Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene.

Motor stereotypies are common in children with autism spectrum disorder (ASD), intellectual disability, or sensory deprivation, as well as in typically developing children ("primary" stereotypies, pCMS). The precise pathophysiological mechanism for motor stereotypies is unknown, although genetic etiologies have been suggested. In this study, we perform whole-exome DNA sequencing in 129 parent-child trios with pCMS and 853 control trios (118 cases and 750 controls after quality control). We report an increased rate of de novo predicted-damaging DNA coding variants in pCMS versus controls, identifying KDM5B as a high-confidence risk gene and estimating 184 genes conferring risk. Genes harboring de novo damaging variants in pCMS probands show significant overlap with those in Tourette syndrome, ASD, and those in ASD probands with high versus low stereotypy scores. An exploratory analysis of these pCMS gene expression patterns finds clustering within the cortex and striatum during early mid-fetal development. Exploratory gene ontology and network analyses highlight functional convergence in calcium ion transport, demethylation, cell signaling, cell cycle and development. Continued sequencing of pCMS trios will identify additional risk genes and provide greater insights into biological mechanisms of stereotypies across diagnostic boundaries.

Factors associated with the unwillingness of Jordanians, Palestinians and Syrians to be vaccinated against COVID-19.

BACKGROUND: The COVID-19 pandemic is expected to continue to inflect immense burdens of morbidity and mortality, not to mention the sever disruption of societies and economies worldwide. One of the major challenges to managing COVID-19 pandemic is the negative attitudes towards vaccines and the uncertainty or unwillingness to receive vaccinations. We evaluated the predictors and factors behind the negative attitudes towards COVID-19 vaccines in 3 countries in the Middle East. METHODS: A cross-sectional, self-administered survey was conducted between the 1st and the 25th of December, 2020. Representative sample of 8619 adults residing in Jordan, West Bank, and Syria, completed the survey via the Web or via telephone interview. The survey intended to assess intent to be vaccinated against COVID-19 and to identify predictors of and reasons among participants unwilling/hesitant to get vaccinated. RESULTS: The total of the 8619 participants included in this study were the ones who answered the question on the intent to be vaccinated. Overall, 32.2% of participants (n = 2772) intended to be vaccinated, 41.6% (n = 3589) didn't intend to get vaccinated, and 26.2% (n = 2258) were not sure. The main factors associated with the willingness to take the vaccine (yes responses) included females, 18-35 years old, Syrians and Jordanians, a large family size, and having received a flu vaccine last year. Reasons for vaccine hesitancy included the lack of rigorous evaluation of the vaccine by the FDA and the possible long-term health risks associated with the vaccines (the wait-and-see approach). CONCLUSION: This survey, conducted in December when the number of cases and deaths per day due to COVID-19 were at or near peak levels of the initial surge in the three regions under investigation. The survey revealed that most of survey's participants (67.8%) were unwilling/hesitant to get vaccinated against COVID-19 with the lack of trust in the approval process of the vaccine being the main concern; the two main characteristics of those participants were more than 35 years old and participants holding a Bachelor's degree or higher. Targeted and multi-pronged efforts will be needed to increase acceptance of COVID-19 vaccine in Jordan, West Bank and Syria.

De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with a genetic risk component, yet identification of high-confidence risk genes has been challenging. In recent years, risk gene discovery in other complex psychiatric disorders has been achieved by studying rare de novo (DN) coding variants. METHODS: We performed whole-exome sequencing in 222 OCD parent-child trios (184 trios after quality control), comparing DN variant frequencies with 777 previously sequenced unaffected trios. We estimated the contribution of DN mutations to OCD risk and the number of genes involved. Finally, we looked for gene enrichment in other datasets and canonical pathways. RESULTS: DN likely gene disrupting and predicted damaging missense variants are enriched in OCD probands (rate ratio, 1.52; p = .0005) and contribute to risk. We identified 2 high-confidence risk genes, each containing 2 DN damaging variants in unrelated probands: CHD8 and SCUBE1. We estimate that 34% of DN damaging variants in OCD contribute to risk and that DN damaging variants in approximately 335 genes contribute to risk in 22% of OCD cases. Furthermore, genes harboring DN damaging variants in OCD are enriched for those reported in neurodevelopmental disorders, particularly Tourette's disorder and autism spectrum disorder. An exploratory network analysis reveals significant functional connectivity and enrichment in canonical pathways, biological processes, and disease networks. CONCLUSIONS: Our findings show a pathway toward systematic gene discovery in OCD via identification of DN damaging variants. Sequencing larger cohorts of OCD parent-child trios will reveal more OCD risk genes and will provide needed insights into underlying disease biology.

Severe Illness Anxiety Treated by Integrating Inpatient Psychotherapy With Medical Care and Minimizing Reassurance.

Illness anxiety disorder (IAD, formerly hypochondriasis) is characterized by preoccupation with fear of serious illness despite medical reassurance. IAD is common, debilitating, challenging to treat, and results in high healthcare utilization. Outpatient management of IAD is challenging because patients can compulsively seek reassurance from numerous providers, which interferes with learning more productive coping skills. We present the case of a woman with severe IAD who presented to the emergency room with increasing frequency over several months, despite regular outpatient medical visits and escalating psychiatric care. We made the unusual decision to hospitalize her for IAD for 1 month, in the absence of typical hospitalization criteria. This hospitalization allowed us to consolidate all medical and psychiatric care into a single provider team and train all staff and family to communicate with her in a consistent manner. We successfully treated her by integrating a general cognitive-behavioral therapy (CBT) protocol into medical care and decision-making. In response to her numerous health concerns, we minimized medical work-up, reassurance, and reactive medication changes, and instead used the concerns as opportunities to reinforce the psychotherapy. This approach allowed us to simplify her medication regimen and manage her co-morbid hypertension and vitamin deficiencies. Though inpatient hospitalization is likely infeasible in most cases of IAD, outpatient providers may create similar treatment plans based on the example of our case report, without needing highly specialized expertise. Such a plan would require a straightforward understanding of IAD psychology, which we review here, combined with readily accessible tools including a universal CBT protocol, online CBT courses, and clinical symptom scales. We discuss our approach for responding to health concerns, maintaining therapeutic alliance, integrating CBT principles into patient interactions, and managing medications. Since patients with IAD share health concerns with all providers, staff, and family, we also include our own IAD communication guide, appropriate for a general audience, that demonstrates how to respond in these conversations.

Ondansetron Is an Effective Alternative to Decrease the Incidence of Postspinal Hypotension in Healthy Subjects Undergoing Infra-Umbilical Surgeries Compared To Combined Volume Loading and Vasoconstrictors: Randomized Controlled Trial.

BACKGROUND: One of the important and predicted physiological effects of spinal anaesthesia is hypotension. A range of strategies including mechanical interventions, intravenous fluids and vasoconstrictor drugs have been used to minimise or prevent spinal anaesthesia-induced hypotension. Observational studies suggest that ondansetron reduces the incidence of post-spinal hypotension (PSH) and support the use of combined fluid preloading and vasoconstrictors for this purpose (but with limited doses) to avoid side effects as fluid overload and tachycardia respectively. AIM: As no RCT had ever compared the use of Ondansetron alone with combined vasoconstrictors and fluid preload, so, this randomised controlled trial has evaluated the efficacy of the use of ondansetron alone compared to the combined use of fluid preload and vasoconstrictors to decrease the incidence of spinal hypotension. METHODS: Ninety patients of ASA grade I between the age of 18 and 45 years scheduled to undergo elective surgical procedures on the lower extremity or lower abdomen under spinal anaesthesia were included in the study. The patients were randomly allocated into two groups of 45 each. Group I patients (ondansetron group) received 4 mg ondansetron in 5 ml normal saline (IV) 15 minutes before induction of spinal anaesthesia. Group II patients (combination group) received preloading with 7.5 ml/kg/min of Ringer's lactate over 10 minute period preceding the spinal block followed by intravenous bolus of 2.5 mg ephedrine in the first and second minute and 2.5 mg ephedrine every 5 minutes for the next 20 minutes after the injection of spinal anesthetic drug. Non-invasive measurement of mean arterial pressures, heart rate, reactive hypertension, nausea and vomiting were documented. RESULTS: The incidence of hypotension following the subarachnoid block in Group I (ondansetron group) was 17.6% versus group II (combination group) was 13.3%, while difference among the groups is statistically insignificant (P = 0.082). Group IV fluids alone could reverse hypotension in 57.1% of patients in group I 33.3% in group II. 42.9% of patients in group I and 67.7% in group II could not be managed with IV fluids alone and had to be treated with 5 mg boluses of ephedrine for reversal of hypotension. The difference in the mean number of fluid boluses and a dose of ephedrine used between both groups was statistically insignificant (P = 0.11 and P = 0.21). HR showed a significant increase in group II and a statistically insignificant change in group I with a statistically significant difference in the heart rate (HR) between both groups (P < 0.05). Reactive hypertension, nausea and vomiting between both groups were statistically insignificant. CONCLUSION: The preemptive use of Ondansetron alone versus combined vasoconstrictors with fluid preload significantly reduces the incidence of post-spinal hypotension (PSH) with no significant difference between both regimens. Furthermore, they also reduced consumption of the used vasoconstrictors and fluids to correct hypotension.

Systematic tissue-specific functional annotation of the human genome highlights immune-related DNA elements for late-onset Alzheimer's disease.

Continuing efforts from large international consortia have made genome-wide epigenomic and transcriptomic annotation data publicly available for a variety of cell and tissue types. However, synthesis of these datasets into effective summary metrics to characterize the functional non-coding genome remains a challenge. Here, we present GenoSkyline-Plus, an extension of our previous work through integration of an expanded set of epigenomic and transcriptomic annotations to produce high-resolution, single tissue annotations. After validating our annotations with a catalog of tissue-specific non-coding elements previously identified in the literature, we apply our method using data from 127 different cell and tissue types to present an atlas of heritability enrichment across 45 different GWAS traits. We show that broader organ system categories (e.g. immune system) increase statistical power in identifying biologically relevant tissue types for complex diseases while annotations of individual cell types (e.g. monocytes or B-cells) provide deeper insights into disease etiology. Additionally, we use our GenoSkyline-Plus annotations in an in-depth case study of late-onset Alzheimer's disease (LOAD). Our analyses suggest a strong connection between LOAD heritability and genetic variants contained in regions of the genome functional in monocytes. Furthermore, we show that LOAD shares a similar localization of SNPs to monocyte-functional regions with Parkinson's disease. Overall, we demonstrate that integrated genome annotations at the single tissue level provide a valuable tool for understanding the etiology of complex human diseases. Our GenoSkyline-Plus annotations are freely available at http://genocanyon.med.yale.edu/GenoSkyline.