Agreement between self-, mother and father proxy-reports on health-related quality of life in adolescents with Tourette syndrome.

This study aimed to investigate agreement and discrepancies between parent proxy- and adolescent self-reports on assessments of adolescents' health-related quality of life (HRQoL), and the role that individual factors may play in parent-adolescent agreement, in a sample of adolescents with Tourette syndrome (TS) compared to a control group of healthy adolescents. Adolescents aged 12-18 years diagnosed with TS were recruited with their parents from primary and secondary referral centres. Adolescent healthy controls were matched for gender and age. Adolescents and each of their parents completed a set of questionnaires including a HRQoL evaluation of adolescent, the 'Vécu et Santé Perçue de l'Adolescent'. Mother-adolescent, father-adolescent and mother-father agreements on adolescents' HRQoL scores were investigated at individual and group level, both in TS and control groups. Data were available for 75 adolescents, 75 mothers and 63 fathers, in the TS group. Agreement between mother, father proxy-reports and TS adolescents self-reports of HRQoL varied from poor to good, without significant difference with the control group. In TS group, mothers and fathers underestimated adolescents' HRQoL in 'Psychological well-being' subscale and mothers underestimated it in 'Physical 'well-being' subscale, while controls overestimated adolescents' HRQoL in these subscales. Larger mother-adolescent discrepancies for 'Psychological well-being' and 'Physical well-being' subscales were associated with internalizing symptoms. Regarding future studies, comprehensive evaluation of the various dimensions of adolescents' HRQoL with TS requires the integration of the perspectives of both adolescents, mothers and fathers. Clinicians should take into account this point to provide comprehensive care and services.

An automated single-molecule FRET platform for high-content, multiwell plate screening of biomolecular conformations and dynamics.

Single-molecule FRET (smFRET) has become a versatile tool for probing the structure and functional dynamics of biomolecular systems, and is extensively used to address questions ranging from biomolecular folding to drug discovery. Confocal smFRET measurements are amongst the widely used smFRET assays and are typically performed in a single-well format. Thus, sampling of many experimental parameters is laborious and time consuming. To address this challenge, we extend here the capabilities of confocal smFRET beyond single-well measurements by integrating a multiwell plate functionality to allow for continuous and automated smFRET measurements. We demonstrate the broad applicability of the multiwell plate assay towards DNA hairpin dynamics, protein folding, competitive and cooperative protein-DNA interactions, and drug-discovery, revealing insights that would be very difficult to achieve with conventional single-well format measurements. For the adaptation into existing instrumentations, we provide a detailed guide and open-source acquisition and analysis software.

Tourette syndrome research highlights from 2022.

This is the ninth yearly article in the Tourette Syndrome Research Highlights series, summarizing selected research reports from 2022 relevant to Tourette syndrome. The authors briefly summarize reports they consider most important or interesting.

Tourette syndrome and other tic disorders of childhood.

Tics are repetitive, patterned, and nonrhythmic movements or vocalizations/audible sounds that are misplaced in context. Phenomenology and characteristics of tics (e.g., premonitory urge, suppressibility) differentiate them from compulsions, stereotypies, functional tic-like behaviors, and other types of hyperkinetic movement disorders. With a prevalence of approximately 1% in school-aged boys, Tourette syndrome (TS) is considered a common childhood-onset neurodevelopmental disorder, defined by the combination of at least two motor tics and at least one phonic tic lasting more than 1 year. TS is a highly heritable disorder, with a wide spectrum of severity. In some individuals, tics can cause pain, distress, functional impairment, or stigmatization. About 90% of individuals with TS have at least one mental health comorbidity (attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, anxiety/depressive disorders). These comorbidities significantly impact patients' quality of life and must therefore be screened and managed accordingly in this population. Treatment of tics is based on behavioral therapies targeting tics (habit reversal training included in the comprehensive behavioral intervention for tics, and exposure and response prevention for tics), in association with medication if needed (e.g., alpha-2-agonists, second-generation antipsychotics). Deep brain stimulation is considered an experimental option in the most severe, treatment-resistant patients. In adulthood, less than 25% of individuals still have moderate or severe tics.

Neurofilament Light Chain: A Translational Safety Biomarker for Drug-Induced Peripheral Neurotoxicity.

Branaplam is a splicing modulator previously under development as a therapeutic agent for Spinal Muscular Atrophy Type 1 and Huntington's disease. Branaplam increased the levels of survival motor neuron protein in preclinical studies and was well tolerated in early clinical studies; however, peripheral neurotoxicity was observed in a preclinical safety study in juvenile dogs. The aim of this study was to determine whether serum neurofilament light chain (NfL) concentrations in dogs could serve as a monitoring biomarker for branaplam-induced peripheral neurotoxicity. A 30-week time-course investigative study in dogs treated with vehicle control (negative control), neurotoxic pyridoxine (positive control), or branaplam was conducted to assess neuropathology, nerve morphometry, electrophysiological measurements, gene expression profiles, and correlation to NfL serum concentrations. In branaplam-treated animals, a mild to moderate nerve fiber degeneration was observed in peripheral nerves correlating with increased serum NfL concentrations, but there were no observed signs or changes in electrophysiological parameters. Dogs with pyridoxine-induced peripheral axonal degeneration displayed clinical signs and electrophysiological changes in addition to elevated serum NfL. This study suggests that NfL may be useful as an exploratory biomarker to assist in detecting and monitoring treatment-related peripheral nerve injury, with or without clinical signs, associated with administration of branaplam and other compounds bearing a neurotoxic risk.

Correction: Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome.

[This corrects the article DOI: 10.5334/tohm.464.].

A data-driven approach for modelling Karst spring discharge using transfer function noise models.

Karst aquifers are important sources of fresh water on a global scale. The hydrological modelling of karst spring discharge, however, still poses a challenge. In this study we apply a transfer function noise (TFN) model in combination with a bucket-type recharge model to simulate karst spring discharge. The application of the noise model for the residual series has the advantage that it is more consistent with assumptions for optimization such as homoscedasticity and independence. In an earlier hydrological modeling study, named Karst Modeling Challenge (KMC; Jeannin et al., J Hydrol 600:126-508, 2021), several modelling approaches were compared for the Milandre Karst System in Switzerland. This serves as a benchmark and we apply the TFN model to KMC data, subsequently comparing the results to other models. Using different data-model-combinations, the most promising data-model-combination is identified in a three-step least-squares calibration. To quantify uncertainty, the Bayesian approach of Markov-chain Monte Carlo (MCMC) sampling is subsequently used with uniform priors for the previously identified best data-model combination. The MCMC maximum likelihood solution is used to simulate spring discharge for a previously unseen testing period, indicating a superior performance compared to all other models in the KMC. It is found that the model gives a physically feasible representation of the system, which is supported by field measurements. While the TFN model simulated rising limbs and flood recession especially well, medium and baseflow conditions were not represented as accurately. The TFN approach poses a well-performing data-driven alternative to other approaches that should be considered in future studies.

Reliability and accuracy of single-molecule FRET studies for characterization of structural dynamics and distances in proteins.

Single-molecule Förster-resonance energy transfer (smFRET) experiments allow the study of biomolecular structure and dynamics in vitro and in vivo. We performed an international blind study involving 19 laboratories to assess the uncertainty of FRET experiments for proteins with respect to the measured FRET efficiency histograms, determination of distances, and the detection and quantification of structural dynamics. Using two protein systems with distinct conformational changes and dynamics, we obtained an uncertainty of the FRET efficiency ≤0.06, corresponding to an interdye distance precision of ≤2 Å and accuracy of ≤5 Å. We further discuss the limits for detecting fluctuations in this distance range and how to identify dye perturbations. Our work demonstrates the ability of smFRET experiments to simultaneously measure distances and avoid the averaging of conformational dynamics for realistic protein systems, highlighting its importance in the expanding toolbox of integrative structural biology.

Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome.

BACKGROUND: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. METHODS: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. RESULTS: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. CONCLUSIONS: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome.

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

European Society for the Study of Tourette Syndrome 2022 criteria for clinical diagnosis of functional tic-like behaviours: International consensus from experts in tic disorders.

BACKGROUND AND PURPOSE: In 2020, health professionals witnessed a dramatic increase in referrals of young people with rapid onset of severe tic-like behaviours. We assembled a working group to develop criteria for the clinical diagnosis of functional tic-like behaviours (FTLBs) to help neurologists, pediatricians, psychiatrists, and psychologists recognize and diagnose this condition. METHODS: We used a formal consensus development process, using a multiround, web-based Delphi survey. The survey was based on an in-person discussion at the European Society for the Study of Tourette Syndrome (ESSTS) meeting in Lausanne in June 2022. Members of an invited group with extensive clinical experience working with patients with Tourette syndrome and FTLBs discussed potential clinical criteria for diagnosis of FTLBs. An initial set of criteria were developed based on common clinical experiences and review of the literature on FTLBs and revised through iterative discussions, resulting in the survey items for voting. RESULTS: In total, 24 members of the working group were invited to participate in the Delphi process. We propose that there are three major criteria and two minor criteria to support the clinical diagnosis of FTLBs. A clinically definite diagnosis of FTLBs can be confirmed by the presence of all three major criteria. A clinically probable diagnosis of FTLBs can be confirmed by the presence of two major criteria and one minor criterion. CONCLUSIONS: Distinguishing FTLBs from primary tics is important due to the distinct treatment paths required for these two conditions. A limitation of the ESSTS 2022 criteria is that they lack prospective testing of their sensitivity and specificity.

The spectrum of functional tic-like behaviours: Data from an international registry.

BACKGROUND AND PURPOSE: Between 2019 and 2022, there was a marked rise in adolescents/young adults seeking urgent help for functional tic-like behaviours (FTLBs). Given the global scale of this phenomenon, we aimed to pool cases from different institutions in an international registry to better characterize this spectrum and facilitate future longitudinal observation. METHODS: An international collaborative group from 10 tertiary referral centres for tic disorders collected retrospective data on FTLB patients who sought specialists' attention between the last quarter of 2019 and June 2022. An audit procedure was used for collection of data, which comprised demographics, course of presentation and duration, precipitating and predisposing factors, phenomenology, comorbidities, and pharmacological treatment outcome. RESULTS: During the study period, we collected data on 294 patients with FTLBs, 97% of whom were adolescents and young adults and 87% of whom were female. FTLBs were found to have a peak of severity within 1 month in 70% of patients, with spontaneous remissions in 20%, and a very high frequency of complex movements (85%) and vocalizations (81%). Less than one-fifth of patients had pre-existing primary tic disorder, 66% had comorbid anxiety disorders, 28% comorbid depressive disorders, 24% autism spectrum disorder and 23% attention deficit/hyperactivity disorder. Almost 60% explicitly reported exposure to tic-related social media content. The vast majority of pharmacologically treated patients did not report benefit with tic-suppressing medications. CONCLUSIONS: Our data from the largest multicentre registry of FTLBs to date confirm substantial clinical differences from primary tic disorders. Social modelling was the most relevant contributing factor during the pandemic. Future longitudinal analyses from this database may help understand treatment approaches and responsiveness.

How does Tourette syndrome impact adolescents' daily living? A text mining study.

Tourette syndrome is a neurodevelopmental disease in which clinical manifestations are essentially present during childhood and adolescence, corresponding to one of the critical development phases. However, its consequences on the daily lives of young patients have been insufficiently investigated. Here, we aimed to investigate this using a statistical text mining approach, allowing for the analysis of a large volume of free textual data. Sixty-two adolescents with Tourette syndrome participated in an interview in which they discussed their daily life (i) in school, (ii) at home, and (iii) with strangers, (iv) the aspect of Tourette syndrome which caused the most difficulty, and (v) their thoughts regarding their future as adults. Following data pre-processing, these corpora were analyzed separately using the IRAMUTEQ software through factorial correspondence analysis to identify the most commonly recurring topics of each corpus, and their relations with clinical features. The main difficulty corpus was directly related to comorbidities of Tourette syndrome. Daily life at home was correlated with executive functioning. Difficulties at school were related to a higher severity of tics. Thoughts regarding future daily life were worst for the youngest patients and were correlated with executive functioning and a higher depression score. Taken altogether, our results highlighted that social stigma was a pervasive topic among our corpora. From a clinical standpoint, tic severity was especially related to difficulties at school, while comorbidities had a high impact on social daily living and cost for managing both tics and symptoms of comorbidities. TRIAL REGISTRATION: clinicaltrials.gov/ct2/show/NCT04179435.

Results of a Randomized Clinical Trial of Speech After Early Neurostimulation in Parkinson's Disease.

BACKGROUND: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone. OBJECTIVE: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments. METHODS: STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months. RESULTS: Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III. CONCLUSION: At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Decision-making under risk and ambiguity in adults with Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) as well as its most common comorbidities are associated with a higher propensity for risky behaviour in everyday life. However, it is unclear whether this increased risk propensity in real-life contexts translates into a generally increased attitude towards risk. We aimed to assess decision-making under risk and ambiguity based on prospect theory by considering the effects of comorbidities and medication. METHODS: Fifty-four individuals with TS and 32 healthy controls performed risk and ambiguity decision-making tasks under both gains and losses conditions. Behavioural and computational parameters were evaluated using (i) univariate analysis to determine parameters difference taking independently; (ii) supervised multivariate analysis to evaluate whether our parameters could jointly account for between-group differences (iii) unsupervised multivariate analysis to explore the potential presence of sub-groups. RESULTS: Except for general 'noisier' (less consistent) decisions in TS, we showed no specific risk-taking behaviour in TS or any relation with tics severity or antipsychotic medication. However, the presence of comorbidities was associated with distortion of decision-making. Specifically, TS with obsessive-compulsive disorder comorbidity was associated with a higher risk-taking profile to increase gain and a higher risk-averse profile to decrease loss. TS with attention-deficit hyperactivity disorder comorbidity was associated with risk-seeking in the ambiguity context to reduce a potential loss. CONCLUSIONS: Impaired valuation of risk and ambiguity was not related to TS per se. Our findings are important for clinical practice: the involvement of individuals with TS in real-life risky situations may actually rather result from other factors such as psychiatric comorbidities.

[Endoscopic Ultrasound Drainage of the Gallbladder in Acute Cholecystitis in Patients at High Surgical Risk]. / Endosonografische Drainage der Gallenblase wegen akuter Cholezystitis bei Patienten mit hohem Operationsrisiko.

BACKGROUND: The standard treatment for acute cholecystitis is laparoscopic cholecystectomy. Alternative procedures are used for patients at high surgical risk. Percutaneous drainage is widely available. The alternative of transpapillary drainage of the gallbladder via the ductus cysticus has only limited prospects of success. With the widespread use of interventional endoscopic ultrasound and the development of new stent systems, endoscopic ultrasound gallbladder drainage has proven to be a safe and reliable procedure. MATERIAL AND METHOD: We retrospectively report on our experiences in 11 consecutive patients with endoscopic ultrasound gallbladder drainage in acute cholecystitis between December 2018 and January 2021. RESULTS: 11 patients with acute cholecystitis with a mean age of 84.5 years (70-95 years) are reported. All patients had severe general comorbidities or advanced abdominal tumours or a combination of these conditions. After interdisciplinary debate, the indication for interventional therapy was made. This was carried out in 9 cases by means of endosonographic drainage alone and in 2 cases by means of percutaneous and two-stage endosonographic drainage. Technical success was achieved in 10 cases (91%), clinical success in 9 cases (82%). In 2 cases there were procedural complications that led to the operation. CONCLUSION: In the case of high surgical risks, endosonographic drainage of the gall bladder is a safe and definitive therapy. This can be performed alone or in combination with percutaneous drainage. Endoscopic ultrasound drainage is superior to percutaneous drainage alone, due to its lower complication rates and lower rates of necessary follow-up interventions. Therefore, in cases of relatively high surgical risk, endoscopic ultrasound drainage of the gall bladder should be preferred to percutaneous drainage, especially when definitive therapy is required.

Multivariate classification provides a neural signature of Tourette disorder.

BACKGROUND: Tourette disorder (TD), hallmarks of which are motor and vocal tics, has been related to functional abnormalities in large-scale brain networks. Using a fully data driven approach in a prospective, case-control study, we tested the hypothesis that functional connectivity of these networks carries a neural signature of TD. Our aim was to investigate (i) the brain networks that distinguish adult patients with TD from controls, and (ii) the effects of antipsychotic medication on these networks. METHODS: Using a multivariate analysis based on support vector machine (SVM), we developed a predictive model of resting state functional connectivity in 48 patients and 51 controls, and identified brain networks that were most affected by disease and pharmacological treatments. We also performed standard univariate analyses to identify differences in specific connections across groups. RESULTS: SVM was able to identify TD with 67% accuracy (p = 0.004), based on the connectivity in widespread networks involving the striatum, fronto-parietal cortical areas and the cerebellum. Medicated and unmedicated patients were discriminated with 69% accuracy (p = 0.019), based on the connectivity among striatum, insular and cerebellar networks. Univariate approaches revealed differences in functional connectivity within the striatum in patients v. controls, and between the caudate and insular cortex in medicated v. unmedicated TD. CONCLUSIONS: SVM was able to identify a neuronal network that distinguishes patients with TD from control, as well as medicated and unmedicated patients with TD, holding a promise to identify imaging-based biomarkers of TD for clinical use and evaluation of the effects of treatment.

Science-Based Approach to Harmonize Contraception Recommendations in Clinical Trials and Pharmaceutical Labels.

This review presents a European Federation of Pharmaceutical Industries and Association/PreClinical Development Expert Group (EFPIA-PDEG) topic group consensus on a data-driven approach to harmonized contraception recommendations for clinical trial protocols and product labeling. There is no international agreement in pharmaceutical clinical trial protocols or product labeling on when/if female and/or male contraception is warranted and for how long after the last dose. This absence of consensus has resulted in different recommendations among regions. For most pharmaceuticals, contraception recommendations are generally based exclusively on nonclinical data and/or mechanism. For clinical trials, contraception is the default position and is maintained for women throughout clinical development, whereas appropriate information can justify removing male contraception. Conversely, contraception is only recommended in product labeling when warranted. A base case rationale is proposed for whether or not female and/or male contraception is/are warranted, using available genotoxicity and developmental toxicity data. Contraception is generally warranted for both male and female subjects treated with mutagenic pharmaceuticals. We propose as a starting point that contraception is not typically warranted when the margin is 10-fold or greater between clinical exposure at the maximum recommended human dose and exposure at the no observed adverse effect level (NOAEL) for purely aneugenic pharmaceuticals and for pharmaceuticals that induce fetal malformations or embryo-fetal lethality. Other factors are discussed, including contraception methods, pregnancy testing, drug clearance, options for managing the absence of a developmental toxicity NOAEL, drug-drug interactions, radiopharmaceuticals, and other drug modalities. Overall, we present a data-driven rationale that can serve as a basis for consistent contraception recommendations in clinical trials and in product labeling across regions.

The French version of the Gilles de la Tourette Syndrome Quality of Life Scale for adolescents (GTS-QOL-French-Ado): Adaptation and psychometric evaluation.

INTRODUCTION: The aim of this study was to create a new version of the French GTS-QOL adapted to adolescents with GTS aged 12-16 years (GTS-QOL-French-Ado) and to evaluate its psychometric properties. METHODS: We assessed the psychometric properties of the GTS-QOL-French-Ado in 84 adolescents (mean age 13.6 years, standard deviation 1.2) in terms of factor structure, internal consistency, reliability and convergent validity with the Child Depression Inventory (CDI), the Multidimensional Anxiety Scale for Children (MASC), the Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey (MOVES) and the French "Vécu et Santé Perçue de l'Adolescent" (VSP-A), a generic self-administered measure of health-related quality of life (HRQoL) in adolescents. RESULTS: Exploratory factor analysis of the GTS-QOL-French-Ado resulted in a 5-factor solution. The GTS-QOL-French-Ado demonstrated good acceptability with missing values per subscale ranging from 0% to 1.2%, good internal consistency for four of the five subscales with Cronbach's alpha ranging from 0.56 to 0.87 and good test-retest reliability with intraclass correlation coefficients ranging from 0.74 (95% CI: 0.52-0.86) to 0.82 (95% CI: 0.66-0.91). Convergent validity was supported by correlations with CDI, MASC, MOVES, VSP-A and clinical variables. DISCUSSION: The GTS-QOL-French-Ado is the first disease-specific HRQoL tool for French-speaking adolescents with GTS aged 12-16 years, and shows good psychometric properties. Further psychometric testing on responsiveness to change would be of great interest.