A platform for predicting mechanism of action based on bacterial transcriptional responses identifies an unusual DNA gyrase inhibitor.

In the search for much-needed new antibacterial chemical matter, a myriad of compounds have been reported in academic and pharmaceutical screening endeavors. Only a small fraction of these, however, are characterized with respect to mechanism of action (MOA). Here, we describe a pipeline that categorizes transcriptional responses to antibiotics and provides hypotheses for MOA. 3D-printed imaging hardware PFIboxes) profiles responses of Escherichia coli promoter-GFP fusions to more than 100 antibiotics. Notably, metergoline, a semi-synthetic ergot alkaloid, mimics a DNA replication inhibitor. In vitro supercoiling assays confirm this prediction, and a potent analog thereof (MLEB-1934) inhibits growth at 0.25 µg/mL and is highly active against quinolone-resistant strains of methicillin-resistant Staphylococcus aureus. Spontaneous suppressor mutants map to a seldom explored allosteric binding pocket, suggesting a mechanism distinct from DNA gyrase inhibitors used in the clinic. In all, the work highlights the potential of this platform to rapidly assess MOA of new antibacterial compounds.

Incidence of Subsequent Mental Health Disorders and Social Adversity Following Pediatric Concussion: A Longitudinal, Population-Based Study.

OBJECTIVE: To determine the long-term risk of new adverse psychosocial outcomes among adolescents diagnosed with a concussion compared with those not diagnosed. STUDY DESIGN: A retrospective, population-based cohort study was conducted. Adolescents (10-18 years) with a physician-diagnosed concussion between 2000 and 2005 were matched on neighborhood and age with 5 controls without concussion from the general population. New-onset mental health disorders, medication use, social, and justice outcomes were extracted using datasets linked to the population data repository. Adolescents were followed for 11-16 years. Adjusted hazard ratios (95% CIs) were estimated. RESULTS: In total, 2082 adolescents with a concussion were matched to 10 510 without. Adolescents with a concussion had an increased risk of any mental health disorder (HR 1.34; 95% CI 1.25-1.45), mood disorder (HR 1.30; 95% 1.18-1.43), psychosis (HR 1.43; 95% CI 1.18-1.74), substance abuse disorder (HR 1.67; 95% 1.31-2.14), and receiving a psychotropic prescription (HR 1.31; 95% CI 1.20-1.42). Female adolescents had an increased risk of ADHD following concussion (HR 1.89; 95% CI 1.17-3.05). Adolescents with a concussion had an increased risk of being accused (HR 1.22; 95% CI 1.11-1.34), victim (HR 1.29; 95% CI 1.11-1.48), or witness (HR 1.16; 95% CI 1.01-1.32) of a crime, or contact with Child and Family Services (HR 1.33; 95% CI 1.10-1.62). There was no association between concussion and attempting or completing suicide, receiving housing support, or collecting income support. CONCLUSIONS: Concussion was associated with an increased risk for multiple adverse psychosocial outcomes. Future work should focus on early identification of those at risk of these outcomes to help optimize longitudinal medical care and support.

Current Use and Future Considerations for Concussion Telemedicine Healthcare in Canada.

OBJECTIVE: To examine the use of telemedicine among Canadian concussion providers and clinics before and after the COVID-19 pandemic onset and identify barriers and facilitators for future use. METHODS: Ninety-nine concussion clinics and healthcare providers across Canada that offered one or more clinical concussion-related service were identified using standardized online searches and approached to complete a cross-sectional online survey. RESULTS: Thirty clinics or providers completed the survey and two completed subsections of the survey (response rate of 32.3%). Only 28.1% of respondents indicated that they used telemedicine to provide care prior to the COVID-19 pandemic. Providers most commonly using telemedicine prior to the pandemic were occupational therapists and physicians, while the most commonly used services were in-person videoconferencing and eConsultation. Most respondents (87%) indicated their clinic's use of telemedicine changed following the onset of the COVID-19 pandemic including new use of in-person video-conferencing, telephone calls, and eConsultation. Ninety-three percent indicated that they would consider using telemedicine to provide care to their concussion patients once the pandemic was over. Barriers needed to be overcome to facilitate use or greater use of telemedicine-based services were the inability to conduct a complete physical examination, lack of appropriate reimbursement, lack of start-up, and maintenance funding and medico-legal risk. CONCLUSION: Telemedicine was used by a minority of Canadian concussion clinics and providers prior to the COVID-19 pandemic but was rapidly adopted by many facilities. This study provides important insight into the factors that must be considered to optimize use of telemedicine in concussion care in the future.

Synthetic Genetic Interactions Reveal a Dense and Cryptic Regulatory Network of Small Noncoding RNAs in Escherichia coli.

Over the past 20 years, we have learned that bacterial small noncoding RNAs (sRNAs) can rapidly effect changes in gene expression in response to stress. However, the broader role and impact of sRNA-mediated regulation in promoting bacterial survival has remained elusive. Indeed, there are few examples where disruption of sRNA-mediated gene regulation results in a discernible change in bacterial growth or survival. The lack of phenotypes attributable to loss of sRNA function suggests that either sRNAs are wholly dispensable or functional redundancies mask the impact of deleting a single sRNA. We investigated synthetic genetic interactions among sRNA genes in Escherichia coli by constructing pairwise deletions in 54 genes, including 52 sRNAs. Some 1,373 double deletion strains were studied for growth defects under 32 different nutrient stress conditions and revealed 1,131 genetic interactions. In one example, we identified a profound synthetic lethal interaction between ArcZ and CsrC when E. coli was grown on pyruvate, lactate, oxaloacetate, or d-/l-alanine, and we provide evidence that the expression of ppsA is dysregulated in the double deletion background, causing the conditionally lethal phenotype. This work employs a unique platform for studying sRNA-mediated gene regulation and sheds new light on the genetic network of sRNAs that underpins bacterial growth. IMPORTANCE sRNAs have long been purported to be a critical mechanism by which bacteria respond to stress; however, uncovering growth phenotypes for sRNA deletion strains in E. coli and related bacteria has proven particularly challenging. In contrast, the deletion of hfq, a chaperone required for the activity of many sRNAs in E. coli, results in striking growth defects in E. coli under a variety of medium conditions and chemical stressors. Here, we examined the importance of hfq and sRNA deletion strains for E. coli growth in nutrient-limited medium supplemented with 30 different carbon sources. We then systematically combined sRNA deletion mutations, creating a library of 1,373 sRNA double deletion strains, which we screened for growth under the same conditions, yielding 43,936 individual growth measurements. Our data uncovered more than 1,000 growth phenotypes for sRNA double deletion strains, shedding light on complicated networks of sRNA regulation that underpin bacterial survival under nutrient stress.

Antibacterial Activity of Metergoline Analogues: Revisiting the Ergot Alkaloid Scaffold for Antibiotic Discovery.

Metergoline is a semisynthetic ergot alkaloid identified recently as an inhibitor of the Gram-negative intracellular pathogen Salmonella Typhimurium (S. Tm). With the previously unknown antibacterial activity of metergoline, we explored structure-activity relationships (SARs) with a series of carbamate, urea, sulfonamide, amine, and amide analogues. Cinnamide and arylacrylamide derivatives show improved potency relative to metergoline against Gram-positive bacteria, and pyridine derivative 38 is also effective against methicillin-resistant Staphylococcus aureus (MRSA) in a murine skin infection model. Arylacrylamide analogues of metergoline show modest activity against wild-type (WT) Gram-negative bacteria but are more active against strains of efflux-deficient S. Tm and hyperpermeable Escherichia coli. The potencies against WT strains of E. coli, Acinetobacter baumannii, and Burkholderia cenocepacia are also improved considerably (up to >128-fold) with the outer-membrane permeabilizer SPR741, suggesting that the ergot scaffold represents a new lead for the development of new antibiotics.

Addressing the Shadow Pandemic: COVID-19 Related Impacts, Barriers, Needs, and Priorities to Health Care and Support for Women Survivors of Intimate Partner Violence and Brain Injury.

Intimate partner violence (IPV) affects 1 in 3 women and has intensified during the COVID-19 pandemic. Although most injuries are to the head, face, and neck, leaving survivors vulnerable to sustaining traumatic brain injury (TBI), the intersection of IPV and TBI remains largely unrecognized. This article reports on COVID-19-related effects, barriers, needs, and priorities to health care and support services for women survivors of IPV-TBI. Using a participatory research model, we engaged 30 stakeholders in virtual meetings drawn from an IPV-TBI Knowledge to Practice Network in two virtual meetings. Stakeholders included women survivors, service providers, researchers, and decision makers across the IPV, TBI, and healthcare sectors. Data were gathered through small group breakout sessions facilitated by the research team using semistructured discussion guides. Sessions were recorded, transcribed verbatim, and analyzed using thematic analysis techniques. Stakeholders were given the opportunity to contribute to the analysis and knowledge transfer through member checking activities. Ethics approval was obtained through the University of Toronto. Stakeholders shared that COVID-19 has increased rates and severity of IPV and barriers to services and help-seeking. These effects have been exacerbated by infrastructure difficulties in rural and remote areas, including limited access to services. They noted the need to carefully consider implications of virtual care such as safety, privacy, and usability. Requests from survivors for peer support have increased significantly, indicating a need for more formalized and better-supported peer roles. Stakeholders further noted that an overwhelming lack of awareness of the intersection of IPV-TBI continues. Increasing education and awareness among health care and IPV service providers, survivors, and the public remains a priority. The COVID-19 pandemic has intensified IPV-TBI, increased challenges for women survivors, and accentuated the continued lack of IPV-TBI awareness. Key recommendations for health care and rehabilitation to address this priority are discussed.

The Intersection of Intimate Partner Violence and Traumatic Brain Injury: Findings From an Emergency Summit Addressing System-Level Changes to Better Support Women Survivors.

BACKGROUND: Traumatic brain injury (TBI) occurring during intimate partner violence (IPV) is a largely unrecognized but significant public health crisis. One in 3 women will experience IPV in their lifetime, up to 75% of whom will sustain a TBI as a result. This article reports on the systems-level findings from a national summit to address barriers, needs, and priorities related to healthcare and support services for women survivors of IPV-TBI. OBJECTIVES: (1) To identify key needs, facilitators, and barriers to care for women survivors of IPV presenting with TBI; and (2) to cocreate ideas for resources and principles for identification, clinical care, and support for healthcare practitioners who treat women exposed to IPV and TBI. METHODS: Using a community-based participatory research approach, we engaged 30 stakeholders-drawn from a national IPV-TBI Knowledge-to-Practice (K2P) Network including diverse women survivors, service providers, researchers, and decision makers-in 2 half-day virtual meetings. Data were gathered through small group breakout sessions using semistructured discussion guides. Sessions were recorded, transcribed verbatim, and analyzed using thematic analysis techniques. Stakeholders contributed to the analysis and knowledge translation through member-checking activities. Ethics approval was obtained through the University of Toronto. FINDINGS: Three main systems-level themes arose during these discussions: (1) the need for trauma-informed, anti-racist, and equitable health and social care systems; (2) the need for cross-pollination of knowledge between disciplines; and (3) the need for systems-level support for integrated and coordinated care. This article explores these needs and provides recommendations and suggestions for paths forward. CONCLUSIONS: The findings of this project enhance understanding of system-level needs among women survivors and provide a template for a national agenda for IPV-TBI research and practice.

Clinical Outcomes of Pediatric Acute Sport- and Non-Sport-Related Concussions.

OBJECTIVES: The objectives were to examine clinical characteristics, length of recovery, and the prevalence of delayed physician-documented recovery, compare clinical outcomes among those with sport-related concussion (SRC) and non-sport-related concussion (nSRC), and identify risk factors for delayed recovery. METHODS: Included patients (8-18 years) were assessed ≤14 days post-injury at a multidisciplinary concussion program and diagnosed with an acute SRC or nSRC. Physician-documented clinical recovery was defined as returning to pre-injury symptom status, attending full-time school without symptoms, completing Return-to-Sport strategy as needed, and normal physical examination. Delayed physician-documented recovery was defined as >28 days post-injury. RESULTS: Four hundred and fifteen patients were included (77.8% SRC). There was no difference in loss of consciousness (SRC: 9.9% vs nSRC: 13.0%, p = 0.39) or post-traumatic amnesia (SRC: 24.1% vs SRC: 31.5%, p = 0.15) at the time of injury or any differences in median Post-Concussion Symptom Scale scores (SRC: 20 vs nSRC: 23, p = 0.15) at initial assessment. Among those with complete clinical follow-up, the median physician-documented clinical recovery was 20 days (SRC: 19 vs nSRC: 23; p = 0.37). There was no difference in the proportion of patients who developed delayed physician-documented recovery (SRC: 27.7% vs nSRC: 36.1%; p = 0.19). Higher initial symptom score increased the risk of delayed physician-documented recovery (IRR: 1.39; 95% CI: 1.29, 1.49). Greater material deprivation and social deprivation were associated with an increased risk of delayed physician-documented recovery. CONCLUSIONS: Most pediatric concussion patients who undergo early medical assessment and complete follow-up appear to make a complete clinical recovery within 4 weeks, regardless of mechanism.

Sport-Related Structural Brain Injury and Return to Play: Systematic Review and Expert Insight.

BACKGROUND: Sport-related structural brain injury (SRSBI) is intracranial pathology incurred during sport. Management mirrors that of non-sport-related brain injury. An empirical vacuum exists regarding return to play (RTP) following SRSBI. OBJECTIVE: To provide key insight for operative management and RTP following SRSBI using a (1) focused systematic review and (2) survey of expert opinions. METHODS: A systematic literature review of SRSBI from 2012 to present in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a cross-sectional survey of RTP in SRSBI by 31 international neurosurgeons was conducted. RESULTS: Of 27 included articles out of 241 systematically reviewed, 9 (33.0%) case reports provided RTP information for 12 athletes. To assess expert opinion, 31 of 32 neurosurgeons (96.9%) provided survey responses. For acute, asymptomatic SRSBI, 12 (38.7%) would not operate. Of the 19 (61.3%) who would operate, midline shift (63.2%) and hemorrhage size > 10 mm (52.6%) were the most common indications. Following SRSBI with resolved hemorrhage, with or without burr holes, the majority of experts (>75%) allowed RTP to high-contact/collision sports at 6 to 12 mo. Approximately 80% of experts did not endorse RTP to high-contact/collision sports for athletes with persistent hemorrhage. Following craniotomy for SRSBI, 40% to 50% of experts considered RTP at 6 to 12 mo. Linear regression revealed that experts allowed earlier RTP at higher levels of play (ß = -0.58, 95% CI -0.111, -0.005, P = .033). CONCLUSION: RTP decisions following structural brain injury in athletes are markedly heterogeneous. While individualized RTP decisions are critical, aggregated expert opinions from 31 international sports neurosurgeons provide key insight. Level of play was found to be an important consideration in RTP determinations.

Preliminary clinical algorithm to optimise remote delivery of paediatric concussion care in Canada's North.

Concussion is a form of traumatic brain injury that affects thousands of children and adolescents across Canada annually. With timely access to comprehensive medical care, the majority of patients with acute concussion will recover within 1-4 weeks. Those who develop persistent post-concussion symptoms often benefit from early recognition and referral to multi-disciplinary concussion clinics that have the personnel and resources to meet their complex needs. Youth who live in remote and isolated communities within Canada's North, a significant proportion of whom are Indigenous, face unique barriers and obstacles to accessing primary and specialised concussion care. Although telemedicine has recently emerged as a tool that can help address these gaps in care, there are presently no clinical guidelines or tools available to assist multi-disciplinary concussion clinics in providing remote concussion care to these medically underserved patients. Here we incorporate literature from a scoping review and our early institutional experience to present an evidence-informed preliminary clinical algorithm and resources to help guide and optimise remote paediatric concussion care delivery in Canada's North. We also discuss how innovative technologies and partnerships can be leveraged to enhance the delivery of safe, equitable, cost-effective and culturally appropriate care to these communities.

Overcoming Acquired and Native Macrolide Resistance with Bicarbonate.

The growing challenge of microbial resistance emphasizes the importance of new antibiotics or reviving strategies for the use of old ones. Macrolide antibiotics are potent bacterial protein synthesis inhibitors with a formidable capacity to treat life-threatening bacterial infections; however, acquired and intrinsic resistance limits their clinical application. In the work presented here, we reveal that bicarbonate is a potent enhancer of the activity of macrolide antibiotics that overcomes both acquired and intrinsic resistance mechanisms. With a focus on azithromycin, a highly prescribed macrolide antibiotic, and using clinically relevant pathogens, we show that physiological concentrations of bicarbonate overcome drug resistance by increasing the intracellular concentration of azithromycin. We demonstrate the potential of bicarbonate as a formulation additive for topical use of azithromycin in treating a murine wound infection caused by Pseudomonas aeruginosa. Further, using a systemic murine model of methicillin-resistant Staphylococcus aureus (MRSA) infection, we demonstrate the potential role of physiological bicarbonate, naturally abundant in the host, to enhance the activity of azithromycin against macrolide-resistant MRSA. In all, our findings suggest that macrolide resistance, observed in the clinical microbiology laboratory using standard culturing techniques, is a poor predictor of efficacy in the clinic and that observed resistance should not necessarily hamper the use of macrolides. Whether as a formulation additive for topical use or as a natural component of host tissues, bicarbonate is a powerful potentiator of macrolides with the capacity to overcome drug resistance in life-threatening bacterial infections.

Benign Paroxysmal Positional Vertigo After Pediatric Sports-Related Concussion.

OBJECTIVE: Report the clinical findings and outcomes among pediatric patients diagnosed with benign paroxysmal positional vertigo (BPPV) after sports-related concussion (SRC). DESIGN: Retrospective case series. SETTING: Multidisciplinary pediatric concussion program. PATIENTS: Patients younger than 19 years with a sport or recreation activity-related concussion referred for comprehensive vestibular physiotherapy assessment. MAIN OUTCOME MEASURE: Symptom resolution after targeted particle repositioning (PR). RESULTS: During the study period, 115 pediatric SRC patients underwent vestibular physiotherapy assessment including 12 (10.4%) who were diagnosed with BPPV. Unilateral posterior semicircular canal (SCC) BPPV was diagnosed in 8/12 (75%) patients, and unilateral anterior SCC BPPV diagnosed in 4/12 (25%) patients. Benign paroxysmal positional vertigo was successfully treated in all patients with a mean of 1.58 targeted PR maneuvers (range = 1-4). CONCLUSIONS: Comprehensive management of pediatric SRC requires a multidisciplinary approach to address the heterogeneous pathophysiology of persistent postconcussion symptoms. Pediatric SRC patients with coexisting BPPV should be considered for targeted PR.

Delayed Symptom Onset Following Pediatric Sport-Related Concussion.

Objective: (1) To examine the prevalence of delayed symptom onset (DSO) among pediatric sport-related concussion (SRC) patients as well as the effect of symptom onset on initial symptom severity, length of recovery, and development of delayed recovery; (2) to evaluate the impact of symptom onset on sideline management. Methods: We conducted a prospective study of pediatric SRC patients (<20 years of age) evaluated at a multi-disciplinary concussion program. Patients underwent initial medical assessment by a single neurosurgeon and a structured interview by a research assistant. Patients were classified as experiencing early symptom onset (symptom onset <15 min from the time of the suspected injury; ESO) or DSO (≥15 min from the time of the suspected injury). Results: A total of 144 SRC patients (61.1% male; mean age 14.6 years, SD 1.8) evaluated a median of 5.0 days (IQR 4.0, 9.0) post-injury were included in the study. Among these patients, 120 (83.3%) reported experiencing ESO while 24 (16.7%) experienced DSO following injury. Among those that experienced DSO the median length of time from the suspected injury to symptom onset was 60.0 min (IQR 20.0, 720.0). No significant differences were observed in symptom severity at initial medical assessment (median Post-Concussion Symptom Scale score 20.0 vs. 18.0, p = 0.35), length of physician-document clinical recovery (median 22.0 vs. 24.0 days; p = 0.46) or the proportion of those who developed delayed physician-documented clinical recovery (34.4 vs. 42.1%, p = 0.52) among patients with ESO or DSO. Patients who reported experiencing ESO were significantly more likely to be immediately removed from play at the time of their suspected injury compared to those who experienced DSO (71.6% vs. 29.2%; p < 0.0001). Conclusions: This study suggests that an important proportion of children and adolescents who sustain an acute SRC experience DSO. DSO is associated with lower rates of immediate removal from play at the time of suspected injury. Secondary study findings highlight the need for improved sport stakeholder concussion education and standardized concussion protocols that mandate the immediate and permanent removal of all youth with a suspected concussion until they undergo medical assessment.

Magnetic Resonance Imaging Biomarkers of Brain Connectivity in Predicting Outcome after Mild Traumatic Brain Injury: A Systematic Review.

There is growing interest in developing magnetic resonance imaging (MRI) biomarkers of brain connectivity from resting-state functional (rs-fMRI) and diffusion tensor imaging (DTI) to aid in the diagnosis and management of patients with mild traumatic brain injury (mTBI). To determine whether early MRI biomarkers of brain connectivity are useful in predicting outcome after mTBI, we conducted a systematic review using the following inclusion criteria: 1) patients aged >16 years with mTBI, 2) MRI performed during the first month post-injury, 3) outcome measure available, 4) control group, and 5) original article published in a peer-reviewed journal. Of the 1351 citations identified, 14 studies met inclusion criteria (5 rs-fMRI and 10 DTI; 680 patients with mTBI vs. 436 controls) including those where MRI was performed from <12 h to 1 month post-injury. The most common clinical outcome measure used in these studies was symptom burden using the Rivermead Post-Concussion Questionnaire. The most frequently studied brain connectivity MRI biomarkers were global functional connectivity, default-mode network, and fractional anisotropy (FA). Despite the scant evidence and considerable methodological heterogeneity observed among studies, we conclude that brain connectivity MRI biomarkers obtained within 1 month of injury may be potentially useful in predicting outcome in mTBI. Further longitudinal studies are needed to evaluate the effect of mTBI on MRI-based brain connectivity biomarkers and examine how incorporation of these tests can inform the clinical care of individual mTBI patients.

Potentiation of Antibiotics against Gram-Negative Bacteria by Polymyxin B Analogue SPR741 from Unique Perturbation of the Outer Membrane.

Therapeutics targeting Gram-negative bacteria have the challenge of overcoming a formidable outer membrane (OM) barrier. Here, we characterize the action of SPR741, a novel polymyxin B (PMB) analogue shown to potentiate several large-scaffold antibiotics in Gram-negative pathogens. Probing the surface topology of Escherichia coli using atomic force microscopy revealed substantial OM disorder at concentrations of SPR741 that lead to antibiotic potentiation. Conversely, very little cytoplasmic membrane depolarization was observed at these same concentrations, indicating that SPR741 acts predominately on the OM. Truncating the lipopolysaccharide (LPS) core with genetic perturbations uniquely sensitized E. coli to SPR741, suggesting that LPS core residues keep SPR741 at the OM, where it can potentiate a codrug, rather than permit its entry to the cytoplasmic membrane. Further, a promoter activity assay revealed that SPR741 challenge induced the expression of RcsAB, a stress sensor for OM perturbation. Together, these results indicate that SPR741 interacts predominately with the OM, in contrast to the dual action of PMB and colistin at both the outer and cytoplasmic membranes.

Evaluation of Early Submaximal Exercise Tolerance in Adolescents with Symptomatic Sport-related Concussion.

PURPOSE: This study aimed to compare cardiorespiratory response to a graded aerobic exercise challenge between adolescents with symptomatic sport-related concussion (SSRC) and healthy control subjects. METHODS: A quasiexperimental nonrandomized study at a multidisciplinary pediatric concussion program was conducted. Thirty-four adolescents with SSRC (19 males and 15 females) and 40 healthy control subjects (13 males and 27 females) completed the Buffalo Concussion Treadmill Testing (BCTT) until either symptom exacerbation or volitional fatigue. Main outcome measures included heart rate (HR), oxygen consumption (V˙O2), carbon dioxide production (V˙CO2), and minute ventilation (V˙E) at rest and at test termination, and change from rest in variables (ΔHR, ΔV˙O2, ΔV˙CO2, and ΔV˙E) during the first five stages of the BCTT. Main outcomes were analyzed using three-way mixed-model ANOVA, with group status (control vs SSRC) and sex (male vs female) as between-subject factors, and time (BCTT stage) as the within-subject factor. RESULTS: No group differences in resting HR, systolic and diastolic blood pressure, ΔV˙O2, V˙CO2, and V˙E were observed. During the first five stages of the BCTT, no group differences in ΔV˙O2, V˙CO2, and V˙E were observed; however, SSRC patients demonstrated higher RPE (P < 0.0005) compared with control subjects. No sex-based differences were observed among SSRC patients on measures collected at rest and during early stages of BCTT. CONCLUSIONS: Although SSRC patients exhibited higher RPE during a graded aerobic exercise challenge, no differences in cardiorespiratory response were observed compared with control subjects exercising at equivalent workloads. Further work is needed to elucidate the physiological mechanisms underlying exercise intolerance after SSRC.

The Potential of Telemedicine to Improve Pediatric Concussion Care in Rural and Remote Communities in Canada.

Concussion is a form of mild traumatic brain injury that affects thousands of Canadian children and adolescents annually. Despite national efforts to harmonize the recognition and management of pediatric concussion in Canada, timely access to primary and specialized care following this injury remains a challenge for many patients especially those who live in rural and remote communities. To address similar challenges facing patients with stroke and other neurological disorders, physicians have begun to leverage advances in telemedicine to improve the delivery of specialized neurological care to those living in medically underserved regions. Preliminary studies suggest that telemedicine may be a safe and cost-effective approach to assist in the medical care of select patients with acute concussion and persistent post-concussion symptoms. Here we provide an overview of telemedicine, teleneurology, the principles of concussion assessment and management, as well as the current state of concussion care in Canada. Utilizing preliminary evidence from studies of telemedicine in concussion and experience from comprehensive systems of care for stroke, we outline steps that must be taken to evaluate the potential of telemedicine-based concussion networks to improve the care of pediatric concussion patients living in underserved rural and remote communities in Canada.

Primary care management of concussion in Canada.

Concussion has emerged as an important public health issue affecting thousands of Canadians annually. Health care providers including paediatricians, family and emergency medicine physicians, nurses, and nurse practitioners are commonly tasked with the responsibility of providing primary care to patients with acute concussion and those with persistent post-concussion symptoms. In July 2017, Parachute, in collaboration with the Public Health Agency of Canada and Sport Canada released the Canadian Guideline on Concussion in Sport that outlines a standardized and evidence-based approach to the recognition, diagnosis, and management of youth and adults with suspected concussion. In this report, we provide a brief overview of the important roles of primary care providers in the medical assessment, management, and prevention of concussion as outlined in this national best practice guideline.

Evaluation of a pilot paediatric concussion telemedicine programme for northern communities in Manitoba.

Pediatric concussion patients living in northern communities in Canada can face unique challenges accessing primary and specialized healthcare. In this study we report the clinical characteristics, healthcare utilization, outcomes and estimated cost avoidance associated with a pilot pediatric concussion telemedicine program established between a multi-disciplinary pediatric concussion program in Winnipeg, Manitoba and a hospital in Thompson, Manitoba. From October 1st- July 1st, 2018, 20 patients were evaluated; mean age 13.1 years, 15 (75%) males and 14 (70%) self-identified as Indigenous. Injury mechanisms included hockey (50%), falls (35%) and assaults (15%). Median time from referral to initial consultation was 2.0 days. After screening by the neurosurgeon, 90% of patients underwent initial consultation via real-time videoconferencing with 80% managed exclusively through telemedicine. At the end of the study, 90% met the criteria for clinical recovery, one remained in treatment and one was discharged to a headache neurologist. Sixty-six telemedicine encounters were completed including 57 videoconferencing appointments and 9 telephone follow-ups representing an estimated cost avoidance of $40,972.94. This study suggests telemedicine may be a useful approach to assist pediatric concussion programs with delivering timely, safe and cost-effective care to patients living in medically underserviced remote and northern communities in Canada.

RNA surveillance by uridylation-dependent RNA decay in Schizosaccharomyces pombe.

Uridylation-dependent RNA decay is a widespread eukaryotic pathway modulating RNA homeostasis. Terminal uridylyltransferases (Tutases) add untemplated uridyl residues to RNA 3'-ends, marking them for degradation by the U-specific exonuclease Dis3L2. In Schizosaccharomyces pombe, Cid1 uridylates a variety of RNAs. In this study, we investigate the prevalence and impact of uridylation-dependent RNA decay in S. pombe by transcriptionally profiling cid1 and dis3L2 deletion strains. We found that the exonuclease Dis3L2 represents a bottleneck in uridylation-dependent mRNA decay, whereas Cid1 plays a redundant role that can be complemented by other Tutases. Deletion of dis3L2 elicits a cellular stress response, upregulating transcription of genes involved in protein folding and degradation. Misfolded proteins accumulate in both deletion strains, yet only trigger a strong stress response in dis3L2 deficient cells. While a deletion of cid1 increases sensitivity to protein misfolding stress, a dis3L2 deletion showed no increased sensitivity or was even protective. We furthermore show that uridylyl- and adenylyltransferases cooperate to generate a 5'-NxAUUAAAA-3' RNA motif on dak2 mRNA. Our studies elucidate the role of uridylation-dependent RNA decay as part of a global mRNA surveillance, and we found that perturbation of this pathway leads to the accumulation of misfolded proteins and elicits cellular stress responses.