Wide Age Range Research Articles

An artificial intelligence-based model for prediction of atrial fibrillation from single-lead sinus rhythm electrocardiograms facilitating screening.

Screening for atrial fibrillation (AF) is recommended in the European Society of Cardiology guidelines. Yields of detection can be low due to the paroxysmal nature of the disease. Prolonged heart rhythm monitoring might be needed to increase yield but can be cumbersome and expensive. The aim of this study was to observe the accuracy of an artificial intelligence (AI)-based network to predict paroxysmal AF from a normal sinus rhythm single-lead ECG. A convolutional neural network model was trained and evaluated using data from three AF screening studies. A total of 478 963 single-lead ECGs from 14 831 patients aged ≥65 years were included in the analysis. The training set included ECGs from 80% of participants in SAFER and STROKESTOP II. The remaining ECGs from 20% of participants in SAFER and STROKESTOP II together with all participants in STROKESTOP I were included in the test set. The accuracy was estimated using the area under the receiver operating characteristic curve (AUC). From a single timepoint ECG, the artificial intelligence-based algorithm predicted paroxysmal AF in the SAFER study with an AUC of 0.80 [confidence interval (CI) 0.78-0.83], which had a wide age range of 65-90+ years. Performance was lower in the age-homogenous groups in STROKESTOP I and STROKESTOP II (age range: 75-76 years), with AUCs of 0.62 (CI 0.61-0.64) and 0.62 (CI 0.58-0.65), respectively. An artificial intelligence-enabled network has the ability to predict AF from a sinus rhythm single-lead ECG. Performance improves with a wider age distribution.

Age-related reference intervals for ambulatory electrocardiographic parameters in healthy individuals.

The advent of novel monitoring technologies has dramatically increased the use of ambulatory electrocardiography (AECG) devices. However, few studies have conducted detailed large-scale investigations on the incidence of arrhythmias over 24 h, especially ectopy, in healthy individuals over a wide age range. This study aimed to investigate the incidence of arrhythmias detected using AECG and associated factors, in healthy individuals, over a wide age range. In this cross-sectional study, we performed AECG on 365 healthy volunteers (median [interquartile range]: 48 [36, 67], 20-89 years, 165 men) under free-running conditions for 24 h. Ultrasonic echocardiography and heart rate variability analysis were performed to explore the factors associated with the incidence of arrhythmias. The 97.5th percentile of single ventricular ectopy (VE) was 149/day, 254/day, and 1,682/day in the 20-39-, 40-59- and 60-89-year age groups, respectively; that of single supraventricular ectopy (SVE) was 131/day, 232/day, and 1,063/day, respectively. Multivariate analysis revealed that aging was the only independent significant factor influencing the frequency of VE (β = 0.207, P = 0.001). Age (β = 0.642, P < 0.001), body mass index (BMI) (β = -0.112, P = 0.009), and the root mean square of successive differences in RR intervals (β = 0.097, P = 0.035) were factors significantly associated with SVE frequency. Age-specific reference intervals of VE and SVE in a large population of healthy participants over a wide age range were generated. VE and SVE increased with age; SVE was influenced by BMI and the aging-induced decrease in parasympathetic tone activity.

Oxygen Uptake Efficiency Slope in South American Healthy Adults: COMPREHENSIVE REFERENCE VALUES AND INTERNATIONAL COMPARISONS.

The purpose of this study is to provide comprehensive reference values for oxygen uptake efficiency slope (OUES) in healthy adults. International heterogeneity was also explored through published databases. A cross-sectional study was conducted with treadmill cardiopulmonary exercise testing (CPX) from a Brazilian healthy adult sample, in which absolute OUES and values normalized by weight and body surface area (BSA) were calculated. Data were stratified by sex and age group. Prediction equations were calculated using age and anthropometric variables. International data were pooled and differences were explored using factorial analysis of variance or the t test, as appropriate. The OUES age-related patterns were calculated using regression analysis. A total of 3544 CPX were included (1970 males and 1574 females) and the age ranged from 20-80 yr. Males had higher values than females for OUES, OUES/kg, and OUES/BSA. Lower values were found with aging and the data followed a quadratic regression curve. Reference value tables and predictive equations were provided for absolute and normalized OUES in both sexes. International comparisons of absolute OUES values among Brazilian, European, and Japanese data revealed substantial heterogeneity. The OUES/BSA measure minimized the discrepancies between Brazilian and European data. Our study provided comprehensive OUES reference values in a large healthy adult sample from South America with a wide age range and included absolute and normalized values. Differences observed between Brazilian and European data were reduced in the BSA-normalized OUES.

IBEAT V2.0: a multisite-applicable, deep learning-based pipeline for infant cerebral cortical surface reconstruction.

The human cerebral cortex undergoes dramatic and critical development during early postnatal stages. Benefiting from advances in neuroimaging, many infant brain magnetic resonance imaging (MRI) datasets have been collected from multiple imaging sites with different scanners and imaging protocols for the investigation of normal and abnormal early brain development. However, it is extremely challenging to precisely process and quantify infant brain development with these multisite imaging data because infant brain MRI scans exhibit (a) extremely low and dynamic tissue contrast caused by ongoing myelination and maturation and (b) inter-site data heterogeneity resulting from the use of diverse imaging protocols/scanners. Consequently, existing computational tools and pipelines typically perform poorly on infant MRI data. To address these challenges, we propose a robust, multisite-applicable, infant-tailored computational pipeline that leverages powerful deep learning techniques. The main functionality of the proposed pipeline includes preprocessing, brain skull stripping, tissue segmentation, topology correction, cortical surface reconstruction and measurement. Our pipeline can handle both T1w and T2w structural infant brain MR images well in a wide age range (from birth to 6 years of age) and is effective for different imaging protocols/scanners, despite being trained only on the data from the Baby Connectome Project. Extensive comparisons with existing methods on multisite, multimodal and multi-age datasets demonstrate superior effectiveness, accuracy and robustness of our pipeline. We have maintained a website, iBEAT Cloud, for users to process their images with our pipeline ( http://www.ibeat.cloud ), which has successfully processed over 16,000 infant MRI scans from more than 100 institutions with various imaging protocols/scanners.

A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status.

Guidance on clozapine dosing in treatment-resistant schizophrenia is based largely on data from White young adult males. This study aimed to investigate the pharmacokinetic profiles of clozapine and N-desmethylclozapine (norclozapine) across the age range, accounting for sex, ethnicity, smoking status and body weight. A population pharmacokinetic model, implemented in Monolix, that linked plasma clozapine and norclozapine via a metabolic rate constant, was used to analyse data from a clozapine therapeutic drug monitoring service, 1993-2017. There were 17 787 measurements from 5960 patients (4315 male) aged 18-86 years. The estimated clozapine plasma clearance was reduced from 20.2 to 12.0L h-1 between 20 and 80 years. Model-based dose predictions to attain a predose plasma clozapine concentration of 0.35 mg L-1 was 275 (90% prediction interval 125, 625) mg day-1 in nonsmoking, White males weighing 70 kg and aged 40 years. The corresponding predicted dose was increased by 30% in smokers, decreased by 18% in females, and was 10% higher and 14% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. Overall, the predicted dose decreased by 56% between 20 and 80 years. The large sample size and wide age range of the patients studied allowed precise estimation of dose requirements to attain predose clozapine concentration of 0.35 mg L-1 . The analysis was, however, limited by the absence of data on clinical outcome and future studies are required to determine optimal predose concentrations specifically in those aged over 65 years.

Food as a key disgust elicitor in infancy and childhood: Previous research and opportunities for future study.

Disliked foods may have important value in the study of the development of disgust. The current review draws from literature across disciplines, including theories of disgust and studies of the development of eating behavior and food preferences, to highlight food as an important category of disgust responses across a wide age range, including children as young as 3 years old and adults. Children's disgust responses to certain types of food are considered to be both innate and culturally constrained behaviors, and their perceptions of other people's food choices indicate potential links between foods and cultural groups. We end by discussing several ongoing and future research areas, including connections between disgust responses and food rejection in infancy and children's food rejection behaviors across cultures.

Applying Functional Imaging to Clinical Practice: Are We Making Progress Toward Its Promise?

Applying Functional Imaging to Clinical Practice: Are We Making Progress Toward Its Promise?

25-hydroxyvitamin D level is associated with greater grip strength across adult life span: a population-based cohort study.

Maintaining muscle function throughout life is critical for healthy ageing. Although in vitro studies consistently indicate beneficial effects of 25-hydroxyvitamin D (25-OHD) on muscle function, findings from population-based studies remain inconclusive. We therefore aimed to examine the association between 25-OHD concentration and handgrip strength across a wide age range and assess potential modifying effects of age, sex and season. We analysed cross-sectional baseline data of 2576 eligible participants out of the first 3000 participants (recruited from March 2016 to March 2019) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Multivariate linear regression models were used to assess the relation between 25-OHD levels and grip strength while adjusting for age, sex, education, smoking, season, body mass index, physical activity levels, osteoporosis and vitamin D supplementation. Compared to participants with deficient 25-OHD levels (<30 nmol/L), grip strength was higher in those with inadequate (30 to <50 nmol/L) and adequate (≥50 to ≤125 nmol/L) levels (ßinadequate = 1.222, 95% CI: 0.377; 2.067, P = 0.005; ßadequate = 1.228, 95% CI: 0.437; 2.019, P = 0.002). Modelling on a continuous scale revealed grip strength to increase with higher 25-OHD levels up to ~100 nmol/L, after which the direction reversed (ßlinear = 0.505, 95% CI: 0.179; 0.830, P = 0.002; ßquadratic = -0.153, 95% CI: -0.269; -0.038, P = 0.009). Older adults showed weaker effects of 25-OHD levels on grip strength than younger adults (ß25OHDxAge = -0.309, 95% CI: -0.594; -0.024, P = 0.033). Our findings highlight the importance of sufficient 25-OHD levels for optimal muscle function across the adult life span. However, vitamin D supplementation should be closely monitored to avoid detrimental effects.

Mediation Effect of Obesity on the Association of Age at Menarche With Blood Pressure Among Women in Southwest China.

Background Previous studies have been inconsistent about the association between age at menarche and high blood pressure. Little is known about such association across a wide range of menarcheal ages in less developed ethnic minority regions in China. We aimed to explore the association between age at menarche and high blood pressure (BP; ≥140/90 mm Hg) and to examine the mediating effect of obesity and the moderating effect of menopausal status on this association. Methods and Results A total of 45 868 women from the baseline data of the CMEC (China Multi-Ethnic Cohort) were included in this study. Binary logistic regression was used to analyze the relationship between age at menarche and high BP, and the mediation model was used to evaluate the mediating effects of body mass index and waist circumference on the association of age at menarche with high BP. The mean age at enrollment and age at menarche of participants in our study were 49.3 (SD=10.7) and 14.7 (SD=2.1) years, respectively. Late menarche was associated with a lower risk of high BP (odds ratio, 0.831 [95% CI, 0.728-0.950]). The risk of high BP decreased by 3.1% with each year's delay in the onset of menarche (P for trend <0.001). Body mass index and waist circumference could partially mediate the association of age at menarche and high BP with the indirect effect of body mass index (odds ratio, 0.998 [95% CI, 0.997-0.998]) and waist circumference (odds ratio, 0.999 [95% CI, 0.998-0.999]). Inaddition,the mediation effects were modified by the status of menopause. Conclusions Women with late menarche have a lower risk of high BP, and obesity could be one of the important mediators. Obesity prevention is an efficient strategy to reduce the association between age at menarche and high BP, especially in premenopausal women.

Effects of Aging Uncertainty on the Estimation of Growth Functions of Major Tuna Species

Fishery stock assessment requires accurate specification of the growth function of target species, and aging uncertainty is an important factor that affects the estimation of growth parameters. In this study, we used simulations to study the effects of two types of aging uncertainty, aging error and sampled age range, on the parameter estimation of the Von Bertalanffy growth function, including asymptotic length (L∞), growth coefficient (k), and theoretical age in the year at zero length (t0) of five important tuna species. We found that the uncertainty of the estimated growth curves increased with increasing aging errors. When aging errors were fixed among ages, the effects of age range on estimation error of growth parameters were different among species and growth parameters. When the aging error increased with age, the estimation uncertainty of L∞ and k was the greatest when only young age groups were sampled, while the estimation uncertainty of t0 was the greatest when only old age groups were sampled. Therefore, reducing the aging error and sampling individuals with a wider age range are important for increasing the accuracy and decreasing the uncertainty of the estimated growth function, which will further reduce the uncertainty in fishery stock assessment.

An integrated model on purchase intentions of typical and tax-deductible saving products: The roles of retirement goal clarity and age

Previous research on retirement planning largely focuses on the general tendency to save for retirement. By integrating two theoretical models, namely, interdisciplinary psycho-motivation model and the theory of reasoned action, the present study aims to advance the previous work to examine the effects of social (social norms and social support) and psychological (future time perspective and financial literacy) factors on behavioral intentions for purchasing specific financial products for retirement. Cross-sectional data were obtained from 598 Hong Kong Chinese working adults of a wide age range. Mediation analysis showed that retirement goal clarity could partly account for the effects of financial literacy, social norms, and social support on the purchase intentions of both annuity and other saving products in the commercial market. Additional moderated mediation analyses revealed a stronger mediating effect of retirement goal clarity on the relationship between social norms and annuity products in younger workers than that in older workers. Findings of this study provide valuable insights into the roles of retirement goal clarity and age in the purchase intentions of financial products for retirement. The examination of the newly launched tax-deductible products in younger and older workers further discloses these products are relatively more attractive to younger individuals as a means of financial retirement planning.

Mapping PedsQL™ scores to CHU9D utility weights for children with chronic conditions in a multi-ethnic and deprived metropolitan population

PurposeThe Child Health Utility-9 Dimensions (CHU9D) is a patient-reported outcome measure to generate Quality-Adjusted Life Years (QALYs), recommended for economic evaluations of interventions to inform funding decisions. When the CHU9D is not available, mapping algorithms offer an opportunity to convert other paediatric instruments, such as the Paediatric Quality of Life Inventory™ (PedsQL), onto the CHU9D scores.This study aims to validate current PedsQL to CHU9D mappings in a sample of children and young people of a wide age range (0 to 16 years of age) and with chronic conditions. New algorithms with improved predictive accuracy are also developed.MethodsData from the Children and Young People’s Health Partnership (CYPHP) were used (N = 1735). Four regression models were estimated: ordinal least squared, generalized linear model, beta-binomial and censored least absolute deviations. Standard goodness of fit measures were used for validation and to assess new algorithms.ResultsWhile previous algorithms perform well, performance can be enhanced. OLS was the best estimation method for the final equations at the total, dimension and item PedsQL scores levels. The CYPHP mapping algorithms include age as an important predictor and more non-linear terms compared with previous work.ConclusionThe new CYPHP mappings are particularly relevant for samples with children and young people with chronic conditions living in deprived and urban settings. Further validation in an external sample is required.Trial registration number NCT03461848; pre-results.

Концепция очевидного времени в современной социолингвистике: преимущества и недостатки методологии

The article is devoted to the analysis of the concept of apparent time used by modern sociolinguistics to identify the social features of the use of language by various socio-demographic groups. There are a number of problems that can be solved by using this empirical method. The first problem is the “constraints”: which language changes are possible and which are not. Historical data can only show what changes have already occurred, but not what changes are possible/impossible. The second is the problem of “embedding”: how a language changes reach all (or almost all) the community members. The third problem is “assessment”: how community members react to language changes and what impact their assessments have on the course or nature of changes. The fourth is a “transitional” problem: how does the language change from one state at the moment A to another state at the moment B. Finally, the fifth problem is “actualization”: why there is a change in a particular language, when and where it occurs. The founders of the method, Weinreich, Labov and Herzog, argued that these important problems can only be solved by observing the change of language as it arises and from different social points of view, including a wide range of ages, social statuses and places of residence. The difficulties of applying this concept are considered: there are few comparable real-time data on earlier periods; methods of early work and socio-demographic characteristics do not correspond to modern research needs. The ways to overcome these difficulties are proposed: research should be of a longitudinal nature with the unification of the methodology for obtaining empirical data.

Assessing phonological short-term memory in Greek: Reliability and validity of a non-word repetition test.

This study explores the reliability and validity of a NWR task in a large cohort of 387 TD Greek-speaking children aged 7-13 years attending elementary (Grades 2-6) and secondary school (Grade 1), divided into six age groups. Further, the relationship between NWR and reading fluency skills as well as the predictive value of the NWR on reading fluency skills in TD children are examined. To investigate the external reliability of the NWR task, test-retest reliability was performed, and excellent test-retest reliability was found. Internal reliability was explored with Cronbach's alpha coefficient and good reliability was found. To explore convergent validity, correlation analysis between NWR and reading fluency was conducted and significant and strong correlations were found for all age groups excepted 2 (ages 9-10 and 12-13). To examine predictive validity, regression analysis was conducted between these two variables and showed that performance on NWR contributed significantly to reading fluency skills, suggesting that NWR skills are a good predictor of reading skills. Finally, it was explored whether the relevant scores increase as a function of age and found significant differences between groups that differed in 2 years or more, while this difference was no longer significant after 10 years. This finding suggests that phonological STM increases in capacity along with age, but only until the age of 10, where it seems to reach a ceiling. In addition, linear regression analysis showed that age contributed significantly to performance on NWR test. To sum up, the present study provides normative data of a NWR test for a wide age range, which does not exist in the Greek language (particularly for ages over 9 years) and it can be concluded that the present NWR test can be successfully used as a reliable and valid measure of phonological STM in the age range that was examined in this study.

Normative Data of Fugl Meyer Assessment on Upper Extremity in Post Stroke Population

Background: Stroke is clinically diagnosed as an acute, localized neurological impairment that is caused by vascular damage (infarction, hemorrhage) to the central nervous system. This main leading cause of demise and dysfunction worldwide resulting in frequent deficit, hemiplegia, which briefly affects upper limb. This multicentered study is the first to provide updated normative reference values for FMA-UE in post stroke adults in wide range of age in Pakistan’s population.&#x0D; Objective: To determine Pakistani normative values of Fugl-Meyer Assessment on upper extremity in post Stroke Population.&#x0D; Methods: Descriptive cross-sectional study on 1260 post-stroke patients was conducted in various public and private physiotherapy centers of country using Fugl-Meyer Assessment (Upper-Extremity) FMA-UE scale after ethical approval. Hemiplegic survivors of both genders aged 45-75 years were taken using convenience sampling technique, informed consent was taken. Statistics was done using SPSS version25.&#x0D; Results: Patients included were 88.3% ischemic and 11.7% hemorrhagic. 44.1% were in acute phase (less than 2 weeks) while 55.9% were in sub-acute (2 weeks to 6 months) phase. Mean score of FMA-UE was 88.63±30.09. The cutoff score/mean value for motor impairment and sensation was recorded as 41.49 ±19.7 and 8.6±3.9 while passive joint motion and pain were calculated 18.93±5.47 and 19.57±5.1 respectively.&#x0D; Conclusion: The scoring, in acute and subacute phases, accentuate the need to follow Pakistani specific modified norms in Asian inhabitants instead of reference values applicable on western population.&#x0D; Keywords: Fugl-Meyer scale, Hemiplegia, Motor control, Post Stroke, Upper extremity.

Factors associated with changes in the objectively measured physical activity among Japanese adults: A longitudinal and dynamic panel data analysis.

Factors associated with dynamic changes in the objectively measured physical activity have not been well understood. We aimed to 1) evaluate the longitudinal change in the physical activity trajectory according to sex which is associated with age and to 2) determine the factors associated with the dynamic change in physical activity-related variables across a wide age range among Japanese adults. This longitudinal prospective study included 689 Japanese adults (3914 measurements) aged 26-85 years, whose physical activity data in at least two surveys were available. Physical activity-related variables, such as intensity (inactive, light [LPA; 1.5 to 2.9 metabolic equivalents (METs)], moderate-to-vigorous [MVPA; ≥3.0 METs]), total energy expenditure (TEE), physical activity level (PAL), and step count, were evaluated using a validated triaxial accelerometer. Statistical analysis involved the latent growth curve models and random-effect panel data multivariate regression analysis. During a mean follow-up period of 6.8 years, physical activity was assessed an average of 5.1 times in men and 5.9 times in women. The profiles for the inactive time, LPA (only men), MVPA, step count, PAL, and TEE showed clear curvature, indicating an accelerated rate of change around the age of 70. In contrast, other variables exhibited minimal or no curvature over the age span. The MVPA trajectory was positively associated with alcohol consumption, hand grips, leg power, and trunk flexibility and negatively associated with age, local area, body mass index (BMI), comorbidity score, and heart rate over time. Our results indicated that the physical activity trajectory revealed clear curvature, accelerated rate of change around the age of 70, and determined physical health and fitness and BMI as dynamic factors associated with physical activity changes. These findings may be useful to help support populations to achieve and maintain the recommended level of physical activity.

Muscle and visceral fat infiltration: A potential mechanism to explain the worsening of obstructive sleep apnea with age

Study objectivesAging is a major risk factor for obstructive sleep apnoea (OSA) and is associated with increased upper airway collapsibility, but the mechanisms are largely unknown. We hypothesized that the increase in OSA severity and upper airway collapsibility with age are partially mediated by upper airway, visceral and muscle fat infiltration. MethodsMale subjects underwent full polysomnography, upper airway collapsibility determination (Pcrit) after sleep induction with midazolam, upper airway and abdominal computed tomography. Tongue and abdominal muscle fat infiltration were assessed by the determination of muscle attenuation with computed tomography. ResultsEighty-four males with a wide range of age (47 ± 13 years, range 22–69 years) and apnea-hypopnea index (AHI) (30 [14–60] events/h, range 1–90 events/h), were studied. Younger and older males were grouped according to the mean age. Despite similar body mass-index (BMI), older subjects had higher AHI, higher Pcrit, larger neck and waist circumference, higher visceral and upper airway fat volumes (P < 0.01) as compared to younger subjects. Age was associated with OSA severity, Pcrit, neck and waist circumference, upper airway fat volume and visceral fat (P < 0.05), but not with BMI. Older subjects had lower tongue and abdominal muscle attenuation as compared to younger subjects (P < 0.001). Age was inversely associated with tongue and abdominal muscle attenuation, indicating muscle fat infiltration. ConclusionsThe associations between age, upper airway fat volume, visceral and muscle fat infiltration may help to explain the worsening of OSA and increased upper airway collapsibility with aging.

Huge Recurrent Mucoepidermoid Carcinoma of Parotid - a Rare Presentation.

Mucoepidermoid carcinoma is the commonest primary malignant salivary gland tumor in both children and adults and constitutes around 2.8-16% of all salivary gland tumors. There is a wide age range of 3 to 95 years with a mean age of 47 years. We reported a case of 85 years old female patient, who presented to the department of Surgical Oncology, Srinivasan Medical College and Hospital, Trichy, with history of right parotid swelling for past 25 years, who had undergone Superficial parotidectomy 10 years back, followed by recurrence of tumor with huge increase in size, around 20cm in greatest dimension. Right Completion Radical Parotidectomy with Modified Radical neck dissection type 1 with Cervical Rotation Flap cover was done and histopathological examination of the surgical specimen confirmed as high grade Mucoepidermoid carcinoma. Following surgery, the patient's outcome is better, uneventful with periodic regular follow-up.

Dimensional Structure of MAPS-15: Validation of the Multidimensional Academic Procrastination Scale.

Academic procrastination is a complex behavior that hampers the cyclical process of self-regulation in learning, impeding the flow of actions necessary to achieve the goals and sub-goals that students have set out to attain. It has a high frequency of occurrence and has been linked to lessened student performance and a decrease in psychological and physical well-being. The objective of this study is to analyze the psychometric characteristics of a new academic procrastination scale MAPS-15 (Multidimensional Academic Procrastination Scale) applicable in self-regulated learning environments through a cross-validation study (exploratory factor analysis and confirmatory factor analysis). The sample consisted of 1289 students from a distance/online university, with a wide age range and sociocultural variability. The students completed self-reported online questionnaires on two dates: during the university access and adaptation phase and before the first period of compulsory exams. One-, two- and three-factor structures were tested as well as a second-order structure. The results support a three-dimensional structure of MAPS-15: core procrastination, a pure dimension of procrastinating behavior and difficulty in carrying out the action; poor time management, a dimension related to time organization and perceived control over time; and work disconnection, a dimension conceptually related to lack of persistence, and work interruptions.

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.