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Objective: Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are used for stroke prevention in patients with carotid stenosis. It remains unclear which surgical approach produces the best outcomes for elderly and frail patients. We investigated the impact of age and frailty on 30-day combined outcomes of death, stroke, and myocardial infarction (MI) in patients who received CEA or CAS for severe symptomatic carotid stenosis., Methods: A retrospective analysis of the NSQIP database identified patients with severe carotid stenosis who received either CEA or CAS between 2015 and 2020 for study inclusion. Frailty was measured by the Modified Frailty Index 5-item (mFI-5), which stratified patients as non-frail (score=0), pre-frail (=1), frail (=2), or severely frail (=3). Age was subdivided into 65 years or younger, 66-84 years, and 85 years or older. The primary outcome was 30-day combined rates of death, stroke, and MI, as analyzed by multivariate logistic regression analyses, adjusted for sex, body mass index, smoking status, anesthetic type, and contralateral carotid stenosis., Results: A total of 18,074 patients were included in analyses, of which 14,428 received CEA (80 %) and 3646 received CAS (20 %). Mean age was 70.8 and 70.5 years for CEA and CAS, respectively. The rate of combined outcome of death, stroke or MI at 30 days was significantly higher in CEA (3.3 %) than CAS (1.3 %) (χ 2 =41.90, p < 0.001). Increasing frailty was associated with higher rates of the primary outcome in CEA patients (χ 2 =30.26, p < 0.001) but not CAS (χ 2 =6.95, p = 0.07). A 6-component risk score was constructed for the combined outcomes in CEA, which predicted adverse events with 80.7 % accuracy., Conclusions: Age and frailty have a significant impact on the risk of death, stroke, and MI at 30 days in patients with severe, symptomatic carotid stenosis who receive CEA, but not CAS., Non-Standard Abbreviations and Acronyms: Body mass index (BMI), carotid artery stenting (CAS), carotid endarterectomy (CEA), current procedural technology (CPT), myocardial infarction (MI), modified Frailty Index 5-item (mFI-5), American College of Surgeons National Surgical Quality Improvement Program (NSQIP)., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Identifying peripheral nerve surgery procedure (PNSP) competencies is crucial to ensure adequate resident training. We examine PNSP training at neurosurgical centers in the US and Canada to compare resident-reported competence, PNSP exposure, and resident technical abilities in performing 3 peripheral nerve coaptations (PNC)., Methods: Resident-reported PNSP competence and PNSP exposure data were collected using questionnaires from neurosurgical residents at North American neurosurgical training centers. Exposure and self-reported competency were correlated with technical skills. Technical PNC variables collected included: time-to-completion, nerve-handling from video-analysis, independent and blinded visual-analog-scale (VAS) PNC quality grading by 3 judges, and training level., Results: A total of 40 neurosurgical residents participated in the study. Although self-reported competency scores correlated with procedural exposure (P < 0.01, rs = 0.88), a discrepancy was found between the degree of self-reported competency and amount of exposure. The discrepancy was greater in senior residents. A significant VAS difference was found between PNC types with the direct-suture and connector-assister groups scoring higher than connector-only (P = 0.02, P < 0.01, respectively). No difference was observed between training level and VAS grading, nor time-to completion (P = 0.33 and 0.25, respectively). No correlation was found between self-reported competency performing PNSPs and PNC VAS scores, nor nerve handling., Conclusions: Despite more exposure and a higher self-reported PNSP competency in senior residents, no difference was seen between senior/junior residents in PNC quality. A discrepancy in PNSP exposure and self-reported competency exists. This information will provide guidance for the direction of resident PNS training., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Few studies investigated the mechanisms of treatment-resistant depression (TRD) leading to the worsened survival outcome, and economic evidence was mostly restricted to short follow-ups. We aimed to examine the association and potential mediators between TRD and all-cause mortality, and estimate a longer-term associated health resource utilisation pattern., Methods: This was a population-based cohort study using territory-wide electronic medical records in Hong Kong. Incident depression patients diagnosed in 2014 were followed up from the first diagnosis to death or December 2019 for TRD identification. We matched the TRD cohort 1:4 to the non-TRD cohort on propensity scores estimated by age, sex, history of physical disorders, and history of psychiatric conditions before depression diagnoses., Findings: 18% of incident patients developed TRD within six years of follow-up. Cox model showed that patients with TRD had 1⋅52-fold (95% CI: 1⋅14-2⋅02) greater risk of all-cause mortality, compared with non-TRD patients. Path analysis suggested that post-TRD psychiatric conditions significantly mediated 41⋅6% of mortality in patients with TRD (p=0.003). TRD was associated with 1⋅8-fold (95%CI: 1⋅63-2⋅00) higher healthcare costs compared to non-TRD patients over six years in negative binomial regression, with higher costs for both psychiatric and non-psychiatric services utilisation in all settings., Interpretation: Identifying patients with TRD and subsequent monitoring for post-TRD psychiatric diagnoses could be a way to reduce premature mortality. Multidisciplinary care involving both psychiatric and general medical professionals is also warranted to relieve the multifaceted impacts on healthcare resources and overall cost., Funding: Unconditional educational grant from Janssen., Competing Interests: X Li received research grants from Research Fund Secretariat of the Food and Health Bureau (HMRF, HKSAR), Research Grants Council Early Career Scheme (RGC/ECS, HKSAR), Janssen and Pfizer; internal funding from the University of Hong Kong; consultancy fee from Merck Sharp & Dohme, unrelated to this work; H Luo received research grants Research Grants Council Early Career Scheme (RGC/ECS, HKSAR) unrelated to this work. S Chan received research support from GRF, Research Grant Council; HMRF, Food and Health Bureau. FTT Lai was supported by the RGC Postdoctoral Fellowship 2020/21 (inaugural exercise) funded by the Research Grants Council, University Grants Committee, Hong Kong SAR. J F Hayes was supported by the Wellcome Trust (211085/Z/18/Z), University College London Hospitals NIHR Biomedical Research Centre and the NIHR ARC North Thames Academy. He received consultancy fees from the Wellcome Trust and Juli Health, unrelated to this work. P Ip received research grants from Research Fund Secretariat of the Food and Health Bureau (HMRF, HKSAR), Research Grants Council (GRF and CRF, HKSAR) and project grant from the Hong Kong Jockey Club Charities Trust. EWY Chan received honorarium from the Hospital Authority, research grants from Innovation and Technology Commission of HKSAR, Narcotics Division of the Security Bureau of HKSAR, National Health and Medical Research Council (NHMRC, Australia), National Natural Science Foundation of China (NSFC), Research Fund Secretariat of the Food and Health Bureau (HMRF, HKSAR), Research Grants Council (RGC, HKSAR), Wellcome Trust; Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Pfizer, RGA, Takeda and Novartis, and consultancy fee from Novartis outside the submitted work. She is also the President of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), Hong Kong Regional Chapter. ICK Wong received research funding outside the submitted work from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Takeda, the Hong Kong RGC, and the Hong Kong Health and Medical Research Fund, National Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia, and has also received speaker fees from Janssen and Medice over the past three years. He is also an independent non-executive director of Jacobson Medical in Hong Kong., (© 2022 The Authors.)

Background Context: Traditionally, a nonoperative approach has been favored for elderly patients with lumbar spondylolisthesis due to a perceived higher risk of morbidity with surgery. However, most studies have used an arbitrary age cut-off to define "elderly" and this research has yielded conflicting results., Purpose: The purpose of this study was to investigate the impact of frailty on morbidity after surgery for degenerative lumbar spondylolisthesis treated with a posterior approach., Study Design: A retrospective cohort study was performed., Patient Sample: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database, with years 2010 to 2018 included in this study. Patients who received posterior lumbar spine decompression with or without single level posterior instrumented fusion for degenerative lumbar spondylolisthesis were included. Patients who received anterior and/or lateral approaches were excluded., Outcome Measures: The primary outcome was Clavien-Dindo grade IV complication. Secondary outcomes were readmission, reoperation, and discharge to location other than home., Methods: Patient demographics and comorbidities were extracted. Logistic regression analysis was performed to investigate the association between outcomes and the Modified Frailty Index-5, adjusting for age, gender, body mass index, smoking status, and surgical procedure performed. A sub-analysis was done to assess the effect of frailty in three different age groups (18-45 years, 46-65 years, and >65 years) for the two surgical cohorts., Results: There were 15,658 patients in this study. The mean age was 62.5 years. Approximately 70% of the patients received decompression with fusion. Frailty was significantly associated with an increased risk of major complication, unplanned readmission, reoperation, and non-home discharge. The risk increased with increasing frailty. For patients who received decompression, frailty was associated with a higher risk of readmission and non-home discharge in patients >65 years. For patients who received decompression and fusion, frailty was associated with a higher risk of complications, readmission, and non-home discharge in patients >65 years., Conclusions: Frailty is independently associated with a higher risk of morbidity after posterior surgery in patients with lumbar spondylolisthesis, especially in patients older than 65. These data are of significance to clinicians in planning treatment for these patients., Competing Interests: Declarations of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: With an aging population, there are an increasing number of elderly patients undergoing spine surgery. Recent literature in other surgical specialties suggest frailty to be an important predictor of outcomes., Purpose: The aim of this review was to examine the association between frailty and outcomes after spine surgery., Study Design: A systematic review was performed., Patient Sample: Electronic databases from 1946 to 2020 were searched to identify articles on frailty and spine surgery., Outcome Measures: The primary outcome was adverse events. Secondary outcomes included other measures of morbidity, mortality, and patient outcomes., Methods: Sample size, mean age, age limitation, data source, study design, primary pathology, surgical procedure performed, follow-up period, assessment of frailty used, surgical outcomes, and impact of frailty on outcomes were extracted from eligible studies. Quality and bias were assessed using the PRISMA 27-point item checklist and the QUADAS-2 tool., Results: Thirty-two studies were selected for review, with a total of 127,813 patients. There were eight different frailty indices/measures. Regardless of how frailty was measured, frailty was associated with an increased risk of adverse events, mortality, extended length of stay, readmission, and nonhome discharge., Conclusion: There is strong evidence that frailty is associated with an increased risk of morbidity and mortality in patients who received spine surgery. However, it remains inconclusive whether frailty impacts patient outcomes and quality of life after surgery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Three hundred million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment compared with other patients. This review provides an overview of global policies that optimize development, licensing, pricing, and reimbursement of orphan drugs., Methods: Pharmaceutical legislation and policies related to access and regulation of orphan drugs were examined from 194 World Health Organization member countries and 6 areas. Orphan drug policies (ODPs) were identified through internet search, emails to national pharmacovigilance centers, and systematic academic literature search. Texts from selected publications were extracted for content analysis., Results: One hundred seventy-two drug regulation documents and 77 academic publications from 162 countries/areas were included. Ninety-two of 200 countries/areas (46.0%) had documentation on ODPs. Thirty-four subthemes from content analysis were categorized into 6 policy themes, namely, orphan drug designation, marketing authorization, safety and efficacy requirements, price regulation, incentives that encourage market availability, and incentives that encourage research and development. Countries/areas with ODPs were statistically wealthier (gross national income per capita = $10 875 vs $3950, P < .001). Country/area income was also positively correlated with the scope of the respective ODP (correlation coefficient = 0.57, P < .001)., Conclusions: Globally, the number of countries with an ODP has grown rapidly since 2013. Nevertheless, disparities in geographical distribution and income levels affect the establishment of ODPs. Furthermore, identified policy gaps in price regulation, incentives that encourage market availability, and incentives that encourage research and development should be addressed to improve access to available and affordable orphan drugs., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Blunt chest wall injuries are a significant cause of mortality and morbidity in trauma patients. Accurate identification and description of chest wall injuries by the radiologist can aid in guiding proper patient management. The American Association for the Surgery of Trauma (AAST) has devised a classification system based on severity. This article describes the features of each injury grade according to the AAST injury scale and discusses the implications for management. Additionally, common mechanisms of blunt chest trauma and multimodal imaging techniques are discussed.

Transitional age youth with a history of mood disorders, such as major depressive disorder, are uniquely vulnerable to clinical destabilization and relapse in the context of life transition. Moving from a structured adolescence to a more independent and potentially more demanding young adult life can result in worsening symptoms and barriers to effective help-seeking. Transitional age youth newly diagnosed are exposed to their first course of treatment of a potentially chronic condition. This article describes the challenges inherent in navigating this life transition, and also offers strategies to promote a successful "launch" into adulthood., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain. We demonstrate the ability of anti-CD19-AbTCR-T cells to trigger antigen-specific cytokine production, degranulation, and killing of CD19-positive cancer cells in vitro and in xenograft mouse models. By using the same anti-CD19 binding moiety on an AbTCR compared to a CAR platform, we demonstrate that AbTCR activates cytotoxic T-cell responses with a similar dose-response as CD28/CD3ζ CAR, yet does so with less cytokine release and results in T cells with a less exhausted phenotype. Moreover, in comparative studies with the clinically validated CD137 (4-1BB)-based CAR, CTL019, our anti-CD19-AbTCR shows less cytokine release and comparable tumor inhibition in a patient-derived xenograft leukemia model., Competing Interests: Y.X., Z.Y., L.H.H., P.Z., L.L., B.Z., S.G., J.L., J.F.M., V.W.C., H.L., and C.L. are employees of and have equity ownership and/or stock options in Eureka Therapeutics, Inc. S.A.G. is a scientific advisor to Eureka Therapeutics with stock options in the company. D.M.B. is a consultant to Eureka Therapeutics. Other associations: S.A.G. has received research and/or clinical trial support from Novartis, Servier and Kite. He consults for, has participated in ad boards, or serves on study steering committees or scientific advisory boards for the following companies: Novartis, Adaptimmune, TCR2, Juno, GlaxoSmithKline, Cellectis, Vertex, Roche and Janssen. He is listed on a patent related to toxicity management in cell therapy managed by University of Pennsylvania and CHOP policies.

This article reviews the current state of diagnosis and treatment of schizophrenia, describing the recent proliferation of research in high-risk psychosis spectrum conditions, which are different from childhood-onset and early onset schizophrenia, and findings of psychotic-like experiences in the normal population. Taken from adult and childhood literature, clinical quandaries in accurate diagnosis, and treatment gaps in co-occurring, or sometimes confounding, conditions are discussed. Thoughts on the impact of schizophrenia on an emerging adulthood trajectory are offered. Recent best practices in the treatment of schizophrenia are consistent with a recovery-oriented model of mental health services for transitional age youth., (Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.)

Seizures have considerable impact on a patient's quality of life. While guidelines have been articulated to direct clinicians in their management of patients with IMD who suffer from seizure, there have been few attempts to identify the seizure rate in IMD and to determine which primary cancers may be associated with an increased seizure incidence. To determine the incidence of seizure in patients with IMD. A systematic review on seizure incidence in patients with IMD from the magnetic resonance imaging (MRI) era was performed. Articles published between January 2000 and July 2014 with thirty or more consecutive adult patients were included in this study. Seizure rate was calculated using a pooled data analysis. Differences between observed and expected seizure rates between primary tumour sites were examined using the Chi square statistic and adjusted standardized residuals. The systematic search produced 18 relevant studies, with a total study population of 2012 patients. 14.6% (n = 294) had seizures. There was a significant association between primary tumour site and seizure rates. The seizure rate in patients with primary melanoma tumours was significantly greater than expected (z = 2.7; p = .006). The seizure rate in patients with primary prostate tumours was significantly lower than expected (z = -2.6; p = .008). Patients with intracranial metastasis are at significant risk for developing seizure, though at a significantly lower incidence than was estimated by studies performed during the CT era. Seizure rates appear to be greater in certain primary tumours, such as melanoma.

The number of students entering post-secondary education with already diagnosed disabilities is on the rise and mirrors the percentage of children in primary and secondary public schools with registered disabilities. Requirements governed by civil rights laws fundamentally change when comparing the support schools have to provide to students during primary and secondary school with disability access in postsecondary higher education. Psychiatrists may be asked to assist with scholastic disability at any stage of education and need to know about available supports and the parameters of disability in schools. Specifically, special attention should to be made in preparation for transition to postsecondary education when prior accommodations exist.

Objective: The purpose of this article is to determine the effectiveness of a hands-on continuing education program for practicing child and adolescent psychiatrists (CAPs) with a focus on best practices in transitioning psychiatric patients to college. The plan was to build on the unique knowledge and skill set of CAPs, use audience and facilitator feedback from prior programs to inform program content, structure, and format, and incorporate findings from the evolving literature., Methods: A 3-h interactive workshop was designed with an emphasis on audience participation. The workshop was divided into three main segments: didactics, whole group discussion/brainstorming, and small group discussion of illustrative case vignettes., Results: Improvements and changes in knowledge, skills, and attitudes related to transition planning were identified by program participants. Quantitative feedback in the form of course evaluations, pre- and posttests, and a 6-month follow-up questionnaire indicate that the use of interactive teaching techniques is a productive learning experience for practicing CAPs. Qualitative feedback was that the discussion of the case vignettes was the most helpful., Discussion: The use of a workshop format is an effective strategy to engage practicing CAPs in learning about and implementing best practices to support the transition of their patients to college and into young adulthood. Comprehensive and proactive transition planning, facilitated by clinicians, should promote the wellness of college-bound patients and help to reduce the potential risks in the setting of an upcoming transition.

Background: Delay to neurosurgical care can result in significant morbidity and mortality. In this study, we aim to identify and quantify the sources of delay to neurosurgical consultation and care at a rural setting in Kenya., Methods: A mixed-methods, cross-sectional analysis of all patients admitted to the neurosurgical department at Kijabe Hospital (KH) was conducted: A retrospective analysis of admissions from October 1 to December 31, 2013 and a prospective analysis from June 2 to June 20, 2014. Sources of delay were categorized and quantified. The Kruskal-Wallis test was used to identify an overall significant difference among diagnoses. The Mann-Whitney U test was used for pairwise comparisons within groups; the Bonferroni correction was applied to the alpha level of significance (0.05) according to the number of comparisons conducted. IBM SPSS version 22.0 (SPSS, Chicago, IL) was used for statistical analyses., Results: A total of 332 admissions were reviewed (237 retrospective, 95 prospective). The majority was pediatric admissions (median age: 3 months). Hydrocephalus (35%) and neural tube defects (NTDs; 27%) were most common. At least one source of delay was identified in 192 cases (58%); 39 (12%) were affected by multiple sources. Delay in primary care (PCPs), in isolation or combined with other sources, comprised 137 of total (71%); misdiagnosis or incorrect management comprised 46 (34%) of these. Finances contributed to delays in 25 of 95 prospective cases. At a median delay of 49 and 200.5 days, the diagnoses of hydrocephalus and tumors were associated with a significantly longer delay compared with NTDs (P < 0.001)., Conclusion: A substantial proportion of patients experienced delays in procuring pediatric neurosurgical care. Improvement in PCP knowledge base, implementation of a triage and referral process, and development of community-based funding strategies can potentially reduce these delays.

Altered airway smooth muscle (ASM) function and enrichment of the extracellular matrix (ECM) with interstitial collagen and fibronectin are major pathological features of airway remodeling in asthma. We have previously shown that these ECM components confer enhanced ASM proliferation in vitro, but their action on its newly characterized secretory function is unknown. Here, we examined the effects of fibronectin and collagen types I, III, and V on IL-1beta-dependent secretory responses of human ASM cells, and characterized the involvement of specific integrins. Cytokine production (eotaxin, RANTES, and GM-CSF) was evaluated by ELISA, RT-PCR, and flow cytometry. Function-blocking integrin mAbs and RGD (Arg-Gly-Asp)-blocking peptides were used to identify integrin involvement. IL-1beta-dependent release of eotaxin, RANTES, and GM-CSF was enhanced by fibronectin and by fibrillar and monomeric type I collagen, with similar changes in mRNA abundance. Collagen types III and V had no effect on eotaxin or RANTES release but did modulate GM-CSF. Analogous changes in intracellular cytokine accumulation were found, but in <25% of the total ASM cell population. Function-blocking Ab and RGD peptide studies revealed that alpha2beta1, alpha5beta1, alphavbeta1, and alphavbeta3 integrins were required for up-regulation of IL-1beta-dependent ASM secretory responses by fibronectin, while alpha2beta1 was an important transducer for type I collagen. Thus, fibronectin and type I collagen enhance IL-1beta-dependent ASM secretory responses through a beta1 integrin-dependent mechanism. Enhancement of cytokine release from ASM by these ECM components may contribute to airway wall inflammation and remodeling in asthma.

To evaluate whether beta-catenin signaling has a role in the regulation of angiogenesis in colon cancer, a series of angiogenesis-related gene promoters was analyzed for beta-catenin/TCF binding sites. Strikingly, the gene promoter of human vascular endothelial growth factor (VEGF, or VEGF-A) contains seven consensus binding sites for beta-catenin/TCF. Analysis of laser capture microdissected human colon cancer tissue indicated a direct correlation between up-regulation of VEGF-A expression and adenomatous polyposis coli (APC) mutational status (activation of beta-catenin signaling) in primary tumors. In metastases, this correlation was not observed. Analysis by immunohistochemistry of intestinal polyps in mice heterozygous for the multiple intestinal neoplasia gene (Min/+) at 5 months revealed an increase and redistribution of VEGF-A in proximity to those cells expressing nuclear beta-catenin with a corresponding increase in vessel density. Transfection of normal colon epithelial cells with activated beta-catenin up-regulated levels of VEGF-A mRNA and protein by 250-300%. When colon cancer cells with elevated beta-catenin levels were treated with beta-catenin antisense oligodeoxynucleotides, VEGF-A expression was reduced by more than 50%. Taken together, our observations indicate a close link between beta-catenin signaling and the regulation of VEGF-A expression in colon cancer.