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Pediatric Annals Jul 2024Fragile X syndrome is the most commonly inherited form of intellectual disability. Identifying fragile X syndrome at a young age can be quite challenging because the... (Review)
Review
Fragile X syndrome is the most commonly inherited form of intellectual disability. Identifying fragile X syndrome at a young age can be quite challenging because the classical physical features usually present in late childhood or early adolescence; therefore, it is important to consider genetic testing for all males with unexplained developmental delays, intellectual disability, and autism, females with developmental delays, intellectual disability or autism, and a family history of fragile X gene disorders. There is no specific treatment to manage fragile X syndrome. Still, a prompt referral for early intervention is essential to help maximize the child's learning potential, as well as a referral to child psychology if any behavioral concerns are present. It is of paramount importance for families with a history of fragile X syndrome to have access to genetic counseling as it can aid in future reproductive decisions and the risk of future recurrences of this condition. .
Topics: Fragile X Syndrome; Humans; Child; Male; Genetic Testing; Female; Genetic Counseling; Pediatricians; Adolescent; Pediatrics
PubMed: 38949875
DOI: 10.3928/19382359-20240502-08 -
JAMA Neurology Jul 2024Understanding the association between clinically defined relapses and radiological activity in multiple sclerosis (MS) is essential for patient treatment and therapeutic...
IMPORTANCE
Understanding the association between clinically defined relapses and radiological activity in multiple sclerosis (MS) is essential for patient treatment and therapeutic development.
OBJECTIVE
To investigate clinical events identified as relapses but not associated with new T2 lesions or gadolinium-enhanced T1 lesions on brain and spinal cord magnetic resonance imaging (MRI).
DESIGN, SETTING, AND PARTICIPANTS
This multicenter observational cohort study was conducted between January 2015 and June 2023. Data were extracted on June 8, 2023, from the French MS registry. All clinical events reported as relapses in patients with relapsing-remitting MS were included if brain and spinal cord MRI was performed within 12 and 24 months before the event, respectively, and 50 days thereafter with gadolinium injection.
EXPOSURES
Events were classified as relapses with active MRI (RAM) if a new T2 lesion or gadolinium-enhanced T1 lesion appeared on brain or spinal cord MRI or as acute clinical events with stable MRI (ACES) otherwise.
MAIN OUTCOMES AND MEASURES
Factors associated with ACES were investigated; patients with ACES and RAM were compared regarding Expanded Disability Status Scale (EDSS) course, relapse rate, confirmed disability accrual (CDA), relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and transition to secondary progressive (SP) MS, and ACES and RAM rates under each disease-modifying therapy (DMT) were estimated.
RESULTS
Among 31 885 clinical events, 637 in 608 patients (493 [77.4%] female; mean [SD] age, 35.8 [10.7] years) were included. ACES accounted for 166 (26.1%) events and were more likely in patients receiving highly effective DMTs, those with longer disease duration (odds ratio [OR], 1.04; 95% CI, 1.01-1.07), or those presenting with fatigue (OR, 2.14; 95% CI, 1.15-3.96). ACES were associated with significant EDSS score increases, lower than those found for RAM. Before the index event, patients with ACES experienced significantly higher rates of relapse (relative rate [RR], 1.21; 95% CI, 1.01-1.46), CDA (hazard ratio [HR], 1.54; 95% CI, 1.13-2.11), and RAW (HR, 1.72; 95% CI, 1.20-2.45). Patients with ACES were at significantly greater risk of SP transition (HR, 2.58; 95% CI, 1.02-6.51). Although RAM rate decreased with DMTs according to their expected efficacy, ACES rate was stable across DMTs.
CONCLUSIONS AND RELEVANCE
The findings in this study introduce the concept of ACES in MS, which accounted for one-fourth of clinical events identified as relapses.
PubMed: 38949816
DOI: 10.1001/jamaneurol.2024.1961 -
Effects of Sjogren's Syndrome on essential hypertension: a two-sample mendelian randomization study.Minerva Cardiology and Angiology Jul 2024Sjogren's Syndrome (SS) plays important roles in the development of essential hypertension. Nevertheless, with the limitation of reverse causality and confounder in...
BACKGROUND
Sjogren's Syndrome (SS) plays important roles in the development of essential hypertension. Nevertheless, with the limitation of reverse causality and confounder in observational studies, such a relationship remains unclear. We aimed to assess the causal relationship of SS and hypertension by the Mendelian randomization (MR) approach.
METHODS
We used MR to investigate a causal association between SS and essential hypertension. Inverse variance weighted (IVW), MR Egger regression, Maximum likelihood, Weighted median, and MR pleiotropy residual sum and outlier test (MR-PRESSO) were used in this MR analysis.
RESULTS
In this study, we found that the ratio of IVW is 1.00024 (95% CI: 1.00013- 1.00036, P=0.0387), This result was also confirmed by sensitivity analysis methods such as Maximum likelihood is 1.00025 (95% CI: 1.00013-1.00037, P=0.036), MR Egger is 1.00071 (95% CI: 1.00047-1.00095, P=0.0045), and Weighted median is 1.00040 (95% CI: 1.00021- 1.00059, P=0.0322). And MR-Egger intercept method revealed the absence of horizontal pleiotropy in this investigation (P>0.05). The Cochran's Q Test indicated an absence of heterogeneity among them (P>0.05). Heterogeneity and horizontal pleiotropy tests further demonstrate that the results of MR are relatively stable. The above results all suggest that pSS may promote the risk of hypertension.
CONCLUSIONS
Our study provides evidence of a causal relationship of SS and hypertension. It is suggested to pay attention to early screening for hypertension, reduce disability and mortality rates, and improve patient prognosis in patients with SS.
PubMed: 38949761
DOI: 10.23736/S2724-5683.24.06522-0 -
PharmacoEconomics - Open Jul 2024Understanding the socioeconomic burden of multiple sclerosis (MS) is essential to inform policymakers and payers. Real-world studies have associated increasing costs and...
BACKGROUND AND OBJECTIVE
Understanding the socioeconomic burden of multiple sclerosis (MS) is essential to inform policymakers and payers. Real-world studies have associated increasing costs and worsening quality of life (QoL) with disability progression. This study aims to further evaluate the impact of cognition, fatigue, upper and lower limb function (ULF, LLF) impairments, and disease progression per Expanded Disability Status Scale (EDSS) level, on costs and QoL.
METHODS
This was a cross-sectional cohort study including 20,988 patients from the German NeuroTransData MS registry from 2009 to 2019. QoL analyses were based on EQ-5D-5L. Cost analyses included indirect/direct medical and non-medical costs. Eight subgroups, ranging from 439 to 1812 patients were created based on presence of measures for disease progression (EDSS), cognition (Symbol Digit Modalities Test [SDMT]), fatigue (Modified Fatigue Impact 5-Item Scale [MFIS-5]), ULF (Nine-Hole Peg Test [9HPT]), and LLF (Timed 25-Foot Walk [T25FW]). Multivariable linear regression assessed the independent effect of each test's score on QoL and costs, while adjusting for EDSS and 12 other confounders.
RESULTS
Lower QoL was associated with decreasing cognition (p < 0.001), worsening ULF (p = 0.025), and increasing fatigue (p < 0.0001); however, the negative impact of LLF worsening on QoL was not statistically significant (p = 0.54). Higher costs were associated with decreasing cognition (p < 0.001), worsening of ULF (p = 0.0058) and LLF (p = 0.049), and increasing fatigue (p < 0.0001). Each 1-scale-step worsening function of SDMT, MFIS-5, 9HPT, and T25FW scores resulted in €170, €790, €330, and €520 higher costs, respectively. Modeling disability progression based on SDMT, MFIS-5, 9HPT, and T25FW scores as an interaction with EDSS strata found associations with lower QoL and higher costs at variable EDSS ranges.
CONCLUSIONS
Disease progression in MS measured by 9HPT, SDMT, and MFIS-5 had a significant negative impact on QoL and broad socioeconomic costs independent of EDSS. T25FW had a significant negative association with costs. Cognition, fatigue, ULF, and LLF have stronger impact on costs and QoL in patients with higher EDSS scores. Additional determinants of MS disability status, including SDMT, MFIS-5, 9HPT, and T25FW, should be considered for assessing cost effectiveness of novel therapeutics for MS.
PubMed: 38949748
DOI: 10.1007/s41669-024-00501-x -
Annals of Dyslexia Jun 2024Reading proficiency is important because it has life-long consequences and influences success in other academic areas. Many students with behavior problems are poor...
Reading proficiency is important because it has life-long consequences and influences success in other academic areas. Many students with behavior problems are poor readers and many students with learning disabilities have more behavior problems than their typical peers. We conducted a correlational meta-analysis to examine the association between reading and externalizing behavior in students ages 5-12. We identified 33 studies that reported 88 effect sizes. Using a random-effects linear regression model with robust variance estimation, we found a significant, negative correlation (r= -0.1698, SE = 0.01, p < 0.0001) between reading and externalizing behavior. We tested several moderators related to measurement and sample characteristics. We found that rater type, behavior dimension (e.g., aggression), time between longitudinal measurement points, age of the sample, and percentage male of the sample moderated the relation between reading and behavior. Whether the reading assessment measured comprehension or word reading and socioeconomic status of the sample did not moderate the relation. Understanding the association between reading and externalizing behavior has implications for disability identification and intervention practices for children in elementary school. Future research should examine shared cognitive factors and environmental influences that explain the relation between the constructs.
PubMed: 38949745
DOI: 10.1007/s11881-024-00307-w -
Drugs Jul 2024Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can induce progressive disability if not properly treated early. Over the last 20...
Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can induce progressive disability if not properly treated early. Over the last 20 years, the improvement of knowledge on the pathogenesis of the disease has made available several drugs targeting key elements of the pathogenetic process, which now represent the preferred treatment option after the failure of first-line therapy with conventional drugs such as methotrexate (MTX). To this category of targeted drugs belong anti-cytokine or cell-targeted biological agents and more recently also Janus kinase inhibitors (JAKis). In the absence to date of specific biomarkers to guide the therapeutic choice in the context of true precision medicine, the choice of the first targeted drug after MTX failure is guided by treatment cost (especially after the marketing of biosimilar products) and by the clinical characteristics of the patient (age, sex, comorbidities and compliance) and the disease (presence or absence of autoantibodies and systemic or extra-articular manifestations), which may influence the efficacy and safety profile of the available products. This viewpoint focuses on the decision-making process underlying the personalized approach to RA therapy and will analyse the evidence in the literature supporting the choice of individual products and in particular the differential choice between biological drugs and JAKis.
PubMed: 38949688
DOI: 10.1007/s40265-024-02059-8 -
ELife Jul 2024Tubulin posttranslational modifications (PTMs) modulate the dynamic properties of microtubules and their interactions with other proteins. However, the effects of...
Tubulin posttranslational modifications (PTMs) modulate the dynamic properties of microtubules and their interactions with other proteins. However, the effects of tubulin PTMs were often revealed indirectly through the deletion of modifying enzymes or the overexpression of tubulin mutants. In this study, we directly edited the endogenous tubulin loci to install PTM-mimicking or -disabling mutations and studied their effects on microtubule stability, neurite outgrowth, axonal regeneration, cargo transport, and sensory functions in the touch receptor neurons of . We found that the status of β-tubulin S172 phosphorylation and K252 acetylation strongly affected microtubule dynamics, neurite growth, and regeneration, whereas α-tubulin K40 acetylation had little influence. Polyglutamylation and detyrosination in the tubulin C-terminal tail had more subtle effects on microtubule stability likely by modulating the interaction with kinesin-13. Overall, our study systematically assessed and compared several tubulin PTMs for their impacts on neuronal differentiation and regeneration and established an in vivo platform to test the function of tubulin PTMs in neurons.
Topics: Animals; Tubulin; Protein Processing, Post-Translational; Caenorhabditis elegans; Microtubules; Caenorhabditis elegans Proteins; Acetylation; Axons; Phosphorylation; Nerve Regeneration; Kinesins
PubMed: 38949652
DOI: 10.7554/eLife.94583 -
Human Brain Mapping Jul 2024Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and...
Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.
Topics: Humans; Adolescent; Female; Aged; Adult; Child; Young Adult; Male; Brain; Aged, 80 and over; Child, Preschool; Middle Aged; Aging; Magnetic Resonance Imaging; Neuroimaging; Sample Size
PubMed: 38949537
DOI: 10.1002/hbm.26768 -
Archives of Suicide Research : Official... Jul 2024There is a growing body of evidence on suicide risk in family carers, but minimal research on parents caring for children with disabilities and long-term illnesses. The...
OBJECTIVE
There is a growing body of evidence on suicide risk in family carers, but minimal research on parents caring for children with disabilities and long-term illnesses. The aim of this study was to conduct the first dedicated research on suicide risk in parent carers and identify: (1) the number of parent carers experiencing suicidal thoughts and behaviors, and (2) the risk and protective factors for suicidality in this population.
METHOD
A cross-sectional survey of parent carers in England ( = 750), co-produced with parent carers. Suicidal thoughts and behaviors were measured with questions from the Adult Psychiatric Morbidity Survey. Frequencies summarized the proportion of carers experiencing suicidal thoughts and behaviors. Logistic regressions identified risk and protective factors.
RESULTS
42% of parents had experienced suicidal thoughts and behaviors while caring for a disabled or chronically ill child. Only half had sought help for these experiences. Depression, entrapment, dysfunctional coping, and having a mental health diagnosis prior to caring, were significant risk factors.
CONCLUSION
Parent carers contemplate suicide at levels that exceed those of other family carers and the general public. There is an urgent need, in policy and practice, to recognize parent carers as a priority group for prevention and intervention.
PubMed: 38949265
DOI: 10.1080/13811118.2024.2363230 -
Spine Jul 2024An observational registry-based study.
STUDY DESIGN
An observational registry-based study.
OBJECTIVE
We investigated the long-term patterns of sick leave among patients undergoing surgery for lumbar disk herniation using two nationwide databases to study the achievement of post-surgery return to work (RTW).
SUMMARY OF BACKGROUND DATA
The ability to RTW is increasingly recognized as an essential outcome measure for spine surgery.
METHODS
The study included 13,698 patients aged 18 to 60 on sick leave undergoing surgery for lumbar disk herniation from January 2007 through January 2019. Data from the Norwegian Registry for Spine Surgery (NORspine) and the Norwegian Labour and Welfare Administration (NAV) were linked. Certified sick leave around the time of surgery was assessed. The patients were further categorized according to the length of pre-surgery sick leave, and the rate of sustainable RTW for the different groups was compared using survival analysis. The association between successful surgical outcomes, defined by a 30% improvement in Oswestry Disability Index score, and achievement of sustainable RTW was analyzed using a logistic regression model.
RESULTS
Two years after surgery, 76% of the patients had returned to work. Shorter pre-surgery sick leave was associated with a higher proportion and rate of achieved sustainable RTW: Among patients with sick leave of less than 30 days, a total of 99% achieved sustainable RTW (median 46 d); only 40% of patients with longer-lasting work assessment allowance achieved the same goal within two years. Successful surgical outcomes were associated with sustainable RTW for all patient groups, but the impact of surgical success on RTW declined as sick leave extended beyond 180 days.
CONCLUSION
Most patients had returned to work two years after lumbar disk herniation surgery. Shorter pre-surgery sick leave was associated with achieving faster and more sustainable RTW. Successful surgical outcomes had less impact on patients with extended sick leave.
LEVEL OF EVIDENCE
III.
PubMed: 38949248
DOI: 10.1097/BRS.0000000000005082