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We conducted a retrospective population-based, matched cohort study using the National Health Insurance Research Database to estimate healthcare resource utilisation (HRU) and costs in patients with newly diagnosed AL amyloidosis in Taiwan. Cases were matched 10:1 by age, sex, and area of residence to patients without AL amyloidosis (comparators) randomly selected from the database during the same time period. Annual all-cause HRU and costs for 3 years were quantified. AL amyloidosis-attributable costs were obtained by subtracting all-cause HRU costs incurred by comparators from cases. The mean age of all patients was 60.78 years and 59.07% were male. Co-morbidities were more frequent in cases than comparators. By 6 months after diagnosis, 12.1% of cases had died versus 0.9% of comparators. In the first year, cases had 103% more outpatient visits, 177% more emergency room visits, were hospitalised 4-times more frequently, and spent 5.5-times more days in hospital than comparators, and total healthcare costs were > sixfold higher. Costs incurred during the first year after diagnosis accounted for 55% of the 3-year cumulative cost. High HRU costs associated with delayed diagnosis and end-organ damage indicate a need for earlier diagnosis and more effective treatments for AL amyloidosis., (© 2024. The Author(s).)

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.

Background: We conducted a nationwide population-based case-control study to analyse potential predisposing factors for hearing loss (HL) that present during the fetal, perinatal, and postnatal periods in prematurely born children., Methods: This study enrolled 21,576 children born at < 37 weeks of gestation; 3,596 with HL and 17,980 with normal hearing born between 2002 and 2015, matched for sex, age at diagnosis, and enrollment time. Data were abstracted from the concatenation of three nationwide databases for overall risk factors till the diagnosis of HL., Results: Maternal HL, maternal diabetes, particularly type 1 diabetes mellitus, and at or before 32 weeks of gestation were the major obstetric risk factors for HL. Prematurely born children who were born via cesarean section and received a combination of antenatal steroids and magnesium sulfate exhibited a significantly reduced risk of developing HL. Ear malformation was a critical predictor for HL. The major postnatal risk factors included seizure and ototoxic drugs use. Premature infants diagnosed with more than 1 diagnosis of bronchopulmonary dysplasia, necrotizing enterocolitis, and intracerebral hemorrhage were at an increased risk of developing HL. Congenital CMV infection and recurrent acute otitis were also independent postnatal factors for HL in prematurely born children., Conclusion: To reduce the incidence of childhood HL in prematurely born children, aggressive management of premature birth-related consequences and treatable causes and longitudinal audiological follow-up with early detection and adequate intervention are crucial., Competing Interests: Declaration of competing interest No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

The link between neonatal jaundice and urinary tract infection (UTI) remains debated, with congenital kidney and urinary tract anomalies (CAKUT) potentially playing a role. This population-based study aimed to analyze the correlations between neonatal jaundice, CAKUT, and concomitant UTI. The study cohort consisted of 2,078,122 live births from 2004 to 2014. We linked several population-based datasets in Taiwan to identify infants with unexplained neonatal jaundice and their mothers. The primary outcome was the rate of CAKUT occurring within 3 years after delivery, and the presence of concomitant UTI during neonatal jaundice hospitalization. Infants with neonatal jaundice had a significantly higher risk of CAKUT (adjusted odds ratio [aOR] 1.24, 95% confidence interval [CI] 1.11-1.39) during early childhood. Among the subtypes of CAKUT, obstructive uropathy, vesicoureteral reflux and other CAKUT were associated with an increased risk of neonatal jaundice. Infants who underwent intensive phototherapy, had a late diagnosis (> 14 days of postnatal age) or underwent a prolonged duration of phototherapy (> 3 days) exhibited a higher risk of concomitant UTI compared to other infants with jaundice. Our findings indicate a notable association between neonatal jaundice and increased risks of UTIs in the context of CAKUT. This study underscore the importance of vigilant monitoring and timely interventions for neonates presenting with jaundice, while acknowledging the complexity and variability in the progression of CAKUT and its potential connection to UTIs., (© 2024. The Author(s).)

Aim: Estimate patient counts, treatment patterns and outcomes of a subset of patients with early breast cancer (EBC) presenting with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive features, who are at high-risk of recurrence, in Taiwan. Materials & methods: Data from Taiwan's National Health Insurance Research Database and Taiwan Cancer Registry from 1 January 2011 to 31 December 2020 were analyzed. Results: There were 4500 patients with high-risk EBC (10.4% of all patients with EBC) from 2012 to 2018, with an annual average incidence of 643 that increased over time. Five-year progression was 24.8% in patients with high-risk EBC and 8-year survival was low (69.6%). Conclusion: Patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive high-risk EBC clinical features are an increasing high-risk subset of all patients with EBC.

Background: We estimated healthcare resource utilization (HRU) and costs in patients with generalized myasthenia gravis (gMG) in Taiwan., Methods: This retrospective population-based, matched cohort study used the National Health Insurance Research Database to identify prevalent patients with gMG (cases) in 2019. In total, 2537 cases were matched (1:4) by age, sex, and urbanization level to 10148 randomly selected patients without gMG (comparators). A generalized linear regression model predicted the frequency of HRU and costs among service users. Costs attributable to gMG were obtained by subtracting all-cause HRU costs incurred by comparators from cases., Results: The mean age of all patients was 54.99 years and 55.97% were female. Compared with comparators, cases had significantly higher rates of hypertension (33.03%/24.26%), diabetes mellitus (18.92%/11.37%), malignancies (16.00%/4.08%), cardiovascular disease (11.35%/8.12%), thyroid-related conditions (5.99%/1.16%), respiratory illness/disorders (4.38%/1.22%), and neurotic disorders (4.65%/2.6%). Amongst users of healthcare resources, cases had a mean 10 additional outpatient visits, 0.62 inpatient stays, and 0.49 emergency room visits in 2019 compared with comparators ( p  < 0.0001 for all). The mean (standard deviation) difference in all-cause healthcare costs between cases and comparators was NT$ 94997 (76431) [US$ 3133 (2521)], and was significantly higher for all categories (outpatient, inpatient, emergency room, drugs; p  < 0.0001 for all). Among employed persons, 13.18%/7.59% of cases/comparators changed employment status during the study ( p  < 0.0001)., Conclusion: gMG presents a substantial burden on HRU and healthcare costs in Taiwan. A high attrition rate from full-time employment suggests additional societal costs. Improved treatments are needed to alleviate the burden of disease on individuals, healthcare systems, and economies., Competing Interests: KH is an employee of Janssen Asia Pacific and YL is an employee of Epidemiology, Office of the Chief Medical Officer, Johnson & Johnson. KH and YL hold stock in Johnson & Johnson. The remaining 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 © 2023 Shen, Herr, Liu, Yang and Tang.)

Background: The prevalence of myasthenia gravis is increasing in many countries, including Asia. As treatment options expand, population-based information about the disease burden can inform health technology assessments., Methods: We conducted a population-based retrospective cohort study using the Taiwan National Healthcare Insurance Research database and Death Registry to describe the epidemiology, disease burden and treatment patterns of generalized myasthenia gravis (gMG) from 2009 to 2019. Episodes of hepatitis B virus (HBV) infection or reactivation were explored., Results: The number of patients with gMG increased from 1,576 in 2009 to 2,638 in 2019 and the mean (standard deviation) age from 51.63 (17.32) to 55.38 (16.29) years. The female:male ratio was 1.3:1. Frequently reported co-morbidities were hypertension (32-34% of patients), diabetes mellitus (16-21%) and malignancies (12-17%). The prevalence of patients with gMG increased annually from 6.83/100,000 population in 2009 to 11.18/100,000 population in 2019 ( p  < 0.0001). There was no temporal trend in all-cause fatality rates (range 2.76-3.79/100 patients annually) or gMG incidence rates (2.4-3.17/100,000 population annually). First-line treatment was with pyridostigmine (82%), steroids (58%), and azathioprine (11%). There was minimal change in treatment patterns over time. Among 147 new HBV infections, 32 (22%) received ≥4 weeks of antiviral therapy suggesting chronic infection. The HBV reactivation rate was 7.2%., Conclusion: The epidemiology of gMG in Taiwan is evolving rapidly, with higher prevalence rates and increasing involvement of older age-groups suggesting a growing burden of disease and associated healthcare costs. HBV infection or reactivation may pose a previously unrecognized recognized risk for patients with gMG receiving immunosuppressants., Competing Interests: KH is an employee of Janssen Asia Pacific. YL is an employee of Epidemiology, Office of the Chief Medical Officer, Johnson and Johnson. KH and YL hold stock in Johnson & Johnson. The authors declare that this study received funding from Janssen Asia Pacific, a division of Johnson and Johnson Pte Ltd. The funder was involved in the study design and provided medical writing support. The funder was not involved in collection, analysis, interpretation of data or the decision to submit it for publication., (Copyright © 2023 Herr, Shen, Liu, Yang and Tang.)

The incidence rate of AL (light-chain) amyloidosis is not known in Asia. We conducted a retrospective cohort study using the Taiwan National Healthcare Insurance Research database and Death Registry to estimate incidence and all-cause case fatality rates, and characteristics of patients with AL amyloidosis in Taiwan. All patients with confirmed, newly diagnosed AL amyloidosis from 01-Jan-2016 until 31-Dec-2019 were enrolled and followed up until dis-enrolment, death or study end (31-Dec-2019). There were 841 patients with newly diagnosed AL amyloidosis with median age of 61.4 years and 58.7% were men. At diagnosis, cardiac, renal and liver-related diseases were present in 28.54%, 23.19% and 2.14% of patients, respectively. AL amyloidosis age-adjusted annual incidence was 5.73 per million population in 2016 and 5.26 per million population in 2019. All-cause case fatality ranged from 1.7 to 2.9% over the study period and was highest (~10%) in patients ≥ 80 years. Survival was significantly lower in patients with co-morbid cardiac, renal, or liver-related diseases which could indicate organ involvement. The incidence of AL amyloidosis in Taiwan appears to be similar to Western countries. The poor prognosis in patients with co-morbid diseases highlights the need for earlier diagnosis., (© 2022. The Author(s).)

Background/purpose: To evaluate whether a shorter length (20 cm) of C-UCM has potential benefits, compared to immediate cord clamping (ICC), in very preterm babies., Methods: Inborn preterm infants less than 30 weeks of gestational age (GA) were randomly assigned to the 20-cm C-UMC and ICC groups. The primary outcome was the need for packed red blood cell (pRBC) transfusion before the 21st day of life. The secondary outcomes were short- and long-term outcomes related to premature birth., Results: Seventy-six neonates were randomized to the two groups. GA were 27.2 ± 1.8 and 27.5 ± 1.7 weeks (p = 0.389) and birth weights were 987 ± 269 and 1023 ± 313 g (p = 0.601) in the 20-cm C-UCM and ICC groups, respectively. There was no significant difference between the groups in terms of the need for pRBC transfusion before the 21st day of life (59.4% versus 71.8%, adjusted odds ratio [aOR] 0.311, 95% confidence interval [CI] 0.090-1.079). An increased prevalence of late-onset sepsis was observed in the 20-cm C-UCM group compared to the ICC group (21.6% versus 5.1%, aOR 5.434, 95% CI 1.033-23.580). The mortality rates were 13.5% and 2.6% in the 20-cm C-UCM and ICC groups, respectively (aOR 5.339, 95% CI 0.563-50.626). The neurodevelopmental outcomes at 2 years of corrected age between the groups were also not statistically significant., Conclusion: A 20-cm C-UCM showed no effect on reducing the incidence of pRBC transfusion in preterm babies with GA less than 30 weeks compared with ICC in this small-scale randomized controlled trial., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

Prime editing enables the installation of virtually any combination of point mutations, small insertions or small deletions in the DNA of living cells. A prime editing guide RNA (pegRNA) directs the prime editor protein to the targeted locus and also encodes the desired edit. Here we show that degradation of the 3' region of the pegRNA that contains the reverse transcriptase template and the primer binding site can poison the activity of prime editing systems, impeding editing efficiency. We incorporated structured RNA motifs to the 3' terminus of pegRNAs that enhance their stability and prevent degradation of the 3' extension. The resulting engineered pegRNAs (epegRNAs) improve prime editing efficiency 3-4-fold in HeLa, U2OS and K562 cells and in primary human fibroblasts without increasing off-target editing activity. We optimized the choice of 3' structural motif and developed pegLIT, a computational tool to identify non-interfering nucleotide linkers between pegRNAs and 3' motifs. Finally, we showed that epegRNAs enhance the efficiency of the installation or correction of disease-relevant mutations., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The extrauterine growth restriction (EUGR) of very preterm infants has been associated with long-term complications and neurodevelopmental problems. EUGR has been reported at higher rates in low resource settings. There is limited research investigating how metropolitan human milk banks contribute to the growth outcomes of very preterm infants cared in rural areas. The setting of this study is located at a rural county in Taiwan and affiliated with the Taiwan Southern Human Milk Bank. Donor human milk was provided through a novel supplemental system. A renewal nutritional protocol was initiated as a quality improvement project after the affiliated program. This study aimed to compare the clinical morbidities and growth outcome at term equivalent age (TEA) of preterm infants less than 33 weeks of gestational age before (Epoch-I, July 2015-June 2018, n = 40) and after the new implementation (Epoch-II, July 2018-December 2020, n = 42). The Epoch-II group significantly increased in bodyweight z-score at TEA ((-0.02 ± 1.00) versus Epoch-I group (-0.84 ± 1.08), p = 0.002). In multivariate regression models, the statistical difference between two epochs in bodyweight z-score changes from birth to TEA was still noted. Modern human milk banks may facilitate the nutritional protocol renewal in rural areas and improve the growth outcomes of very preterm infants cared for. Establishing more distribution sites of milk banks should be encouraged.

Background: Long-acting injectable (LAI) antipsychotics improve medication adherence in patients with schizophrenia and extend the duration of therapeutic drug levels but with administration of an increased dose. Real-world mortality data in patients prescribed LAIs are lacking. We conducted a population-based cohort study to estimate and compare the incidence rates of all-cause death and completed suicide in patients with schizophrenia/schizoaffective disorder exposed to LAIs and oral antipsychotics., Methods: Patients with a diagnosis of schizophrenia/schizoaffective disorder between January 1, 2015 and November 30, 2019 were enrolled from the Taiwan National Health Insurance Research Database and linked to Death Registry records. Eligible patients were new antipsychotic users. Relative risks of death for each antipsychotic compared with oral paliperidone were evaluated using a Cox proportional hazard model adjusted for age, sex, Charlson Comorbidity Index, index year, bipolar or major depressive or other mood disorders, mental disorders due to drug use, and baseline hospitalization frequency., Results: There were 228,791.08 person-years of follow-up (mean 2.48 years). The incidence rates of all-cause death in users of LAI paliperidone administered monthly (PP1M) and every 3 months (PP3M) were 7.40/1,000 person-years (95% confidence interval 5.94-9.11) and 9.93 (5.88-15.79), respectively. The incidences of completed suicide were 2.03/1,000 person-years (1.32-2.99) and 3.10 (1.14-6.88), respectively. No significant associations were observed between PP1M and PP3M compared to oral paliperidone in incidences of all-cause death or for completed suicide., Discussion: No increased risk of all-cause death or completed suicide was observed in users of antipsychotic LAIs, including PP1M and PP3M.

Background: Neurosurgical treatment of severe bilateral occipital lobe epilepsy usually involves two operations several mos apart., Aim: To evaluate surgical resection of bilateral occipital lobe lesions during a single operation as a treatment for bilateral occipital lobe epilepsy., Methods: This retrospective case series included patients with drug-refractory bilateral occipital lobe epilepsy treated surgically between March 2006 and November 2015., Results: Preoperative evaluation included scalp video-electroencephalography (EEG), magnetic resonance imaging, and PET-CT. During surgery (bilateral occipital craniotomy), epileptic foci and important functional areas were identified by EEG (intracranial cortical electrodes) and cortical functional mapping, respectively. Patients were followed up for at least 5 years to evaluate treatment outcome (Engel grade) and visual function. The 20 patients (12 males) were aged 4-30 years (median age, 12 years). Time since onset was 3-20 years (median, 8 years), and episode frequency was 4-270/mo (median, 15/mo). Common manifestations were elementary visual hallucinations (65.0%), flashing lights (30.0%), blurred vision (20.0%) and visual field defects (20.0%). Most patients were free of disabling seizures (Engel grade I) postoperatively (18/20, 90.0%) and at 1 year (18/20, 90.0%), 3 years (17/20, 85.0%) and ≥ 5 years (17/20, 85.0%). No patients were classified Engel grade IV (no worthwhile improvement). After surgery, there was no change in visual function in 13/20 (65.0%), development of a new visual field defect in 3/20 (15.0%), and worsening of a preexisting defect in 4/20 (20.0%)., Conclusion: Resection of bilateral occipital lobe lesions during a single operation may be applicable in bilateral occipital lobe epilepsy., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To investigate the effects of improved perioperative sleep on pain, analgesic consumption, and postoperative nausea and vomiting (PONV) in patients who were undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA)., Methods: Original studies published from 1 January 1970 to 30 September 2020 were queried in three unique databases using a common search term. The searches sought randomized controlled trials (RCT) investigating the effectiveness of sleep quality or quantity interventions for pain control early after TKA or THA. Grey literature was also searched by screening trial registers. There was no limitation on published language and patients. Two reviewers then assessed studies for eligibility. Eligible studies should have primary outcomes including perioperativeWe have comfirmed the edits. visual analogue scale (VAS) pain score and analgesic consumption; and secondary outcomes including side effects, such as PONV. Data extracted from the literature were abstracted into a comma-separated database spreadsheet using Microsoft Excel. A meta-analysis was then performed. Pooled statistics were calculated with weighting by inverse variance assuming a random effect model. I 2 was calculated as a quantifier of heterogeneity and interpreted according to the Cochrane manual. All data analysis was performed using Revman software., Results: From a total of 1285 potential records identified in the electronic search, six studies eventually fulfilled the eligibility criteria. The six controlled RCTs consisted of 207 patients in the sleep-improving group and 209 patients in the control group. The severity of rest pain was significantly lower in the sleep-improving group compared with the control group at day 1 and day 3 postoperatively; the severity of active pain was significantly lower in the sleep-improving group compared with the control group at day 3 postoperatively. Data concerning analgesic drugs could not undergo a meta-analysis due to the difference of eligible studies. No significant difference was found in the incidence of PONV between the sleep-improving group and the control group., Conclusion: Improved perioperative sleep, regardless of quality or quantity, could significantly reduce the pain level at the early stage after TKA or THA, thus the total amount of analgesic drugs consumed was decreased, without significant increase in the incidence of PONV., (© 2021 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Objective: Antipsychotic agents can increase circulating serum prolactin levels, potentially leading to osteoporosis and increased risk of bone fracture. The risk appears to be lower for atypical antipsychotics. We investigated whether risperidone was associated with an increased fracture risk by estimating the incidence of hip/femur and non-hip/femur fractures in users of risperidone, other atypical, and typical antipsychotics., Methods: This retrospective cohort study with a nested case-control study used claims data from the Taiwan National Healthcare Insurance database. All new users of antipsychotics between 2000-2012 were included. Incident fractures were identified using ICD-9 codes from inpatient records. Cox proportional hazards models compared fracture incidence among exposure groups. Conditional logistic regression models compared antipsychotic exposure among fracture cases versus matched controls., Results: 340,948 patients were included in the analysis. There were 2832 hip/femur fractures and 2693 non-hip/femur fractures: Hip/femur fracture incidence 636.8/100,000 person-years (Risperidone), 885.7/100,000 person-years (Other Atypical), 519.4/100,000 person-years (Typical). The adjusted hazard ratio of hip/femur fracture was 0.92 (95%CI 0.84-1.01) comparing Other Atypical with Risperidone, and 1.00 (95%CI 0.89-1.11) comparing Typical with Risperidone. The adjusted hazard ratio of non-hip/femur fracture was 1.08 (95%CI 0.98-1.20) for Other Atypical versus Risperidone, and 1.10 (95%CI 0.99-1.22) for Typical versus Risperidone. The adjusted odds ratio for hip/femur fractures was 0.92 (95% CI 0.83-1.01) in cases and controls exposed to other atypical antipsychotics compared with risperidone for 1 year prior to fracture date, 0.97 (95% CI 0.87-1.07) during 1-3 years, and 0.92 (95% CI 0.81-1.06) during 3-5 years prior to fracture date. The adjusted odds ratio for non-hip/femur fractures were 1.11 (95% CI 0.99-1.24), 1.02 (95% CI 0.0.91-1.14), and 0.95 (95% CI 0.82-1.09), respectively., Conclusion: There was no increased risk of bone fracture in long-term users of risperidone compared to users of other atypical antipsychotics., Competing Interests: HQ, MS and YL are employees of Janssen Research & Development, Johnson and Johnson, Pte Ltd., which manufactures and markets risperidone. HQ and YL report stock ownership in Johnson and Johnson. SPS and FHCC received grants from Janssen Research Development for the submitted work and consulting fees from Janssen Research & Development. This does not alter the authors' adherence to PLOS ONE policies on sharing data and material. HCW, KYT and WML declare no conflicts of interest.

Background: The long-term predicted value of microvolt T-wave alternans (MTWA) for ventricular tachyarrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains unclear. Our study explored the characteristics of MTWA and its prognostic value when combined with an electrophysiologic study (EPS) in patients with ARVC., Methods: All patients underwent non-invasive MTWA examination with modified moving average (MMA) analysis and an EPS. A positive event was defined as the first occurrence of sudden cardiac death, documented sustained ventricular tachycardia (VT), ventricular fibrillation, or the administration of appropriate implantable cardioverter defibrillator therapy including shock or anti-tachycardia pacing., Results: Thirty-five patients with ARVC (age 38.6 ± 11.0 years; 28 males) with preserved left ventricular (LV) function were recruited. The maximal TWA value (MaxValt) was 17.0 (11.0-27.0) μV. Sustained VT was induced in 22 patients by the EPS. During a median follow-up of 99.9 ± 7.7 months, 15 patients had positive clinical events. When inducible VT was combined with the MaxValt, the area under the curve improved from 0.739 to 0.797. The receiver operating characteristic curve showed that a MaxValt of 23.5 μV was the optimal cutoff value to identify positive events. The multivariate Cox regression model for survival showed that MTWA (MaxValt, hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.01-1.11; P = 0.01) and inducible VT (HR, 5.98; 95% CI, 1.33-26.8; P = 0.01) independently predicted positive events in patients with ARVC., Conclusions: MTWA assessment with MMA analysis complemented by an EPS might provide improved prognostic ability in patients with ARVC with preserved LV function during long-term follow-up.

To determine the natural history of patient with bilateral vocal fold immobility (BVFI), and to identify the factors or predictors associated with the tracheostomy and duration of cannulation for those who require tracheostomy.A retrospective review was carried out at a single tertiary referral center over a 23-year period of infants less than 1 year old who presented with BVFI. All information related to sex, etiology, gestational age at birth, vocal fold (VF) position at diagnosis, presence of concomitant airway disease, age at attainment of VF movement, age at decannulation, and current tracheostomy status were recorded to perform descriptive and comparative analyses.Forty-one patients were enrolled, and the tracheostomy rate was 80.5% (33/41). Those with a median VF position had a higher rate of tracheostomy in comparison with those with a paramedian VF position (P = .003). Among patients who underwent tracheostomy, 77.4% (24/31) were eventually decannulated. The median duration of cannulation was 4.4 years (range: 0.8 - 10.7 years). Those who were found to have attainment of VF movement at less than 1-year-old had a shorter duration of cannulation than others (mean: 1.9 years vs 5.2 years, P < .001). The mortality rate of those patients who received tracheostomy was 9.7% (3/31).Although a high tracheostomy rate was found in BVFI patients, most of them underwent decannulation. The earlier attainment of VF movement is achieved, the shorter duration of cannulation is required. This information is important for physicians while following up BVFI patients who have undergone tracheostomy.

Advances in calcium imaging have made it possible to record from an increasingly larger number of neurons simultaneously. Neuroscientists can now routinely image hundreds to thousands of individual neurons. An emerging technical challenge that parallels the advancement in imaging a large number of individual neurons is the processing of correspondingly large datasets. One important step is the identification of individual neurons. Traditional methods rely mainly on manual or semimanual inspection, which cannot be scaled for processing large datasets. To address this challenge, we focused on developing an automated segmentation method, which we refer to as automated cell segmentation by adaptive thresholding (ACSAT). ACSAT works with a time-collapsed image and includes an iterative procedure that automatically calculates global and local threshold values during successive iterations based on the distribution of image pixel intensities. Thus, the algorithm is capable of handling variations in morphological details and in fluorescence intensities in different calcium imaging datasets. In this paper, we demonstrate the utility of ACSAT by testing it on 500 simulated datasets, two wide-field hippocampus datasets, a wide-field striatum dataset, a wide-field cell culture dataset, and a two-photon hippocampus dataset. For the simulated datasets with truth, ACSAT achieved >80% recall and precision when the signal-to-noise ratio was no less than ∼24 dB.

Background: Anterior temporal lobectomy (ATL) is the standard surgical treatment for temporal lobe epilepsy (TLE), but patients may suffer from recurrent seizures post-surgery. Invasive electrical monitoring plays a critical role in precisely identifying the epileptic foci. This study aimed to evaluate and compare the benefits of long-term invasive electroencephalography (EEG) monitoring and two-stage surgery with the classical approach to examine their effect on post-surgical brain function and complications., Materials and Methods: Patients with TLE (N = 198) who underwent epilepsy surgery were retrospectively evaluated. Diagnosis of TLE was confirmed based on clinical grounds (semiology), EEG findings, and magnetic resonance imaging (MRI). Long-term invasive video EEG was performed; epileptiform discharges were recorded. Patients underwent either classical ATL or modified two-step surgery with electrodes implantation. Histopathological examination was performed. The patients were followed up at 1, 3, and 5 years after surgery., Results: Twenty-three and 175 patients underwent classical ATL and two-stage surgery, respectively. On histopathological examination, inflammation, hippocampal sclerosis, and cortical dysplasia were found to be the leading pathological causes of epileptic foci in both groups. MRI results were not consistent with the pathological findings. Grade II and III Engel scores were more frequent in the ATL group compared to two-stage surgery during follow-up. No postoperative complications were reported in two-stage surgery during follow-up, but one patient had mild hemiplegia in the ATL group., Conclusions: Preoperative invasive monitoring with long-term EEG helps locate the epileptic foci precisely. Postsurgical complications are rare compared to classical ATL, with better prognosis and seizure freedom after surgery., (Copyright © 2018. Published by Elsevier Ltd.)

Excessive metal exposure has been recognized as one of the detrimental factors for brain damage. However, the potential adverse effects induced by heavy metals on monoamine neurotransmitter pathways remains poorly understood. Our study aimed to investigate the possible association between metal exposure and neurotransmitter metabolism. By a cross-sectional investigation, 224 electroplating workers and 213 non-electroplating exposure workers were recruited in the exposure and control groups. Metal exposure levels were analyzed using inductively-coupled plasma mass spectrometry and monoamine neurotransmitter pathway metabolites were measured by ultra-performance liquid chromatography tandem mass spectrometry in human urine samples. Multivariate linear regression model was used to assess the dose-response relationships of urinary metals and neurotransmitter pathway metabolites. Significant dose-dependent trends of urinary vanadium quartiles with all metabolites were observed, and the trends demonstrated significance after multiple testing correction. It also showed that urinary chromium levels were significantly associated with decreased serotonin level and cadmium was positively associated with norepinephrine and epinephrine. In addition, arsenic was positively associated with tryptophan, serotonin, dopamine and norepinephrine. Iron was positively associated with increased homovanillic acid (HVA) and epinephrine while nickel was negatively associated with increased epinephrine levels. Zinc was positively related to tryptophan, kynurenin (KYN), 5-hydroxyindole acetic acid (5-HIAA), dopamine, HVA and norepinephrine. There was no significant association between urinary copper with any other metabolites after adjusting of multiple metal models. Metal exposure may be associated with neurotransmitter metabolism disturbances. The present work is expected to provide some support in the prevention and management of metal-associated neurological diseases., (Copyright © 2017. Published by Elsevier Ltd.)

Background: The DACT (Dishevelled-associated antagonist of β-catenin) family of scaffold proteins may play important roles in tumorigenesis. However, the epigenetic changes of DACT1, 2, 3 and their effect on esophageal squamous cell carcinoma (ESCC) have not been investigated so far. The aim of this study was to investigate the promoter methylation and expression of DACT family, in order to elucidate more information on the role of DACT with regard to the progression and prognosis of ESCC., Methods: MSP and BGS methods were respectively applied to examine the methylation status of DACT; RT-PCR, Western blot and immunohistochemistry methods were respectively used to determine the mRNA and protein expression of DACT; MTT, Colony-formation and Wound-healing assay were performed to assess the effect of DACT1 and DACT2 on proliferation and migration of esophageal cancer cells., Results: Frequent reduced expression of DACT1, DACT2 and DACT3 were found in esophageal cancer cell lines and the expression levels of DACT1 and DACT2 were reversed by 5-Aza-Dc. Decreased mRNA and protein expression of DACT1 and DACT2 were observed in ESCC tumor tissues and were associated with the methylation status of transcription start site (TSS) region. The hypermethylation of CpG islands (CGI) shore region in DACT1 was observed both in tumor and corresponding adjacent tissues but wasn't related to the transcriptional inhibition of DACT1. The methylation status of TSS region in DACT1 and DACT2 and the protein expression of DACT2 were independently associated with ESCC patients' prognosis., Conclusions: The TSS region hypermethylation may be one of the main mechanisms for reduced expression of DACT1 and DACT2 in ESCC. The simultaneous methylation of DACT1 and DACT2 may play important roles in progression of ESCC and may serve as prognostic methylation biomarkers for ESCC patients.

People with schizophrenia, who constitute approximately 0.3-1% of the general population, have a nearly 20% shorter life expectancy than the general population. The incidence of varied types of cancers in patients with schizophrenia is controversial. The majority of previous research has demonstrated that patients who have schizophrenia and cancer have early mortality compared to the general population with cancer. The causes of early mortality in patients with schizophrenia and cancer might be attributed to a lower cancer screening rate and lack of effective treatment, including: (i) patient factors, such as poor lifestyle, passive attitude toward treatment, or comorbidity; (ii) physician factors, such as physician bias, which may decrease the delivery of care for individuals with mental disorders; and (iii) hospital administration factors, such as stigma and discrimination. Additional studies on patients with schizophrenia and cancer are warranted and should include the following: a comprehensive review of previous studies; a focus on differentiating the specific types of cancer; and methods for improvement. To decrease the early mortality of patients with schizophrenia, the following measures are proposed: (i) enhance early detection and early treatment, such as increasing the cancer screening rate for patients with schizophrenia; (ii) provide effective, timely treatment and rehabilitation; (iii) improve patients' psychiatric symptoms and cognitive impairment; (iv) promote healthy behavior in the general population and emphasize healthy lifestyles in vulnerable populations; and (v) remove the stigma of schizophrenia. To reduce disparities in physical health, public health strategies and welfare policies must continue to focus on this group of patients., (© 2016 The Authors. Psychiatry and Clinical Neurosciences © 2016 Japanese Society of Psychiatry and Neurology.)

BaFe12O19 is a popular M-type hexaferrite with a Néel temperature of 720 K and is of enormous commercial value ($3 billion/year). It is an incipient ferroelectric with an expected ferroelectric phase transition extrapolated to lie at 6 K but suppressed due to quantum fluctuations. The theory of quantum criticality for such uniaxial ferroelectrics predicts that the temperature dependence of the electric susceptibility χ diverges as 1/T(3), in contrast to the 1/T(2) dependence found in pseudo-cubic materials such as SrTiO3 or KTaO3. In this paper we present evidence of the susceptibility varying as 1/T(3), i.e. with a critical exponent γ = 3. In general γ = (d + z - 2)/z, where the dynamical exponent for a ferroelectric z = 1 and the dimension is increased by 1 from deff = 3 + z to deff = 4 + z due to the effect of long-range dipole interactions in uniaxial as opposed to multiaxial ferroelectrics. The electric susceptibility of the incipient ferroelectric SrFe12O19, which is slightly further from the quantum phase transition is also found to vary as 1/T(3).

Geometric frustration and quantum fluctuations may prohibit the formation of long-range ordering even at the lowest temperature, and therefore liquid-like ground states could be expected. A good example is the quantum spin liquid in frustrated magnets. Geometric frustration and quantum fluctuations can happen beyond magnetic systems. Here we propose that quantum electric-dipole liquids, analogues of quantum spin liquids, could emerge in frustrated dielectrics where antiferroelectrically coupled electric dipoles reside on a triangular lattice. The quantum paraelectric hexaferrite BaFe12O19 with geometric frustration represents a promising candidate for the proposed electric-dipole liquid. We present a series of experimental lines of evidence, including dielectric permittivity, heat capacity and thermal conductivity measured down to 66 mK, to reveal the existence of an unusual liquid-like quantum phase in BaFe12O19, characterized by itinerant low-energy excitations with a small gap. The possible quantum liquids of electric dipoles in frustrated dielectrics open up a fresh playground for fundamental physics.

Objective: The heterogeneous nature of mesenchymal stem cells (MSCs) and the absence of known MSC-specific biomarkers make it challenging to define MSC phenotypes and characteristics. In this study, we compared the phenotypic and functional features of human placenta-derived MSCs with those of human dermal fibroblasts in vitro in order to identify a biomarker that can be used to increase the purity of MSCs in a primary culture of placenta-derived cells., Materials and Methods: Liquid chromatography-tandem mass spectrometry analysis was used to analyze and compare the proteome of human placenta-derived MSCs with that of fibroblasts. Quantitative real-time polymerase chain reaction, immunofluorescence, and flow cytometry were used to determine expression levels of EphA2 in placenta-derived MSCs. EphA2-positive cells were enriched by magnetic-activated cell sorting or with a cell sorter. An shRNA-mediated EphA2 knockdown was used to assess the role of EphA2 in MSC response to Tumor necrosis factor (TNF)-α stimulation., Results: Analysis of proteomics data from MSCs and fibroblasts resulted in the identification of the EphA2 surface protein biomarker, which could reliably distinguish MSCs from fibroblasts. EphA2 was significantly upregulated in placenta-derived MSCs when compared to fibroblasts. EphA2 played an important role in MSC migration in response to inflammatory stimuli, such as TNF-α. EphA2-enriched MSCs were also more responsive to inflammatory stimuli in vitro when compared to unsorted MSCs, indicating a role for EphA2 in the immunomodulatory functionality of MSCs., Conclusion: EphA2 can be used to distinguish and isolate MSCs from a primary culture of placenta-derived cells. EphA2-sorted MSCs exhibited superior responsiveness to TNF-α signaling in an inflammatory environment compared with unsorted MSCs or MSC-like cells., (Copyright © 2015. Published by Elsevier B.V.)

The large tumour suppressor 1 (LATS1) signalling network has been proved to be an essential regulator within the cell, participating in multiple cellular phenotypes. However, it is unclear concerning the clinical significance of LATS1 and the regulatory mechanisms of 17-Allylamino-17- demethoxygeldanamycin (17-AAG) in lung adenocarcinoma (LAC). The aim of the present study was to investigate the correlation of LATS1 and yes-associated protein (YAP) expression with clinicopathological characteristics in LAC patients, and the effects of 17-AAG on biological behaviours of LAC cells. Subcutaneous LAC tumour models were further established to observe the tumour growth in nude mice. The results showed that the positive expression of LATS1 was significantly lowered (26.7% versus 68.0%, P < 0.001), while that of YAP was elevated (76.0% versus 56.0%, P = 0.03) in LAC tissues compared to the adjacent non-cancerous tissues; LAST1 expression was negatively correlated with YAP expression (r = 0.432, P < 0.001) and lymphatic invasion of the tumour (P = 0.015). In addition, 17-AAG inhibited proliferation and invasion, and induced cell apoptosis and cycle arrest in LAC cells together with increased expression of E-cadherin and p-LATS1, and decreased expression of YAP and connective tissue growth factor. Tumour volumes and weight were much smaller in 17-AAG-treated groups than those in untreated group (P < 0.01). Taken together, our findings indicate that decreased expression of LATS1 is associated with lymphatic invasion of LAC, and 17-AAG suppresses growth and invasion of LAC cells via regulation of the LATS1/YAP pathway in vitro and in vivo, suggesting that we may provide a promising therapeutic strategy for the treatment of human LAC., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Human single-strand (ss) DNA binding proteins 1 (hSSB1) has been shown to participate in DNA damage response and maintenance of genome stability by regulating the initiation of ATM-dependent signaling. ATM phosphorylates hSSB1 and prevents hSSB1 from ubiquitin-proteasome-mediated degradation. However, the E3 ligase that targets hSSB1 for destruction is still unknown. Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation. Furthermore, cells overexpression of Fbxl5 abrogated the cellular response to DSBs, including activation of ATM and phosphorylation of ATM targets and exhibited increased radiosensitivity, chemosensitivity and defective checkpoint activation after genotoxic stress stimuli. Moreover, the protein levels of hSSB1 and Fbxl5 showed an inverse correlation in lung cancer cells lines and clinical lung cancer samples. Therefore, Fbxl5 may negatively modulate hSSB1 to regulate DNA damage response, implicating Fbxl5 as a novel, promising therapeutic target for lung cancers., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Group B Sox domain transcription factors play conserved roles in the specification and development of the nervous system in higher metazoans. However, we know comparatively little about how these transcription factors regulate gene expression, and the analysis of Sox gene function in vertebrates is confounded by functional compensation between three closely related family members. In Drosophila, only two group B Sox genes, Dichaete and SoxN, have been shown to function during embryonic CNS development, providing a simpler system for understanding the functions of this important class of regulators., Results: Using a combination of transcriptional profiling and genome-wide binding analysis we conservatively identify over 1000 high confidence direct Dichaete target genes in the Drosophila genome. We show that Dichaete plays key roles in CNS development, regulating aspects of the temporal transcription factor sequence that confer neuroblast identity. Dichaete also shows a complex interaction with Prospero in the pathway controlling the switch from stem cell self-renewal to neural differentiation. Dichaete potentially regulates many more genes in the Drosophila genome and was found to be associated with over 2000 mapped regulatory elements., Conclusions: Our analysis suggests that Dichaete acts as a transcriptional hub, controlling multiple regulatory pathways during CNS development. These include a set of core CNS expressed genes that are also bound by the related Sox2 gene during mammalian CNS development. Furthermore, we identify Dichaete as one of the transcription factors involved in the neural stem cell transcriptional network, with evidence supporting the view that Dichaete is involved in controlling the temporal series of divisions regulating neuroblast identity.

Objective: This study aimed to estimate the incidence and relative risk of stroke and post-stroke all-cause mortality among patients with bipolar disorder., Methods: This study identified a study population from the National Health Insurance Research Database (NHIRD) between 1999 and 2003 that included 16,821 patients with bipolar disorder and 67,284 age- and sex-matched control participants without bipolar disorder. The participants who had experienced a stroke between 1999 and 2003 were excluded and were randomly selected from the NHIRD. The incidence of stroke (ICD-9-CM code 430-438) and patient survival after stroke were calculated for both groups using data from the NIHRD between 2004 and 2010. A Cox proportional-hazards model was used to compare the seven-year stroke-free survival rate and all-cause mortality rate across the two cohorts after adjusting for confounding risk factors., Results: A total of 472 (2.81%) patients with bipolar disorder and 1,443 (2.14%) controls had strokes over seven years. Patients with bipolar disorder were 1.24 times more likely to have a stroke (95% CI = 1.12-1.38; p<0.0001) after adjusting for demographic characteristics and comorbid medical conditions. In addition, 513 (26.8%) patients who had a stroke died during the follow-up period. The all-cause mortality hazard ratio for patients with bipolar disorder was 1.28 (95% CI = 1.06-1.55; p = 0.012) after adjusting for patient, physician and hospital variables., Conclusions: The likelihood of developing a stroke was greater among patients with bipolar disorder than controls, and the all-cause mortality rate was higher among patients with bipolar disorder than controls during a seven-year follow-up period.

Background: Group B Sox domain transcription factors play important roles in metazoan central nervous system development. They are, however, difficult to study as mutations often have pleiotropic effects and other Sox family members can mask phenotypes due to functional compensation. In Drosophila melanogaster, the Sox gene Dichaete is dynamically expressed in the embryonic CNS, where it is known to have functional roles in neuroblasts and the ventral midline. In this study, we use inducible dominant negative proteins in combination with ChIP, immunohistochemistry and genome-wide expression profiling to further dissect the role of Dichaete in these two tissues., Results: We generated two dominant negative Dichaete constructs, one lacking a DNA binding domain and the other fused to the Engrailed transcriptional repressor domain. We expressed these tissue-specifically in the midline and in neuroblasts using the UAS/GAL4 system, validating their use at the phenotypic level and with known target genes. Using ChIP and immunohistochemistry, we identified two new likely direct Dichaete target genes, commisureless in the midline and asense in the neuroectoderm. We performed genome-wide expression profiling in stage 8-9 embryos, identifying almost a thousand potential tissue-specific Dichaete targets, with half of these genes showing evidence of Dichaete binding in vivo. These include a number of genes with known roles in CNS development, including several components of the Notch, Wnt and EGFR signalling pathways., Conclusions: As well as identifying commisureless as a target, our data indicate that Dichaete helps establish its expression during early midline development but has less effect on its established later expression, highlighting Dichaete action on tissue specific enhancers. An analysis of the broader range of candidate Dichaete targets indicates that Dichaete plays diverse roles in CNS development, with the 500 or so Dichaete-bound putative targets including a number of transcription factors, signalling pathway components and terminal differentiation genes. In the early neurectoderm we implicate Dichaete in the lateral inhibition pathway and show that Dichaete acts to repress the proneural gene asense. Our analysis also reveals that dominant negatives cause off-target effects, highlighting the need to use other experimental data for validating findings from dominant negative studies.

Although the magnetoelectric effects - the mutual control of electric polarization by magnetic fields and magnetism by electric fields, have been intensively studied in a large number of inorganic compounds and heterostructures, they have been rarely observed in organic materials. Here we demonstrate magnetoelectric coupling in a metal-organic framework [(CH3)2NH2]Mn(HCOO)3 which exhibits an order-disorder type of ferroelectricity below 185 K. The magnetic susceptibility starts to deviate from the Curie-Weiss law at the paraelectric-ferroelectric transition temperature, suggesting an enhancement of short-range magnetic correlation in the ferroelectric state. Electron spin resonance study further confirms that the magnetic state indeed changes following the ferroelectric phase transition. Inversely, the ferroelectric polarization can be improved by applying high magnetic fields. We interpret the magnetoelectric coupling in the paramagnetic state in the metal-organic framework as a consequence of the magnetoelastic effect that modifies both the superexchange interaction and the hydrogen bonding.

To study the mitochondrial DNA (mtDNA) polymorphisms in a total of 232 individuals from five ethnic populations (Daur, n=45; Ewenki, n=47; Korean, n=48; Mongolian, n=48; Oroqen, n=44) in northern China, we analyzed the control region sequences and typed for a number of characteristic mutations in coding regions (especially the region 14576-16047), by direct sequencing or restriction-fragment-length-polymorphism (RFLP) analysis. With the exception of 14 individuals belonging to the European-specific haplogroups R2, H, J, and T, the mtDNAs considered could be assigned into the East Asian-specific haplogroups described recently. The polymorphisms in cytochrome b sequence were found to be very informative for defining or supporting the haplogroups status of East Asian mtDNAs in addition to the reported regions 10171-10659 and 14055-14590 in our previous study. The haplogroup distribution frequencies varied in the five ethnic populations, but in general they all harbored a large amount of north-prevalent haplogroups, such as D, G, C, and Z, and thus were in agreement with their ethnohistory of northern origin. The two populations (Ewenki and Oroqen) with small population census also show concordant features in their matrilineal genetic structures, with lower genetic diversities observed.