Search

Background Atezolizumab plus bevacizumab (atezo-bev) has been recommended for advanced hepatocellular carcinoma (HCC). High-dose external beam radiotherapy (RT) is recognized for its excellent local tumor control. The efficacy and safety of concurrent atezo-bev with RT for highly advanced HCC has been minimally explored. Methods In this preliminary retrospective study, we assessed patients with highly advanced HCC, characterized by Vp4 portal vein thrombosis or tumors exceeding 50% of liver volume, who received concurrent atezo-bev and RT (group A). Group A included 13 patients who received proton radiation at a dose of 72.6 GyE in 22 fractions, and one patient who received photon radiation at a dose of 54 Gy in 18 fractions. This group was compared with 34 similar patients treated atezo-bev alone as a control (group B). The primary objectives were to evaluate the objective response rate (ORR), overall survival (OS), and safety. Results Baseline characteristics were similar between groups, except for a higher incidence of Vp4 portal vein thrombosis in group A (78.6% vs. 21.4%, P  = .05). Group A achieved a higher ORR (50.0% vs. 11.8%, P  < .01) and a longer OS (not reached vs. 5.5 months, P  = .01) after a median follow-up of 5.2 months. Multivariate analysis indicated that concurrent RT independently favored longer OS (hazard ratio: 0.18; 95% CI, 0.05-0.63, P  < .01). Group A did not increase any grade adverse events (78.6% vs. 58.8%, P  = .19) or severe adverse events of grade ≥ 3 (14.3% vs. 14.7%, P  = .97) compared to group B. Conclusions The concurrent high-dose external beam radiotherapy appears to safely enhance the effectiveness of atezolizumab plus bevacizumab for highly advanced patients with HCC. Further studies are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is a prevalent health condition in Taiwan that places individuals at higher risk of cardiovascular disease, diabetes, and stroke. Therefore, the identification of risk factors associated with MetS is crucial. The aim of this study was to investigate the association of uric acid and MetS in a Taiwanese community with a middle-aged and elderly population. Methods: This cross-sectional study enrolled residents aged 50–90 years living in one community. All of the subjects received a standardized personal interview, including a structured questionnaire, anthropometric measurements, and blood samples were collected for laboratory testing. MetS was defined as excess waist circumference, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Multiple logistic regression models were used to evaluate uric acid tertiles associated with MetS. Results: A total of 400 subjects were enrolled in the analysis. The overall prevalence of MetS was 35.8%. The prevalence of MetS increased gradually with increasing serum uric acid levels (p value < 0.001). A significant association between uric acid and cardiometabolic risk factors was confirmed, with a Pearson's correlation coefficient for waist circumference of 0.30 (p < 0.001), a coefficient for systolic blood pressure of 0.13 (p = 0.01), a coefficient for triglycerides of 0.33 (p < 0.001), and a coefficient for high-density lipoprotein of −0.30 (p < 0.001). The adjusted odds ratio (OR) of the high uric acid tertile level for MetS was 2.48 (95% CI = 1.31–4.71, p = 0.01). The area under the ROC curve (AUC) for uric acid in predicting MetS was 0.621 (p < 0.001). Conclusions: The prevalence of MetS in our study population is high. High serum uric acid levels are independently associated with the presence of MetS among the middle-aged and elderly Taiwanese population. [ABSTRACT FROM AUTHOR]

Background: The management of knee osteoarthritis involves various treatment strategies. It is important to explore alternative therapies that are both safe and effective. Collagen peptides have emerged as a potential intervention for knee osteoarthritis. This study aims to evaluate the analgesic effects and safety of collagen peptide in patients diagnosed with knee osteoarthritis. Methods: We conducted a systematic literature search following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Multiple databases including PubMed, Scopus, EMBASE, Web of Science, Cochrane, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) published up to 27 May 2023 that focused on the analgesic outcomes and adverse events associated with collagen peptides or hydrolyzed collagen in patients with osteoarthritis. We assessed the quality of the included studies and the strength of evidence using the Cochrane ROB 2.0 tool and Grading of Recommendations, Assessment, Development, and Evaluations. Results: Four trials involving 507 patients with knee osteoarthritis were included and analyzed using the random-effects model. All these trials were considered to have a high risk of bias. Our results revealed a significant difference in pain relief between the collagen peptide group and the placebo group in patients with knee osteoarthritis (standardized mean difference: − 0.58; 95% CI − 0.98, − 0.18, p = 0.004; I2: 68%; quality of evidence: moderate). However, there was no significant difference in the risk of adverse events between collagen peptide and placebo (odds ratio: 1.66; 95% CI 0.99, 2.78, p = 0.05; I2: 0%; quality of evidence: very low). Conclusions: Our findings demonstrate significant pain relief in patients with knee osteoarthritis who received collagen peptides compared to those who received placebo. In addition, the risk of adverse events did not differ significantly between the collagen peptide group and the placebo group. However, due to potential biases and limitations, well-designed randomized controlled trials are needed to validate and confirm these findings. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) causes cognitive dysfunction and long-term impairments. This study aims to examine the effectiveness of acupuncture on the recovery of consciousness in TBI patients. This is a retrospective, multi-institutional cohort study. We enrolled patients with newly diagnosed TBI from 1 January 2007 to 3 August 2021, aged 20 years and older, from the Chang Gung Research Database (CGRD). The outcome was defined based on the difference between the first and last Glasgow Coma Scale (GCS). A total of 2163 TBI patients were analyzed, and 237 (11%) received acupuncture in the treatment period. Generally, the initial GCS was lower in the acupuncture users (11 vs. 14). For the results of our study, a higher proportion of acupuncture patients achieved significant improvement (GCS differences ≥ 3) compared to non-acupuncture users (46.0% vs. 22.4%, p-value < 0.001). The acupuncture users had a 2.11 times higher chance of achieving a significant improvement when considering all assessable covariates (adjusted odds ratio (aOR) 2, 11, 95% confidence interval [CI]: 1.31–3.40; p-value = 0.002). Using 1:1 propensity score matching (PSM), the acupuncture users still had better outcomes than the non-acupuncture users (45.3% vs. 32.9%, p-value = 0.020). In conclusion, this study suggests that acupuncture treatment may be beneficial for TBI patients. [ABSTRACT FROM AUTHOR]

Elders have a higher rate of return visits to the emergency department (ED) than other patients. It is critical to understand the risk factors for return visits to the ED by elders. The aim of this study was to determine the factors associated with return visits to the ED by elders. This study retrospectively reviewed the hospital charts of elders who returned to the ED within 72 h after discharge from ED. The risk factors identified in the Triage Risk Screening Tool were applied in this study. Of the elders discharged from the ED, 8.64% made a return visit to the ED within 72 h. The highest revisit rate occurred within 24 h after discharge. Factors associated with return ED visits within 24 h by elders were difficulty walking and having discharge care needs. The factor associated with ED return visits within 24–48 h was polypharmacy. Difficulty walking, having discharge care needs, and hospitalization within the past 120 days were associated with return visits made within 48–72 h following discharge. Identifying the reasons for return visits to the ED and providing a continuous review of geriatric assessment and discharge planning could reduce unnecessary revisits. [ABSTRACT FROM AUTHOR]

Simple Summary: Oral cancer (OC) is prevalent cancer worldwide, with varying incidence rates in different regions. To analyze the secular trend of the incidence of OC in Taiwan, this study used data from the national cancer registry database between 1980 and 2019. The study used the age-period-cohort model and average annual percentage change (AAPC) to examine the characteristic of incidence. The study also used Spearman's correlation to determine the correlation between age-standard incidence rates (ASR) of OC and related risk factors. Results indicated that ASR of OC increased in men and women from 1980–1984 to 2015–2019. The age-period-cohort model revealed a peak incidence rate in the 1975 cohort in men, followed by a declining trend. The study found a correlation between the incidence of OC and changes in cigarette and alcohol consumption and the production of betel quid. Therefore, the study recommends avoiding these risk factors to prevent OC. Oral cancer (OC) is one of the most common cancers worldwide, and its incidence has regional differences. In this study, the cancer registry database obtained from 1980 to 2019 was used to analyze the characteristic of incidence of OC by average annual percentage change (AAPC) and an age–period–cohort model. Spearman's correlation was used to analyze the relationship between the age-standard incidence rates (ASR) of OC and related risk factors. Our results showed that the ASR of OC increased from 4.19 to 27.19 per 100,000 population with an AAPC of 5.1% (95% CI = 3.9–6.3, p value < 0.001) in men and from 1.16 to 2.8 per 100,000 population with an AAPC of 3.1% (95% CI = 2.6–3.6, p value < 0.001) in women between 1980–1984 and 2015–2019. The age–period–cohort model reported a trend of rising then declining for the rate ratio in men, with peaks occurring in the 1975 cohort, with a rate ratio of 6.80. The trend of incidence of oral cancer was related to changes in the consumption of cigarettes and alcohol and production of betel quid, with r values of 0.952, 0.979 and 0.963, respectively (all p values < 0.001). We strongly suggest avoiding these risk factors in order to prevent OC. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have identified common risk factors for cerebral stroke worldwide. Some of these factors include hypertension, diabetes, smoking, excessive drinking, and dyslipidemia. It is important to note, however, that genetic factors can also contribute to the occurrence of stroke. Here, we evaluated the association of ischemic stroke with rs12514417 polymorphism of the alcohol metabolizing gene, aldehyde dehydrogenase 7A1 (ALDH7A1) and alcohol consumption. Methods: Taiwan Biobank (TWB) data collected between 2008 and 2015 were available for 17,985 subjects. The odd ratios for stroke were obtained using logistic regression models. Results: Among eligible subjects (n = 17,829), 897 had ischemic stroke and 70 had hemorrhagic stroke. Subjects with ischemic stroke were older (mean ± SE, 58.45 ± 8.19 years vs. 48.33 ± 10.89 years, p < 0.0001) and had a higher body mass index (BMI) than the stroke-free individuals. The risk of ischemic stroke was significantly higher among subjects with the ALDH7A1 rs12514417 TG + GG genotype who also consumed alcohol at least 150 ml/week (odds ratio (OR), 1.79; 95% confidence interval (CI), 1.18–2.72). We found that rs12514417 genotype and alcohol consumption (at least 150 ml/week) showed a significant interaction (p for interaction = 0.0266). Stratification based on alcohol exposure and ALDH7A1 rs12514417 genotypes indicated that ischemic stroke risk was significantly higher among alcohol drinkers with the TG + GG genotype than in those with the TT genotype (OR, 1.64, 95% CI: 1.15–2.33). Conclusion: Our study suggests that the combination of ALDH7A1 rs12514417 TG + GG genotype and alcohol exposure of at least 150 ml/week may increase the risk of ischemic stroke in Taiwanese adults. [ABSTRACT FROM AUTHOR]

Background: Vitamin D supplements are readily available as over-the-counter preparations. However, although rare, cases of vitamin D overdose still occur and are associated with nephrocalcinosis and life-threatening hypercalcemia. Errors in manufacturing of nutritional supplements may be a cause of vitamin D intoxication in children. This study aimed to identify factors associated with vitamin D overdose-related nephrocalcinosis in children due to manufacturing errors in supplements. Methods: This retrospective study reviewed medical charts of pediatric patients with non-registered supplement-related vitamin D overdose at a tertiary referral hospital between 2006 and 2011. Clinical and laboratory characteristics of patients with or without nephrocalcinosis were evaluated. Receiver operating characteristics curve and area under the receiver operating characteristics curve were used to determine the most predictive value of each characteristic. Results: A total of 44 patients (males: 29; age: 7–62 months) were included. Age ≤ 16.5 months, body weight ≤ 10.25 kg, body height ≤ 78.5 cm, body surface area (BSA) ≤ 0.475 m2, 25-hydroxyvitamin D3 ≥ 143 ng/mL, and calcium ≥ 10.65 mg/dL were predictive of developing nephrocalcinosis with a sensitivity and specificity of > 60%. Univariant analysis revealed that BSA was the most significant anthropometric prognostic factor (odds ratio: 12.09; 95% confidence interval: 2.61–55.72; P = 0.001). Conclusions: Children with smaller BSAs were more vulnerable to high-dose vitamin D3-related nephrocalcinosis. Physicians and parents should be aware of the potential adverse effects of vitamin D overdose in children. A higher resolution version of the Graphical abstract is available as Supplementary information [ABSTRACT FROM AUTHOR]

Advance care planning (ACP) is a process that helps people prepare to make decisions about their future medical care. We sought to understand who was received billed ACP visits and measure the association with health care utilization, cost, and mortality. We used a randomly sampled 20 % cohort of Medicare fee-for-service (FFS) beneficiaries' files to conduct a retrospective cohort study. Beneficiaries with a billed ACP visit were matched to controls using a 2-stage propensity score matching process that included assigning a pseudo-ACP visit date for controls. Outcomes included healthcare utilization, mortality, and total medical cost per month. We used descriptive statistics for univariate analysis and fit multilevel logistic regression, multilevel linear regression, or Cox regression models. We identified 183,513 beneficiaries who received any billed ACP visit and 550,539 matched controls. Of those who had a ACP visit, the mean age was 76.5 years and high-risk comorbidities were common: 16 % dementia, 10 % congestive heart failure, 10 % cancer. Beneficiaries who had an ACP visit had slightly more health care utilization than controls. Beneficiaries who had an ACP visit were more likely to die (3.1% vs. 1.0 %, p < 0.01, OR=3.0, 95 %CI 2.9–3.2) in the unadjusted and adjusted analyses compared to matched controls. Total monthly medical costs were 33 % higher among beneficiaries who had an ACP visit. Our results suggest that ACP visits may be preferentially utilized amongst individuals with higher risk of mortality. There may be an opportunity to increase ACP visits among older adults at lower risk for mortality. This article suggests that ACP visits are likely targeted to older adults with a higher risk of mortality than those at lower risk of mortality suggesting an opportunity to reach people before they are facing end-of-life decisions. [ABSTRACT FROM AUTHOR]

Objective: To determine the risk and time trends of heart failure (HF) leading to hospitalization in individuals newly diagnosed as having polymyositis/dermatomyositis (PM/DM) relative to non‐PM/DM controls at the general population level. Methods: A retrospective cohort study was conducted using data from a nationwide insurance database in Taiwan. Patients with incident PM/DM and without a history of HF were selected between 2000 and 2013. Unmatched and propensity score–matched cohorts were established separately. A multivariable Cox proportional hazards regression model was used to estimate the adjusted hazard ratio (HR) for the risk of HF in the unmatched cohort. In the propensity score–matched cohort, general population controls were selected and matched at a 1:1 ratio to the patients with PM/DM based on propensity scores, which accounted for the confounding factors of age, sex, index date (year) of first diagnosis, comorbidities, and medication usage. The cumulative incidence of HF was estimated using the Kaplan‐Meier method. A stratified Cox proportional hazards model was used to calculate the HR for the risk of HF events at different follow‐up time points among patients with PM/DM compared with non‐PM/DM controls in the propensity score–matched cohort. Results: In the unmatched cohort, the study assessed 2,025 patients with PM/DM and 196,109 general population controls. Results of multivariable Cox regression analysis, adjusted for age, sex, comorbidities, and medication usage, revealed a greater risk of HF leading to hospitalization in the PM/DM group than in the control group (adjusted HR 3.29, 95% confidence interval [95% CI] 2.60–4.18). After matching based on propensity score, a total of 1,997 pairs of PM/DM patients and general population controls were identified. In this propensity score–matched cohort, the cumulative incidence of HF in patients with PM/DM at 3 years, 5 years, and 10 years was 3.3%, 4.4%, and 7.4%, respectively. The absolute difference in HF risk in the PM/DM group compared with the control group was 1.8% at 3 years, 2.1% at 5 years, and 3.0% at 10 years. Compared with general population controls, patients with PM/DM exhibited an augmented risk of HF (HR 2.06, 95% CI 1.36–3.12). Analyses stratified according to follow‐up time point revealed that the increased risk of HF persisted for up to 10 years after the PM/DM diagnosis. Conclusion: These results indicate that the risk of HF leading to hospitalization was increased in patients with PM/DM throughout the study period, supporting the need for greater vigilance in the monitoring of patients with PM/DM for the development of this potentially lethal complication. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to examine the association between obstructive sleep apnea (OSA) diagnosis and diverse types of injuries. Design: This population‐based retrospective cohort study compared records from 2000 to 2013 in the Taiwan National Health Insurance Research Database. Methods: 3025 patients identified with OSA were compared against the control cohort consisting of 12,100 age‐ and sex‐matched patients. Cox proportional hazards regression analysis was performed to estimate the effects of OSA on injury risk. Findings: Patients with OSA exhibited a significantly higher overall incidence of injury of 2599 per 100,000 person‐years compared to the control cohort (2248 per 100,000 person‐years). After the confounding factors were considered, subjects with OSA showed a higher risk of injury than subjects in the control group (adjusted hazard ratio [HR] = 1.78, 95% confidence interval [CI] = 1.64–1.93). The risk of unintentional injury (traffic, poisoning, falls) and intentional injury (suicide) in the group of patients with OSA was higher than that in the controls. Conclusions: Our study strongly supports the conclusion that adults with OSA are at increased risk of injury. Clinical relevance: The present results indicate the significance of OSA as a predictor of injury risk, which will provide valuable information for clinical practice and injury prevention. [ABSTRACT FROM AUTHOR]

Aims: To examine nurse documentation of assessments using standard risk assessment forms in older inpatients, and to determine the value of such assessment. Design: Cross‐sectional retrospective chart review. Methods: This retrospective review of risk evaluation documentation in patients' medical records focused on skin, continence, medical complications, nutrition, cognition, mobility, medications and pain. Results: A total of 1000 medical records from Taiwan hospitals were reviewed from January 2016 to December 2017, and 379 from Australian hospitals were reviewed from March 2011 to February 2012. Taiwanese patients with documented assessment of skin (aOR =2.94, 95%CI =1.88–4.54), nutrition (aOR =3.22, 95%CI =1.08–9.59), cognition (aOR =2.61, 95%CI =1.32–5.16) and pain (aOR =5.01, 95%CI=1.63–15.38) had significantly higher odds of developing new problems; while Australian patients with documented assessments of continence (aOR =11.55, 95%CI =1.48–90.45) and nutrition (aOR =12.90, 95%CI =1.67–99.06) had significantly higher odds of developing new problems. Discussion: Nursing assessments and interventions documented in standard risk assessment forms help clinical nurses detect new preventable problems and prevent harm in older hospital inpatients across geographic locations and hospital types. Standard nursing forms can be used in clinical practice to guide proactive care by nurses to prevent harm during hospitalisation. Impact: Older inpatients are at risk of preventable harm and new health problems. The present study found that incorporating eight factors sensitive to nursing care into standard risk assessment forms can help reduce preventable harm in older inpatients. In addition, these forms guide assessment and intervention effectively in different countries. [ABSTRACT FROM AUTHOR]

Purpose. Patients with central serous chorioretinopathy (CSC) typically present with acute visual impairment and metamorphopsia. The disease previously has been associated with psychological stress. Population-based cohort studies on the risk of CSC among patients with nonorganic sleep disturbance (NOSD) are limited. An early sign of psychiatric disorder was probably sleep disturbance. Furthermore, psychological stress may be caused by sleep disturbance. We investigated the relationship between NOSD and the incidence of CSC. Design. Longitudinal cohort study. Participants. We used the Longitudinal Health Insurance Database and collected the data of 53,743 NOSD patients without CSC between 2000 and 2005 as the study group. Four-fold controls were selected randomly from those without neither sleep disturbance nor a CSC history with frequency matching of age, sex, and index-year. Methods. The difference in sex, age group, comorbidities, and steroid use between the two groups was analyzed by the χ2 test. Cox-proportional hazard regression was utilized to estimate the hazard ratio (HR) and 95% confidence intervals (95% CI) for comparison of the two groups. Kaplan–Meier analysis was applied to measure the cumulative incidence of CSC. Furthermore, the log-rank test was used to test the incidence difference between the two groups. Main Outcome Measures. The incidence rate of CSC in the following years until 2011 was detected. Results. During a mean follow-up of 7.36 ± 2.88 years, NOSD patients had a higher incidence of CSC than the controls (3.10 vs. 1.86 per 10,000 person-years; adjusted HR, 1.65; 95% CI, 1.34–2.02). Men had a higher risk of CSC than women. Sensitivity analyses stratified by sex, age group, or comorbidity condition showed consistently that NOSD patients had a higher risk of CSC than their controls. Dose-response showed that higher NOSD severity had even higher CSC risk. Conclusions. NOSD is an independent indicator for the increased risk of subsequent CSC development. [ABSTRACT FROM AUTHOR]

Objective: Previous case–control studies have suggested that women with migraine have lower risk of developing breast cancer, but conflicting results were noted in cohort studies. We investigated the association between migraine and breast cancer incidence in a nationwide population-based cohort study. Methods: We identified 25,606 women with migraine between 2000 and 2013 from the National Health Insurance Research Database in Taiwan. Each migraineur was randomly frequency matched with four women without migraine by age and index year of migraine diagnosis. Cox's proportional hazard regression analysis was performed to estimate the association between migraine on the risk of developing breast cancer. Results: With a mean follow-up of 7.3 years, 234 and 978 breast malignancies occurred in the migraine cohort and matched cohort, respectively. Migraine was not associated with the risk of breast cancer (adjusted hazard ratio = 1.03, 95% confidence interval = 0.89–1.21). Among women with migraine, independent risk factors for breast cancer included older age, alcohol-related illness, and receipt of a greater number of breast cancer screening examinations, and independent protective factors included the use of antihypertensive agents, statins, and nonsteroidal anti-inflammatory drugs. Further analyses indicated that women with ≥4 medical visits for migraine per year had a significantly greater risk of breast cancer than the matched cohort. Conclusions: Migraine was not associated with a decreased risk of developing breast cancer among Taiwanese women. Further prospective studies on other geographic populations or on the association between migraine frequency and the risk of developing breast cancer are warranted to validate our findings. [ABSTRACT FROM AUTHOR]

Summary Background/objective The effect of eating habits and sedentary lifestyle on obesity has been extensively examined and supported; however, few studies have examined the association of sleep duration with obesity in Taiwan. To redress this gap, this study investigated the association of sleep duration with overweight and obesity in community-dwelling Taiwanese adults. Methods A cross-sectional study was performed using the 2005–2008 Nutrition and Health Survey in Taiwan (NAHSIT). A logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of the association of sleep duration with overweight and obesity. Nightly sleep duration was divided into three groups: >6 to <9 h (normal), ≤6 h (short), and ≥9 h (long). Results A total of 1548 adults aged 20–64 years were examined in this study. The adjusted ORs of obesity for short and long sleep duration relative to a normal sleep duration were 1.31 (95% CI 1.01, 1.76) and 1.64 (95% CI 1.04, 2.61), respectively. No significant association of sleep duration with overweight was observed. Conclusions The present study suggests that both short and long sleep duration are associated with obesity risk. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to evaluate the association between radioiodine (I-131) therapy for thyroid cancer and the risk of stroke in Taiwan. Methods A total of 10 104 of the patients aged 20 years or older, who were newly diagnosed with thyroid cancer during 2000-2010, were recruited and classified into 2 cohorts according to whether they received I-131 therapy through 1:1 propensity score matching. The cumulative Kaplan-Meier curves for the incidence of stroke in the 2 cohorts were compared using the log-rank test. Results After adjustment for age, sex, and comorbidities, the I-131 therapy group showed no significantly higher risk of ischemic stroke (adjusted HR [aHR] = 1.05; 95% confidence interval [CI] = 0.82-1.34) or hemorrhagic stroke (aHR = 1.06; 95% CI = 0.58-1.93) than did the non-I-131 therapy group. Conclusion The I-131 treatment for thyroid cancer did not increase the risk of stroke during 10-year follow-up. [ABSTRACT FROM AUTHOR]

Background/purpose: Non-vitamin K antagonist oral anticoagulants (NOACs) have a half-life of around 12 h. We aimed to clarify if there was any effect modification by dosing (once- or twice-daily) regimens in Asian patients.Methods: Phase III randomized controlled trials of NOACs compared with warfarin in Asian patients with atrial fibrillation (AF) were identified and extracted from PubMed, CENTRAL, and CINAHL databases through November 2016. Outcomes were pooled by dosing regimens with the Mantel-Haenszel fixed-effects model. The risk ratio (RR) and 95% confidence interval (CI) were calculated. Effect differences between once- and twice-daily NOACs were assessed with Bucher indirect comparisons using common estimates, once heterogeneity was low, and with the Bayesian method.Results: From 6 trials, there was no effect modification by dosing regimens in the risk of stroke or systemic embolism across ethnicities (all interaction P > 0.05). Both dosing regimens were associated with a greater reduction in the risk of major bleeding in Asian patients (RR, 0.63 (95% CI, 0.47-0.85) and 0.57 (95% CI, 0.43-0.75), for once- and twice-daily NOACs, respectively). In Asian patients, risks of hemorrhagic stroke and intracranial hemorrhage were lower with once- (RR, 0.41 (95% CI, 0.21-0.80) and 0.29 (95% CI, 0.16-0.53)) and twice-daily NOACs (RR, 0.25 (95% CI, 0.12-0.51) and 0.38 (95% CI, 0.23-0.65)), compared with warfarin. There was no effect difference favoring any of NOAC regimens evaluated by Bucher and Bayesian methods.Conclusion: In Asian patients with AF, NOACs, regardless of dosing regimens, have a similar feature of preserved efficacy with improved safety compared with warfarin. [ABSTRACT FROM AUTHOR]

Background: Headache such as migraine is associated with stroke. Studies focused on primary headache disorders (PHDs) as a risk factor for stroke are limited. The purpose of this population-based cohort study was to explore whether patients with PHDs were at a high risk for developing stroke. Methods: A total of 1346 patients with PHDs were enrolled and compared with 5384 age-, gender- and co-morbidity-matched control cohorts. International Classification of Diseases, Clinical Modification codes were administered for the definition of PHDs, stroke, and stroke risk factors. Cox proportional-hazards regressions were performed for investigating hazard ratios (HR). Results: PHDs patients exhibited a 1.49 times (95% CI :1.15-1.98, p < 0.01) higher risk for developing ischaemic stroke compared with that of control cohorts. Both migraine (HR = 1.22, 95% CI :1.13-1.97, p < 0.05) and tension-type headache (HR = 2.29, 95% CI :1.22-2.80, p < 0.01) were associated with an increased risk of ischemic stroke. Females with PHDs were at greater risk of developing ischaemic stroke (HR = 1.49, 95% CI :1.13-1.90, p < 0.01) than those without PHDs. PHDs patient aged 45 to 64 years displayed significantly higher risk to develop ischaemic stroke (HR = 1.50, 95% CI: 1.11-2.10, p < 0.05) than the matched controls. The impact of PHDs on ischaemic stroke risk became gradually apparent by different following time intervals beyond 2 years after first diagnosis. Conclusion: PHDs is suggestive of an incremental risk for ischaemic stroke with gender-dependent, age-specific and time-dependent characteristics. [ABSTRACT FROM AUTHOR]

Background: Although the comorbidity of migraine and restless legs syndrome (RLS) has been well-documented, the association between RLS and migraine frequency has yet to be elucidated. The present study aims to evaluate the prevalence of RLS among individuals who experience low-frequency, high-frequency, or chronic migraine presenting with and without aura. Methods: We conducted a cross-sectional, case-controlled study involving 505 participants receiving outpatient headache treatment. Standardized questionnaires were administered to collect information on experiences of migraine, RLS, sleep quality, anxiety, depression, and demographics. Participants were categorized into low-frequency (1-8/month), high-frequency (9-14/month), and chronic (≥15/month) headache groups. RLS was diagnosed according to the criteria outlined by the International RLS Study Group (IRLSSG). The Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS) were used to assess sleep quality and identify symptoms of anxiety and depression. Associations between migraine frequency and RLS prevalence were investigated using multivariate linear and logistic regression. Results: Univariate analysis revealed an effect of migraine frequency on RLS prevalence ( p = 0.026), though this effect did not persist following adjustment for baseline characteristics ( p = 0.256). The trend was robust in patients whose migraines presented with auras ( p = 0.002; p = 0.043) but not in those without auras ( p and p > 0.05). Higher anxiety [odds ratio (OR) = 1.18, p = 0.019] and sleep disturbance (OR = 1.17, p = 0.023) scores were associated with higher RLS prevalence. Conclusions: Higher migraine frequency correlates with a higher prevalence of RLS, particularly among patients with auras. [ABSTRACT FROM AUTHOR]

BACKGROUND: Different results are reported for the relationship between regional variation in medical spending and disease prognosis for acute illness and for cancer. Our objective was to investigate the association between hospital medical care spending intensity and mortality rates in cancer patients. METHODS: A total of 80,597 patients with incident cancer diagnosed in 2002 were identified from the National Health Insurance Research Database of Taiwan, Republic of China. The Cox proportional hazards model was used to compare the 5-year survival rates of patients treated at hospitals with different spending intensities after adjusting for possible confounding and risk factors. RESULTS: After adjustment for patient characteristics, treatment modality, and hospital volume, an association was found between lower hospital spending intensity and poorer survival rates. The 5-year survival rate expressed by hazard ratios was 1.36 (95% confidence interval [CI]: 1.30-1.43, p < .001) for colorectal cancer, 1.18 (95% CI: 1.08-1.29, p < .001) for lung cancer, 1.13 (95% CI: 1.05-1.22, p = .002) for hepatoma, 1.16 (95% CI: 1.07-1.26, p < .001) for breast cancer, and 1.23 (95% CI: 1.10-1.39, p = .001) for prostate cancer. CONCLUSION: Our preliminary findings indicate that higher hospital spending intensity was associated with lower mortality rates in patients being treated for lung cancer, breast cancer, colorectal cancer, prostate cancer, hepatoma, or head and neck cancer. The cancer stages were unavailable in this series, and more research linked with the primary data may be necessary to clearly address this issue. [ABSTRACT FROM AUTHOR]

Colorectal adenomas are considered to be precursors of colorectal cancer. B-vitamins (i.e., folate, vitamin B6and B12) are involved in homocysteine metabolism and play an important role as coenzymes in 1-carbon metabolism, which is thought to have a critical role in the progression of colorectal polyps. The purpose of this study was to examine the effects of B-vitamins and homocysteine on the risk of developing colorectal polyps. Forty-eight participants with colorectal polyps [29 adenomatous polyps (AP), 19 hyperplastic polyps (HP)], and 96 age- and sex-matched healthy controls were recruited. Fasting blood was drawn from each participant to measure hematological parameters, plasma pyridoxal 5′-phosphate (PLP), serum folate and vitamin B12, and plasma homocysteine. Participants with AP and HP had significantly higher plasma homocysteine levels than did healthy controls. There was no significant difference in serum folate and vitamin B12and plasma PLP among the 3 groups. B-vitamins had no significant effect on the risk of colorectal polyps. However, participants with higher plasma homocysteine [odds ratio (OR) = 1.87, 95% confidence interval (CI) = 1.13, 3.08) level exhibited significantly increased risk of colorectal polyps after adjusting for potential confounders. Plasma homocysteine was a strong predictor of the risk of colorectal polyps in participants with adequate B-vitamins status. [ABSTRACT FROM PUBLISHER]

Objectives:To compare intensiveness of use of child preventive health services (CPHS) between cross-cultural immigrant families and native-born families in Taiwan and to explore factors associated with differences in intensiveness of CPHS use. Design:Cross-cultural immigrant families were defined as families where the mother was an immigrant from another southeast Asian country. In native-born families, both parents were Taiwanese-born. Data were collected from 318 immigrant mothers and 340 native-born mothers of children aged 7 years or younger in a cross-sectional survey in central Taiwan. A social determinants framework of health inequities was constructed, and ordinal logistic regression models were used to examine the effect of four domains of intermediary determinants on the relationship between family type and underuse of CPHS: CPHS-related factors, medical-related factors, maternal acculturation factors, and sociodemographic/socioeconomic characteristics. Results:Cross-cultural immigrant families were less likely to intensively use CPHS than native-born families. This difference appeared to be mediated by the greater likelihood of having an older child or a lower educated father in cross-cultural families. Conclusion:Findings of this study highlight the importance of promoting health behaviors and combating health inequities and social inequalities for cross-cultural immigrant families in Taiwan from a sociodemographic/socioeconomic and political context. [ABSTRACT FROM PUBLISHER]

Aim Dentin hypersensitivity, caused by the exposure and patency of dentinal tubules, can affect patients' quality of life. The aim of this study was to undertake a systematic review and a network meta-analysis, comparing the effectiveness in resolving dentin hypersensitivity among different in-office desensitizing treatments. Materials and Methods A literature search was performed with electronic databases and by hand until December 2011. The included trials were divided into six treatment groups as placebo, physical occlusion, chemical occlusion, nerve desensitization, laser therapy and combined treatments. The treatment effects between groups were estimated with standardized mean differences by using a Bayesian network meta-analysis. Results Forty studies were included. The standardized mean difference between placebo and physical occlusion was −2.57 [95% credible interval ( CI): −4.24 to −0.94]; placebo versus chemical occlusion was −2.33 (95% CI: −3.65 to −1.04); placebo versus nerve desensitization was −1.72 (95% CI: −4.00 to 0.52); placebo versus laser therapy was −2.81 (95% CI: −4.41 to −1.24); placebo versus combined treatment was −3.47 (95% CI: −5.99 to −0.96). The comparisons of the five active treatments showed no significant differences. Conclusions The results from network meta-analysis showed that most active treatment options had significantly better treatment outcome than placebo. [ABSTRACT FROM AUTHOR]

Background: The lack of good evidence for improved outcomes in children and young infants with febrile urinary tract infection (UTI) after aggressive treatment for vesicoureteral reflux (VUR) has raised doubts regarding the need for routine voiding cystourethrography (VCUG), and the appropriate imaging evaluation in these children remains controversial. Objectives: This prospective study aimed to determine whether abnormalities found on acute dimercaptosuccinic acid (DMSA) scan and ultrasound (US) can help indicate the necessity of voiding cystourethrography (VCUG) in young infants. Methods: For 3.5 years, all infants younger than 3 months presenting with first febrile UTI were prospectively studied. All infants were hospitalized and investigated using US (<3 days after admission), DMSA scan (<5 days after admission), and VCUG (7-10 days after antibiotic treatment) after diagnosis. The association among findings of US, DMSA scan, and VCUG were evaluated. Results: From 220 infants, there were abnormal results in 136 (61.8%) US and in 111 (50.5%) DMSA scans. By US, ten infants (4.5%) with abscess or structural abnormalities other than VUR were diagnosed. High-grade (III-V) VUR was present in 39 patients (17.7%). The sensitivities for high-grade VUR of renal US alone (76.9%) or DMSA scan alone (82.1%) were not as good as that of the 'OR rule' strategy, which had 92.3% sensitivity and 94.3% negative predictive value. Conclusions: To screen high-grade VUR in young infants with febrile UTI, US and acute DMSA scan could be performed first. VCUG is only indicated when abnormalities are apparent on either US or DMSA scan or both. [ABSTRACT FROM AUTHOR]

Simple Summary: Regorafenib after sorafenib therapy improved survival in patients with advanced hepatocellular carcinoma in the RESORCE study. The aim of our retrospective study was to investigate the predictors of response and outcome of regorafenib therapy in patients with unresectable hepatocellular carcinoma in whom sorafenib therapy had failed. We demonstrated that albumin-bilirubin grade at the initiation of regorafenib therapy is an independent predictor of disease control, progression-free survival, and overall survival. Patients with albumin-bilirubin grade 2 and an alpha-fetoprotein level of ≥20 ng/mL had the worst progression-free survival (after regorafenib therapy) and overall survival (after regorafenib and sorafenib therapy). Thus, a combination of albumin-bilirubin grade and alpha-fetoprotein level can be used to stratify patients with unresectable hepatocellular carcinoma by progression-free survival and overall survival probability for sorafenib–regorafenib sequential therapy. In the RESORCE study, regorafenib after sorafenib therapy improved survival in patients with advanced hepatocellular carcinoma (HCC). In total, 88 patients with unresectable HCC who received sorafenib–regorafenib sequential therapy were enrolled. The objective response rate and disease control rate were 19.3% and 48.9%, respectively, for regorafenib therapy (median duration: 8.1 months). Median progression-free survival (PFS) after regorafenib therapy was 4.2 months (95% CI: 3.2–5.1). The median overall survival (OS; from initiation of either sorafenib or regorafenib) was not reached in this cohort. According to multivariate Cox regression analyses, albumin-bilirubin (ALBI) grade at the initiation of regorafenib therapy is an independent predictor of disease control, PFS, and OS. Moreover, the combination of ALBI grade 2 and an alpha-fetoprotein (AFP) level of ≥20 ng/mL was an independent predictor of PFS (hazard ratio (HR): 3.088, 95% CI: 1.704–5.595; p < 0.001) for regorafenib therapy, and OS for both regorafenib (HR: 3.783, 95% CI: 1.316–10.88; p = 0.014) and sorafenib–regorafenib sequential (HR: 4.603, 95% CI: 1.386–15.29; p = 0.013) therapy. A combination of ALBI grade and AFP level can be used to stratify patients with unresectable HCC by PFS and OS probability for sorafenib–regorafenib sequential therapy. [ABSTRACT FROM AUTHOR]

Background: Delayed post-polypectomy bleeding (PPB) is a major complication of polypectomy. The effect of prophylactic hemoclipping on delayed PPB is uncertain. The aim of this study was to evaluate the effectiveness of prophylactic hemoclipping and identify the risk factors of delayed PPB.Methods: Patients with polyps sized 6 to 20 mm underwent snare polypectomy from 2015 to 2017 were retrospectively reviewed. The patients with prophylactic hemoclipping for delayed PPB prevention were included in the clipping group, and those without prophylactic hemoclipping were included in the non-clipping group. The incidence of delayed PPB and time to bleeding were compared between the groups. Multivariate analysis was used to identify the risk factors of delayed PPB. Propensity score matching was used to minimize potential bias.Results: After propensity score matching, 612 patients with 806 polyps were in the clipping group, and 576 patients with 806 polyps were in the non-clipping group. There were no significant differences in the incidence of delayed PPB and days to bleeding between two groups (0.8% vs 1.3%, p = 0.4; 3.4 ± 1.94 days vs 4.13 ± 3.39 days, p = 0.94). In the multivariate analysis, the polyp size [Odds ratio (OR):1.16, 95% confidence interval (CI):1.01-1.16, p = 0.03), multiple polypectomies (OR: 4.64, 95% CI:1.24-17.44, p = 0.02) and a history of anticoagulant use (OR:37.52, 95% CI:6.49-216.8, p < 0.001) were associated with delayed PPB.Conclusions: In polyps sized 6 to 20 mm, prophylactic hemoclip placement did not decrease the risk of delayed PPB. Patients without risk factors including multiple polypectomies and anticoagulant use are no need to performing prophylactic hemoclipping. [ABSTRACT FROM AUTHOR]

Although many studies have shown the association between smoking and the increased incidence and adverse prognosis of head and neck squamous cell carcinoma (HNSCC), the mechanisms and pharmaceutical targets involved remain unclear. Here, we integrated gene expression signatures, genetic alterations, and survival analyses to identify prognostic indicators and therapeutic targets for smoking HNSCC patients, and we discovered that the FDA-approved drug varenicline inhibits the target for cancer cell migration/invasion. We first identified 18 smoking-related and prognostic genes for HNSCC by using RNA-Seq and clinical follow-up data. One of these genes, CHRNB4 (neuronal acetylcholine receptor subunit beta-4), increased the risk of death by approximately threefold in CHRNB4-high expression smokers compared to CHRNB4-low expression smokers (log rank, p = 0.00042; hazard ratio, 2.82; 95% CI, 1.55–5.14), former smokers, and non-smokers. Furthermore, we examined the functional enrichment of co-regulated genes of CHRNB4 and its 246 frequently occurring copy number alterations (CNAs). We found that these genes were involved in promoting angiogenesis, resisting cell death, and sustaining proliferation, and contributed to much worse outcomes for CHRNB4-high patients. Finally, we performed CHRNB4 gene editing and drug inhibition assays, and the results validate these observations. In summary, our study suggests that CHRNB4 is a prognostic indicator for smoking HNSCC patients and provides a potential new therapeutic drug to prevent recurrence or distant metastasis. [ABSTRACT FROM AUTHOR]

Background: Hyperlactatemia is known to be associated with adverse outcome in critical illness. In this study, we attempted to identify if hyperlactatemia on emergency department (ED) arrival is a reliable predictor for in-hospital mortality in necrotizing fasciitis (NF) patients. Method: A prospective cohort study of hospitalized patients with NF was conducted in two tertiary teaching hospitals in Taiwan between March 2010 and March 2018. Blood samples were collected in the ED upon arrival, and the lactate levels were determined. Sequential organ failure assessment (SOFA) scores were calculated during the first 24 h after admission. All collected data were statistically analyzed. Result: Of the 707 NF patients, 40 (5.66%) died in the hospital. The median (interquartile range) blood lactate level in all NF patients was 3.6 mmol/l (2.2–4.8). The blood lactate level upon ED arrival was significantly associated with mortality (odds ratio [OR] = 1.35; 95% confidence interval [CI], 1.30–1.46; P < 0.001), even after adjustment for age and SOFA score (OR = 1.27; P < 0.001). Multivariate regression analysis showed that a high blood lactate level (OR = 1.17; 95% CI, 1.07–1.29; P = 0.001) and a high SOFA score (OR = 1.15; 95% CI, 1.11–1.20; P < 0.001) were independent risk factors for in-hospital mortality in NF. Blood lactate achieved an area under-the-receiver-operating-characteristic curve (AUC) of 0.79 (P < 0.001) for predicting mortality that was similar to that of SOFA score (AUC = 0.82; P < 0.001). Blood lactate displayed a sensitivity of 62% and a specificity of 86% in predicting mortality at the optimal cutoff value of 5.80 mmol/l. Conclusion: In necrotizing fasciitis patients, hyperlactatemia on ED arrival is independently associated with in-hospital mortality. NF patients with hyperlactatemia on ED arrival should be closely monitored for signs of deterioration and consider early and aggressive intervention to prevent mortality. [ABSTRACT FROM AUTHOR]

Background: Necrotizing fasciitis (NF) is a rapidly progressive infectious disease that primarily involves the fascia and subcutaneous tissue. If not promptly treated, it can lead to morbidity as well as mortality. It can affect any part of the body, most commonly the extremities. Early and aggressive surgical treatment is the proper way of management. The purpose of this study was to identify the risk factors for mortality in late amputation among NF patients that may be used in routine clinical practice to prevent mortality. Methods: A retrospective cohort study of hospitalized patients with NF was conducted in a tertiary teaching hospital in Taiwan between March 2015 and March 2018. All collected data were statistically analyzed. Results: A total of 582 patients with NF were included; 35 of them had undergone amputation (7 primary and 28 late amputations), with a 6% amputation rate. Thirteen amputated patients still died eventually (all in the late amputation group). Significant risk factors for mortality identified in the late amputation group included hemorrhagic bullae (p = 0.001, OR 4.7, 95% confidence interval (CI) 2.68–8.69), peripheral vascular disease (p < 0.001, OR 3.2, 95% CI 1.12–10.58), bacteremia (p = 0.021, OR 2.87, 95% CI 2.07–5.96), and Laboratory Risk Indicator of Necrotizing Fasciitis (LRINEC) score > 8 (p < 0.001, OR 1.97, 95% CI 1.28–4.61). Vibrio vulnificus was the main causative organism based on our study, but the microbiology results showed no significant correlation. Conclusion: NF patients with hemorrhagic bullae, comorbidity with peripheral vascular disease, presence of bacteremia, or LRINEC score > 8 should receive early and primary amputation in order to prevent mortality. [ABSTRACT FROM AUTHOR]

Background Treatment with statin may be beneficial for patients with chronic kidney disease (CKD). However, the debate over the clinical importance of statin in patients with predialysis advanced CKD remains unresolved. Objectives The objective of the article was to evaluate the effect of statin on mortality, cerebrovascular, and renal outcomes in patients with predialysis advanced CKD and dyslipidemia. Methods Data on predialysis advanced CKD patients were retrieved from the National Health Insurance Research Database based on the guidelines for prescribing regular erythropoietin-stimulating agent in CKD patients. Patients with dyslipidemia were further selected and divided into 2 groups by their statin use after the prescribed erythropoietin-stimulating agent. All-cause mortality and cerebrovascular and renal outcomes were analyzed after propensity score matching. Results There were 2016 and 14,412 patients in the statin and nonstatin groups. Their average follow-up periods were 3.7 and 3.0 years, respectively. After 1:2 propensity score matching, the annual all-cause mortality rate was higher in the nonstatin than in the statin group (143.99 vs 109.50 per 1000 person-years; P < .001; hazard ratio: 0.73; 95% confidence interval: 0.68–080). The annual risk of ischemic stroke ( P = .186) and intracranial hemorrhage ( P = .322) were not significantly different between the 2 groups. The nonstatin group had a higher risk of dialysis than the statin group (1269.45 vs 1095.00 per 1000 person-years; P = .002). Adverse events were not significant between the 2 groups. Conclusions Statins may reduce the all-cause mortality and reduced the risk of dialysis in patients with predialysis advanced CKD and dyslipidemia. However, statins have no impact on ischemic–hemorrhage stroke. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) is a Schedule II illicit drug in Taiwan. A 12-month legal–medical joint intervention program has been developed for first-time METH offenders during deferred prosecution. Risk factors associated with METH relapse use among these individuals were unknown. We enrolled a total of 449 METH offenders referred by the Taipei District Prosecutor's Office to Taipei City Psychiatric Center. The study defines relapse as having any positive urine toxicology result or self-report of METH use during 12-month treatment. We compared demographic and clinical variables between a relapse group and nonrelapse group and used a Cox proportional hazards model to determine variables associated with time to relapse. Of all participants, 37.8 % relapsed to use METH and 23.2 % were noncompleters in the one-year follow-up. Compared to the nonrelapse group, the relapse group had lower educational attainment, more severe psychological symptoms, longer duration of METH use, higher odds of polysubstance use, higher craving severity, and higher odds of positive baseline urine. The Cox analysis revealed individuals with positive urine results and higher craving severity at baseline were at higher risks of METH relapse (hazard ratio [95 % CI]: 3.85 [2.61–5.68] and 1.71 [1.19–2.46], respectively, p < 0.001). Baseline positive urine results and high craving could also predict a shorter length of time to relapse than their respective counterparts. Positive urine screening for METH at baseline and high craving severity are two indicators of an increased risk of drug relapse. Tailored treatment plans incorporating these findings to prevent relapse are warranted in our joint intervention program. • A joint legal–medical intervention program provides 12-month addiction treatment. • We followed 449 individuals with methamphetamine offense receiving the treatment. • 37.8 % had methamphetamine relapse and 26.5 % discontinued the 12-month treatment. • Baseline urine positive of methamphetamine and high craving increased relapse risk. • Tailored treatment incorporating these findings is warranted in the joint program. [ABSTRACT FROM AUTHOR]

Objectives: To study norovirus gastroenteritis infection among residents and health care workers (HCWs) during an outbreak in a nursing home by investigating the attack rate and positive diagnostic rate for norovirus by reverse transcription–polymerase chain reaction (RT-PCR). Methods: All members in a Chang Gung Memorial Hospital–affiliated nursing home from November 17, 2006, to November 25, 2006, including 236 residents and 125 HCWs, whose available medical records were available were consecutively included in the retrospective analysis. Fecal specimens of symptomatic residents and HCWs were tested for norovirus by RT-PCR. In addition, routine stool analysis and a stool culture study were conducted to identify the bacterial and parasitic agents. The fecal specimens of asymptomatic residents and HCWs were tested only for norovirus by RT-PCR. Results: The outbreak was controlled within 9 days during the outbreak period. There were 51 symptomatic cases, 41 residents and 10 HCWs, during the norovirus outbreak. The odds ratio (OR) of the attack rate in the residents was approximately 2.4 times higher than that in the HCWs (OR: 2.4; 95% confidence interval [CI]: 1.2–5.0; P = .015). Norovirus was detected in 59 (30.6%) of 193 residents and in 11 (10.5%) of 105 HCWs who provided stool specimens for the study by RT-PCR. The OR of the positive diagnostic rate for norovirus by RT-PCR in the residents was approximately 3.8 times higher than that in the HCWs (OR: 3.8; 95% CI: 1.9–7.5; P < .001). Conclusions: During an outbreak of norovirus gastroenteritis in a nursing home, the infection can be easily transmitted from person to person and affects both residents and HCWs. In addition, residents had a higher risk of norovirus gastroenteritis infection than HCWs. [Copyright &y& Elsevier]