determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption modifier variants of the HTT CAG and CCG repeat in a cohort of individuals with Huntington disease (HD). MethodsWe screened symptomatic HD participants from the UBC HD Biobank and 5 research sites for sequence variants. After variant identification, we examined the clinical impact and frequency in the reduced penetrance range. ResultsParticipants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of Total Motor Score by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of 2 symptomatic HD participants with diagnostic repeats below the pathogenetic range. ConclusionOur findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cutoff ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse HTT CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.

Dusza człowieka we współczesnym świecie. Dwa ujęcia: Wisławy Szymborskiej oraz Olgi Tokarczuk i ich przemieszczenie w przekładzie

The article offers an analysis of the linguistic-cultural concept of dusza/soul present in two literary works by contemporary Polish Nobel-Prize winners, as well as in their translations to English: Wisława Szymborska’s poem Trochę o duszy and Olga Tokarczuk’s story Zgubiona dusza. Their English translations are, respectively: A Few Words on the Soul (trans. Stanisław Barańczak and Clare Cavanagh) and The Lost Soul (trans. Antonia Lloyd-Jones). Alternative translation attempts by BA translation students at the University of National Education Commission in Kraków are also discussed. The two texts share the idea that today’s world, with its haste, attention deficit, and consumerism, is not a friendly place for the human soul. In their search for the human soul, both authors prompt similar solutions: a person must return to a small world of their own, or their inner reality, far from fast progress and globalisation. The present analysis takes a cognitive-ethnolinguistic perspective and begins by considering the entity named dusza in Polish and soul in English as cultural-linguistic concepts, tracing the similarities and differences conventionalised in the two languages, and thus the status of those concepts in the respective linguistic worldviews. This leads to an interpretation of Szymborska’s poem and Tokarczuk’s story as non-standard, individual, literary realisations of the standard worldview shared by the community of speakers of Polish. In this context, the English translations can be viewed as records documenting the transfer of the Polish concept of dusza to a new cultural-linguistic location. This approach is grounded in the idea of culture as an iceberg, where individual texts are viewed as expressions of an underlying cultural content.