Generating Clinical-Grade Gene-Disease Validity Classifications Through the ClinGen Data Platforms.

Clinical genetic laboratories must have access to clinically validated biomedical data for precision medicine. A lack of accessibility, normalized structure, and consistency in evaluation complicates interpretation of disease causality, resulting in confusion in assessing the clinical validity of genes and genetic variants for diagnosis. A key goal of the Clinical Genome Resource (ClinGen) is to fill the knowledge gap concerning the strength of evidence supporting the role of a gene in a monogenic disease, which is achieved through a process known as Gene-Disease Validity curation. Here we review the work of ClinGen in developing a curation infrastructure that supports the standardization, harmonization, and dissemination of Gene-Disease Validity data through the creation of frameworks and the utilization of common data standards. This infrastructure is based on several applications, including the ClinGen GeneTracker, Gene Curation Interface, Data Exchange, GeneGraph, and website.

Reboot coaching programme: a mixed-methods evaluation assessing resilience, confidence, burnout and depression in medical students.

BACKGROUND: Poor mental health in medical students is a global concern. Effective interventions are required, which are tailored towards the training-related stressors medical students experience. The Reboot coaching programme is an online, tailored intervention based on cognitive-behavioural principles. AIMS: To evaluate whether the Reboot coaching programme tailored for medical students was feasible and associated with improvements in mental health outcome indicators. METHODS: Medical students participated in two group online workshops and a one-to-one coaching call with a Reboot-trained licensed psychological therapist. Participants provided data at: baseline (T1), post-workshops (T2), post-coaching call (T3) and 4-month follow-up (T4). Outcome measures included resilience, confidence, burnout and depression. Feedback was provided regarding the workshops at T2. RESULTS: 115 participants (93/80.9% women; mage = 23.9; SD = 2.8) were recruited, 83 (72.2%) completed all intervention elements and 82 (71.3%) provided T4 data, surpassing recruitment and retention targets. There were significant improvements following baseline in resilience (ps < .001), confidence (ps < .001), burnout (ps < .001) and depression (ps ≤ .001). Most participants agreed the workshops imparted useful skills (n = 92; 99%) and would recommend Reboot to others (n = 89; 95.6%). CONCLUSIONS: Existing interventions have produced mixed results regarding their effectiveness in improving medical students' mental health. Reboot is a feasible intervention in this group which is associated with improvements in resilience, confidence, burnout and depression. Further controlled studies of Reboot are now needed.

ClinGen Variant Curation Interface: a variant classification platform for the application of evidence criteria from ACMG/AMP guidelines.

BACKGROUND: Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking. RESULTS: Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines. The VCI is among a suite of tools developed by the NIH-funded Clinical Genome Resource (ClinGen) Consortium and supports an FDA-recognized human variant curation process. Essential to this is the ability to enable collaboration and peer review across ClinGen Expert Panels supporting users in comprehensively identifying, annotating, and sharing relevant evidence while making variant pathogenicity assertions. To facilitate evidence-based improvements in human variant classification, the VCI is publicly available to the genomics community. Navigation workflows support users providing guidance to comprehensively apply the ACMG/AMP evidence criteria and document provenance for asserting variant classifications. CONCLUSIONS: The VCI offers a central platform for clinical variant classification that fills a gap in the learning healthcare system, facilitates widespread adoption of standards for clinical curation, and is available at https://curation.clinicalgenome.org.

Ultrasound and electrical stimulator-guided obturator nerve block with phenol in the treatment of hip adductor spasticity in long-term care patients: a randomized, triple blind, placebo controlled study.

OBJECTIVE: To evaluate the effectiveness of ultrasound-guided phenol nerve block in the treatment of severe hip adductor spasticity in long-term care patients. METHODS: Double-blind placebo-controlled trial with a 9-month follow-up period. SETTING: A 250-bed long-term care hospital and the infirmary units of 5 regional hospitals. PARTICIPANTS: Twenty-six long-term care patients with bilateral severe chronic hip adductor spasticity affecting perineal hygiene and nursing care. INTERVENTIONS: Patients were randomized to 2 groups that received ultrasound and electrical stimulator guided obturator nerve block using either 5% phenol in aqueous solution or saline. MAIN OUTCOME MEASURES: The primary outcome measure was the Modified Ashworth Scale, which reflected the severity of hip adductor spasticity. Secondary outcomes included Goal Attainment Scale (GAS), hygiene score, distances between the knees during fast and slow passive hip abductions; passive range of movement for hip extension and knee extension. Pain was assessed using the Pain Assessment in Advanced Dementia Scale. RESULTS: Twenty-six patients (7 males; mean age = 77, standard deviation = 14) were recruited. At week 6 post-injection, 12/16 (75%) patients in the treatment group vs 1/10 (10%) patients in the control group had at least 1-point reduction of Modified Ashworth Scale (P = .001) on both hip adductors. There was also significant improvement in the GAS, as well as the hygiene score, resting position, and distances between the knees during fast and slow passive hip abductions in the treatment group, which persisted until week 36. No significant difference in the Pain Assessment in Advanced Dementia Scale was found between the 2 groups. No serious phenol nerve block related adverse effects were reported. CONCLUSIONS: Obturator neurolysis with 5% aqueous phenol as guided by both ultrasound and electrical stimulation can safely and effectively reduce hip adductor spasticity, thus, improving hygiene scores and patient-centered outcomes measured by the GAS in affected long-term care residents.

Can botulinum toxin decrease carer burden in long term care residents with upper limb spasticity? A randomized controlled study.

OBJECTIVE: To evaluate whether botulinum toxin can decrease the burden for caregivers of long term care patients with severe upper limb spasticity. METHOD: This was a double-blind placebo-controlled trial with a 24-week follow-up period. SETTING: A 250-bed long term care hospital, the infirmary units of 3 regional hospitals, and 5 care and attention homes. PARTICIPANTS: Participants included 55 long term care patients with significant upper limb spasticity and difficulty in basic upper limb care. INTERVENTIONS: Patients were randomized into 2 groups that received either intramuscular botulinum toxin A or saline. MAIN OUTCOME MEASURES: The primary outcome measure was provided by the carer burden scale. Secondary outcomes included goal attainment scale, measure of spasticity by modified Ashworth score, passive range of movement for shoulder abduction, and elbow extension and finger extension. Pain was assessed using the Pain Assessment in Advanced Dementia Scale. RESULTS: A total of 55 patients (21 men; mean age = 69, SD =18) were recruited. At week 6 post-injection, 18 (60%) of 30 patients in the treatment group versus 2 (8%) of 25 patients in the control group had a significant 4-point reduction of carer burden scale (P < .001). There was also significant improvement in the goal attainment scale, as well as the modified Ashworth score, resting angle, and passive range of movement of the 3 regions (shoulder, elbow, and fingers) in the treatment group which persisted until week 24. There were also fewer spontaneous bone fractures after botulinum toxin injection, although this did not reach statistical significance. No significant difference in Pain Assessment in Advanced Dementia scale was found between the 2 groups. No serious botulinum toxin type A-related adverse effects were reported. CONCLUSION: Long term care patients who were treated for upper limb spasticity with intramuscular injections of botulinum toxin A had a significant decrease in the caregiver burden. The treatment was also associated with improved scores on patient-centered outcome measures.