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We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.

The insufficient investigations on the changes of spinal structures during traction prevent further exploring the possible therapeutic mechanism of cervical traction. A blind randomized crossover-design study was conducted to quantitatively compare the intervertebral disc spaces between axial and anterior lean cervical traction in sitting position. A total of 96 radiographic images from the baseline measurements, axial and anterior lean tractions in 32 asymptomatic subjects were digitized for further analysis. The intra- and inter-examiner reliabilities for measuring the intervertebral disc spaces were in good ranges (ICCs = 0.928-0.942). With the application of anterior lean traction, the statistical increases were detected both in anterior and in posterior disc spaces compared to the baseline (0.29 mm and 0.24 mm; both P < 0.01) and axial traction (0.16 mm and 0.35 mm; both P < 0.01). The greater intervertebral disc spaces obtained during anterior lean traction might be associated with the more even distribution of traction forces over the anterior and posterior neck structures. The neck extension moment through mandible that generally occurred in the axial traction could be counteracted by the downward force of head weight during anterior lean traction. This study quantitatively demonstrated that anterior lean traction in sitting position provided more intervertebral disc space enlargements in both anterior and posterior aspects than axial traction did. These findings may serve as a therapeutic reference when cervical traction is suggested. [ABSTRACT FROM AUTHOR]

BACKGROUND: Substantial evidence supports the use of adjuvant trastuzumab with chemotherapy for patients with human epidermal growth factor receptor (HER)-2(+) breast cancer; however, a lesser amount of data is available to guide use of this therapy in older patients and in those with significant medical comorbidities. The goal of the current study was to understand how patient age and health status impact oncologists' decisions to recommend adjuvant therapy in older women with HER-2(+) breast cancer. METHODS: Medical oncologists (n = 151) participated in an online survey regarding treatment recommendations for a hypothetical patient of varying age and health status with tumor stage 2, nodal stage 2, estrogen receptor-negative, HER-2(+) breast cancer. Survey respondents recommended either chemotherapy plus trastuzumab, chemotherapy alone, trastuzumab alone, or no therapy. The effect of age and health status on therapeutic recommendations was assessed. FINDINGS: As the hypothetical patient's age increased or health status deteriorated, oncologists were less likely to recommend a combination of chemotherapy plus trastuzumab. In contrast, oncologists were more likely to recommend either trastuzumab alone or no therapy for patients with advanced age and deteriorating health status. Chemotherapy alone was recommended by only 7.5% of respondents, on average. INTERPRETATION: With limited evidence-based data for the treatment of older women with early-stage HER-2(+) breast cancer, medical oncologists recommend a diverse array of therapeutic approaches. With increasing age and declining health status they were less likely to recommend chemotherapy plus trastuzumab and more likely to recommend single-agent trastuzumab or no therapy. [ABSTRACT FROM AUTHOR]

PURPOSE: The management of craniopharyngioma does not have a consensus. Extensive surgery may be associated with major complications. The purpose of this study was to evaluate local tumor control and survival after limited surgery and postoperative radiotherapy. METHODS AND MATERIALS: Thirty patients with craniopharyngioma were treated at SUNY Upstate Medical University in Syracuse, NY from 1967 to 2000. The group consisted of 13 males and 17 females, and the median age was 35 years. The median follow-up was 71 months. Only two patients underwent complete tumor resection. Eighteen patients underwent subtotal resection, and 10 underwent decompressive surgery (ventriculoperitoneal shunt or cyst aspiration). Most (20/ 28) patients who had less than total resection received immediate postoperative radiotherapy. Four patients received conventional radiotherapy for recurrence. Gamma knife radiosurgery was used as part of the primary treatment in two patients and at the time of local tumor recurrence in three patients. RESULTS: The local control rate, including after salvage treatment, was 91% and 83% at 5 and 10 years, respectively. Salvage was radiotherapy, gamma knife or surgery. Ultimate local tumor control appeared better for patients who underwent subtotal resection (100% and 89% at 5 and 10 years, respectively) than for those who did not undergo resection (61% and 61% at 5 and 10 years, respectively). The overall survival was 93% and 83% at 5 and 10 years, respectively. Two patients underwent gross total resection, and one patient experienced recurrence 6 years after the surgery and was treated by gamma knife radiosurgery. Both patients are well without recurrence at 3 and 7 years after the initial surgery. Survival also appeared to be improved for the group who underwent subtotal resection (100% and 90% at 5 and 10 years, respectively) versus those who did not undergo surgery (73% and 73% at 5 and 10 years, respectively). The dose of radiotherapy > or = 50 Gy had no impact on local control or survival. Ten patients experienced surgery-related complications, and five had radiotherapy-related complications, including visual, cranial nerve, motor, and endocrine deficits. CONCLUSION: The extent of surgery appears to be an important prognostic factor for predicting outcome, although this may represent selection bias. Long-term disease control is excellent after subtotal resection and postoperative radiotherapy. Encouraging initial results have been seen with gamma knife radiosurgery, and the potential for gamma knife radiosurgery to replace more extensive surgical resection should be further explored. [ABSTRACT FROM AUTHOR]

Objective: Genetic causes are often overlooked in patients with epilepsy of unknown etiology, particularly in adults. We aimed to evaluate clinical features of genetic epilepsy and the utility of genetic testing., Methods: We retrospectively screened consecutive unrelated adult epilepsy patients at an epilepsy clinic from April 2022 to May 2023. Patients with unknown etiology or special brain lesions were classified as unexplained epilepsy. In them, patients with young-onset seizures or family history of seizures who were recommended for and ultimately underwent genetic testing using either panel next-generation sequencing (NGS) or whole-exome sequencing (WES) were enrolled. A definite or probable genetic diagnosis was established through genotype-phenotype correlation. We compared the demographic characteristics between genetic epilepsy and other etiologies., Results: Of the 374 adult epilepsy patients, 258 were classified as unexplained epilepsy, 129 were suspected of having genetic epilepsy due to young-onset seizures or a positive family history, 33 underwent genetic testing; 13 harbored variants classified as pathogenic, and 6 reached a definite genetic diagnosis, resulting in a yield of 18%. Among the 27 patients without a definite genetic diagnosis, 7 had a nongenetic structural etiology. Patients with genetic etiology exhibited greater multisystem involvement particularly multiple structural anomalies and early childhood-onset seizures, but wasn't directly correlated with young-onset seizures or a positive family history. The diagnostic yield was comparable between panel NGS and WES., Significance: In adult patients with unexplained epilepsy, genetic epilepsy is more associated with multisystem involvement and multiple structural anomalies but not family history of seizures or young-onset seizures., (© 2024 International League Against Epilepsy.)

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2I) have been suggested to reduce new-onset cancer amongst type-2 diabetes mellitus (T2DM) patients. This study aims to compare the risks of prostate cancer between SGLT2I and dipeptidyl peptidase-4 inhibitors (DPP4I) amongst T2DM patients., Design, Setting and Participants: This was a retrospective population-based cohort study of prospectively recorded data on male patients with T2DM who were prescribed either SGLT2I or DPP4I between 1 st January 2015 and 31 st December 2020 from Hong Kong., Methods: The primary outcome was new-onset prostate cancer. The secondary outcomes included cancer-related mortality and all-cause mortality. Propensity score matching (1:1 ratio) using the nearest neighbor search was performed and multivariable Cox regression was applied. A three-arm analysis including the glucagon-like peptide-1 receptor agonist (GLP1a) cohort was conducted., Results: This study included 42129 male T2DM patients (median age: 61.0 years old [SD: 12.2]; SGLT2I: n = 17,120; DPP4I: n = 25,009). In the propensity score matched cohort, the number of prostate cancers was significantly lower in SGLT2I users (n = 60) than in DPP4I (n = 102). Over a follow-up duration of 5.61 years, SGLT2I was associated with lower prostate cancer risks (HR: 0.45; 95% CI: 0.30-0.70) than DPP4I after adjustments. The subgroup analyses showed that the interactions between SGLT2I and age, hypertension, heart failure, and GLP-1a were not statistically significant. The result remained consistent in the sensitivity analysis., Conclusion: The study demonstrated SGLT2I was associated with lower risks of new-onset prostate cancer after propensity score matching and adjustments compared to DPP4I amongst T2DM patients., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Type 2 diabetes mellitus (T2DM) may be a risk factor for development of hepatocellular carcinoma (HCC). The association between risk of developing HCC and treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) is currently unknown. This study aimed to compare the risk of new-onset HCC in patients treated with SGLT2i versus DPP4i., Methods: This was a retrospective cohort study of patients with T2DM in Hong Kong receiving either SGLT2i or DPP4i between January 1, 2015, and December 31, 2020. Patients with concurrent DPP4i and SGLT2i use were excluded. Propensity score matching (1:1 ratio) was performed by using the nearest neighbor search. Multivariable Cox regression was applied to identify significant predictors., Results: A total of 62,699 patients were included (SGLT2i, n=22,154; DPP4i, n=40,545). After matching (n=44,308), 166 patients (0.37%) developed HCC: 36 in the SGLT2i group and 130 in the DPP4i group over 240,269 person-years. Overall, SGLT2i use was associated with lower risks of HCC (hazard ratio [HR], 0.42; 95% CI, 0.28-0.79) compared with DPP4i after adjustments. The association between SGLT2i and HCC development remained significant in patients with cirrhosis or advanced fibrosis (HR, 0.12; 95% CI, 0.04-0.41), hepatitis B virus (HBV) infection (HR, 0.32; 95% CI, 0.17-0.59), or hepatitis C virus (HCV) infection (HR, 0.41; 95% CI, 0.22-0.80). The results were consistent in different risk models, propensity score approaches, and sensitivity analyses., Conclusions: SGLT2i use was associated with a lower risk of HCC compared with DPP4i use after adjustments, and in the context of cirrhosis, advanced fibrosis, HBV infection, and HCV infection.

Purpose: Carotid artery web (CaW) is a rare focal fibromuscular dysplasia that can lead to embolic strokes with large vessel occlusion. This condition can be effectively treated with endovascular thrombectomy (EVT). Our study aims to assess the prevalence of CaW among patients with acute ischemic stroke (AIS) who underwent EVT and to compare the clinical characteristics of CaW with other carotid artery pathologies., Methods: We enrolled consecutive patients with AIS who underwent EVT at a single medical center and two regional teaching hospitals in Taiwan from September 2014 to December 2021. We compared CaW with carotid dissection (CaD) and carotid large artery atherosclerosis (CaLAA) in terms of patient demographics and thrombus histological findings., Results: Of the 576 AIS patients who underwent EVT, four (mean age: 50 years) were diagnosed with CaW, resulting in a prevalence of 0.69%. Among these four patients, three experienced successful reperfusion after EVT and achieved functional independence (defined as a modified Rankin Scale score ≤2) three months post-stroke. Importantly, none of the CaW patients suffered a recurrent stroke within one year. Patients with CaW were younger than those with CaD or CaLAA, and exhibited fewer vascular risk factors. Additionally, CaW was associated with distal occlusion sites. The thrombus composition in CaW patients was similar to that in CaD patients., Conclusions: In conclusion, CaW is a rare finding among Asian patients with carotid artery disease who undergo for AIS. It is more prevalent in younger patients with a limited number of vascular risk factors., Competing Interests: Declaration of competing interest A conflict of interest occurs when an individual's objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. JFMA Editors strive to ensure that what is published in the Journal is as balanced, objective and evidence-based as possible. Since it can be difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any potential conflicts of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Routinely collected electronic health records (EHRs) data contain a vast amount of valuable information for conducting epidemiological studies. With the right tools, we can gain insights into disease processes and development, identify the best treatment and develop accurate models for predicting outcomes. Our recent systematic review has found that the number of big data studies from Hong Kong has rapidly increased since 2015, with an increasingly common application of artificial intelligence (AI). The advantages of big data are that i) the models developed are highly generalisable to the population, ii) multiple outcomes can be determined simultaneously, iii) ease of cross-validation by for model training, development and calibration, iv) huge numbers of useful variables can be analyzed, v) static and dynamic variables can be analyzed, vi) non-linear and latent interactions between variables can be captured, vii) artificial intelligence approaches can enhance the performance of prediction models. In this paper, we will provide several examples (cardiovascular disease, diabetes mellitus, Brugada syndrome, long QT syndrome) to illustrate efforts from a multi-disciplinary team to identify data from different modalities to develop models using territory-wide datasets, with the possibility of real-time risk updates by using new data captured from patients. The benefit is that only routinely collected data are required for developing highly accurate and high-performance models. AI-driven models outperform traditional models in terms of sensitivity, specificity, accuracy, area under the receiver operating characteristic and precision-recall curve, and F1 score. Web and/or mobile versions of the risk models allow clinicians to risk stratify patients quickly in clinical settings, thereby enabling clinical decision-making. Efforts are required to identify the best ways of implementing AI algorithms on the web and mobile apps., Competing Interests: Declaration of Competing Interest 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The Heidenhain variant Creutzfeldt-Jakob disease (CJD) is characterized by isolated visual symptoms at disease onset, which may mimic numerous ophthalmological disorders. Anti-recoverin autoantibody can be found in patients with autoimmune-related retinopathies. The presence of this antibody with visual symptoms might be confusing in the early stages of the Heidenhain variant CJD. We describe the first case of an anti-recoverin antibody found in the Heidenhain variant CJD who presented with progressive blurred vision then memory deterioration proceeded later. This presentation reinforces the concept that the presence of the anti-recoverin antibody could not exclude the possibility of the Heidenhain variant of CJD in highly suspicious patients with initial isolated visual disturbance.

This study aimed to investigate the potential association between glaucoma and peripheral arterial occlusive disease. The study recruited patients, including 101,309 with glaucoma and 1,860,528 without a glaucoma diagnosis, from a population of 2 million patients in the Longitudinal Health Insurance Database. Propensity score matching was performed between the two groups, matching for age, sex, and comorbidities. In total, 95,575 patients with glaucoma and 95,575 patients without glaucoma were analyzed for their risk of developing peripheral arterial occlusive disease. The analysis of the data revealed that the glaucoma group had a higher incidence density (ID = 4.13) of peripheral arterial occlusive disease than the non-glaucoma group (ID = 3.42). The relative risk for the glaucoma group was 1.21 (95% C.I. = 1.15-1.28). Cox proportional hazard model analysis indicated that the glaucoma group had a higher risk of developing peripheral arterial occlusive disease (HR = 1.18; 95% C.I. = 1.12-1.25). The subgroup analysis of the risk of PAOD showed that the glaucoma group had a higher risk of developing peripheral arterial occlusive disease in the age group of 20 to 39 ( p for interaction = 0.002). In conclusion, patients with glaucoma were associated with a higher risk of subsequent peripheral arterial occlusive disease compared with those without a diagnosis of glaucoma.

Study Objectives: Machine learning (ML) models have been employed in the setting of sleep disorders. This review aims to summarize the existing data about the role of ML techniques in the diagnosis, classification, and treatment of sleep-related breathing disorders., Methods: A systematic search in Medline, EMBASE, and Cochrane databases through January 2022 was performed., Results: Our search strategy revealed 132 studies that were included in the systematic review. Existing data show that ML models have been successfully used for diagnostic purposes. Specifically, ML models showed good performance in diagnosing sleep apnea using easily obtained features from the electrocardiogram, pulse oximetry, and sound signals. Similarly, ML showed good performance for the classification of sleep apnea into obstructive and central categories, as well as predicting apnea severity. Existing data show promising results for the ML-based guided treatment of sleep apnea. Specifically, the prediction of outcomes following surgical treatment and optimization of continuous positive airway pressure therapy can be guided by ML models., Conclusions: The adoption and implementation of ML in the field of sleep-related breathing disorders is promising. Advancements in wearable sensor technology and ML models can help clinicians predict, diagnose, and classify sleep apnea more accurately and efficiently., Citation: Bazoukis G, Bollepalli SC, Chung CT, et al. Application of artificial intelligence in the diagnosis of sleep apnea. J Clin Sleep Med . 2023;19(7):1337-1363., (© 2023 American Academy of Sleep Medicine.)

Introduction: Temporalis muscle thickness (TMT) is a surrogate marker for sarcopenia. This study investigated the association of TMT with clinical outcomes in patients receiving endovascular thrombectomy (EVT) for stroke involving acute large vessel occlusion (LVO)., Material and Methods: We enrolled consecutive patients who had undergone EVT between September 2014 and December 2021 at three thrombectomy-capable institutes. TMT was measured through preprocedural computerized tomography angiography. The clinical variables affecting TMT were investigated. The associations between TMT and clinical functional outcomes, defined using the modified Rankin scale, were also studied., Results: A total of 657 patients were included (mean age: 72.0 ± 12.7 years; male: 52.1%). The mean TMT was 6.35 ± 1.84 mm. Younger age, male sex, higher body mass index, and premorbid functional independence were associated with larger TMT in both univariate and multivariate linear regression (P <.05). Ordinal logistic regression revealed that TMT was associated with better clinical outcomes at 90 days (P trend  = 0.047); multivariate logistic regression indicated that larger TMT was an independent predictor (adjusted odds ratio: 1.14, 95% confidence interval: 1.03-1.27, P = 0.02) of favorable functional independence (modified Rankin scale score: 0-2). The effect was stronger in older patients (≥80 years) than younger patients, as revealed by interaction modeling analysis (P interaction  = 0.06)., Conclusion: TMT is associated with age, sex, body mass index, and premorbid functional status. Larger TMT is associated with better outcomes after EVT. The effects of TMT are more pronounced in older adults, indicating that sarcopenia may have influence on stroke outcomes., Competing Interests: Declaration of Competing Interest 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 © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Cancer is currently the second leading cause of death globally. There is much uncertainty regarding the comparative risks of new-onset overall cancer and pre-specified cancer for Type 2 diabetes mellitus (T2DM) patients on sodium-glucose cotransporter 2 inhibitors (SGLT2I) versus DPP4I., Methods: This population-based cohort study patients included patients who were diagnosed with T2DM and administered either SGLT2 or DPP4 inhibitors between 1 January 2015 and 31 December 2020 in public hospitals of Hong Kong., Results: This study included 60,112 T2DM patients (mean baseline age: 62.1 ± 12.4 years, male: 56.36%), of which 18,167 patients were SGLT2I users and 41,945 patients were dipeptidyl peptidase 4 inhibitor (DPP4I) users. Multivariable Cox regression found that SGLT2I use was associated with lower risks of all-cause mortality (HR: 0.92; 95% CI: 0.84-0.99; p= 0.04), cancer-related mortality (HR: 0.58; 95% CI: 0.42-0.80; p ≤ 0.001) and new diagnoses of any cancer (HR: 0.70; 95% CI: 0.59-0.84; p ≤ 0.001). SGLT2I use was associated with a lower risk of new-onset breast cancer (HR: 0.51; 95% CI: 0.32-0.80; p ≤ 0.001), but not of other malignancies. Subgroup analysis on the type of SGLT2I, dapagliflozin (HR: 0.78; 95% CI: 0.64-0.95; p = 0.01) and ertugliflozin (HR: 0.65; 95% CI: 0.43-0.98; p = 0.04) use was associated with lower risks of new cancer diagnosis. Dapagliflozin use was also linked to lower risks of breast cancer (HR: 0.48; 95% CI: 0.27-0.83; p = 0.001)., Conclusion: Sodium-glucose cotransporter 2 inhibitor use was associated with lower risks of all-cause mortality, cancer-related mortality and new-onset overall cancer compared to DPP4I use after propensity score matching and multivariable adjustment., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Brugada syndrome (BrS) is a complex arrhythmogenic disease associated with an increased risk of sudden cardiac death (SCD). The role of electrophysiological study (EPS) for risk stratification purposes of asymptomatic BrS patients remains still controversial. This study aims to summarize the existing data about the role of electrophysiological study for arrhythmic risk stratification of BrS patients without a prior history of aborted SCD or fatal arrhythmic event. Two independent investigators (G.B. and G.T.) performed a systematic search in the MedLine database and Cochrane library from their inception until April 2022 without any limitations. The reference lists of the relevant research studies as well as the relevant review studies and meta-analyses were manually searched. Nineteen studies were included in the final analysis. The included studies enrolled 6218 BrS patients (mean age: 46.9 years old, males: 76%) while 4265 (68.6%) patients underwent an EPS. The quantitative synthesis showed that a positive EPS study was significantly associated with arrhythmic events in BrS patients (RR, 1.74 [1.23-2.45]; P = 0.002; I2 = 63%]. By including the studies that provided data on the association of EPS with arrhythmic events during follow-up in patients without a prior history of aborted SCD or fatal arrhythmic event, the association between positive EPS study and future arrhythmic events remained significant (RR, 1.60 [1.08-2.36]; P = 0.02; I2 = 19%). In conclusion, EPS is a useful invasive tool for the risk stratification of BrS patients and can be used to identify the population of BrS patients who may be candidates for primary prevention of SCD with implantable cardioverter-defibrillator (ICD) implantation., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Androgen deprivation therapy (ADT), used increasingly in the treatment of prostate cancer (PCa), negatively influences glycemic control in diabetes and is associated with an increased risk of diabetes complications where hospitalization commonly ensues. Metformin could decrease the metabolic consequences of ADT and enhance its effect. This study examined the association of metformin use with healthcare resources utilization among diabetic, PCa patients receiving ADT., Methods: Diabetic adults with PCa on ADT in Hong Kong between December 1999 and March 2021 were identified. Patients with <6 months of concurrent metformin and ADT use were excluded. All included patients were followed up until September 2021. The outcomes were hospital attendances and related costs., Results: In total, 1,284 metformin users and 687 non-users were studied. Over 8,045 person-years, 9,049 accident and emergency (A&E), and 21,262 inpatient attendances, with 11,2781 days of hospitalization were observed. Metformin users had significantly fewer A&E attendances (incidence rate ratio (IRR): 0.61 [95% confidence interval 0.54-0.69], p < 0.001), inpatient attendances (IRR: 0.57 [0.48-0.67], p < 0.001), and days of hospitalization (IRR: 0.55 [0.42-0.72], p < 0.001). Annual attendance costs were lower for metformin users than non-users (cost ratio: 0.28 [0.10-0.80], p = 0.017)., Conclusions: Metformin use was associated with decreased hospital attendances, days of hospitalization, and associated costs, which could help reduce healthcare resource utilization following ADT in the treatment of PCa., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Understanding health care resource utilisation and its associated costs are important for identifying areas of improvement regarding resource allocations. However, there is limited research exploring this issue in the setting of Brugada syndrome (BrS).This was a retrospective territory-wide study of BrS patients from Hong Kong. Healthcare resource utilisation for accident and emergency (A&E), inpatient and specialist outpatient attendances were analyzed over a 19-year period, with their associated costs presented in US dollars. A total of 507 BrS patients with a mean presentation age of 49.9 ± 16.3 years old were included. Of these, 384 patients displayed spontaneous type 1 electrocardiographic (ECG) Brugada pattern and 77 patients had presented with ventricular tachycardia/ventricular fibrillation (VT/VF). At the individual patient level, the median annualized costs were $110 (52-224) at the (A&E) setting, $6812 (1982-32414) at the inpatient setting and $557 (326-1001) for specialist outpatient attendances. Patients with initial VT/VF presentation had overall greater costs in inpatient ($20161 [9147-189215] vs $5290 [1613-24937],P < 0.0001) and specialist outpatient setting ($776 [438-1076] vs $542 [293-972],P = 0.015) compared to those who did not present VT. In addition, patients without Type 1 ECG pattern had greater median costs in the specialist outpatient setting ($7036 [3136-14378] vs $4895 [2409-10554],p=0.019). There is a greater health care demand in the inpatient and specialist outpatient settings for BrS patients. The most expensive attendance type was inpatient setting stay at $6812 per year. The total median annualized cost of BrS patients without VT/VF presentation was 78% lower compared to patients with VT/VF presentation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The management of Brugada Syndrome (BrS) patients at intermediate risk of arrhythmic events remains controversial. The present study evaluated the predictive performance of different risk scores in an Asian BrS population and its intermediate risk subgroup. This retrospective cohort study included consecutive patients diagnosed with BrS from January 1, 1997 to June 20, 2020 from Hong Kong. The primary outcome is sustained ventricular tachyarrhythmias. Two novel risk risk scores and 7 machine learning-based models (random survival forest, Ada boost classifier, Gaussian naïve Bayes, light gradient boosting machine, random forest classifier, gradient boosting classifier and decision tree classifier) were developed. The area under the receiver operator characteristic curve (AUC) [95% confidence intervals] was compared between the different models. This study included 548 consecutive BrS patients (7% female, age at diagnosis: 50 ± 16 years, follow-up: 84 ± 55 months). For the whole cohort, the score developed by Sieira et al showed the best performance (AUC: 0.806 [0.747-0.865]). A novel risk score was developed using the Sieira score and additional variables significant on univariable Cox regression (AUC: 0.855 [0.808-0.901]). A simpler score based on non-invasive results only showed a statistically comparable AUC (0.784 [0.724-0.845]), improved using random survival forests (AUC: 0.942 [0.913-0.964]). For the intermediate risk subgroup (N = 274), a gradient boosting classifier model showed the best performance (AUC: 0.814 [0.791-0.832]). A simple risk score based on clinical and electrocardiographic variables showed a good performance for predicting VT/VF, improved using machine learning., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The presence of multiple comorbidities increases the risk of all-cause mortality, but the effects of the comorbidity sequence before the baseline date on mortality remain unexplored. This study investigated the relationship between coronary heart disease (CHD), atrial fibrillation (AF) and heart failure (HF) through their sequence of development and the effect on all-cause mortality risk in type 2 diabetes mellitus. Methods: This study included patients with type 2 diabetes mellitus prescribed antidiabetic/cardiovascular medications in public hospitals of Hong Kong between 1 January 2009 and 31 December 2009, with follow-up until death or 31 December 2019. The Cox regression was used to identify comorbidity sequences predicting all-cause mortality in patients with different medication subgroups. Results: A total of 249,291 patients (age: 66.0 ± 12.4 years, 47.4% male) were included. At baseline, 7564, 10,900 and 25,589 patients had AF, HF and CHD, respectively. Over follow-up (3524 ± 1218 days), 85,870 patients died (mortality rate: 35.7 per 1000 person-years). Sulphonylurea users with CHD developing later and insulin users with CHD developing earlier in the disease course had lower mortality risks. Amongst insulin users with two of the three comorbidities, those with CHD with preceding AF (hazard ratio (HR): 3.06, 95% CI: [2.60−3.61], p < 0.001) or HF (HR: 3.84 [3.47−4.24], p < 0.001) had a higher mortality. In users of lipid-lowering agents with all three comorbidities, those with preceding AF had a higher risk of mortality (AF-CHD-HF: HR: 3.22, [2.24−4.61], p < 0.001; AF-HF-CHD: HR: 3.71, [2.66−5.16], p < 0.001). Conclusions: The sequence of comorbidity development affects the risk of all-cause mortality to varying degrees in diabetic patients on different antidiabetic/cardiovascular medications.

Left ventricular non-compaction cardiomyopathy (LVNC) is a congenital heart disease with autosomal dominant inheritance. This review aims to summarize the existing data about the predictors of fatal arrhythmias in patients with LVNC. Medline and Cochrane library databases were searched from inception to November 2021 for articles on LVNC. The reference lists of the relevant research studies as well as the relevant review studies and meta-analyses were also searched. Clinical symptoms and electrocardiogram findings such as left bundle branch block are significantly associated with ventricular arrhythmias. Other non-invasive tools such as Holter monitoring, echocardiography, and cardiac magnetic resonance (CMR) can provide additional value for risk stratification. CMR-derived left and right ventricular ejection fraction, left ventricular end-diastolic diameter, late gadolinium enhancement, and non-compacted to compacted myocardium ratio are predictive of ventricular arrhythmias. An electrophysiological study can provide additional prognostic data in patients with LVNC who are at moderate risk of ventricular arrhythmias. Risk stratification of LVNC patients with no prior history of a fatal arrhythmic event remains challenging. Symptoms assessment, electrocardiogram, Holter monitoring, and cardiac imaging should be performed on every patient, while an electrophysiological study should be performed for moderate-risk patients. Large cohort studies are needed for the construction of score models for arrhythmic risk stratification purposes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Coronavirus Disease-2019 (COVID-19) vaccination has been associated with the development of carditis, especially in children and adolescent males. However, the rates of these events in the global setting have not been explored in a systematic manner. The aim of this systematic review and meta-analysis is to investigate the rates of carditis in children and adolescents receiving COVID-19 vaccines., Methods: PubMed, Embase and several Latin American databases were searched for studies. The number of events, and where available, at-risk populations were extracted. Rate ratios were calculated and expressed as a rate per million doses received. Subgroup analysis based on the dose administered was performed. Subjects ≤ 19 years old who developed pericarditis or myocarditis following COVID-19 vaccination were included., Results: A total of 369 entries were retrieved. After screening, 39 articles were included. Our meta-analysis found that 343 patients developed carditis after the administration of 12,602,625 COVID-19 vaccination doses (pooled rate per million: 37.76; 95% confidence interval [CI] 23.57, 59.19). The rate of carditis was higher amongst male patients (pooled rate ratio: 5.04; 95% CI 1.40, 18.19) and after the second vaccination dose (pooled rate ratio: 5.60; 95% CI 1.97, 15.89). In 301 cases of carditis (281 male; mean age: 15.90 (standard deviation [SD] 1.52) years old) reported amongst the case series/reports, 261 patients were reported to have received treatment. 97.34% of the patients presented with chest pain. The common findings include ST elevation and T wave abnormalities on electrocardiography. Oedema and late gadolinium enhancement in the myocardium were frequently observed in cardiac magnetic resonance imaging (CMR). The mean length of hospital stay was 3.91 days (SD 1.75). In 298 out of 299 patients (99.67%) the carditis resolved with or without treatment., Conclusions: Carditis is a rare complication after COVID-19 vaccination across the globe, but the vast majority of episodes are self-limiting with rapid resolution of symptoms within days. Central illustration. Balancing the benefits of vaccines on COVID-19-caused carditis and post-vaccination carditis., (© 2022. The Author(s).)

Context: Diabetes mellitus (DM) is associated with the development of pancreatic cancer (PaC), but few large-scale studies have examined its predictive risk factors., Objective: The present study aims to examine the predictors for PaC in patients with type 2 diabetes mellitus (T2DM) in a territory-wide, retrospective cohort study., Methods: This was a territory-wide, retrospective cohort study of patients with T2DM mellitus older than 40 years with no prior history of PaC. Baseline demographics, use of antidiabetic medications, comorbidities, and biochemical parameters were extracted. Cox regression was used to calculate hazard ratios (HR) with 95% CI. Subgroup analyses based on chronic kidney disease (CKD) stages were performed., Results: This study consisted of 273 738 patients (age = 65.4 ± 12.7 years, male = 48.2%, follow-up duration = 3547 ± 1207 days, disease duration = 4.8 ± 2.3 years), of whom 1148 developed PaC. The number of antidiabetic medications prescribed (HR: 1.20; 95% CI, 1.01-1.42; P = .040), diabetic microvascular complications (HR: 1.91; 95% CI, 1.30-2.81; P < .001), chronic kidney disease (HR: 1.81; 95% CI, 1.25-2.64; P = .002), use of acarbose (HR: 2.24; 95% CI, 1.35-3.74; P = .002), and use of glucagon-like peptide-1 receptor agonist (HR: 4.00; 95% CI: 1.28-12.53, P = .017) were associated with PaC development on multivariable Cox regression adjusting for the duration of DM, mean glycated hemoglobin A 1c , and history of pancreatic diseases. Stage 3A CKD or below was associated with PaC but not stage 3B or beyond., Conclusion: Diabetic microvascular complications, especially stage 1, 2, and 3A CKD, were associated with PaCs., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: This study examined the clinical characteristics, genetic basis, healthcare utilisation and costs of catecholaminergic ventricular tachycardia (CPVT) patients from a Chinese city., Methods: This was a territory-wide retrospective cohort study of consecutive CPVT patients at public hospitals or clinics in Hong Kong. Healthcare resource utilisation for accident and emergency (A&E), inpatient and outpatient attendances were analysed over 19 years (2001-2019) followed by calculations of annualised costs (in USD)., Results: Sixteen patients with a median presentation age (interquartile range (IQR) of 11 (9-14) years old) were included. Fifteen patients (93.8%) were initially symptomatic. Ten patients had both premature ventricular complexes (PVCs) and ventricular tachycardia/fibrillation (VT/VF). One patient had PVCs without VT/VF. Genetic tests were performed on 14 patients (87.5%). Eight (57.1%) tested positive for the ryanodine receptor 2 (RyR2) gene. Seven variants have been described elsewhere (c.14848G > A, c.12475C > A, c.7420A > G, c.11836G > A, c.14159T > C, c.10046C > T and c.7202G > A). c.14861C > G is a novel RyR2 variant not been reported outside this cohort. Patients were treated with beta-blockers (n = 16), amiodarone (n = 3) and verapamil (n = 2). Sympathectomy (n = 8) and implantable-cardioverter defibrillator implantation (n = 3) were performed. Over a median follow-up of 13.3 years (IQR: 8.4-18.1) years, six patients exhibited incident VT/VF. At the patient level, the median (IQR) annualised costs for A&E, inpatient and outpatient attendances were $ 66 (40-95), $ 10521 (5240-66887) and $ 791 (546-1105), respectively., Conclusions: All patients presented before the age of 19. The yield of genetic testing was 57%. The most expensive attendance type was inpatient stays, followed by outpatients and A&E attendances., Competing Interests: The authors declare no conflict of interest. Gary Tse, Tong Liu, and Sharen Lee are serving as the Guest Editors of this journal. We declare that Gary Tse, Tong Liu, and Sharen Lee have no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Konstantinos P. Letsas., (Copyright: © 2022 The Author(s). Published by IMR Press.)

Peripheral artery occlusive disease (PAOD) and deep vein thrombosis (DVT) can cause a variety of acute and chronic vascular complications and put patients at risk of subsequent sepsis. This study aimed to determine whether DVT compared with PAOD patients would increase the risk of sepsis. This study recruited 43,535 patients newly diagnosed as having PAOD and 6932 patients who were newly diagnosed as having DVT from a population of 2 million patients from the Longitudinal Health Insurance Database. Propensity score matching (PSM) between the PAOD and DVT groups was performed for age, sex, comorbidities, and prior antibiotic administration. A total of 4383 patients with PAOD and 4383 patients with DVT were analyzed for risk of sepsis. The incidence density of sepsis per 1000 person years for patients with PAOD was 25.75 (95% CI = 23.90 to 27.74) and 35.61 (95% CI = 33.29 to 38.09) for patients with DVT. After age, sex, associated comorbidities, and antibiotic administration were adjusted for, the risk of sepsis for the DVT group was 1.46-fold (95% CI = 1.32-1.62) higher than that for the PAOD group. In conclusion, patients with DVT were associated with a higher risk of subsequent sepsis than patients with PAOD. Aging was another risk factor.

Brugada syndrome (BrS) is a rare disorder characterized by coved or saddle-shaped ST-segment elevation in the right precordial leads on the electrocardiogram. Risk stratification in BrS remains challenging. A number of clinical, electrocardiographic, programmed ventricular stimulation and genetic risk factors have been identified as important predictors of future major arrhythmic events. There is a positive association between the number of risk factors and arrhythmic events. Hence, a multi-parametric approach would provide comprehensive risk assessment and more accurate risk stratification, assisting in therapeutic decisions making, including implantable cardioverter-defibrillator placement or identification of low-risk individuals. However, the extent to which each variable influences the risk and non-linear interactions between the different risk variables make risk stratification challenging. This paper aims to provide a focused review of the multi-parametric risk models for BrS risk stratification published in the literature., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cardiovascular diseases are one of the leading global causes of mortality. Currently, clinicians rely on their own analyses or automated analyses of the electrocardiogram (ECG) to obtain a diagnosis. However, both approaches can only include a finite number of predictors and are unable to execute complex analyses. Artificial intelligence (AI) has enabled the introduction of machine and deep learning algorithms to compensate for the existing limitations of current ECG analysis methods, with promising results. However, it should be prudent to recognize that these algorithms also associated with their own unique set of challenges and limitations, such as professional liability, systematic bias, surveillance, cybersecurity, as well as technical and logistical challenges. This review aims to increase familiarity with and awareness of AI algorithms used in ECG diagnosis, and to ultimately inform the interested stakeholders on their potential utility in addressing present clinical challenges., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2022.)

Ventricular arrhythmias (VAs) and sudden cardiac death (SCD) are significant adverse events that affect the morbidity and mortality of both the general population and patients with predisposing cardiovascular risk factors. Currently, conventional disease-specific scores are used for risk stratification purposes. However, these risk scores have several limitations, including variations among validation cohorts, the inclusion of a limited number of predictors while omitting important variables, as well as hidden relationships between predictors. Machine learning (ML) techniques are based on algorithms that describe intervariable relationships. Recent studies have implemented ML techniques to construct models for the prediction of fatal VAs. However, the application of ML study findings is limited by the absence of established frameworks for its implementation, in addition to clinicians' unfamiliarity with ML techniques. This review, therefore, aims to provide an accessible and easy-to-understand summary of the existing evidence about the use of ML techniques in the prediction of VAs. Our findings suggest that ML algorithms improve arrhythmic prediction performance in different clinical settings. However, it should be emphasized that prospective studies comparing ML algorithms to conventional risk models are needed while a regulatory framework is required prior to their implementation in clinical practice., Competing Interests: Competing interests The authors declare that they have no competing interests.

Global sea-level rise, the effect of climate change, poses a serious threat to rice production owing to saltwater intrusion and the accompanying increase in salt concentration. The reclaimed lands, comprising 22.1% of rice production in Korea, now face the crisis of global sea-level rise and a continuous increase in salt concentration. Here, we investigated the relationship between the decrease in seed quality and the transcriptional changes that occur in the developing rice seeds under salt stress. Compared to cultivation on normal land, the japonica rice cultivar, Samgwang, grown on reclaimed land showed a greatly increased accumulation of minerals, including sodium, magnesium, potassium, and sulfur, in seeds and a reduced yield, delayed heading, decreased thousand grain weight, and decreased palatability and amylose content. Samgwang showed phenotypical sensitivity to salt stress in the developing seeds. Using RNA-seq technology, we therefore carried out a comparative transcriptome analysis of the developing seeds grown on reclaimed and normal lands. In the biological process category, gene ontology enrichment analysis revealed that the upregulated genes were closely associated with the metabolism of biomolecules, including amino acids, carboxylic acid, lignin, trehalose, polysaccharide, and chitin, and to stress responses. MapMan analysis revealed the involvement of upregulated genes in the biosynthetic pathways of abscisic acid and melatonin and the relationship of trehalose, raffinose, and maltose with osmotic stress. Interestingly, many seed storage protein genes encoding glutelins and prolamins were upregulated in the developing seeds under salt stress, indicating the negative effect of the increase of storage proteins on palatability. Transcription factors upregulated in the developing seeds under salt stress included, in particular, bHLH, MYB, zinc finger, and heat shock factor, which could act as potential targets for the manipulation of seed quality under salt stress. Our study aims to develop a useful reference for elucidating the relationship between seed response mechanisms and decreased seed quality under salt stress, providing potential strategies for the improvement of seed quality under salt stress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Chung, Hong, Lee, Lee, Koh and Jung.)

Malignant mesothelioma is a neoplasm of serosal surfaces, most commonly affecting the pleura. The peritoneum, pericardium, and tunica vaginalis are less frequently involved. Malignant mesothelioma with EWSR1-ATF1 fusion in young adults was recently reported in the literature. Here, we present two pediatric cases of EWSR1-ATF1 translocation-associated malignant mesothelioma in the peritoneum and pericardium respectively. Both cases lacked a known exposure history. Microscopy in both cases showed predominantly epithelioid morphology with ample eosinophilic cytoplasm, and immunohistochemistry was positive for pan-keratin, calretinin, and WT1. Both cases showed EWSR1-ATF1 gene rearrangement by RNA sequencing, which was instrumental in confirming the diagnosis of malignant mesothelioma and to exclude more common pediatric sarcomas, especially in the context of limited sampling.

Salivary gland tumors represent a diverse group of neoplasms that occasionally pose a diagnostic challenge for pathologists, particularly with limited sampling. Gene fusions, which may reflect genetic drivers, are increasingly recognized in a subset of these neoplasms, and can be leveraged for diagnostic purposes. We performed a retrospective analysis on a cohort of 80 benign and malignant salivary gland tumors, enriched for subtypes known to harbor recurrent fusion events, to validate the diagnostic use of a targeted RNA sequencing assay to detect fusion transcripts. Testing identified fusion genes in 71% (24/34) of pleomorphic adenoma and carcinoma-ex-pleomorphic adenoma, with 56% of cases showing rearrangement of PLAG1 and 15% HMGA2. In addition to confirming known partners for these genes, novel PLAG1 fusion partners were identified, including DSTN, NTF3, and MEG3; CNOT2 was identified as a novel fusion partner for HMGA2. In adenoid cystic carcinoma, 95% of cases (19/20) were positive for a fusion event. MYB was rearranged in 60% (12/20), MYBL1 in 30% (6/20), and NFIB in 5% (1/20); two tumors exhibited novel fusion products, including NFIB-TBPL1 and MYBL1-VCPIP1. Fusion genes were identified in 64% (9/14) of cases of mucoepidermoid carcinoma; MAML2 was confirmed to partner with either CRTC1 (43%) or CRTC3 (21%). One salivary duct carcinoma was found to harbor a novel RAPGEF6-ACSL6 fusion gene. Finally, as anticipated, gene fusions were not detected in any of the five acinic cell carcinomas included in the cohort. In summary, targeted RNA sequencing represents a diagnostically useful ancillary technique for identifying a variety of existing, and novel, fusion transcripts in the classification of salivary gland neoplasms., (© 2021 Wiley Periodicals LLC.)

The classification of undifferentiated soft tissue tumors continues to evolve with the expanded application of molecular analysis in clinical practice. We report three cases of a unique soft tissue tumor in young children (5 months to 2 years old) displaying a purely fibromyxoid histology, with positive staining for desmin and CD34. In two cases, RNA sequencing detected a YWHAZ-PLAG1 gene fusion, while in the third case, a previously unreported EEF1A1-PLAG1 fusion was identified. PLAG1 fusions have been reported in several pathologic entities including pleomorphic adenoma, myoepithelial tumors of skin and soft tissue, and lipoblastoma, the latter occurring preferentially in young children. In these tumors, expression of a full length PLAG1 protein comes under the control of the constitutively active promoter of the partner gene in the fusion, and the current cases conform to that model. Overexpression of PLAG1 was confirmed by diffusely positive immunostaining for PLAG1 in all three cases. Our findings raise the possibility of a novel fibromyxoid neoplasm in childhood associated with these rare PLAG1 fusion variants. The only other report of a PLAG1-YWHAZ fusion occurred in a pediatric tumor diagnosed as a "fibroblastic lipoblastoma." This finding raises the possibility of a relationship with our three cases, even though our cases lacked any fat component. Further studies with regard to a shared pathogenesis are required., (© 2020 Wiley Periodicals LLC.)

Cadmium (Cd) is a non-essential metal with no known biological function and a broad range of toxic effects in biological systems. We used whole-transcriptome sequencing (RNA-seq) to study the effects of Cd 2+ toxicity in zebrafish liver cells, ZFL. The results of an RNA-Seq analysis of ZFL cells exposed to 5, 10 or 20 μM Cd 2+ for 4- or 24-h. The differentially expressed genes affected by Cd 2+ were analyzed by using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to study the regulated pathways. Cd 2+ regulated the expression of genes associated with cellular Cu, Zn, and Fe homeostasis, DNA replication leading to cell cycle arrest and apoptosis, and glutathione metabolism. Cd 2+ boosted up the amino acid synthesis, possibly to support the glutathione metabolism for tackling the oxidative stress generated from Cd 2+ . Cd 2+ stimulation was similar to heat or xenobiotics, based on the responses from ZFL such as endoplasmic reticulum stress and protein folding. We linked also those finding of gene activations relating to carcinogenesis of Cd. This paper provides a comprehensive analysis of the expression profiles induced by Cd 2+ exposure in ZFL cells, as well as useful insights into the specific toxic effects., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC patients with overexpressed or mutated epidermal growth factor receptor (EGFR) related to disease progression are treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Acquired drug resistance after TKI treatments has been a major focus for development of NSCLC therapies. This study aimed to establish afatinib-resistant cell lines from which afatinib resistance-associated genes are identified and the underlying mechanisms of multiple-TKI resistance in NSCLC can be further investigated. Nude mice bearing subcutaneous NSCLC HCC827 tumors were administered with afatinib at different dose intensities (5-100 mg/kg). We established three HCC827 sublines resistant to afatinib (IC 50 > 1 μM) with cross-resistance to gefitinib (IC 50 > 5 μM). cDNA microarray revealed several of these sublines shared 27 up- and 13 down-regulated genes. The mRNA expression of selective novel genes - such as transmembrane 4 L six family member 19 (TM4SF19), suppressor of cytokine signaling 2 (SOCS2), and quinolinate phosphoribosyltransferase (QPRT) - are responsive to afatinib treatments only at high concentrations. Furthermore, c-MET amplification and activations of a subset of tyrosine kinase receptors were observed in all three resistant cells. PHA665752, a c-MET inhibitor, remarkably increased the sensitivity of these resistant cells to afatinib (IC 50 = 12-123 nM). We established afatinib-resistant lung cancer cell lines and here report genes associated with afatinib resistance in human NSCLC. These cell lines and the identified genes serve as useful investigational tools, prognostic biomarkers of TKI therapies, and promising molecule targets for development of human NSCLC therapeutics., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Sunscreen chemicals, such as benzophenones (BPs), are common environmental contaminants that are posing a growing health concern due to their increasing presence in water, fish, and human systems. Benzoresorcinol (BP1), oxybenzone (BP3), and dioxybenzone (BP8) are the most commonly used BPs for their ability to protect from sunburn by absorbing a broad spectrum of ultraviolet radiation. In this study, zebrafish larvae were used as an in vivo model to investigate the potential risks and molecular mechanisms of the toxic effects of BPs. The effects of these BPs on the gene expression in the aryl hydrocarbon receptor pathway, estrogen receptor pathway, and sex differentiation were detected using quantitative real-time PCR. All BPs were found to function as agonists of the estrogen receptors α and β1, indicating that these BPs likely undergo similar molecular metabolism in vivo, whereby they can activate cytochrome P450 genes and promote the expression of CYP19A and DMRT1. Furthermore, the gene expression profile of larvae after BP3 exposure was evaluated using a whole transcriptome sequencing approach. BP3 affected estradiol biosynthesis and sex differentiation. It also regulated gonadotropin-releasing hormone, thus interfering with the endocrine system. As a xenobiotic toxicant, BP3 upregulated the expression of cytochrome P450 genes (CYP1A and CYP3A65) and glutathione metabolism-related genes (GSTA, GSTM, and GSTP). It also interfered with the nervous system by regulating the calcium signaling pathway. These findings will be useful for understanding the toxicity mechanisms and metabolism of BPs in aquatic organisms and promote the regulation of these chemicals in the environment., Competing Interests: Declaration of competing interest We declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The clinical and economical value of routine submission of hernia sacs for pathological examination and scheduled clinic follow-ups after inguinal hernia and hydrocele repair has been questioned. Herein, we assessed the institutional variability in these routine practices., Methods: We retrospectively reviewed patients who underwent unilateral or bilateral inguinal hernia and/or hydrocele repair, open or laparoscopically, at our institution from 2015 to 2018., Results: 1181 patients were included (1074 inguinal hernias and 157 hydroceles). Of 531 specimens obtained from 446 (38%) patients, 515 (97%) were normal. 16 (3%) abnormal pathological findings included 7 with mesothelial hyperplasia, 5 with nonfunctional genital ductal remnants, 3 with ectopic adrenal cortical tissues, and 1 epidydimal structure which was not recognized at the time of surgery. 418 (35%) patients had scheduled clinic follow-ups 65 (IQR 46-94) days postoperatively. 44 (4%) patients with unexpected postoperative Emergency Department visits within 30 days of surgery were identified. Only one patient required inpatient treatment, and the rest did not require intervention or admission. The total direct cost of analyzing specimens during the study period was $30,798 CAD ($10,266/year). The average cost to detect a potentially significant finding was $1924.88/specimen and $2053.20/patient., Conclusions: Routine pathological examination of hernia sacs and scheduled clinic follow-ups were associated with significant costs and predominantly nonsignificant findings. They should therefore be reserved for patients with a high clinical suspicion of injuries/abnormalities or risk factors for potential complications., Level of Evidence: This is a level III evidence study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Whereas neuroblastoma is the most common extracranial solid tumor of childhood, less than 5% of cases occur in adults. Pediatric neuroblastoma shows marked heterogeneity of histology and molecular biology. Information about this tumor in adults is limited, especially regarding molecular biology. We report a series of nine neuroblastoma cases diagnosed in adulthood (18 to 40 years old) with molecular biologic characterization in seven. All tumors were Schwannian stroma-poor, and mostly poorly differentiated. Tumors expressed neural markers including PHOX2B, NB84, synaptophysin, chromogranin, CD56, neuron-specific enolase, and PGP9.5. Two out of six cases expressed ALK and one had the F1174 L mutation reported in childhood neuroblastoma. Fluorescent in situ hybridization (FISH) revealed MYCN amplification in 2/7 cases, chromosome 1p deletion in 1/5 cases and 17q gain in 4/4 cases. One in five cases showed loss of ATRX expression by immunohistochemistry and alternate lengthening of telomeres by FISH. Zero out of five cases showed rearrangement of the TERT gene by FISH, but one case showed high level amplification. In conclusion, the morphology and immunophenotype of adult-onset neuroblastoma are similar to pediatric cases although less differentiated than some childhood tumors. Similarly, molecular genetic alterations in adult-onset neuroblastoma are not unique to this age group. However, 80% of cases tested showed genetic changes that would promote maintenance of telomeres, which is a molecular marker of high risk cases. This may help explain the poor response in adults to pediatric treatment protocols. Additional studies to characterize the biology of this tumor in the adult age group will facilitate the design of more personalized therapeutic approaches., (© 2019 Wiley Periodicals, Inc.)

Alveolar soft part sarcoma (ASPS) is a rare malignancy that, since its initial description, remains a neoplasm of uncertain histogenesis. The disease-defining molecular event characterizing the diagnosis of ASPS is the ASPSCR1-TFE3 fusion gene. Following identification of an index case of ASPS with a novel TFE3 fusion partner, we performed a retrospective review to determine whether this represents an isolated event. We identified two additional cases, for a total of three cases lacking ASPSCR1 partners. The average patient age was 46 years (range, 17-65); two patients were female. The sites of origin included the transverse colon, foot, and dura. Each case exhibited a histomorphology typical of ASPS, and immunohistochemistry was positive for TFE3 in all cases. Routine molecular testing of the index patient demonstrated a HNRNPH3-TFE3 gene fusion; the remaining cases were found to have DVL2-TFE3 or PRCC-TFE3 fusion products. The latter two fusions have previously been identified in renal cell carcinoma; to our knowledge, this is the first report of a HNRNPH3-TFE3 gene fusion. These findings highlight a heretofore underrecognized genetic diversity in ASPS, which appears to more broadly molecularly overlap with that of translocation-associated renal cell carcinoma and PEComa. These results have immediate implications in the diagnosis of ASPS since assays reliant upon ASPSCR1 may yield a false negative result. While these findings further understanding of the molecular pathogenesis of ASPS, issues related to the histogenesis of this unusual neoplasm remain unresolved., (© 2019 Wiley Periodicals, Inc.)

Congenital neuroblastoma with placental involvement is exceptionally rare, but mortality is high. Detailed examination of placenta including MYCN amplification and segmental chromosomal aberrations should be performed in all suspected cases, as it is noninvasive and readily available. Maternal dissemination has not been reported. In this manuscript, we describe an infant with placental diagnosis of MYCN nonamplified congenital neuroblastoma. This is the first report of a recurrence of congenital 4S neuroblastoma following resolution in which MYCN amplification is only detected in the recurrence. Germline sequencing using a large comprehensive cancer panel did not reveal variants in candidate cancer predisposition genes.

Spitzoid neoplasms typically affect young individuals and include Spitz nevus, atypical Spitz tumor, and Spitzoid melanoma. Spitz tumors can exhibit gene fusions involving the receptor tyrosine kinases NTRK1, NTRK3, ALK, ROS1, RET, or MET, or the serine-threonine kinase BRAF. Because most studies have been based on adult cases, we studied ALK fusions in Spitz nevi occurring in pediatric patients. Twenty-seven cases were screened for ALK expression by immunohistochemistry, and 6 positive cases were identified. These cases were studied further using the TruSight RNA Fusion Panel, and in 4 cases, exon 20 of the ALK gene was found to be fused to exon 14 of the MLPH (melanophilin) gene, a gene fusion that has only been reported in a Spitz nevus in an adult. The remaining 2 cases showed no fusion of ALK with any gene. The cases with the MLPH-ALK fusion showed a similar histology to that described for Spitz nevi with ALK fusions, with spindle-shaped and epithelioid melanocytes in fusiform nests with a plexiform growth pattern and infiltrative border. We created a breakapart fluorescence in situ hybridization assay for MLPH, and all 4 cases with the MLPH-ALK fusion were positive, whereas the other 23 cases in the study were negative. Thus, ALK and MLPH were fused only to each other in our series. Melanophilin is part of the melanosome trafficking apparatus together with MYO5a, TPM3, and RAB27a, all constitutively expressed in melanocytes. Kinase fusions involving MYO5A and TPM3 have been reported in Spitz tumors, and our series adds MLPH to this group., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The aims of this study were to identify the clinical characteristics of an anastomotic sinus and to assess the validity of delaying stoma closure in patients until the complete resolution of an anastomotic sinus., Methods: The subject patients are those who had undergone a resection of rectal cancer from 2011 to 2017, who had a diversion ileostomy protectively or therapeutically and who developed a sinus as a sequelae of anastomotic leakage. The primary outcomes that were measured were the incidence, management and outcomes of an anastomotic sinus., Results: Of the 876 patients who had undergone a low anterior resection, 14 (1.6%) were found to have had an anastomotic sinus on sigmoidoscopy or a gastrografin enema before their ileostomy closure. In the 14 patients with a sinus, 7 underwent ileostomy closure as scheduled, with a mean closure time of 4.1 months. The remaining 7 patients underwent ileostomy repair, but it was delayed until after the follow-up for the widening of the sinus opening by using digital dilation, with a mean closure time of 6.9 months. Four of those remaining seven patients underwent stoma closure even though their sinus condition had not yet been completely resolved. No pelvic septic complications occurred after closure in any of the 14 patients with an anastomotic sinus, but 2 of the 14 needed a rediversion due to a severe anastomotic stricture., Conclusion: Patients with an anastomotic sinus who had been carefully selected underwent successful ileostomy closure without delay.

Hepatoblastoma is the most common hepatic malignancy of childhood with known genetic predispositions and perinatal risk factors, with rare case reports occurring in the setting of cirrhosis. This case describes a young patient with cirrhosis attributed to early-onset hereditary hemochromatosis who was diagnosed with hepatoblastoma with uncommon histologic findings, evidence of chemotherapy resistance who ultimately succumbed to her disease. It is important to consider diagnoses beyond hepatocellular carcinoma in this scenario and consider early biopsy. With atypical histology, the tumor may respond poorly to conventional treatment and aggressive surgery or intensive therapy should be contemplated.