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Supplemental Digital Content is available in the text., The COVID-19 pandemic caused substantial disruptions in medical education. The University of British Columbia (UBC) MD Undergraduate Program (MDUP) is the sixth-largest medical school in North America. MDUP students and faculty developed a joint response to these disruptions to address the curriculum and public health challenges that the pandemic posed. After clinical activities were suspended in March 2020, third- and fourth-year MDUP students formed a COVID-19 Medical Student Response Team (MSRT) to support frontline physicians, public health agencies, and community members affected by the pandemic. A nimble organizational structure was developed across 4 UBC campuses to ensure a rapid response to meet physician and community needs. Support from the faculty ensured the activities were safe for the public, patients, and students and facilitated the provision of curricular credit for volunteer activities meeting academic criteria. As of June 19, 2020, more than 700 medical students had signed up to participate in 68 projects. The majority of students participated in projects supporting the health care system, including performing contact tracing, staffing public COVID-19 call centers, distributing personal protective equipment, and creating educational multimedia products. Many initiatives have been integrated into the MDUP curriculum as scholarly activities or paraclinical electives for which academic credit is awarded. This was made possible by the inherent flexibility of the MDUP curriculum and a strong existing partnership between students and faculty. Through this process, medical students were able to develop fundamental leadership, advocacy, communication, and collaboration skills, essential competencies for graduating physicians. In developing a transparent, accountable, and inclusive organization, students were able to effectively meet community needs during a crisis and create a sustainable and democratic structure capable of responding to future emergencies. Open dialogue between the MSRT and the faculty allowed for collaborative problem solving and the opportunity to transform disruption into academic innovation.

There is increasing recognition that epilepsy can be associated with a broad spectrum of comorbidities. While epileptic seizures are an essential element of epilepsy in children, there is a spectrum of neurological, mental health and cognitive disorders that add to the disease burden of childhood epilepsy resulting in a decreased quality of life. The most common comorbid conditions in childhood epilepsy include depression, anxiety, autism spectrum disorders, sleep disorders, attention deficits, cognitive impairment, and migraine. While epilepsy can result in comorbidities, many of the comorbidities of childhood have a bi-directional association, with the comorbid condition increasing risk for epilepsy and epilepsy increasing the risk for the comorbid condition. The bidirectional feature of epilepsy and the comorbidities suggest a common underlying pathological basis for both the seizures and comorbid condition. While recognition of the comorbid conditions of pediatric epilepsies is increasing, there has been a lag in the development of effective therapies partly out of concern that drugs used to treat the comorbid conditions could increase seizure susceptibility. There is now some evidence that most drugs used for comorbid conditions are safe and do not lower seizure threshold. Unfortunately, the evidence showing drugs are effective in treating many of the childhood comorbidities of epilepsy is quite limited. There is a great need for randomized, placebo-controlled drug trials for efficacy and safety in the treatment of comorbidities of childhood epilepsy.

[ ]it was estimated that 171 million registered users, or 52% of the US population, visited public libraries more than 1 35 billion times over the course of one year 1 Lower-income Americans, Hispanics, and African Americans are more likely to affirm that public libraries positively affect their lives and communities than are other Americans 2 US public libraries and public library staff have provided safe spaces and intensive support for people experiencing mental illness and substance abuse, homelessness, immigration challenges, and trauma 3 Even in disenfranchised communities, such as many in the segregated neighborhoods of Chicago, Illinois, amid area gun violence, deep poverty, and isolation, libraries offer a safe space, and librarians are well trusted to support information access across racial/ethnic and other diversity divides NAVIGATING WELLNESS In recognition of the importance of disease and illness prevention to public health, the US Preventive Services Task Force (USPSTF) was formed in 1984 as an independent group of national experts in prevention and evidence-based medicine that works to improve the health of all Americans by making evidence-based recommendations about clinical preventive services 6 Building on the infrastructure developed in Health for All, researchers and the Library Partnership Advisory Committee successfully applied for National Library of Medicine grant funding to scale the partnership efforts beyond clinical trials-and to health and wellness more broadly [ ]a trial implemented in urban neighborhoods selected to reach diverse, underserved communities found that participatory research in the public library system offers a scalable approach to reduce cancer health disparities 7 The Health for All public libraryacademic partnership we describe is an e· ample of how public libraries can serve as a safe space to support health disparity populations in dismantling the information divides that perpetuate health inequities At this time, the COVID-19 pandemic is having a disproportionate adverse impact on health disparities populations in the United States, which may be further exacerbated if these populations forego' or face barriers to participating in COVID-19 trials or utilizing COVID-19 vaccines or therapies that may be fortho:miing [ ]initiatives at public libraries such as Health for All an are now more important than ever

The progressive myoclonic epilepsies are a rare but devastating group of syndromes characterized by epileptic myoclonus, typically action-induced, neurological regression, medically refractory epilepsy and a variety of other signs and symptoms depending on the specific syndrome. Most of the progressive myoclonic epilepsies begin in normally developing children with the onset of the disorder heralded by myoclonic and other seizure types. While there is a considerable amount of heterogeneity in the conditions, medical intractability to epilepsy, particularly myoclonic seizures, is a core feature. With the increasing use of molecular genetic techniques, mutations and their abnormal protein products are being delineated, providing a basis for disease-based therapy. However, genetic and enzyme replacement or substrate removal are in the nascent stage and the primary therapy is through antiepileptic drugs. Epilepsy in children with progressive myoclonic seizures is notoriously difficult to treat. Because of the rarity of the disorder there have been few double-blinded, placebo-controlled trials in PME and drugs are chosen based on small open-label trials or extrapolation of data from drug trials of other syndromes with myoclonic seizures. In this review the major PME syndromes, their neurogenetic basis, pathophysiological underpinning, electroencephalographic features and currently available treatments are provided.

Twelve evidence-based profiles of roles across the translational workforce and two patients were made available through clinical and translational science (CTS) Personas, a project of the Clinical and Translational Science Awards (CTSA) Program National Center for Data to Health (CD2H). The persona profiles were designed and researched to demonstrate the key responsibilities, motivators, goals, software use, pain points, and professional development needs of those working across the spectrum of translation, from basic science to clinical research to public health. The project’s goal was to provide reliable documents that could be used to inform CTSA software development projects, educational resources, and communication initiatives. This paper presents the initiative to create personas for the translational workforce, including the methodology, engagement strategy, and lessons learned. Challenges faced and successes achieved by the project may serve as a roadmap for others searching for best practices in the creation of Persona profiles.

Vitamin D deficiency during critical illness has been associated with worsened outcomes. Because most critically ill patients with severe traumatic injuries are vitamin D deficient, we investigated the efficacy and safety of cholecalciferol therapy for these patients.Fifty-three patients (17 years of age) admitted to the trauma intensive care unit who had a serum 25-hydroxy vitamin D (25-OH vit D) concentration20 ng/mL were given 10,000 IU of cholecalciferol daily. Efficacy was defined as achievement of a 25-OH vit D of 30-79.9 ng/mL. Safety was evaluated by the presence of hypercalcemia (serum ionized calcium [iCa]1.32 mmol/L) or hypervitaminosis D (25-OH vit D79.9 nmol/L). Patients were monitored for 2 weeks during cholecalciferol therapy.Twenty-four patients (45%) achieved target 25-OH vit D. No patients experienced hypervitaminosis D. Hypercalcemia occurred in 40% (n = 21) of patients; 2 patients experienced an iCa1.49 nmol/L. 25-OH vit D was significantly greater for those who developed hypercalcemia (37.2 + 11.2 vs 28.4 + 5.6 ng/mL, respectively, P0.001) by the second week of cholecalciferol. Of 24 patients who achieved target 25-OH vit D, 14 (58%) experienced hypercalcemia in contrast to 24% of patients (7 out of 29) who did not achieve target 25-OH vit D (P = 0.024).Cholecalciferol normalized serum 25-OH vit D concentrations in less than half of patients yet was associated with a substantial proportion of patients with hypercalcemia without hypervitaminosis D.

Background\ud Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.\ud Methods\ud Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required.\ud Results\ud Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals.\ud Conclusions\ud Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.

Background/objectives High-quality research provides an evidence base for optimal practice care in clinical settings, yet, little is known about the nature and extent of randomized control trials (RCTs) conducted in Australian nursing homes (NHs). Research from other settings and other countries is not necessarily transferable to the Australian NH sector. We sought to identify and describe RCTs conducted in Australia which investigated interventions targeted at improving care for NH residents. Design The design of this study comprised a systematic literature search with a narrative review. Studies were included if they were RCTs published after 2000, conducted in an Australian NH, and evaluated a health intervention which may have directly or indirectly benefitted the NH resident. Setting Australian NHs. Participants Nursing home residents. Measurements Jurisdiction (state or territory where the study was conducted), number of NHs recruited in each trial, number of residents included in each trial, intervention characteristics, comparator characteristics, and characteristics of outcome. Results Only 43 articles reporting on 39 RCTs were identified. In contrast, 30 Australian musculoskeletal RCTs were published in just 2 years (2011-2012). Most of the RCTs identified were conducted in New South Wales (n = 14), Queensland (n = 10), and Victoria (n = 9). The mean number of NHs included in each trial was 22.4 (standard deviation (SD) = 27.0), with a median of 14.5 (interquartile range (IQR) = 27.8), while the mean number of residents included was 412.4 (SD = 921) with a median of 187 (IQR = 341.0). The most common interventions targeted: managing dementia (n = 20), prevention of falls (n = 7), and addressing mental health issues (n = 6). Conclusion This review provides evidence of the paucity of high-quality research in the form of RCTs, in the Australian NH setting and demonstrates the need for Australia to improve its research capability in the NH sector.

Objective The objective of this study was to evaluate long-term safety and tolerability outcomes in two open-label extension (OLE) studies of adjunctive eslicarbazepine acetate (ESL) in children with focal seizures. Methods Safety data from patients aged 4–17 years in OLEs of Studies 2093-208 and -305 were pooled and analyzed. Studies 208 and 305 were randomized, double-blind, placebo-controlled studies of adjunctive treatment with ESL in children with focal seizures refractory to treatment with 1–2 antiseizure drugs; patients could continue into uncontrolled OLEs (up to 5 years total duration). The OLEs evaluated the safety and tolerability of ESL (10–30 mg/kg/day; maximum 1200 mg/day). Results The 1-year OLE and post-1-year OLE safety populations comprised 337 and 177 ESL-treated patients, respectively. The overall incidence of treatment-emergent adverse events (TEAEs) with ESL was 64.1% during the 1-year OLE and 52.5% during the post-1-year OLE. Nasopharyngitis, partial seizures, vomiting, pyrexia, headache, somnolence, and respiratory tract infection were the most frequently reported TEAEs during the 1-year OLE. The overall incidence of serious adverse events (AEs) was 8.9% during the 1-year OLE and 10.2% during the post-1-year OLE. Partial seizures (1.2%) and pneumonia (1.2%) were the most frequently reported serious AEs during the 1-year OLE. The overall incidence of TEAEs leading to discontinuation was 4.2% during the 1-year OLE and 0.6% during the post-1-year OLE. Partial seizures (1.5%) was the most frequently reported TEAE leading to discontinuation during the 1-year OLE. Conclusions Overall, long-term treatment with ESL was generally well tolerated in pediatric patients aged 4–17 years with focal seizures. TEAEs were comparable to those observed in adults with no new events of concern.

Background Granulomatosis with polyangiitis and Behçet’s disease can occur during pregnancy and may be treated by ophthalmologists, rheumatologists, and obstetricians. We hypothesized that specialty training would affect the way physicians selected therapy. Methods Using an online questionnaire, 209 uveitis specialists, 853 rheumatologists, and 2500 obstetricians were surveyed. Respondents were given clinical vignettes containing a female patient who was contemplating pregnancy or in the first trimester and was diagnosed with granulomatosis with polyangiitis or Behçet’s disease. Results In the patient with granulomatosis with polyangiitis, therapy choice between specialties for biologic versus non-biologic systemic immunosuppressive medications was significantly different for both the non-pregnant and pregnant patient (p Conclusions Specialty training affects how physicians manage granulomatosis with polyangiitis and Behçet’s disease. Development of inter-specialty guidelines and treatment plans may improve outcomes, communication, and patient care.

Supplemental Digital Content is available in the text., Objectives: Non-mortality septic shock outcomes (e.g., Sequential Organ Failure Assessment score) are important clinical endpoints in pivotal sepsis trials. However, comparisons of observed longitudinal non-mortality outcomes between study groups can be biased if death is unequal between study groups or is associated with an intervention (i.e., informative censoring). We compared the effects of vasopressin versus norepinephrine on the Sequential Organ Failure Assessment score in the Vasopressin and Septic Shock Trial to illustrate the use of joint modeling to help minimize potential bias from informative censoring. Design: Secondary analysis of the Vasopressin and Septic Shock Trial data. Setting: Twenty-seven ICUs in Canada, Australia, and United States. Subjects: Seven hundred sixty-three participants with septic shock who received blinded vasopressin (n = 389) or norepinephrine infusions (n = 374). Measurements and Main Results: Sequential Organ Failure Assessment scores were calculated daily until discharge, death, or day 28 after randomization. Mortality was numerically higher in the norepinephrine arm (28 d mortality of 39% vs 35%; p = 0.25), and there was a positive association between higher Sequential Organ Failure Assessment scores and patient mortality, characteristics that suggest a potential for bias from informative censoring of Sequential Organ Failure Assessment scores by death. The best-fitting joint longitudinal (i.e., linear mixed-effects model) and survival (i.e., Cox proportional hazards model for the time-to-death) model showed that norepinephrine was associated with a more rapid improvement in the total Sequential Organ Failure Assessment score through day 4, and then the daily Sequential Organ Failure Assessment scores converged and overlapped for the remainder of the study period. Conclusions: Short-term reversal of organ dysfunction occurred more rapidly with norepinephrine compared with vasopressin, although differences between study arms did not persist after day 4. Joint models are an accessible methodology that could be used in critical care trials to assess the effects of interventions on the longitudinal progression of key outcomes (e.g., organ dysfunction, biomarkers, or quality of life) that may be informatively truncated by death or other censoring events.

Background Syphilis and toxoplasmosis are two infectious conditions that can occur during pregnancy. Both these diseases can have ocular manifestations and thus are treated by ophthalmologists and obstetricians. We hypothesized that specialty training would affect the way physicians selected therapy. Results A total of 209 uveitis specialists and approximately 2500 obstetricians across the USA were surveyed using an online questionnaire distributed via listserv and social media posts. Survey respondents were given a series of clinical vignettes containing case examples of a female patient who was either contemplating pregnancy or in the first trimester and was diagnosed with either syphilis or toxoplasmosis. The questionnaire included a total of four case scenarios with questions relating to the management of these diseases, as well as pregnancy counseling. For the syphilis vignette, a total of 97 physicians responded to the survey questions. Choices of therapy between physician specialty differed significantly (p = 0.0001); however, pregnancy status did not seem to affect therapy choice in syphilis. A total of 96 physicians responded to the survey questions pertaining to the toxoplasmosis vignette. For a non-pregnant patient diagnosed with toxoplasmosis, the differences in therapy choice between specialties were not significant; however, when the patient was pregnant, therapy choice was significantly different between specialties (p = 0.0001). Conclusions Differences exist between ophthalmologists and obstetricians concerning the therapy for syphilis and toxoplasmosis during pregnancy. Inter-specialty collaboration is needed to develop consistent criteria to improve the management of these patients.

ObjectiveTo determine whether spindle activity differs in young children with and without autism.MethodsWe investigated differences in spindle density, duration, and oscillatory features in 135 young children with autism, developmental delay without autism (DD), or typical development (TD) and secondarily assessed the dimensional relationship between spindle density and both cognitive ability and social functioning.ResultsCompared to TD, both spindle density (Cohend0.93, 95% confidence interval [CI] 0.49–1.37) and duration (Cohend0.58, 95% CI 0.15–1.01) were significantly decreased in autism. Spindle density was also significantly reduced in autism compared to DD (Cohend0.61, 95% CI 0.13–1.09). Decreased spindle frequency in autism compared to both TD (Cohend0.47, 95% CI 0.04–0.90) and DD (Cohend0.58, 95% CI 0.10–1.06) did not survive correction. The DD group did not differ significantly from the TD group on any spindle parameter. These results, suggesting a relationship between spindle density and autism but not DD, were further illustrated in exploratory analyses, wherein nonverbal ratio IQ (RIQ) and the Vineland Socialization domain standard score were strongly correlated with spindle density in the full sample (r= 0.33,p≤ 001 andr= 0.41,p≤ 001, respectively) but not within group. After nonverbal RIQ was accounted for, the relationship between spindle density and Vineland Socialization remained statistically significant (r= 0.23,p< 0.01). However, Vineland Socialization scores accounted for the relationship between spindle density and nonverbal RIQ (r= 0.04,p= 0.67).ConclusionIn a large cohort of young children with autism, spindle density was reduced compared to groups of age-matched children with DD or TD. Alterations in the maturational trajectory of spindles may provide valuable insight into the neurophysiologic differences related to behavior in disorders of neurodevelopment.

Objectives To assess tolerability and efficacy of lacosamide in adults with cerebrovascular epilepsy etiology (CVEE). Materials and methods Exploratory post hoc analyses of a double-blind, initial monotherapy trial of lacosamide vs carbamazepine-controlled release (carbamazepine-CR) (SP0993; NCT01243177); a double-blind conversion to lacosamide monotherapy trial (SP0902; NCT00520741); and an observational study of adjunctive lacosamide added to one antiepileptic drug (SP0973 VITOBA; NCT01098162). Patients with CVEE were identified based on epilepsy etiology recorded at baseline. Results In the initial monotherapy trial, 61 patients had CVEE (lacosamide: 27; carbamazepine-CR: 34). 20 (74.1%) patients on lacosamide (27 [79.4%] on carbamazepine-CR) reported treatment-emergent adverse events (TEAEs), most commonly (≥10%) headache, dizziness, and fatigue (carbamazepine-CR: headache, dizziness). A numerically higher proportion of patients on lacosamide than carbamazepine-CR completed 6 months (22 [81.5%]; 20 [58.8%]) and 12 months (18 [66.7%]; 17 [50.0%]) treatment without seizure at last evaluated dose. In the conversion to monotherapy trial, 26/30 (86.7%) patients with CVEE reported TEAEs, most commonly (≥4 patients) dizziness, convulsion, fatigue, headache, somnolence, and cognitive disorder. During lacosamide monotherapy, 17 (56.7%) patients were 50% responders and six (20.0%) were seizure-free. In the observational study, 36/83 (43.4%) patients with CVEE reported TEAEs, most commonly (≥5%) fatigue and dizziness. Effectiveness was assessed for 75 patients. During the last 3 months, 60 (80%) were 50% responders and 42 (56.0%) were seizure-free. Conclusions These exploratory post hoc analyses suggested lacosamide was generally well tolerated and effective in patients with CVEE, with data from the initial monotherapy trial suggesting numerically better efficacy than carbamazepine-CR.

Emergency Medicine is a rewarding discipline but ‘burnout’ can be a problem that Emergency Physicians (EPs) wishing to sustain a long career should take steps to avoid. Particular issues affect those working in regional and remote areas where professional isolation and lack of support may potentially predispose to burnout. Issues specifically affecting senior EPs, especially cognitive and physical decline have largely been neglected. Allowances should be made for experienced EPs approaching retirement from clinical work but who may also still have much to offer.

Signal transducer and activator of transcription (STAT1)1 gain of function (GOF) pathogenic variants have been associated with increased levels of phosphorylated STAT1 and STAT1-dependent cellular responses. Delayed dephosphorylation was proposed as the underlying mechanism leading to the characteristically raised pSTAT1 levels. We examined the levels of STAT1 protein and message as well as rates of STAT1 phosphorylation, dephosphorylation, and degradation associated with STAT1 GOF pathogenic variants. Fresh peripheral blood mononuclear cells (PBMC) from 14 STAT1 GOF patients carrying 10 different pathogenic variants in the coiled-coil, DNA binding, and SH2 domains and healthy donors were used to study STAT1 levels and phosphorylation (pSTAT1) following IFNγ and IFNα stimulation. STAT1 protein levels were measured by flow cytometry and immunoblot. STAT1 mRNA levels were measured using quantitative reverse transcription PCR. STAT1 protein degradation was studied using cycloheximide. Patient IFNγ and IFNα induced peak pSTAT1 was higher than in healthy controls. The velocity of pSTAT1 dephosphorylation after treatment of IFNγ stimulated CD14+ monocytes with the Janus Kinase (JAK)-inhibitor ruxolitinib was significantly faster in patient cells. STAT1 protein levels in patient CD14+ monocytes and CD3+ T cells were higher than in healthy donors. There was a strong and positive correlation between CD14+ STAT1 protein levels and peak pSTAT1 levels. Patient fresh PBMC STAT1 mRNA levels were increased at rest and after 16 h of incubation. STAT1 protein degradation was similar in patient and healthy volunteer cells. Patient IFNγ receptors 1 and 2 and JAK2 levels were normal. One patient in our cohort was treated with the oral JAK inhibitor ruxolitinib. Treatment was associated with normalization of both STAT1 protein and peak pSTAT1 levels. After JAK inhibitor treatment was stopped the patient's CD14+ monocyte STAT1 protein and peak phosphorylation levels increased proportionally. These findings suggest that patients with STAT1 GOF mutations have higher levels of total STAT1 protein, leading to high levels of pSTAT1 after stimulation, despite rapid STAT1 dephosphorylation and normal degradation.

Objectives To examine the nature and frequency of deaths due to thermal injuries from cigarette smoking reported to Australian coroners and to examine the decisions which surround these deaths. Design Retrospective cohort study. Setting and participants Residents dwelling in accredited nursing homes whose deaths were reported to coroners between 1 July 2000 and 30 June 2013 and attributed to thermal injuries from cigarette smoking. Measures A descriptive analysis was undertaken to report socio-demographic characteristics of the deceased, medical history, mobility, level of observation, safety equipment provided/used, nursing home location, decision to smoke, timing of incident, time from incident to death, incident findings, mechanism of death, formal reports attached and coroners' recommendations. Results Ten deaths of nursing home residents due to thermal injury from cigarette smoking were reported in Australia over a 13-year period. The median age of residents was 78 years (IQR = 15.25); nine residents were female and one was male. Seven residents had impaired mobility with three residents being wheelchair bound and one resident bed bound. None of the residents were supervised by staff while they smoked, and none of the residents utilised any safety equipment to minimise harm. Burns/thermal injury was the mechanism of harm in most cases. Conclusions This national study confirms that thermal injuries caused by cigarette smoking in nursing homes result in fatalities, particularly in the absence of supervision. It also demonstrates the complex tension arising from balancing autonomy with safety. Implications for practice Nurses and aged care practitioners should endeavour to give effect to each resident's wishes while mitigating the risk of harm. The supervision requirements for cigarette smoking residents should be tailored to the needs of individual residents and staff should try to ensure that residents who require supervision receive it.

Introduction Effective colorectal cancer (CRC) prevention and screening requires sensitive detection of all advanced neoplasias (CRC and advanced adenomas [AA]). However, existing noninvasive screening approaches cannot accurately detect adenomas with high sensitivity. Methods Here, we describe a multifactor assay (RNA-FIT test) that combines 8 stool-derived eukaryotic RNA biomarkers, patient demographic information (smoking status), and a fecal immunochemical test (FIT) to sensitively detect advanced colorectal neoplasias and other non-advanced adenomas in a 1,305-patient, average-risk, prospective cohort. This cohort was supplemented with a 22-patient retrospective cohort consisting of stool samples obtained from patients diagnosed with AA or CRC before treatment or resection. Participants within these cohorts were evaluated with the RNA-FIT assay and an optical colonoscopy. RNA-FIT test results were compared with colonoscopy findings. Results Model performance was assessed through 5-fold internal cross-validation of the training set (n = 939) and by using the model on a hold out testing set (n = 388). When used on the hold out testing set, the RNA-FIT test attained a 95% sensitivity for CRC (n = 22), 62% sensitivity for AA (n = 52), 25% sensitivity for other non-AA (n = 139), 80% specificity for hyperplastic polyps (n = 74), and 85% specificity for no findings on a colonoscopy (n = 101). Discussion The RNA-FIT assay demonstrated clinically relevant detection of all grades of colorectal neoplasia, including carcinomas, AAs, and ONAs. This assay could represent a noninvasive option to screen for both CRC and precancerous adenomas.

SummaryObjective To evaluate treatment responses in benign familial neonatal epilepsy (BFNE). Methods We recruited patients with BFNE through a multicenter international collaboration and reviewed electroclinical and genetic details, and treatment response. All patients were tested at minimum for mutations/deletions in the KCNQ2, KCNQ3, and SCN2A genes. Results Nineteen patients were included in this study. A family history of neonatal seizures was positive in 16 patients, and one additional patient had a family history of infantile seizures. Mutations or deletions of KCNQ2 were found in 14, and of KCNQ3 in 2, of the 19 patients. In all patients, seizures began at 2–5 days of life and occurred multiple times per day. Four patients developed status epilepticus. Seizures were focal, alternating between hemispheres, and characterized by asymmetric tonic posturing associated with apnea and desaturation, followed by unilateral or bilateral asynchronous clonic jerking. Twelve of 19 patients were treated with multiple medications prior to seizure cessation. Seventeen of (88%) 19 patients were seizure-free within hours of receiving oral carbamazepine (CBZ) or oxcarbazepine (OXC). Earlier initiation of CBZ was associated with shorter hospitalization (p < 0.01). No side effects of CBZ were reported. All patients had normal development and remain seizure-free at a mean follow-up period of 7.8 years (6 months–16 years). Significance This study provides evidence that CBZ is safe and rapidly effective in neonates with BFNE, even in status epilepticus. We propose that CBZ should be the drug of choice in benign familial neonatal seizures.

SummaryAims To compare three glycoprotein IIb/IIIa receptor antagonists (GPIs) in terms of platelet inhibition and major adverse cardiac events (MACEs), and assess the rate of bleeding and MACEs between GPIs and coadministered P2Y12 agents. Methods Eighty-three acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) with planned GPI use were randomized to receive high-dose bolus tirofiban, double-bolus eptifibatide, or abciximab followed by a 12-hour infusion. Glycoprotein IIb/IIIa platelet receptor inhibition was measured at baseline and at 10 minutes, 1 hour, and 24 hours postbolus dose. Major adverse cardiac events and bleeding complications at 30 days were documented. The incidence of MACEs and bleeding in patients receiving ticagrelor or prasugrel were compared to those given clopidogrel. Results There were no statistically significant differences in platelet inhibition between GPIs at 10 minutes (P=.085) and 1 hour (P=.337). At 24 hours, abciximab achieved statistically significantly higher median [interquartile range] platelet inhibition (75 [65–88]%) compared to tirofiban (28 [3–56]%; P

Alcohol is one of the most widely available psychoactive substances globally. Many accept the risks associated with alcohol consumption for reasons such as social engagement and feelings of pleasure. Alcohol consumption in a nursing home (NH) setting highlights the moral and logistical challenges of balancing the need for a safe living and working environment with the dignity of risk (DoR) and personal autonomy of residents. This analysis explores public health, human rights, and legal frameworks in their approach to a NH resident's choice to drink alcohol. Key issues under the public health framework include the medical risks associated with alcohol consumption, whether residents with impaired cognitive functioning have the capacity to make a decision about alcohol consumption, and the practical and ethical implications of supplying alcohol to residents. Under a legal framework, NHs must consider the legal imperative to respect residents' rights, the possibility of liability in negligence, duties owed to employees, the existence of substitute decision-makers, and liquor licensing laws. Fundamental considerations under the human rights framework include the damaging psychological effects of risk-avoidance and the importance of inclusive risk assessment processes. Alcohol policies should incorporate elements from all 3 frameworks. There is limited data publicly available about alcohol policies in NHs. Further research is needed to establish current practice and to evaluate the merits and disadvantages of different policies. Establishing inclusive and thorough decision-making processes is key to achieving better consumer-directed care.

Objectives To conduct a systematic review of literature examining the establishment and operation of clinical ethical committees (CECs) in long-term care (LTC). Design Systematic review. Setting and Participants LTC recipients/family or staff. Methods Five databases (Ovid Medline, Ovid Cochrane Library, Ovid PsycINFO, Ovid EMBASE, and CINAHL via EbscoHost) were systematically searched from their inception to May 8, 2020. The initial search was conducted on August 22, 2017, and updated on May 8, 2020, to identify peer-reviewed studies, commentaries, or editorials. The quality of studies was assessed using the Mixed Methods Appraisal Tool. Results Thirty-three articles were identified for inclusion, of which 13 were primary studies. Most articles were set in the United States. The purpose of establishing a CEC in LTC was typically to assist in dealing with ethical issues and improve the quality of care. The articles described the roles of CECs to include prospective case consultation, case review, policy development, and ethics education. Articles rarely reported whether the CEC was required by or enshrined in law. Membership of CECs was between 4 and 20 members and most commonly included nursing staff, physicians, and directors/administrators. The rationale behind the membership was rarely described. For case consultation, articles described that CECs were typically convened upon referral. The resident issues which a CEC could address included end-of-life care decisions, autonomy/self-determination, and medical treatment decisions. The staff issues addressed by CECs included medical treatment decisions, end-of-life care decisions, and decision-making issues. The decision-making process followed by CECs varied. The outcome of a CEC meeting was typically a recommendation, whereas the implementation of CEC recommendations and decisions were rarely reported. Conclusions and Implications This systematic review identifies how CECs operate in the LTC setting. CECs have the potential to provide valuable support in addressing complex ethical issues in LTC; however, empirical research is required to determine their efficacy in the LTC setting.

The presence of obesity may confound cholecalciferol dosing in vitamin D-deficient patients owing to potentially decreased bioavailability. The aim of this retrospective study was to evaluate cholecalciferol therapy in vitamin D-deficient, critically ill trauma patients with and without obesity.Adult patients with severe traumatic injuries who had a serum 25-hydroxyvitamin D (25-OH vit D)50nmol/L were prescribed 10 000 IU of liquid cholecalciferol daily. Efficacy was defined as achievement of a 25-OH vit D of 75 to 200nmol/L. Safety was evaluated by the presence of hypercalcemia (serum ionized calcium1.32 mmol/L). Fifty-three patients (18 obese, 35 non-obese) were identified for study.Despite similar baseline concentrations (36 ± 7 versus 37 ± 7 nmol/L; P = NS), 25-OH vit D response was attenuated for those with obesity after 1 and 2 wk of cholecalciferol therapy (51 ± 18 versus 66 ± 27nmol/L, P0.01; 68 ± 19 versus 92 ± 25nmol/L, P0.01, respectively). Patients with obesity also tended to experience less hypercalcemia (22% versus 49% of patients, respectively) post-cholecalciferol therapy.Obesity alters the response to cholecalciferol therapy in critically ill patients with severe traumatic injuries.

Chronic pain is a leading cause of disability among active duty service members in the U.S. armed forces. Standard rehabilitative care and complementary and integrative health therapies are used for chronic pain rehabilitation. However, the optimal sequence and duration of these therapies has yet to be determined. This article describes a sequential multiple assignment randomized trial (SMART) protocol being used to identify the optimal components and sequence of standard rehabilitative care and complementary and integrative health therapies for reducing pain impact and improving other patient outcomes. Active duty service members referred to Madigan Army Medical Center for treatment of chronic pain are being recruited to the Determinants of the Optimal Dose and Sequence of Functional Restoration and Integrative Therapies study. Study participants are randomized to either standard rehabilitative care (physical and occupational therapy and psychoeducation) or complementary and integrative health therapies (chiropractic, acupuncture, yoga and psychoeducation). Those participants who do not respond to the first 3 weeks of treatment are randomized to receive an additional 3 weeks of either (1) the alternative treatment or (2) the first-stage treatment plus the alternative treatment. This study will also determine factors associated with treatment response that can support clinical decision making, such as baseline fitness, pain catastrophizing, kinesiophobia, post-traumatic stress, pain self-efficacy, and biological indicators. The information gained from this research will be applicable to all integrative chronic pain rehabilitation programs throughout the U.S. Department of Defense and the U.S. Department of Veterans Affairs, and the broader rehabilitation community.

Most antiepileptic drugs (AEDs) receive regulatory approval for children years after the drug is available in adults, encouraging off-label use of the drug in children and hindering attempts to obtain quality pediatric data in controlled trials. Extrapolating adult efficacy data to pediatrics can reduce the time between approval in adults and that in children. To extrapolate efficacy from adults to children, several assumptions must be supported, such as (1) a similar disease progression and response to interventions in adults and children, and (2) similar exposure response in adults and children. The Pediatric Epilepsy Academic Consortium for Extrapolation (PEACE) addressed these assumptions in focal-onset seizures (FOS), the most common seizure type in both adults and children. PEACE reviewed the biological and clinical evidence that supported the assumptions that children with FOS have a similar disease progression and response to intervention as adults with FOS. After age 2 years, the pathophysiological underpinnings of FOS and the biological milieu in which seizures are initiated and propagated in children, seizure semiology, electroencephalographic features, etiology and AED response to FOS in children are similar to those in adults with FOS. PEACE concluded that extrapolation of efficacy data in adults to pediatrics in FOS is supported by strong scientific and clinical evidence. However, safety and pharmacokinetic (PK) data cannot be extrapolated from adults to children. Based on extrapolation, eslicarbazepine is now approved for children with FOS, down to age 4 years. Perampanel, lacosamide and brivaracetam are now undergoing PK and safety studies for the purposes of extrapolation down to age 2 or 4 years. When done in conjunction with PK and safety investigations in children, extrapolation of adult data from adults to children can reduce the time delay between approval of effective and safe AEDs in adults and approval in children.

In order to maintain stable upright stance, the postural control system must account for the continuous perturbations to the body's center-of-mass including those caused by spontaneous respiration. Both aging and disease increase "posturo-respiratory synchronization;" which reflects the degree to which respiration affects postural sway fluctuations over time. Tai Chi training emphasizes the coordination of respiration and bodily movements and may therefore optimize the functional interaction between these two systems. The purpose of the project was to examine the effect of Tai Chi training on the interaction between respiration and postural control in older adults. We hypothesized that Tai Chi training would improve the ability of the postural control system to compensate for respiratory perturbations and thus, reduce posturo-respiratory synchronization. Participants were recruited from supportive housing facilities and randomized to a 12-week Tai Chi intervention (n=28; 86 ± 5 yrs) or educational-control program (n=34, 85 ± 6 yrs). Standing postural sway and respiration were simultaneously recorded with a force plate and respiratory belt under eyes-open and eyes-closed conditions. Posturo-respiratory synchronization was determined by quantifying the variation of the phase relationship between the dominant oscillatory mode of respiration and corresponding oscillations within postural sway. Groups were similar in age, gender distribution, height, body mass, and intervention compliance. Neither intervention altered average sway speed, sway magnitude or respiratory rate. As compared to the education-control group, however, Tai Chi training reduced posturo-respiratory synchronization when standing with eyes open or closed (p

In epileptic encephalopathy, the seizures and interictal epileptiform activity create additional neurocognitive dysfunction beyond that due to the underlying etiology. Treatment leading to a reduction in seizures or interictal abnormalities may help improve neurocognitive function in these situations. The focus of our discussion is reviewing data that support the concept that treatment can impact outcome independent of the etiology in some cases.

Testicular metastases are a rare finding. Typically, a testicular metastasis will present as a complication of progressive disease or as a primary sign of malignancy. Excluding lymphoma and leukemia, prostate cancer is the most common primary site that metastasizes to the testes. Testicular metastases resulting from squamous cell carcinoma of the lung have rarely been reported in previous literature. Here, we report a case of stage IV squamous cell carcinoma of the lung with metastases to the brain and multiple bilateral lung lesions. Following palliative systemic chemotherapy, this patient was found to have a right testicular mass. Pathology reports confirmed that this was a testicular metastasis of squamous cell lung carcinoma origin.

Summary Expediting pediatric access to new antiseizure drugs is particularly compelling, because epileptic seizures are the most common serious neurological symptom in children. Analysis of antiepileptic drug (AED) efficacy outcomes of randomized controlled trials, conducted during the past 20 years in different populations and a broad range of study sites and countries, has shown considerable consistency for each drug between adult and pediatric populations. Historically, the majority of regulatory approvals for AEDs have been for seizure types and not for specific epilepsy syndromes. Available data, both anatomical and neurophysiological, support a similar pathophysiology of focal seizures in adults and young children, and suggest that by age 2 years the structural and physiological milieu upon which seizures develop is similar. Although the distribution of specific etiologies and epilepsy syndromes is different in children from in adults, this should not impact approvals of efficacy based on seizure type, because the pathophysiology of focal seizures and the drug responsiveness of these seizure types are quite similar. Safety and pharmacokinetics cannot be extrapolated from adults to children. The scientific rationale, clinical consensus, and published data support a future approach accepting efficacy data from adult trials and focusing exclusively on prospective pharmacokinetic, tolerability, and safety studies and long-term follow-up in children. Whereas tolerability studies can be compared easily in children and adults, safety studies require large numbers of patients followed for many years.

Seizure-provoking factors circulate late in gestation during normal pregnancy, but do not readily gain access to the brain due to the protective nature of the blood-brain barrier. In particular, efflux transporters are powerful ATP-driven pumps that actively prevent unwanted compounds from entering the brain. We hypothesized that acute inhibition of efflux transporters at the blood-brain barrier would result in spontaneous seizures in pregnant rats. We further hypothesized that the blood-brain barrier protects the maternal brain from seizure by increasing expression and/or activity of p-glycoprotein (P-gp), a major efflux transporter. Main blood-brain barrier efflux transporters were inhibited in-vivo in nonpregnant (Nonpreg) and pregnant (Preg; d19) Sprague Dawley rats (n = 8/group). Seizures were monitored in conscious animals for 8 hours via chronically implanted electroencephalography (EEG) electrodes in the hippocampus and motor cortex and time-synced video. P-gp activity was measured via a calcein accumulation assay in freshly isolated cortical and hippocampal capillaries from Preg (d20) and Nonpreg rats (n = 8–16/group), to assess regional susceptibility to transporter inhibition. P-gp expression, capillary density, and microglial activation as a measure of neuroinflammation were quantified using immunohistochemistry (n = 4–6/group). Efflux transporter inhibition elicited hippocampal seizures within 1 hour in 100% of Preg rats that was not associated with neuroinflammation or elevated tumor necrosis factor alpha (TNFα) or vascular endothelial growth factor (VEGF), but negatively correlated with levels of estradiol. Hippocampal seizures were considerably less prevalent in Nonpreg rats. However, behavioral seizures in the motor cortex developed of similar severity in both groups of rats, demonstrating regional heterogeneity in response to efflux transporter inhibition. Basal P-gp activity was similar between groups, however, exposure to serum from Preg rats significantly decreased P-gp activity in the hippocampus, but not cortex, compared to serum from Nonpreg rats (0.29±0.1 units/sec in Preg vs. 0.06±0.02 units/sec in Nonpreg rats; p < 0.05) that was not associated with elevated TNFα or VEGF. Thus, pregnancy differentially increased the susceptibility of the hippocampus to seizures in response to blood-brain barrier efflux transporter inhibition that may be due to the inhibitory effect of circulating factors in pregnancy on P-gp activity in the hippocampus.

Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.

Examining degenerative sensory and reflexive activity among people with peripheral neuropathy (PN) is important for clinical examinations and understanding relevant neural impairments. However, other than the test of presynaptic inhibition, the reliability of other related tests is largely unknown. The purpose of this project was to examine the test-retest reliability of lower extremity sensory and reflexive measures in people with PN. Twelve participants (8 women, 4 men, age = 72.5 ± 9.2 years) diagnosed with PN were assessed on two occasions at least 7 d apart. Plantar sensitivity, H-reflex and active and passive ankle proprioception (AAP and PAP) were tested. Paired student's t-test and Intraclass correlation coefficients (ICC) were used for statistical analysis. Significant difference was observed in AAP at 0º position (p = 0.04). No other significant differences were observed. Moderate to high reliability was observed at measures of Plantar sensitivity (0.92), peak to peak H (0.71) and M (0.84) waves, latency between H and M (0.78), H-Index (0.85), AAP (0.62) and PAP index (0.60). Low reliability was observed of other parameters. The measures of Hmax, Mmax, latency, H-Index, plantar sensitivity and AAPPAP indices of proprioception tests can be measured reliably for further study in this population.

Flow cytometric cell sorting of biological specimens has become prevalent in basic and clinical research laboratories. These specimens may contain known or unknown infectious agents, necessitating precautions to protect instrument operators and the environment from biohazards arising from the use of sorters. To this end the International Society of Analytical Cytology (ISAC) was proactive in establishing biosafety guidelines in 1997 (Schmid et al., Cytometry 1997;28:99-117) and subsequently published revised biosafety standards for cell sorting of unfixed samples in 2007 (Schmid et al., Cytometry Part A J Int Soc Anal Cytol 2007;71A:414-437). Since their publication, these documents have become recognized worldwide as the standard of practice and safety precautions for laboratories performing cell sorting experiments. However, the field of cytometry has progressed since 2007, and the document requires an update. The new Standards provides guidance: (1) for laboratory design for cell sorter laboratories; (2) for the creation of laboratory or instrument specific Standard Operating Procedures (SOP); and (3) on procedures for the safe operation of cell sorters, including personal protective equipment (PPE) and validation of aerosol containment.

The energy cost (EC) of walking is different for typically developing (TD) and children with cerebral palsy (CP). The associated factors of EC are not fully understood in children with CP. We assessed the relationship between EC and age, body surface area (BSA), and gross motor function measure (GMFM). We retrospectively examined data collected between 2003 and 2011 on 276 children aged 4-18 years who were classified as Gross Motor Function Classification System level I, n=79; II, n=123; and III, n=74. Energy cost was assessed while children walked 6-8 min at a comfortable, self-selected speed using their typical walking aids and/or orthoses as part of a clinical gait analysis. During the test, participants wore a breath-by-breath portable gas analysis system, measuring oxygen consumption. To calculate EC (J/kg/m), oxygen consumption was converted to J/kg/min and divided by walking speed. Data were analyzed using linear regression model. Energy cost correlated inversely with age (β=-0.16, R2=0.02, P=0.01), BSA (β=-3.35, R2=0.11, P0.0001), and GMFM (β=-0.12, R2=0.42, P0.0001). In the multiple linear regression model, GMFM was the most potent correlate of EC, BSA explained another 10% of the variance (R2=0.53), and age was a marginally significant correlate of EC (P=0.08). In summary, in children with CP in our study, EC decreased as GMFM and BSA increased, and GMFM was the most potent correlate of EC.

The highest incidence of seizures in humans occurs during the first year of life. The high susceptibility to seizures in neonates and infants is paralleled by animal studies showing a high propensity to seizures during early life. The immature brain is highly susceptible to seizures because of an imbalance of excitation and inhibition. While the primary outcome determinant of early-life seizures is etiology, there is evidence that seizures which are frequent or prolonged can result in long-term adverse consequences, and there is a consensus that recurrent early-life seizures should be treated. Unfortunately, seizures in many neonates and children remain refractory to therapy. There is therefore a pressing need for new seizure drugs as well as antiepileptic targets in children. In this review, we focus on mechanisms of early-life seizures, such as hypoxia-ischemia, and novel molecular targets, including the hyperpolarization-activated cyclic nucleotide-gated channels.

In March 2012 the Institute of Medicine (IOM) released the report, Epilepsy Across The Spectrum: Promoting Health and Understanding. This report examined the public health dimensions of the epilepsies with a focus on the following four areas: public health surveillance and data collection and integration; population and public health research; health policy, health care, and human services; and education for providers, people with epilepsy and their families, and the public. The report provided recommendations and research priorities for future work in the field of epilepsy that relate to increasing the power of data on epilepsy; prevention of epilepsy; improving health care for people with epilepsy; improving health professional education about epilepsy; improving quality of life for people with epilepsy; improving education about epilepsy for people with epilepsy and families; and raising public awareness about epilepsy. For this article, the authors selected one research priority from each of the major chapter themes in the IOM report: expanding and improving the quality of epidemiologic surveillance in epilepsy; developing improved interventions for people with epilepsy and depression; expanding early identification/screening for learning impairments in children with epilepsy; evaluating and promoting effective innovative teaching strategies; accelerating research on the identification of risk factors and interventions that increase employment and improve quality of life for people with epilepsy and their families; assessing the information needs of people with epilepsy and their families associated with epilepsy-related risks, specifically sudden unexpected death in epilepsy; and developing and conducting surveys to capture trends in knowledge, awareness, attitudes, and beliefs about epilepsy over time and in specific population subgroups. For each research priority selected, examples of research are provided that will advance the field of epilepsy and improve the lives of people with epilepsy. The IOM report has many other research priorities for researchers to consider developing to advance the field of epilepsy and better the lives of people with epilepsy.

Influenza virus is the most frequently reported viral cause of rhabdomyolysis. A 7-year-old child is presented with rhabdomyolysis associated with parainfluenza type 2 virus. Nine cases of rhabdomyolysis associated with parainfluenza virus have been reported. Complications may include electrolyte disturbances, acute renal failure, and compartment syndrome.

Infantile spasms, one of the catastrophic epilepsies, can be a diagnostic challenge since the clinical manifestations may be subtle and may mimic benign conditions. Because of the rarity of the condition, primary care physicians and pediatricians may never see a case of infantile spasms during their career and may be unfamiliar with the seizure semiology. This is a serious issue since there is evidence that early diagnosis and treatment may improve outcome. Patients and families are increasingly using the internet more than their physician as a source of medical information about epilepsy. The reliance on using the internet for diagnostic information raises concerns about the accuracy of posted material that has not undergone professional review. To assess the quality of information being obtained about infantile spasms, we reviewed written and video content addressing infantile spasms on the internet. A total of 135 websites and 156 videos were reviewed for accuracy. Using the search terms Infantile Spasms and West Syndrome, we report that the majority of the written and video information provided was accurate and provided important and pertinent information. We conclude that internet searches provide accurate and pragmatic information about infantile spasms that has the potential for reducing the delay between the onset of the spasms and medical intervention.

Intravenous loop diuretics remain a first-line component in the management of acute heart failure and suggestions to the contrary are not based on sound evidence nor supported by internationally recognised guidelines on the subject.

Research was conducted to evaluate conversations about epilepsy between community-based neurologists and patients. Adverse effects of antiepileptic drugs and mood/behavioral issues were infrequently discussed, and neurologists and patients disagreed about these issues postvisit. Follow-up research was conducted to assess the impact of a previsit assessment tool on discussions of epilepsy. Twenty neurologists reviewed a tool incorporating questions from validated instruments (Adverse Events Profile [AEP] and Neurological Disorders Depression Inventory for Epilepsy [NDDI-E]). Naturally occurring interactions between neurologists and 60 patients were recorded. Neurologists and patients were interviewed separately. All components were transcribed and analyzed using sociolinguistics. Using the previsit assessment tool increased the number of discussions about adverse effects and mood/behavioral issues and increased neurologist-patient agreement about issues postvisit. Visit length did not increase significantly when the tool was used. Ten months after follow-up research, 50% of neurologists reported continuing to use the tool in everyday practice with patients with epilepsy.