Evidence for conservation of primordial ~12-hour ultradian gene programs in humans under free-living conditions.

While circadian rhythms are entrained to the once daily light-dark cycle of the sun, many marine organisms exhibit ~12h ultradian rhythms corresponding to the twice daily movement of the tides. Although human ancestors emerged from circatidal environment millions of years ago, direct evidence of ~12h ultradian rhythms in humans is lacking. Here, we performed prospective, temporal transcriptome profiling of peripheral white blood cells and identified robust ~12h transcriptional rhythms from three healthy participants. Pathway analysis implicated ~12h rhythms in RNA and protein metabolism, with strong homology to the circatidal gene programs previously identified in Cnidarian marine species. We further observed ~12h rhythms of intron retention events of genes involved in MHC class I antigen presentation, synchronized to expression of mRNA splicing genes in all three participants. Gene regulatory network inference revealed XBP1, and GABP and KLF transcription factor family members as potential transcriptional regulators of human ~12h rhythms. These results suggest that human ~12h biological rhythms have a primordial evolutionary origin with important implications for human health and disease.

Achondroplasia and severe sensorineural hearing loss: The role of active bone conduction implants.

The BONEBRIDGE is a partially implantable, transcutaneous bone conduction device that can be used to treat conductive or mixed mild-to-moderate hearing loss in patients who do not attain sufficient improvement from conventional hearing aids. The following case report describes sequential bilateral BONEBRIDGE implantation in a 25-year-old patient with achondroplasia and bilateral mixed-hearing loss with a significant sensorineural component in the setting of chronic suppurative otitis media. Although the patient did not meet the approved BONEBRIDGE criteria, implantation was successful with improvements in audiological outcomes and self-reported quality of life. There were no reported complications at 5-years post-implantation.

Connectomic profiling and Vagus nerve stimulation Outcomes Study (CONNECTiVOS): a prospective observational protocol to identify biomarkers of seizure response in children and youth.

INTRODUCTION: Vagus nerve stimulation (VNS) is a neuromodulation therapy that can reduce the seizure burden of children with medically intractable epilepsy. Despite the widespread use of VNS to treat epilepsy, there are currently no means to preoperatively identify patients who will benefit from treatment. The objective of the present study is to determine clinical and neural network-based correlates of treatment outcome to better identify candidates for VNS therapy. METHODS AND ANALYSIS: In this multi-institutional North American study, children undergoing VNS and their caregivers will be prospectively recruited. All patients will have documentation of clinical history, physical and neurological examination and video electroencephalography as part of the standard clinical workup for VNS. Neuroimaging data including resting-state functional MRI, diffusion-tensor imaging and magnetoencephalography will be collected before surgery. MR-based measures will also be repeated 12 months after implantation. Outcomes of VNS, including seizure control and health-related quality of life of both patient and primary caregiver, will be prospectively measured up to 2 years postoperatively. All data will be collected electronically using Research Electronic Data Capture. ETHICS AND DISSEMINATION: This study was approved by the Hospital for Sick Children Research Ethics Board (REB number 1000061744). All participants, or substitute decision-makers, will provide informed consent prior to be enrolled in the study. Institutional Research Ethics Board approval will be obtained from each additional participating site prior to inclusion. This study is funded through a Canadian Institutes of Health Research grant (PJT-159561) and an investigator-initiated funding grant from LivaNova USA (Houston, TX; FF01803B IIR).

An open-label prospective pilot trial of nucleus accumbens deep brain stimulation for children with autism spectrum disorder and severe, refractory self-injurious behavior: study protocol.

BACKGROUND: Children and youth with autism spectrum disorder (ASD) may manifest self-injurious behaviors (SIB) that may become severe and refractory with limited pharmacologic or behavioral treatment options. Here, we present the protocol of a prospective, mixed-methods study to assess the safety and efficacy of deep brain stimulation (DBS) of the nucleus accumbens (NAcc) for children and youth with ASD and severe, refractory SIB. METHODS: This is a prospective, single-center, single-cohort, open-label, non-randomized pilot trial of 6 patients. Participants will be recruited through specialized behavioral clinics with persistent severe and refractory SIB following standard and intensive interventions. Following NAcc-DBS, participants will be enrolled in the study for 12 months. The primary objectives of the study are safety and feasibility, assessed by rate of recruitment and identification of factors impacting adherence to follow-up and study protocol. Potential treatment efficacy will be assessed by changes in the Children's Yale-Brown Obsessive-Compulsive Scale in ASD (CYBOCS-ASD), the Behavior Problems Index (BPI), the Inventory of Statements about Self-Injury (ISAS) and the Repetitive Behavior Scale-Revised (RBS-R) questionnaires. Additional clinical outcomes will be assessed, including measures of participant and caregiver quality of life, actigraph measurements, and positron emission tomography (PET) changes following DBS. DISCUSSION: This study will be the first to evaluate the effect of DBS of the NAcc on a pediatric population in a controlled, prospective trial. Secondary outcomes will improve the understanding of behavioral, neuro-imaging, and electrophysiologic changes in children with ASD and SIB treated with DBS. This trial will provide an estimated effect size of NAcc-DBS for severe refractory SIB in children with ASD in preparation for future comparative trials. TRIAL REGISTRATION: Registration on ClinicalTrials.gov was completed on 12 June 2019 with the Identifier: NCT03982888 .

Efficacy of antiviral therapies for COVID-19: a systematic review of randomized controlled trials.

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to pose a significant threat to public health worldwide. The purpose of this study was to review current evidence obtained from randomized clinical trials on the efficacy of antivirals for COVID-19 treatment. METHODS: A systematic literature search was performed using PubMed to identify randomized controlled trials published up to September 4, 2021 that examined the efficacy of antivirals for COVID-19 treatment. Studies that were not randomized controlled trials or that did not include treatment of COVID-19 with approved antivirals were excluded. Risk of bias was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) method. Due to study heterogeneity, inferential statistics were not performed and data were expressed as descriptive statistics. RESULTS: Of the 2,284 articles retrieved, 31 (12,440 patients) articles were included. Overall, antivirals were more effective when administered early in the disease course. No antiviral treatment demonstrated efficacy at reducing COVID-19 mortality. Sofosbuvir/daclatasvir results suggested clinical improvement, although statistical power was low. Remdesivir exhibited efficacy in reducing time to recovery, but results were inconsistent across trials. CONCLUSIONS: Although select antivirals have exhibited efficacy to improve clinical outcomes in COVID-19 patients, none demonstrated efficacy in reducing mortality. Larger RCTs are needed to conclusively establish efficacy.

Common data elements reported on middle meningeal artery embolization in chronic subdural hematoma: an interactive systematic review of recent trials.

Cross study heterogeneity has limited the evidence based evaluation of middle meningeal artery embolization (MMAE) as a treatment for chronic subdural hematoma (CSDH). Ongoing trials and prospective studies suggest that heterogeneity in upcoming publications may detract from subsequent meta-analyses and systemic reviews. This study aims to describe this data heterogeneity to promote harmonization with common data elements (CDEs) in publications. ClinicalTrials.gov and PubMed were searched for published or ongoing prospective trials of MMAE. The Nested Knowledge AutoLit living review platform was utilized to classify endpoints from randomized control trials (RCTs) and prospective cohort studies comparing MMAE with other treatments. The qualitative synthesis feature was used to determine cross study overlap of outcome related data elements. Eighteen studies were included: 12 RCTs, two non-randomized controlled studies, two prospective single arm trials, one combined prospective and retrospective controlled study, and one prospective cohort study. The most commonly reported data element was recurrence (15/18), but seven heterogenous (non-comparable) definitions were used for 'recurrence'. Mortality was reported in 10/18 studies, but no common timepoint was reported in more than four studies. Re-intervention and CSDH volume were reported in eight studies, CSDH width in seven, and no other outcome was common across more than five studies. There was significant heterogeneity in data element collection even among prospective registered trials of MMAE. Even among CDEs, variation in definition and timepoints prevented harmonization. A standardized approach based on CDEs may be necessary to facilitate future meta-analyses and evidence driven evaluation of MMAE treatment of CSDH.

The Child & Youth CompreHensIve Longitudinal Database for Deep Brain Stimulation (CHILD-DBS).

PURPOSE: Deep brain stimulation (DBS) is a common tool for the treatment of movement disorders in adults; however, it remains an emerging treatment modality in children with a growing number of indications, including epilepsy and dystonia. The Child & Youth CompreHensIve Longitudinal Database of DBS (CHILD-DBS) study aims to prospectively collect relevant data on quality of life (QoL), safety, efficacy, and long-term neurodevelopmental outcomes following DBS in children. METHODS: Data are collected and managed using the Research Electronic Data Capture (REDCap). This database aims to collect multicentre comprehensive and longitudinal clinical, QoL, imaging and electrophysiologic data for children under the age of 19 undergoing DBS. RESULTS: Both general and indication-specific measures are collected at baseline and at four time points postoperatively: 6 months, 1 year, 2 years, and 3 years. The database encompasses QoL metrics for children, including the PedsQL (Pediatric Quality of Life Inventory, generic), QOLCE (Quality of Life in Childhood Epilepsy Questionnaire, parent-rated), CHU 9D (Child Health Utility 9D), and KIDSCREEN. Caregiver clinical and QoL metrics, including QIDS (Quick Inventory of Depressive Symptomatology), GAD-7 (Generalized Anxiety Disorder 7-item scale), and CarerQoL-7D (The Care-related Quality of Life Instrument), are similarly prospectively collected. Healthcare resource utilization is also assessed before and after DBS. Lastly, stimulation parameters and radiographic and electrophysiologic data are collected within the database. CONCLUSIONS: The development of the current prospective paediatric DBS database with carefully selected physical and psychosocial outcomes and assessments will complement existing efforts to enhance and facilitate multisite collaboration to further understand the role of DBS in childhood.

Family Medicine Residents' Perspectives in Dermatology Training.

This article was migrated. The article was marked as recommended. Purpose:Dermatological concerns are one of the most common presentations in family practice. Residents often feel inadequately prepared to address these concerns after graduation. This preliminary qualitative study was conducted to gain insight from residents about their post-graduate training in dermatology with a family physician practicing in dermatology. Methods:Family medicine residents (within five years of graduation) who completed their training at an academic family medicine centre in rural Southwestern Ontario affiliated with the local University's Department of Family Medicine were interviewed (n=7). Phenomenological analysis was performed on the interviews using qualitative principles of immersion and emergence. Results: Three main themes based on training with a family physician were identified: 1) Personal Enrichment, 2) Professional Enrichment, and 3) Understanding of System Barriers and Facilitators. Conclusion: Training with a family physician practicing in dermatology is useful for residents to gain comfort and skills in the discipline, allowing them to better serve their patients when in independent practice.

Correction to: Assessment of a virtual reality temporal bone surgical simulator: a national face and content validity study.

Following publication of the original article [1], the authors identified incorrect ordering and incorrect files being used for Figs. 1, 2 and 3.

Assessment of a virtual reality temporal bone surgical simulator: a national face and content validity study.

BACKGROUND: Trainees in Otolaryngology-Head and Neck Surgery must gain proficiency in a variety of challenging temporal bone surgical techniques. Traditional teaching has relied on the use of cadavers; however, this method is resource-intensive and does not allow for repeated practice. Virtual reality surgical training is a growing field that is increasingly being adopted in Otolaryngology. CardinalSim is a virtual reality temporal bone surgical simulator that offers a high-quality, inexpensive adjunct to traditional teaching methods. The objective of this study was to establish the face and content validity of CardinalSim through a national study. METHODS: Otolaryngologists and resident trainees from across Canada were recruited to evaluate CardinalSim. Ethics approval and informed consent was obtained. A face and content validity questionnaire with questions categorized into 13 domains was distributed to participants following simulator use. Descriptive statistics were used to describe questionnaire results, and either Chi-square or Fishers exact tests were used to compare responses between junior residents, senior residents, and practising surgeons. RESULTS: Sixty-two participants from thirteen different Otolaryngology-Head and Neck Surgery programs were included in the study (32 practicing surgeons; 30 resident trainees). Face validity was achieved for 5 out of 7 domains, while content validity was achieved for 5 out of 6 domains. Significant differences between groups (p-value of < 0.05) were found for one face validity domain (realistic ergonomics, p = 0.002) and two content validity domains (teaching drilling technique, p = 0.011 and overall teaching utility, p = 0.006). The assessment scores, global rating scores, and overall attitudes towards CardinalSim, were universally positive. Open-ended questions identified limitations of the simulator. CONCLUSION: CardinalSim met acceptable criteria for face and content validity. This temporal bone virtual reality surgical simulation platform may enhance surgical training and be suitable for patient-specific surgical rehearsal for practicing Otolaryngologists.

Active Transcutaneous Bone Conduction Implant: Audiometric Outcomes Following a Novel Middle Fossa Approach With Self-Drilling Screws.

OBJECTIVE: To present surgical and audiometric outcomes of patients implanted with an active transcutaneous bone conduction implant following the novel middle fossa surgical approach with self-drilling screws. STUDY DESIGN: Retrospective review. SETTING: Tertiary care center. PATIENTS: Thirty-seven adults with either conductive or mixed hearing loss that met indications for an active transcutaneous bone conduction implant were consecutively implanted from April, 2013 to May, 2018. INTERVENTION: Unilateral middle fossa implantation of an active transcutaneous bone conduction implant. MAIN OUTCOME MEASURES: Patient charts were reviewed for surgical outcomes and complications over the 6-year period. Preoperative air conduction, preoperative bone conduction, and 3-month postoperative aided thresholds were recorded. Speech perception was assessed using CNC words and AzBio sentences. Pure-tone averages (PTAs; measured at 0.5, 1.0, 2.0 and 3.0 kHz), air-bone gap, and functional gain were calculated. RESULTS: Mean air conduction and bone conduction PTAs (±standard deviation) of the implanted ear were 66.8 dB (±14.9 dB) and 21.9 dB (±14.0 dB), respectively. Mean aided PTA was 26.5 dB (± 8.5 dB). The average functional gain was 40.3 dB (±19.0 dB). Favorable speech perception outcomes were observed. No complications or instances of revision surgery were reported, with a mean follow-up time of 32 months (range, 9-71 mo). CONCLUSIONS: This is the first paper to describe outcomes of patients implanted with an active transcutaneous bone conduction implant via the middle fossa with self-drilling screws. Favorable surgical outcomes were observed with a follow-up of up to 6 years.

Response to commentary on "the middle fossa approach with self-drilling screws: a novel technique for BONEBRIDGE implantation".

The aim of this letter is to respond to a commentary on a published article on the middle fossa approach to BONEBRIDGE implantation with self-drilling screws published by the senior authors.

The Consequences of Oromandibular Dystonia on Communicative Participation: A Qualitative Study of the Insider's Experiences.

Purpose The purpose of this study was to obtain a self-reported account of the experience of living with oromandibular dystonia (OMD) to gain a better understanding of both the daily facilitators and barriers to communicative participation and the strategies used for adapting to life with OMD. Method Eight individuals with OMD and dysarthria participated in 1 face-to-face, semistructured interview. Interviews were audio-recorded and transcribed verbatim. Qualitative, phenomenological methods of coding, immersion, and emergence were used in the analysis of interview data. Results Three major themes and 7 subthemes emerged from the analysis of interview data. First, "speaking is different now" provided examples of how speech changes are manifested in various life situations. Second, "my roles have changed" addressed how OMD has impacted work, home, and social roles. Third, "I accept it and move on" involved finding strategies that help and adopting a different perspective. Conclusion We suggest that the management of OMD must take a more holistic approach by addressing consequences beyond the physical symptoms and be tailored to each individual based on his or her personal concerns and goals.

The middle fossa approach with self-drilling screws: a novel technique for BONEBRIDGE implantation.

BACKGROUND: Bone conduction implants can be used in the treatment of conductive or mixed hearing loss. The BONEBRIDGE bone conduction implant (BB-BCI) is an active, transcutaneous device. BB-BCI implantation can be performed through either the transmastoid or retrosigmoid approach with their respective limitations. Here, we present a third, novel approach for BB-BCI implantation. OBJECTIVE: Describe the detailed surgical technique of BB-BCI implantation through a middle fossa approach with self-drilling screws and present preliminary audiometric outcome data following this approach. METHODS: A single institution, retrospective chart review was completed for patients implanted with the BB-BCI via the middle fossa approach. Preoperative planning and modelling were performed using 3D Slicer. Audiological testing was performed pre- and post-operatively following standard audiometric techniques. RESULTS: Forty patients underwent BB-BCI implantation using the middle fossa approach. Modelling techniques allowed for implantation through the use of external landmarks, obviating the need for intraoperative image guidance. The surgical technique was refined over time through experience and adaptation. Mean follow-up was 29 months (range 3-71 months) with no surgical complications, favourable cosmesis, and expected audiometric outcomes. An average functional gain of 39.6 dB (± 14.7 SD) was found. CONCLUSION: The middle fossa technique with self-drilling screws is a safe and effective option for BONEBRIDGE implantation. As a reference for other groups considering this approach, an annotated video has been included as a supplement to the study.

The role of social media in selective dorsal rhizotomy for children: information sharing and social support.

PURPOSE: Selective dorsal rhizotomy (SDR) is a surgical treatment for spasticity, primarily in cerebral palsy (CP). There is a growing trend for patients to seek medical information from their peers on social media platforms. This study qualitatively and quantitatively assessed the use of social media as an information-sharing and support-seeking tool by patients and caregivers. METHODS: A search was performed on Facebook, Twitter, and YouTube. Public information was quantitatively assessed by category, users, year of creation, and country of origin. Representative samples of comments and posts were then qualitatively assessed by thematic analysis. RESULTS: One hundred eighty-five Facebook groups and pages, 97 YouTube videos, and 14 Twitter accounts were identified, based in 13 countries. SDR and CP groups had a mean membership of 3063 and 2339, respectively; SDR and CP pages had a mean number of "likes" of 1650 and 10,711, respectively. Total YouTube video views were 593,135 (mean 6115). Total Twitter followers were 62,609 (mean 2160). Qualitative analysis identified seven categories of comments: emotional support and forming connections (22.34%), sharing information and advice (15.96%), appreciation and successes (31.91%), challenges and difficulties (8.51%), advertising/offering services (4.79%), inequities and access (4.79%), and social media as a second opinion (11.7%). CONCLUSIONS: This study outlines the use of social media platforms in the distribution of information regarding SDR. We highlight the importance placed by patients and caregivers on the advice of their peers. The current report should inform healthcare providers' interactions with patients with respect to information seeking and provision of support.

Exploring attitudes toward physician-assisted death in patients with life-limiting illnesses with varying experiences of palliative care: a pilot study.

BACKGROUND: On February 6th, 2015, the Supreme Court of Canada ruled that competent adults suffering intolerably from a grievous and irremediable medical condition have the right to the assistance of a physician in ending their own lives, an act known as physician-assisted death, and later defined as medical assistance in dying, allowing for provision by a physician or a nurse practitioner. As of June 6th, 2016, this is no longer illegal across Canada. There is strong support amongst the general population for physician-assisted death, however there is no recent data on the attitudes of terminally ill patients. Our main objective was to gain information on terminally ill patients' general and personal attitudes toward physician-assisted death. METHODS: This is an exploratory pilot study. We surveyed three groups of patients with life-limiting diagnoses: one with new referrals to palliative care; one with no palliative care involvement; and one with prior and ongoing management by a palliative care team. Respondents were surveyed twice, approximately two weeks apart, and rated their general attitudes toward physician-assisted death and the hypothetical consideration of physician-assisted death for oneself on a five-point Likert scale at baseline and follow-up. Respondents with new referrals to palliative care were surveyed before and after palliative care consultation. This study was approved by The Western University Health Sciences Research Ethics Board and Lawson Health Research Institute. RESULTS: We surveyed 102 participants, 70 of whom completed both surveys (31% dropout rate). Participants in all groups predominantly responded between somewhat agree (4 on a 5-point Likert scale) and strongly agree (5 on the Likert scale) when asked about their general attitude toward physician-assisted death. Patients with prior palliative care involvement reported the highest average ratings of hypothetical consideration of physician-assisted death for oneself on a 5-point Likert scale (3.4 at baseline; 3.9 at follow-up), followed by patients with a new palliative consultation (3.2 at baseline; 3.3 at follow-up), and patients with no palliative involvement (2.6 at baseline; 2.9 at follow-up). CONCLUSIONS: Given the preliminary results of this pilot study, we can conclude that terminally ill patients generally agree that physician-assisted death should be available to patients with life-limiting illnesses. Furthermore, descriptive data show a trend for higher hypothetical consideration of physician-assisted death in those patients with prior and ongoing palliative care involvement than patients without palliative involvement. Responses in all groups remained fairly consistent over the two-week period.

Self-Rated Communication-Related Quality of Life of Individuals With Oromandibular Dystonia Receiving Botulinum Toxin Injections.

PURPOSE: In this preliminary study, we examined self-rated communication-related quality of life (CR-QoL) of 10 control participants and 10 individuals with oromandibular dystonia (OMD) and dysarthria receiving therapeutic botulinum toxin (BoNT-A) injections. METHOD: Participants with OMD and associated dysarthria self-rated CR-QoL pre- and post- BoNT-A injection using the American Speech-Language-Hearing Association's Quality of Communication Life Scale (ASHA QCL; Paul et al., 2004). Control participants self-rated CR-QoL during a single experimental visit. RESULTS: Significant differences were found between control participants and participants with OMD on ratings of CR-QoL across all 5 domains and subdomains of the ASHA QCL. No significant differences in CR-QoL were found over the course of the BoNT-A treatment cycle. CONCLUSIONS: CR-QoL was rated lower by participants with OMD as compared with control participants across all ASHA QCL domains/subdomains with "socialization/activities" and "confidence/self-concept" having the largest effect sizes. No differences in CR-QoL were found over the course of the treatment cycle. We advocate for outcome measures that include patient report. The use of patient-reported outcome measures in conjunction with objective or impairment-based outcome measures can help inform meaningful clinical indicators of treatment success. This study adds novel information that may aid our understanding of the experience of living with OMD in this underserviced clinical population.