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Competing Interests: The authors report no conflicts of interest.

Background: Viral infections can cause acute respiratory distress syndrome (ARDS), systemic inflammation, and secondary cardiovascular complications. Lung macrophage subsets change during ARDS, but the role of heart macrophages in cardiac injury during viral ARDS remains unknown. Here we investigate how immune signals typical for viral ARDS affect cardiac macrophage subsets, cardiovascular health, and systemic inflammation., Methods: We assessed cardiac macrophage subsets using immunofluorescence histology of autopsy specimens from 21 patients with COVID-19 with SARS-CoV-2-associated ARDS and 33 patients who died from other causes. In mice, we compared cardiac immune cell dynamics after SARS-CoV-2 infection with ARDS induced by intratracheal instillation of Toll-like receptor ligands and an ACE2 (angiotensin-converting enzyme 2) inhibitor., Results: In humans, SARS-CoV-2 increased total cardiac macrophage counts and led to a higher proportion of CCR2 + (C-C chemokine receptor type 2 positive) macrophages. In mice, SARS-CoV-2 and virus-free lung injury triggered profound remodeling of cardiac resident macrophages, recapitulating the clinical expansion of CCR2 + macrophages. Treating mice exposed to virus-like ARDS with a tumor necrosis factor α-neutralizing antibody reduced cardiac monocytes and inflammatory MHCII lo CCR2 + macrophages while also preserving cardiac function. Virus-like ARDS elevated mortality in mice with pre-existing heart failure., Conclusions: Our data suggest that viral ARDS promotes cardiac inflammation by expanding the CCR2 + macrophage subset, and the associated cardiac phenotypes in mice can be elicited by activating the host immune system even without viral presence in the heart., Competing Interests: Disclosures M.N. has received funds or material research support from Alnylam, Biotronik, CSL Behring, GlycoMimetics, GSK, Medtronic, Novartis, and Pfizer, as well as consulting fees from Lilly, Biogen, Gimv, IFM Therapeutics, Molecular Imaging, Sigilon, and Verseau Therapeutics. The other authors report no conflicts.

Objective: The aim of the study is to document the current state of musculoskeletal (MSK) medicine education across nationally accredited undergraduate medical programs., Design: A cross-sectional survey design was used to gather curricular data on the following three musculoskeletal themes: (1) anatomy education, (2) preclinical education, and (3) clerkship education., Results: The survey had a 100% response rate with all 14 English-language medical schools in Canada responding. The mean time spent teaching musculoskeletal anatomy was 29.8 hrs (SD ± 13.7, range = 12-60), with all but one program using some form of cadaveric-based instruction. Musculoskeletal preclinical curricula averaged 58.0 hrs (SD ± 53.4, range = 6-204), with didactic lectures, case-based learning, and small group tutorials being the most common modes of instruction. Curricular content varied greatly, with only 25% of "core or must-know" musculoskeletal topics being covered in detail by all programs. Musculoskeletal training in clerkship was required by only 50% of programs, most commonly being 2 wks in duration., Conclusions: Results document the large variability and curricular inadequacies that exist in musculoskeletal education across nationally accredited allopathic programs and highlight the need for the identification and implementation of more consistent musculoskeletal curricular content and educational standards by all nationally accredited medical programs., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Given the widespread recognition that postsurgical movement-evoked pain is generally more intense, and more functionally relevant, than pain at rest, the authors conducted an update to a previous 2011 review to re-evaluate the assessment of pain at rest and movement-evoked pain in more recent postsurgical analgesic clinical trials., Methods: The authors searched MEDLINE and Embase for postsurgical pain randomized controlled trials and meta-analyses published between 2014 and 2023 in the setting of thoracotomy, knee arthroplasty, and hysterectomy using methods consistent with the original 2011 review. Included trials and meta-analyses were characterized according to whether they acknowledged the distinction between pain at rest and movement-evoked pain and whether they included pain at rest and/or movement-evoked pain as a pain outcome. For trials measuring movement-evoked pain, pain-evoking maneuvers used to assess movement-evoked pain were tabulated., Results: Among the 944 included trials, 504 (53%) did not measure movement-evoked pain (vs. 61% in 2011), and 428 (45%) did not distinguish between pain at rest and movement-evoked pain when defining the pain outcome (vs. 52% in 2011). Among the 439 trials that measured movement-evoked pain, selection of pain-evoking maneuver was highly variable and, notably, was not even described in 139 (32%) trials (vs. 38% in 2011). Among the 186 included meta-analyses, 94 (51%) did not distinguish between pain at rest and movement-evoked pain (vs. 71% in 2011)., Conclusions: This updated review demonstrates a persistent limited proportion of trials including movement-evoked pain as a pain outcome, a substantial proportion of trials failing to distinguish between pain at rest and movement-evoked pain, and a lack of consistency in the use of pain-evoking maneuvers for movement-evoked pain assessment. Future postsurgical trials need to (1) use common terminology surrounding pain at rest and movement-evoked pain, (2) assess movement-evoked pain in virtually every trial if not contraindicated, and (3) standardize movement-evoked pain assessment with common, procedure-specific pain-evoking maneuvers. More widespread knowledge translation and mobilization are required in order to disseminate this message to current and future investigators., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Objective: To describe a virtual, competency-based skin and wound care (SWC) skills training model. The ECHO (Extension for Community Healthcare Outcomes) Ontario SWC pivoted from an in-person boot camp to a virtual format because of the COVID-19 pandemic., Methods: An outcome-based program evaluation was conducted. Participants first watched guided commentary and videos of experts performing in nine SWC multiskills videos, then practiced and video-recorded themselves performing those skills; these recordings were assessed by facilitators. Data were collected using pre-post surveys and rubric-based assessments. Descriptive statistics and thematic analysis were applied to data analysis., Results: Fifty-five healthcare professionals participated in the virtual boot camp, measured by the submission of at least one video. A total of 216 videos were submitted and 215 assessment rubrics were completed. Twenty-nine participants completed the pre-boot camp survey (53% response rate) and 26 responded to the post-boot camp survey (47% response rate). The strengths of the boot camp included the applicability of virtual learning to clinical settings, boot camp supplies, tool kits, and teaching strategies. The analysis of survey responses indicated that average proficiency scores were greater than 80% for three videos, 50% to 70% for three of the videos, and less than 50% for three of the videos. Participants received lower scores in local wound care and hand washing points of contact. The barriers of the boot camp included technical issues, time, level of knowledge required at times, and lack of equipment and access to interprofessional teams., Conclusions: This virtual ECHO SWC model expanded access to practical skills acquisition. The professional development model presented here is generalizable to other healthcare domains., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: M. W. D. Thorne has received honoraria from Biogen, Novartis, EMS Serono, and Roche to participate in Ad boards and attend medical conferences. S. M. Mirsattari has received honoraria for speaking engagements for UCB Canada Inc, Eisai Co. Ltd (Canada), and Sunovion Pharmaceuticals Canada Inc. He has been a member of the Epilepsy National Advisory Board for UCB Canada Inc, Eisai Co Ltd (Canada), Sunovion Pharmaceuticals Canada Inc, Jazz Pharmaceuticals Inc, and Paladin Labs Inc. The other authors report no conflicts of interest.

Abstract: Although just-in-time training (JIT) is increasingly used in simulation-based health professions education, its impact on learning, performance, and patient outcomes remains uncertain. The aim of this study was to determine whether JIT simulation training leads to improved learning and performance outcomes. We included randomized or nonrandomized interventional studies assessing the impact of JIT simulation training (training conducted in temporal or spatial proximity to performance) on learning outcomes among health professionals (trainees or practitioners). Of 4077 citations screened, 28 studies were eligible for inclusion. Just-in-time training simulation training has been evaluated for a variety of medical, resuscitation, and surgical procedures. Most JIT simulation training occurred immediately before procedures and lasted between 5 and 30 minutes. Despite the very low certainty of evidence, this systematic review suggests JIT simulation training can improve learning and performance outcomes, in particular time to complete skills. There remains limited data on better patient outcomes and collateral educational effects., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Society for Simulation in Healthcare.)

Background: Person-first language (PFL) is a linguistic prescription, which places a person before their disease. It is considered an important tool to reduce stigma. However, PFL is not routinely used across the scientific literature, particularly in patients with overweight or obesity. Patients with idiopathic intracranial hypertension (IIH) face various stigmas through high rates of poverty, female gender, and frequent rates of comorbidities. Non-PFL language use intersects and worsen the health inequities faced by these patients., Methods: A systematic review of case reports. MEDLINE and EMBASE were searched for all case reports with "pseudotumor cerebri" [MESH] OR "Idiopathic Intracranial Hypertension" as key word between January 1974 and August 2022. The primary criterion was the article's inclusion of patients with overweight or obesity. The secondary criterion was the article's discussion regarding obesity as risk factor. Articles not meeting primary or secondary criteria were excluded., Results: Approximately 514/716 (71.8%) articles used non-PFL language. The publication year was predictive of non-PFL language: 1976-1991 (82.3%) vs 1992-2007 (72.3%, P = 0.0394) and 2008-2022 (68.3%, P = 0.0056). Non-PFL was significantly higher in obesity compared with other medical conditions (60.3% vs 7.3%, P < 0.001). The patient gender (P = 0.111) and ethnicity (P = 0.697), author's specialty (P = 0.298), and primary English-speaking status (P = 0.231), as well as the journal's impact factor (P = 0.795), were not predictive of non-PFL., Conclusions: Most literature focused on IIH use non-PFL when discussing overweight or obesity, regardless of the patient's gender and ethnicity, journal's impact factor, senior author's specialty, and English-speaking status. Non-PFL use is much more common when discussing obesity compared with other medical conditions. Appropriate use of PFL can decrease stigma and, more importantly, decrease the intersectionality of health stigma faced by patients with IIH., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by North American Neuro-Ophthalmology Society.)

Purpose of Review: Health technology assessment (HTA) of cancer drugs is important to identify whether drugs should be publicly funded. With increasing use of surrogate end points in clinical trials including breast cancer, a review of literature was done to synthesize evidence for validation of these surrogate end points and their potential role in HTA decisions pertaining to breast cancer., Findings: Disease free survival (DFS) in human epidermal receptor 2 (HER2) positive early breast cancer remains the only validated surrogate end point. Other surrogate end points like pathological complete response (pCR) and event free survival (EFS) in early breast cancer (EBC) and objective response rate (ORR) and progression free survival (PFS) in advanced disease have not been validated for overall survival (OS). Moreover, surrogate end points for quality of life (QOL) have not been established and drugs that improve PFS can have detrimental effect on QOL. End points like pCR have excellent prognostic utility in individual patients but have weak correlation with survival at trial level., Summary: Most surrogate end points used in breast cancer do not predict OS or QOL which makes it challenging to use them for decisions regarding public funding of cancer drugs. These findings are relevant to HTA agencies prior to making drug reimbursement decisions., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Surgery is an effective treatment for drug-resistant epilepsy, which modifies the brain's structure and networks to regulate seizure activity. Our objective was to examine the relationship between brain structure and function to determine the extent to which this relationship affects the success of the surgery in controlling seizures. We hypothesized that a stronger association between brain structure and function would lead to improved seizure control after surgery., Methods: We constructed functional and structural brain networks in patients with drug-resistant focal epilepsy by using presurgery functional data from intracranial EEG (iEEG) recordings, presurgery and postsurgery structural data from T1-weighted MRI, and presurgery diffusion-weighted MRI. We quantified the relationship (coupling) between structural and functional connectivity by using the Spearman rank correlation and analyzed this structure-function coupling at 2 spatial scales: (1) global iEEG network level and (2) individual iEEG electrode contacts using virtual surgeries. We retrospectively predicted postoperative seizure freedom by incorporating the structure-function connectivity coupling metrics and routine clinical variables into a cross-validated predictive model., Results: We conducted a retrospective analysis on data from 39 patients who met our inclusion criteria. Brain areas implanted with iEEG electrodes had stronger structure-function coupling in seizure-free patients compared with those with seizure recurrence ( p = 0.002, d = 0.76, area under the receiver operating characteristic curve [AUC] = 0.78 [95% CI 0.62-0.93]). Virtual surgeries on brain areas that resulted in stronger structure-function coupling of the remaining network were associated with seizure-free outcomes ( p = 0.007, d = 0.96, AUC = 0.73 [95% CI 0.58-0.89]). The combination of global and local structure-function coupling measures accurately predicted seizure outcomes with a cross-validated AUC of 0.81 (95% CI 0.67-0.94). These measures were complementary to other clinical variables and, when included for prediction, resulted in a cross-validated AUC of 0.91 (95% CI 0.82-1.0), accuracy of 92%, sensitivity of 93%, and specificity of 91%., Discussion: Our study showed that the strength of structure-function connectivity coupling may play a crucial role in determining the success of epilepsy surgery. By quantitatively incorporating structure-function coupling measures and standard-of-care clinical variables into presurgical evaluations, we may be able to better localize epileptogenic tissue and select patients for epilepsy surgery., Classification of Evidence: This is a Class IV retrospective case series showing that structure-function mapping may help determine the outcome from surgical resection for treatment-resistant focal epilepsy., (© 2023 American Academy of Neurology.)

Background and Objectives: In medically refractory temporal lobe epilepsy (TLE), 30%-50% of patients experience substantial language decline after resection in the language-dominant hemisphere. In this study, we investigated the contribution of white matter fiber bundle damage to language change at 3 and 12 months after surgery., Methods: We studied 127 patients who underwent TLE surgery from 2010 to 2019. Neuropsychological testing included picture naming, semantic fluency, and phonemic verbal fluency, performed preoperatively and 3 and 12 months postoperatively. Outcome was assessed using reliable change index (RCI; clinically significant decline) and change across timepoints (postoperative scores minus preoperative scores). Functional MRI was used to determine language lateralization. The arcuate fasciculus (AF), inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus, middle longitudinal fasciculus (MLF), and uncinate fasciculus were mapped using diffusion MRI probabilistic tractography. Resection masks, drawn comparing coregistered preoperative and postoperative T1 MRI scans, were used as exclusion regions on preoperative tractography to estimate the percentage of preoperative tracts transected in surgery. Chi-squared assessments evaluated the occurrence of RCI-determined language decline. Independent sample t tests and MM-estimator robust regressions were used to assess the impact of clinical factors and fiber transection on RCI and change outcomes, respectively., Results: Language-dominant and language-nondominant resections were treated separately for picture naming because postoperative outcomes were significantly different between these groups. In language-dominant hemisphere resections, greater surgical damage to the AF and IFOF was related to RCI decline at 3 months. Damage to the inferior frontal subfasciculus of the IFOF was related to change at 3 months. In language-nondominant hemisphere resections, increased MLF resection was associated with RCI decline at 3 months, and damage to the anterior subfasciculus was related to change at 3 months. Language-dominant and language-nondominant resections were treated as 1 cohort for semantic and phonemic fluency because there were no significant differences in postoperative decline between these groups. Postoperative seizure freedom was associated with an absence of significant language decline 12 months after surgery for semantic fluency., Discussion: We demonstrate a relationship between fiber transection and naming decline after temporal lobe resection. Individualized surgical planning to spare white matter fiber bundles could help to preserve language function after surgery., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Resting energy expenditure (REE) comprises 60% of total energy expenditure and variations may be associated with gestational weight gain (GWG). This study aims to explore the usability and feasibility of REE guided intervention for GWG in obese and overweight women. We conducted a prospective cohort study in LuHe Hospital of Capital Medical University in Beijing, China between May 1, 2017 and May 31, 2018. Obese/overweight women who had routine prenatal care visit at 10 to 13 weeks of gestation, were recruited after written informed consent was obtained. The intervention group (those women who were recruited between January 1 and May 31, 2018) used REE calculated daily total energy to manage GWG, while the control group (those women who were recruited between May 1 and December 31, 2017) used prepregnancy body mass index calculated daily total energy to manage GWG. GWG and daily total energy between the 2 groups were recorded from 10 to 13 weeks of gestation to delivery. A total of 68 eligible women (35 in intervention group and 33 in control group) were included in the final analysis. Daily total energy in the intervention group increased less than the control group, especially from 2nd trimester to 3rd trimester (1929.54 kcal/d vs. 2138.33 kcal/d). The variation of daily total energy from 1st trimester to 3rd trimester in the intervention group was lower than the control group (226.17 kcal/d vs 439.44 kcal/d). Overall GWG of the intervention group (13.45 kg) was significantly lower than the control group (18.20 kg). The percentage of excess-GWG in the intervention group (31.42%) was also significantly lower than the control (57.57%). Findings from our pilot study suggest that diet recommendation basting on REE may improve management of GWG in obese/overweight women., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Genome-wide association studies have discovered a link between genetic variants on human chromosome 15q26.1 and increased coronary artery disease (CAD) susceptibility; however, the underlying pathobiological mechanism is unclear. This genetic locus contains the FES (FES proto-oncogene, tyrosine kinase) gene encoding a cytoplasmic protein-tyrosine kinase involved in the regulation of cell behavior. We investigated the effect of the 15q26.1 variants on FES expression and whether FES plays a role in atherosclerosis., Methods and Results: Analyses of isogenic monocytic cell lines generated by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that monocytes with an engineered 15q26.1 CAD risk genotype had reduced FES expression. Small-interfering-RNA-mediated knockdown of FES promoted migration of monocytes and vascular smooth muscle cells. A phosphoproteomics analysis showed that FES knockdown altered phosphorylation of a number of proteins known to regulate cell migration. Single-cell RNA-sequencing revealed that in human atherosclerotic plaques, cells that expressed FES were predominately monocytes/macrophages, although several other cell types including smooth muscle cells also expressed FES . There was an association between the 15q26.1 CAD risk genotype and greater numbers of monocytes/macrophage in human atherosclerotic plaques. An animal model study demonstrated that Fes knockout increased atherosclerotic plaque size and within-plaque content of monocytes/macrophages and smooth muscle cells, in apolipoprotein E-deficient mice fed a high fat diet., Conclusions: We provide substantial evidence that the CAD risk variants at the 15q26.1 locus reduce FES expression in monocytes and that FES depletion results in larger atherosclerotic plaques with more monocytes/macrophages and smooth muscle cells. This study is the first demonstration that FES plays a protective role against atherosclerosis and suggests that enhancing FES activity could be a potentially novel therapeutic approach for CAD intervention.

Objective: To assess the prevalence, magnitude, and disclosure status of industry funding in editorial boards of surgery journals., Summary of Background Data: Financial COI can bias research. Although authors seeking to publish in peer-reviewed surgery journals are required to provide COI disclosures, editorial board members' COI disclosures are generally not disclosed to readers., Methods: We present a cross-sectional analysis of industry funding to editorial board members of high-impact surgery journals. We reviewed top US-based surgery journals by impact factor to determine the presence of financial COI in members of each journal's editorial board. The prevalence and magnitude of COI was determined using 2018 industry reported payments found in the Centers for Medicare and Medicaid Services Open Payments database. Journal websites were also reviewed looking for the presence of editorial board disclosure statements., Results: A total of 1002 names of editorial board members from the top 10 high-impact American surgery journals were identified. Of 688 individual physicians based in the USA, 452 (65.7%) were found to have received industry payments in 2018, totaling $21,916,503 with a median funding amount per physician of $1253 (interquartile range $156-$10,769). Funding levels varied by surgical specialty and journal. Editorial board disclosure information was found in only 3.3% of physicians., Conclusions: Industry funding to editorial board members of high impact surgery journals is prevalent and underreported. Mechanisms of disclosure for COI are needed at the editorial board level to provide readers full transparency. This would acknowledge this COI of editorial board members, and thereby attempt to potentially further reduce the risk of bias in editorial decisions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Investigations of healthcare harm often overlook the valuable insights of patients and families. Our review aimed to explore the perspectives of key stakeholders when patients and families were involved in serious incident investigations., Methods: The authors searched three databases (Medline, PsycInfo, and CINAHL) and Connected Papers software for qualitative studies in which patients and families were involved in serious incident investigations until no new articles were found., Results: Twenty-seven papers were eligible. The perspectives of patients and families, healthcare professionals, nonclinical staff, and legal staff were sought across acute, mental health and maternity settings. Most patients and families valued being involved; however, it was important that investigations were flexible and sensitive to both clinical and emotional aspects of care to avoid compounding harm. This included the following: early active listening with empathy for trauma, sincere and timely apology, fostering trust and transparency, making realistic timelines clear, and establishing effective nonadversarial communication. Most staff perceived that patient and family involvement could improve investigation quality, promote an open culture, and help ensure future safety. However, it was made difficult when multidisciplinary input was absent, workload and staff turnover were high, training and support needs were unmet, and fears surrounded litigation. Potential solutions included enhancing the clarity of roles and responsibilities, adequately training staff, and providing long and short-term support to stakeholders., Conclusions: Our review provides insights to ensure patient and family involvement in serious incident investigations considers both clinical and emotional aspects of care, is meaningful for all key stakeholders, and avoids compounding harm. However, significant gaps in the literature remain., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The aim of the study is to evaluate a novel point-of-care ultrasound (POCUS) educational curriculum for pediatric residents., Methods: The cohort study in graduate medical education was completed from January 2017 to March 2019. Postgraduate year 1 (PGY1) pediatric residents attended the educational curriculum that consisted of 3 half-day sessions over a 3-month period. Each session consisted of a lecture (introduction, extended focused assessment with sonography for trauma, soft tissue/musculoskeletal, cardiac, and resuscitative applications) followed by supervised hands-on scanning sessions. Group ratio was 3 learners to 1 machine/expert instructor. Main outcome measures included pre- and post-written test scores, as well as objective structured clinical examination (OSCE) scores., Results: Forty-nine PGY1 residents (78% women) completed the curriculum. The mean (SD) pretest score was 68% (8.5), and the mean posttest score was 83% (8.3) with a difference of 15 (95% confidence interval, 12.5-17.6; P < 0.001). Mean (SD) focused assessment with sonography for trauma OSCE score after the curriculum was 88.7% (11.9). The number of PGY1 pediatric residents that were comfortable performing POCUS examinations increased from pretraining to posttraining for soft tissue/musculoskeletal (14%-61%, P < 0.001), extended focused assessment with sonography for trauma (24%-90%, P < 0.001), and cardiac (18%-86%, P < 0.001). All participants found the curriculum useful, and 42 of 49 (86%) stated the curriculum increased their ability to acquire and interpret images., Conclusions: Postgraduate year 1 pediatric residents learned the basics of POCUS through 3 brief educational sessions. The increase in posttest scores demonstrated improved POCUS knowledge, and the high OSCE score demonstrated their ability to acquire ultrasound images. Point-of-care ultrasound guidelines are needed for pediatric residency programs., Competing Interests: Disclosure: No author endorses any conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To test the hypotheses that overall survival and cancer-specific survival after breast cancer diagnosis would be lower in persons with multiple sclerosis (MS) as compared to persons without MS using a retrospective matched cohort design., Methods: We applied a validated case definition to population-based administrative data in Manitoba and Ontario, Canada, to identify women with MS. We linked the MS cohorts to cancer registries to identify women with breast cancer. Then we selected 4 breast cancer controls without MS matched on birth year, cancer diagnosis year, and region. We compared all-cause survival between cohorts using Cox proportional hazards regression adjusting for age at cancer diagnosis, cancer diagnosis period, income quintile, region, and Elixhauser comorbidity score. We compared cancer-specific survival between cohorts using a multivariable cause-specific hazards model. We pooled findings between provinces using meta-analysis., Results: We included 779 patients with MS and 3,116 controls with breast cancer. Most patients with stage data (1,976/2,822 [70.0%]) were diagnosed with stage I or II breast cancer and the mean (SD) age at diagnosis was 57.8 (10.7) years. After adjustment for covariates, MS was associated with a 28% increased hazard for all-cause mortality (hazard ratio [HR] 1.28; 95% confidence interval [CI] 1.08-1.53), but was not associated with altered cancer-specific survival (HR 0.98; 95% CI 0.65-1.46)., Conclusion: Women with MS have lower all-cause survival after breast cancer diagnosis than women without MS. Future studies should confirm these findings in other populations and identify MS-specific factors associated with worse prognosis., (© 2021 American Academy of Neurology.)

Background: Registry-based randomized controlled trials allow for outcome ascertainment using routine health data (RHD). While this method provides a potential solution to the rising cost and complexity of clinical trials, comparative analyses of outcome ascertainment by clinical end point committee (CEC) adjudication compared with RHD sources are sparse. Among cardiovascular trials, we set out to systematically compare the incidence of cardiovascular events and estimated randomized treatment effects ascertained from RHD versus traditional clinical evaluation and adjudication., Methods: We searched MEDLINE (1976 to August 2020) for studies where outcome ascertainment was performed by both RHD and CEC adjudication to compare the incidence of cardiovascular events and treatment effects. We derived ratios of hazard ratios to compare treatment effects from RHD and CEC adjudication. We pooled ratios of hazard ratios using an inverse variance random-effects meta-analysis., Results: Nine studies (1988-2020; 32 156 patients) involving 10 randomized control trials compared outcome ascertainment with RHD and CEC in patients with or at risk of cardiovascular disease. There was a high degree of agreement and interrater reliability between CEC and RHD outcome determination for all-cause mortality (agreement percentage: 98.4%-100% and κ: 0.95-1.0) and cardiovascular mortality (agreement percentage: 97.8%-99.9% and κ: 0.66-0.99). For myocardial infarction, the κ values ranged from 0.67-0.98, and for stroke the values ranged from 0.52-0.89. In contrast, the κ value for peripheral artery disease was low (κ: 0.27). There was little difference in the randomized treatment effect derived from CEC and RHD ascertainment of events based on the ratios of hazard ratio, with pooled ratios of hazard ratios ranging from 0.93 (95% CI, 0.63-1.39) for cardiovascular mortality to 1.27 (95% CI, 0.67-2.41) for stroke., Conclusions: Clinical outcome ascertainment using retrospectively acquired RHD displayed high levels of agreement with CEC adjudication for identifying all-cause mortality and cardiovascular outcomes. Importantly, cardiovascular treatment effects in randomized control trials determined from RHD and CEC resulted in similar point estimates. Overall, our review supports the use of RHD as a potential alternative source for clinical outcome ascertainment in cardiovascular trials. Validation studies with prospectively planned linkage are warranted.

Objective: Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in BMPR2 -the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppresses the proliferation of healthy endothelial cells. However, the impact of BMPR2 loss on the antiproliferative actions of BMP9 has yet to be assessed. Approach and Results: BMP9 suppressed proliferation in blood outgrowth endothelial cells from healthy control subjects but increased proliferation in blood outgrowth endothelial cells from pulmonary arterial hypertension patients with BMPR2 mutations. This shift from growth suppression to enhanced proliferation was recapitulated in control human pulmonary artery endothelial cells following siRNA-mediated BMPR2 silencing, as well as in mouse pulmonary endothelial cells isolated from endothelial-conditional Bmpr2 knockout mice ( Bmpr2 EC -/- ). BMP9-induced proliferation was not attributable to altered metabolic activity or elevated TGFβ (transforming growth factor beta) signaling but was linked to the prolonged induction of the canonical BMP target ID1 in the context of BMPR2 loss. In vivo, daily BMP9 administration to neonatal mice impaired both retinal and lung vascular patterning in control mice ( Bmpr2 EC+/+ ) but had no measurable effect on mice bearing a heterozygous endothelial Bmpr2 deletion ( Bmpr2 EC +/- ) and caused excessive angiogenesis in both vascular beds for Bmpr2 EC -/- mice., Conclusions: BMPR2 loss reverses the endothelial response to BMP9, causing enhanced proliferation. This finding has potential implications for the proposed translation of BMP9 as a treatment for pulmonary arterial hypertension and suggests the need for focused patient selection in clinical trials.

Objective: To investigate the functional correlates of recurrent secondarily generalized seizures in temporal lobe epilepsy (TLE) using task-based fMRI as a framework to test for epilepsy-specific network rearrangements. Because the thalamus modulates propagation of temporal lobe onset seizures and promotes cortical synchronization during cognition, we hypothesized that occurrence of secondarily generalized seizures, i.e., focal to bilateral tonic-clonic seizures (FBTCS), would relate to thalamic dysfunction, altered connectivity, and whole-brain network centrality., Methods: FBTCS occur in a third of patients with TLE and are a major determinant of disease severity. In this cross-sectional study, we analyzed 113 patients with drug-resistant TLE (55 left/58 right), who performed a verbal fluency fMRI task that elicited robust thalamic activation. Thirty-three patients (29%) had experienced at least one FBTCS in the year preceding the investigation. We compared patients with TLE-FBTCS to those without FBTCS via a multiscale approach, entailing analysis of statistical parametric mapping (SPM) 12-derived measures of activation, task-modulated thalamic functional connectivity (psychophysiologic interaction), and graph-theoretical metrics of centrality., Results: Individuals with TLE-FBTCS had less task-related activation of bilateral thalamus, with left-sided emphasis, and left hippocampus than those without FBTCS. In TLE-FBTCS, we also found greater task-related thalamotemporal and thalamomotor connectivity, and higher thalamic degree and betweenness centrality. Receiver operating characteristic curves, based on a combined thalamic functional marker, accurately discriminated individuals with and without FBTCS., Conclusions: In TLE-FBTCS, impaired task-related thalamic recruitment coexists with enhanced thalamotemporal connectivity and whole-brain thalamic network embedding. Altered thalamic functional profiles are proposed as imaging biomarkers of active secondary generalization., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Question: Does surgery or conservative management of recurring diverticulitis/ongoing symptoms results in a higher quality of life (QoL) at 5-year follow-up., Design: Randomized controlled trial., Setting: Multicenter trial in the Netherlands., Patients: Patients aged 18 to 75 years, who presented with either ongoing abdominal complaints (for >3 months) and/or frequently recurring left-sided diverticulitis (>2 episodes in 2 years) after an objectified (via Computed Tomography, Ultrasound or Endoscopy) episode of diverticulitis were included in this study., Intervention: Elective Sigmoid Resection within 6 weeks vs. Conservative Management MAIN OUTCOME:: QoL at 5-year follow-up, as measured by the Gastrointestinal Quality of Life Index (GIQLI). Secondary outcomes included additional QoL assessments (including the EuroQoL-5D-3L, Visual Analogue Score for pain, and the short form 36 health survey) RESULTS:: The intention to treat analysis showed the surgical group had a higher quality of life (GIQLI) score than the conservative group (mean difference 9.7, 95% confidence interval 1.7-17.7, P = 0.018), which approached but did not meet the minimum important difference of 10. This difference was achieved in 67% of those in the operative group versus 57% in the conservative group (many of who eventually underwent surgery)., Conclusions: The study results demonstrate that HRQOL at 5-year follow-up may be improved in patients undergoing surgical resection, although this difference did not meet the MID for the GIQLI.

Background: The authors previously reported that perioperative aspirin and/or clonidine does not prevent a composite of death or myocardial infarction 30 days after noncardiac surgery. Moreover, aspirin increased the risk of major bleeding and clonidine caused hypotension and bradycardia. Whether these complications produce harm at 1 yr remains unknown., Methods: The authors randomized 10,010 patients with or at risk of atherosclerosis and scheduled for noncardiac surgery in a 1:1:1:1 ratio to clonidine/aspirin, clonidine/aspirin placebo, clonidine placebo/aspirin, or clonidine placebo/aspirin placebo. Patients started taking aspirin or placebo just before surgery; those not previously taking aspirin continued daily for 30 days, and those taking aspirin previously continued for 7 days. Patients were also randomly assigned to receive clonidine or placebo just before surgery, with the study drug continued for 72 h., Results: Neither aspirin nor clonidine had a significant effect on the primary 1-yr outcome, a composite of death or nonfatal myocardial infarction, with a 1-yr hazard ratio for aspirin of 1.00 (95% CI, 0.89 to 1.12; P = 0.948; 586 patients [11.8%] vs. 589 patients [11.8%]) and a hazard ratio for clonidine of 1.07 (95% CI, 0.96 to 1.20; P = 0.218; 608 patients [12.1%] vs. 567 patients [11.3%]), with effect on death or nonfatal infarction. Reduction in death and nonfatal myocardial infarction from aspirin in patients who previously had percutaneous coronary intervention at 30 days persisted at 1 yr. Specifically, the hazard ratio was 0.58 (95% CI, 0.35 to 0.95) in those with previous percutaneous coronary intervention and 1.03 (95% CI, 0.91to 1.16) in those without (interaction P = 0.033). There was no significant effect of either drug on death, cardiovascular complications, cancer, or chronic incisional pain at 1 yr (all P > 0.1)., Conclusions: Neither perioperative aspirin nor clonidine have significant long-term effects after noncardiac surgery. Perioperative aspirin in patients with previous percutaneous coronary intervention showed persistent benefit at 1 yr, a plausible sub-group effect.

Background: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required., Methods: Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams., Results: Of 17 genes reported as being causative for LQTS, 9 ( AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1 ) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes ( KCNQ1, KCNH2, SCN5A ) were curated as definitive genes for typical LQTS. Another 4 genes ( CALM1, CALM2, CALM3, TRDN ) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene ( CACNA1C ) had moderate level evidence for causing LQTS., Conclusions: More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.

Background: The optimal duration of cardiac rhythm monitoring after emergency department (ED) presentation for syncope is poorly described. We sought to describe the incidence and time to arrhythmia occurrence to inform decisions regarding duration of monitoring based on ED risk stratification., Methods: We conducted a prospective cohort study with enrolled adult patients (≥16 years old) presenting within 24 hours of syncope at 6 EDs. We collected baseline characteristics, time of syncope and ED arrival, and the Canadian Syncope Risk Score (CSRS) risk category. We followed subjects for 30 days, and our adjudicated primary outcome was serious arrhythmic conditions (arrhythmias, interventions for arrhythmias, and unexplained death). After excluding patients with an obvious serious condition on ED presentation and those with missing CSRS predictors, we used Kaplan-Meier analysis to describe the time to serious arrhythmic outcomes., Results: A total of 5581 patients (mean age, 53.4 years; 54.5% females; 11.6% hospitalized) were available for analysis, including 346 (6.2%) for whom the 30-day follow-up was incomplete and who were censored at the last follow-up time. A total of 417 patients (7.5%) experienced serious outcomes, 207 of which (3.7%; 95% CI, 3.3%-4.2%) were arrhythmic (161 arrhythmias, 30 cardiac device implantations, 16 unexplained deaths). Overall, 4123 (73.9%) were classified as CSRS low risk, 1062 (19.0%) medium risk, and 396 (7.1%) high risk. The CSRS accurately stratified subjects as low risk (0.4% risk for 30-day arrhythmic outcome), medium risk (8.7% risk), and high risk (25.3% risk). One-half of arrhythmic outcomes were identified within 2 hours of ED arrival in low-risk patients and within 6 hours in medium- and high-risk patients, and the residual risk after these cut points were 0.2% for low-risk, 5.0% for medium-risk, and 18.1% for high-risk patients. Overall, 91.7% of arrhythmic outcomes among medium- and high-risk patients, including all ventricular arrhythmias, were identified within 15 days. None of the low-risk patients experienced ventricular arrhythmia or unexplained death, whereas 0.9% of medium-risk patients and 6.3% of high-risk patients experienced them ( P<0.0001)., Conclusions: Serious underlying arrhythmia was often identified within the first 2 hours of ED arrival for CSRS low-risk patients and within 6 hours for CSRS medium- and high-risk patients. Outpatient cardiac rhythm monitoring for 15 days for selected medium-risk patients and all high-risk patients discharged from the hospital should also be considered.

Background: Contemporary outcomes after surgical management of thoracic aortic disease have improved; however, the impact of sex-related differences is poorly understood., Methods: A total of 1653 patients (498 [30.1%] female) underwent thoracic aortic surgery with hypothermic circulatory arrest between 2002 and 2017 in 10 institutions of the Canadian Thoracic Aortic Collaborative. Outcomes of interest were in-hospital death, stroke, and a modified Society of Thoracic Surgeons-defined composite for mortality or major morbidity (stroke, renal failure, deep sternal wound infection, reoperation, prolonged ventilation). Multivariable logistic regression was used to determine independent predictors of these outcomes., Results: Women were older (mean±SD, 66±13 years versus 61±13 years; P<0.001), with more hypertension and renal failure, but had less coronary disease, less previous cardiac surgery, and higher ejection fraction than men. Rates of aortic dissection were similar between women and men. Rates of hemiarch, and total arch repair were similar between the sexes; however, women underwent less aortic root reconstruction including aortic root replacement, Ross, or valve-sparing root operations (29% versus 45%; P<0.001). Men experienced longer cross-clamp and cardiopulmonary bypass times, but similar durations of circulatory arrest, methods of cerebral perfusion, and nadir temperatures. Women experienced a higher rate of mortality (11% versus 7.4%; P=0.02), stroke (8.8% versus 5.5%; P=0.01), and Society of Thoracic Surgeons-defined composite end point for mortality or major morbidity (31% versus 27%; P=0.04). On multivariable analyses, female sex was an independent predictor of mortality (odds ratio, 1.81; P<0.001), stroke (odds ratio, 1.90; P<0.001), and Society of Thoracic Surgeons-defined composite end point for mortality or major morbidity (odds ratio, 1.40; P<0.001)., Conclusions: Women experience worse outcomes after thoracic aortic surgery with hypothermic circulatory arrest. Further investigation is required to better delineate which measures may reduce sex-related outcome differences after complex aortic surgery.

Background: Mitotic fission is increased in pulmonary arterial hypertension (PAH), a hyperproliferative, apoptosis-resistant disease. The fission mediator dynamin-related protein 1 (Drp1) must complex with adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here, we examine the role of 2 recently discovered, poorly understood Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51), in normal vascular cells and explore their dysregulation in PAH., Methods: Immunoblots of pulmonary artery smooth muscle cells (control, n=6; PAH, n=8) and immunohistochemistry of lung sections (control, n=6; PAH, n=6) were used to assess the expression of MiD49 and MiD51. The effects of manipulating MiDs on cell proliferation, cell cycle, and apoptosis were assessed in human and rodent PAH pulmonary artery smooth muscle cells with flow cytometry. Mitochondrial fission was studied by confocal imaging. A microRNA (miR) involved in the regulation of MiD expression was identified using microarray techniques and in silico analyses. The expression of circulatory miR was assessed with quantitative reverse transcription-polymerase chain reaction in healthy volunteers (HVs) versus patients with PAH from Sheffield, UK (plasma: HV, n=29, PAH, n=27; whole blood: HV, n=11, PAH, n=14) and then confirmed in a cohort from Beijing, China (plasma: HV, n=19, PAH, n=36; whole blood: HV, n=20, PAH, n=39). This work was replicated in monocrotaline and Sugen 5416-hypoxia, preclinical PAH models. Small interfering RNAs targeting MiDs or an miR mimic were nebulized to rats with monocrotaline-induced PAH (n=4-10)., Results: MiD expression is increased in PAH pulmonary artery smooth muscle cells, which accelerates Drp1-mediated mitotic fission, increases cell proliferation, and decreases apoptosis. Silencing MiDs (but not other Drp1 binding partners, fission 1 or mitochondrial fission factor) promotes mitochondrial fusion and causes G1-phase cell cycle arrest through extracellular signal-regulated kinases 1/2- and cyclin-dependent kinase 4-dependent mechanisms. Augmenting MiDs in normal cells causes fission and recapitulates the PAH phenotype. MiD upregulation results from decreased miR-34a-3p expression. Circulatory miR-34a-3p expression is decreased in both patients with PAH and preclinical models of PAH. Silencing MiDs or augmenting miR-34a-3p regresses experimental PAH., Conclusions: In health, MiDs regulate Drp1-mediated fission, whereas in disease, epigenetic upregulation of MiDs increases mitotic fission, which drives pathological proliferation and apoptosis resistance. The miR-34a-3p-MiD pathway offers new therapeutic targets for PAH., (© 2018 American Heart Association, Inc.)

Background: Accurate conflict of interest (COI) statements are important, as a known COI may invalidate study results due to the potential risk of bias., Objective: To determine the accuracy of self-declared COI statements in robotic studies and identify risk factors for undeclared payments., Methods: Robotic surgery studies were identified through EMBASE and MEDLINE and included if published in 2015 and had at least one American author. Undeclared COI were determined by comparing the author's declared COI with industry reported payments found in the "Open Payments" database for 2013 and 2014. Undeclared payments and discrepancies in the COI statement were determined. Risk factors were assessed for an association with undeclared payments at the author and study level., Results: A total of 458 studies (2253 authors) were included. Approximately, 240 (52%) studies had 1 or more author receive undeclared payments and included 183 where "no COI" was explicitly declared, and 57 with no declaration statement present. Moreover, 21% of studies and 18% of authors with a COI declared it so in a COI statement. Studies that had undeclared payments from Intuitive were more likely to recommend robotic surgery compared with those that declared funding (odds ratio 4.29, 95% confidence interval 2.55-7.21)., Conclusions: We found that it was common for payments from Intuitive to be undeclared in robotic surgery articles. Mechanisms for accountability in COI reporting need to be put into place by journals to achieve appropriate transparency to those reading the journal article.

Despite advances in our understanding of the pathophysiology and the management of pulmonary arterial hypertension (PAH), significant therapeutic gaps remain for this devastating disease. Yet, few innovative therapies beyond the traditional pathways of endothelial dysfunction have reached clinical trial phases in PAH. Although there are inherent limitations of the currently available models of PAH, the leaky pipeline of innovative therapies relates, in part, to flawed preclinical research methodology, including lack of rigour in trial design, incomplete invasive hemodynamic assessment, and lack of careful translational studies that replicate randomized controlled trials in humans with attention to adverse effects and benefits. Rigorous methodology should include the use of prespecified eligibility criteria, sample sizes that permit valid statistical analysis, randomization, blinded assessment of standardized outcomes, and transparent reporting of results. Better design and implementation of preclinical studies can minimize inherent flaws in the models of PAH, reduce the risk of bias, and enhance external validity and our ability to distinguish truly promising therapies form many false-positive or overstated leads. Ideally, preclinical studies should use advanced imaging, study several preclinical pulmonary hypertension models, or correlate rodent and human findings and consider the fate of the right ventricle, which is the major determinant of prognosis in human PAH. Although these principles are widely endorsed, empirical evidence suggests that such rigor is often lacking in pulmonary hypertension preclinical research. The present article discusses the pitfalls in the design of preclinical pulmonary hypertension trials and discusses opportunities to create preclinical trials with improved predictive value in guiding early-phase drug development in patients with PAH, which will need support not only from researchers, peer reviewers, and editors but also from academic institutions, funding agencies, and animal ethics authorities., (© 2018 American Heart Association, Inc.)

Objective: To determine the prevalence, management and outcomes of patients with flail chest injuries, compared to patients without flail chest injuries (single rib fractures and multiple rib fractures without a flail segment)., Design: Retrospective cohort study., Setting: Ontario, Canada., Participants: Ontario residents over the age of 16 years who had been admitted to hospital with a chest wall injury from 2004 to 2015 were identified using administrative health care databases., Main Outcome Measurements: Outcomes included treatment modalities such as rate of surgical repair, days on mechanical ventilation, days in the intensive care unit, days in hospital, rate of chest tube placement; and rates of complication, including pneumonia, tracheostomy, readmission, and death., Results: In total 117,204 patients with fractures of the chest wall were identified. Of the entire cohort, 1.5% of them had a flail chest injury, 41% had multiple rib fractures, and 58% had single rib fractures. Patients with flail chest injuries had significantly worse outcomes compared to patients with multiple rib fractures in all categories (P < 0.0001). Similarly, patients with multiple rib fractures had significantly worst outcomes compared with patients with single rib fractures (P < 0.0001). Only 4.5% of patients with flail chest injuries were treated surgically, however, the number increased from 1% before 2010 to 10% after 2010 (P < 0.0001). After adjustment for potential confounders, patients with flail chest injuries treated surgically had a reduced risk of early mortality compared to those treated nonoperatively (OR 0.16, P = 0.019)., Conclusions: Surgical stabilization of flail chest injuries has increased significantly in recent years. The results of this study provide preliminary evidence that the increasing rate of surgical intervention may be warranted by reducing mortality., Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Fibromyalgia is a syndrome characterized by chronic widespread pain and associated with sleep disturbance, depression, fatigue, and cognitive dysfunction. Polypharmacy is commonly used, but supportive evidence is limited. Most fibromyalgia trials focus primarily on pain reduction with monotherapy. This trial compares a pregabalin-duloxetine combination to each monotherapy. Using a randomized, double-blind, 4-period crossover design, participants received maximally tolerated doses of placebo, pregabalin, duloxetine, and pregabalin-duloxetine combination-for 6 weeks. Primary outcome was daily pain (0-10); secondary outcomes included global pain relief, Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events, and other measures. Of 41 participants randomized, 39 completed ≥2 treatments. Daily pain during placebo, pregabalin, duloxetine, and combination was 5.1, 5.0, 4.1, and 3.7, respectively (P < 0.05 only for combination vs placebo, and pregabalin). Participants (%) reporting ≥moderate global pain relief were 18%, 39%, 42%, and 68%, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). Fibromyalgia Impact Questionnaire scores were 42.9, 37.4, 36.0, and 29.8, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). SF-36 scores were 50.2, 55.7, 56.0, and 61.2, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). Medical Outcomes Study Sleep Scale scores were 48.9, 35.2, 46.1, and 32.1, respectively (P < 0.05 only for combination vs placebo, and duloxetine). BDI-II scores were 11.9, 9.9, 10.7, and 8.9, respectively (P < 0.05 only for combination vs placebo). Moderate-severe drowsiness was more frequent during combination vs placebo. Combining pregabalin and duloxetine for fibromyalgia improves multiple clinical outcomes vs monotherapy. Continued research should compare this and other combinations to monotherapy for fibromyalgia.

Objective: To evaluate the association between physical activity (PA) and multiple sclerosis (MS) disease activity, depression, and fatigue in a cohort of children with MS and monophasic acquired demyelinating syndrome (mono-ADS)., Methods: In this cross-sectional study of consecutive patients attending a specialized pediatric MS clinic, we administered the PedsQL Multidimensional Fatigue Scale, Center for Epidemiological Studies Depression Scale, and Godin Leisure-Time Exercise Questionnaire. Quantitative MRI analysis was performed to obtain whole brain and T2 lesion volume in a subset of participants (n = 60)., Results: A total of 110 patients (79 mono-ADS; 31 MS; 5-18 years; M:F 1:1.2) were included. Patients with MS reported less strenuous (33.21 ± 31.88 metabolic equivalents [METs] vs 15.97 ± 22.73 METs, p = 0.002) and total (44.48 ± 39.35 METs vs 67.28 ± 59.65 METs; p = 0.0291) PA than those with mono-ADS. Patients with MS who reported greater amounts of moderate PA METs had fewer sleep/rest fatigue symptoms (r = -0.4). Participation in strenuous PA was associated with smaller T2 lesion volumes (r = -0.66) and lower annualized relapse rate (r = -0.66). No associations were found between total brain volume and participation in PA., Conclusions: Children with MS are less physically active than children with mono-ADS. Reasons for this are unclear, but may be related to ongoing disease activity, perceived limitations, or symptoms such as depression or fatigue. Children with MS reporting higher levels of strenuous PA had lower T2 lesion volumes and lower relapse rates, suggesting a potential protective effect of strenuous PA in this population. Further longitudinal studies are needed to establish the relationship of PA to MS symptoms and disease activity in this population., (© 2015 American Academy of Neurology.)

Objective: To determine the availability, accessibility, and affordability of EEG, EMG, CSF analysis, head CT, and brain MRI for neurologic disorders across countries., Methods: An online, 60-question survey was distributed to neurology practitioners in 2014 to assess the presence, wait time, and cost of each test in private and public health sectors. Data were stratified by World Bank country income group. Affordability was calculated with reference to the World Health Organization's definition of catastrophic health expenditure as health-related out-of-pocket expenditure of >40% of disposable household income, and assessment of providers' perceptions of affordability to the patient., Results: Availability of EEG and EMG is correlated with higher World Bank income group (correlation coefficient 0.38, test for trend p = 0.046; 0.376, p = 0.043); CSF, CT, and MRI did not show statistically significant associations with income groups. Patients in public systems wait longer for neurodiagnostic tests, especially MRI, EEG, and urgent CT (p < 0.0001). The mean cost per test, across all tests, was lower in the public vs private sector (US $55.25 vs $214.62, p < 0.001). Each drop in World Bank income group is associated with a 29% decrease in the estimated share of the population who can afford a given test (95% confidence interval -33.4, 25.2; p < 0.001). In most low-income countries surveyed, only the top 10% or 20% of the population was able to afford tests below catastrophic levels. In surveyed lower-middle-income countries, >40% of the population, on average, could not afford neurodiagnostic tests., Conclusions: Neurodiagnostic tests are least affordable in the lowest income settings. Closing this "diagnostic gap" for countries with the lowest incomes is essential., (© 2015 American Academy of Neurology.)

Large bony defects followed by resection of the mandible need to be reconstructed by various surgical techniques such as the fibular flap. In this article, we report the case of mandibular reconstruction with autologous human bone marrow mesenchymal stem cells and autogenous bone graft, followed by placement of dental implants and prosthodontic treatment in a patient who has been failed to reconstruct mandibular bone defect after resection of mandible.

Background: Postoperative residual neuromuscular blockade (NMB), defined as a train-of-four (TOF) ratio of <0.9, is an established risk factor for critical postoperative respiratory events and increased morbidity. At present, little is known about the occurrence of residual NMB in Canada. The RECITE (Residual Curarization and its Incidence at Tracheal Extubation) study was a prospective observational study at 8 hospitals in Canada investigating the incidence and severity of residual NMB., Methods: Adult patients undergoing open or laparoscopic abdominal surgery expected to last <4 hours, ASA physical status I-III, and scheduled for general anesthesia with at least 1 dose of a nondepolarizing neuromuscular blocking agent for endotracheal intubation or maintenance of neuromuscular relaxation were enrolled in the study. Neuromuscular function was assessed using acceleromyography with the TOF-Watch SX. All reported TOF ratios were normalized to the baseline values. The attending anesthesiologist and all other observers were blinded to the TOF ratio (T4/T1) results. The primary and secondary objectives were to determine the incidence and severity of residual NMB (TOF ratio <0.9) just before tracheal extubation and at arrival at the postanesthesia care unit (PACU)., Results: Three hundred and two participants were enrolled. Data were available for 241 patients at tracheal extubation and for 207 patients at PACU arrival. Rocuronium was the NMB agent used in 99% of cases. Neostigmine was used for reversal of NMB in 73.9% and 72.0% of patients with TE and PACU data, respectively. The incidence of residual NMB was 63.5% (95% confidence interval, 57.4%-69.6%) at tracheal extubation and 56.5% (95% confidence interval, 49.8%-63.3%) at arrival at the PACU. In an exploratory analysis, no statistically significant differences were observed in the incidence of residual NMB according to gender, age, body mass index, ASA physical status, type of surgery, or comorbidities (all P > 0.13)., Conclusions: Residual paralysis is common at tracheal extubation and PACU arrival, despite qualitative neuromuscular monitoring and the use of neostigmine. More effective detection and management of NMB is needed to reduce the risks associated with residual NMB.

Abdominal aortic aneurysms (AAAs) are a chronic condition that often progress over years to produce a weakened aorta with increased susceptibility for rupture, and currently, there are no pharmacological treatments available to slow disease progression. AAA development has been characterized by increased expression of cyclooxygenase-2 (COX-2), and inactivation of COX-2 before disease initiation reduces AAA incidence in a mouse model of the disease. The current study determined the effectiveness of COX-2 inhibition on AAA progression when treatment was begun after initiation of the disease. COX-2 inhibitor treatment with celecoxib was initiated after angiotensin II-induced AAA formation in a strain of nonhyperlipidemic mice that we have previously identified as highly susceptible to AAA development. When analyzed at different time points during progression of the disease, celecoxib treatment significantly reduced the incidence and severity of AAAs. The celecoxib treatment also protected the mice from aortic rupture and death. The aneurysmal lesion displayed an altered smooth muscle cell (SMC) phenotype, whereas celecoxib treatment was associated with increased expression of differentiated SMC markers and reduced dedifferentiation marker expression during AAA progression. Maintenance of a differentiated SMC phenotype is associated with the effectiveness of COX-2 inhibition for limiting AAA progression in nonhyperlipidemic mice.

Cardiac rehabilitation (CR) is most often provided in a hospital setting. Home-based models of care have been developed to overcome geographic, among other, barriers in patients at a lower risk. This study assessed whether clinical and geographic factors were related to the use of either a hospital-based or a home-based program. Secondary analysis was undertaken within a study of 1268 cardiac outpatients recruited from 97 cardiologist practices where clinical data were extracted. Participants completed a survey including the Duke Activity Status Index. They reported CR utilization in a second survey mailed 9 months later, including CR site and program model. Geographic information systems were used to determine the distances and the drive times to the CR site attended from patients' homes. Overall, 469 (37.0%) participants attended CR at one of 41 programs. Of the 373 (79.5%) participants with complete geographic data, 43 (11.5%) reported attending home-based CR. The sole clinical difference was in activity status, where patients attending a hospital-based program had lower activity status (P<0.01). There were no differences in model attended on the basis of geographic parameters including urban versus rural dwelling or drive times (P>0.05). In conclusion, only one-tenth of outpatients participated in a home-based program, and this allocation was unrelated to geographic considerations. Although patients should continue to be appropriately triaged on the basis of clinical risk to ensure safety, more targeted allocation of patients to home-based services may be warranted. This may optimize the degree of participation and potentially patient outcomes.

Background: Obtaining blood from children for research studies can be difficult, particularly for controls. One solution is to obtain samples during elective surgery; however, consideration must be given to the potential effects of the timing of phlebotomy., Observations: Ten children were recruited and phlebotomy was carried out during a preoperative clinic visit and intraoperatively immediately after the induction of anesthesia but before the start of surgery. CBCs, VWF, and FVIII levels were measured at both time points and no significant differences were seen., Conclusions: This negative result may be beneficial to pediatric research by suggesting that early intraoperative blood collection for controls does not affect the results.

The purpose of this study was to investigate the dimensions of emotional health in two population-based groups (Finland and Canada) of adolescents (ages 13 and 15 years) who self-identify as having a disability or chronic condition, as conceptualized by the WHO International Classification of Functioning, Disability and Health. Data from the 2002 WHO Health Behaviour in School-aged Children survey were used to compare the prevalence of emotional health (items on feeling low, feeling nervous) within and between countries. Eighteen percent of the Canadian and Finnish samples indicated they had a long-time disability, illness or medical condition. Canadian adolescents with disability or chronic conditions felt low significantly more frequently than their classmates without disability or chronic conditions. In both countries, students with disabilities who had more than one functional difficulty were significantly more likely to report feeling low and nervous. These results illustrate that the severity of disability as measured by the number of functional difficulties, and not merely the presence of disability or chronic condition, or particular functional difficulties, may play an important role in the emotional health of adolescents. Health promotion programs may use this information to guide practice to support the emotional health of students with disabilities.

Purpose: This study compared the kinematics and kinetics of the knee joint during traditional step-over-step (SOS) and compensatory step-by-step lead-leg (SBSL) and trail-leg (SBST) stair ambulation patterns., Methods: Seventeen (M:9) healthy adults completed five trials of ascent and descent using three different stepping patterns: 1) SBSL, 2) SBST, and 3) SOS. Kinematics and kinetics were collected with an optoelectronic motion-tracking system and a force plate embedded into a four-step staircase. An inverse-dynamics link-segment model (QGAIT system) was used to calculate the net joint kinetics., Results: During stair ascent, different peak anteroposterior (AP) forces were observed across all three stepping patterns (SOS > SBSL > SBST, P < 0.05). During ascent, the flexion moments of SOS (0.96 N x m x kg(-1)) and SBSL (0.97 N x m x kg(-1)) patterns were similar and much larger than the SBST moments (0.14 N x m x kg(-1)). In the descent conditions, the initial AP peak force for SOS was larger than that of SBSL and SBST. However, the second peak force for SOS (4.92 N x kg(-1)) and SBST (4.68 N x kg(-1)) were larger than SBSL (1.57 N x kg(-1)). During descent, the initial peak flexion moment for the SOS pattern was larger than SBSL and SBST, whereas during the second peak, SOS (1.05 N x m x kg(-1)) and SBST (1.11 N x m x kg(-)) were no different and larger than SBSL (0.18 N x m x kg(-1))., Conclusion: Overall, SBSL during ascent and SBST during descent had the highest loads. These results increase our understanding of alternative stepping patterns and have important clinical (reduction of loading on injured/diseased leg) and rehabilitation implications.

Purpose: There are 2 methods of corneal tissue procurement currently in widespread use: in situ extraction of the corneal button directly to preservation media and whole-globe enucleation of eyes with removal of the button to preservation media at a later time. This study evaluates the effects of these 2 procurement procedures on the initial quality of donor corneal tissue., Methods: Slit-lamp examination results and endothelial cell counts were compared for a total of 468 donor corneas harvested at 2 remote locations: one where in situ procurement was practiced and the other that used whole-globe enucleation procedures., Results: In both univariate and multivariate analysis, in situ corneas were found to have a lower incidence of moderate or severe haze and folds in Descemet membrane. No differences in mean endothelial cell counts were noted between the 2 populations of donated tissue., Conclusions: In situ procurement of corneal tissue results in higher initial corneal tissue quality than whole-globe procedures.

Objectives: Children on farms experience high risks for fall injuries. This study characterized the causes and consequences of fall injuries in this pediatric population., Methods: A retrospective case series was assembled from registries in Canada and the United States. A new matrix was used to classify each fall according to initiating mechanisms and injuries sustained on impact., Results: Fall injuries accounted for 41% (484/1193) of the case series. Twenty percent of the fall injuries were into the path of a moving hazard (complex falls), and 91% of complex falls were related to farm production. Sixty-one percent of complex falls from heights occurred while children were not working. Fatalities and hospitalized injuries were overrepresented in the complex falls., Conclusions: Pediatric fall injuries were common. This analysis provides a novel look at this occupational injury control problem.

Background: Obesity is a growing health issue in Canada, and identifying the determinants of weight gain is important for the development of appropriate prevention strategies., Purpose: To quantify the association between musculoskeletal fitness (MSF) and subsequent weight gain and development of obesity., Methods: The sample included 606 participants (20-69 yr; 291 men, 315 women) from the Physical Activity Longitudinal Study (PALS), a follow-up of participants from the 1981 Canadian Fitness Survey. Standardized assessments of height, weight, MSF (push-ups, sit-ups, grip strength, and trunk flexibility), and cardiorespiratory fitness were made at baseline (1981). Follow-up data on self-reported height and weight and body mass index (BMI) were collected by survey in 2002-2004. Logistic regression was used to predict obesity and weight gain of > or = 10 kg between 1981 and 2002-2004., Results: During the 20-yr follow-up, the prevalence of obesity (BMI > or = 30 kg.m(-2)) increased from 3.1 to 15.2%, reflecting a mean weight gain of 7.4 kg (men: 6.7 kg; women: 8.1 kg). Further, independent of age, sex, baseline BMI, physical activity, cardiorespiratory fitness, smoking, alcohol consumption, and income, low MSF was associated with significantly higher odds of having gained at least 10 kg during follow-up (OR: 1.78, 95% CI: 1.14-2.79)., Conclusions: The results indicate that MSF is a significant predictor of weight gain during a 20-yr period. Promoting participation in activities that enhance MSF may be beneficial in attenuating age-related weight gain and in preventing obesity among Canadians.

Study Design: Biomechanical analysis of the movement of the lumbar spinal nerve roots (NRs)., Objectives: The characteristics of the movement of lumbar spinal NRs corresponding to the change of posture were three-dimensionally analyzed in nonsimulated and simulated adhesion conditions using a porcine model., Summary of Background Data: There is a paucity of data on the movement of NRs., Materials and Methods: Thirty two NRs of four pig cadavers were investigated. (study 1) Two tantalum beads were sutured on respective NRs from L3 to L6. Five beads were put into each bony structure as reference points. The porcine body was put on the cage designed for three-dimensional radiostereometric analysis. Two oblique radiographs were simultaneously taken at flexion, neutral, and extension. (study 2) After study 1, either L4 NR was ligated onto the adjacent bone to mimic monoradicular adhesion. Radiographs were taken in the same manner. The movements of the beads on NRs relative to immobile standard points in each vertebra were analyzed., Results: The movement of NRs was characterized as a combination of stretching/slackening and pendulum motion. The distance that NRs were stretched/slackened, the excursion, and the angles that NRs moved were: 0.39 +/- 0.29 mm, 1.81 +/- 0.63 mm, and 10.46 +/- 5.93 degrees (in nonadhesion), and 0.30 +/- 0.20 mm, 1.02 +/- 0.50 mm, and 7.13 +/- 3.79 degrees (in simulated adhesion), respectively., Conclusion: Adhesion might play a part in the pathogenesis of lumbar spinal disorders because mechanical irritation secondary to stretching/slackening and pendulum motion might be concentrated at the distal part of NRs, adjacent to adhesion site, which has less cerebrospinal fluid and is close to dorsal root ganglion.