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Objective: Dysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context., Methods: We used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth., Results: Inhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise, gcgr deficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice., Conclusions: Our findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming., Competing Interests: Declaration of competing interest Hai Yan is an employee of REMD Biotherapeutics Inc. which licensed one of the glucagon receptor antibodies used for some of the studies in this manuscript. All other authors have no interests to declare., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: Dysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context., Methods: We used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth., Results: Inhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise, gcgr deficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice., Conclusion: Our findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming., Competing Interests: DECLARATION OF COMPETING INTERESTS The authors declare no conflicts of interests.

Background: Atrial fibrillation (AF) in patients resuscitated from cardiac arrest (CA) is associated with increased short-term mortality. However, whether this is because AF adversely affects early resuscitation success, causes post-resuscitation morbidity, or because it is a marker for patient co-morbidities, remains unclear. We aimed to determine the prevalence of AF in patients with ROSC to test the hypothesis that AF is associated with increased risk of rearrest and to determine its impact on mortality and stroke risk., Methods: We performed a retrospective study of emergency medical services patients with OHCA and ROSC. To examine long-term morbidity and mortality due to AF, an additional observational cohort analysis was performed using a large electronic health record (EHR) database., Results: One hundred nineteen patients with ROSC prior to ED arrival were identified. AF was observed in 39 (33%) of patients. Rearrest was not different between AF and no AF groups (44% vs. 41%, p = 0.94). In the EHR analysis, mortality at one year in patients who developed AF was 59% vs. 39% in no AF patients. Odds of stroke was 5x greater in AF patients (p < 0.001), with the majority not anticoagulated (93%, p < 0.001) and comorbidities were greater p < 0.001)., Conclusions: AF was common following ROSC and not associated with rearrest. AF after CA was associated with increased mortality and stroke risk. These data suggest rhythm control for AF in the immediate post-ROSC period is not warranted; however, vigilance is required for patients who develop persistent AF, particularly with regards to stroke risk and prevention., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [All authors have contributed to the scientific content of this work and approved this manuscript with agreement to submit this work to Resuscitation. This manuscript has not been published and is not under consideration for publication elsewhere. There are no conflicts of interest to declare in regard to this work. We also fully agree with the Editorial Policies of Resuscitation.]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: To assess preferences and outcome expectations for vagus nerve stimulation (VNS) and corpus callosotomy (CC) surgeries in the treatment of atonic seizure in Lennox-Gastaut syndrome (LGS)., Methods: A total of 260 surveys were collected from patients are caregivers of LGS patients via Research Electronic Data Capture (REDCap)., Results: Respondents reported an average acceptable atonic seizure reduction rate of 55.9% following VNS and 74.7% following CC. 21.3% (n = 50) were willing to be randomized. Respondents reported low willingness for randomization and a higher seizure reduction expectation with CC., Conclusion: Our findings guide surgical approaches for clinicians to consider patient preference in order to design future studies comparing effectiveness between these two procedures., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes in patients with cystic fibrosis (CF). However, ETI effects on impaired mucosal homeostasis and host defense at the molecular and cellular levels in the airways of patients with CF remain unknown. Objectives: To investigate effects of ETI on the transcriptome of nasal epithelial and immune cells from children with CF at the single-cell level. Methods: Nasal swabs from 13 children with CF and at least one F508del allele aged 6 to 11 years were collected at baseline and 3 months after initiation of ETI, subjected to single-cell RNA sequencing, and compared with swabs from 12 age-matched healthy children. Measurements and Main Results: Proportions of CFTR -positive cells were decreased in epithelial basal, club, and goblet cells, but not in ionocytes, from children with CF at baseline and were restored by ETI therapy to nearly healthy levels. Single-cell transcriptomics revealed an impaired IFN signaling and reduced expression of major histocompatibility complex classes I and II encoding genes in epithelial cells of children with CF at baseline, which was partially restored by ETI. In addition, ETI therapy markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Conclusions: Pharmacological improvement of CFTR function improves innate mucosal immunity and reduces immune cell inflammatory responses in the upper airways of children with CF at the single-cell level, highlighting the potential to restore epithelial homeostasis and host defense in CF airways by early initiation of ETI therapy.

Increasingly long and complex informed consents have yielded studies demonstrating comparatively low participant comprehension and satisfaction with traditional face-to-face approaches. In parallel, interest in electronic consents for clinical and research genomics has steadily increased, yet limited data are available for trio-based genomic discovery studies. We describe the design, development, implementation, and validation of an electronic iConsent application for trio-based genomic research deployed to support genomic studies of cerebral palsy. iConsent development incorporated stakeholder perspectives including researchers, patient advocates, institutional review board members, and genomic data-sharing considerations. The iConsent platform integrated principles derived from prior electronic consenting research and elements of multimedia learning theory. Participant comprehension was assessed in an interactive teachback format. The iConsent application achieved nine of ten proposed desiderata for effective patient-focused electronic consenting for genomic research. Overall, participants demonstrated high comprehension and retention of key human subjects' considerations. Enrollees reported high levels of satisfaction with the iConsent, and we found that participant comprehension , iConsent clarity , privacy protections , and study goal explanations were associated with overall satisfaction . Although opportunities exist to optimize iConsent, we show that such an approach is feasible, can satisfy multiple stakeholder requirements, and can realize high participant satisfaction and comprehension while increasing study reach., Competing Interests: Conflicts of Interest Paul Gross is President and CEO of the CP Research Network, which contributed to the funding of this project. Mr. Gross personally made financial contributions (donations) to CPRN to support this work, but receives no financial compensation related to either. Dr. Noritz has consulted for Abbott Nutrition, unrelated to this project. Dr. Shrader receives research funding from NIH and serves on the National Advisory Board for Medical Rehabilitative Research for NIH/NICHD.

Objective: To determine how physicians approach pharmacologic dystonia treatment in people with CP and assess physician readiness to participate in a randomized trial comparing existing pharmacologic dystonia treatments., Methods: We administered a REDCap survey to physician members of the American Academy of Cerebral Palsy and Developmental Medicine and of the Child Neurology Society to assess which pharmacologic agents they use to treat dystonia in CP and their preferred indications and dosing., Results: Of 479 physicians surveyed, 240 (50%) responded. Respondents treated functionally limiting (95%) and generalized (57%) dystonia and most commonly used six medications: baclofen (95%), trihexyphenidyl (79%), gabapentin (67%), carbidopa/levodopa (55%), clonazepam (55%), and diazepam (54%). Baclofen was preferred in people with co-existing spasticity (81%), gabapentin was preferred in people with co-existing pain (49%), and trihexyphenidyl was avoided in people with constipation (34%) or urinary retention (42%). Preferred dosing regimens followed published regimens for dystonia, when available, but otherwise followed published regimens for other CP symptoms (spasticity and seizures). Baclofen was preferred by 64% of respondents as first line treatment, but there was no clear consensus on second or third-line medications. Most respondents (51%) were comfortable randomizing their patients to receive any of the six most commonly used medications used to treat dystonia in CP., Conclusions: This study summarizes current indications and dosing for the six most commonly used medications to treat dystonia in CP as per treating physicians in the US and Canada and also demonstrates physician support for a randomized trial comparing the effectiveness of these treatments., Competing Interests: Conflict of Interest Disclosures (includes financial disclosures): The authors report no disclosures or conflicts of interest concerning the research related to this manuscript.

Objective: The aim of this study was to evaluate the association of annual trauma patient volume on outcomes for emergency medical services (EMS) agencies., Background: Regionalization of trauma care saves lives. The underlying concept driving this is a volume-outcome relationship. EMS are the entry point to the trauma system, yet it is unknown if a volume-outcome relationship exists for EMS., Methods: A retrospective analysis of prospective cohort including 8 trauma centers and 20 EMS air medical and metropolitan ground transport agencies. Patients 18 to 90 years old with injury severity scores ≥9 transported from the scene were included. Patient and agency-level risk-adjusted regression determined the association between EMS agency trauma patient volume and early mortality., Results: A total of 33,511 were included with a median EMS agency volume of 374 patients annually (interquartile range: 90-580). Each 50-patient increase in EMS agency volume was associated with 5% decreased odds of 6-hour mortality (adjusted odds ratio=0.95; 95% CI: 0.92-0.99, P =0.03) and 3% decreased odds of 24-hour mortality (adjusted odds ratio=0.97; 95% CI: 0.95-0.99, P =0.04). Prespecified subgroup analysis showed EMS agency volume was associated with reduced odds of mortality for patients with prehospital shock, requiring prehospital airway placement, undergoing air medical transport, and those with traumatic brain injury. Agency-level analysis demonstrated that high-volume (>374 patients/year) EMS agencies had a significantly lower risk-standardized 6-hour mortality rate than low-volume (<374 patients/year) EMS agencies (1.9% vs 4.8%, P <0.01)., Conclusions: A higher volume of trauma patients transported at the EMS agency level is associated with improved early mortality. Further investigation of this volume-outcome relationship is necessary to leverage quality improvement, benchmarking, and educational initiatives., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Effective trauma system organization is crucial to timely access to care and requires accurate understanding of injury and resource locations. Many systems rely on home zip codes to evaluate geographic distribution of injury; however, few studies have evaluated the reliability of home as a proxy for incident location after injury., Methods: We analyzed data from a multicenter prospective cohort collected from 2017 to 2021. Injured patients with both home and incident zip codes were included. Outcomes included discordance and differential distance between home and incident zip code. Associations of discordance with patient characteristics were determined by logistic regression. We also assessed trauma center catchment areas based on home versus incident zip codes and variation regionally at each center., Results: Fifty thousand one hundred seventy-five patients were included in the analysis. Home and incident zip codes were discordant in 21,635 patients (43.1%). Injuries related to motor vehicles (aOR: 4.76 [95% CI 4.50-5.04]) and younger adults 16-64 (aOR: 2.46 [95% CI 2.28-2.65]) were most likely to be discordant. Additionally, as injury severity score increased, discordance increased. Trauma center catchment area differed up to two-thirds of zip codes when using home versus incident location. Discordance rate, discordant distance, and catchment area overlap between home and incident zip codes all varied significantly by geographic region., Conclusions: Home location as proxy for injury location should be used with caution and may impact trauma system planning and policy, especially in certain populations. More accurate geolocation data are warranted to further optimize trauma system design., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Post-acute coronary syndrome pharmaceutical interviews were set up in our establishment. The objective of this study was to assess their impact on patient knowledge and their benefit at one year on medication compliance, cardiovascular risk factors (smoking, overweight, dyslipidemia) and the recurrence rate., Methods: Two groups were formed, an experimental group of patients who had benefited from pharmaceutical interviews and a control group of patients who had not benefited from them. The knowledge of the patients was measured using a quizz carried out before the interview and one month after for the experimental group, then one year after hospitalization for the two groups. A one-year follow-up of medication compliance assessed, control of cardiovascular risk factors and the rate of recurrence of acute coronary syndrome was carried out in both groups., Results: A significant increase in knowledge (P<0.001) after the pharmaceutical interview and its maintenance over time were observed in the experimental group. One year after hospitalization, in the experimental group, the average score on the knowledge quizz (9.2/10) was significantly higher (P<0.005) than that of the control group (6.6/10); medication compliance was significantly better (P<0.05) and greater smoking cessation was observed., Conclusions: These encouraging results should be highlighted in order to perpetuate and develop such approaches around patient care., (Copyright © 2022 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Objective: Clinical trials in early diffuse SSc have consistently shown a placebo group response with a declining modified Rodnan skin score (mRSS), with negative outcomes. Our objective was to identify strategies using clinical characteristics or laboratory values to improve trial design., Methods: We identified early diffuse SSc patients first seen at the University of Pittsburgh from 1980-2015. Eligible patients had ≥3 visits, with at least two mRSS scores within the first year of follow-up. We performed Kaplan-Meier analyses, group-based trajectory analysis of mRSS scores, followed by multivariable regression analysis and classification tree analysis. We applied the results to the abatacept in early diffuse systemic sclerosis (ASSET) trial outcome data., Results: We identified 403 patients with <18 months, and 514 with <36 months disease duration. The median number of mRSS follow-up scores was 14 (interquartile range 8, 25). All methodologic approaches identified skin thickness progression rate, RNA polymerase III (RNAP3) antibody positivity and presence of tendon friction rubs (TFR) as predictors of mRSS trajectory over 5 years of follow-up, and thereby as potential enrichment variables. When applied to the ASSET data, adjustment for both RNAP3 and TFR demonstrated reduction of the placebo mRSS response, particularly at 6 months. A significant difference in the ACR Composite Response Index in Systemic Sclerosis (CRISS) score was found with adjustment by RNAP3 at 6 months, and TFR or RNAP3 at 12 months., Conclusion: Adjustment for both RNAP3 and TFR predicts mRSS trajectory and diminished the mRSS decline in ASSET placebo group, and identified significant differences in CRISS. RNAP3, particularly, is a stratification or enrichment approach to improve early diffuse SSc trial design., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The pathophysiology of obstructive sleep apnea in pregnancy remains poorly understood and studies examining the effect of treatment with positive airway pressure on pregnancy have been limited., Objective: This study aimed to perform a randomized controlled trial of positive airway pressure treatment for obstructive sleep apnea in pregnancy., Study Design: Participants with a body mass index ≥30 kg/m 2 underwent polysomnography at 14 to 20 weeks' gestation (visit 1) and those with obstructive sleep apnea (apnea-hypopnea index ≥5 but <50) were enrolled. In phase 1, participants were randomized to autotitrating positive airway pressure vs sham positive airway pressure; in phase 2, the sham arm was replaced with a sleep hygiene control. Participants returned at 28 to 31 weeks' gestation (visit 2). The mean arterial blood pressure, uterine artery Doppler pulsatility index, endoglin, soluble FMS-like tyrosine kinase 1 levels, and placental growth factor levels were measured, as well as fasting glucose and insulin to calculate insulin resistance (homeostatic model assessment for insulin resistance). The primary outcome was a composite of the uterine artery Doppler pulsatility index, soluble FMS-like tyrosine kinase 1 to placental growth factor ratio, and the homeostatic model assessment for insulin resistance. For secondary analyses, each outcome variable was analyzed independently. Adherence to treatment was examined., Results: A total of 241 participants completed visit 1, and 89 (37%) had an apnea-hypopnea index between 5 and 50. Of the those, 51 participants were randomized in phase 1 and 38 in phase 2. There was no significant difference in our primary outcome by treatment group. In secondary analyses, the uterine artery Doppler pulsatility index was lower in participants on autotitrating positive airway pressure when compared with sleep hygiene controls. Otherwise, there were no differences in the mean arterial blood pressure, angiogenic markers, or metabolic markers in phase 1, phase 2, or across the entire study. The overall adherence to autotitrating positive airway pressure therapy was low, but the mean use was greater in phase 2 (0.3±0.6 hours/night vs 1.3±2.3 hours/night; P=.10). For those on active therapy, fasting glucose values decreased as adherence increased., Conclusion: This randomized controlled trial of autotitrating positive airway pressure in pregnancy did not find any differences in a composite primary cardiometabolic risk profile between the treatment groups. Higher autotitrating positive airway pressure adherence was associated with lower fasting glucose levels. The use of a sham positive airway pressure control arm in phase1 may have negatively impacted adherence to active treatment., (Copyright © 2022. Published by Elsevier Inc.)

Background: To describe the incidence and factors predicting visual outcome in patients with infectious endophthalmitis following intravitreal anti-VEGF injection., Methods: Retrospective, single-site, cohort study. Patients with acute endophthalmitis within 6 weeks of intravitreal anti-VEGF injection who were referred to our practice after inciting injection or were injected by us between January 2010 and July 2017 were included. All patients received intravitreal antibiotics with either vitreous/anterior chamber tap (TAP) or pars plana vitrectomy. Visual outcomes pre/post treatment, baseline variables (age, gender, ocular disease) and cultures results were studied., Results: Seventy eyes of 69 patients were included. Presenting VA was the strongest factor associated with final visual outcome after adjusting for other variables including culture status and baseline VA (p = .0002). Cultures were positive in 62.8% of eyes and were associated with worse visual outcome (p = .0087). Growth of Streptococcus or microorganisms other than coagulase negative Staphylococci (CNS) was also associated with worse prognosis, regardless of baseline and presenting VA (p = .0002). The crude incidence of post-injection endophthalmitis was 0.028% in our practice (40 eyes in 143,628 injections) during the study time. No significant difference was found between pre-filled bevacizumab versus ranibizumab or aflibercept drawn from a vial., Conclusions: In a large, single center, retrospective study, the incidence of acute endophthalmitis post anti-VEGF injection was relatively low. Worse visual acuity at presentation of endophthalmitis and growth of Streptococcus or organisms other than CNS were associated with the worst visual outcomes., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Study Objectives: To evaluate the impact of sleep-disordered breathing (SDB) on vascular, angiogenic and metabolic analytes in pregnancy., Methods: Participants with a body mass index ≥30 kg/m 2 underwent polysomnography at 14-20 weeks gestation (visit 1). Participants with SDB (defined as an apnea-hypopnea index ≥5 events/h) were then enrolled in a separate trial. SDB-negative participants returned for a polysomnogram at 28-31 weeks (visit 2) and were recategorized as persistent-negative SDB or new-onset SDB. Mean arterial blood pressure, mean uterine artery Doppler pulsatility index, endoglin, soluble Feline McDonough Sarcoma-like tyrosine kinase 1, placental growth factor, and the homeostatic model assessment for insulin resistance were measured after each visit. Our primary outcome was a composite of uterine artery Doppler pulsatility index, soluble FMS-like tyrosine kinase 1/placental growth factor ratio, and homeostatic model assessment for insulin resistance. For secondary analyses, each outcome variable was analyzed independently., Results: A total of 242 and 130 participants completed visit 1 and visit 2, respectively. Newly diagnosed SDB was present in 37% of individuals at visit 1 and 31% of individuals at visit 2. No significant differences in our composite outcome vector were observed in individuals with and without SDB at either visit. In our secondary analysis, mean arterial blood pressure (88.7 ± 7.3 mm Hg vs 85.4 ± 7.1 mm Hg, P = .04) and fasting glucose (92.4 ± 15.2 mg/dL vs 86.6 ± 11.5 mg/dL, P = .05) were higher in participants with early pregnancy SDB. These associations were not observed for new-onset SDB. No associations were observed between uterine artery Doppler pulsatility index and angiogenic markers and SDB in pregnancy., Conclusions: SDB in early pregnancy was not associated with our composite primary outcome but was associated with higher mean arterial blood pressure and fasting glucose. The pathophysiologic changes that occur in pregnant individuals with SDB and how they lead to an increased risk of preeclampsia and gestational diabetes remain poorly understood., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Sleep Disordered Breathing, Obesity and Pregnancy Study (SOAP); URL: https://clinicaltrials.gov/ct2/show/NCT02086448; Identifier: NCT02086448., Citation: Onslow ML, Wolsk J, Wisniewski S, et al. The association between sleep-disordered breathing and maternal endothelial and metabolic markers in pregnancies complicated by obesity. J Clin Sleep Med . 2023;19(1):97-109., (© 2023 American Academy of Sleep Medicine.)

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing., Objective: STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients., Methods: Sitting, nonambulatory SMA patients (biallelic SMN1 loss, three SMN2 copies, aged 6-<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6-<24 months) and older (24-<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls., Results: Thirty-two patients were enrolled and completed the study (medium dose, n = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P < 0.01)., Conclusions: Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history.

Host response to infection involves the activation of the complement system leading to the production of anaphylatoxins C3a and C5a. Complement factor C5a exerts its effect through the activation of C5aR1, chemotactic receptor 1, and triggers the G protein-coupled signaling cascade. Orthosteric and allosteric antagonists of C5aR1 are a novel strategy for anti-inflammatory therapies. Here, we discuss recent crystal structures of inactive C5aR1 in terms of an inverted orientation of helix H8, unobserved in other GPCR structures. An analysis of mutual interactions of subunits in the C5aR1-G protein complex has provided new insights into the activation mechanism of this distinct receptor. By comparing two C5aR receptors C5aR1 and C5aR2 we explained differences between their signaling pathways on the molecular level. By means of molecular dynamics we explained why C5aR2 cannot transduce signal through the G protein pathway but instead recruits beta-arrestin. A comparison of microsecond MD trajectories started from active and inactive C5aR1 receptor conformations has provided insights into details of local and global changes in the transmembrane domain induced by interactions with the Gα subunit and explained the impact of inverted H8 on the C5aR1 activation., Competing Interests: The authors have declared that no competing interests exist.

We are in an emerging era of gene-based therapeutics with significant promise for rare genetic disorders. The potential is particularly significant for genetic central nervous system disorders that have begun to achieve Food and Drug Administration approval for select patient populations. This review summarizes the discussions and presentations of the National Institute of Mental Health-sponsored workshop "Gene-Based Therapeutics for Rare Genetic Neurodevelopmental Psychiatric Disorders," which was held in January 2021. Here, we distill the points raised regarding various precision medicine approaches related to neurodevelopmental and psychiatric disorders that may be amenable to gene-based therapies., Competing Interests: Declaration of interests B.L.D. serves an advisory role and/or receives sponsored research support from Homology Medicines, Saliogen Therapeutics, Patch Bio, Moment Bio, Panorama Medicines, Resilience, Spirovant Sciences, Novartis (NBIR), Roche, and Sanofi. G.G. is a scientific co-founder of Voyager Therapeutics and Aspa Therapeutics and holds equity in these companies. G.G. is an inventor on patents with potential royalties licensed to Voyager Therapeutics, Aspa Therapeutics, RegenxBio, and other biopharmaceutical companies. A.M.B. is a beneficiary of a licensing agreement with Axovant Gene Therapies (royalties) and is an inventor on a patent pending related to a GALC Vector: Optimized GALC Genes and Expression Cassettes and Their Use (PCT/US2019/067727). J.D.B. is a consultant for BridgeBio Pharma and received sponsored research support from Takeda California, Inc. G.R.C. is a previous employee of Sio Gene Therapies. S.J.G. received royalty income from Abeona Therapeutics and Taysha Gene Therapies. R.J.K. is an employee of Biogen. A.S. is an employee and shareholder of BridgeBio Pharma. H.Y.Z. is co-founder of Cajal Neuroscience, on the Board of Directors of Regeneron Pharmaceuticals, Inc., the Scientific Advisory Board of The Column Group, and the Institutional Advisory Board of VIB. T.R.F. is a paid consultant for Ferring Ventures, SA. S.T.-W. is an employee of Novartis. M.S. received sponsored research support from Novartis, Biogen, Astellas, Aeovian, Bridgebio, and Aucta and has served on scientific advisory boards for Novartis, Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics, and Alkermes., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

SPR1NT ( NCT03505099 ) was a Phase III, multicenter, single-arm study to investigate the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated at ≤6 weeks of life. Here, we report final results for 14 children with two copies of SMN2, expected to develop spinal muscular atrophy (SMA) type 1. Efficacy was compared with a matched Pediatric Neuromuscular Clinical Research natural-history cohort (n = 23). All 14 enrolled infants sat independently for ≥30 seconds at any visit ≤18 months (Bayley-III item #26; P < 0.001; 11 within the normal developmental window). All survived without permanent ventilation at 14 months as per protocol; 13 maintained body weight (≥3rd WHO percentile) through 18 months. No child used nutritional or respiratory support. No serious adverse events were considered related to treatment by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for children expected to develop SMA type 1, highlighting the urgency for universal newborn screening., (© 2022. The Author(s).)

Most children with biallelic SMN1 deletions and three SMN2 copies develop spinal muscular atrophy (SMA) type 2. SPR1NT ( NCT03505099 ), a Phase III, multicenter, single-arm trial, investigated the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated within six postnatal weeks. Of 15 children with three SMN2 copies treated before symptom onset, all stood independently before 24 months (P < 0.0001; 14 within normal developmental window), and 14 walked independently (P < 0.0001; 11 within normal developmental window). All survived without permanent ventilation at 14 months; ten (67%) maintained body weight (≥3rd WHO percentile) without feeding support through 24 months; and none required nutritional or respiratory support. No serious adverse events were considered treatment-related by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention., (© 2022. The Author(s).)

Rhenium compounds have shown anti-cancer properties against many different types of cancer cell lines; however, the cellular signaling mechanisms involved in the cytotoxic properties of rhenium-based compounds were never deciphered or reported. In this manuscript, we report the results of an investigation done by RNA sequencing of rhenium treated A549 lung cancer cell lines along with an untreated vehicular control, analyzed by the Ingenuity Pathway Analysis (IPA) software system to decipher the core canonical pathways involved in rhenium induced cancer cell death. A549 EMT lung cancer cell lines were treated with rhenium ligand (Tricarbonylperrhenato(bathocuproine)rhenium(I), PR7) for seven days along with vehicular control. RNA was isolated from the treated and control cells and sequenced by a commercial company (PrimBio Corporation). The RNA sequencing data was analyzed by the INGNUITY software system and the core canonical pathways involved with differential gene expression were identified. Our report is showing that there are several cellular pathways involved in inducing cell death by rhenium-based compound PR7., Competing Interests: Conflicts of Interest The authors declare no conflicts of interest regarding the publication of this paper.

Introduction/aims: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates peroxisome proliferator-activated receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants., Methods: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo. The study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated., Results: A total of 64 (single-dose cohort) and 37 (multiple-dose cohort) participants were included in the study. After single doses of 1 to 120 mg, ASP0367 was rapidly absorbed, with median time to maximum plasma concentration (t max ) of 1.50 to 2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, t max was delayed 1.7 hours. After multiple once-daily doses, mean half-life of ASP0367 10 to 75 mg ranged from 14.1 to 17.5 hours; steady state was reached after 4 days. Negligible accumulation was observed after repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild to moderate in severity; none were considered drug-related. No clinically significant changes were observed on laboratory or electrocardiographic evaluation. Treatment- and dose-dependent upregulation of six PPARδ target genes was observed with single and multiple doses of ASP0367., Discussion: ASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants., (© 2021 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Background: The use of antibiotic-loaded acrylic cement for treating periprosthetic joint infections remains controversial. We hypothesized that the raw rate of surgical site infection (SSI) is lower after using cement loaded with high-dose gentamicin and clindamycin than after using cement loaded with standard-dose gentamicin for implant fixation during 1-stage hip and knee revision arthroplasty for infection., Methods: One hundred seventy-one continuous patients operated by 2 experienced surgeons during a 2-year period were included in the study. All patients were followed for 24 months. The primary endpoint was the raw rate of SSI after 2 years of follow-up time., Results: The raw rate of SSI after 2 years of follow-up time was significantly lower in the study group (13%) than in the control group (26%) (P = .03) with an odds ratio of 0.42 (P = .03). These SSIs were new infections rather than a recurrence/persistence of the initial infection., Conclusion: The cement used in the study group significantly reduced the risk of SSI relative to the cement used in the control group. Routine use of this high-dose dual antibiotic-loaded cement can be considered during 1-stage knee or hip revision arthroplasty for infection., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: There is a paucity of data regarding cause-specific mortality following a perioperative stroke. In this study, we aim to establish the risk of cause-specific mortality associated with perioperative stroke following cardiac and vascular procedures at 30 days, 90 days, and 1-year postoperative. It is hoped that this fund of knowledge will enhance perioperative risk stratification and medical management for patients who have suffered a perioperative stroke., Methods: This is a retrospective cohort study evaluating 277,654 cardiac and vascular surgical patients dually documented within the Inpatient Discharge Claims Database and the Pennsylvania Department of Health Death Statistics database. A univariate assessment followed by a multivariate logistic regression analysis was used to determine the odds of cerebrovascular, cardiovascular, pulmonary, malignancy, infectious, and dementia causes of mortality following perioperative stroke., Results: Perioperative stroke significantly increased the odds of overall mortality (P<0.0001) as well as cause-specific mortality in all categories (P<0.05) except dementia (P=0.8907) at all-time endpoints. Cerebrovascular-related mortality was most impacted by perioperative stroke [adjusted odds ratio: 34.5 (29.1, 40.9), P<0.0001 at 30 d]., Conclusions: Perioperative stroke in the cardiac and vascular surgical population is associated with increased odds of overall, cerebrovascular, cardiovascular, pulmonary, malignancy, and infectious causes of mortality at 30 days, 90 days, and 1-year postoperatively when compared with patients who did not experience a perioperative stroke., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established., Objective: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19., Design, Setting, and Participants: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2., Interventions: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days., Main Outcomes and Measures: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication., Results: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar., Conclusions and Relevance: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated., Trial Registration: ClinicalTrials.gov Identifier: NCT04498273.

Objectives: Clinical trials in early diffuse cutaneous systemic sclerosis (SSc) using the modified Rodnan skin score (mRSS) as the primary outcome measure have most often been negative. We wanted to assess how the definition of disease onset (first SSc manifestation vs first non-Raynaud manifestation) and varying lengths of disease duration at trial entry as an inclusion criteria functioned. Our objective was to optimize trial inclusion criteria., Methods: We used the prospective, observational University of Pittsburgh Scleroderma Cohort to identify early diffuse SSc patients first evaluated between 1980 and 2015. All had <3 years from first SSc (n = 481) or first non-Raynaud manifestation (n = 514) and three or more mRSS scores. We used descriptive, survival and group-based trajectory analyses to compare the different definitions of disease onset and disease duration as inclusion criteria for clinical trials., Results: There was no appreciable difference between using first SSc manifestation compared with first non-Raynaud manifestation as the definition of disease onset. Compared with other disease durations, <18 months of disease had >70% of patients fitting into trajectories with worsening cutaneous disease over 6 months of follow-up. Longer disease durations demonstrated the majority of patients with trajectories showing an improvement in mRSS (regression to the mean) over 6 months., Conclusions: Regardless of whether the first SSc or first non-Raynaud manifestation is used to define disease onset, duration of <18 months at enrolment is preferable. A longer disease duration criterion more frequently results in regression to the mean of the mRSS score, and likely contributes to negative trial outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US., Methods: STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7-8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 10 14 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed)., Findings: From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0-5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26-100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91-100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8-44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 [67%] of 33), upper respiratory infection (11 [33%]), and increased alanine aminotransferase (nine [27%]). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study., Interpretation: STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit-risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline., Funding: Novartis Gene Therapies., Competing Interests: Declaration of interests EM reports personal fees from Novartis Gene Therapies, Biogen, Roche, and Scholar Rock; and grants from Biogen including support for disease registries (the International SMA Consortium Registry). FM reports grants and personal fees from Novartis Gene Therapies (including participation in the STR1VE-EU grant and the SPR1NT study) and Roche (including participation in the JEWELFISH trial of risdiplam and the olesoxime trial); and grants, personal fees, and other from Biogen (including participation in the SHINE trial and being principal investigator of the UK SMA REACH UK registry). GB received speaker and consulting fees from Novartis Gene Therapies, AveXis, and Roche. RM and CB received personal fees from Biogen, Novartis Gene Therapies, and Roche for consulting and are principal investigators of spinal muscular atrophy studies funded by these sponsors. OB-T declares no competing interests. SC participated in Novartis Gene Therapies and Scholar Rock advisory boards. AD received personal fees and is principal investigator of spinal muscular atrophy studies sponsored by Novartis Gene Therapies. ND received personal fees from Biogen and Roche (for the advisory board in the SUNFISH trial) and is principal investigator of the Belgium spinal muscular atrophy registry funded by Biogen. LS received grants and personal fees from Biogen, Novartis Gene Therapies, and Roche; and personal fees from Cytokinetics. VS received consultancy fees from Novartis Gene Therapies. HO, DC, ST-W, NM, and AV are employees of Novartis Gene Therapies. DC, ST-W, NM, and AV own Novartis stock or other equities., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy., Objective: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data., Methods: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated., Results: The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients., Conclusions: Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity., (© 2021. The Author(s).)

Background: Ultrasound (US)-guided hip joint injections are commonly performed for patients with suspected or known intra-articular hip pain. Lidocaine is a well-established local anesthetic used prior to hip joint injections, but it is often associated with discomfort during infiltration. Bacteriostatic saline is an alternative local anesthetic that has been shown to be less painful during infiltration for superficial injections., Objective: To compare infiltrative pain and anesthetic efficacy of bacteriostatic saline (0.9% benzyl alcohol) with a standard local anesthetic (buffered 1% lidocaine) used for local anesthesia prior to US-guided intra-articular hip corticosteroid injections., Design: Double-blinded, randomized controlled trial., Setting: Tertiary care medical center., Participants: Sixty eight patients age 18-80 (mean 54.8) years referred for US-guided intra-articular hip corticosteroid injections., Intervention: Patients were randomized to receive a US-guided hip joint corticosteroid injection using either bacteriostatic saline or buffered 1% lidocaine for preinjection local anesthesia., Main Outcome Measures: Visual Analog Scale (VAS) for pain (0-100) during local anesthetic infiltration as well as during the intra-articular injection. Adverse events were also recorded., Results: There were no significant differences between bacteriostatic saline and buffered lidocaine with respect to pain during local anesthetic infiltration or during the subsequent intra-articular injection. Pain VAS during local anesthetic infiltration was 13.2 (95% confidence interval [CI] 7.8, 18.5) in the bacteriostatic saline group and 14.0 (95% CI 9.4, 18.5) in the buffered 1% lidocaine group (P = .82). Furthermore, pain VAS during the intra-articular injection was 20.7 (95% CI 14.1, 27.3) in the bacteriostatic saline group and 15.7 (95% CI 10.9, 20.3) in the buffered 1% lidocaine group (P = .57). No adverse events occurred., Conclusions: Bacteriostatic saline is a safe and comparably effective alternative to buffered 1% lidocaine for local anesthesia before US-guided hip joint injections and may be considered for subcutaneous/periarticular anesthesia during similar musculoskeletal procedures., (© 2020 American Academy of Physical Medicine and Rehabilitation.)

Background and Objectives: Filtering the deluge of new research to facilitate evidence synthesis has proven to be unmanageable using current paradigms of search and retrieval. Crowdsourcing, a way of harnessing the collective effort of a "crowd" of people, has the potential to support evidence synthesis by addressing this information overload created by the exponential growth in primary research outputs. Cochrane Crowd, Cochrane's citizen science platform, offers a range of tasks aimed at identifying studies related to health care. Accompanying each task are brief, interactive training modules, and agreement algorithms that help ensure accurate collective decision-making.The aims of the study were to evaluate the performance of Cochrane Crowd in terms of its accuracy, capacity, and autonomy and to examine contributor engagement across three tasks aimed at identifying randomized trials., Study Design and Setting: Crowd accuracy was evaluated by measuring the sensitivity and specificity of crowd screening decisions on a sample of titles and abstracts, compared with "quasi gold-standard" decisions about the same records using the conventional methods of dual screening. Crowd capacity, in the form of output volume, was evaluated by measuring the number of records processed by the crowd, compared with baseline. Crowd autonomy, the capability of the crowd to produce accurate collectively derived decisions without the need for expert resolution, was measured by the proportion of records that needed resolving by an expert., Results: The Cochrane Crowd community currently has 18,897 contributors from 163 countries. Collectively, the Crowd has processed 1,021,227 records, helping to identify 178,437 reports of randomized controlled trials (RCTs) for Cochrane's Central Register of Controlled Trials. The sensitivity for each task was 99.1% for the RCT identification task (RCT ID), 99.7% for the RCT identification task of trials from ClinicalTrials.gov (CT ID), and 97.7% for the identification of RCTs from the International Clinical Trials Registry Platform (ICTRP ID). The specificity for each task was 99% for RCT ID, 98.6% for CT ID, and 99.1% for CT ICTRP ID. The capacity of the combined Crowd and machine learning workflow has increased fivefold in 6 years, compared with baseline. The proportion of records requiring expert resolution across the tasks ranged from 16.6% to 19.7%., Conclusion: Cochrane Crowd is sufficiently accurate and scalable to keep pace with the current rate of publication (and registration) of new primary studies. It has also proved to be a popular, efficient, and accurate way for a large number of people to play an important voluntary role in health evidence production. Cochrane Crowd is now an established part of Cochrane's effort to manage the deluge of primary research being produced., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Mild traumatic brain injury (TBI) is experienced by 55.9 million people globally each year. The symptoms of mild TBI are diverse and sometimes long-lasting, requiring frequent use of pharmacological interventions to mitigate them. A thorough understanding of the data supporting pharmacological interventions is important for decision-making among clinicians treating this common injury., Objective: To systematically review studies of pharmacological interventions and their associations with symptom burden reduction among patients with mild TBI and to use an evidence-based model to identify potential directions for future research that may aid in clinical decision-making., Evidence Review: A systematic review was performed in PubMed, Scopus, and Web of Science. Search strings modified for the advanced search interfaces of each search engine were developed in consultation with a librarian and included combinations of search terms, such as brain concussion, post-concussion syndrome, mild traumatic brain injury, and pharmacological treatment. Articles published between January 1, 2000, and July 1, 2020, were analyzed. Studies were included if (1) they were clinical studies with discrete analyses of participants with mild TBI or complicated mild TBI, (2) they were assessments of a pharmacological intervention, (3) they included human participants, and (4) they were published in a peer-reviewed journal in the English language. Studies were excluded if the severity of TBI among participants could not be ascertained (ie, inadequate definition of mild TBI) and the inclusion criteria for the study required intracranial hemorrhage. A total of 23 studies examining 20 pharmacological interventions met the inclusion criteria. Risk of bias was assessed using the Cochrane Risk of Bias for Randomized Trials (for randomized clinical trials) and the Cochrane Risk of Bias in Non-Randomized Studies of Interventions (for all other studies). Data were analyzed from June to September 2020., Findings: A total of 1495 articles were identified; of those, 131 articles were excluded as duplicates. Titles and abstracts were screened for inclusion and exclusion criteria among the remaining 1364 articles, and 134 of those articles received a full-text review. After exclusions, 23 studies (11 randomized clinical trials, 7 prospective observational studies, 3 retrospective observational studies, and 2 case studies) examining 20 pharmacological interventions were identified for inclusion in the systematic review. Studies included 22 distinct participant populations comprising 8277 participants with mild TBI and 45 participants without TBI. Among 23 total studies, 8 studies specifically addressed the pediatric population, 9 studies had a low risk of bias, and 16 studies reported symptom burden reduction. Of the 20 pharmacological interventions examined in the studies, methylphenidate, sertraline hydrochloride, ondansetron, amitriptyline, and melatonin were the only medications included in multiple studies., Conclusions and Relevance: This systematic review found a limited number of high-quality, clinically meaningful studies, particularly among children and individuals in the acute stage of injury; therefore, performing an evidence-based analysis that would inform clinical decision-making was not possible. Future studies are needed to focus on standardizing measures and increasing sample sizes (including large multicenter clinical trials) to generate a body of research that may provide additional options for the treatment of patients with mild TBI.

Background: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy., Methods: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 10 14 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed)., Findings: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus)., Interpretation: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1., Funding: Novartis Gene Therapies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background & Aims: Spinal muscular atrophy (SMA) is an autosomal recessive, childhood-onset motor neuron disease. Onasemnogene abeparvovec (OA) is a gene therapy designed to address SMA's root cause. In pivotal mouse toxicology studies, the liver was identified as a major site of OA toxicity. Clinical data reflect elevations in serum aminotransferase concentrations, with some reports of serious acute liver injury. Prophylactic prednisolone mitigates these effects. Herein, we aim to provide pragmatic, supportive guidance for identification, management, and risk mitigation of potential drug-induced liver injury., Methods: Data from 325 patients with SMA who had received OA through 31 December 2019, in 5 clinical trials, a managed access program (MAP), and a long-term registry (RESTORE), and through commercial use, were analyzed. Liver-related adverse events, laboratory data, concomitant medications, and prednisolone use were analyzed., Results: Based on adverse events and laboratory data, 90 of 100 patients had elevated liver function test results (alanine aminotransferase, and/or aspartate aminotransferase, and/or bilirubin concentrations). Of these, liver-associated adverse events were reported for 34 of 100 (34%) and 10 of 43 (23%) patients in clinical trials and MAP/RESTORE, respectively. Two patients in MAP had serious acute liver injury, which resolved completely. While all events in the overall population resolved, prednisolone treatment duration varied (range: 33-229 days), with a majority receiving prednisolone for 60-120 days. More than 60% had elevations in either alanine aminotransferase, aspartate aminotransferase, or bilirubin concentrations prior to dosing. Greater than 40% received potentially hepatotoxic concomitant medications., Conclusions: Hepatotoxicity is a known risk associated with OA use. Practitioners should identify contributing factors and mitigate risk through appropriate monitoring and intervention., Lay Summary: Onasemnogene abeparvovec is a type of medicine called a "gene therapy," which is used to treat babies and young children who have a rare, serious inherited condition called "spinal muscular atrophy" (SMA). It works by supplying a fully functioning copy of the survival motor neuron or SMN gene, which then helps the body produce enough SMN protein. However, it can cause an immune response that could lead to an increase in enzymes produced by the liver. This article provides information about the liver injury and how to prevent and recognize if it happens, so that it may be treated properly., Competing Interests: Conflicts of interest DC, KM, AK, RS, FM, ST-W, FFT, GK-U and PK are employees of Novartis, and own Novartis stock or other equities. HJM has participated in ad boards and medical symposia for Novartis Gene Therapies (formerly AveXis, Inc.). Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Spinal muscular atrophy is a progressive, recessively inherited monogenic neurologic disease, the genetic root cause of which is the absence of a functional survival motor neuron 1 gene. Onasemnogene abeparvovec (formerly AVXS-101) is an adeno-associated virus serotype 9 vector-based gene therapy that delivers a fully functional copy of the human survival motor neuron gene. We report anti-adeno-associated virus serotype 9 antibody titers for patients with spinal muscular atrophy when they were screened for eligibility in the onasemnogene abeparvovec clinical trials (intravenous and intrathecal administration) and managed access programs (intravenous). Through December 31, 2019, 196 patients and 155 biologic mothers were screened for anti-adeno-associated virus serotype 9 binding antibodies with an enzyme-linked immunosorbent assay. Of these, 15 patients (7.7%) and 23 biologic mothers (14.8%) had titers >1:50 on their initial screening tests. Eleven patients (5.6%) had elevated titers on their final screening tests. The low percentage of patients with exclusionary antibody titers indicates that most infants with spinal muscular atrophy type 1 should be able to receive onasemnogene abeparvovec. Retesting may identify patients whose antibody titers later decrease to below the threshold for treatment, and retesting should be considered for patients with anti-adeno-associated virus serotype 9 antibody titers >1:50., Competing Interests: J.W.D. reports financial relationships with Novartis Gene Therapies, Inc., Affinia Therapeutics, Biogen, Cytokinetics, Ionis, Pfizer, Roche, and Sarepta, and royalties from Athena Diagnostics. R.S.F. has served as an advisor to Novartis Gene Therapies, Inc., Ionis, Biogen, and Roche, and received licensing fees from the Children’s Hospital of Philadelphia related to development of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale. E.M. has received personal compensation for clinical trial consulting and serving on scientific advisory boards from Novartis Gene Therapies, Inc. K.J.S. has received personal compensation from Novartis Gene Therapies, Inc., for serving as an advisory board member, and from Biogen for serving as a visiting professor; and has received research support from Novartis Gene Therapies, Inc., and Biogen-sponsored clinical trials. M.M. is an employee of Novartis Gene Therapies, Inc. R.v.O. and S.T.-W. are employees of Novartis Gene Therapies, Inc., and own Novartis stock or other equities. J.R.M. declares no competing interests., (© 2021 The Authors.)

Background and Objectives: The Cochrane Central Register of Controlled Trials (CENTRAL) is compiled from a number of sources, including PubMed and Embase. Since 2017, we have increased the number of sources feeding into CENTRAL and improved the efficiency of our processes through the use of application programming interfaces, machine learning, and crowdsourcing.Our objectives were twofold: (1) Assess the effectiveness of Cochrane's centralized search and screening processes to correctly identify references to published reports which are eligible for inclusion in Cochrane systematic reviews of randomized controlled trials (RCTs). (2) Identify opportunities to improve the performance of Cochrane's centralized search and screening processes to identify references to eligible trials., Methods: We identified all references to RCTs (either published journal articles or trial registration records) with a publication or registration date between 1st January 2017 and 31st December 2018 that had been included in a Cochrane intervention review. We then viewed an audit trail for each included reference to determine if it had been identified by our centralized search process and subsequently added to CENTRAL., Results: We identified 650 references to included studies with a publication year of 2017 or 2018. Of those, 634 (97.5%) had been captured by Cochrane's Centralised Search Service. Sixteen references had been missed by the Cochrane's Centralised Search Service: six had PubMed-not-MEDLINE status, four were missed by the centralized Embase search, three had been misclassified by Cochrane Crowd, one was from a journal not indexed in MEDLINE or Embase, one had only been added to Embase in 2019, and one reference had been rejected by the automated RCT machine learning classifier. Of the sixteen missed references, eight were the main or only publication to the trial in the review in which it had been included., Conclusion: This analysis has shown that Cochrane's centralized search and screening processes are highly sensitive. It has also helped us to understand better why some references to eligible RCTs have been missed. The CSS is playing a critical role in helping to populate CENTRAL and is moving us toward making CENTRAL a comprehensive repository of RCTs., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The use of tranexamic acid (TXA) has recently gained popularity as a treatment modality for epistaxis in the emergency department. Data are presented on the efficacy of the topical use of the intravenous formulation of TXA versus the vasoconstrictor oxymetazoline applied topically in achieving hemostasis in patient presenting to the emergency department with anterior epistaxis. The original article "Comparative Effectiveness of Topically Administered TXA Versus Topical Oxymetazoline Spray for Achieving Hemostasis in Epistaxis" [1] provides complete interpretation of the data. The dataset regarding these treatment modalities has clinical significance toward preventing an avoidable need for escalation of treatment that could potentially increase patient discomfort and prolong emergency department throughput time., (© 2020 The Authors.)

Background: The use of tranexamic acid (TXA) has recently gained popularity as a treatment modality for epistaxis in the emergency department. Previous studies have compared topical TXA to nasal packing. However, topical TXA has not yet been compared with topical oxymetazoline in the treatment of epistaxis., Objectives: This study compares the efficacy of the intravenous formulation of TXA applied topically vs. the vasoconstrictor oxymetazoline applied topically in achieving hemostasis in patients presenting to the emergency department with anterior epistaxis., Methods: In this prospective study, patients presenting to the emergency department with the chief complaint of epistaxis, and meeting inclusion criteria, were allocated into 2 treatment groups; topical oxymetazoline vs. topical application of the intravenous preparation of TXA. Patients were assessed for time to hemostasis in the emergency department as well as the occurrence of rebleeding within the next 48 h after discharge., Results: Hemostasis was achieved in 14 (78%) of the 18 patients in the TXA group compared with 7 (35%) of the 20 patients in the oxymetazoline group. While there were occurrences of rebleeding in the emergency department before discharge and at 48 h in both groups, 11 patients in the TXA group had no recurrence of bleeding compared with 5 in the oxymetazoline group., Conclusion: This study demonstrated that the topical application of the intravenous preparation of TXA is more effective than topical oxymetazoline for achievement of hemostasis in anterior epistaxis. This has clinical significance toward preventing an avoidable need for escalation of treatment that could include applying nasal packing or cautery as well as preventing avoidable return emergency department visits. These outcomes would increase cost, potentially increase patient discomfort, and prolong emergency department throughput time., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Posttransplantation diabetes mellitus (PTDM) is a common and significant complication related to immunosuppressive agents required to prevent organ or cell transplant rejection. To elucidate the effects of 2 commonly used agents, the calcineurin inhibitor tacrolimus (TAC) and the mTOR inhibitor sirolimus (SIR), on islet function and test whether these effects could be reversed or prevented, we investigated human islets transplanted into immunodeficient mice treated with TAC or SIR at clinically relevant levels. Both TAC and SIR impaired insulin secretion in fasted and/or stimulated conditions. Treatment with TAC or SIR increased amyloid deposition and islet macrophages, disrupted insulin granule formation, and induced broad transcriptional dysregulation related to peptide processing, ion/calcium flux, and the extracellular matrix; however, it did not affect regulation of β cell mass. Interestingly, these β cell abnormalities reversed after withdrawal of drug treatment. Furthermore, cotreatment with a GLP-1 receptor agonist completely prevented TAC-induced β cell dysfunction and partially prevented SIR-induced β cell dysfunction. These results highlight the importance of both calcineurin and mTOR signaling in normal human β cell function in vivo and suggest that modulation of these pathways may prevent or ameliorate PTDM.

Given the lack of evidence regarding effective pharmacological and non-pharmacological interventions for pediatric mild traumatic brain injury (mTBI) and the resultant lack of treatment recommendations reflected in consensus guidelines, variation in the management of pediatric mTBI is to be expected. We therefore surveyed practitioners across 15 centers in the United States and Canada who care for children with pediatric mTBI to evaluate common-practice variation in the management of pediatric mTBI. The survey, developed by a panel of pediatric mTBI experts, consisted of a 10-item survey instrument regarding providers' perception of common pediatric mTBI symptoms and mTBI interventions. Surveys were distributed electronically to a convenience sample of local experts at each center. Frequencies and percentages (with confidence intervals [CI]) were determined for survey responses. One hundred and seven respondents (71% response rate) included specialists in pediatric Emergency Medicine, Sports Medicine, Neurology, Neurosurgery, Neuropsychology, Neuropsychiatry, Physical and Occupational Therapy, Physiatry/Rehabilitation, and General Pediatrics. Respondents rated headache as the most prevalently reported symptom after pediatric mTBI, followed by cognitive problems, dizziness, and irritability. Of the 65 (61%; [95% CI: 51,70]) respondents able to prescribe medications, non-steroidal anti-inflammatory medications (55%; [95% CI: 42,68]) and acetaminophen (59%; [95% CI: 46,71]) were most commonly recommended. One in five respondents reported prescribing amitriptyline for headache management after pediatric mTBI, whereas topiramate (8%; [95% CI: 3,17]) was less commonly reported. For cognitive problems, methylphenidate (11%; [95% CI: 4,21]) was used more commonly than amantadine (2%; [95% CI: 0,8]). The most common non-pharmacological interventions were rest ("always" or "often" recommended by 83% [95% CI: 63,92] of the 107 respondents), exercise (59%; [95%CI: 49,69]), vestibular therapy (42% [95%CI: 33,53]) and cervical spine exercises (29% [95%CI: 21,39]). Self-reported utilization for common pediatric mTBI interventions varied widely across our Canadian and United States consortium. Future effectiveness studies for pediatric mTBI are urgently needed to advance the evidence-based care.

Background: Information specialists frequently translate search filters from one interface to another. Publications advise that translation can be complex and should be undertaken carefully., Objectives: To investigate the issues arising when translating the Cochrane Embase RCT search filter from one interface (Ovid) to another (Embase.com)., Methods: We drafted a translation of the Cochrane Ovid RCT filter to run in Embase.com. We compared the line-by-line results of the Ovid filter with the results of the translation. We revised the filter. We identified differences between database versions including records with different publication years and subject headings. Some records were in Embase in one interface but not in the other. We encountered expected interface differences relating to proximity operators. We also encountered unexpected interface issues around truncation and the use of the original title or original abstract field., Discussion: Filter conversion is challenging and time consuming revealing unexpected differences in interfaces and databases. Careful planning can pre-empt some issues, but others may only emerge during testing. We identified interface anomalies that have led database publishers to review aspects of the way their interfaces work., Conclusions: Translators should be vigilant for known and unknown differences in both interfaces and database versions., (© 2019 Health Libraries Group.)

Background: Evidence synthesis reviews in health care rely on the efficient identification of research evidence, particularly evidence from randomised controlled trials (RCTs). There are no recently validated filters to identify RCTs in the Cumulative Index to Nursing and Allied Health Literature (CINAHL Plus)., Objectives: To develop, test and validate a search filter to identify reports of RCTs from CINAHL Plus., Methods: Nine sets of relevant and irrelevant records were identified to develop and test search filters iteratively. Two sets were used to validate the sensitivity and precision of the filters. The performance of two previously published filters and the filter built into EBSCOhost was evaluated., Results: We present a validated filter which offers sensitivity of 0.88 (95% CI: 0.77-0.95) and precision of 0.36 (95% CI: 0.31-0.41). This is comparable to the sensitivity of published filters, but has much better precision., Conclusions: A sensitive and precise filter, developed using records selected based on title and abstract information, is available for identifying reports of RCTs in the CINAHL Plus database via EBSCOhost. Using this filter is likely to reduce the number of results needing to be screened to a quarter of those retrieved by other published filters., (© 2019 Health Libraries Group.)

Objective: Medical devices innovations and associated procedures represent a large part of health facilities budget. The aim of this work was to evaluate the cost of medical devices used during different surgical procedures. This cost was compare with the revenue collected from hospital stay pricing., Method: A prospective analysis of the medical devices used in operating room was carried out for different types of programmed surgeries. For five weeks, references of sterile single-use medical devices used during the interventions were collected., Results: Expenditure on medical devices used during surgical procedures represented 5.7 % of the hospitalization value for an inguinal hernia repair, 12 % for a cholecystectomy, 9.35 % for a colectomy, 14.5 % for a hepatectomy and 7 % for pancreatectomy, any severity index combined. The most important correlations existed between act duration and patient's level of severity and between operating times and consumables expenditure., Conclusion: Cost optimization opportunities are equivalence of some medical devices ranges, purchases with national groupings and potential decreases in operating times related to the use of innovative medical devices., (Copyright © 2018 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Long-term daylight deprivation such as during the Antarctic winter has been shown to lead to delayed sleep timing and sleep fragmentation. We aimed at testing whether retinal sensitivity, sleep and circadian rest-activity will change during long-term daylight deprivation on two Antarctic bases (Concordia and Halley VI) in a total of 25 healthy crew members (mean age: 34 ± 11y; 7f). The pupil responses to different light stimuli were used to assess retinal sensitivity changes. Rest-activity cycles were continuously monitored by activity watches. Overall, our data showed increased pupil responses under scotopic (mainly rod-dependent), photopic (mainly L-/M-cone dependent) as well as bright-blue light (mainly melanopsin-dependent) conditions during the time without direct sunlight. Circadian rhythm analysis revealed a significant decay of intra-daily stability, indicating more fragmented rest-activity rhythms during the dark period. Sleep and wake times (as assessed from rest-activity recordings) were significantly delayed after the first month without sunlight (p < 0.05). Our results suggest that during long-term daylight deprivation, retinal sensitivity to blue light increases, whereas circadian rhythm stability decreases and sleep-wake timing is delayed.

Background: The circadian clock is a fundamental and pervasive biological program that coordinates 24-hour rhythms in physiology, metabolism, and behavior, and it is essential to health. Whereas therapy adapted to time of day is increasingly reported to be highly successful, it needs to be personalized, since internal circadian time is different for each individual. In addition, internal time is not a stable trait, but is influenced by many factors, including genetic predisposition, age, sex, environmental light levels, and season. An easy and convenient diagnostic tool is currently missing., Methods: To establish a validated test, we followed a 3-stage biomarker development strategy: (a) using circadian transcriptomics of blood monocytes from 12 individuals in a constant routine protocol combined with machine learning approaches, we identified biomarkers for internal time; and these biomarkers (b) were migrated to a clinically relevant gene expression profiling platform (NanoString) and (c) were externally validated using an independent study with 28 early or late chronotypes., Results: We developed a highly accurate and simple assay (BodyTime) to estimate the internal circadian time in humans from a single blood sample. Our assay needs only a small set of blood-based transcript biomarkers and is as accurate as the current gold standard method, dim-light melatonin onset, at smaller monetary, time, and sample-number cost., Conclusion: The BodyTime assay provides a new diagnostic tool for personalization of health care according to the patient's circadian clock., Funding: This study was supported by the Bundesministerium für Bildung und Forschung, Germany (FKZ: 13N13160 and 13N13162) and Intellux GmbH, Germany.

Under entrained conditions, the accumulation of homeostatic sleep pressure in the evening is opposed by a strong circadian arousal signal prior to the dim light melatonin onset, called the Wake Maintenance Zone (WMZ). This study aimed at investigating the impact of the WMZ on different cognitive performance tests, as well as on subjective and objective sleepiness. Twelve young male participants completed a constant routine protocol with 40 h of extended wakefulness that included two WMZs. Cognitive tests and saliva samples were assessed hourly, while the electroencephalogram (EEG) was recorded continuously. Participants improved in cognitive response inhibition during WMZ1 (13.5 h awake) and sustained attention during WMZ2 (37.5 h awake), but not in higher executive function tests. There were significant EEG power density reductions in the delta/theta frequency range during WMZ1 and in delta/theta, alpha, and sigma/beta ranges during WMZ2, with a greater change in the sigma/beta range during WMZ2 compared to WMZ1. EEG power reductions coincided during WMZ1 with stable subjective sleepiness and sustained attention. During WMZ2, EEG power reductions were more pronounced and coincided with improved sustained attention. Our results suggest the circadian arousal signal in the evening differently modulates cognitive functions and EEG power depending on the duration of prior wakefulness.

Background: Aberrant glutamate neurotransmission, and in particular dysfunction of the N-methyl-D-aspartate receptor (NMDAR), has been implicated in psychiatric disorders and represents a novel therapeutic target. Low-dose administration of the NMDA antagonist ketamine in healthy volunteers elicits a strong blood oxygenation level dependent (BOLD) imaging signal that can be attenuated by pretreatment with single, therapeutically effective doses of marketed medicines interacting with the glutamate system., Objective: To test the attenuation of the ketamine-induced BOLD signal by pretreatment with either a metabotropic glutamate receptor (mGluR) 2/3 or a mGluR2 agonist in healthy volunteers METHODS: We used a ketamine challenge pharmacological magnetic resonance imaging (phMRI) paradigm to assess the modulatory effects of single acute doses of LY2140023 (pomaglumetad methionil), the methionine prodrug of the mGluR2/3 agonist LY404039 (10, 40, and 160 mg; N = 16 subjects) and of LY2979165, and the alanine prodrug of the selective orthosteric mGluR2 agonist 2812223 (20 and 60 mg; N = 16 subjects)., Results: A reduction in the ketamine-evoked BOLD phMRI signal relative to placebo was observed at the highest doses tested of both LY2140023 and LY2979165. A relationship was observed between reduction of the BOLD signal and increasing plasma levels of 2812223 in the LY2979165 cohort., Conclusions: These results identify pharmacologically active doses of the group II mGluR agonist prodrugs LY2140023 and LY2979165 in humans. They also extend the classes of compounds that have been experimentally shown to reverse the ketamine-evoked phMRI signal in humans, further supporting the use of this method as a neuroimaging biomarker for assessing functional effects.

Squamous cell carcinoma (SCC) of the head and neck can be treated with a combination of modalities. There is an esthetic and functional compromise with midfacial defects secondary to ablative surgery and adjuvant therapies for SCC. Osteoradionecrosis, tissue contracture, and trismus, are all negative side effects of treatment and can impact a patient's function and possibly their nutrition. In this report, we describe a procedure for fabrication of a prosthesis that provides cosmetic improvement and labial competence to maintain caloric intake., (© 2018 by the American College of Prosthodontists.)