Search

Rationale: Intrathoracic paragangliomas are typically found within the intricate posterior mediastinal region adjacent to the vertebrae, often presenting with substantial volume. Surgical excision of such tumors presents formidable challenges and is conventionally performed via open surgical procedures., Patient Concerns: In this report, we present the case of a 53-year-old female patient who presented with the discovery of a left intrathoracic mass during a routine physical examination approximately 1 month prior. She complained of chest tightness and chest pain., Diagnoses: She complained of chest tightness and chest pain. Magnetic resonance imaging of the chest and brachial plexus revealed a mass adjacent to the left upper lung hilum, measuring approximately 78 × 63 × 72 mm. The initial suspicion leaned towards a benign lesion. Notably, there was slight compression of the left first thoracic nerve root and mild compression of the middle and lower trunks of the left brachial plexus. Based on the morphological features of the tumor and imaging findings, we suspected its benign nature., Interventions: We opted for robot-assisted thoracic surgery to resect the mediastinal tumor., Outcomes: Subsequent postoperative pathology confirmed the diagnosis as a paraganglioma. The patient did not experience any notable complications post-surgery, and a 6-month follow-up revealed no signs of recurrence., Lessons: The successful application of the robot-assisted thoracic surgery surgical technique underscores its efficacy in minimally invasive resection of sizable intrathoracic tumors situated in the posterior mediastinum., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use., Methods: Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single adeno-associated virus. We also created a novel adeno-associated virus capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating posttranslationally modified capsid residues. Because a constitutive promoter was needed to drive high expression of these cell fate-altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3' untranslated region of the expression cassette that limits expression to nonmyocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid/cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models., Results: We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model 2 weeks after myocardial infarction, showing that cardiac reprogramming, when delivered in a single, clinically relevant adeno-associated virus vector, can support functional improvement in the postremodeled heart. This benefit was not observed with GFP (green fluorescent protein) or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism., Conclusions: Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury., Competing Interests: Disclosures D.S. is a scientific cofounder of Tenaya Therapeutics. All authors, aside from P.Y., hold or held equity in Tenaya Therapeutics. P.Y. reports no conflicts.

Background: The purpose of this study was to evaluate existing evidence in the field of long non-coding RNAs (lncRNAs) and prognosis of gastric cancer., Methods: A comprehensive literature search was performed through the electronic database. The combined hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of overall survival (OS), disease-free survival (DFS), or progression free survival (PFS) were calculated to assess the strength of the association. Kaplan-Meier (KM) plotter was used to verify lncRNA HOX transcript antisense RNA (HOTAIR) expression and OS., Results: Overall, a significant correlation between high lncRNAs expression and poor OS was explored in patients with gastric cancer (HR = 1.78, P < .001). Subgroup analysis based on statistical methods indicated the high expression of lncRNAs in log-rank (HR = 1.87, P < .001) and multivariate analysis (HR = 1.71, P < .001) were all significantly correlated with the poor OS. Clinicopathological parameters analysis showed the lncRNA expression were significantly associated prognosis, including TNM stage, tumor size, pathological differentiation, lymph nodes metastasis, distance metastasis, invasion depth and Lauren's classification. It was consistent with the verification results of bioinformatics database for lncRNA HOTAIR (P < .001)., Conclusion: Our study confirmed the expression of lncRNAs and clinicopathological features may serve as effective indicators of prognosis in patients with gastric cancer., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) is associated with prognosis in many cancers. The aim of this study was to systematically evaluate the potential correlation between AFAP1-AS1 and the prognosis of digestive system cancers (DSC)., Methods: EMBASE, Web of Science, Cochrane Library, PubMed, Wanfang Data (Chinese), and CNKI (Chinese) were comprehensively searched for literature published from the establishment of the database to September 2021.All case-control studies that met the inclusion criteria were retrieved; additionally manual retrieval and literature tracing was performed. After extracting the relevant data, Revman 5.3.5 software was used for meta-analysis., Results: Eighteen studies were included in analyses, high expression of AFAP1-AS1 was significantly correlated with poor prognosis in DSC, including overall survival (HR = 1.93, 95% CI: 1.72-2.17, P < .001) and disease-free survival/progression-free survival (HR = 1.87, 95% CI: 1.56-2.26, P < .001). In addition, the expression of AFAP1-AS1 was significantly correlated with tumor size, tumor stage, and lymph node metastasis., Conclusion: High expression of AFAP1-AS1 was associated with poor prognosis in DSC. Therefore, it could be used as a potential marker for evaluating prognosis in DSC., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The new World Health Organization (WHO) classification of tumours of the female genital tract (2020) divides endocervical adenocarcinoma (EAC) into human papilloma virus (HPV)-related adenocarcinoma (HPVA) and HPV-independent adenocarcinoma (HPVI) to underscore the morphological and pathogenetic correlation. It may be potentially prognostic. In this study, we appraised the new WHO classification in an independent, single institution-based EAC cohort from China to assess the clinicopathological features and prognostic value among tumour types. Our study cohort contained 402 consecutive, surgically excised EACs consisting of 298 (74.1%) HPVA, 88 (21.9%) HPVI and 16 (4%) adenocarcinomas not otherwise specified (NOS). Usual-type (55.7%) and gastric-type adenocarcinoma (GAC) (18.2%) was the most common type in HPVA and HPVI, respectively. Block p16 staining (94.7% vs 24.4%) and HPV mRNA signal (89.4% vs 0) were more common in HPVA than in HPVI (p<0.001). HPVI or GAC were more frequently associated with prognostically adverse variables including old age, large tumour size, deep invasion of the cervical wall, high tumour stage, spread of the upper genital tract, lymphovascular invasion, and mutant-type p53 expression, compared to HPVA or mucinous/usual-type HPVA, respectively (all p<0.001). In univariate survival analysis, HPVI had a worse overall survival and higher tumour recurrence compared to HPVA (p<0.05). Mucinous-type HPVA showed a worse prognosis than usual-type HPVA, but better than GAC (p<0.001). Multivariate survival analysis demonstrated that HPVI was independently associated with a worse overall survival and tumour recurrence (p<0.05) while GAC was an adverse prognostic factor independently of FIGO stage (p<0.05). Our findings validate the value of the new WHO classification in prognostic stratification and pathogenetic correlation in EAC and its subtypes., (Copyright © 2022 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Objectives: Pediatric neurogastroenterology and motility (PNGM) disorders impose a significant impact on health-related quality of life and cost of health care in children and adolescents. The detailed understanding of its burden across demographic groups is unknown. The objective of our study is to characterize the demographic and hospitalization trends of patients undergoing PNGM tests., Methods: We used Healthcare Cost and Utilization Project (HCUP) Inpatient Database (KID) for years 2003-2016 to perform a trend analysis in US hospitalizations for International Classification of Diseases (ICD)-9 and -10 Clinical Modification (CM)-identified PNGM studies in patients (<18 years of age) with elective admission and a length of stay (LOS) <3 days. The hospitalization rates were analyzed by year, hospital region, facility type, and patient sociodemographic characteristics. Multivariable logistic regression was used to examine factors influencing the receipt of motility studies., Results: There was an overall increase trend in hospitalizations, rates of PNGM studies, and median hospital charges from 2003 to 2016. Patients with private insurance and living in the high-income zip codes were more likely to receive a PNGM study compared with those with governmental insurance and lower income area. Although the race was not found to influence the receipt of the study, a major difference in the LOS was noted across the regions., Conclusions: There are income- and insurance-based differences in the rates of inpatient PNGM studies. PNGM studies significantly add to health care burden. Standardization of PNGM practices across the country may decrease the LOS and associated expenses. Future analysis should include ambulatory PNGM services to understand combined inpatient and outpatient trends., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Abstract: Gain-of-function and loss-of-function mutations in Nav1.7 cause chronic pain and pain insensitivity, respectively. The preferential expression of Nav1.7 in the peripheral nervous system and its role in human pain signaling make Nav1.7 a promising target for next-generation pain therapeutics. However, pharmacological agents have not fully recapitulated these pain phenotypes, and because of the lack of subtype-selective molecular modulators, the role of Nav1.7 in the perception of pain remains poorly understood. Scorpion venom is an excellent source of bioactive peptides that modulate various ion channels, including voltage-gated sodium (Nav) channels. Here, we demonstrate that Buthus martensii Karsch scorpion venom (BV) elicits pain responses in mice through direct enhancement of Nav1.7 activity and have identified Makatoxin-3, an α-like toxin, as a critical component for BV-mediated effects on Nav1.7. Blocking other Nav subtypes did not eliminate BV-evoked pain responses, supporting the pivotal role of Nav1.7 in BV-induced pain. Makatoxin-3 acts on the S3-S4 loop of voltage sensor domain IV (VSD4) of Nav1.7, which causes a hyperpolarizing shift in the steady-state fast inactivation and impairs inactivation kinetics. We also determined the key residues and structure-function relationships for the toxin-channel interactions, which are distinct from those of other well-studied α toxins. This study not only reveals a new mechanism underlying BV-evoked pain but also enriches our knowledge of key structural elements of scorpion toxins that are pivotal for toxin-Nav1.7 interactions, which facilitates the design of novel Nav1.7 selective modulators., (Copyright © 2021 International Association for the Study of Pain.)

Objective: To explore the risk factors for idiopathic REM sleep behavior disorder (RBD) in a community population in Beijing., Methods: Participants aged 55 years and above were recruited from the Beijing Longitudinal Study on Aging II cohort. We identified individuals with possible RBD (pRBD) using the validated RBD Questionnaire-Hong Kong in 2010. A series of environmental, lifestyle, and other potential risk factors were assessed via standardized questionnaires in 2009. Multivariable logistic regression analysis was performed to investigate the association between the studied factors and pRBD., Results: Of 7,225 participants who were free of parkinsonism and dementia, 219 (3.0%) individuals were considered as having pRBD. Participants with pRBD reported more nonmotor and motor symptoms of Parkinson disease (PD) with adjusted odds ratios (ORs) ranging from 1.10 to 4.40. Participants with pRBD were more likely to report a family history of parkinsonism or dementia (OR 3.03, 95% confidence interval [CI] 1.23-7.46). There was a significant association between pRBD and self-reported hyperlipidemia (OR 1.51, 95% CI 1.09-2.10), ever smoking (OR 1.79, 95% CI 1.20-2.65), prior carbon monoxide (CO) poisoning (OR 2.30, 95% CI 1.39-3.83), and nonoccupational exposure to pesticides (OR 2.21, 95% CI 1.40-3.50)., Conclusion: Our study replicated previously reported associations between pRBD and hyperlipidemia, smoking, pesticide exposure, and several prodromal PD symptoms. We also found previously unreported links with a positive family history of parkinsonism or dementia and CO poisoning. Risk factor profiles for pRBD partially resemble those defined for PD, but also differ in distinct ways., (© 2020 American Academy of Neurology.)

Background: Pharmacy dispensing data are frequently used to identify prevalent medication use as a predictor or covariate in observational research studies. Although several methods have been proposed for using pharmacy dispensing data to identify prevalent medication use, little is known about their comparative performance., Objectives: The authors sought to compare the performance of different methods for identifying prevalent outpatient medication use., Research Design: Outpatient pharmacy fill data were compared with medication reconciliation notes denoting prevalent outpatient medication use at the time of hospital admission for a random sample of 207 patients drawn from a national cohort of patients admitted to Veterans Affairs hospitals. Using reconciliation notes as the criterion standard, we determined the test characteristics of 12 pharmacy database algorithms for determining prevalent use of 11 classes of cardiovascular and diabetes medications., Results: The best-performing algorithms included a 180-day fixed look-back period approach (sensitivity, 93%; specificity, 97%; and positive predictive value, 89%) and a medication-on-hand approach with a grace period of 60 days (sensitivity, 91%; specificity, 97%; and positive predictive value, 91%). Algorithms that have been commonly used in previous studies, such as defining prevalent medications to include any medications filled in the prior year or only medications filled in the prior 30 days, performed less well. Algorithm performance was less accurate among patients recently receiving hospital or nursing facility care., Conclusion: Pharmacy database algorithms that balance recentness of medication fills with grace periods performed better than more simplistic approaches and should be considered for future studies which examine prevalent chronic medication use.

Objective: To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS)., Methods: We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820)., Results: Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01 , and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model., Conclusions: We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS., (© 2017 American Academy of Neurology.)

Objective: To study the endoscope anatomy of the petroclival and ventrolateral brainstem regions via the intradural subtemporal keyhole Kawase approach and discuss the feasibility and indications of this approach to the regions., Materials and Methods: Craniotomy procedures performed via the intradural subtemporal keyhole Kawase approach were simulated on 16 sides of 8 adult cadaveric heads fixed by formalin, and the related anatomical structures were observed through the 0-degree endoscope or alternatively 30-degree one. Measurements of the shortest distances from the highest point of arcuate eminence to the 4 anatomic marks and the lengths of the Kawase rhombus were recorded, and the 2 kinds of milled ranges of petrous apex were compared., Result: Most of the related anatomical structures could be clearly observed under the endoscope. The shortest distances from the highest point of arcuate eminence to the foramen spinosum, the greater superficial petrosal nerve hiatus, the intersection of the greater superficial petrosal nerve and mandibular nerve, and the outside edge of the trigeminal impression are 22.90 ± 2.34, 14.05 ± 2.09, 24.94 ± 1.98, 23.49 ± 2.38 mm. The area of routine milled Kawase rhombus is 3.04 ± 0.47 cm, which would increase 0.66 cm on average after the maximum drilling of the petrous apex., Conclusions: The intradural subtemporal keyhole Kawase approach can provide an ideal exposure to the petroclival and ventrolateral brainstem regions via the endoscope with less damaging of the normal structures. It can be used to treat the lesions located in those areas through the natural gap combined with the drilling of petrous apex bone.

Background and Purpose: Cerebral microbleeds (CMB) and white matter lesions (WML) are cerebral small vessel diseases. Hypertension is considered the most important risk factor. Its mechanism is not yet clarified. Our study assessed the association of blood pressure variability (BPV) with CMB and WML progression., Methods: Patients with a history of ischemic stroke within 1 to 6 months were consecutively recruited and followed-up for 12 to 18 months. Blood pressure was measured monthly and controlled to a target level. BPV was quantified by the maximum, standard deviation, coefficient of variation, successive variation, standard deviation independent of mean, and successive variation independent of mean. Magnetic resonance imaging was performed at baseline and the end of the study. CMB and WML were rated using Microbleed Anatomic Rating Scale and Age-Related White Matter Changes scales, respectively. Multiple logistic analyses assessed BPV associations with CMB and WML development., Results: Of 720 patients recruited, 500 and 584 had follow-up results for CMB and WML, respectively; 13.2% and 48.1% showed CMB and WML progression, respectively, over a median of 14 months. Patients with CMB had a higher mean, maximum, standard deviation, coefficient of variation, successive variation, standard deviation independent of the mean, and successive variation independent of the mean in either systolic blood pressure or diastolic blood pressure (P<0.05). Systolic blood pressure variability was an independent risk factor for deep and infratentorial CMB progression, whereas diastolic blood pressure variability was independently associated with CMB development in deep regions. WML progression was not significantly associated with BPV between visits., Conclusions: BPV independently predicts CMB progression in deep and infratentorial regions., Clinical Trial Registration Information: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00202020.

Background and Purpose: Low rates of thrombolysis for ischemic stroke in China have mainly been attributed to delays in presentation to the hospital. This study aimed to evaluate factors associated with these delays., Methods: Data were from a prospective, multicenter, hospital-based registry of patients with acute stroke (ChinaQUEST [Quality Evaluation of Stroke Care and Treatment]), which involved 62 hospitals across a variety of economic and geographic regions in China during 2006. Univariate and multivariate analyses were undertaken to determine associations between variables of interest and delays to hospital presentation., Results: Median time to hospital presentation was 15.0 hours for 6102 cases (interquartile range, 2.8-51.0 hours). A total of 1546 (25%) patients arrived within 3 hours and 2244 (37%) patients arrived within 6 hours after symptom onset. Factors that prolonged time to presentation were: visiting a local doctor before presenting at emergency (OR, 0.48; P<0.001), symptom onset at home (OR, 0.62; P<0.001), transfer to a large (Level III) hospital for management (OR, 0.70; P=0.04), and history of diabetes (OR, 0.78; P=0.01). In contrast, factors that accelerated presentation to the hospital were hemorrhagic stroke (OR, 2.25; P<0.001), history of atrial fibrillation (OR, 1.94; P<0.001), unconsciousness at presentation (OR, 1.91; P<0.001), transfer by ambulance (OR, 1.91; P<0.001), and history of coronary artery disease (OR, 1.20; P=0.04)., Conclusions: Health promotion strategies to improve community awareness of early symptoms of stroke, establishment of an alert system to cater for patients likely to experience stroke at home, and wider availability and use of ambulance services are promising methods to help expedite presentation to hospital poststroke and thereby improve the management of stroke in China.

Background and Purpose: We aimed to describe the uptake of proven secondary prevention strategies for ischemic stroke in urban China., Methods: In a prospective, multicenter, hospital-based registry of 4782 cases of acute ischemic stroke in China during 2006, the use of secondary prevention regimens was evaluated before hospital discharge and 3 and 12 months after stroke. Logistic regression analysis was performed to determine associations between various baseline variables and in-hospital use of antihypertensive, antiplatelet, and lipid-lowering therapies, and to identify variables associated with their continuation at 12 months., Results: In-hospital initiation of antihypertensive (63%), antiplatelet (81%), and lipid-lowering (31%) therapies was influenced favorably by previous use and comorbid cardiovascular risk factors and unfavorably by stroke severity. Antihypertensive use was well-maintained during follow-up, whereas use of antiplatelet and lipid-lowering therapy decreased (66% and 17%, respectively; P<0.001) by 12 months after stroke, with discontinuation related to patient and physician factors., Interpretation: There was a high level of uptake of secondary prevention for ischemic stroke in this nationwide sample of hospitalized patients in urban China. However, use of antiplatelet and lipid-lowering therapy declined substantially after discharge, apparently related to misperceptions of subsequent disease risk by both doctors and patients.

The inappropriate expression of the c-MET cell surface receptor in many human solid tumors necessitates the development of companion diagnostics to identify those patients who could benefit from c-MET targeted therapies. Tumor tissues are formalin fixed and paraffin embedded (FFPE) for histopathologic evaluation, making the development of an antibody against c-MET that accurately and reproducibly detects the protein in FFPE samples an urgent need. We have developed a monoclonal antibody (mAb), designated MET4, from a panel of MET-avid mAbs, based on its specific staining pattern in FFPE preparations. The accuracy of MET4 immunohistochemistry (MET4-IHC) was assessed by comparing MET4-IHC in FFPE cell pellets with immunoblotting analysis. The technical reproducibility of MET4-IHC possessed a percentage coefficient of variability of 6.25% in intra-assay and interassay testing. Comparison with other commercial c-MET antibody detection reagents demonstrated equal specificity and increased sensitivity for c-MET detection in prostate tissues. In cohorts of ovarian cancers and gliomas, MET4 reacted with ovarian cancers of all histologic subtypes (strong staining in 25%) and with 63% of gliomas. In addition, MET4 bound c-MET on the surfaces of cultured human cancer cells and tumor xenografts. In summary, the MET4 mAb accurately and reproducibly measures c-MET expression by IHC in FFPE tissues and can be used for molecular imaging in vivo. These properties encourage further development of MET4 as a multipurpose molecular diagnostics reagent to help to guide appropriate selection of patients being considered for treatment with c-MET-antagonistic drugs.