Implementation of a surgical safety checklist: impact on surgical team perspectives.
The World Health Organization (WHO) surgical safety checklist has been shown to decrease mortality and complications and has been adopted worldwide. However, system flaws and human errors persist. Identifying provider perspectives of patient safety initiatives may identify strategies for improvement. The purpose of this study was to determine provider perspectives of surgical safety checklist implementation in an effort to improve initiatives that enhance surgical patients' safety. In September 2010, a WHO-adapted surgical safety checklist was implemented at our institution. Surgical teams were invited to complete a checklist-focused questionnaire 1 month before and 1 year after implementation. Baseline and follow-up results were compared. A total of 437 surgical care providers responded to the survey: 45% of providers responded at baseline and 64% of providers responded at follow-up. Of the total respondents, 153 (35%) were nurses, 104 (24%) were anesthesia providers, and 180 (41%) were surgeons. Overall, we found an improvement in the awareness of patient safety and quality of care, with significant improvements in the perception of the value of and participation in the time-out process, in surgical team communication, and in the establishment and clarity of patient care needs. Some discordance was noted between surgeons and other surgical team members, indicating that barriers in communication still exist. Overall, approximately 65% of respondents perceived that the checklist improved patient safety and patient care; however, we found a strong negative perception of operating room efficiency. Implementation of a surgical safety checklist improves perceptions of surgical safety. Barriers to implementation exist, but staff feedback may be used to enhance the sustainability and success of patient safety initiatives.


Benchmarking PSI-BLAST in genome annotation.
The recognition of remote protein homologies is a major aspect of the structural and functional annotation of newly determined genomes. Here we benchmark the coverage and error rate of genome annotation using the widely used homology-searching program PSI-BLAST (position-specific iterated basic local alignment search tool). This study evaluates the one-to-many success rate for recognition, as often there are several homologues in the database and only one needs to be identified for annotating the sequence. In contrast, previous benchmarks considered one-to-one recognition in which a single query was required to find a particular target. The benchmark constructs a model genome from the full sequences of the structural classification of protein (SCOP) database and searches against a target library of remote homologous domains (<20 % identity). The structural benchmark provides a reliable list of correct and false homology assignments. PSI-BLAST successfully annotated 40 % of the domains in the model genome that had at least one homologue in the target library. This coverage is more than three times that if one-to-one recognition is evaluated (11 % coverage of domains). Although a structural benchmark was used, the results equally apply to just sequence homology searches. Accordingly, structural and sequence assignments were made to the sequences of Mycoplasma genitalium and Mycobacterium tuberculosis (see http://www.bmm.icnet. uk). The extent of missed assignments and of new superfamilies can be estimated for these genomes for both structural and functional annotations.


UK cost-consequence analysis of aripiprazole in schizophrenia: diabetes and coronary heart disease risk projections (STAR study).
Patients with schizophrenia experience elevated rates of morbidity and mortality, largely due to an increased incidence of cardiovascular disease and diabetes. There is increasing concern that some atypical antipsychotic therapies are associated with adverse metabolic symptoms, such as weight gain, dyslipidaemia and glucose dysregulation. These metabolic symptoms may further increase the risk of coronary heart disease (CHD) and diabetes in this population and, subsequently, the cost of treating these patients' physical health. The STAR study showed that the metabolic side effects of aripiprazole treatment are less than that experienced by those receiving standard-of-care (SOC). In a follow-up study the projected risks for diabetes or CHD, calculated using the Stern and Framingham models, were lower in the aripiprazole treatment group. Assuming the risk of diabetes onset/CHD events remained linear over 10 years, these risks were used to estimate the difference in direct and indirect cost consequences of diabetes and CHD in schizophrenia patients treated with aripiprazole or SOC over a 10-year period. Diabetes costs were estimated from the UKPDS and UK T(2)ARDIS studies, respectively, and CHD costs were estimated using prevalence data from the Health Survey of England and the published literature. All costs were inflated to 2007 costs using the NHS pay and prices index. The number of avoided diabetes cases (23.4 cases per 1,000 treated patients) in patients treated with aripiprazole compared with SOC was associated with estimated total (direct and indirect) cost savings of 37,261,293 pounds over 10 years for the UK population. Similarly, the number of avoided CHD events (3.7 events per 1,000 treated patients) was associated with estimated total cost savings of 7,506,770 pounds over 10 years. Compared with SOC, aripiprazole treatment may provide reductions in the health and economic burden to schizophrenia patients and health care services in the UK as a result of its favourable metabolic profile.


[The military role in a flu pandemic].
Pandemic influenza is a major challenge to emergency preparedness agencies and health systems throughout the world. It requires preparation for a situation of widespread morbidity due to flu and its complications which will lead to a huge burden on the health system in the community and in hospitals, and work absenteeism, also among health care personnel. This may require major involvement of the army in both preparedness and measures to be taken to tackle such an event. This article reviews the different roles armies could take in such a crisis, and presents the Israeli test case. Defense systems are characterized by a number of attributes that may be major advantages during pandemic influenza: crisis management capacities, ability to deal with varied tasks in sub-optimal conditions, logistic resources (fuel, food and water), widespread deployment in the country and sometimes in the world, and the ability to activate people in risky situations, even against their will. The army roles during pandemic outbreaks could include: taking national and regional command of the event, assigning workforce for essential civilian missions, use of logistic and military resources, maintaining public order and implementing public health measures such as isolation and quarantine. In addition, the army must continue its primary role of maintaining the security and guarding the borders of the state, especially in times of global geopolitical changes due to pandemic. Since March 2009, the influenza A/H1N1 2009 virus spread throughout the world, leading the WHO to declare a state of pandemic influenza. According to Israeli preparedness plans, the management of the event was supposed to pass to the defense system. However, due to the moderate severity of the illness, it was decided to leave the management of the event to the health system. In view of the necessity of maintaining military combat capabilities, and the possibility of outbreaks in combat units, which actually occurred, the Israel Defense Forces (IDF) policy for the pandemic was stricter than the policy of the Ministry of Health. Defense systems in Israel and the world should prepare, the sooner the better, for the possibility of a worse pandemic, in which the army may take a major role, especially since regular life in the country, in such a case, would be disturbed.


An 8-Month Systems Toxicology Inhalation/Cessation Study in Apoe-/- Mice to Investigate Cardiovascular and Respiratory Exposure Effects of a Candidate Modified Risk Tobacco Product, THS 2.2, Compared With Conventional Cigarettes.
Smoking cigarettes is a major risk factor in the development and progression of cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD). Modified risk tobacco products (MRTPs) are being developed to reduce smoking-related health risks. The goal of this study was to investigate hallmarks of COPD and CVD over an 8-month period in apolipoprotein E-deficient mice exposed to conventional cigarette smoke (CS) or to the aerosol of a candidate MRTP, tobacco heating system (THS) 2.2. In addition to chronic exposure, cessation or switching to THS2.2 after 2 months of CS exposure was assessed. Engaging a systems toxicology approach, exposure effects were investigated using physiology and histology combined with transcriptomics, lipidomics, and proteomics. CS induced nasal epithelial hyperplasia and metaplasia, lung inflammation, and emphysematous changes (impaired pulmonary function and alveolar damage). Atherogenic effects of CS exposure included altered lipid profiles and aortic plaque formation. Exposure to THS2.2 aerosol (nicotine concentration matched to CS, 29.9 mg/m(3)) neither induced lung inflammation or emphysema nor did it consistently change the lipid profile or enhance the plaque area. Cessation or switching to THS2.2 reversed the inflammatory responses and halted progression of initial emphysematous changes and the aortic plaque area. Biological processes, including senescence, inflammation, and proliferation, were significantly impacted by CS but not by THS2.2 aerosol. Both, cessation and switching to THS2.2 reduced these perturbations to almost sham exposure levels. In conclusion, in this mouse model cessation or switching to THS2.2 retarded the progression of CS-induced atherosclerotic and emphysematous changes, while THS2.2 aerosol alone had minimal adverse effects.


Computed tomography colonography: feasibility of computer-aided polyp detection in a "first reader" paradigm.
: To determine the feasibility of a computer-aided detection (CAD) algorithm as the "first reader" in computed tomography colonography (CTC). : In phase 1 of a 2-part blind trial, we measured the performance of 3 radiologists reading 41 CTC studies without CAD. In phase 2, readers interpreted the same cases using a CAD list of 30 potential polyps. : Unassisted readers detected, on average, 63% of polyps > or =10 mm in diameter. Using CAD, the sensitivity was 74% (not statistically different). Per-patient analysis showed a trend toward increased sensitivity for polyps > or =10 mm in diameter, from 73% to 90% with CAD (not significant) without decreasing specificity. Computer-aided detection significantly decreased interobserver variability (P = 0.017). Average time to detection of the first polyp decreased significantly with CAD, whereas total reading case reading time was unchanged. : Computer-aided detection as a first reader in CTC was associated with similar per-polyp and per-patient detection sensitivity to unassisted reading. Computer-aided detection decreased interobserver variability and reduced the time required to detect the first polyp.


Epigenetic mechanisms regulating normal and malignant haematopoiesis: new therapeutic targets for clinical medicine.
It is now well established that epigenetic phenomena and aberrant gene regulation play a major role in carcinogenesis. These include aberrant gene silencing by imposing inactive histone marks on promoters, aberrant methylation of DNA at CpG islands, and the active repression of promoters by oncoproteins. In addition, many malignant cells also show aberrant gene activation due to constitutively active signalling. The next frontier in cancer research will be to examine how, at the molecular level, small mutations that alter the regulatory phenotype of a cell give rise after a number of cell divisions to the vast deregulation phenomena seen in malignant cells. This review outlines recent insights into how normal cell differentiation in the haematopoietic system is subverted in leukaemia and it introduces the molecular players involved in this process. It also summarises the results of recent clinical trials trying to reverse aberrant epigenetic regulation by employing agents influencing global epigenetic regulators.


Impact of a work-based feedback intervention on student performance during clinical placements in acute-care healthcare settings: a quasi-experimental protocol for the REMARK programme.
Current perspectives present feedback as a dynamic, dialogic process. It is widely accepted that feedback can have an impact on workplace performance, however, how dialogic feedback is enacted with the learner in authentic healthcare settings is less apparent. This paper seeks to describe the design and development of an implementation study to promote the learner voice in the feedback process and improve feedback encounters between learners and learning partners in healthcare settings. A quasi-experimental study design will be used to evaluate whether implementation of a work-based intervention to improve feedback impacts student performance during clinical placements in healthcare settings. Student performance will be measured at three time points: baseline (pre), mid-placement (post-test 1) and end-placement (post-test 2) in keeping with standard assessment processes of the participating university. The intervention is underpinned by Normalisation Process Theory and involves a layered design that targets learners and learning partners using best-practice education strategies. Data regarding participants' engagement with feedback during clinical placements and participants' level of adoption of the intervention will be collected at the completion of the clinical placement period. This study has ethics approval from both Griffith University and Metro South Health Human Research and Ethics committees. Dissemination of results will be local, national and international through forums, seminars, conferences and publications.


Statewide implementation of child trauma-focused practices using the community-based learning collaborative model.
A significant number of youth in the United States experience traumatic events that substantially increase the risk of physical and behavioral health problems across the life span. This public health concern warrants concerted efforts to promote trauma-informed, evidence-based practices that facilitate recovery. Although youth-focused trauma-specific treatments exist, determining effective ways to disseminate and implement these services-so that they are available, accessible, and sustainable-poses an ongoing challenge. This paper describes a comprehensive model for such implementation, the community-based learning collaborative (CBLC), developed as part of Project BEST, a four-phase statewide initiative to promote trauma-focused practices. The CBLC augments the learning collaborative model by including clinical and nonclinical (i.e., broker) professionals from multiple service organizations within a targeted community. CBLCs aim to build capacity for sustained implementation of trauma-focused practices by promoting interprofessional collaboration among those involved in the coordination and provision of these services. This paper describes the iterative development of the CBLC by examining participant completion data across the three completed phases of Project BEST (N = 13 CBLCs; 1,190 participants). Additionally, data from Project BEST's third phase (N = 6 CBLCs; 639 participants) were used to evaluate changes in the frequency of specific practices, pre- to post-CBLC, and post-CBLC perceived utility of CBLC components. High participant completion rates, significant increases in reported trauma-focused practices, and positive ratings of the CBLC's utility provisionally support the feasibility and efficacy of the model's final iteration. Implications for implementation and CBLC improvements are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


The Forgotten Ones: Crafting for Meaning and for Affiliation in the Context of Finnish and Japanese Employees' Off-Job Lives.
In an intensifying working life, it is important for employees to proactively shape their lives beyond work to create opportunities for satisfying personal needs. These efforts can be beneficial for creating and sustaining well-being in terms of vitality. In this study, we focused on off-job crafting (OJC) for meaning and OJC for affiliation, conceptualized as proactive changes in off-job life with the aim of increasing satisfaction of needs for meaning and affiliation, among employees in Finland and Japan, two countries with disparate cultural values. We examined longitudinal within-person relationships between the two OJC dimensions and vitality, as well as the relationships between OJC and contextual variables, such as age and gender. We conducted a longitudinal study over 6 months with three measurement points. A total of 578 Finnish and 228 Japanese employees participated in the study. Hypotheses were tested with latent growth analysis. Increases in OJC for meaning and for affiliation were mostly positively related to increases in vitality over time in both countries. In Finland, age was positively related to OJC for meaning. In Japan, age was negatively related to OJC for meaning, but the female gender was positively related to OJC for affiliation. Focusing on increasing meaning and affiliation in off-job life can be beneficial strategies for employees to feel positively energized. The role of contextual variables and culture in OJC should be examined further in future studies.


Risk assessment of hepatocellular carcinoma development for indeterminate hepatic nodules in patients with chronic hepatitis B.
A risk prediction model for the development of hepatocellular carcinoma (HCC) from indeterminate nodules detected on computed tomography (CT) (RadCT score) in patients with chronic hepatitis B (CHB)-related cirrhosis was proposed. We validated this model for indeterminate nodules on magnetic resonance imaging (MRI). Between 2013 and 2016, Liver Imaging Reporting and Data System (LI-RADS) 2/3 nodules on MRI were detected in 99 patients with CHB. The RadCT score was calculated. The median age of the 72 male and 27 female subjects was 58 years. HCC history and liver cirrhosis were found in 47 (47.5%) and 44 (44.4%) patients, respectively. The median RadCT score was 112. The patients with HCC (n=41, 41.4%) showed significantly higher RadCT scores than those without (median, 119 vs. 107; P=0.013); the Chinese university-HCC and risk estimation for HCC in CHB (REACH-B) scores were similar (both P>0.05). Arterial enhancement, T2 hyperintensity, and diffusion restriction on MRI were not significantly different in the univariate analysis (all P>0.05); only the RadCT score significantly predicted HCC (hazard ratio [HR]=1.018; P=0.007). Multivariate analysis showed HCC history was the only independent HCC predictor (HR=2.374; P=0.012). When the subjects were stratified into three risk groups based on the RadCT score (<60, 60-105, and >105), the cumulative HCC incidence was not significantly different among them (all P>0.05, log-rank test). HCC history, but not RadCT score, predicted CHB-related HCC development from LI-RADS 2/3 nodules. New risk models optimized for MRI-defined indeterminate nodules are required.


High-resolution optical functional mapping of the human somatosensory cortex.
Non-invasive optical imaging of brain function has been promoted in a number of fields in which functional magnetic resonance imaging (fMRI) is limited due to constraints induced by the scanning environment. Beyond physiological and psychological research, bedside monitoring and neurorehabilitation may be relevant clinical applications that are yet little explored. A major obstacle to advocate the tool in clinical research is insufficient spatial resolution. Based on a multi-distance high-density optical imaging setup, we here demonstrate a dramatic increase in sensitivity of the method. We show that optical imaging allows for the differentiation between activations of single finger representations in the primary somatosensory cortex (SI). Methodologically our findings confirm results in a pioneering study by Zeff et al. (2007) and extend them to the homuncular organization of SI. After performing a motor task, eight subjects underwent vibrotactile stimulation of the little finger and the thumb. We used a high-density diffuse-optical sensing array in conjunction with optical tomographic reconstruction. Optical imaging disclosed three discrete activation foci one for motor and two discrete foci for vibrotactile stimulation of the first and fifth finger, respectively. The results were co-registered to the individual anatomical brain anatomy (MRI) which confirmed the localization in the expected cortical gyri in four subjects. This advance in spatial resolution opens new perspectives to apply optical imaging in the research on plasticity notably in patients undergoing neurorehabilitation.


Antidepressant use in pregnancy and the risk of cardiac defects.
Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects. We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders. A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41). The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. (Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.).


Psychological Stress and Coping in Recently Discharged Postsurgical Cancer Patients.
Cancer patients and survivors need to cope with various stressful situations and problems even after treatment. In this study, we sought to investigate psychological stress and coping in recently discharged postsurgical cancer patients. A mail-in questionnaire survey about stress response, perceived illness-related demands, and coping strategies and styles was administered to postsurgical Japanese cancer patients. The questionnaires were returned a week after the patients' discharge from the hospital. Descriptive and nonparametric statistical analyses were used. Forty-two patients completed the questionnaire; their average age was 58.1 years, and 61.9% were female. The stress response scale-18 (SRS-18) score was lower than that reported among the general population. The proportion of patients who were concentrating coping on social support or positive reappraisal was high. The scores for problem- and emotion-focused coping were nearly identical. SRS-18 scores were weakly correlated with those for emotion-focused coping (r = 0.38, P = 0.014). The demographic data were not significantly associated with any of the stress or coping variables. However, SRS-18 scores for patients who had adjuvant therapy and physical, functional disorders were significantly higher than those for patients who did not (P = 0.004 and P = 0.008, respectively). Most of the patients had a low-stress response and used appropriate coping strategies. However, the findings suggest that attention must be paid to stress-coping in patients who have a physical, functional disorder as well as in those receiving adjuvant therapy.


A primary care modification of family-based treatment for adolescent restrictive eating disorders.
Although eating disorders pose a significant threat to the health and well-being of children and adolescents, due to a profound scarcity of specialty providers, only a small percentage of patients receives evidence-based treatment. To improve access to care for restrictive eating disorders, we developed a modified version of Family-Based Treatment to be delivered by primary care providers (PCPs) and conducted a pilot study to evaluate the feasibility and preliminary outcomes of this intervention. Fifteen adolescents (mean age = 15.5 years) with restrictive eating disorders and their caregiver(s) were enrolled in Family-Based Treatment for Primary Care (FBT-PC), delivered by three trained PCPs. Retention for the intervention was high (n = 13, 86.7%). Over the course of 3 months, participants attended an average of 9.2 (SD = 2.8) sessions and experienced a significant increase in BMI percentile from 39.1 to 54.8 (t (13) = -6.71, p < .001; d = .61). FBT-PC appears to be feasible for implementation in the primary care setting and has the potential to improve access to treatment and yield positive outcomes for young patients with restrictive eating disorders.


Prone Positioning Decreases Inhomogeneity and Improves Dorsal Compliance in Invasively Ventilated Spontaneously Breathing COVID-19 Patients-A Study Using Electrical Impedance Tomography.
We studied prone positioning effects on lung aeration in spontaneously breathing invasively ventilated patients with coronavirus disease 2019 (COVID-19). changes in lung aeration were studied prospectively by electrical impedance tomography (EIT) from before to after placing the patient prone, and back to supine. Mixed effect models with a random intercept and only fixed effects were used to evaluate changes in lung aeration. fifteen spontaneously breathing invasively ventilated patients were enrolled, and remained prone for a median of 19 [17 to 21] hours. At 16 h the global inhomogeneity index was lower. At 2 h, there were neither changes in dorsal nor in ventral compliance; after 16 h, only dorsal compliance (βFe +18.9 [95% Confidence interval (CI): 9.1 to 28.8]) and dorsal end-expiratory lung impedance (EELI) were increased (βFe, +252 [95% CI: 13 to 496]); at 2 and 16 h, dorsal silent spaces was unchanged (βFe, -4.6 [95% CI: -12.3 to +3.2]). The observed changes induced by prone positioning disappeared after turning patients back to supine. in this cohort of spontaneously breathing invasively ventilated COVID-19 patients, prone positioning decreased inhomogeneity, increased lung volumes, and improved dorsal compliance.


Cluster or periodic, static or dynamic--the challenge of calculating the g tensor of the solid-state glycine radical.
The calculation of the g tensor of the main (+)NH(3)-˙CH-COO(-) radiation-induced radical in solid-state α-glycine presents a real challenge to computational methods. Density functional calculations of this spectroscopic property struggle with its small anisotropy and the zwitterionic nature of the amino acids in the crystal of this seemingly simple system. Here, several factors influencing the calculated g tensor are examined by comparing with experimental data. The extent of the molecular environment is varied in both a cluster and a periodic approach and dynamic calculations are performed to account for temperature effects. The latter does not necessarily lead to a better agreement with experiment than a static calculation. Application of a periodic approach is straightforward, but an all-electron scheme clearly is favorable. In a cluster approach, the selected basis set and density functional are of less importance, provided a hybrid functional is used to prevent cluster boundary effects. The applied spin-orbit coupling operators and proper treatment of the gauge origin of the magnetic vector potential also seem to be less critical than in other, similar molecular systems. But a careful selection of the cluster size proves to be essential for this glycine radical system. The calculated g tensor varies significantly with increasing cluster size, yielding only a good agreement with experiment when 5-7 glycine molecules in the immediate environment of the central glycine radical are incorporated. Further expansion of the cluster size can even lead to an essentially incorrect description of the radical in the condensed phase, indicating that bigger clusters can become unbalanced.


Combining Multimodal Biomarkers to Guide Deep Brain Stimulation Programming in Parkinson Disease.
Deep brain stimulation (DBS) programming of multicontact DBS leads relies on a very time-consuming manual screening procedure, and strategies to speed up this process are needed. Beta activity in subthalamic nucleus (STN) local field potentials (LFP) has been suggested as a promising marker to index optimal stimulation contacts in patients with Parkinson disease. In this study, we investigate the advantage of algorithmic selection and combination of multiple resting and movement state features from STN LFPs and imaging markers to predict three relevant clinical DBS parameters (clinical efficacy, therapeutic window, side-effect threshold). STN LFPs were recorded at rest and during voluntary movements from multicontact DBS leads in 27 hemispheres. Resting- and movement-state features from multiple frequency bands (alpha, low beta, high beta, gamma, fast gamma, high frequency oscillations [HFO]) were used to predict the clinical outcome parameters. Subanalyses included an anatomical stimulation sweet spot as an additional feature. Both resting- and movement-state features contributed to the prediction, with resting (fast) gamma activity, resting/movement-modulated beta activity, and movement-modulated HFO being most predictive. With the proposed algorithm, the best stimulation contact for the three clinical outcome parameters can be identified with a probability of almost 90% after considering half of the DBS lead contacts, and it outperforms the use of beta activity as single marker. The combination of electrophysiological and imaging markers can further improve the prediction. LFP-guided DBS programming based on algorithmic selection and combination of multiple electrophysiological and imaging markers can be an efficient approach to improve the clinical routine and outcome of DBS patients.


Attitudes towards community gambling venues and support for regulatory reform: an online panel study of residents in New South Wales, Australia.
Harmful gambling has been identified as an important public health issue that affects individuals, families and the broader community. One gambling product, electronic gambling machines (EGMs), has been associated with significant gambling harm in Australia. There has been limited research that has explored community perceptions of EGMs and attitudes towards reform. This study, conducted in NSW, Australia, aimed to explore community use of EGM venues (clubs and hotels containing EGMs), attitudes towards EGMs and whether the use of these venues influenced attitudes towards EGM reform. An online survey was conducted with 500 adults aged 16 years and over, representative of the population for age and gender. Discrete choice and open-ended questions were used to gather data on gambling behaviours, use of and attitudes towards EGMs and EGM venues and support for gambling harm reduction measures. Three quarters of participants had visited an EGM venue in the previous year. Participants who had attended such venues were significantly more likely to use EGMs at least once per month. Participants attended EGM venues for a range of reasons including use of non-gambling facilities such as restaurants, the social aspects of the venue and ease of access to the venue. Some participants also attended EGM venues specifically for the gambling facilities. Most participants identified some negative impacts of EGMs for local communities and were supportive of measures to reduce the number of EGMs and prevent children's exposure to EGMs in such venues. This study shows a high level of support for EGM reform amongst both individuals who attend EGM venues and also those who do not. There is potential for government to further regulate EGMs and the environments where they are located.


Rate and maintenance of improvement of myofascial pain with dry needling alone vs. dry needling with intramuscular electrical stimulation: a randomized controlled trial.
Prospective, randomized. To determine the difference in rate and maintenance of improvement of pain and disability for Dry Needling (DN) compared to Dry Needling with Intramuscular Electrical Stimulation (DN/IMES), in Myofascial Pain Syndrome (MPS). DN and neuromuscular electrical stimulation (NMES) have been shown to be efficacious in treating MPS. DN/IMES for MPS treatment has not been studied extensively, but initial results are promising. Forty-five subjects were randomly assigned to the DN (n = 25) or DN/IMES (n = 20) group. Both groups received six consecutive weekly treatments and completed NDI and NPRS questionnaires (week 0, 3, 6, and 12). Both DN and DN/IMES groups showed significant improvement between weeks 0-6 on NDI (p = 0.008 and 0.00002, respectively) and NPRS scores (0 = 0.017 and p = 0.018, respectively). DN/IMES group showed significant within group changes on the NPRS between weeks 0-3 (p = 0.029). No changes were noted in the DN or DN/IMES groups between week 6-12 on NDI (p = 0.497 and p = 0.714, respectively) or NPRS (p = 0.801 and p = 0.164, respectively). DN and DN/IMES demonstrated improvement and maintenance in disability and pain for 6 weeks. No differences in improvement of disability or pain existed between the groups at week 6 or 12.


Clinical and economic impact of multidrug resistance in nosocomial Acinetobacter baumannii bacteremia.
To investigate the impact of antimicrobial resistance on clinical and economic outcomes among hospitalized patients with multidrug-resistant (MDR) Acinetobacter baumannii bacteremia. A retrospective, matched-cohort study. A tertiary care university teaching hospital. A matched case-control (1 : 1) study was conducted to compare the differences in clinical and economic outcomes of patients with MDR A. baumannii bacteremia and patients with non-MDR A. baumannii bacteremia. Case patients were matched to control patients on the basis of sex, age, severity of underlying and acute illness, and length of hospital stay before onset of bacteremia. Forty-six (95.8%) of 48 cases with MDR A. baumannii bacteremia were eligible for the study and matched with appropriate controls. The sepsis-related mortality rate was 34.8% among cases and 13.0% among controls, for an attributable mortality rate of 21.8% (adjusted odds ratio, 4.1 [95% confidence interval, 1.1-15.7]; P=.036). After the onset of bacteremia, cases and controls had a significantly different length of hospital stay (54.2 vs 34.1 days; P=.006), hospitalization cost (US$9,349 vs US$4,865; P=.001), and antibiotic therapy cost (US$2,257 vs US$1,610; P=.014). Thus, bacteremia due to MDR A. baumannii resulted in 13.4 days of additional hospitalization and US$3,758 of additional costs, compared with bacteremia due to non-MDR A. baumannii. Patients with MDR A. baumannii bacteremia had a higher mortality rate and incurred greater medical costs than patients with non-MDR A. baumannii bacteremia.


Development of Concurrent Retinotopic Maps in the Fly Motion Detection Circuit.
Understanding how complex brain wiring is produced during development is a daunting challenge. In Drosophila, information from 800 retinal ommatidia is processed in distinct brain neuropiles, each subdivided into 800 matching retinotopic columns. The lobula plate comprises four T4 and four T5 neuronal subtypes. T4 neurons respond to bright edge motion, whereas T5 neurons respond to dark edge motion. Each is tuned to motion in one of the four cardinal directions, effectively establishing eight concurrent retinotopic maps to support wide-field motion. We discovered a mode of neurogenesis where two sequential Notch-dependent divisions of either a horizontal or a vertical progenitor produce matching sets of two T4 and two T5 neurons retinotopically coincident with pairwise opposite direction selectivity. We show that retinotopy is an emergent characteristic of this neurogenic program and derives directly from neuronal birth order. Our work illustrates how simple developmental rules can implement complex neural organization.


Basic statistical analysis in genetic case-control studies.
This protocol describes how to perform basic statistical analysis in a population-based genetic association case-control study. The steps described involve the (i) appropriate selection of measures of association and relevance of disease models; (ii) appropriate selection of tests of association; (iii) visualization and interpretation of results; (iv) consideration of appropriate methods to control for multiple testing; and (v) replication strategies. Assuming no previous experience with software such as PLINK, R or Haploview, we describe how to use these popular tools for handling single-nucleotide polymorphism data in order to carry out tests of association and visualize and interpret results. This protocol assumes that data quality assessment and control has been performed, as described in a previous protocol, so that samples and markers deemed to have the potential to introduce bias to the study have been identified and removed. Study design, marker selection and quality control of case-control studies have also been discussed in earlier protocols. The protocol should take ~1 h to complete.


Topologically invariant reaction coordinates for simulating multistate chemical reactions.
Evaluating free energy profiles of chemical reactions in complex environments such as solvents and enzymes requires extensive sampling, which is usually performed by potential of mean force (PMF) techniques. The reliability of the sampling depends not only on the applied PMF method but also the reaction coordinate space within the dynamics is biased. In contrast to simple geometrical collective variables that depend only on the positions of the atomic coordinates of the reactants, the E(gap) reaction coordinate (the energy difference obtained by evaluating a suitable force field using reactant and product state topologies) has the unique property that it is able to take environmental effects into account leading to better convergence, a more faithful description of the transition state ensemble and therefore more accurate free energy profiles. However, E(gap) requires predefined topologies and is therefore inapplicable for multistate reactions, in which the barrier between the chemically equivalent topologies is comparable to the reaction activation barrier, because undesired "side reactions" occur. In this article, we introduce a new energy-based collective variable by generalizing the E(gap) reaction coordinate such that it becomes invariant to equivalent topologies and show that it yields more well behaved free energy profiles than simpler geometrical reaction coordinates.


Multicenter Validation of a Deep Learning Detection Algorithm for Focal Cortical Dysplasia.
To test the hypothesis that a multicenter-validated computer deep learning algorithm detects MRI-negative focal cortical dysplasia (FCD). We used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2-55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity. Overall sensitivity was 93% (137 of 148 FCD detected) using a leave-one-site-out cross-validation, with an average of 6 false positives per patient. Sensitivity in MRI-negative FCD was 85%. In 73% of patients, the FCD was among the clusters with the highest confidence; in half, it ranked the highest. Sensitivity in the independent cohort was 83% (19 of 23; average of 5 false positives per patient). Specificity was 89% in healthy and disease controls. This first multicenter-validated deep learning detection algorithm yields the highest sensitivity to date in MRI-negative FCD. By pairing predictions with risk stratification, this classifier may assist clinicians in adjusting hypotheses relative to other tests, increasing diagnostic confidence. Moreover, generalizability across age and MRI hardware makes this approach ideal for presurgical evaluation of MRI-negative epilepsy. This study provides Class III evidence that deep learning on multimodal MRI accurately identifies FCD in patients with epilepsy initially diagnosed as MRI negative.


A novel method for the determination of the site of glucuronidation by ion mobility spectrometry-mass spectrometry.
Glucuronidation not only plays a detoxifying role in living body, but it also can complicate pharmacological and toxicological profiles of new drug candidates by forming active and reactive conjugated metabolites. The opportunity to elucidate structure of conjugated metabolites has increased in drug metabolism studies at the early development stage. General methodologies for the structure elucidation of glucuronide conjugate(s) include liquid chromatography-tandem mass spectrometry (LC-MS/MS) and NMR spectroscopy. In many cases, LC-MS/MS alone cannot unequivocally identify the site(s) of conjugation in isomeric glucuronidations. In the present study, we established a new strategy for the structure elucidation of glucuronide conjugates using ion mobility spectrometry (IMS)-mass spectrometry. Linear correlation between calculated collision cross-sections (CCS) and actual drift times from IMS was found for each set of parent compound (raloxifene, losartan, telmisartan, and estradiol) and the corresponding MS/MS product ions. Thus, obtained regression lines accurately and selectively projected the actual drift times of authentic standards of glucuronide conjugate based on the theoretical CCS values. The established method was used for the accurate assignment of predominant formation of phenolic glucuronide conjugate (SCH 60663) in the isomeric (phenolic and benzylic) glucuronidations of ezetimibe in the incubated sample with cryopreserved human hepatocytes. This application demonstrates the potential to facilitate the structure identification of glucuronide conjugates at the early development stage of new drug candidates.


Optical studies of the nematic phase of an oxazole-derived bent-core liquid crystal.
Various optical and dynamic light scattering studies have been conducted on the nematic phase of an oxazole-derived bent-core liquid crystal. At optical length scales and in the absence of applied fields, homogeneously aligned samples of this material, which has an oxazole heterocyclic ring in the central core, are found to behave more like a conventional straight-core nematic than a previously investigated ester-based class of bent-core molecules that have a benzene ring as the core linkage between the two arms of the bow-shaped molecule. In particular, the nematic refractive indices of the oxazole compound combine in the standard way [i.e., square root of ((2no2+ne2)/3)] to match the isotropic value throughout the nematic range, and the observed director fluctuation modes have relaxation rates comparable to those of the usual thermotropics. However, polarized light scattering data reveal evidence of weak biaxial fluctuations, and indications of electric-field-induced biaxiality are observed in the refractive index measurements.


The ResD response regulator, through functional interaction with NsrR and fur, plays three distinct roles in Bacillus subtilis transcriptional control.
The ResD response regulator activates transcription of diverse genes in Bacillus subtilis in response to oxygen limitation. ResD regulon genes that are the most highly induced during nitrate respiration include the nitrite reductase operon (nasDEF) and the flavohemoglobin gene (hmp), whose products function in nitric oxide (NO) metabolism. Transcription of these genes is also under the negative control of the NO-sensitive NsrR repressor. Recent studies showed that the NsrR regulon contains genes with no apparent relevance to NO metabolism and that the ResD response regulator and NsrR coordinately regulate transcription. To determine whether these genes are direct targets of NsrR and ResD, we used chromatin affinity precipitation coupled with tiling chip (ChAP-chip) and ChAP followed by quantitative PCR (ChAP-qPCR) analyses. The study showed that ResD and NsrR directly control transcription of the ykuNOP operon in the Fur regulon. ResD functions as an activator at the nasD and hmp promoters, whereas it functions at the ykuN promoter as an antirepressor of Fur and a corepressor for NsrR. This mechanism likely participates in fine-tuning of transcript levels in response to different sources of stress, such as oxygen limitation, iron limitation, and exposure to NO.


Assessment of the feed additive consisting of Lactiplantibacillus plantarum (formerly Lactobacillus plantarum) DSM 12836 for all animal species for the renewal of its authorisation (Lactosan GmbH & Co KG).
Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the assessment of the application for renewal of authorisation of Lactiplantibacillus plantarum (formerly Lactobacillus plantarum) DSM 12836, as a technological additive for all animal species. The applicant has provided evidence that the additive currently in the market complies with the existing conditions of authorisation. There was no new evidence that would lead the FEEDAP Panel to reconsider its previous conclusions. Thus, the Panel concluded that the additive remains safe for all animal species, consumer and the environment under the authorised conditions of use. The additive was not irritant to skin and eyes but is considered a skin and respiratory sensitiser. The present application for renewal of the authorisation did not include a proposal for amending or supplementing the conditions of the original authorisation that would have an impact on the efficacy of the additive. Therefore, there was no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.


Diurnal ventilation via mouthpiece: survival in end-stage Duchenne patients.
The present study aimed to assess the impact of diurnal mouthpiece intermittent positive pressure ventilation (MIPPV) as the extension of the nasal intermittent positive pressure ventilation (NIPPV) in Duchenne muscular dystrophy (DMD). In total, 42 DMD patients aged 15-33 yrs, normocapnic at night with NIPPV and receiving MIPPV since end-diurnal hypercapnia, were studied. Transcutaneous CO2 tension (Pt,CO2) was prospectively monitored at the end of the day, before and after MIPPV initiation. Vital capacity (VC), breathing pattern and maximal inspiratory strength were measured. Patients were asked to score the presence (1 point) or absence (0 point) of seven respiratory-linked symptoms before and after MIPPV establishment. Survival rates reached 88, 77, 58 and 51% after 1, 3, 5 and 7 yrs, respectively. The mean survival rate was 31 yrs. VC stabilised during 5 yrs with MIPPV. Symptom scores significantly decreased and Pt,CO2 normalised during the day (8.17 +/- 2.22 to 5.78 +/- 0.73 kPa). No accident and minor side-effects were observed in this 184 cumulated patient-yrs study. In conclusion, daytime mouthpiece ventilation is safe, prolongs survival and stabilises vital capacity in Duchenne muscular dystrophy patients. It is recommended on the condition that patients are equipped with a self-supporting harness.


The Origins and Psychology of Human Cooperation.
Humans are an ultrasocial species. This sociality, however, cannot be fully explained by the canonical approaches found in evolutionary biology, psychology, or economics. Understanding our unique social psychology requires accounting not only for the breadth and intensity of human cooperation but also for the variation found across societies, over history, and among behavioral domains. Here, we introduce an expanded evolutionary approach that considers how genetic and cultural evolution, and their interaction, may have shaped both the reliably developing features of our minds and the well-documented differences in cultural psychologies around the globe. We review the major evolutionary mechanisms that have been proposed to explain human cooperation, including kinship, reciprocity, reputation, signaling, and punishment; we discuss key culture-gene coevolutionary hypotheses, such as those surrounding self-domestication and norm psychology; and we consider the role of religions and marriage systems. Empirically, we synthesize experimental and observational evidence from studies of children and adults from diverse societies with research among nonhuman primates.


Nuclear Overhauser effect studies of the conformations and binding site environments of deoxynucleoside triphosphate substrates bound to DNA polymerase I and its large fragment.
The conformations and binding site environments of Mg2+TTP and Mg2+dATP bound to Escherichia coli DNA polymerase I and its large (Klenow) fragment have been investigated by proton NMR. The effect of the large fragment of Pol I on the NMR line widths of the protons of Mg2+TTP detected one binding site for this substrate with a dissociation constant of 300 +/- 100 microM and established simple competitive binding of deoxynucleoside triphosphates at this site in accord with previous equilibrium dialysis experiments with whole Pol I [Englund, P. T., Huberman, J.A., Jovin, T.M., & Kornberg, A. (1969) J. Biol. Chem. 244, 3038]. Primary negative nuclear Overhauser effects were used to calculate interproton distances on enzyme-bound Mg2+dATP and Mg2+TTP. These distances established that each substrate was bound with an anti-glycosidic torsional angle (chi) of 50 +/- 10 degrees for Mg2+dATP and 40 +/- 10 degrees for Mg2+TTP. The sugar pucker of both substrates was predominantly O1'-endo, with a C5'-C4'-C3'-O3' exocyclic torsional angle (delta) of 95 +/- 10 degrees for Mg2+dATP and 100 +/- 10 degrees for Mg2+TTP. The consistency of these conformations with those previously proposed, on the basis of distances from Mn2+ at the active site [Sloan, D. L., Loeb, L. A., Mildvan, A.S., & Feldman, R.J. (1975) J. Biol. Chem. 250, 8913], indicates a unique conformation for each bound nucleotide. The chi and delta values of the bound substrates are appropriate for nucleotide units of B DNA.(ABSTRACT TRUNCATED AT 250 WORDS)


Alzheimer's associated inflammation, potential drug targets and future therapies.
Alzheimer's disease is the most common cause of dementia in the elderly population. The most widely used treatment for Alzheimer's disease at present is acetylcholinesterase inhibitors, which aim to prolong cognitive function through increased synaptic activity, without providing neuroprotection. This treatment is only symptomatic and provides modest outcomes for patients. The recent elucidation of the inflammatory pathways involved in Alzheimer's disease however, has opened doors for better treatment and prevention by identification of areas of therapeutic intervention that target the cause of the disease rather than the symptoms. This review describes the inflammatory pathways that are thought to be present in Alzheimer's disease and some of the new therapies that have shown promise, via alteration or inhibition of these pathways. Some of the therapies included in this review, which have already demonstrated beneficial effects in the treatment of Alzheimer's disease, or have the potential to do so, are nonsteroidal anti-inflammatory drugs, statins, RAGE antagonists and antioxidants.


Computerized physician order entry in the critical care environment: a review of current literature.
The implementation of health information technology (HIT) is accelerating, driven in part by a growing interest in computerized physician order entry (CPOE) as a tool for improving the quality and safety of patient care. Computerized physician order entry could have a substantial impact on patients in intensive care, where the potential for medical error is high, and the clinical workflow is complex. In 2009, only 17% of hospitals had functional CPOE systems in place. In intensive care unit (ICU) settings, CPOE has been shown to reduce the occurrence of some medication errors, but evidence of a beneficial effect on clinical outcomes remains limited. In some cases, new error types have arisen with the use of CPOE. Intensive care unit workflow and staff relationships have been affected by CPOE, often in unanticipated ways. The design of CPOE software has a strong impact on user acceptance. Intensive care unit-specific order sets lessen the cognitive workload associated with the use of CPOE and improve user acceptance. The diffusion of new technological innovations in the ICU can have unintended consequences, including changes in workflow, staff roles, and patient outcomes. When implementing CPOE in critical care areas, both organizational and technical factors should be considered. Further research is needed to inform the design and management of CPOE systems in the ICU and to better assess their impact on clinical end points, cost-effectiveness, and user satisfaction.


A new model for cancer research in France.
The new French National Cancer Institute is unique in Europe in that it associates all aspects of cancer care, research and patient advocacy in one single umbrella body. It brings together all sectors of the cancer field in a patient-centred, multidisciplinary approach to the disease. By facilitating national, European and international collaborations, it aims to attack the disease with a strong and united front.


Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy.
Antioxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes, providing a rationale for a potential therapeutic value in diabetic patients. The effects of the antioxidant alpha-lipoic acid (thioctic acid) were studied in two multicenter, randomized, double-blind placebo-controlled trials. In the Alpha-Lipoic Acid in Diabetic Neuropathy Study, 328 patients with NIDDM and symptomatic peripheral neuropathy were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (ALA 1,200 mg; 600 mg; 100 mg) or placebo (PLAC) over 3 weeks. The total symptom score (TSS) (pain, burning, paresthesia, and numbness) in the feet decreased significantly from baseline to day 19 in ALA 1,200 and ALA 600 vs. PLAC. Each of the four individual symptom scores was significantly lower in ALA 600 than in PLAC after 19 days (all P < 0.05). The total scale of the Hamburg Pain Adjective List (HPAL) was significantly reduced in ALA 1,200 and ALA 600 compared with PLAC after 19 days (both P < 0.05). In the Deutsche Kardiale Autonome Neuropathie Studie, patients with NIDDM and cardiac autonomic neuropathy diagnosed by reduced heart rate variability were randomly assigned to treatment with a daily oral dose of 800 mg alpha-lipoic acid (ALA) (n = 39) or placebo (n = 34) for 4 months. Two out of four parameters of heart rate variability at rest were significantly improved in ALA compared with placebo. A trend toward a favorable effect of ALA was noted for the remaining two indexes. In both studies, no significant adverse events were observed. In conclusion, intravenous treatment with alpha-lipoic acid (600 mg/day) over 3 weeks is safe and effective in reducing symptoms of diabetic peripheral neuropathy, and oral treatment with 800 mg/day for 4 months may improve cardiac autonomic dysfunction in NIDDM.


Preventable proportion of intubation-associated pneumonia: Role of adherence to a care bundle.
The aim of the present study was to estimate the preventable proportion of Intubation-Associated Pneumonia (IAP) in the Intensive Care Units (ICUs) participating in the Italian Nosocomial Infections Surveillance in ICUs (SPIN-UTI) network, taking into account differences in intrinsic patients' risk factors, and additionally considering the compliance with the European bundle for IAP prevention. A prospective patient-based survey was conducted and all patients staying in ICU for more than 2 days were enrolled in the surveillance. Compliance with the bundle was assessed using a questionnaire for each intubated patient. A twofold analysis by the parametric g-formula was used to compute the number of infections to be expected if the infection incidence in all ICUs could be reduced to that one of the top-tenth-percentile-ranked ICUs and to that one of the ICU with the highest compliance to all five bundle components. A total of 1,840 patients and of 17 ICUs were included in the first analysis showing a preventable proportion of 44% of IAP. In a second analysis on a subset of data, considering compliance with the European bundle, a preventable proportion of 40% of IAP was shown. A significant negative trend of IAP incidences was observed with increasing number of bundle components performed (p<0.001) and a strong negative correlation between these two factors was shown (r = -0.882; p = 0.048). The g-formula controlled for time-varying factors is a valuable approach for estimating the preventable proportion of IAP and the impact of interventions, based entirely on an observed population in a real-world setting. However, both the study design that cannot definitively prove a causative relationship between bundle compliance and IAP risk, and the small number of patients included in the care bundle compliance analysis, may represent limits of the study and further and larger studies should be conducted.


Foot pain: is current or past shoewear a factor?
Foot pain is common, yet few studies have examined the condition in relationship to shoewear. In this cross-sectional study of men and women from the population-based Framingham Study, the association between foot pain and type of shoewear was examined. Data were collected on 3,378 members of the Framingham Study who completed the foot examination in 2002-2008. Foot pain (both generalized and at specific locations) was measured by the response to the question "On most days, do you have pain, aching or stiffness in either foot?" Shoewear was recorded for the present time and 5 past age categories, by the subject's choice of the appropriate shoe from a list. The responses were categorized into 3 groups (good, average, or poor shoes). Sex-specific multivariate logistic regression models were used to examine the effect of shoewear (average shoes were the referent group) on generalized and location-specific foot pain, adjusting for age and weight. In women, compared with average shoes, those who wore good shoes in the past were 67% less likely to report hindfoot pain (P = 0.02), after adjusting for age and weight. In men, there was no association between foot pain, at any location, and shoewear, possibly due to the fact that <2% wore bad shoe types, making it difficult to see any relationship. Even after taking age and weight into account, past shoewear use in women remained associated with hindfoot pain. Future studies should address specific support and structural features of shoewear.


Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial.
Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum β-lactamase producers. To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, -∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting. anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.


Localization of the microsatellite probe DXS426 between DXS7 and DXS255 on Xp and linkage to X-linked retinitis pigmentosa.
The microsatellite marker DXS426 maps to the interval Xp21.1-Xp11.21, the chromosomal region which contains two loci for X-linked retinitis pigmentosa (XLRP; RP2 and RP3). We have refined the localization of DXS426 both physically, by mapping it to a deletion which spans the interval Xp21.3-Xp11.23, and genetically, by studying multiply informative crossovers which indicate that DXS426 lies between DXS7 and DXS255 (i.e., Xp11.4-Xp11.22). As this is the region which contains the RP2 gene, RP2 families could be identified on the basis of linkage of XLRP to DXS426. Multiply informative crossovers in two RP2 families indicate that the most likely location of the RP2 gene is between DXS426 and DXS7. DXS426 is therefore an important highly informative marker for the purposes of carrier detection and early diagnosis of RP2 and for the localization of the disease gene.


Hybrid PGS-PCL microfibrous scaffolds with improved mechanical and biological properties.
Poly(glycerol sebacate) (PGS) is a biodegradable elastomer that has generated great interest as a scaffold material due to its desirable mechanical properties. However, the use of PGS in tissue engineering is limited by difficulties in casting micro- and nanofibrous structures, due to high temperatures and vacuum required for its curing and limited solubility of the cured polymer. In this paper, we developed microfibrous scaffolds made from blends of PGS and poly(ε-caprolactone) (PCL) using a standard electrospinning set-up. At a given PGS:PCL ratio, higher voltage resulted in significantly smaller fibre diameters (reduced from ∼4 µm to 2.8 µm; p < 0.05). Further increase in voltage resulted in the fusion of fibres. Similarly, higher PGS concentrations in the polymer blend resulted in significantly increased fibre diameter (p < 0.01). We further compared the mechanical properties of electrospun PGS:PCL scaffolds with those made from PCL. Scaffolds with higher PGS concentrations showed higher elastic modulus (EM), ultimate tensile strength (UTS) and ultimate elongation (UE) (p < 0.01) without the need for thermal curing or photocrosslinking. Biological evaluation of these scaffolds showed significantly improved HUVEC attachment and proliferation compared to PCL-only scaffolds (p < 0.05). Thus, we have demonstrated that simple blends of PGS prepolymer with PCL can be used to fabricate microfibrous scaffolds with mechanical properties in the range of a human aortic valve leaflet.


Genomic and proteomic analyses of the fungus Arthrobotrys oligospora provide insights into nematode-trap formation.
Nematode-trapping fungi are "carnivorous" and attack their hosts using specialized trapping devices. The morphological development of these traps is the key indicator of their switch from saprophytic to predacious lifestyles. Here, the genome of the nematode-trapping fungus Arthrobotrys oligospora Fres. (ATCC24927) was reported. The genome contains 40.07 Mb assembled sequence with 11,479 predicted genes. Comparative analysis showed that A. oligospora shared many more genes with pathogenic fungi than with non-pathogenic fungi. Specifically, compared to several sequenced ascomycete fungi, the A. oligospora genome has a larger number of pathogenicity-related genes in the subtilisin, cellulase, cellobiohydrolase, and pectinesterase gene families. Searching against the pathogen-host interaction gene database identified 398 homologous genes involved in pathogenicity in other fungi. The analysis of repetitive sequences provided evidence for repeat-induced point mutations in A. oligospora. Proteomic and quantitative PCR (qPCR) analyses revealed that 90 genes were significantly up-regulated at the early stage of trap-formation by nematode extracts and most of these genes were involved in translation, amino acid metabolism, carbohydrate metabolism, cell wall and membrane biogenesis. Based on the combined genomic, proteomic and qPCR data, a model for the formation of nematode trapping device in this fungus was proposed. In this model, multiple fungal signal transduction pathways are activated by its nematode prey to further regulate downstream genes associated with diverse cellular processes such as energy metabolism, biosynthesis of the cell wall and adhesive proteins, cell division, glycerol accumulation and peroxisome biogenesis. This study will facilitate the identification of pathogenicity-related genes and provide a broad foundation for understanding the molecular and evolutionary mechanisms underlying fungi-nematodes interactions.


Pollution from Fossil-Fuel Combustion is the Leading Environmental Threat to Global Pediatric Health and Equity: Solutions Exist.
Fossil-fuel combustion by-products are the world's most significant threat to children's health and future and are major contributors to global inequality and environmental injustice. The emissions include a myriad of toxic air pollutants and carbon dioxide (CO₂), which is the most important human-produced climate-altering greenhouse gas. Synergies between air pollution and climate change can magnify the harm to children. Impacts include impairment of cognitive and behavioral development, respiratory illness, and other chronic diseases-all of which may be "seeded" in utero and affect health and functioning immediately and over the life course. By impairing children's health, ability to learn, and potential to contribute to society, pollution and climate change cause children to become less resilient and the communities they live in to become less equitable. The developing fetus and young child are disproportionately affected by these exposures because of their immature defense mechanisms and rapid development, especially those in low- and middle-income countries where poverty and lack of resources compound the effects. No country is spared, however: even high-income countries, especially low-income communities and communities of color within them, are experiencing impacts of fossil fuel-related pollution, climate change and resultant widening inequality and environmental injustice. Global pediatric health is at a tipping point, with catastrophic consequences in the absence of bold action. Fortunately, technologies and interventions are at hand to reduce and prevent pollution and climate change, with large economic benefits documented or predicted. All cultures and communities share a concern for the health and well-being of present and future children: this shared value provides a politically powerful lever for action. The purpose of this commentary is to briefly review the data on the health impacts of fossil-fuel pollution, highlighting the neurodevelopmental impacts, and to briefly describe available means to achieve a low-carbon economy, and some examples of interventions that have benefited health and the economy.


Self-Assisted Standing Enabled by Non-Invasive Spinal Stimulation after Spinal Cord Injury.
Neuromodulation of spinal networks can improve motor control after spinal cord injury (SCI). The objectives of this study were to (1) determine whether individuals with chronic paralysis can stand with the aid of non-invasive electrical spinal stimulation with their knees and hips extended without trainer assistance, and (2) investigate whether postural control can be further improved following repeated sessions of stand training. Using a double-blind, balanced, within-subject cross-over, and sham-controlled study design, 15 individuals with SCI of various severity received transcutaneous electrical spinal stimulation to regain self-assisted standing. The primary outcomes included qualitative comparison of need of external assistance for knee and hip extension provided by trainers during standing without and in the presence of stimulation in the same participants, as well as quantitative measures, such as the level of knee assistance and amount of time spent standing without trainer assistance. None of the participants could stand unassisted without stimulation or in the presence of sham stimulation. With stimulation all participants could maintain upright standing with minimum and some (n = 7) without external assistance applied to the knees or hips, using their hands for upper body balance as needed. Quality of balance control was practice-dependent, and improved with subsequent training. During self-initiated body-weight displacements in standing enabled by spinal stimulation, high levels of leg muscle activity emerged, and depended on the amount of muscle loading. Our findings indicate that the lumbosacral spinal networks can be modulated transcutaneously using electrical spinal stimulation to facilitate self-assisted standing after chronic motor and sensory complete paralysis.


Directionality in the Relationship of Self-regulation, Self-efficacy, and Mood Changes in Facilitating Improved Physical Activity and Nutrition Behaviors: Extending Behavioral Theory to Improve Weight-Loss Treatment Effects.
To improve understanding of directionality in the dynamic relationships among psychosocial predictors of behavioral changes associated with weight loss. In women with obesity participating in a new behavioral weight-loss treatment that emphasizes physical activity (n = 53; body mass index = 34.7 ± 3.3 kg/m2), mediation and moderated-mediation models were fit to assess directionality in the self-efficacy-self-regulation change relationship and additional effects of mood change and its basis on fruit/vegetable intake and physical activity behaviors through month 6 and from months 6 to 24. Self-regulation was a stronger predictor of change in self-efficacy than vice versa. Mood change did not moderate the relationships significantly between changes in self-efficacy and/or self-regulation, and weight loss behavior. Emotional eating significantly changed mediated relationships between changes in mood and fruit/vegetable intake through month 6 (95% confidence interval, -0.05 to 0.00). Findings clarified relationships of self-efficacy, self-regulation, and mood in the prediction of weight loss behaviors, and informed behavioral treatments for improved outcomes.


Rupture of an extended object: a many-body Kramers calculation.
We show how an extended object's strain field is redistributed when the material ruptures under by thermal activation. Through analytical calculations and molecular dynamics simulations, we show that in a polymer chain the distribution is exponentially localized around the point of rupture. The length scale of localization is determined by the strain and microscopic parameters of the interaction potential. We also derive an analytic expression for the rate of bond rupture by consistently treating the collective modes of the chain and the effect of dissipation on those modes. Our theoretical estimates are of the same order of magnitude as those obtained by simulations, as compared to earlier theories which had overestimated the rate of rupture by approximately two orders of magnitude. It is also noteworthy that the correction comes about through the effective attempt frequency rather than the effective barrier height.


VAV2 regulates epidermal growth factor receptor endocytosis and degradation.
Vav proteins are guanine nucleotide exchange factors for Rho GTPases that regulate cell adhesion, motility, spreading and proliferation in response to growth factor signalling. In this work, we show that Vav2 expression delayed epidermal growth factor receptor (EGFR) internalization and degradation, and enhanced EGFR, ERK and Akt phosphorylations. This effect of Vav2 on EGFR degradation is dependent on its guanine nucleotide exchange function. Knockdown of Vav2 in HeLa cells enhanced EGFR degradation and reduced cell proliferation. epidermal growth factor stimulation led to co-localization of Vav2 with EGFR and Rab5 in endosomes. We further show that the effect of Vav2 on EGFR stability is modulated by its interaction with two endosome-associated proteins and require RhoA function. Thus, in this work, we report for the first time that Vav2 can regulate growth factors receptor signalling by slowing receptor internalization and degradation through its interaction with endosome-associated proteins.


A lectin-mediated resistance of higher fungi against predators and parasites.
Fruiting body lectins are ubiquitous in higher fungi and characterized by being synthesized in the cytoplasm and up-regulated during sexual development. The function of these lectins is unclear. A lack of phenotype in sexual development upon inactivation of the respective genes argues against a function in this process. We tested a series of characterized fruiting body lectins from different fungi for toxicity towards the nematode Caenorhabditis elegans, the mosquito Aedes aegypti and the amoeba Acanthamoeba castellanii. Most of the fungal lectins were found to be toxic towards at least one of the three target organisms. By altering either the fungal lectin or the glycans of the target organisms, or by including soluble carbohydrate ligands as competitors, we demonstrate that the observed toxicity is dependent on the interaction between the fungal lectins and specific glycans in the target organisms. The toxicity was found to be dose-dependent such that low levels of lectin were no longer toxic but still led to food avoidance by C. elegans. Finally, we show, in an ecologically more relevant scenario, that challenging the vegetative mycelium of Coprinopsis cinerea with the fungal-feeding nematode Aphelenchus avenae induces the expression of the nematotoxic fruiting body lectins CGL1 and CGL2. Based on these findings, we propose that filamentous fungi possess an inducible resistance against predators and parasites mediated by lectins that are specific for glycans of these antagonists.


Gain control in the electrosensory system mediated by descending inputs to the electrosensory lateral line lobe.
The electrosensory lateral line lobe (ELLL) of weakly electric fish, the primary electrosensory processing station, receives a large descending input from the midbrain in addition to the input from the electroreceptor afferents. The role of a major component of this descending input in determining the properties of ELLL output neurons was investigated. The descending input was reduced or eliminated by microinjections of the local anesthetic lidocaine or by small lesions. This treatment increased the responses of the ELLL output neurons to suprathreshold stimuli by about 300% and also increased the size of the neurons' receptive fields for moving electrolocation targets and the resolution with which they encode target distance. The neurons' threshold sensitivity and tuning to amplitude modulation frequency were unchanged by removal of the descending input. The results of this study show that this portion of the descending input to the ELLL normally mediates an inhibition that controls the responsiveness of ELLL output neurons. This descending input could function as a gain control mechanism, allowing the animal to modulate the sensitivity of the electrosensory system in response to changing environmental conditions.


SETD6 regulates NF-κB signaling in urothelial cell survival: Implications for bladder cancer.
Non-muscle invasive bladder cancer has a high recurrence rate of 45-70%, progressing to muscle invasive disease in about 15% of those patients over a 5-year period. Administration of the mycobacterium, Bacillus Calmette-Guerin (BCG) that induces local inflammation resulting in tumor remission in responsive patients is frequently used for treatment. BCG-treated patients with NF-κB del/del genotype have an increased risk of recurrence suggesting an important role of NF-κB in bladder cancer. Since protein methyltransferases play critical roles in modulating chromatin structure and gene expression, we screened a focused array of epigenetic modification genes to identify differential expression between normal urothelial and bladder cancer cells. We found and validated high expression of the SET-domain-containing protein methyltransferase, SETD6. SETD6 monomethylates NF-κB-p65 at lysine 310. Our results show that primary urothelial cells and normal bladder tissue have nearly undetectable message and protein level of SETD6 that increases in transformed urothelial cells and is further increased in bladder cancer cells and tissues. Overexpression of SETD6 in transformed urothelial cells increased cell survival and colony formation while knockdown in cancer cells decreased both parameters. Luciferase reporter assays showed that SETD6 induced the canonical NF-κB signaling pathway. Further, the use of catalytic SETD6 and IκBα mutant shows that SETD6 positively regulates survival by affecting p65 message, protein level and its function as determined by increased expression of NF-κB target genes. Our findings suggest that SETD6 plays an important role in NF-κB regulation and may have an important role in NF-κB-mediated local inflammatory response following BCG treatment.


Bisphenol A as an environmental pollutant with dual genotoxic and DNA-protective effects.
Bisphenol A (BPA) is an endocrine disruptor which has been shown to be a harmful compound for living organisms. It is the main component of the most commonly used plastic products such as plastic bottles, food cans and containers or dental fillings, and other medical aids. Recently, it has become a new environmental pollutant. The current knowledge about the BPA effects (including genotoxic one) on different cells is in many cases contradictory. Thus, the aim of the paper is to study the potential genotoxic effect of BPA. An observation of the genotoxic activity of BPA on human lymphocytes was evaluated by using the alkaline comet assay and a modified comet assay with bacterial DNA repair enzyme Fpg. The potential DNA-protective effect of BPA was tested by using the DNA-topology assay. The results show that rising concentrations of BPA increase the risk of DNA double-strand breaks and modified purines in human lymphocytes. Interestingly, BPA shows an ability to protect plasmid DNA from the damage of iron ions in cell-free system. BPA itself does not induce genotoxic effect to DNA. However, BPA treatment of human lymphocytes leads to the induction of DNA damage. The proposed mechanism of BPA action in the human lymphocytes could be mediated by cell metabolism that induces an oxidative stress and ROS formation. ROS subsequently attack DNA and thus induce DNA damage. According to our results, BPA can be included in the group of substances with dual effects involving genotoxic and DNA-protective activity.


Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis.
Mitochondrial autoantibodies are characteristic of the disease primary biliary cirrhosis (PBC), but the immunoreactive mitochondrial antigens have not been defined. We used a rat liver cDNA library in lambda gt 11-Amp3 to clone a 1370-base pair insert that coded for a polypeptide reactive with PBC sera. This insert was subcloned for expression into pBTA224, a plasmid vector in the same reading frame as lambda-Amp3. A positive clone, designated pRMIT, that expressed a fused polypeptide of 160 kd, was recognized by 25 of 25 sera from patients with PBC and none of 96 sera from normal persons or patients with systemic lupus erythematosus, rheumatoid arthritis, or chronic active hepatitis. This fused polypeptide was shown to correspond with the 70 kd mitochondrial autoantigen by several experiments. First, lysates of pRMIT in J101 absorbed out the 70 kd reactivity of PBC sera when probed against fractionated placental mitochondria. Second, affinity-purified antisera reactive with the fused polypeptide also reacted with the 70 kd mitochondrial antigen. Third, such affinity-purified antisera produced the characteristic anti-mitochondrial pattern of immunofluorescence on tissue sections. Finally, immunization of BALB/c mice with the fused polypeptide elicited antibodies to mitochondria. These murine antibodies reacted with the 70 kd mitochondrial protein and also produced typical mitochondrial immunofluorescence on tissue sections. The nucleotide and amino acid sequence of the recombinant protein, which encodes for approximately a 48 kd protein, showed no significant homologies with known proteins, and there were no homologies with mitochondrial genomic DNA. The availability of a recombinant form of the 70 kd mitochondrial autoantigen will allow several definitive questions to be addressed in PBC, including identification of B cell epitopes, T cell recognition, and a model of PBC in mice.


Metal organic framework synthesis in the presence of surfactants: towards hierarchical MOFs?
The effect of synthesis pH and H2O/EtOH molar ratio on the textural properties of different aluminium trimesate metal organic frameworks (MOFs) prepared in the presence of the well-known cationic surfactant cetyltrimethylammonium bromide (CTAB) at 120 °C was studied with the purpose of obtaining a MOF with hierarchical pore structure. Depending on the pH and the solvent used, different topologies were obtained (namely, MIL-96, MIL-100 and MIL-110). On the one hand, MIL-110 was obtained at lower temperatures than those commonly reported in the literature and without additives to control the pH; on the other hand, MIL-100 with crystallite sizes as small as 30 ± 10 nm could be easily synthesized in a mixture of H2O and EtOH with a H2O/EtOH molar ratio of 3.4 at pH 2.6 in the presence of CTAB. The resulting material displays a hierarchical porosity that combines the microporosity from the MOF and the non-ordered mesopores defined in between the MOF nanoparticles. Interestingly, the maximum of the pore size distribution could be varied between 3 and 33 nm. Finally, at pH 2.5 and using water as a solvent, platelets of MIL-96, a morphology never observed before for this MOF, were synthesized with a (001) preferential crystal orientation, the (001) plane running parallel to the bipyramidal cages of the MIL-96 topology.


The GDNF target Vsnl1 marks the ureteric tip.
Glial cell line-derived neurotrophic factor (GDNF) is indispensable for ureteric budding and branching. If applied exogenously, GDNF promotes ectopic ureteric buds from the Wolffian duct. Although several downstream effectors of GDNF are known, the identification of early response genes is incomplete. Here, microarray screening detected several GDNF-regulated genes in the Wolffian duct, including Visinin like 1 (Vsnl1), which encodes a neuronal calcium-sensor protein. We observed renal Vsnl1 expression exclusively in the ureteric epithelium, but not in Gdnf-null kidneys. In the tissue culture of Gdnf-deficient kidney primordium, exogenous GDNF and alternative bud inducers (FGF7 and follistatin) restored Vsnl1 expression. Hence, Vsnl1 characterizes the tip of the ureteric bud epithelium regardless of the inducer. In the tips, Vsnl1 showed a mosaic expression pattern that was mutually exclusive with β-catenin transcriptional activation. Vsnl1 was downregulated in both β-catenin-stabilized and β-catenin-deficient kidneys. Moreover, in a mouse collecting duct cell line, Vsnl1 compromised β-catenin stability, suggesting a counteracting relationship between Vsnl1 and β-catenin. In summary, Vsnl1 marks ureteric bud tips in embryonic kidneys, and its mosaic pattern demonstrates a heterogeneity of cell types that may be critical for normal ureteric branching.


Children With Inguinal Hernia Repairs: Age and Gender Characteristics.
Objective. This study reports the age and gender characteristics of children with inguinal hernia repairs (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] Operation Codes 530-533). Methods. We used a retrospective cohort study design based on 2 data sources from 2007 to 2011 (the Bureau of National Health Insurance, Department of Health, Taiwan, and a local teaching children's hospital database) and descriptive statistics to analyze the group's age and gender differences as independent variables. Results. The gender ratio was 7 males to 1 female in the general population, whereas the gender ratio in children was 3.5 males to 1 female. Gender difference was found statistically significant in the age subgroup difference: boys (49.1%) were more than girls (39.3%) in ages 1 to 4, while girls (37.8%) were more than boys (23.7%) in ages 5 to 9. Based on the local hospital's data, of those 611 (15%) children born and who received herniorrhaphy, 204 (33.4%) were born as preterm infants and 407 (66.6%) as term infants. The gender ratio among 204 children born prematurely and received herniorrhaphy was 3 males to 1 female. Of those 353 infants under 6 months who received herniorrhaphy, 155 (76%) were preterm infants while 198 (48.6%) were term infants. Conclusion. Early screening of inguinal hernia for children is important and should focus on those born prematurely, particularly those aged <6 months and boys.


Moa's Ark or volant ghosts of Gondwana? Insights from nineteen years of ancient DNA research on the extinct moa (Aves: Dinornithiformes) of New Zealand.
The moa (Aves: Dinornithiformes) of New Zealand represent one of the extinct iconic taxa that define the field of ancient DNA (aDNA), and after almost two decades of genetic scrutiny of bones, feathers, coprolites, mummified tissue, eggshell, and sediments, our knowledge of these prehistoric giants has increased significantly. Thanks to molecular and morphological-based research, the insights that have been obtained into moa phylogenetics, phylogeography, and palaeobiology exceeds that of any other extinct taxon. This review documents the strengths of applying a multidisciplinary approach when studying extinct taxa but also shows that cross-disciplinary controversies still remain at the most fundamental levels, with highly conflicting interpretations derived from aDNA and morphology. Moa species diversity, for example, is still heavily debated, as well as their relationship with other ratites and the mode of radiation. In addition to increasing our knowledge on a lineage of extinct birds, further insights into these aspects can clarify some of the basal splits in avian evolution, and the evolutionary implications of the breakup of the prehistoric supercontinent Gondwana. Did a flightless moa ancestor drift away on proto New Zealand (Moa's Ark) or did a volant ancestor arrive by flight? Here we provide an overview of 19 years of aDNA research on moa, critically assess the attempts and controversies in placing the moa lineage among palaeognath birds, and discuss the factors that facilitated the extensive radiation of moa. Finally, we identify the most obvious gaps in the current knowledge to address the future potential research areas in moa genetics.


Serum Uric Acid Levels and Risk of Metabolic Syndrome: A Dose-Response Meta-Analysis of Prospective Studies.
An excess circulating uric acid level, even within the normal range, is always comorbid with metabolic syndrome (MS), several of its components, and nonalcoholic fatty liver disease (NAFLD), which was regarded as hepatic manifestation of MS; however, these associations remain controversial. This study aimed to quantitatively assess the relationship between the serum uric acid (SUA) levels and the MS/NAFLD risk. We searched for related prospective cohort studies including SUA as an exposure and MS/NAFLD as a result in MEDLINE (PubMed) and EMBASE databases up to January 31, 2015 and July 28, 2015, respectively. Pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) were extracted. A random-effects model was used to evaluate dose-response relationships. On the basis of 11 studies (54 970 participants and 8719 MS cases), a combined RR of 1.72 (95% CI, 1.45-2.03; P < .0001) was observed for the highest SUA level category compared with the lowest SUA level category. Furthermore, based on nine studies (51 249 participants and 8265 MS cases), dose-response analysis suggested that each 1 mg/dL SUA increment was roughly linearly associated with the MS risk (RR, 1.30; 95% CI, 1.22-1.38; P < .0001). Beyond that, SUA level increased NAFLD risk (RR, 1.46; 95% CI, 1.31-1.63). Each 1 mg/dL SUA level increment led to 21% increase in the NAFLD risk. This meta-analysis suggests that higher SUA levels led to an increased risk of MS regardless of the study characteristics, and were consistent with a linear dose-response relationship. In addition, SUA was also a causal factor for the NAFLD risk.


Effects of Coenzyme Q10 on Markers of Inflammation: A Systematic Review and Meta-Analysis.
Chronic inflammation contributes to the onset and development of metabolic diseases. Clinical evidence has suggested that coenzyme Q10 (CoQ10) has some effects on inflammatory markers. However, these results are equivocal. The aim of this systematic review was to assess the effects of CoQ10 on serum levels of inflammatory markers in people with metabolic diseases. Electronic databases were searched up to February 2016 for randomized controlled trials (RCTs). The outcome parameters were related to inflammatory factors, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and C reactive protein (CRP). RevMan software was used for meta-analysis. Meta-regression analysis, Egger line regression test and Begg rank correlation test were performed by STATA software. Nine trials involving 428 subjects were included in this meta-analysis. The results showed that compared with control group, CoQ10 supplementation has significantly improved the serum level of CoQ10 by 1.17μg/ml [MD = 1.17, 95% CI (0.47 to 1.87) μg/ml, I2 = 94%]. Meanwhile, it has significantly decreased TNF-α by 0.45 pg/ml [MD = -0.45, 95% CI (-0.67 to -0.24) pg/ml, I2 = 0%]. No significant difference was observed between CoQ10 and placebo with regard to CRP [MD = -0.21, 95% CI (-0.60 to 0.17) mg/L, I2 = 21%] and IL-6 [MD = -0.89, 95% CI (-1.95 to 0.16) pg/ml, I2 = 84%]. CoQ10 supplementation may partly improve the process of inflammatory state. The effects of CoQ10 on inflammation should be further investigated by conducting larger sample size and well-defined trials of long enough duration.


A haplotype analysis is consistent with the role of functional HTR1B variants in alcohol dependence.
Animal and human studies have suggested that the serotonergic system plays an important role in alcohol consumption and abuse, mainly due to the serotonin receptor 1B (5-HT(1B)) function in the mesolimbic reward pathway. Association studies between the HTR1B gene variants and alcoholism have found significant results. There is also evidence for a complex balancing regulation of the gene by two functional variants in the promoter region (rs11568817 and rs130058), which are in linkage disequilibrium. The aim of this study is to investigate the role of the most relevant variants (rs11568817, rs130058, rs6296 and rs13212041) of the HTR1B gene in the susceptibility to alcohol dependence. The sample comprised 136 Brazilian alcoholics of European descendent and 237 controls. The results suggest an association between a functional variant of the gene (rs11568817) and alcohol dependence (p=0.001). In addition, this association could also be confirmed in an independent sample using imputed data from a GWAS, where marginal significant association (p=0.03, one-tailed) with the same allele was obtained. The pattern of distribution of haplotypes was significantly different between patients and controls (p<0.0001), which is consistent with the role of the two functional variants of the promoter region. In conclusion, our findings point to an association between functional variants in the promoter region of the HTR1B gene and alcohol dependence, supporting previous neurobiological evidences of the involvement of HTR1B variations in alcohol-related phenotypes.


Functional isolation and characterization of human hematopoietic stem cells.
Hematopoietic cells differentiate in steps marked by the acquisition or loss of specific phenotypic characteristics. Human bone marrow cells that were responsive to the early-acting cytokines Kit ligand and interleukin-3 were forced to a metabolic death. The subfraction remaining represented 1 in 10(5) bone marrow mononuclear cells, were determined to be quiescent by cell cycle analysis, and had a stem cell immunophenotype. The cells were highly enriched for long-term culture-initiating cells, were capable of secondary colony formation, and produced both myeloid and lymphoid progeny. Thus, this technically simple strategy led to the efficient purification of cells with characteristics of hematopoietic stem cells.


Proposal of a Selection Protocol for Replication of Studies in Sports and Exercise Science.
To improve the rigor of science, experimental evidence for scientific claims ideally needs to be replicated repeatedly with comparable analyses and new data to increase the collective confidence in the veracity of those claims. Large replication projects in psychology and cancer biology have evaluated the replicability of their fields but no collaborative effort has been undertaken in sports and exercise science. We propose to undertake such an effort here. As this is the first large replication project in this field, there is no agreed-upon protocol for selecting studies to replicate. Criticism of previous selection protocols include claims they were non-randomised and non-representative. Any selection protocol in sports and exercise science must be representative to provide an accurate estimate of replicability of the field. Our aim is to produce a protocol for selecting studies to replicate for inclusion in a large replication project in sports and exercise science. The proposed selection protocol uses multiple inclusion and exclusion criteria for replication study selection, including: the year of publication and citation rankings, research disciplines, study types, the research question and key dependent variable, study methods and feasibility. Studies selected for replication will be stratified into pools based on instrumentation and expertise required, and will then be allocated to volunteer laboratories for replication. Replication outcomes will be assessed using a multiple inferential strategy and descriptive information will be reported regarding the final number of included and excluded studies, and original author responses to requests for raw data.