De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Tourette Syndrome and Tic Disorders in a Swedish School Population : Prevalence, Clinical Assessment, Background, Psychopathology, and Cognitive Function

A total population of 4,479 children (7-15 years of age) attended school in Ludvika & Smedjebacken in 2000. All the school children and their parents were asked to fill in a questionnaire concerning different tics A three-stage procedure was used: tic identification, interview, and clinical assessment. Tourette syndrome, according to DSM IV criteria was found in 25 (0.6%) of the children, another 34 (0.8%) suffered from chronic motor tics (CMT), 24 (0.4%) from chronic vocal tics (CVT) and 214 (4.8%) children had had transient tics (TT) during the last year. Altogether 297 (6.6%) children had or had had some tic disorder. Twenty-five controls without tics and 25 children with TT of the same age, sex and school as the TS children were randomly chosen. They were together with the 34 children with CMT and the 24 children with CVT examined with use of a broad battery of instruments. The mean age of the first symptoms of TS was significantly lower than the onset of chronic motor/vocal tics. A younger age of onset of TS indicated more severe tics. Eighty per cent had a first-degree relative with a psychiatric disorder such as tic disorder, obsessive-compulsive behaviour, attentiondeficit/hyperactivity disorder (ADHD), or depression. A non-significant increase with regard to reduced optimality score in the pre-, peri-, or neonatal periods was found in children with TS compared to controls. No differences were found concerning socio-economic status. Psychiatric comorbid disorders were found in 92% of the children with TS. ADHD was most common. Patterns of psychiatric comorbidity were similar in children with TS and CVT. Children with TS perform poorer than the population in general with respect to cognitive functioning and self-perception. The results are discussed as they relate to the need for case identification, diagnosis, intervention, and treatment

Tourette Syndrome and Tic Disorders in a Swedish School Population : Prevalence, Clinical Assessment, Background, Psychopathology, and Cognitive Function

A total population of 4,479 children (7-15 years of age) attended school in Ludvika & Smedjebacken in 2000. All the school children and their parents were asked to fill in a questionnaire concerning different tics A three-stage procedure was used: tic identification, interview, and clinical assessment. Tourette syndrome, according to DSM IV criteria was found in 25 (0.6%) of the children, another 34 (0.8%) suffered from chronic motor tics (CMT), 24 (0.4%) from chronic vocal tics (CVT) and 214 (4.8%) children had had transient tics (TT) during the last year. Altogether 297 (6.6%) children had or had had some tic disorder. Twenty-five controls without tics and 25 children with TT of the same age, sex and school as the TS children were randomly chosen. They were together with the 34 children with CMT and the 24 children with CVT examined with use of a broad battery of instruments. The mean age of the first symptoms of TS was significantly lower than the onset of chronic motor/vocal tics. A younger age of onset of TS indicated more severe tics. Eighty per cent had a first-degree relative with a psychiatric disorder such as tic disorder, obsessive-compulsive behaviour, attentiondeficit/hyperactivity disorder (ADHD), or depression. A non-significant increase with regard to reduced optimality score in the pre-, peri-, or neonatal periods was found in children with TS compared to controls. No differences were found concerning socio-economic status. Psychiatric comorbid disorders were found in 92% of the children with TS. ADHD was most common. Patterns of psychiatric comorbidity were similar in children with TS and CVT. Children with TS perform poorer than the population in general with respect to cognitive functioning and self-perception. The results are discussed as they relate to the need for case identification, diagnosis, intervention, and treatment

Tourette Syndrome and Tic Disorders in a Swedish School Population : Prevalence, Clinical Assessment, Background, Psychopathology, and Cognitive Function

A total population of 4,479 children (7-15 years of age) attended school in Ludvika & Smedjebacken in 2000. All the school children and their parents were asked to fill in a questionnaire concerning different tics A three-stage procedure was used: tic identification, interview, and clinical assessment. Tourette syndrome, according to DSM IV criteria was found in 25 (0.6%) of the children, another 34 (0.8%) suffered from chronic motor tics (CMT), 24 (0.4%) from chronic vocal tics (CVT) and 214 (4.8%) children had had transient tics (TT) during the last year. Altogether 297 (6.6%) children had or had had some tic disorder. Twenty-five controls without tics and 25 children with TT of the same age, sex and school as the TS children were randomly chosen. They were together with the 34 children with CMT and the 24 children with CVT examined with use of a broad battery of instruments. The mean age of the first symptoms of TS was significantly lower than the onset of chronic motor/vocal tics. A younger age of onset of TS indicated more severe tics. Eighty per cent had a first-degree relative with a psychiatric disorder such as tic disorder, obsessive-compulsive behaviour, attentiondeficit/hyperactivity disorder (ADHD), or depression. A non-significant increase with regard to reduced optimality score in the pre-, peri-, or neonatal periods was found in children with TS compared to controls. No differences were found concerning socio-economic status. Psychiatric comorbid disorders were found in 92% of the children with TS. ADHD was most common. Patterns of psychiatric comorbidity were similar in children with TS and CVT. Children with TS perform poorer than the population in general with respect to cognitive functioning and self-perception. The results are discussed as they relate to the need for case identification, diagnosis, intervention, and treatment

De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk