Search

Background: Transanal endoscopic surgery is the treatment of choice in patients with rectal adenomas that cannot be removed by endoscopy. However, the risk of adenoma recurrence and optimal surveillance is not well defined. The objective of this study was to characterize the timing and frequency of rectal adenoma recurrence after removal by transanal endoscopic surgery and identify recurrence risk factors., Methods: This was a retrospective cohort study of a large, single-center academic institution in Vancouver, BC, Canada. Consecutive patients between May 1, 2007 and September 30, 2016 with pathology-confirmed rectal adenoma treated by primary excision with transanal endoscopic surgery and at least 1 year of confirmed endoscopic follow-up were included. Main outcome measures were recurrence rates following TEM as well as risk factors for recurrence., Results: 297 patients met inclusion criteria. The mean age of patients was 66.5 ± 11.5 years and 57.9% were male. Median follow-up was 623 (range 56-3841) days. A total of 62 recurrences occurred in 41 patients (13.8% of study population). Recurrences were managed with repeat transanal endoscopic surgery or endoscopic resection 67.7% and 25.8% of the time, respectively. Radical resection was required for adenocarcinoma in 4 patients. Recurrence-free survival rates were 93.4% at 1 year, 86.2% at 2 years, and 73.1% at 5 years. After adjusting for individual surgeons, adenoma height, size > 3 cm, high-grade dysplasia, positive margins, and management of the rectal defect, patients who underwent surgery in the latter 5 years of the study had lower odds of recurrence (OR 0.42, 95% CI 0.19, 0.93, p = 0.03)., Conclusions: Rectal adenomas managed by transanal endoscopic surgery are lesions at high risk for recurrence; surveillance should be performed within the first 2 years and continued for a total of at least 5 years. Most recurrences can be successfully treated with repeat TEM or endoscopic resection.

Cyclic vomiting syndrome is an idiopathic chronic periodic disorder of childhood which may persist into the adult years. Although cyclic vomiting syndrome is considered a central nervous system disorder, it is often managed by a pediatric gastroenterologist. The practitioner should not assume a gastrointestinal or non-neurological cause of symptoms especially if there are coexisting neurological symptoms and signs or if vomiting does not bring relief; this suggests a possible central nervous system cause, which may necessitate a pediatric neurology consultation. Examples of central nervous system causes of cyclic vomiting syndrome that can have subjective and objective neurological findings include abdominal migraine, certain types of epilepsy, structural lesions (tumors, Chiari malformation, demyelinating disease), mitochondrial disease, autonomic disorders, fatty acid/organic acid disorders, urea cycle defects, and cannabinoid hyperemesis syndrome. Improved familiarity with cyclic vomiting syndrome and its mimics may improve the time to appropriate diagnosis and may reduce morbidity related to cyclic vomiting syndrome., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Dengue virus (DENV) infection is associated with clinical ocular presentations and here DENV infection of the eye was assessed in mice. In an AG129 mouse model of antibody-dependent enhancement of DENV infection, DENV RNA was detected in the eye and vascular changes were present in the retinae. Intraocular CD8 and IFN-γ mRNA were increased in mice born to DENV-naïve, but not DENV-immune mothers, while TNF-α mRNA was induced and significantly higher in mice born to DENV-immune than DENV-naïve mothers. DENV RNA was detected in the eye following intracranial DENV infection and CD8 mRNA but not IFN-γ nor TNF-α were induced. In all models, viperin was increased following DENV infection. Thus, DENV in the circulation or the brain can infect the eye and stimulate innate immune responses, with induction of viperin as one response that consistently occurs in multiple DENV eye-infection models in both an IFN-dependent and independent manner.

Infiltration of leukocytes within the vessel at sites of inflammation and the subsequent generation of myeloperoxidase-derived oxidants, including hypochlorous acid, are key characteristics of atherosclerosis. Hypochlorous acid is a potent oxidant that reacts readily with most biological molecules, including DNA and RNA. This results in nucleic acid modification and the formation of different chlorinated products. These products have been used as biomarkers of inflammation, owing to their presence in elevated amounts in different inflammatory fluids and diseased tissue, including atherosclerotic lesions. However, it is not clear whether these materials are simply biomarkers, or could also play a role in the development of chronic inflammatory pathologies. In this study, we examined the reactivity of different chlorinated nucleosides with human coronary artery endothelial cells (HCAEC). Evidence was obtained for the incorporation of each chlorinated nucleoside into the cellular RNA or DNA. However, only 8-chloro-adenosine (8ClA) had a significant effect on the cell viability and metabolic activity. Exposure of HCAEC to 8ClA decreased glycolysis, and resulted in a reduction in ATP, with a corresponding increase in the chlorinated analogue, 8Cl-ATP in the nucleotide pool. 8ClA also induced sustained endoplasmic reticulum stress within the HCAEC, which resulted in activation of the unfolded protein response, the altered expression of antioxidant genes and culminated in the release of calcium into the cytosol and cell death by apoptosis. Taken together, these data provide new insight into pathways by which myeloperoxidase activity and resultant hypochlorous acid generation could promote endothelial cell damage during chronic inflammation, which could be relevant to the progression of atherosclerosis., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The decision to offer surgery to an older adult with medical comorbidities involves candid conversations between the surgeon, patient, and caregivers. Tools are available to physicians that facilitate patient empowerment. Beyond short-term risks, the conversation should include the potential for institutional discharge, functional and cognitive decline, and longer term mortality., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Psychological well-being in people with neurological diseases can be compromised due to brain damage or psychological reactions towards chronic disabilities. This systematic review evaluated the efficacy of positive psychological intervention (PPI) in neurological populations., Methods: Previous studies relevant to this topic were identified by searches in PUBMED, EMBASE, MEDLINE, and PSYCINFO databases from Jan 1980 to August 2017., Results: Of 1361 articles identified, 31 studies were included. Nineteen studies were randomized controlled trials. Sixteen studies had sample sizes of less than 30. Twelve studies were rated as high quality using the National Heart, Lung, and Blood Institute (NHLBI) quality assessment tools. Six therapies were found: mindfulness-based approaches, positive savoring, life summary, expressive-based, hope-based interventions, and character strengths. These interventions were shown to improve quality of life, reduce symptomatic distress, and depressive symptoms., Conclusion: PPIs promote well-being among patients with neurological deficits. For PPIs to be considered as an evidence-based practice, more trials with adequate statistical power are required.

Background: Over the last 10 years, there has been a major treatment revolution for early human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to explore the outcome of different neoadjuvant chemotherapy in a tertiary breast cancer centre with early HER2-positive breast cancer as well as factors associated with pathological complete response (pCR) and recurrence-free survival (RFS). The pattern of recurrence was also studied., Methods: This retrospective study analysed the outcome of neoadjuvant chemotherapy during the period 2005 to 2016 in a tertiary referral centre in Hong Kong. Patients were divided into three groups according to the neoadjuvant chemotherapy they received: chemotherapy only (Chemo), chemotherapy plus trastuzumab (Chemo-H) and chemotherapy plus double anti-HER2 therapy (Chemo-DH)., Results: There were 226 cases analysed during the study period. The rate of pCR was 5%, 26% and 60% in Chemo, Chemo-H and Chemo-DH groups, respectively (Chemo vs pooled Chemo-H/DH: p<0.0001; Chemo-H vs Chemo-DH: p<0.0001). This was accompanied by a trend of increased rate of breast conservation therapy in Chemo-DH cohort (p=0.046). Use of double anti-HER2 therapy, older age (>50 years) and hormone receptor negativity were associated with more pCR. pCR was associated with better RFS. Among those with recurrence, the proportion of patients with brain as the only site of recurrence increased remarkably with more efficacious anti-HER2 treatment (0% in Chemo, 8% in Chemo-H, 67% in Chemo-DH)., Conclusion: pCR remains an important predictive factor for improved RFS. In the era of dual anti-HER2 neoadjuvant therapy, brain-only recurrence poses a challenge to disease surveillance and treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1 , has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA., Competing Interests: The authors declare no competing financial interest.

Importance: Breast cancer surgery, the most common cancer operation performed in nursing home residents, is viewed as a low-risk surgical intervention. However, outcomes in patients with high functional dependence and limited life expectancy are poorly understood., Objective: To assess the overall survival and functional status changes after breast cancer surgery in female nursing home residents stratified by surgery type., Design, Setting, and Participants: This study used Medicare claims from 2003 to 2013 to identify 5969 US nursing home residents who underwent inpatient breast cancer surgery. Using the Minimum Data Set Activities of Daily Living (MDS-ADL) summary score, this study examined preoperative and postoperative function and identified patient characteristics associated with 30-day and 1-year mortality and 1-year functional decline after surgery. Cox proportional hazards regression was used to estimate unadjusted and adjusted hazard ratios (HRs) of mortality. Fine-Gray competing risks regression was used to estimate unadjusted and adjusted subhazard ratios (sHRs) of functional decline. Statistical analysis was performed from January 2016 to January 2018., Main Outcomes and Measures: Functional status and death., Results: From 2003 to 2013, a total of 5969 female nursing home residents (mean [SD] age, 82 [7] years; 4960 [83.1%] white) underwent breast cancer surgery: 666 (11.2%) underwent lumpectomy, 1642 (27.5%) underwent mastectomy, and 3661 (61.3%) underwent lumpectomy or mastectomy with axillary lymph node dissection (ALND). The 30-day mortality rates were 8% after lumpectomy, 4% after mastectomy, and 2% after ALND. The 1-year mortality rates were 41% after lumpectomy, 30% after mastectomy, and 29% after ALND. Among 1-year survivors, the functional decline rate was 56% to 60%. The mean MDS-ADL score increased (signifying greater dependency) by 3 points for lumpectomy, 4 points for mastectomy, and 5 points for ALND. In multivariate analysis, poor baseline MDS-ADL score (range, 20-28) was associated with a higher 1-year mortality risk (lumpectomy: HR, 1.92 [95% CI, 1.23-3.00], P = .004; mastectomy: HR, 1.80 [95% CI, 1.35-2.39], P < .001; and ALND: HR, 1.77 [95% CI, 1.46-2.15], P < .001). After multivariate adjustment, preoperative decline in MDS-ADL score (lumpectomy: sHR, 1.59 [95% CI, 1.25-2.03], P < .001; mastectomy: sHR, 1.79; [95% CI, 1.52-2.09], P < .001; and ALND: sHR, 1.72 [95% CI, 1.56-1.91], P < .001) and cognitive impairment (lumpectomy: sHR, 1.27 [95% CI, 1.03-1.56], P = .02; mastectomy: sHR, 1.26 [95% CI, 1.09-1.45], P = .002; and ALND: sHR, 1.14 [95% CI, 1.04-1.24], P = .003) were significantly associated with 1-year functional decline across all breast cancer surgery groups., Conclusions and Relevance: For female nursing home residents who underwent breast cancer surgery, 30-day mortality and survival as well as 1-year mortality and functional decline were high. The 1-year survivors had significant functional decline. This study's findings suggest that this information should be incorporated into collaborative surgical decision-making processes.

Although Hong Kong is one of the richest cities in the world and has some of the best health outcomes such as long life expectancy, little is known about the people who are unable to access healthcare due to lack of financial means. Cross-sectional data from a sample of 2,233 participants aged 18 or above was collected from the first wave of the "Trends and Implications of Poverty and Social Disadvantages in Hong Kong" survey. Socio-demographic factors, lifestyle factors, and physical and mental health conditions associated with people who were unable to seek medical services due to lack of financial means in the past year were examined using forward stepwise logistic regression analyses. Of the 2,233 participants surveyed, 8.4% did not seek medical care due to lack of financial means during the past year. They were more likely to be income-poor. With respect to physical and mental health, despite having less likelihood to have multimorbidity, they tended to have higher levels of both anxiety and stress, poorer physical and mental health-related quality of life, and suffer from more severe disability and pain symptoms affecting their daily activities, when compared to the rest of the Hong Kong population. People who were denied of medical care due to financial barriers are generally sicker than people in the general Hong Kong population, implying that those with greater healthcare needs may have financial difficulties in receiving timely and appropriate medical care. Our findings suggest that inequity in healthcare utilization remains a critical issue in Hong Kong., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To elicit decisions that diverse older adults and surrogates perceive as serious, difficult, or important and explore what helped them make those decisions., Design: Focus groups (N=13) in which participants were asked to recall serious, difficult, or important medical decisions and what helped them make those decisions., Setting: Clinics, support groups and senior centers., Participants: Diverse English- and Spanish-speaking older adults (age: mean 78, range 64-89) and surrogates (age: mean 57, range 33-76) (29% African American, 26% white, 26% Asian or Pacific Islander, 19% Hispanic) (N=69)., Measurements: We used thematic analysis to analyze transcripts., Results: We identified 168 decisions. Older adults from all racial and ethnic groups frequently recalled cancer treatment decisions and decisions about chronic illness management. Surrogates described decisions about transitions in care and medical crises. Older adults valued self-sufficiency and maximizing survival and relied on personal experiences as often as medical advice. In all racial and ethnic groups, surrogates valued avoiding suffering for loved ones., Conclusion: Diverse older adults and surrogates perceive life-threatening illness and day-to-day decisions about chronic disease to be serious, difficult, and important. The surrogates' goal of avoiding suffering of older adults may differ from older adults' priorities of self-sufficiency and maximizing survival. Clinicians should support older adults and surrogates in identifying important and difficult decisions and learn about the values and information sources they bring to decision-making. With this knowledge, clinicians can customize decision support and achieve person-centered care., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

Given the significant impact that psychosocial factors and epilepsy treatments can have on the health-related quality of life (HRQOL) of individuals with epilepsy and their families, there is great clinical interest in the role of psychological evaluation and treatments to improve HRQOL and comorbidities. Therefore, the International League Against Epilepsy (ILAE) charged the Psychology Task Force with the development of recommendations for clinical care based on evaluation of the evidence from their recent Cochrane review of psychological treatments in individuals with epilepsy. The literature search for a recent Cochrane review of randomized controlled trials investigating psychological treatments for individuals with epilepsy constitutes the key source of evidence for this article. To provide practical guidance to service providers, we provide ratings on study research designs based on (1) the American Academy of Neurology's Level of Evidence system and (2) the Grading of Recommendations, Assessment, Development, and Evaluation system. This paper is the culmination of an international collaboration process involving pediatric and adult psychologists, neurologists, psychiatrists, and neuropsychiatrists. The process and conclusions were reviewed and approved by the ILAE Executive Committee. The strongest evidence for psychological interventions was identified for the most common mental health problems, including depression, neurocognitive disturbances, and medication adherence. Psychological interventions targeting the enhancement of HRQOL and adherence and a decrease in comorbidity symptoms (anxiety, depression) should be incorporated into comprehensive epilepsy care. There is a range of psychological strategies (ie, cognitive behavioral therapy and mindfulness-based therapies) that show promise for improving the lives of persons with epilepsy, and clinical recommendations are provided to assist epilepsy health care providers in treating the comorbidities and challenges associated with epilepsy and its treatments., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Cardiac myosin binding protein C (MYBPC3) is the most commonly mutated gene associated with hypertrophic cardiomyopathy (HCM). Haploinsufficiency of full-length MYBPC3 and disruption of proteostasis have both been proposed as central to HCM disease pathogenesis. Discriminating the relative contributions of these 2 mechanisms requires fundamental knowledge of how turnover of WT and mutant MYBPC3 proteins is regulated. We expressed several disease-causing mutations in MYBPC3 in primary neonatal rat ventricular cardiomyocytes. In contrast to WT MYBPC3, mutant proteins showed reduced expression and failed to localize to the sarcomere. In an unbiased coimmunoprecipitation/mass spectrometry screen, we identified HSP70-family chaperones as interactors of both WT and mutant MYBPC3. Heat shock cognate 70 kDa (HSC70) was the most abundant chaperone interactor. Knockdown of HSC70 significantly slowed degradation of both WT and mutant MYBPC3, while pharmacologic activation of HSC70 and HSP70 accelerated degradation. HSC70 was expressed in discrete striations in the sarcomere. Expression of mutant MYBPC3 did not affect HSC70 localization, nor did it induce a protein folding stress response or ubiquitin proteasome dysfunction. Together these data suggest that WT and mutant MYBPC3 proteins are clients for HSC70, and that the HSC70 chaperone system plays a major role in regulating MYBPC3 protein turnover.

This study assessed blood levels of cortisol and cytokines (inflammatory and non-inflammatory) in members of the regular Canadian Armed Forces (CAF), and examined the associations between sex, age, and adiposity and circulating levels of cortisol as well as pro- and anti-inflammatory cytokines. As part of a larger ranging project, 331 blood samples were collected from a representative population of the total CAF, which included officers and noncommissioned women and men from the Air Force, Navy, and Army. The blood samples were analyzed for levels of cortisol, C-reactive protein (CRP), adiponectin, and 20 cytokines (which included interleukins, interferons, and tumor necrosis factors). Higher levels of adiponectin were found in women compared with men (median and interquartile range; 16.71 (7.68-25.32) vs 5.81 (3.52-13.19) μg/mL), and higher levels of interleukin (IL)-18 in men compared with women (89.25 (84.03-94.48) vs 75.91 (69.70-82.13) pg/mL). An association between age and levels of stress and inflammatory cytokines was observed, with CRP, IL-18, IL-2 and adiponectin all increasing with increasing age. However, contrary to trends seen in the general population, cortisol levels decreased with increasing age. Levels of CRP and IL-18 increased with an increase in adiposity, while adiponectin levels decreased. Most importantly, at the entire cohort level, a low detection rate for most of the cytokines was observed with 17 out of 22 cytokines having a detection below 10%., In Conclusion: In this CAF population, although an association between age and inflammatory cytokines was observed, both sex and adiposity had a small impact on levels of cortisol and cytokines.

Background: Positive psychological interventions (PPI) are increasingly employed as a coping strategy with physical and mental conditions, including neurological diseases. Its effectiveness on improving wellbeing in people with epilepsy (PWE) has been shown in a few studies. This study aimed to explore factors related to participants' willingness to engage in psychological interventions from the perspective of patients with epilepsy., Methods: Participants answered a needs assessment questionnaire eliciting information about their illness perception (Brief Illness Perception Questionnaire (Brief-IPQ)), emotions (Hospital Anxiety and Depression Scale (HADS)), willingness to participate in psychological interventions, preferences in types of PPI and intervention designs, as well as barriers in seeking mental health services., Results: A total of 154 patients with epilepsy participated, with a mean age of 37.3years (range 16-86years). Most patients had focal epilepsy (68.2%), and drug-resistant (59.1%). Majority (71.4%) of them indicated a strong willingness to participate in PPI. Out of nine types of PPI, character strengths, mindfulness-based and expressive-based interventions were highly preferred. Those with negative illness perception (p=0.001), anxiety (p=0.004), and being unemployed (p=0.048) were more willing to participate in PPI. Most participants preferred group rather than individual session, and a shorter duration (30min) was favored by most., Conclusion: This study captured the self-report willingness to participate in psychological interventions. Findings suggested that psychological interventions delivered in short-group session were highly preferred. Future study is required to determine the feasibility of such design for patients with epilepsy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Collagen is prevalent in the microenvironment of many cancer types and has been demonstrated to play an important role during disease progression. We previously showed the importance of hypoxic gradients in sarcoma cell migration. Here, we utilized an oxygen gradient collagen gel platform to determine the impact of collagen fiber density and hypoxic gradient on sarcoma cell migration. The oxygen gradient was created by regulating the oxygen diffusion coefficient along with the cellular oxygen consumption rate. Collagen fiber density in the hydrogels is modified by changing the preincubation period of the collagen gel solution at 4 °C, controlling fiber density independently of collagen concentration and oxygen tension. High fiber density gels have wider and longer fibers but a similar microscale pore size with a larger nanoscale pore size and quicker stress relaxation time, compared to the low fiber density gel. Both gels have the same Young's modulus. We analyzed responses of sarcoma cells encapsulated in the different hydrogels for 3 days. In the nonhypoxic low fiber density constructs, sarcoma cells exhibit a larger aspect ratio, and the matrix has less fiber alignment compared to the nonhypoxic high fiber density constructs. Interestingly, we found a minimal effect of fiber density on cell migration and the ability of the cells to degrade the matrix in nonhypoxic constructs. When compared with hypoxic constructs, we observed the opposite trend, where cells in low fiber density constructs exhibit a lower aspect ratio and the matrix has more aligned fibers compared to hypoxic high fiber density constructs. Sarcoma cells encapsulated in high fiber density hypoxic gels migrated faster and degraded the matrix more rapidly compared to the low fiber density hypoxic constructs. Overall, we show that hypoxic cell migration and matrix degradation are enhanced in high fiber density gels, while hypoxic matrix alignment is prominent in low fiber density gels. Our results suggest that the differences in cellular responses under hypoxic gradients are due to the hydrogel architecture including fiber density, size (length and width), and stress relaxation.

Objective: Given the significant impact epilepsy can have on health-related quality of life (HRQoL) of individuals with this condition and their families, there is great clinical interest in evidence-based psychological treatments aimed at enhancing well-being in people with epilepsy (PWE). An evaluation of the current evidence is needed to assess the effects of psychological treatments for PWE on HRQoL outcomes to inform future therapeutic recommendations and research designs., Methods: The operational definition of psychological treatments included a broad range of interventions that use psychological or behavioral techniques designed to improve HRQoL, psychiatric comorbidities, and seizure frequency and severity for adults and children with epilepsy. A systematic literature search was conducted in line with Cochrane criteria for randomized controlled trials (RCTs) and quasi-RCTs investigating psychological treatments and using HRQoL outcome measures as primary or secondary outcome measures. Standard methodological procedures required by the Cochrane Collaboration were used for data collection and analysis., Results: Twenty-four completed RCTs were included in this review (2439 participants). Based on satisfactory methodological homogeneity, data from 9 studies (468 participants) providing Quality of Life in Epilepsy-31 (QOLIE-31) outcomes were pooled for meta-analyses, showing significant mean changes for QOLIE-31 total score and 6 subscales. The significant mean changes of QOLIE-31 total score (mean improvement of 5.68 points; 95% confidence interval = 3.11-8.24, P < .0001) and 3 subscales (emotional well-being, energy/fatigue, overall quality of life [QoL]) exceeded the threshold of minimally important change, indicating a clinically meaningful postintervention improvement of QoL. Overall, the meta-analysis quality of evidence was characterized as "moderate" due to the risk of bias present in 8 of the 9 included studies (Handbook for Systematic Reviews of Interventions, Version 5.1.0, 2011, Chapters 8 and 12). A narrative synthesis was conducted for all trials and outcomes that were not entered in the meta-analysis., Significance: These results provide moderate-quality evidence that psychological treatments for adults with epilepsy may enhance HRQoL in people with epilepsy., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Background: Given the significant impact epilepsy can have on the health-related quality of life (HRQoL) of individuals with epilepsy and their families, there is great clinical interest in evidence-based psychological treatments, aimed at enhancing psychological well-being in people with epilepsy. A review of the current evidence was needed to assess the effects of psychological treatments for people with epilepsy on HRQoL outcomes, in order to inform future therapeutic recommendations and research designs., Objectives: To assess the effects of psychological treatments for people with epilepsy on HRQoL outcomes., Search Methods: We searched the following databases on 20 September 2016, without language restrictions: Cochrane Epilepsy Group Specialized Register, CENTRAL, MEDLINE PsycINFO, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). We screened the references from included studies and relevant reviews, and contacted researchers in the field for unpublished studies., Selection Criteria: We considered randomized controlled trials (RCTs) and quasi-RCTs for this review. HRQoL was the main outcome measure. For the operational definition of 'psychological treatments', we included a broad range of treatments that used psychological or behavioral techniques designed to improve HRQoL, seizure frequency and severity, and psychiatric comorbidities for adults and children with epilepsy, compared to treatment as usual (TAU) or an active control group., Data Collection and Analysis: We used standard methodological procedures expected by the Cochrane Collaboration., Main Results: We included 24 completed RCTs, with a total of 2439 participants. Eleven studies investigated psychological interventions, such as cognitive, behavioral, and mindfulness-based interventions. The remaining studies were classified as educational interventions (N = 7), self-management interventions (N = 3), adherence interventions (N = 1), and mixed interventions (N = 2). Two studies investigated interventions for children and adolescents, and five studies investigated interventions for adolescents and adults. Based on satisfactory clinical and methodological homogeneity, we pooled data from six adult studies, two studies on adolescents and adults, and one on adolescents and young adults (468 participants) for HRQoL, measured with the Quality of Life in Epilepsy-31 (QOLIE-31). We found significant mean changes for the QOLIE-31 total score and six subscales (emotional well-being, energy and fatigue, overall QoL, seizure worry, medication effects, and cognitive functioning). The mean changes of the QOLIE-31 total score (mean improvement of 5.68 points (95% CI 3.11 to 8.24; P < 0.0001), and three subscales, emotional well-being (mean improvement of 7.03 points (95% CI 2.51 to 11.54; P = 0.002); energy and Fatigue (mean improvement of 6.90 points (95% CI 3.49 to 10.31; P < 0.0001); and overall QoL (mean improvement of 6.47 points (95% CI 2.68 to 10.25; P = 0.0008) exceeded the threshold of minimally important change (MIC), indicating a clinically meaningful post-intervention improvement of QoL. We downgraded the quality of the evidence provided by the meta-analysis because of serious risk of bias in some of the included studies. Consequentially, these results provided evidence of moderate quality that psychological treatments for adults with epilepsy may enhance overall QoL in people with epilepsy., Authors' Conclusions: Implications for practice: Psychological interventions and self-management interventions improved QoL, and emotional well-being, and reduced fatigue in adults and adolescents with epilepsy. Adjunctive use of psychological treatments for adults and adolescents with epilepsy may provide additional benefits to QoL in those who incorporate patient-centered management., Implications for Research: Authors should strictly adhere to the CONSORT guidelines to improve the quality of reporting on their interventions. A thorough description of the intervention protocol is necessary to ensure reproducibility.When researching psychological treatments for people with epilepsy, the use of Quality of Life in Epilepsy Inventories (QOLIE-31, QOLIE-31-P, and QOLIE-89) would increase comparability. There is a critical gap in pediatric RCTs for psychological treatments, particularly those that use an epilepsy-specific measure of HRQoL.Finally, in order to increase the overall quality of study designs, adequate randomization with allocation concealment and blinded outcome assessment should be pursued when conducting RCTs. As attrition is often high in research that requires active participant participation, an intention-to-treat analysis should be carried out.

Background: Interventional cardiologists have one of the highest annual radiation exposures yet systems of care that promote radiation safety in cardiac catheterization labs are lacking. This study sought to reduce the frequency of radiation exposure, for PCI procedures, above 1.5Gy in labs utilizing a Phillips system at our local institution by 40%, over a 12-month period., Methods: We performed a time series study to assess the impact of different interventions on the frequency of radiation exposure above 1.5Gy. Process measures were percent of procedures where collimation and magnification were used and percent of completion of online educational modules. Balancing measures were the mean number of cases performed and mean fluoroscopy time., Interventions: Information sessions, online modules, policies and posters were implemented followed by the introduction of a new lab with a novel software (AlluraClarity©) to reduce radiation dose., Results: There was a significant reduction (91%, p<0.05) in the frequency of radiation exposure above 1.5Gy after utilizing a novel software (AlluraClarity©) in a new Phillips lab. Process measures of use of collimation (95.0% to 98.0%), use of magnification (20.0% to 14.0%) and completion of online modules (62%) helped track implementation. The mean number of cases performed and mean fluoroscopy time did not change significantly., Conclusion: While educational strategies had limited impact on reducing radiation exposure, implementing a novel software system provided the most effective means of reducing radiation exposure., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

The lateral membrane plays an important role in the mechanical stability of epithelial cell sheet in steady state. In addition, the lateral membrane is continuously remodeled during dynamic processes such as cell extrusion, cytokinesis, and intercellular cell movement. In wound healing, the lateral membrane must be built from flat and spread cells that had crawled into the area of the wound. Thus, forming the lateral membrane is a phenomenon that occurs not only in development but also during homeostatic maintenance and regeneration of differentiated epithelial tissues., Competing Interests: Competing interests: The author declares that she has no competing interests.No competing interests were disclosed.No competing interests were disclosed.

Hormone replacement therapy (HRT) affects the incidence and potential progression of colorectal cancer (CRC). As HRT primarily consists of estrone sulfate (E 1 S), understanding whether this conjugated estrogen is transported and metabolized in CRC will define its potential effect in this malignancy. Here, we show that a panel of CRC cell lines (Colo205, Caco2, HCT116, HT-29) have steroid sulfatase (STS) activity, and thus can hydrolyze E 1 S. STS activity is significantly higher in CRC cell lysate, suggesting the importance of E 1 S transport in intracellular STS substrate availability. As E 1 S transport is regulated by the expression pattern of certain solute carrier organic anion transporter polypeptides, we show that in CRC OATP4A1 is the most abundantly expressed transporter. All four CRC cell lines rapidly transported E 1 S into cells, with this effect significantly inhibited by the competitive OATP inhibitor BSP. Transient knockdown of OATP4A1 significantly disrupted E 1 S uptake. Examination of estrogen receptor status showed ERα was present in Colo205 and Caco2 cells. None of the cells expressed ERβ. Intriguingly, HCT116 and HT29 cells strongly expressed the G protein coupled estrogen receptor (GPER), and that stimulation of this receptor with estradiol (E 2 ) and G1, a GPER agonist, significantly ( p < 0.01) increased STS activity. Furthermore, tamoxifen and fulvestrant, known GPER agonist, also increased CRC STS activity, with this effect inhibited by the GPER antagonist G15. These results suggest that CRC can take up and hydrolyze E 1 S, and that subsequent GPER stimulation increases STS activity in a potentially novel positive feedback loop. As elevated STS expression is associated with poor prognosis in CRC, these results suggest HRT, tamoxifen and fulvestrant may negatively impact CRC patient outcomes.

Objectives: A simple and reliable biomarker for Crohn disease (CD) would be a valuable clinical tool. We hypothesized that anti-Saccharomyces cerevisiae antibody (ASCA) may be present in the stool of patients with CD. Accordingly, we measured ASCA in the stool and serum of children and adolescents with known or suspected inflammatory bowel disease (IBD)., Methods: We included 114 patients 19 years or younger (73 boys) with IBD, including 83 patients with CD and 31 subjects without CD (28 with ulcerative colitis, and 3 patients with suspected IBD but without evidence of chronic inflammation at the time of their endoscopy and colonoscopy). Fecal and serum samples were analyzed using semiquantitative ASCA enzyme-linked immunoassays., Results: Median ASCA levels were significantly elevated in the stool (P = 0.04) and serum (P = 0.0008) of patients with CD, when compared to levels observed in patients without CD. Fecal ASCA levels were similarly more elevated in patients with active CD, relative to levels observed in patients with active ulcerative colitis and acute colitis (P = 0.004). Among patients with CD, fecal and serum ASCA levels were higher (P = 0.01 and 0.01, respectively) in patients with more recently diagnosed disease., Conclusions: Fecal ASCA levels are higher in patients with active and newly diagnosed disease. Data from the present study suggest that measurement of fecal ASCA levels could represent a novel noninvasive biomarker for use in evaluating patients with suspected or known IBD. Further studies are necessary to better define the value of fecal ASCA measurements in identifying CD and response to therapy in children and young adults.

Objectives: Biliary atresia (BA) is a progressive fibroinflammatory cholangiopathy affecting the bile ducts of neonates. Although BA is the leading indication for pediatric liver transplantation, the etiology remains elusive. Adducin 3 (ADD3) and X-prolyl aminopeptidase 1 (XPNPEP1) are 2 genes previously identified in genome-wide association studies as potential BA susceptibility genes. Using zebrafish, we investigated the importance of ADD3 and XPNPEP1 in functional studies., Methods: To determine whether loss of either gene leads to biliary defects, we performed morpholino antisense oligonucleotide (MO) knockdown studies targeting add3a and xpnpep1 in zebrafish. Individuals were assessed for decreases in biliary function and the presence of biliary defects. Quantitative polymerase chain reaction was performed on pooled 5 days postfertilization larvae to assess variations in transcriptional expression of genes of interest., Results: Although both xpnpep1 and add3a are expressed in the developing zebrafish liver, only knockdown of add3a produced intrahepatic defects and decreased biliary function. Similar results were observed in homozygous add3a mutants. MO-mediated knockdown of add3a also showed higher mRNA expression of hedgehog (Hh) targets. Inhibition of Hh signaling rescued biliary defects caused by add3a knockdown. Combined knockdown of add3a and glypican-1 (gpc1), another mediator of Hh activity that is also a BA susceptibility gene, resulted in more severe biliary defects than knockdown of either alone., Conclusions: Our results support previous studies identifying ADD3 as a putative genetic risk factor for BA susceptibility. Our results also provide evidence that add3a may be affecting the Hh pathway, an important factor in BA pathogenesis., Competing Interests: The authors report no conflicts of interest.

Objectives: To develop a prediction index for 1-year mortality after hip fracture in older adults that includes predictors from a wide range of domains., Design: Retrospective cohort study., Settings: Health and Retirement Study (HRS)., Participants: HRS participants who experienced hip fracture between 1992 and 2010 as identified according to Medicare claims data (N = 857)., Measurements: Outcome measure was death within 1 year of hip fracture. Predictor measures were participant demographic characteristics, socioeconomic status, social support, health, geriatric symptoms, and function. Variables independently associated with 1-year mortality were identified, and best-subsets regression was used to identify the final model. The selected variables were weighted to create a risk index. The index was internally validated using bootstrapping to estimate model optimism., Results: Mean age at time of hip fracture was 84, and 76% of the participants were women. There were 235 deaths (27%) during the 1-year follow up. Five predictors of mortality were included in the final model: aged 90 and older (2 points), male sex (2 points), congestive heart failure (2 points), difficulty preparing meals (2 points), and not being able to drive (1 point). The point scores of the index were associated with 1-year mortality, with 0 points predicting 10% risk and 7 to 9 points predicting 66% risk. The c-statistic for the final model was 0.73, with an estimated optimism penalty of 0.01, indicating very little evidence of overfitting., Conclusion: The prognostic index combines demographic, comorbidity, and function variables and can be used to differentiate between individuals at low and high risk of 1-year mortality after hip fracture., Competing Interests: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Hypoxia is a critical factor in the progression and metastasis of many cancers, including soft tissue sarcomas. Frequently, oxygen (O2) gradients develop in tumors as they grow beyond their vascular supply, leading to heterogeneous areas of O2 depletion. Here, we report the impact of hypoxic O2 gradients on sarcoma cell invasion and migration. O2 gradient measurements showed that large sarcoma mouse tumors (>300 mm(3)) contain a severely hypoxic core [≤0.1% partial pressure of O2 (pO2)] whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1-6% pO2). To analyze tumor invasion, we used O2-controllable hydrogels to recreate the physiopathological O2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer distance in the hypoxic hydrogels compared with nonhypoxic hydrogels. To model the effect of the O2 gradient accurately, we examined individual sarcoma cells embedded in the O2-controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through hypoxia-inducible factor-1α (HIF-1α) activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O2 tension. Treatment with minoxidil, an inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Overall, we show that O2 acts as a 3D physicotactic agent during sarcoma tumor invasion and propose the O2-controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets., Competing Interests: The authors declare no conflict of interest.

Objective: To examine the feasibility of active surveillance for low volume Gleason sum (GS) 3 + 4 disease compared to GS 3 + 3 disease., Patients and Methods: Retrospective review of 929 patients, with biopsy proven GS 3 + 3 and 3 + 4 PCa, undergoing upfront radical prostatectomy (RP) was performed. Suitability for AS was adapted from protocols by Royal Marsden Hospital, University of Toronto, and PRIAS by allowing Gleason 3 + 4 disease. The outcomes assessed were adverse pathology at RP (upgrading ≥GS 4 + 3 and/or upstaging ≥pT3) and biochemical recurrence (BCR) after RP., Results: Adverse pathology at RP was compared between GS 3 + 3 vs 3 + 4 groups. When selecting patients using Royal Marsden (n = 714) or University of Toronto (n = 699) protocols, there was statistically significantly more adverse pathology at RP in GS 3 + 4 group (21% vs 31%, P = 0.0028 and 19% vs 33%, P=<0.001 respectively). Using the more stringent PRIAS protocol (n = 198), there was no statistical significant difference in groups. There was no difference in BCR survival between biopsy GS 3 + 3 and 3 + 4 groups, regardless of which AS protocol assessed. Pre-operative PSA and clinical staging were the predictors for BCR., Conclusion: Presence of Gleason 3 + 4 at biopsy, when compared to 3 + 3, increases the risk of adverse pathology being present at radical prostatectomy for less stringent selection criteria. When considering AS, a stricter protocol such as PRIAS, limiting PSA density and number of positive cores to ≤2, appears to decrease the risk of adverse pathology. No differences in BCR were seen between biopsy 3 + 3 and 3 + 4 disease, regardless of AS selection criteria., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

Alterations in lipid oxidation during exercise have been well studied, but limited data exists on the effects of passive heat exposure and exercise in the heat on changes in lipid oxidation. This study was designed to examine: (1) the effects of heat exposure on lipid metabolism during passive heating and subsequent exercise in the heat by focusing on changes in whole-body lipid oxidation and plasma lipid concentrations, and (2) the effects of extended passive pre-heating on exercise performance in the heat. Male participants (n=8) were passively heated for 120 min at 42 °C, then exercised on a treadmill in the same temperature at 50% V̇O2 max for 30 min (HEAT). This same procedure was followed on a separate occasion at 23 °C (CON). Results showed that lipid oxidation rates were not different between HEAT and CON during passive heating or exercise. However, non-esterified fatty acid (NEFA) concentrations were significantly higher following passive heating (618 µM, 95% CI: 479-757) compared to CON (391 µM, 95% CI: 270-511). The same trend was observed following exercise (2036 µM, 95% CI: 1604-2469 for HEAT and 1351 µM, 95% CI: 1002-1699). Triacylglycerol, phospholipid and cholesterol levels were not different between HEAT and CON at any point. Four of 8 participants could not complete 30 min of exercise in HEAT, resulting in a 14% decline in total external work. Rate of perceived exertion over the final 5 min of exercise was higher in HEAT (9.5) than CON (5). We conclude that: (1) heat exposure results in increased circulating NEFA at rest and during exercise without changes in whole-body lipid utilization, and (2) passive pre-heating reduces work capacity during exercise in the heat and increases the perceived intensity of a given workload., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Birth-related acute profound hypoxic-ischaemic brain injury has specific patterns of damage including the paracentral lobules., Objective: To test the hypothesis that there is anatomically coherent regional volume loss of the corpus callosum as a result of this hemispheric abnormality., Materials and Methods: Study subjects included 13 children with proven acute profound hypoxic-ischaemic brain injury and 13 children with developmental delay but no brain abnormalities. A computerised system divided the corpus callosum into 100 segments, measuring each width. Principal component analysis grouped the widths into contiguous anatomical regions. We conducted analysis of variance of corpus callosum widths as well as support vector machine stratification into patient groups., Results: There was statistically significant narrowing of the mid-posterior body and genu of the corpus callosum in children with hypoxic-ischaemic brain injury. Support vector machine analysis yielded over 95% accuracy in patient group stratification using the corpus callosum centile widths., Conclusion: Focal volume loss is seen in the corpus callosum of children with hypoxic-ischaemic brain injury secondary to loss of commissural fibres arising in the paracentral lobules. Support vector machine stratification into the hypoxic-ischaemic brain injury group or the control group on the basis of corpus callosum width is highly accurate and points towards rapid clinical translation of this technique as a potential biomarker of hypoxic-ischaemic brain injury.

This study compared delusional dimensions and attribution biases along the continuum of psychosis. Participants completed questionnaires on delusion-like beliefs and attributions. Although patients with first-episode psychosis (N = 70) endorsed fewer delusion-like beliefs than non-clinical individuals with psychotic-like experiences (N = 12), they scored highest on delusional conviction, distress and preoccupation, followed by non-clinical individuals with psychotic-like experiences, and then healthy controls (N = 642). Self-serving bias was found in patients and non-clinical individuals with psychotic-like experiences, but not in healthy controls. Personalizing bias for negative events was not significantly different across the three groups. When compared with healthy controls, non-clinical individuals with psychotic-like experiences had an exaggerated self-serving bias, but were not more marked in personalizing bias. Self-serving bias and personalizing bias were both associated with delusional dimensions. However, the association between self-serving bias and number of delusion-like beliefs was stronger among patients than non-clinical participants. Future research could investigate the extent to which self-serving bias, in combination with an appraisal of delusional ideation as convincing, distress, and preoccupying, contributes to the development of clinical delusions.

Objective: To investigate the effectiveness of mindfulness-based therapy (MT) and social support (SS) in patients with drug-resistant epilepsy., Methods: We performed an assessor-blinded randomized control trial. Sixty patients with drug-resistant epilepsy were randomly allocated to MT or SS (30 per group). Each group received 4 biweekly intervention sessions. The primary outcome was the change in the total score of the Patient-Weighted Quality of Life in Epilepsy Inventory (QOLIE-31-P). Secondary outcomes included seizure frequency, mood symptoms, and neurocognitive functions. The assessors were blinded to the patient's intervention grouping. Results were analyzed using general linear model with repeated measure., Results: Following intervention, both the MT (n=30) and SS (n=30) groups had an improved total QOLIE-31-P, with an improvement of +6.23 for MT (95% confidence interval [CI] +4.22 to +10.40) and +3.30 for SS (95% CI +1.03 to +5.58). Significantly more patients in the MT group had a clinically important improvement in QOLIE-31-P (+11.8 or above) compared to those who received SS (11 patients vs 4 patients). Significantly greater reduction in depressive and anxiety symptoms, seizure frequency, and improvement in delayed memory was observed in the MT group compared with the SS group., Conclusions: We found benefits of short-term psychotherapy on patients with drug-resistant epilepsy. Mindfulness therapy was associated with greater benefits than SS alone in quality of life, mood, seizure frequency, and verbal memory., Classification of Evidence: This study provides Class II evidence that mindfulness-based therapy significantly improves quality of life in patients with drug-resistant epilepsy., (© 2015 American Academy of Neurology.)

The present study investigated the neuropsychological effects of bilateral deep brain stimulation (DBS) on subthalamic nucleus (STN) in Chinese-Cantonese patients with idiopathic Parkinson's disease (PD). Twenty-seven patients were prospectively recruited from the Movement Disorder Clinic at the Hong Kong Prince of Wales Hospital. Neuropsychological evaluations were performed at baseline, 6 and 12 months following the DBS procedure. Assessment battery included standardized tests on global cognitive function, verbal memory, non-verbal memory, confrontation naming, visuospatial organization, attention and executive functions. Anxiety and depressive symptoms were measured by two self-reported questionnaires. Results demonstrated diminished performance on a category fluency task that occurred at 6 months post-operatively and persisted at 12-month re-evaluation; 29.6-33.3 % of patients showed reduction of more than 1 SD (standard deviation) at post-operative measure. Conversely, performance on an immediate recall task in a verbal memory test was found to improve significantly at the same time point and persisted through 12 months after surgery; 22.2-25.9 % showed an improvement (≥1 SD). Psychologically, anxiety symptoms were statistically decreased and the significant reduction occurred at 12 months after surgery. Patients who reported a moderate to severe level of anxiety reduced from 51.9 to 18.5 %. Our findings concurred with most evidences on the effects of STN-DBS on verbal fluency; on the other hand, we demonstrated improvement of immediate verbal memory that warranted further investigation.

Objective: To determine the time to benefit of using flexible sigmoidoscopy for colorectal cancer screening., Design: Survival meta-analysis., Data Sources: A Cochrane Collaboration systematic review published in 2013, Medline, and Cochrane Library databases., Eligibility Criteria: Randomized controlled trials comparing screening flexible sigmoidoscopy with no screening. Trials with fewer than 100 flexible sigmoidoscopy screenings were excluded., Results: Four studies were eligible (total n = 459,814). They were similar for patients' age (50-74 years), length of follow-up (11.2-11.9 years), and relative risk for colorectal cancer related mortality (0.69-0.78 with flexible sigmoidoscopy screening). For every 1000 people screened at five and 10 years, 0.3 and 1.2 colorectal cancer related deaths, respectively, were prevented. It took 4.3 years (95% confidence interval 2.8 to 5.8) to observe an absolute risk reduction of 0.0002 (one colorectal cancer related death prevented for every 5000 flexible sigmoidoscopy screenings). It took 9.4 years (7.6 to 11.3) to observe an absolute risk reduction of 0.001 (one colorectal cancer related death prevented for every 1000 flexible sigmoidoscopy screenings)., Conclusion: Our findings suggest that screening flexible sigmoidoscopy is most appropriate for older adults with a life expectancy greater than approximately 10 years., (© Tang et al 2015.)

A significant proportion of emergency urological admissions are comprised of ureteric colic presenting as loin pain. A variety of alternative pathologies present in this manner and should be considered during systematic assessment. We report the case of a patient admitted with severe unilateral back and flank pain after strenuous deadlift exercise. Clinical examination and subsequent investigation following a significant delay demonstrated acute paraspinal compartment syndrome (PCS) after an initial misdiagnosis of ureteric colic. The patient was managed conservatively. We review the current literature surrounding the rare diagnosis of PCS and discuss the management options.

The Earth's core is mostly an Fe-Ni alloy with a fraction of light elements (~10 wt%, mainly O, S and Si). Accumulation of these light elements under the core-mantle boundary (CMB) may lead to chemical stratification. Seismic observations have been presented both for and against the stratification in the topmost region of the outer core. Here we investigate the structure under the CMB using differential travel times between SKKS and S3KS waves. We obtain 606 high-quality S3KS-SKKS differential travel times with global path coverage. Result from a Bayesian inversion of these differential times indicates that the seismic velocity in the top 800 km of the outer core is ~0.07% on average lower than that in model PREM. The depth-dependent velocity profile, in particular a low-velocity zone of up to ~0.25% lower than PREM at ~80 km below the CMB, strongly favors the existence of stratification at the top of the outer core.

Objective: To present the result and experience of subthalamic nucleus deep brain stimulation for Parkinson's disease., Design: Case series., Setting: Prince of Wales Hospital, Hong Kong., Patients: A cohort of patients with Parkinson's disease received subthalamic nucleus deep brain stimulation from September 1998 to January 2010. Patient assessment data before and after the operation were collected prospectively., Results: Forty-one patients (21 male and 20 female) with Parkinson's disease underwent bilateral subthalamic nucleus deep brain stimulation and were followed up for a median interval of 12 months. For the whole group, the mean improvements of Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III were 32.5% and 31.5%, respectively (P<0.001). Throughout the years, a multidisciplinary team was gradually built. The deep brain stimulation protocol evolved and was substantiated by updated patient selection criteria and outcome assessment, integrated imaging and neurophysiological targeting, refinement of surgical technique as well as the accumulation of experience in deep brain stimulation programming. Most of the structural improvement occurred before mid-2005. Patients receiving the operation before June 2005 (19 cases) and after (22 cases) were compared; the improvements in UPDRS part III were 13.2% and 55.2%, respectively (P<0.001). There were three operative complications (one lead migration, one cerebral haematoma, and one infection) in the group operated on before 2005. There was no operative mortality., Conclusions: The functional state of Parkinson's disease patients with motor disabilities refractory to best medical treatment improved significantly after subthalamic nucleus deep brain stimulation. A dedicated multidisciplinary team building, refined protocol for patient selection and assessment, improvement of targeting methods, meticulous surgical technique, and experience in programming are the key factors contributing to the improved outcome.

Objective: To assess the role of centralized pathological review in penile cancer management., Materials and Methods: Newly diagnosed squamous cell carcinomas (SCC) of the penis, including squamous cell carcinoma in situ (CIS), from biopsy specimens were referred from 15 centres to the regional supra-network multidisciplinary team (Sn-MDT) between 1 January 2008 and 30 March 2011. Biopsy histology reports and slides from the respective referring hospitals were reviewed by the Sn-MDT pathologists. The biopsy specimens' histological type, grade and stage reported by the Sn-MDT pathologist were compared with those given in the referring hospital pathology report, as well as with definitive surgery histology. Any changes in histological diagnosis were sub-divided into critical changes (i.e. those that could alter management) and non-critical changes (i.e. those that would not affect management)., Results: A total of 155 cases of squamous cell carcinoma or CIS of the penis were referred from 15 different centres in North-West England. After review by the Sn-MDT, the histological diagnosis was changed in 31% of cases and this difference was statistically significant. A total of 60.4% of the changes were deemed to be critical changes that resulted in a significant change in management. When comparing the biopsy histology reported by the Sn-MDT with the final histology from the definitive surgical specimens, a good correlation was generally found., Conclusions: In the present study a significant proportion of penile cancer histology reports were revised after review by the Sn-MDT. Many of these changes altered patient management. The present study shows that accurate pathological diagnosis plays a crucial role in determining the correct treatment and maximizing the potential for good clinical outcomes in penile cancer. In the case of histopathology, centralization has increased exposure to penile cancer and thereby increased diagnostic accuracy, and should therefore be considered the 'gold standard'., (© 2013 The Authors. BJU International © 2013 BJU International.)

Dense-plasma-focus (DPF) Z-pinch devices are sources of copious high-energy electrons and ions, x rays, and neutrons. The mechanisms through which these physically simple devices generate such high-energy beams in a relatively short distance are not fully understood and past optimization efforts of these devices have been largely empirical. Previously we reported on fully kinetic simulations of a DPF and compared them with hybrid and fluid simulations of the same device. Here we present detailed comparisons between fully kinetic simulations and experimental data on a 1.2 kJ DPF with two electrode geometries, including neutron yield and ion beam energy distributions. A more intensive third calculation is presented which examines the effects of a fully detailed pulsed power driver model. We also compare simulated electromagnetic fluctuations with direct measurement of radiofrequency electromagnetic fluctuations in a DPF plasma. These comparisons indicate that the fully kinetic model captures the essential physics of these plasmas with high fidelity, and provide further evidence that anomalous resistivity in the plasma arises due to a kinetic instability near the lower hybrid frequency.

Objectives: Within health psychology, habit - the tendency to enact action automatically as a learned response to contextual cues - is most commonly quantified using the 'Self-Report Habit Index', which assesses behavioural automaticity, or measures combining self-reported behaviour frequency and context stability. Yet, the use of self-report to capture habit has proven controversial. This study used 'think-aloud' methods to investigate problems experienced when completing these two measures., Design: Cross-sectional survey with think-aloud study., Methods: Twenty student participants narrated their thoughts while completing habit measures applied to four health-related behaviours (active commuting, unhealthy snacking, and one context-free and one context-specific variant of alcohol consumption). Data were coded using thematic analysis procedures., Results: Problems were found in 10% of responses. Notable findings included participants lacking confidence in reporting automaticity, struggling to recall behaviour or cues, differing in interpretations of 'commuting', and misinterpreting items., Conclusions: While most responses were unproblematic, and further work is needed to investigate habit self-reports among larger and more diverse samples, findings nonetheless question the sensitivity of the measures, and the conceptualization of habit underpinning common applications of them. We offer suggestions to minimize these problems. Statement of contribution What is already known on this subject? Habit is most commonly measured within health psychology via the Self-Report Habit Index, or a combination of self-reported behaviour frequency and contextual stability. The suitability of self-report for capturing automatic processes has been questioned. What does this study add? This is the first study of how people interpret and respond to self-report habit measures. Results show the potential for errors in recalling automaticity, cues, and behaviours. We discuss practical and theoretical challenges to assessing habit in health behaviours., (© 2013 The British Psychological Society.)

Growing evidence suggests a bidirectional interaction between epileptic seizures and psychological states, fuelling the interest in the development and application of psychobehavioral therapy for people with epilepsy (PWE). The objective of this article is to review the various psychobehavioral therapies in regard to their application, hypothesized mechanisms, and effectiveness. Most psychobehavioral therapy aims at improving psychological well-being and seizure control. Behavioral approaches, cognitive-behavioral therapy (CBT), and mind-body interventions are the most widely applied approaches for PWE. Cognitive-behavioral therapy, mind-body approaches, and multimodel educative interventions have consistently demonstrated positive effects on enhancing well-being. Nevertheless, the effects on seizure control remain inconsistent, partly attributable to small clinical trials and inadequate control groups. Assessor-blinded randomized controlled trials with sufficient power and carefully defined therapeutic components corresponding with objective and subjective outcome measures are recommended for future trial designs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We have designed and built a Dense Plasma Focus (DPF) Z-pinch device using a kJ-level capacitor bank and a hollow anode, and fueled by a cylindrically symmetric gas puff. Using this device, we have measured peak deuteron beam energies of up to 400 keV at 0.8 kJ capacitor bank energy and pinch lengths of ∼6 mm, indicating accelerating fields greater than 50 MV/m. Neutron yields of on the order of 10(7) per shot were measured during deuterium operation. The cylindrical gas puff system permitted simultaneous operation of DPF with a radiofrequency quadrupole accelerator for beam-into-plasma experiments. This paper describes the machine design, the diagnostic systems, and our first results.

Background: Although FOLFOX (infusional fluorouracil/leucovorin plus oxaliplatin) is established as a standard chemotherapeutic regimen, the long term efficacy of adjuvant XELOX (oral capecitabine plus intravenous oxaliplatin) in Asian colorectal cancer (CRC) patients remains anecdotal. Moreover, uncertainties persist as to whether pharmacogenetic differences in Asian populations preclude equally tolerable and effective administration of these drugs., Method: One hundred consecutive patients with resected colorectal cancer received adjuvant XELOX (oxaliplatin 130 mg/m2 on day 1 plus capecitabine 900 mg/m2 twice daily on day 1 to 14 every 3 weeks for 8 cycles) at Queen Mary Hospital, Hong Kong. Endpoints monitored during follow-up were disease-free survival (DFS) and disease recurrence, overall survival (OS) and adverse events (AEs)., Results: The median patient age was 56 years, 56% were diagnosed with rectal cancer and 44% with colonic cancer. After a median follow-up of 4.3 years (95% confidence interval, 3.2-4.7), 24 recurrences were confirmed including 13 patients who died due to progressive disease. Four-year DFS was 81% in colon cancer patients and 67% in rectal cancer patients (p=0.06 by log-rank test). For the cohort as a whole, OS was 90% at 3 years and 84% at 5 years. Treatment-related AEs led to early withdrawal in four patients. The commonest non-hematological AEs were neuropathy (91%), hand-foot syndrome (49%) and diarrhea (46%), while the commonest grade 3/4 AEs were neutropenia (11%) and diarrhea (10%)., Conclusion: These results confirm the favourable long term survival benefit with good tolerability in using adjuvant XELOX in treating East Asian colorectal cancer patients.

Cognitive deficits and psychological impairments are often associated with seizures. In order to describe the neuropsychological profiles of adult patients with epilepsy (PWEs) in Hong Kong China, a total of 186 PWEs were recruited with 102 being drug-responsive and 84 being drug-resistant. Symptoms of depression, anxiety, and epilepsy-specific quality of life (QOL) were measured. Cognitive assessments consisted of intelligence, memory, verbal and visual abilities, and executive function. Neurocognitive impairments were prevalent among PWEs, and patients with drug-resistant epilepsy had significantly more impaired psychological and cognitive profiles. Thirty-nine percent and 30% of patients with drug-resistant epilepsy reported moderate to severe levels of anxiety and depression, respectively, versus 16% and 7% of patients with drug-responsive epilepsy. The most commonly occurring cognitive deficit was memory. Thirty-five percent to 47% of patients with drug-resistant epilepsy and 26% to 35% of patients with drug-responsive epilepsy were compromised in verbal recall memory. Our findings also suggested significant correlations between psychological well-being and cognitive performance. Patients who reported more psychological symptoms tended to perform worse in neurocognitive tests. Identification and management of neuropsychological difficulties in PWEs are important and should be included in primary epilepsy care., (© 2013.)

Background: In some series of malrotation small numbers of children are described in whom the position of the duodenojejunal flexure was considered to be normal on straight anteroposterior (AP) view of an upper gastrointestinal (UGI) series., Objective: The purpose of this study was to illustrate children with disorders of midgut rotation in whom the diagnosis was difficult because on the straight AP view of the UGI series the duodenojejunal flexure was either not clearly depicted or was projected to the left of the midline close to its expected normal position at or close to the level of the duodenal cap., Materials and Methods: We reviewed 111 children with malrotation to determine the frequency that duodenojejunal flexure was not clearly depicted or was close to normal position., Results: Seven patients had close to normal position of duodenojejunal flexure on AP view. The correct diagnosis was made on initial UGI series in four patients based on other features on AP and lateral views. In two of the other three patients, a repeat UGI series facilitated the correct diagnosis. In the final patient, an abnormal position of a nasojejunal tube suggested the correct diagnosis., Conclusion: Accurate diagnosis of anomalies of midgut rotation requires careful assessment of the entire duodenal sweep on both AP and lateral views to avoid false-negative interpretations.

Many major psychiatric illnesses have been associated with excessive and prolonged release of glucocorticoid stress hormones potentially leading to deleterious neuronal effects. Recent studies have suggested that oxidative stress is associated with psychiatric illnesses. Oxidative stress is an overproduction of reactive oxygen species (ROS) that overwhelms the cellular antioxidant capacity. The mitochondria are responsible for most oxygen consumption and are a major source of ROS production. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase also contributes significantly to ROS production. This study aims to elucidate the effects of glucocorticoids on oxidative damage to protein, mitochondrial function, NADPH oxidase activity, and antioxidant capacity. Rat pheochromocytoma PC12 cells were treated with corticosterone at concentrations of 0.031, 0.063, and 0.125 mmol/l for 24 h. Protein carbonylation, activities of mitochondrial complex I and III, activity of NADPH oxidase, total antioxidant capacity, and activities of superoxide dismutase (SOD) and catalase (CAT) were analyzed. We found that chronic treatment with corticosterone increased the amount of protein carbonylation in PC12 cells. Complex I activity was decreased with corticosterone treatment, while no change was seen in complex III activity or NADPH oxidase activity. Total antioxidant capacity was increased at the lowest dosage level tested. Although corticosterone treatment had no effect on CAT activity, corticosterone at the highest dosage significantly decreased SOD activity. These results suggest that excessive glucocorticoid activity can increase oxidative damage to protein, possibly by inhibiting activities of mitochondrial complex I and antioxidant enzyme SOD., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Several studies have indicated that Sonic hedgehog (Shh) regulates the expansion of dopaminergic (DA) progenitors and the subsequent generation of mature DA neurons. This prevailing view has been based primarily on in vitro culture results, and the exact in vivo function of Shh signaling in the patterning and neurogenesis of the ventral midbrain (vMB) remains unclear., Methods: We characterized the transcriptional codes for the vMB progenitor domains, and correlated them with the expression patterns of Shh signaling effectors, including Shh, Smoothened, Patched, Gli1, Gli2 and Gli3., Results: While Shh and its downstream effectors showed robust expression in the neurogenic niche for DA progenitors at embryonic day (E)8 to E8.5, their expression shifted to the lateral domains from E9.5 to E12.5. Consistent with this dynamic change, conditional mutants with region-specific removal of the Shh receptor Smoothened in the vMB progenitors (Shh-Cre;Smo(fl/fl)) showed a transient reduction in DA progenitors and DA neurons at E10.5, but had more profound defects in neurons derived from the more lateral domains, including those in the red nucleus, oculomotor nucleus, and raphe nuclei. Conversely, constitutive activation of Smoothened signaling in vMB (Shh-Cre;SmoM2) showed transient expansion of the same progenitor population. To further characterize the nature of Shh-Smoothened signaling in vMB, we examined the BAT-GAL reporter and the expression of Wnt1 in vMB, and found that the antagonistic effects of Shh and Wnt signaling critically regulate the development of DA progenitors and DA neurons., Conclusion: These results highlight previously unrecognized effects of Shh-Smoothened signaling in the region-specific neurogenesis within the vMB.

Background: Dendritic cells (DCs) are potent antigen-presenting cells critical for immunity. We previously demonstrated a significant association between pre-transplant blood myeloid dendritic cell (mDC) and plasmacytoid dendritic cell (pDC) deficiency and post-transplant BK viremia in renal transplant recipients. In the current post-hoc analysis, we studied the association of these same pre-transplant DC levels with other post-transplant outcomes., Methods: Pre-transplant peripheral blood mDC and pDC levels were quantified using flow cytometry in 78 patients undergoing kidney transplantation. Post-transplant outcomes were analyzed, including infection, rejection, and patient death, with a median follow-up of 5.3 years. Associations between DC levels and outcomes were assessed using logistic regression analysis and Cox proportional hazards models., Results: An independent association of mDC levels with post-transplant cytomegalovirus infection (adjusted odds ratio 7.0, P = 0.01) and patient death (adjusted hazard ratio 13.0, P = 0.015) was found. No associations were demonstrated between levels of either DC subtype and bacterial infections or rejection., Conclusions: Pre-transplant mDC deficiency is significantly associated with CMV infection and death after kidney transplantation., (© 2012 John Wiley & Sons A/S.)