Screening for Sexually Transmitted Infections in Adolescent Girls and Young Women in Mombasa, Kenya: Feasibility, Prevalence, and Correlates.
As adolescents and young women become sexually active, they are at risk of adverse reproductive health outcomes including sexually transmitted infections (STIs). We assessed feasibility and acceptability of STI screening among 15- to 24-year-old women in Mombasa, Kenya. After sensitization activities, participants were recruited from 3 high schools and 1 university. Study staff conducted informational sessions. Students interested in participating were given consent forms to take home, and invited to visit our clinic for STI screening. During clinic visits, participants completed a self-administered questionnaire and provided a urine specimen for STI testing using a nucleic acid amplification test. Between August 2014 and March 2015, 463 high school and 165 university students collected consent forms. Of these, 293 (63%) from high schools versus 158 (95%) from university attended clinic for STI screening (P < 0.001). Of the 150 (33%) who reported any history of insertive vaginal sex, 78 (52.0%) reported condom use at the last sex act, 31 (20.7%) reported using modern nonbarrier contraceptive methods, and 37 (24.7%) reported not using any contraception at the last sex act. Twenty-six (5.8%) participants were diagnosed with STIs (7 [1.6%] Neisseria gonorrhoeae, 16 [3.6%] Chlamydia trachomatis, 3 [0.7%] Trichomonas vaginalis). In multivariable analyses, reporting receptive vaginal sex without a condom was associated with having a laboratory confirmed STI (odds ratio, 6.21; 95% confidence interval, 1.72-22.28). These findings support the need for reproductive health interventions to reduce the risk of STIs in a population of adolescent girls and young women in East Africa.


Photon antibunching in the photoluminescence spectra of a single carbon nanotube.
We report the first observation of photon antibunching in the photoluminescence from single carbon nanotubes. The emergence of a fast luminescence decay component under strong optical excitation indicates that Auger processes are partially responsible for inhibiting two-photon generation. Additionally, the presence of exciton localization at low temperatures ensures that nanotubes emit photons predominantly one by one. The fact that multiphoton emission probability can be smaller than 5% suggests that carbon nanotubes could be used as a source of single photons for applications in quantum cryptography.


Reversal of cardiomyopathy in propionic acidemia after liver transplantation: a 10-year follow-up.
Cardiomyopathy is a frequent complication in propionic acidemia. It is mostly rapidly fatal and independent of the metabolic control or medical intervention. Here, we present the reversal of a severe cardiomyopathy after liver transplantation in a patient with propionic acidemia and the long-term stability after ten years. Liver transplantation in patients with propionic acidemia may be considered a valid and long-lasting treatment when cardiomyopathy is progressive and unresponsive to medical therapy.


Fluorescent cholangiography in a mouse model: an innovative method for improved laparoscopic identification of the biliary anatomy.
Real-time imaging of the biliary anatomy may facilitate safe and timely completion of laparoscopic cholecystectomy. This study sought to determine whether the unique autofluorescent properties of bile could facilitate intraoperative identification of the biliary anatomy in mice using fluorescent cholangiography. Fluorimetry was performed on samples of mouse bile to determine excitation and emission spectra. For seven mice, chevron laparotomy was performed, followed by liver retraction to expose the porta hepatis. Using stereomicroscopy, photographs were taken in brightfield and fluorescent modes without a change in depth or focus. Six surgical residents evaluated the pictures and identified the gallbladder, cystic duct, common bile duct, and whether the cystic duct joined the right hepatic duct or the common bile duct. Fluorimetry demonstrated autofluorescence of bile at an excitation wavelength of 475 nm. Intense emission was observed at 480 nm. At these settings, fluorescent stereomicroscopy easily identified the gallbladder and biliary tree in mice. This technique decreased diagnostic errors of the biliary anatomy 11-fold (2% vs 22%; p < 0.01), as compared with brightfield visualization. Fluorescent stereomicroscopy also was used to diagnose bile leak, obstruction, and complex anatomy. Using a prototype 5-mm laparoscope equipped with fluorescent filters, the results were reproduced. Fluorescent cholangiography based solely on the autofluorescence of bile may facilitate real-time identification of the biliary anatomy during laparoscopic procedures, without the need for extraneous dye administration or the use of radiography. This technique has the potential to decrease the rate of iatrogenic biliary tract injuries during laparoscopic cholecystectomy.


Enterococcus faecalis Manganese Exporter MntE Alleviates Manganese Toxicity and Is Required for Mouse Gastrointestinal Colonization.
Bacterial pathogens encounter a variety of nutritional environments in the human host, including nutrient metal restriction and overload. Uptake of manganese (Mn) is essential for Enterococcus faecalis growth and virulence; however, it is not known how this organism prevents Mn toxicity. In this study, we examine the role of the highly conserved MntE transporter in E. faecalis Mn homeostasis and virulence. We show that inactivation of mntE results in growth restriction in the presence of excess Mn, but not other metals, demonstrating its specific role in Mn detoxification. Upon growth in the presence of excess Mn, an mntE mutant accumulates intracellular Mn, iron (Fe), and magnesium (Mg), supporting a role for MntE in Mn and Fe export and a role for Mg in offsetting Mn toxicity. Growth of the mntE mutant in excess Fe also results in increased levels of intracellular Fe, but not Mn or Mg, providing further support for MntE in Fe efflux. Inactivation of mntE in the presence of excess iron also results in the upregulation of glycerol catabolic genes and enhanced biofilm growth, and addition of glycerol is sufficient to augment biofilm growth for both the mntE mutant and its wild-type parental strain, demonstrating that glycerol availability significantly enhances biofilm formation. Finally, we show that mntE contributes to colonization of the antibiotic-treated mouse gastrointestinal (GI) tract, suggesting that E. faecalis encounters excess Mn in this niche. Collectively, these findings demonstrate that the manganese exporter MntE plays a crucial role in E. faecalis metal homeostasis and virulence.


Adaptive imaging system with spatial light modulator for robust shape measurement of partially specular objects.
In imaging systems, when specular surfaces responding sensitively to varying illumination conditions are imaged on groups of CCD pixels using imaging optics, the obtained image usually suffers from pixel saturation, resulting in smearing or blooming phenomena. These problems are then serious obstacles when applying structured light-based optical profiling methods to the shape measurement of general objects with partially specular surfaces. Therefore, this paper combines a phase-based profiling system with an with an adaptive spatial light modulator in the imaging part for measuring the three-dimensional shapes of objects with an advanced dynamic range. The use of a spatial light modulator in front of a CCD camera prevents the image sensor from being saturated, as the pixel transmittance is controlled by monitoring the input images and providing modulator feedback signals over time and space. When using the proposed system, since the projected fringes are effectively imaged on the CCD without any pixel saturation, phase information according to the object's shape can be correctly extracted from non-saturated images. The configuration of the proposed system and transmittance control scheme are explained in detail, plus the performance is verified through a series of experiments, in which phase information was successfully extracted from areas that are not normally measurable due to saturation. Based on the results, the proposed shape measurement system showed a more advanced adaptive dynamic range when compared with a conventional system.


Do school teachers and primary contacts in residential youth care institutions recognize mental health problems in adolescents?
Studies show that adolescents living in residential youth care (RYC) institutions experience more mental health problems than others. This paper studies how well teachers and primary contacts in RYC institutions recognize adolescents' mental health problems as classified by The Child and Adolescent Psychiatric Assessment diagnostic interviews (CAPA). All residents between 12 and 23 years of age living in RYC institutions in Norway and enrolled in school at the time of data collection were invited to participate in the study. Of the 601 available children, 400 participated in the study, namely 230 girls, mean age = 16.9 years, SD = 1.2 and 170 boys, mean age = 16.5 years, SD = 1.5. The Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF) were used. The sensitivity and specificity of these instruments were studied. We observed a significant gap between the mental health problems diagnosed by the CAPA interviews and the problems reported by primary contacts on the CBCL and by teachers on the TRF. The CBCL showed a higher sensitivity than the TRF, whereas the TRF showed a higher specificity than the CBCL. Both primary contacts and teachers classified externalizing problems fairly well such as ADHD in both genders and conduct disorder in girls. Both teachers and primary contacts, however, had more problems detecting internalizing problems. Teachers may have a tendency to view most students as healthy and to underestimate the severity of their problems, whereas primary contacts may tend to overestimate the number of problems and view adolescents as sicker than they really are. The Child Welfare System should revise their intake procedures to detect possible problems early on and to introduce the necessary treatment. It is important to identify factors that increase healthy school adaption in order for these adolescents to accomplish school in a proper way since education is important for a successful adult life.


Thermal unfolding of calreticulin. Structural and thermodynamic characterization of the transition.
Calreticulin (CRT) is a calcium-binding protein that participates in several cellular processes including the control of protein folding and homeostasis of Ca2+. Its folding, stability and functions are strongly controlled by the presence of Ca2+. The oligomerization state of CRT is also relevant for its functions. We studied the thermal transitions of monomers and oligomers of CRT by differential scanning calorimetry (DSC), circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR) in the presence and absence of Ca2+. We found three and two components for the calorimetric transition in the presence and absence of Ca2+ respectively. The presence of several components was also supported by CD and FTIR spectra acquired as a function of the temperature. The difference between the heat capacity of the native and the unfolded state strongly suggests that interactions between protein domains also contribute to the heat uptake in a calorimetry experiment. We found that once unfolded at high temperature the process is reversible and the native state can be recovered upon cooling only in the absence of Ca2+. We also propose a new simple method to obtain pure CRT oligomers.


Effect of early measles vaccine on pneumococcal colonization: A randomized trial from Guinea-Bissau.
Measles vaccine (MV) may have non-specific beneficial effects for child health and particularly seems to prevent respiratory infections. Streptococcus pneumoniae is the leading cause of bacterial pneumonia among children worldwide, and nasopharyngeal colonization precedes infection. We investigated whether providing early MV at 18 weeks of age reduced pneumococcal colonization and/or density up to 9 months of age. The study was conducted in 2013-2014 in Guinea-Bissau. Pneumococcal vaccine was not part of the vaccination program. Infants aged 18 weeks were block-randomized 2:1 to early or no early MV; at age 9 months, all children were offered MV as per current policy. Nasopharyngeal swabs were taken at baseline, age 6.5 months, and age 9 months. Pneumococcal density was determined by q-PCR. Prevalence ratios of pneumococcal colonization and recent antibiotic treatment (yes/no) by age 6.5 months (PR6.5) and age 9 months (PR9) were estimated using Poisson regression with robust variance estimates while the pneumococcal geometric mean ratio (GMR6.5 and GMR9) was obtained using OLS regression. Analyses included 512 children; 346 early MV-children and 166 controls. At enrolment, the pneumococcal colonization prevalence was 80% (411/512). Comparing early MV-children with controls, the PR6.5 was 1.02 (95%CI = 0.94-1.10), and the PR9 was 1.04 (0.96-1.12). The GMR6.5 was 1.02 (0.55-1.89), and the GMR9 was 0.69 (0.39-1.21). Early MV-children tended to be less frequently treated with antibiotics prior to follow up (PR6.5 0.60 (0.34-1.05) and PR9 0.87 (0.50-1.53)). Antibiotic treatment was associated with considerably lower colonization rates, PR6.5 0.85 (0.71-1.01) and PR9 0.66 (0.52-0.84), as well as lower pneumococcal density, GMR6.5 0.32 (0.12-0.86) and GMR9 0.52 (0.18-1.52). Early MV at age 18 weeks had no measurable effect on pneumococcal colonization prevalence or density. Higher consumption of antibiotics among controls may have blurred an effect of early MV. clinicaltrials.gov NCT01486355.


Global stroke statistics 2022.
Contemporary data on stroke epidemiology and the availability of national stroke clinical registries are important for providing evidence to improve practice and support policy decisions. To update the most current incidence, case-fatality, and mortality rates on stroke and identify national stroke clinical registries worldwide. We searched multiple databases (based on our existing search strategy) to identify new original papers, published between 1 November 2018 and 15 December 2021, that met ideal criteria for data on stroke incidence and case-fatality, and added these to the studies reported in our last review. To identify national stroke clinical registries, we updated our last search, using PubMed, from 6 February 2015 until 6 January 2022. We also screened reference lists of review papers, citation history of papers, and the gray literature. Mortality codes for International Classification of Diseases (ICD)-9 and ICD-10 were extracted from the World Health Organization (WHO) for each country providing these data. Population denominators were obtained from the United Nations (UN) or WHO (when data were unavailable in the UN database). Crude and adjusted stroke mortality rates were calculated using country-specific population denominators, and the most recent years of mortality data available for each country. Since our last report in 2020, there were two countries (Chile and France) with new incidence studies meeting criteria for ideal population-based studies. New data on case-fatality were found for Chile and Kenya. The most current mortality data were available for the year 2014 (1 country), 2015 (2 countries), 2016 (11 countries), 2017 (10 countries), 2018 (19 countries), 2019 (36 countries), and 2020 (29 countries). Four countries (Libya, Solomon Islands, United Arab Emirates, and Lebanon) reported mortality data for the first time. Since our last report on registries in 2017, we identified seven more national stroke clinical registries, predominantly in high-income countries. These newly identified registries yielded limited information. Up-to-date data on stroke incidence, case-fatality, and mortality continue to provide evidence of disparities and the scale of burden in low- and middle-income countries. Although more national stroke clinical registries were identified, information from these newly identified registries was limited. Highlighting data scarcity or even where a country is ranked might help facilitate more research or greater policy attention in this field.


What Is the Association between Absolute Child Poverty, Poor Governance, and Natural Disasters? A Global Comparison of Some of the Realities of Climate Change.
The paper explores the degree to which exposure to natural disasters and poor governance (quality of governance) is associated with absolute child poverty in sixty-seven middle- and low-income countries. The data is representative for about 2.8 billion of the world´s population. Institutionalist tend to argue that many of society's ills, including poverty, derive from fragile or inefficient institutions. However, our findings show that although increasing quality of government tends to be associated with less poverty, the negative effects of natural disasters on child poverty are independent of a country´s institutional efficiency. Increasing disaster victims (killed and affected) is associated with higher rates of child poverty. A child´s estimated odds ratio to be in a state of absolute poverty increases by about a factor of 5.7 [95% CI: 1.7 to 18.7] when the average yearly toll of disasters in the child´s country increases by one on a log-10 scale. Better governance correlates with less child poverty, but it does not modify the correlation between child poverty and natural disasters. The results are based on hierarchical regression models that partition the variance into three parts: child, household, and country. The models were cross-sectional and based on observational data from the Demographic Health Survey and the Multiple Indicator Cluster Survey, which were collected at the beginning of the twenty-first millennium. The Sustainable Development Goals are a principle declaration to halt climate change, but they lack a clear plan on how the burden of this change should be shared by the global community. Based on our results, we suggest that the development agencies should take this into account and to articulate more equitable global policies to protect the most vulnerable, specifically children.


Atorvastatin-induced cell toxicity in yeast is linked to disruption of protein isoprenylation.
Statins, used to treat hypercholesterolemia, are one of the most frequently prescribed drug classes in the developed world. However, a significant proportion of users suffer symptoms of myotoxicity, and currently, the molecular mechanisms underlying myotoxicity remain ambiguous. In this study, Saccharomyces cerevisiae was exploited as a model system to gain further insight into the molecular mechanisms of atorvastatin toxicity. Atorvastatin-treated yeast cells display marked morphological deformities, have reduced cell viability and are highly vulnerable to perturbed mitochondrial function. Supplementation assays of atorvastatin-treated cells reveal that both loss of viability and mitochondrial dysfunction occur as a consequence of perturbation of the sterol synthesis pathway. This was further investigated by supplementing statin-treated cells with various metabolites of the sterol synthesis pathway that are believed to be essential for cell function. Ergosterol, coenzyme Q and a heme precursor were all ineffective in the prevention of statin-induced mitochondrial disruption and cell death. However, the addition of geranylgeranyl pyrophosphate and farnesyl pyrophosphate significantly restored cell viability, although these did not overcome petite induction. This highlights the pleiotropic nature of statin toxicity, but has established protein prenylation disruption as one of the principal mechanisms underlying statin-induced cell death in yeast.


Three-factor models versus time series models: quantifying time-dependencies of interactions between stimuli in cell biology and psychobiology for short longitudinal data.
Signal integration determines cell fate on the cellular level, affects cognitive processes and affective responses on the behavioural level, and is likely to be involved in psychoneurobiological processes underlying mood disorders. Interactions between stimuli may subjected to time effects. Time-dependencies of interactions between stimuli typically lead to complex cell responses and complex responses on the behavioural level. We show that both three-factor models and time series models can be used to uncover such time-dependencies. However, we argue that for short longitudinal data the three factor modelling approach is more suitable. In order to illustrate both approaches, we re-analysed previously published short longitudinal data sets. We found that in human embryonic kidney 293 cells cells the interaction effect in the regulation of extracellular signal-regulated kinase (ERK) 1 signalling activation by insulin and epidermal growth factor is subjected to a time effect and dramatically decays at peak values of ERK activation. In contrast, we found that the interaction effect induced by hypoxia and tumour necrosis factor-alpha for the transcriptional activity of the human cyclo-oxygenase-2 promoter in HEK293 cells is time invariant at least in the first 12-h time window after stimulation. Furthermore, we applied the three-factor model to previously reported animal studies. In these studies, memory storage was found to be subjected to an interaction effect of the beta-adrenoceptor agonist clenbuterol and certain antagonists acting on the alpha-1-adrenoceptor / glucocorticoid-receptor system. Our model-based analysis suggests that only if the antagonist drug is administer in a critical time window, then the interaction effect is relevant.


Treatment of established lung metastases with tumor-infiltrating lymphocytes derived from a poorly immunogenic tumor engineered to secrete human TNF-alpha.
The growth of a poorly immunogenic methylcholanthrene (MCA)-induced murine (m) sarcoma genetically engineered to secrete human (h) TNF-alpha (MCA-102-hTNF) was studied. MCA-102-hTNF tumor cells were implanted in animals bearing three- or 7-day pulmonary metastases established with the parental line MCA-102-WT (wild type). This model approximates the clinical situation in which patients with metastatic cancer would be vaccinated with autologous tumor genetically modified to stimulate the host immune response. Reduction in the number of pulmonary metastases was occasionally seen but was not consistently reproducible. Other cytokine-producing tumors had either no effect on distant pulmonary metastases (mIL-4, IFN-gamma) or a mild, inconclusive effect similar to hTNF-alpha (mTNF-alpha). Significant growth inhibition of MCA-102-hTNF was noted in animals bearing pulmonary metastases. This inhibition was: 1) tumor specific (regression occurred only in animals bearing pulmonary metastases from the same parental line), 2) TNF specific (it was inhibited by in vivo administration of anti hTNF mAbs), 3) dependent on cellular immunity (immune-depletion with anti-CD4 or CD8 mAbs permitted growth). Tumor-infiltrating lymphocytes (TIL) could not be grown from MCA-102-WT or MCA-102-hTNF tumors nor from MCA-102-WT subcutaneous implants in mice bearing MCA-102-WT pulmonary metastases. However, TIL could be grown from hTNF-secreting tumors implanted in mice bearing MCA-102-WT metastases. These TIL were therapeutic against established lung metastases from the parental tumor in adoptive immunotherapy models. These studies suggest a strategy for using gene modified tumors for the therapy of established cancer.


Near Real-time Surveillance for Consequences of Health Policies Using Sequential Analysis.
New health policies may have intended and unintended consequences. Active surveillance of population-level data may provide initial signals of policy effects for further rigorous evaluation soon after policy implementation. This study evaluated the utility of sequential analysis for prospectively assessing signals of health policy impacts. As a policy example, we studied the consequences of the widely publicized Food and Drug Administration's warnings cautioning that antidepressant use could increase suicidal risk in youth. This was a retrospective, longitudinal study, modeling prospective surveillance, using the maximized sequential probability ratio test. We used historical data (2000-2010) from 11 health systems in the US Mental Health Research Network. The study cohort included adolescents (ages 10-17 y) and young adults (ages 18-29 y), who were targeted by the warnings, and adults (ages 30-64 y) as a comparison group. Outcome measures were observed and expected events of 2 possible unintended policy outcomes: psychotropic drug poisonings (as a proxy for suicide attempts) and completed suicides. We detected statistically significant (P<0.05) signals of excess risk for suicidal behavior in adolescents and young adults within 5-7 quarters of the warnings. The excess risk in psychotropic drug poisonings was consistent with results from a previous, more rigorous interrupted time series analysis but use of the maximized sequential probability ratio test method allows timely detection. While we also detected signals of increased risk of completed suicide in these younger age groups, on its own it should not be taken as conclusive evidence that the policy caused the signal. A statistical signal indicates the need for further scrutiny using rigorous quasi-experimental studies to investigate the possibility of a cause-and-effect relationship. This was a proof-of-concept study. Prospective, periodic evaluation of administrative health care data using sequential analysis can provide timely population-based signals of effects of health policies. This method may be useful to use as new policies are introduced.


Quality of life in young people with congenital heart disease is better than expected.
Improved treatments for patients with congenital heart disease (CHD) have led to a growing interest in long-term functional outcomes such as health-related quality of life (HRQoL). Studies on HRQoL in children with CHD have contradicting results. Therefore, we compared HRQoL of children with CHD with that of current healthy peers and stratify CHD cases by severity and diagnostic subgroups. We included 514 patients (191 girls) aged 7-17 (12.9±3.1) years who were recruited at our institution between July 2014 and May 2017. The self-reported and age-adapted KINDL questionnaire was used to assess HRQoL. Patient data were compared with that of a recent control group of 734 healthy children (346 girls, 13.4±2.1 years). Patients with CHD scored at least as high as healthy peers in HRQoL (CHD: 78.6±9.8; healthy: 75.6±10.1; P<0.001). After correction for sex and age, patients with CHD presented a 2.3-point higher HRQoL (P<0.001). The sex-specific and age-specific analyses showed that there were no differences between boys with and without CHD in childhood (P=0.255), but in adolescence, boys with CHD had on average 3.9-point higher scores (P=0.001), whereas girls with CHD had statistically higher HRQoL perception than healthy girls in childhood (4.2 points; P=0.003) and adolescence (4.2 points; P=0.005). There were no differences between the severity classes or diagnostic subgroups in the total HRQoL score or in the six subdomains. The high HRQoL in young patients with CHD suggests that they can cope well with their disease burden. This holds true for all severity classes and diagnostic subgroups.


Met-RANTES reduces vascular and tubular damage during acute renal transplant rejection: blocking monocyte arrest and recruitment.
Chemokines are thought to contribute to the cellular infiltrate characteristic of renal transplant rejection. We show that Met-RANTES, a chemokine receptor antagonist, suppresses recruitment of inflammatory cells into renal allografts. In a renal transplant model (Fisher RT1(lvl) rat kidney into Lewis RT1(l) rat) where no additional immune suppressant was used, Met-RANTES-treated animals showed a significant reduction in vascular injury score (16.10 +/- 5.20 vs. 62.67 +/- 18.64) and tubular damage score (15.70 +/- 5.22 vs. 33.00 +/- 6.44) relative to untreated animals. In a more severe rejection model (Brown-Norway RT1(n) rat kidney into Lewis RT1(1) rat), Met-RANTES significantly augmented low-dose cyclosporin A treatment to reduce all aspects of renal injury including interstitial inflammation (score 71.00 +/- 6.10 vs. 157.30 +/- 21.30). The majority of infiltrating cells in these models (60-70%) consisted of monocytes. Potential mechanisms of action of Met-RANTES were tested using monocyte attachment assays on microvascular endothelium under physiological flow conditions. Preexposure of microvascular endothelium to RANTES resulted in RANTES immobilization and RANTES-induced firm adhesion of monocytes only after prestimulation of the endothelium with IL-1beta. Met-RANTES completely inhibited this RANTES-mediated arrest. Thus, Met-RANTES may counter acute rejection by blocking leukocyte firm adhesion to inflamed endothelium.


3D gait assessment in young and elderly subjects using foot-worn inertial sensors.
This study describes the validation of a new wearable system for assessment of 3D spatial parameters of gait. The new method is based on the detection of temporal parameters, coupled to optimized fusion and de-drifted integration of inertial signals. Composed of two wirelesses inertial modules attached on feet, the system provides stride length, stride velocity, foot clearance, and turning angle parameters at each gait cycle, based on the computation of 3D foot kinematics. Accuracy and precision of the proposed system were compared to an optical motion capture system as reference. Its repeatability across measurements (test-retest reliability) was also evaluated. Measurements were performed in 10 young (mean age 26.1±2.8 years) and 10 elderly volunteers (mean age 71.6±4.6 years) who were asked to perform U-shaped and 8-shaped walking trials, and then a 6-min walking test (6MWT). A total of 974 gait cycles were used to compare gait parameters with the reference system. Mean accuracy±precision was 1.5±6.8cm for stride length, 1.4±5.6cm/s for stride velocity, 1.9±2.0cm for foot clearance, and 1.6±6.1° for turning angle. Difference in gait performance was observed between young and elderly volunteers during the 6MWT particularly in foot clearance. The proposed method allows to analyze various aspects of gait, including turns, gait initiation and termination, or inter-cycle variability. The system is lightweight, easy to wear and use, and suitable for clinical application requiring objective evaluation of gait outside of the lab environment.


Seizure control after radiosurgery for cerebral arteriovenous malformations: a 25-year experience.
Seizures are the second-most common presenting symptom in patients with lobar arteriovenous malformations (AVMs). However, few studies have assessed the long-term effect of stereotactic radiosurgery (SRS) on seizure control. The authors of this study assess the outcome of SRS for these patients to identify prognostic factors associated with seizure control. Patients with AVM who presented with a history of seizure and underwent SRS at the authors' institution between 1987 and 2012 were retrospectively assessed. The total cohort included 155 patients with a mean follow-up of 86 months (range 6-295 months). Primary outcomes assessed were seizure frequency, antiepileptic drug regimen, and seizure freedom for 6 months prior to last follow-up. Seizure-free status was achieved in 108 patients (70%), with an additional 23 patients (15%) reporting improved seizure frequency as compared to their pre-SRS status. The median time to seizure-free status was estimated to be 12 months (95% CI 0-27 months) as evaluated via Kaplan-Meier survival analysis. The mean seizure frequency prior to SRS was 14.2 (95% CI 5.4-23.1) episodes per year. Although not all patients tried, the proportion of patients successfully weaned off all antiepileptic drugs was 18% (28/155 patients). On multivariate logistic regression, focal impaired awareness seizure type (also known as complex partial seizures) and superficial venous drainage were significantly associated with a decreased odds ratio for seizure-free status at last follow-up (OR 0.37 [95% CI 0.15-0.92] for focal impaired awareness seizures; OR 0.36 [95% CI 0.16-0.81] for superficial venous drainage). The effects of superficial venous drainage on seizure outcome were nonsignificant when excluding patients with < 2 years of follow-up. AVM obliteration did not correlate with long-term seizure freedom (p = 0.202, chi-square test). This study suggests that SRS improves long-term seizure control and increases the likelihood of being medication free, independently of AVM obliteration. Patients with focal impaired awareness seizures were less likely to obtain long-term seizure relief.


Stability Indicating HPTLC Determination of Meloxicam.
A simple, selective, precise and stability-indicating high-performance thin layer chromatographic method of analysis of meloxicam both as a bulk drug and in formulation has been developed. The mobile phase selected was ethyl acetate:cyclohexane:glacial acetic acid (6.5:3.5:0.02% v/v/v). The calibration curve of the drug was linear in the range of 100-500 ng. The spectrodensitometric analysis was carried out in the absorbance mode at 353 nm. The mean (±RSD) values of slope, correlation coefficient and intercept were 3183.8±0.358, 0.9996±0.0321 and 13012±7.1 respectively. The system precision and the method precision studies were carried out with RSD of 0.83 and 1.89 respectively. The limit of detection and quantitation were 30 ng and 99 ng respectively. The mean percent recovery was found to be 100.3%. The method was used to analyze meloxicam from marketed tablet formulation in the presence of commonly used excipients.


Diet: from food to stone.
Dietary factors have been shown to influence urine composition and modulate the risk of kidney stone disease. With the rising prevalence of stone disease in many industrialized nations, dietary modification as therapy to improve lithogenic risk factors and prevent stone recurrence has gained appeal, as it is both relatively inexpensive and safe. While some dietary measures, such as a high fluid intake, have been shown in long-term randomized clinical trials to have durable effectiveness, other dietary factors have been subjected to only short-term clinical or metabolic studies and their efficacy has been inferred. Herein, we review the current literature regarding the role of diet in stone formation, focusing on both the effect on urinary stone risk factors and the effect on stone recurrence.


Guns, germs, and trees determine density and distribution of gorillas and chimpanzees in Western Equatorial Africa.
We present a range-wide assessment of sympatric western lowland gorillas Gorilla gorilla gorilla and central chimpanzees Pan troglodytes troglodytes using the largest survey data set ever assembled for these taxa: 59 sites in five countries surveyed between 2003 and 2013, totaling 61,000 person-days of fieldwork. We used spatial modeling to investigate major drivers of great ape distribution and population trends. We predicted density across each taxon's geographic range, allowing us to estimate overall abundance: 361,900 gorillas and 128,700 chimpanzees in Western Equatorial Africa-substantially higher than previous estimates. These two subspecies represent close to 99% of all gorillas and one-third of all chimpanzees. Annual population decline of gorillas was estimated at 2.7%, maintaining them as Critically Endangered on the International Union for Conservation of Nature and Natural Resources (IUCN) Red List. We quantified the threats to each taxon, of which the three greatest were poaching, disease, and habitat degradation. Gorillas and chimpanzees are found at higher densities where forest is intact, wildlife laws are enforced, human influence is low, and disease impacts have been low. Strategic use of the results of these analyses could conserve the majority of gorillas and chimpanzees. With around 80% of both subspecies occurring outside protected areas, their conservation requires reinforcement of anti-poaching efforts both inside and outside protected areas (particularly where habitat quality is high and human impact is low), diligent disease control measures (including training, advocacy, and research into Ebola virus disease), and the preservation of high-quality habitat through integrated land-use planning and implementation of best practices by the extractive and agricultural industries.


Using administrative health data to describe colorectal and lung cancer care in New South Wales, Australia: a validation study.
Monitoring treatment patterns is crucial to improving cancer patient care. Our aim was to determine the accuracy of linked routinely collected administrative health data for monitoring colorectal and lung cancer care in New South Wales (NSW), Australia. Colorectal and lung cancer cases diagnosed in NSW between 2000 and 2002 were identified from the NSW Central Cancer Registry (CCR) and linked to their hospital discharge records in the NSW Admitted Patient Data Collection (APDC). These records were then linked to data from two relevant population-based patterns of care surveys. The main outcome measures were the sensitivity and specificity of data from the CCR and APDC for disease staging, investigative procedures, curative surgery, chemotherapy, radiotherapy, and selected comorbidities. Data for 2917 colorectal and 1580 lung cancer cases were analysed. Unknown disease stage was more common for lung cancer in the administrative data (18%) than in the survey (2%). Colonoscopies were captured reasonably accurately in the administrative data compared with the surveys (82% and 79% respectively; 91% sensitivity, 53% specificity) but all other colorectal or lung cancer diagnostic procedures were under-enumerated. Ninety-one percent of colorectal cancer cases had potentially curative surgery recorded in the administrative data compared to 95% in the survey (96% sensitivity, 92% specificity), with similar accuracy for lung cancer (16% and 17%; 92% sensitivity, 99% specificity). Chemotherapy (~40% sensitivity) and radiotherapy (sensitivity≤30%) were vastly under-enumerated in the administrative data. The only comorbidity that was recorded reasonably accurately in the administrative data was diabetes. Linked routinely collected administrative health data provided reasonably accurate information on potentially curative surgical treatment, colonoscopies and comorbidities such as diabetes. Other diagnostic procedures, comorbidities, chemotherapy and radiotherapy were not well enumerated in the administrative data. Other sources of data will be required to comprehensively monitor the primary management of cancer patients.


In the face of contradictory evidence: report of the Dietary Guidelines for Americans Committee.
Concerns that were raised with the first dietary recommendations 30 y ago have yet to be adequately addressed. The initial Dietary Goals for Americans (1977) proposed increases in carbohydrate intake and decreases in fat, saturated fat, cholesterol, and salt consumption that are carried further in the 2010 Dietary Guidelines Advisory Committee (DGAC) Report. Important aspects of these recommendations remain unproven, yet a dietary shift in this direction has already taken place even as overweight/obesity and diabetes have increased. Although appealing to an evidence-based methodology, the DGAC Report demonstrates several critical weaknesses, including use of an incomplete body of relevant science; inaccurately representing, interpreting, or summarizing the literature; and drawing conclusions and/or making recommendations that do not reflect the limitations or controversies in the science. An objective assessment of evidence in the DGAC Report does not suggest a conclusive proscription against low-carbohydrate diets. The DGAC Report does not provide sufficient evidence to conclude that increases in whole grain and fiber and decreases in dietary saturated fat, salt, and animal protein will lead to positive health outcomes. Lack of supporting evidence limits the value of the proposed recommendations as guidance for consumers or as the basis for public health policy. It is time to reexamine how US dietary guidelines are created and ask whether the current process is still appropriate for our needs.


Antidiabetic activity of aqueous root extract of Ichnocarpus frutescens in streptozotocin-nicotinamide induced type-II diabetes in rats.
To evaluate the antidiabetic activity of aqueous extract of roots of Ichnocarpus frutescens in streptozotocin-nicotinamide induced type-II diabetes in rats. Streptozotocin-nicotinamide induced type-II diabetic rats (n = 6) were administered aqueous root extract (250 and 500 mg/kg, p.o.) of Ichnocarpus frutescens or vehicle (gum acacia solution) or standard drug glibenclamide (0.25 mg/kg) for 15 days. Blood samples were collected by retro-orbital puncture and were analyzed for serum glucose on days 0, 5, 10, and 15 by using glucose oxidase-peroxidase reactive strips and a glucometer. For oral glucose tolerance test, glucose (2 g/kg, p.o.) was administered to nondiabetic control rats and the rats treated with glibenclamide (10 mg/kg, p.o.) and aqueous root extract of Ichnocarpus frutescens. The serum glucose levels were analyzed at 0, 30, 60, and 120 min after drug administration. The effect of the extract on the body weight of the diabetic rats was also observed. The aqueous root extract of Ichnocarpus frutescens (250 and 500 mg/kg, p.o.) induced significant reduction (P < 0.05) of fasting blood glucose levels in streptozotocin-nicotinamide induced type-II diabetic rats on the 10(th) and 15(th) days. In the oral glucose tolerance test, the extract increased the glucose tolerance. It also brought about an increase in the body weight of diabetic rats. It is concluded that Ichnocarpus frutescens has significant antidiabetic activity as it lowers the fasting blood sugar level in diabetic rats and increases the glucose tolerance.


Bridging near and remote Oceania: mtDNA and NRY variation in the Solomon Islands.
Although genetic studies have contributed greatly to our understanding of the colonization of Near and Remote Oceania, important gaps still exist. One such gap is the Solomon Islands, which extend between Bougainville and Vanuatu, thereby bridging Near and Remote Oceania, and include both Austronesian-speaking and Papuan-speaking groups. Here, we describe patterns of mitochondrial DNA (mtDNA) and nonrecombining Y chromosome (NRY) variation in over 700 individuals from 18 populations in the Solomons, including 11 Austronesian-speaking groups, 3 Papuan-speaking groups, and 4 Polynesian Outliers (descended via back migration from Polynesia). We find evidence for ancient (pre-Lapita) colonization of the Solomons in old NRY paragroups as well as from M2-M353, which probably arose in the Solomons ∼9,200 years ago and is the most frequent NRY haplogroup there. There are no consistent genetic differences between Austronesian-speaking and Papuan-speaking groups, suggesting extensive genetic contact between them. Santa Cruz, which is located in Remote Oceania, shows unusually low frequencies of mtDNA and NRY haplogroups of recent Asian ancestry. This is in apparent contradiction with expectations based on archaeological and linguistic evidence for an early (∼3,200 years ago), direct colonization of Santa Cruz by Lapita people from the Bismarck Archipelago, via a migration that "leapfrogged" over the rest of the Solomons. Polynesian Outliers show dramatic island-specific founder events involving various NRY haplogroups. We also find that NRY, but not mtDNA, genetic distance is correlated with the geographic distance between Solomons groups and that historically attested spheres of cultural interaction are associated with the recent genetic structure of Solomons groups, as revealed by mtDNA HV1 sequence and Y-STR haplotype diversity. Our results fill an important lacuna in human genetic studies of Oceania and aid in understanding the colonization and genetic history of this region.


Sampling from the mental number line: how are approximate number system representations formed?
Nonsymbolic comparison tasks are commonly used to index the acuity of an individual's Approximate Number System (ANS), a cognitive mechanism believed to be involved in the development of number skills. Here we asked whether the time that an individual spends observing numerical stimuli influences the precision of the resultant ANS representations. Contrary to standard computational models of the ANS, we found that the longer the stimulus was displayed, the more precise was the resultant representation. We propose an adaptation of the standard model, and suggest that this finding has significant methodological implications for numerical cognition research.


Immunological biomarkers improve the accuracy of clinical risk models of infection in the acute phase of ischemic stroke.
Infection is an independent risk factor for adverse outcome in stroke patients. The risk of developing an infection in this setting is partly related to a stroke-induced immunodepression, in which a shift to a predominant Th2 (immunosuppressive) phenotype has been postulated to play a major role. Our aim was to study whether clinical variables or changes in plasma cytokine expression can predict poststroke infections. Medical records of 92 stroke patients were reviewed, and the baseline concentration of cytokines from the Th1/Th2 system was determined. Clinical and serological predictors of incident infections and their prognostic significance were sought by means of univariate and multivariate analysis, and two predictive models for developing an infection were constructed by combining independent predictors (strictly clinical in one, and both clinical and serological in the other) for this outcome. The improvement conferred by the addition of immunological markers to the clinical model was assessed by comparing their respective ROC curves and by improvement (Net Reclassification Index and Integrated Discriminator Improvement) analysis. Nineteen patients (20.7% of the study sample) developed an infection. Ongoing antiplatelet therapy at symptom onset (OR 0.02, 95% CI 0.001-0.23, p = 0.001), diabetes mellitus (OR 9.96, 95% CI 1.32-75.29, p = 0.03), IL-13 level <33 pg/ml (OR 84.16, 95% CI 2.53-2795.18, p = 0.01) and interferon-γ level >8.4 pg/ml (OR 60.17, 95% CI 1.78-2037.23, p = 0.02) were independently associated with the development of infections during hospital admission. The combined regression model predicted infection with an accuracy of 93.4%, an improvement in the predictive capacity of 17% (p < 0.001). Infection was associated with a worse neurological status at hospital discharge (median NIHSS score 11 (6-18) vs. 4 (1-11.5), p = 0.014). This study shows that bloodstream biomarkers are useful to improve the accuracy of clinical prognostic models for infection in the acute phase of stroke. The clinical predictors of infection in the acute phase of stroke are relatively well established in the medical literature, but further research to identify the optimal combination of biomarkers (possibly inflammatory and stress markers) to be included in a clinically useful model is needed. Such a model could be subsequently used in clinical trials to assess the effect of prophylactic and/or early antibiotic therapy in this setting, a currently controversial issue in this field.


Social function in multiple X and Y chromosome disorders: XXY, XYY, XXYY, XXXY.
Klinefelter syndrome (47,XXY) was initially described in the context of its endocrinologic and physical features; however, subsequent studies have revealed specific impairments in verbal skills and social functioning. Males with sex chromosomal aneuploidies are known to have variability in their developmental profile with the majority presenting with expressive language deficits. As a consequence of language delays, they have an increased likelihood of language-based learning disabilities and social-emotional problems that may persist through adulthood. Studies on males with 47,XXY have revealed unique behavioral and social profiles with possible vulnerability to autistic traits. The prevalence of males with more than one extra sex chromosome (e.g., 48,XXYY and 48,XXXY) and an additional Y (e.g., 47,XYY) is less common, but it is important to understand their social functioning as it provides insight into treatment implications.


Comparison of changes in electroencephalographic measures during induction of general anaesthesia: influence of the gamma frequency band and electromyogram signal.
Recent research has shown that high-frequency, gamma-band electroencephalographic (EEG) oscillations (40-60 Hz) may be an important marker of the conscious state. We compared the ability of the bispectral index (BIS) to distinguish the awake and anaesthetized states during the induction of general anaesthesia with: (i) components of the BIS (BetaRatio, SynchFastSlow); (ii) a new EEG variable--the median frequency of the first time derivative of the EEG signal (SE50d); and (iii) the SE50d derived from an EEG signal that has had the frequencies above 30 Hz removed (SE50d(30Hz)). Two groups of subjects were studied: (i) nine volunteers undergoing a short propofol infusion until loss of response to verbal command, and (ii) 84 patients undergoing routine anaesthesia for a variety of surgical procedures. In the volunteer group, the changes in the BetaRatio and SE50d were comparable with changes in the BIS. The changes in the SE50d(30Hz) were less consistent. In the patient group, the BIS components were equivalent to the BIS in separating the awake from the surgically anaesthetized states (area under receiver operating curve: BIS 0.95, SE50d 0.95, BetaRatio 0.96). Using the submental electromyogram (EMG) signal to estimate the frontalis EMG (30-47 Hz) signal, the changes in EMG signal were, on average, about one-tenth the magnitude of the EEG. We conclude that: (i) there exist simpler derived EEG variables that are similar in accuracy to the BIS; (ii) it is important to avoid filtering out the EEG frequencies above 30 Hz; and (iii) in most patients the confounding effects of the frontalis EMG on the EEG are minimal.


Effects of a cannabinoid agonist on spinal nociceptive neurons in a rodent model of neuropathic pain.
The effects of the synthetic cannabinoid WIN 55,212-2 on heat-evoked firing of spinal wide dynamic range (WDR) neurons were examined in a rodent model of neuropathic pain. Fifty-eight WDR neurons (1 cell/animal) were recorded from the ipsilateral spinal dorsal horns of rats with chronic constriction injury (CCI) and sham-operated controls. Relative to sham-operated controls, neurons recorded in CCI rats showed elevations in spontaneous firing, noxious heat-evoked responses, and afterdischarge firing as well as increases in receptive field size. WIN 55,212-2 (0.0625, 0.125, and 0.25 mg/kg, intravenous) dose-dependently suppressed heat-evoked activity and decreased the receptive field areas of dorsal horn WDR neurons in both nerve injured and control rats with a greater inhibition in CCI rats. At the dose of 0.125 mg/kg iv, WIN 55,212-2 reversed the hyperalgesia produced by nerve injury. The effect of intravenous administration of WIN 55,212-2 appears to be centrally mediated because administration of the drug directly to the ligated nerve did not suppress the heat-evoked neuronal activity in CCI rats. Pretreatment with the cannabinoid CB(1) receptor antagonists SR141716A or AM251, but not the CB(2) antagonist SR144528, blocked the effects. These results provide a neural basis for reports of potent suppression by cannabinoids of the abnormal sensory responses that result from nerve injury.


Implications of practice setting on clinical outcomes and efficiency of care in the delivery of physical therapy services.
Retrospective analysis of episodes of care. To assess the implications of practice setting (hospital outpatient settings versus private practice) on clinical outcomes and efficiency of care in the delivery of physical therapy services. Many patients with musculoskeletal conditions benefit from care provided by physical therapists. The majority of physical therapists deliver services in either a private practice setting or in a hospital outpatient setting. There have not been any recent studies comparing whether clinical outcomes or efficiency of care differ based on practice setting. Practices that use the Focus On Therapeutic Outcomes, Inc system were surveyed to determine the specific type of setting in which outcomes were collected in patients with musculoskeletal impairments. Patient outcome data over 12 months (2011-2012) were extracted from the database and analyzed to identify differences in the functional status achieved and the efficiency of the care delivery process between private practices and hospital outpatient settings. The data suggest that patients experience more efficient care when receiving physical therapy in hospital outpatient settings compared to private practice settings, as demonstrated by 3.1 points of greater improvement in functional status over 2.9 fewer physical therapy visits. However, the difference in improvement between settings is less than the minimum clinically important difference of 9 points in functional status outcome score. In this cohort, our data suggest that more efficient care was delivered in the hospital outpatient setting compared to the private practice setting. However, we cannot conclude that care delivered in the hospital setting is more cost-effective, because it is possible that any difference in efficiency of care favoring the hospital outpatient setting is more than offset by higher costs of care.


An expanded age range for meningococcal meningitis: molecular diagnostic evidence from population-based surveillance in Asia.
To understand epidemiologic patterns of meningococcal disease in Asia, we performed a retrospective molecular analysis of cerebrospinal fluid (CSF) specimens collected in prospective surveillance among children aged < 5 years of age in China, South Korea, and Vietnam. A total of 295 isolates and 2,302 CSFs were tested by a meningococcal species- and serogroup-specific polymerase chain reaction (PCR) assay targeting the Neisseria meningitidis (Nm) ctrA gene. Multi-locus sequence typing (MLST) was performed in Nm gene amplification analysis and incidence rates for meningococcal meningitis were estimated. Among 295 isolates tested, 10 specimens from Vietnam were confirmed as serogroup B and all were Sequence Type (ST) 1576 by MLST. Among the 2,032 CSF specimen tested, 284 (14%) were confirmed by PCR (ctrA gene), including 67 (23.6%) from China, 92 (32.4%) from Korea, and 125 (44.0%) from Vietnam. Neonates and infants aged < 6 months of age accounted for more than 50% of Nm-PCR positive CSF. Two CSF specimens from Vietnam were identified as serogroup B using MLST. In addition, 44 specimens underwent sequencing to confirm meningococcal serogroup; of these, 21 (48%) were serogroup C, 12 (27%) were serogroup X, 9 (20%) were serogroup Y and 2 (5%) were serogroup B. The incidence rates of meningococcal meningitis among children < 5 years of age was highest in Vietnam (7.4/100,000 [95% CI, 3.6-15.3] followed by Korea (6.8/100,000 [95% CI, 3.5-13.5] and China (2.1/100,000) [95% CI, 0.7-6.2]). These results suggest that there is a previously undetected, yet substantial burden of meningococcal meningitis among infants and young children. Standardized, sensitive and specific molecular diagnostic assays with Nm serogrouping capacity are needed throughout Asia to understand the true burden of N. meningitidis disease.


An investigation of microbial adhesion to natural and synthetic polysaccharide-based films and its relationship with the surface energy components.
In recent years, polysaccharide-based films have been developed for many applications. Some of these are in the pharmaceutical industry, where the adhesion of microorganisms to surfaces is a concern. After adhesion of a microorganism to a solid surface has taken place, the subsequent biofilm formed can act as a vehicle for spreading infections. The aim of this study is to compare the bacterial adhesion of E. coli and S. aureus from a contaminated solid model (Tryptone Soya Agar) to a range of polysaccharide-based films. These polysaccharide-based films consist of different natural starches (potato, cassava, wheat, pea and rice) and synthetic polymers hydroxyl-propyl cellulose (HPC) and carboxyl methyl cellulose (CMC)). The surface energy parameters of the films were calculated from the contact angle measurements by the sessile drop method. Apolar and polar liquids (water, formamide and hexadecane) and the Lifshitz-Van der Waals/acid-base (LW/AB) approach were used according to the method of Van Oss, Chaundhury and Good. The surface properties of the films were also correlated to the microbial adhesion. This indicated that, for both E. coli and S. aureus, the surface roughness did not affect the microbial adhesion. Only gamma(sAB) had any correlation with the microbial adhesion and gamma(sLW) was almost constant for all the various polysaccharide films tested. In addition, the electron-donor properties of the materials, exhibited via gamma(s+), were positively correlated with the adhesion of S. aureus but not with E. coli. This was in agreement with the results of the MATS (Microbial Adhesion To Solvents) test performed on the two bacteria. This revealed that only S. aureus presented an electron-acceptor characteristic.


The predictive power of physical function assessed by questionnaire and physical performance measures for subsequent disability.
To compare the predictive power of physical function assessed by questionnaire and physical performance measures for subsequent disability in community-dwelling elderly persons. Prospective cohort study. Participants were 813 aged 70 years and older, elderly Japanese residing in the community, included in the Tsurugaya Project, who were not disabled at the baseline in 2003. Physical function was assessed by the questionnaire of "Motor Fitness Scale". Physical performance measures consisted of maximum walking velocity, timed up and go test (TUG), leg extension power, and functional reach test. The area under the curve (AUC) of the receiver operating characteristic curve for disability was used to compare screening accuracy between Motor Fitness Scale and physical performance measures. Incident disability, defined as certification for long-term care insurance, was used as the endpoint. We observed 135 cases of incident disability during follow-up. The third or fourth quartile for each measure was associated with a significantly increased risk of disability in comparison with the highest quartile. The AUC was 0.70, 0.72, 0.70, 0.68, 0.69 and 0.74, for Motor Fitness Scale, maxi- mum walking velocity, TUG, leg extension power, functional reach test, and total performance score, respectively. The predictive power of physical function assessed by the Motor Fitness Scale was equivalent to that assessed by physical performance measures. Since Motor Fitness Scale can evaluate physical function safely and simply in comparison with physical performance tests, it would be a practical tool for screening persons at high risk of disability.


Metal ion assisted interface re-engineering of a ferritin nanocage for enhanced biofunctions and cancer therapy.
The bottom-up self-assembly of protein subunits into supramolecular nanoarchitectures is ubiquitously exploited to recapitulate and expand the features of natural proteins to advance nanoscience in medicine. Various chemical and biological re-engineering approaches are available to render diverse functions in the given proteins. They are, unfortunately, capable of compromising protein integrity and stability after extensive modifications. In this study, we introduce a new protein re-engineering method, metal ion assisted interface re-engineering (MAIR), to serve as a robust and universal strategy to extend the functions of self-assembly proteins by boosting structural features to advance their diverse biomedical applications. In particular, the MAIR strategy was applied to a widely used natural protein, ferritin, as a model protein to coordinate with copper ions in its mutagenic artificial metal binding domain. Structure directed rational protein mutagenesis was carried out at the C2 interface amino acid residues of the ferritin subunit for metal ion coordination site optimization. Copper binding at the artificial binding pocket was highly specific over the other divalent ions present in physiological fluids, and the structurally embedded copper ion in turn strengthened the overall protein integrity and stability. In the presence of isotopic copper-64, the interface re-engineered ferritin worked as a chelator-free molecular nanoprobe with an extraordinarily high specific activity to allow PET imaging of tumors in live animals. We also found that the re-engineered ferritin coordinating with copper ions demonstrates high drug loading capacity of a widely used anti-cancer agent, doxorubicin (DOX), to achieve significant drug retention at the tumor site and enhance tumor regression for improved anti-cancer effects. The MAIR approach, thus, exploited the copper ion to facilitate efficient one-step labeling of mutant ferritin derivatives for simultaneous molecular imaging and drug delivery. The reported interface re-engineering strategy provides an unparalleled opportunity to expand protein biofunctions to serve as a new theranostic agent in cancer research.


[Assessment of dietary intake and urinary excretion of sodium and potassium in adults].
Hypertension is associated with elevated sodium and low potassium intakes. The determination of sodium and potassium intake by dietary records is inaccurate, being its measurement from 24-h urine collection the reference method. To determine urinary sodium and potassium excretion in adults. To compare dietary sodium and potassium intake and their excretion from an isolated urine sample against the reference method. Seventy healthy adults aged 35 ± 8 years with a body mass index 25 ± 2 kg/m² (36 women) were studied. Urine was collected over 24 h, including an isolated urine sample taken in fasting conditions. Additionally, three 24-h dietary records were performed. Reported sodium and potassium intake was 2,720 ± 567 and 1,068 ± 433 mg/day, respectively. In turn, urinary excretion of sodium and potassium was 4,770 ± 1,532 and 1,852 ± 559 mg/day, respectively. These latter values were significantly higher than those obtained by dietary records. Furthermore, the urinary sodium and potassium excretion estimated from an isolated urine sample was 4,839 ± 1,355 and 1,845 ± 494 mg/day, respectively. These values were similar to those obtained with a 24 h urine collection. Dietary records underestimated electrolyte intake when compared with the reference method. Using an isolated urine sample to estimate electrolyte intake may be a reliable alternative.


Anti-basal ganglia antibodies in primary obsessive-compulsive disorder: systematic review and meta-analysis.
Autoimmune-mediated basal ganglia dysfunction is implicated in the pathophysiology of neuropsychiatric disorders commonly manifesting with obsessive-compulsive features (e.g. Sydenham chorea). The relationship between autoimmunity and primary obsessive-compulsive disorder (OCD), however, is less clear. To pool data on serum and cerebrospinal fluid (CSF) anti-basal ganglia antibody (ABGA) positivity in primary OCD (without neurological or autoimmune comorbidity) relative to controls or neuropsychiatric disorders previously associated with increased odds of ABGA positivity. We performed electronic database and hand-searches for studies meeting pre-specified eligibility criteria from which we extracted data using a standardised form. We calculated pooled estimates of ABGA positivity using a random-effects model. Seven case-control studies totalling 844 participants met the eligibility criteria. Meta-analysis showed that a significantly greater proportion of those with primary OCD were ABGA seropositive compared with various controls (odds ratio (OR) = 4.97, 95% CI 2.88-8.55, P<0.00001). This effect was not associated with heterogeneity or publication bias, and remained significant after stratifying the analysis by age, gender, disease severity, illness duration, immunostaining methodology, study quality, publication type, kind of control group, and sample size. There were no significant differences in ABGA seropositivity for comparisons between primary OCD and Tourette syndrome, attention-deficit hyperactivity disorder or paediatric acute-onset neuropsychiatric syndrome. of one study testing CSF samples showed that a significantly greater proportion of participants with primary OCD were ABGA CSF-positive compared with healthy controls (OR = 5.60, 95% CI 1.04-30.20, P = 0.045). Odds of ABGA seropositivity are increased fivefold in primary OCD compared with controls, but are comparable to those associated with disorders previously associated with ABGA, providing circumstantial evidence of autoimmunity in a subset of those with primary OCD. Further experimental studies are needed to ascertain whether this relationship is causal.


Genetic polymorphisms in the hypothalamic pathway in relation to subsequent weight change--the DiOGenes study.
Single nucleotide polymorphisms (SNPs) in genes encoding the components involved in the hypothalamic pathway may influence weight gain and dietary factors may modify their effects. We conducted a case-cohort study to investigate the associations of SNPs in candidate genes with weight change during an average of 6.8 years of follow-up and to examine the potential effect modification by glycemic index (GI) and protein intake. Participants, aged 20-60 years at baseline, came from five European countries. Cases ('weight gainers') were selected from the total eligible cohort (n = 50,293) as those with the greatest unexplained annual weight gain (n = 5,584). A random subcohort (n = 6,566) was drawn with the intention to obtain an equal number of cases and noncases (n = 5,507). We genotyped 134 SNPs that captured all common genetic variation across the 15 candidate genes; 123 met the quality control criteria. Each SNP was tested for association with the risk of being a 'weight gainer' (logistic regression models) in the case-noncase data and with weight gain (linear regression models) in the random subcohort data. After accounting for multiple testing, none of the SNPs was significantly associated with weight change. Furthermore, we observed no significant effect modification by dietary factors, except for SNP rs7180849 in the neuromedin β gene (NMB). Carriers of the minor allele had a more pronounced weight gain at a higher GI (P = 2 x 10⁻⁷). We found no evidence of association between SNPs in the studied hypothalamic genes with weight change. The interaction between GI and NMB SNP rs7180849 needs further confirmation.


Orangutans venture out of the rainforest and into the Anthropocene.
Conservation benefits from understanding how adaptability and threat interact to determine a taxon's vulnerability. Recognizing how interactions with humans have shaped taxa such as the critically endangered orangutan (Pongo spp.) offers insights into this relationship. Orangutans are viewed as icons of wild nature, and most efforts to prevent their extinction have focused on protecting minimally disturbed habitat, with limited success. We synthesize fossil, archeological, genetic, and behavioral evidence to demonstrate that at least 70,000 years of human influence have shaped orangutan distribution, abundance, and ecology and will likely continue to do so in the future. Our findings indicate that orangutans are vulnerable to hunting but appear flexible in response to some other human activities. This highlights the need for a multifaceted, landscape-level approach to orangutan conservation that leverages sound policy and cooperation among government, private sector, and community stakeholders to prevent hunting, mitigate human-orangutan conflict, and preserve and reconnect remaining natural forests. Broad cooperation can be encouraged through incentives and strategies that focus on the common interests and concerns of different stakeholders. Orangutans provide an illustrative example of how acknowledging the long and pervasive influence of humans can improve strategies to preserve biodiversity in the Anthropocene.


Impairment of glutathione metabolism in human gastric epithelial cells treated with vacuolating cytotoxin from Helicobacter pylori.
Helicobacter pylori vacuolating cytotoxin (VacA) is believed to be one of the factors that induces gastric disease. Our previous study indicated that VacA causes a decrease in the intracellular ATP level in human gastric epithelial cells, suggesting to impair mitochondrial membrane potential followed by a decrease in energy metabolism (Kimura et al., Microb. Pathog., 1999, 26: 45--52). In the present study, we investigated whether the decrease in ATP level affects glutathione metabolism, in which its synthesis and efflux are ATP-dependent. Treatment of AZ-521 human gastric epithelial cells with 120 nM VacA for 6 h suppressed the efflux of oxidized glutathione (GSSG) in a dose- and time-dependent manner. The efflux of GSSG from the cells and glutathione (GSH) synthesis of cells treated with VacA were approximately 50 and 70% of those of the control, respectively. The turnover rate of intracellular GSH was also suppressed by VacA. Viability of the cells pretreated with VacA, then further incubated with H(2)O(2), was decreased by 50% at 6 h and 70% at 12 h. These results suggested that VacA impairs GSH metabolism in the gastric epithelial cells, which weakens the resistance of the cells against oxidative stress or cellular redox regulation by GSH.


Urinary sodium and potassium excretion and risk of cardiovascular events.
The precise relationship between sodium and potassium intake and cardiovascular (CV) risk remains uncertain, especially in patients with CV disease. To determine the association between estimated urinary sodium and potassium excretion (surrogates for intake) and CV events in patients with established CV disease or diabetes mellitus. Observational analyses of 2 cohorts (N = 28,880) included in the ONTARGET and TRANSCEND trials (November 2001-March 2008 from initial recruitment to final follow-up). We estimated 24-hour urinary sodium and potassium excretion from a morning fasting urine sample (Kawasaki formula). We used restricted cubic spline plots to describe the association between sodium and potassium excretion and CV events and mortality, and to identify reference categories for sodium and potassium excretion. We used Cox proportional hazards multivariable models to determine the association of urinary sodium and potassium with CV events and mortality. CV death, myocardial infarction (MI), stroke, and hospitalization for congestive heart failure (CHF). At baseline, the mean (SD) estimated 24-hour excretion for sodium was 4.77 g (1.61); and for potassium was 2.19 g (0.57). After a median follow-up of 56 months, the composite outcome occurred in 4729 (16.4%) participants, including 2057 CV deaths, 1412 with MI, 1282 with stroke, and 1213 with hospitalization for CHF. Compared with the reference group with estimated baseline sodium excretion of 4 to 5.99 g per day (n = 14,156; 6.3% participants with CV death, 4.6% with MI, 4.2% with stroke, and 3.8% admitted to hospital with CHF), higher baseline sodium excretion was associated with an increased risk of CV death (9.7% for 7-8 g/day; hazard ratio [HR], 1.53; 95% CI, 1.26-1.86; and 11.2% for >8 g/day; HR, 1.66; 95% CI, 1.31-2.10), MI (6.8%; HR, 1.48; 95% CI, 1.11-1.98 for >8 g/day), stroke (6.6%; HR, 1.48; 95% CI, 1.09-2.01 for >8 g/day), and hospitalization for CHF (6.5%; HR, 1.51; 1.12-2.05 for >8 g/day). Lower sodium excretion was associated with an increased risk of CV death (8.6%; HR, 1.19; 95% CI, 1.02-1.39 for 2-2.99 g/day; 10.6%; HR, 1.37; 95% CI, 1.09-1.73 for <2 g/day), and hospitalization for CHF (5.2%; HR, 1.23; 95% CI, 1.01-1.49 for 2-2.99 g/day) on multivariable analysis. Compared with an estimated potassium excretion of less than 1.5 g per day (n = 2194; 6.2% with stroke), higher potassium excretion was associated with a reduced risk of stroke (4.7% [HR, 0.77; 95% CI, 0.63-0.94] for 1.5-1.99 g/day; 4.3% [HR, 0.73; 95% CI, 0.59-0.90] for 2-2.49 g/day; 3.9% [HR, 0.71; 95% CI, 0.56-0.91] for 2.5-3 g/day; and 3.5% [HR, 0.68; 95% CI, 0.49-0.92] for >3 g/day) on multivariable analysis. The association between estimated sodium excretion and CV events was J-shaped. Compared with baseline sodium excretion of 4 to 5.99 g per day, sodium excretion of greater than 7 g per day was associated with an increased risk of all CV events, and a sodium excretion of less than 3 g per day was associated with increased risk of CV mortality and hospitalization for CHF. Higher estimated potassium excretion was associated with a reduced risk of stroke.


Burden of non-hip, non-vertebral fractures on quality of life in postmenopausal women: the Global Longitudinal study of Osteoporosis in Women (GLOW).
Among 50,461 postmenopausal women, 1,822 fractures occurred (57% minor non-hip, non-vertebral [NHNV], 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D, followed by major NHNV and hip fractures. Decreases in physical function and health status were greatest for spine or hip fractures. There is growing evidence that NHNV fractures result in substantial morbidity and healthcare costs. The aim of this prospective study was to assess the effect of these NHNV fractures on quality of life. We analyzed the 1-year incidences of hip, spine, major NHNV (pelvis/leg, shoulder/arm) and minor NHNV (wrist/hand, ankle/foot, rib/clavicle) fractures among women from the Global Longitudinal study of Osteoporosis in Women (GLOW). Health-related quality of life (HRQL) was analyzed using the EuroQol EQ-5D tool and the SF-36 health survey. Among 50,461 women analyzed, there were 1,822 fractures (57% minor NHNV, 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D summary scores, followed by major NHNV and hip fractures. The number of women with mobility problems increased most for those with major NHNV and spine fractures (both +8%); spine fractures were associated with the largest increases in problems with self care (+11%), activities (+14%), and pain/discomfort (+12%). Decreases in physical function and health status were greatest for those with spine or hip fractures. Multivariable modeling found that EQ-5D reduction was greatest for spine fractures, followed by hip and major/minor NHNV. Statistically significant reductions in SF-36 physical function were found for spine fractures, and were borderline significant for major NHNV fractures. This prospective study shows that NHNV fractures have a detrimental effect on HRQL. Efforts to optimize the care of osteoporosis patients should include the prevention of NHNV fractures.


Long-Acting C-Peptide and Neuropathy in Type 1 Diabetes: A 12-Month Clinical Trial.
Lack of C-peptide in type 1 diabetes may be an important contributing factor in the development of microvascular complications. Replacement of native C-peptide has been shown to exert a beneficial influence on peripheral nerve function in type 1 diabetes. The aim of this study was to evaluate the efficacy and safety of a long-acting C-peptide in subjects with type 1 diabetes and mild to moderate peripheral neuropathy. A total of 250 patients with type 1 diabetes and peripheral neuropathy received long-acting (pegylated) C-peptide in weekly dosages of 0.8 mg (n = 71) or 2.4 mg (n = 73) or placebo (n = 106) for 52 weeks. Bilateral sural nerve conduction velocity (SNCV) and vibration perception threshold (VPT) on the great toe were measured on two occasions at baseline, at 26 weeks, and at 52 weeks. The modified Toronto Clinical Neuropathy Score (mTCNS) was used to grade the peripheral neuropathy. Plasma C-peptide rose during the study to 1.8-2.2 nmol/L (low dose) and to 5.6-6.8 nmol/L (high dose). After 52 weeks, SNCV had increased by 1.0 ± 0.24 m/s (P < 0.001 within group) in patients receiving C-peptide (combined groups), but the corresponding value for the placebo group was 1.2 ± 0.29 m/s. Compared with basal, VPT had improved by 25% after 52 weeks of C-peptide therapy (Δ for combined C-peptide groups: -4.5 ± 1.0 μm, placebo group: -0.1 ± 0.9 μm; P < 0.001). mTCNS was unchanged during the study. Once-weekly subcutaneous administration of long-acting C-peptide for 52 weeks did not improve SNCV, other electrophysiological variables, or mTCNS but resulted in marked improvement of VPT compared with placebo.


Centrosomal MPF triggers the mitotic and morphogenetic switches of fission yeast.
Activation of mitosis-promoting factor (MPF) drives mitotic commitment. In human cells active MPF appears first on centrosomes. We show that local activation of MPF on the equivalent organelle of fission yeast, the spindle pole body (SPB), promotes Polo kinase activity at the SPBs long before global MPF activation drives mitotic commitment. Artificially promoting MPF or Polo activity at various locations revealed that this local control of Plo1 activity on G2 phase SPBs dictates the timing of mitotic commitment. Cytokinesis of the rod-shaped fission yeast cell generates a naive, new, cell end. Growth is restricted to the experienced old end until a point in G2 phase called new end take off (NETO) when bipolar growth is triggered. NETO coincided with MPF activation of Plo1 on G2 phase SPBs (ref. 4). Both MPF and Polo activities were required for NETO and both induced NETO when ectopically activated at interphase SPBs. NETO promotion by MPF required polo. Thus, local MPF activation on G2 SPBs directs polo kinase to control at least two distinct and temporally separated, cell-cycle transitions at remote locations.


Practical use of dabigatran etexilate for stroke prevention in atrial fibrillation.
Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug-drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice.


Nanoparticle conjugation of CpG enhances adjuvancy for cellular immunity and memory recall at low dose.
In subunit vaccines, strong CD8(+) T-cell responses are desired, yet they are elusive at reasonable adjuvant doses. We show that targeting adjuvant to the lymph node (LN) via ultrasmall polymeric nanoparticles (NPs), which rapidly drain to the LN after intradermal injection, greatly enhances adjuvant efficacy at low doses. Coupling CpG-B or CpG-C oligonucleotides to NPs led to better dual-targeting of adjuvant and antigen (codelivered on separate NPs) in cross-presenting dendritic cells compared with free adjuvant. This led to enhanced dendritic cell maturation and T helper 1 (Th1)-cytokine secretion, in turn driving stronger effector CD8(+) T-cell activation with enhanced cytolytic profiles and, importantly, more powerful memory recall. With only 4 μg CpG, NP-CpG-B could substantially protect mice from syngeneic tumor challenge, even after 4 mo of vaccination, compared with free CpG-B. Together, these results show that nanocarriers can enhance vaccine efficacy at a low adjuvant dose for inducing potent and long-lived cellular immunity.


Teaching of public health ethics in India: a mapping exercise.
Public health ethics has been receiving increasing attention in recent years. Frequently, public health practitioners have to confront complex decisions, with numerous and often conflicting ethical implications. The objective of this study was to obtain information on the teaching of public health ethics in India by making a detailed examination of the public health and community medicine curricula. The specific areas of interest included the content and structure of the courses and electives available to students. The results of this study indicate that ethics courses are yet to find their rightful place in the teaching of public health in India. The curricula vary across institutes in terms of the time and content devoted to the teaching of public health ethics. It is suggested that public health programmes in India develop and incorporate ethics courses so as to keep pace with the emerging challenges in the field. An interdisciplinary consortium should preferably be formed at the national level to take up this academic endeavour.


Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus.
To evaluate pre- and postoperative clinical parameters associated with improvement of diabetes up to 4 years after laparoscopic Roux-en-Y gastric bypass (LRYGBP) in patients with type 2 diabetes mellitus (T2DM). The surgical treatment of morbid obesity leads to dramatic improvement in the comorbidity status of most patients with T2DM. However, little is known concerning what preoperative clinical factors are associated with postoperative long-term improvement in diabetes in the morbidly obese patient with diabetes. METHODS We evaluated pre- and postoperative data, including demographics, duration of diabetes, metabolic parameters, and clinical outcomes, in all patients with impaired fasting glucose (IFG) and type T2DM undergoing LRYGBP from July 1997 to May 2002. During this 5-year period, 1160 patients underwent LRYGBP and 240 (21%) had IFG or T2DM. Follow up was possible in 191 of 240 patients (80%). There were 144 females (75%) with a mean preoperative age of 48 years (range, 26-67 years). After surgery, weight and body mass index decreased from 308 lbs and 50.1 kg/m2 to 211 lbs and 34 kg/m2 for a mean weight loss of 97 lbs and mean excess weight loss of 60%. Fasting plasma glucose and glycosylated hemoglobin concentrations returned to normal levels (83%) or markedly improved (17%) in all patients. A significant reduction in use of oral antidiabetic agents (80%) and insulin (79%) followed surgical treatment. Patients with the shortest duration (<5 years), the mildest form of T2DM (diet controlled), and the greatest weight loss after surgery were most likely to achieve complete resolution of T2DM. LRYGBP resulted in significant weight loss (60% percent of excess body weight loss) and resolution (83%) of T2DM. Patients with the shortest duration and mildest form of T2DM had a higher rate of T2DM resolution after surgery, suggesting that early surgical intervention is warranted to increase the likelihood of rendering patients euglycemic.


Evidence for young volcanism on Mercury from the third MESSENGER flyby.
During its first two flybys of Mercury, the MESSENGER spacecraft acquired images confirming that pervasive volcanism occurred early in the planet's history. MESSENGER's third Mercury flyby revealed a 290-kilometer-diameter peak-ring impact basin, among the youngest basins yet seen, having an inner floor filled with spectrally distinct smooth plains. These plains are sparsely cratered, postdate the formation of the basin, apparently formed from material that once flowed across the surface, and are therefore interpreted to be volcanic in origin. An irregular depression surrounded by a halo of bright deposits northeast of the basin marks a candidate explosive volcanic vent larger than any previously identified on Mercury. Volcanism on the planet thus spanned a considerable duration, perhaps extending well into the second half of solar system history.


Cancer nanomedicine: focus on recent developments and self-assembled peptide nanocarriers.
The applications of nanoparticulate drug delivery have received abundant interest in the field of cancer diagnosis and treatment. By virtue of their unique features and design, nanomedicines have made remarkable progress in eliminating dreadful tumors. Research in cancer nanomedicine has spanned multitudes of drug delivery systems that possess high tumor targeting ability, sensitivity towards tumor microenvironments and improved efficacy. Various nanocarriers have been developed and approved for anti-tumor drug targeting. These nanocarriers, i.e., liposomes, micelles, nanotubes, dendrimers and peptides, offer a wide range of advantages, such as high selectivity, multi-functionality, specificity, biocompatibility and precise control of drug release. Nanomedicines based on self-assembled peptide carrier systems have been developed in recent years for cancer targeting. Self-assembled peptides have tremendous properties of forming targeted drug delivery vehicles such as nanohydrogels with unique features and functionality. In this review article, we discuss some developments in cancer nanomedicine. We present a diverse range of nanotargeted drug-delivery systems.


Early use of inhaled corticosteroids in the emergency department treatment of acute asthma.
Systemic corticosteroid therapy is central to the management of acute asthma. The use of inhaled corticosteroids (ICS) may also be beneficial in this setting. To determine the benefit of ICS for the treatment of patients with acute asthma managed in the emergency department (ED). We identified controlled clinical trials from the Cochrane Airways Group specialised register of controlled trials. Bibliographies from included studies, known reviews, and texts also were searched. The latest search was September 2012. We included randomised controlled trials (RCTs) and quasi-RCTs. Studies were included if patients presented to the ED or its equivalent with acute asthma, and were treated with ICS or placebo, in addition to standard therapy. Two review authors independently selected potentially relevant articles, and then independently selected articles for inclusion. Methodological quality was independently assessed by two review authors. There were three different types of studies that were included in this review: 1) studies comparing ICS vs. placebo, with no systemic corticosteroids given to either treatment group, 2) studies comparing ICS vs. placebo, with systemic corticosteroids given to both treatment groups, and 3) studies comparing ICS alone versus systemic corticosteroids. For the analysis, the first two types of studies were included as separate subgroups in the primary analysis (ICS vs. placebo), while the third type of study was included in the secondary analysis (ICS vs. systemic corticosteroid). Data were extracted independently by two review authors if the authors were unable to verify the validity of extracted information. Missing data were obtained from the authors or calculated from other data presented in the paper. Where appropriate, individual and pooled dichotomous outcomes were reported as odds ratios (OR) with 95% confidence intervals (CIs). Where appropriate, individual and pooled continuous outcomes were reported as mean differences (MD) or standardized mean differences (SMD) with 95% CIs. The primary analysis employed a fixed-effect model and a random-effects model was used for sensitivity analysis. Heterogeneity is reported using I-squared (I(2)) statistics. Twenty trials were selected for inclusion in the primary analysis (13 paediatric, seven adult), with a total number of 1403 patients. Patients treated with ICS were less likely to be admitted to hospital (OR 0.44; 95% CI 0.31 to 0.62; 12 studies; 960 patients) and heterogeneity (I(2) = 27%) was modest. This represents a reduction from 32 to 17 hospital admissions per 100 patients treated with ICS in comparison with placebo. Subgroup analysis of hospital admissions based on concomitant systemic corticosteroid use revealed that both subgroups indicated benefit from ICS in reducing hospital admissions (ICS and systemic corticosteroid versus systemic corticosteroid: OR 0.54; 95% CI 0.36 to 0.81; 5 studies; N = 433; ICS versus placebo: OR 0.27; 95% CI 0.14 to 0.52; 7 studies; N = 527). However, there was moderate heterogeneity in the subgroup using ICS in addition to systemic steroids (I(2) = 52%). Patients receiving ICS demonstrated small, significant improvements in peak expiratory flow (PEF: MD 7%; 95% CI 3% to 11%) and forced expiratory volume in one second (FEV(1): MD 6%; 95% CI 2% to 10%) at three to four hours post treatment). Only a small number of studies reported these outcomes such that they could be included in the meta-analysis and most of the studies in this comparison did not administer systemic corticosteroids to either treatment group. There was no evidence of significant adverse effects from ICS treatment with regard to tremor or nausea and vomiting. In the secondary analysis of studies comparing ICS alone versus systemic corticosteroid alone, heterogeneity among the studies complicated pooling of data or drawing reliable conclusions. ICS therapy reduces hospital admissions in patients with acute asthma who are not treated with oral or intravenous corticosteroids. They may also reduce admissions when they are used in addition to systemic corticosteroids; however, the most recent evidence is conflicting. There is insufficient evidence that ICS therapy results in clinically important changes in pulmonary function or clinical scores when used in acute asthma in addition to systemic corticosteroids. Also, there is insufficient evidence that ICS therapy can be used in place of systemic corticosteroid therapy when treating acute asthma. Further research is needed to clarify the most appropriate drug dosage and delivery device, and to define which patients are most likely to benefit from ICS therapy. Use of similar measures and reporting methods of lung function, and a common, validated, clinical score would be helpful in future versions of this meta-analysis.


Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial.
Depressive symptoms are a major cause of disability in bipolar disorder and there are few safe and effective treatments. The combination of lamotrigine plus quetiapine potentially offers improved outcomes for people with bipolar depression. We aimed to determine if combination therapy with quetiapine plus lamotrigine leads to greater improvement in depressive symptoms over 12 weeks than quetiapine monotherapy plus lamotrigine placebo. In this double-blind, randomised, placebo-controlled, parallel group, 2 × 2 factorial trial (CEQUEL), patients with DSM-IV bipolar disorder I or II, who were aged 16 years or older, and required new treatment for a depressive episode, were enrolled from 27 sites in the UK. Patients were randomly assigned (1:1) by an adaptive minimisation algorithm to lamotrigine or placebo and to folic acid or placebo. Participants and investigators were masked to the treatment groups. The primary outcome was improvement in depressive symptoms at 12 weeks with the Quick Inventory of Depressive Symptomatology-self report version 16 (QIDS-SR16). Analysis was by modified intention-to-treat. This trial is registered with EUdraCT, number 2007-004513-33. Between Oct 21, 2008, and April 27, 2012, 202 participants were randomly assigned; 101 to lamotrigine and 101 to placebo. The mean difference in QIDS-SR16 total score between the group receiving lamotrigine versus the placebo group at 12 weeks was -1·73 ([95% CI -3·57 to 0·11]; p=0·066) and at 52 weeks was -2·69 ([-4·89 to -0·49]; p=0·017). Folic acid was not superior to placebo. There was a significant interaction (p=0·028), with folic acid reducing the effectiveness of lamotrigine at 12 weeks. The mean difference on QIDS-SR16 was -4·14 ([95% CI -6·90 to -1·37]; p=0·004) for patients receiving lamotrigine without folic acid compared with 0·12 ([-2·58 to 2·82]; p=0·931) for those receiving lamotrigine and folic acid. Addition of lamotrigine to quetiapine treatment improved outcomes. Folic acid seems to nullify the effect of lamotrigine. CEQUEL should encourage clinicians and patients to consider lamotrigine for bipolar depression, but also to be aware that concurrent folic acid might reduce its effectiveness. Medical Research Council.


ICIRAS: Research and reconciliation with indigenous peoples in rural health journals.
We aim to promote discussion about an Indigenous Cultural Identity of Research Authors Standard (ICIRAS) for academic journal publications. This is based on a gap in research publishing practice where Indigenous peoples' identity is not systematically and rigorously flagged in rural health research publications. There are widespread reforms, in different research areas, to counter the reputation of scientific research as a vehicle of racism and discrimination against the world's Indigenous peoples. Reflecting on these broader movements, the editorial teams of three rural health journals-the Australian Journal of Rural Health, the Canadian Journal of Rural Medicine, and Rural and Remote Health-recognised that Indigenous peoples' identity could be embedded in authorship details. An environmental scan (through a cultural safety lens where Indigenous cultural authority is respected, valued, and empowered) of literature was undertaken to detect the signs of inclusion of Indigenous peoples in research. This revealed many ways in which editorial boards of Journals could systematically improve their process so that there is 'nothing about Indigenous people, without Indigenous people' in rural health research publications. Improving the health and wellbeing of Indigenous peoples worldwide requires high quality research evidence. The philosophy of cultural safety supports the purposeful positioning of Indigenous peoples within the kaleidoscope of cultural knowledges as identified contributors and authors of research evidence. The ICIRAS is a call-to-action for research journals and institutions to rigorously improve publication governance that signals "Editing with IndigenUs and for IndigenUs".


Forward Genetic Screen in Caenorhabditis elegans Suggests F57A10.2 and acp-4 As Suppressors of C9ORF72 Related Phenotypes.
An abnormally expanded GGGGCC repeat in C9ORF72 is the most frequent causal mutation associated with amyotrophic lateral sclerosis (ALS)/frontotemporal lobar degeneration (FTLD). Both gain-of-function (gf) and loss-of-function (lf) mechanisms have been involved in C9ORF72 related ALS/FTLD. The gf mechanism of C9ORF72 has been studied in various animal models but not in C. elegans. In the present study, we described mutant C9ORF72 modeling in C. elegans and report the finding of two suppressor genes. We made transgenes containing 9 or 29 repeats of GGGGCC in C9ORF72, driven by either the hsp-16 promoters or the unc-119 promoter. Transgenic worms were made to carry such transgenes. Phenotypic analysis of those animals revealed that Phsp-16::(G4C2)29::GFP transgenic animals (EAB 135) displayed severe paralysis by the second day of adulthood, followed by lethality, which phenotypes were less severe in Phsp-16::(G4C2)9::GFP transgenic animals (EAB242), and absent in control strains expressing empty vectors. Suppressor genes of this locomotor phenotype were pursued by introducing mutations with ethyl methanesulfonate in EAB135, screening mutant strains that moved faster than EAB135 by a food-ring assay, identifying mutations by whole-genome sequencing and testing the underlying mechanism of the suppressor genes either by employing RNA interference studies or C. elegans genetics. Three mutant strains, EAB164, EAB165 and EAB167, were identified. Eight suppressor genes carrying nonsense/canonical splicing site mutations were confirmed, among which a nonsense mutation of F57A10.2/VAMP was found in all three mutant strains, and a nonsense mutation of acp-4/ACP2 was only found in EAB164. Knock down/out of those two genes in EAB135 animals by feeding RNAi/introducing a known acp-4 null allele phenocopied the suppression of the C9ORF72 variant related movement defect in the mutant strains. Translational conformation in a mammalian system is required, but our worm data suggest that altering acp-4/ACP2 encoding lysosomal acid phosphatase may provide a potential therapeutic method of reducing acp-4/ACP2 levels, as opposed or complementary to directly reducing C9ORF72, to relieve C9ORF72-ALS phenotypes. It also suggests that the C9ORF72-ALS/FTLD may share a pathophysiologic mechanism with vesicle-associated membrane protein-associated protein B, a homolog of F57A10.2/VAMP, which is a proven ALS8 gene.