Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer.
In the last few years, microRNAs (miRNA) have started a revolution in molecular biology and emerged as key players in the carcinogenesis. They have been identified in various tumor types, showing that different sets of miRNAs are usually deregulated in different cancers. To identify the miRNA signature that was specific for oral squamous cell carcinoma (OSCC), we first examined expression profiles of 148 miRNAs in a panel of 18 OSCC cell lines and the immortalized oral keratinocyte line RT7 as a control. Compared with RT7, the expression of 54 miRNAs (36.5%) was frequently down-regulated in OSCC lines (<0.5-fold expression, >or=66.7% of 18 lines). Among these 54 miRNAs, we further analyzed four of these miRNAs (i.e., miR-34b, miR-137, miR-193a, and miR-203), located around CpG islands, to identify tumor-suppressive miRNAs silenced through aberrant DNA methylation. The expression of those four genes was restored by treatment with 5-aza-2'-deoxycytidine in OSCC cells lacking their expression. In addition, expression levels of the four miRNAs were inversely correlated with their DNA methylation status in the OSCC lines. In primary tumors of OSCC with paired normal oral mucosa, down-regulation of miRNA expression through tumor-specific hypermethylation was more frequently observed for miR-137 and miR-193a than for miR-34b and miR-203. Moreover, the ectopic transfection of miR-137 or miR-193a into OSCC lines lacking their expressions significantly reduced cell growth, with down-regulation of the translation of cyclin-dependent kinase 6 or E2F transcription factor 6, respectively. Taken together, our results clearly show that miR-137 and miR-193a are tumor suppressor miRNAs epigenetically silenced during oral carcinogenesis.


Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection.
Recent outbreaks of the Ebola virus (EBOV) have focused attention on the dire need for antivirals to treat these patients. We identified pyronaridine tetraphosphate as a potential candidate as it is an approved drug in the European Union which is currently used in combination with artesunate as a treatment for malaria (EC50 between 420 nM-1.14 μM against EBOV in HeLa cells). Range-finding studies in mice directed us to a single 75 mg/kg i.p. dose 1 hr after infection which resulted in 100% survival and statistically significantly reduced viremia at study day 3 from a lethal challenge with mouse-adapted EBOV (maEBOV). Further, an EBOV window study suggested we could dose pyronaridine 2 or 24 hrs post-exposure to result in similar efficacy. Analysis of cytokine and chemokine panels suggests that pyronaridine may act as an immunomodulator during an EBOV infection. Our studies with pyronaridine clearly demonstrate potential utility for its repurposing as an antiviral against EBOV and merits further study in larger animal models with the added benefit of already being used as a treatment against malaria.


Attitudes toward depression among Japanese non-psychiatric medical doctors: a cross-sectional study.
Under-recognition of depression is common in many countries. Education of medical staff, focusing on their attitudes towards depression, may be necessary to change their behavior and enhance recognition of depression. Several studies have previously reported on attitudes toward depression among general physicians. However, little is known about attitudes of non-psychiatric doctors in Japan. In the present study, we surveyed non-psychiatric doctors' attitude toward depression. The inclusion criteria of participants in the present study were as follows: 1) Japanese non-psychiatric doctors and 2) attendees in educational opportunities regarding depression care. We conveniently approached two populations: 1) a workshop to depression care for non-psychiatric doctors and 2) a general physician-psychiatrist (G-P) network group. We contacted 367 subjects. Attitudes toward depression were measured using the Depression Attitude Questionnaire (DAQ), a 20-item self-report questionnaire developed for general physicians. We report scores of each DAQ item and factors derived from exploratory factor analysis. We received responses from 230 subjects, and we used DAQ data from 187 non-psychiatric doctors who met the inclusion criteria. All non-psychiatric doctors (n = 187) disagreed with "I feel comfortable in dealing with depressed patients' needs," while 60 % (n = 112) agreed with "Working with depressed patients is heavy going." Factor analysis indicated these items comprised a factor termed "Depression should be treated by psychiatrists" - to which 54 % of doctors (n = 101) agreed. Meanwhile, 67 % of doctors (n = 126) thought that nurses could be useful in depressed patient support. The three factors derived from the Japanese DAQ differed from models previously derived from British GP samples. The attitude of Japanese non-psychiatric doctors concerning whether depression should be treated by psychiatrists was markedly different to that of British GPs. Japanese non-psychiatric doctors believe that depression care is beyond the scope of their duties. It is suggested that educational programs or guidelines for depression care developed in other countries such as the UK are not directly adaptable for Japanese non-psychiatric doctors. Developing a focused educational program that motivates non-psychiatric doctors to play a role in depression care is necessary to enhance recognition and treatment of depression in Japan.


Comparing the rates of speciation and extinction between phylogenetic trees.
Over the past decade or so it has become increasingly popular to use reconstructed evolutionary trees to investigate questions about the rates of speciation and extinction. Although the methodology of this field has grown substantially in its sophistication in recent years, here I will take a step back to present a very simple model that is designed to investigate the relatively straightforward question of whether the tempo of diversification (speciation and extinction) differs between two or more phylogenetic trees, without attempting to attribute a causal basis to this difference. It is a likelihood method, and I demonstrate that it generally shows type I error that is close to the nominal level. I also demonstrate that parameter estimates obtained with this approach are largely unbiased. As this method can be used to compare trees of unknown relationship, it will be particularly well-suited to problems in which a difference in diversification rate between clades is suspected, but in which these clades are not particularly closely related. As diversification methods can easily take into account an incomplete sampling fraction, but missing lineages are assumed to be missing at random, this method is also appropriate for cases in which we have hypothesized a difference in the process of diversification between two or more focal clades, but in which many unsampled groups separate the few of interest. The method of this study is by no means an attempt to replace more sophisticated models in which, for instance, diversification depends on the state of an observed or unobserved discrete or continuous trait. Rather, my intention is to provide a complementary approach for circumstances in which a simpler hypothesis is warranted and of biological interest.


Strong and graded associations between level of asthma severity and all-cause hospital care use and costs in the UK.
Hospital admissions account for a large share of the healthcare costs incurred by people with asthma. We assessed the hospital care use and costs associated with asthma severity using the UK Biobank cohort and linked healthcare data. Adult participants with asthma at recruitment were classified using their prescription data into mild and moderate-to-severe asthma and matched separately to asthma-free controls by age, sex, ethnicity and location. The associations of asthma, by severity, with the annual number of all-cause hospital admissions, days spent in hospital and hospital costs were estimated over a 10-year follow-up period using three specifications of negative binomial regression models that differed according to the sociodemographic and clinical characteristics adjusted for. Of the 25 031 participants with active asthma, 80% had mild asthma and 20% had moderate-to-severe asthma. Compared with participants with mild asthma, those with moderate-to-severe asthma were on average 2.7 years older, more likely to be current (13.7% vs 10.4%) or previous (40.2% vs 35.2%) smokers, to have a higher body mass index (BMI), and to be suffering from a variety of comorbid diseases. Following adjustments for age, sex, ethnicity and location, people with mild asthma experienced on average 36% more admissions (95% CI 28% to 40%), 43% more days in hospital (95% CI 35% to 51%) and 36% higher hospital costs (95% CI 31% to 41%) annually than asthma-free individuals, while people with moderate-to-severe asthma experienced excesses of 93% (95% CI 81% to 107%), 142% (95% CI 124% to 162%) and 98% (95% CI 88% to 108%), respectively. Further adjustments for socioeconomic deprivation, smoking status, BMI and comorbidities resulted in smaller though still highly significant positive associations, graded by severity, between asthma and hospital use and costs. Strong graded associations are reported between asthma severity and the extent of hospital use and costs in the UK. These findings could inform future assessments of the value of asthma management interventions.


Diagnosing malaria infected cells at the single cell level using focal plane array Fourier transform infrared imaging spectroscopy.
New methods are needed to rapidly identify malaria parasites in blood smears. The coupling of a Focal Plane Array (FPA) infrared microscope system to a synchrotron light source at IRENI enables rapid molecular imaging at high spatial resolution. The technique, in combination with hyper-spectral processing, enables imaging and diagnosis of early stage malaria parasites at the single cell level in a blood smear. The method relies on the detection of distinct lipid signatures associated with the different stages of the malaria parasite and utilises resonant Mie extended multiplicative scatter correction to pre-process the spectra followed by full bandwidth image deconvolution to resolve the single cells. This work demonstrates the potential of focal plane technology to diagnose single cells in a blood smear. Brighter laboratory based infrared sources, optical refinements and higher sensitive detectors will soon see the emergence of focal plane array imaging in the clinical environment.


Adaphostin-induced oxidative stress overcomes BCR/ABL mutation-dependent and -independent imatinib resistance.
The BCR/ABL kinase has been targeted for the treatment of chronic myelogenous leukemia (CML) by imatinib mesylate. While imatinib has been extremely effective for chronic phase CML, blast crisis CML and Ph+ acute lymphoblastic leukemia (ALL) are often resistant. In particular, mutation of the T315 residue in the bcr/abl activation loop renders cells highly resistant to imatinib and to second-generation kinase inhibitors such as BMS-354825 or AMN107. Adaphostin is a tyrphostin that was originally intended to inhibit the BCR/ABL kinase by competing with its peptide substrates. Recent findings have in addition implicated reactive oxygen species (ROS) in the cytotoxic mechanism of adaphostin. In view of this unique mode of action, we examined the effects of adaphostin on numerous imatinib-resistant leukemia models, including imatinib-resistant CML and Ph+ ALL cell lines, cells harboring point mutations in BCR/ABL, and specimens from imatinib-resistant CML patients, using assays for intracellular ROS, apoptosis, and clonogenicity. Every model of imatinib resistance examined remained fully sensitive to adaphostin-induced cell death. Collectively, these data suggest that ROS generation by adaphostin overcomes even the most potent imatinib resistance in CML and Ph+ ALL.


Awakening after cardiac arrest and post resuscitation hypothermia: are we pulling the plug too early?
Time to awakening after out-of-hospital cardiac arrest (OHCA) and post-resuscitation therapeutic hypothermia (TH) varies widely. We examined the time interval from when comatose OHCA patients were rewarmed to 37°C to when they showed definitive signs of neurological recovery and tried to identify potential predictors of awakening. With IRB approval, a retrospective case study was performed in OHCA patients who were comatose upon presentation to a community hospital during 2006-2010. They were treated with TH (target of 33°C) for 24h, rewarmed, and discharged alive. Comatose patients were generally treated medically after TH for at least 48h before any decision to withdraw supportive care was made. Pre-hospital TH was not used. Data are expressed as medians and interquartile range. The 89 patients treated with TH in this analysis were divided into three groups based upon the time between rewarming to 37°C and regaining consciousness. The 69 patients that regained consciousness in ≤48h after rewarming were termed "early-awakeners". Ten patients regained consciousness 48-72h after rewarming and were termed "intermediate-awakeners". Ten patients remained comatose and apneic >72h after rewarming but eventually regained consciousness; they were termed "late-awakeners". The ages for the early, intermediate and late awakeners were 56 [49,65], 62 [48,74], and 58 [55,65] years, respectively. Nearly 67% were male. Following rewarming, the time required to regain consciousness for the early, intermediate and late awakeners was 9 [2,18] (range 0-47), 60.5 [56,64.5] (range 49-71), and 126 [104,151]h (range 73-259), respectively. Within 90 days of hospital admission, favorable neurological function based on a Cerebral Performance Category (CPC) score of 1 or 2 was reported in 67/69 early, 10/10 intermediate, and 8/10 late awakeners. Following OHCA and TH, arbitrary withdrawal of life support <48h after rewarming may prematurely terminate life in many patients with the potential for full neurological recovery. Additional clinical markers that correlate with late awakening are needed to better determine when withdrawal of support is appropriate in OHCA patients who remain comatose >48h after rewarming.


Liquid crystal polymers with motile surfaces.
In analogy with developments in soft robotics it is anticipated that soft robotic functions at surfaces of objects may have a large impact on human life with respect to comfort, health, medical care and energy. In this review, we demonstrate the possibilities and versatilities of liquid crystal networks and elastomers being explored for soft robotics, with an emphasis on motile surface properties, such as topographical dynamics. Typically the surfaces reversibly transfer from a flat state to a pre-designed corrugated state under various stimuli. But also reversible conversion between different corrugated states is feasible. Generally, the driving triggers are heat, light, electricity or contact with pH changing media. Also, the macroscopic effects of those dynamic topographies, such as altering the friction, wettability and/or performing work are illustrated. The review concludes with the existing challenges as well as outlook opportunities.


Early endoscope-assisted hematoma evacuation in patients with supratentorial intracerebral hemorrhage: case selection, surgical technique, and long-term results.
Currently, the effectiveness of minimally invasive evacuation of intracerebral hemorrhage (ICH) utilizing the endoscopic method is uncertain and the technique is considered investigational. The authors analyzed their experience with this method in terms of case selection, surgical technique, and long-term results. The authors performed a retrospective analysis of the clinical and radiographic data obtained in 68 patients treated with endoscope-assisted ICH evacuation. Rebleeding, morbidity, and mortality were recorded as primary end points. Hematoma evacuation rate was calculated by comparing the pre- and postoperative CT scans. Glasgow Coma Scale scores and scores on the extended Glasgow Outcome Scale (GOSE) were recorded at the 6-month postoperative follow-up. The technical aspect of this report explains details of the procedure, the instruments that are used, the methods for hemostasis, and the role of hemostatic agents in the management of intraoperative hemorrhage. The pertinent literature was reviewed and summarized. All surgeries were performed within 12 hours of ictus, and 84% of the surgeries were performed within 4 hours. The mortality rate was 5.9%, and surgery-related morbidity occurred in 3 cases (4.4%). The hematoma evacuation rate was 93% overall-96% in the putaminal group, 86% in the thalamic group, and 98% in the subcortical group. The rebleeding rate was 1.5%. The mean operative time was 85 minutes, and the average blood loss was 56 ml. The mean GOSE score was 4.9 at 6-month follow-up. The authors acknowledge the limitations of these preliminary results in a small number of patients. The data suggest that early endoscope-assisted ICH evacuation is safe and effective in the management of supratentorial ICH. The rebleeding, morbidity, and mortality rates are low compared with rates reported in the literature for the traditional craniotomy method. This study also showed that early and complete evacuation of ICH may lead to improved outcomes in selected patients. However, the safety and efficacy of endoscope-assisted ICH evacuation should be further investigated in a large, prospective, randomized trial.


Fate of selected pharmaceutically active compounds in the integrated fixed film activated sludge process.
The potential for integrated fixed film activated sludge (IFAS) processes to achieve enhanced transformation of pharmaceuticals relative to conventional activated sludge (CAS) processes was assessed. Previous studies have focused on direct comparisons of parallel reactors with and without fixed film carriers and little information is available on the impacts of how varying operating parameters impact the differences in observed pharmaceutical compound (PC) transformation capabilities between CAS reactors and those equipped with both an activated sludge (AS) and fixed film carriers. The testing was carried out using bench scale sequencing batch reactors fed with authentic municipal wastewater and operated at selected combinations of temperature and solids retention time (SRT). PC transformation efficiencies were assessed in a 22 factorial design that employed the IFAS and CAS processes, operated in parallel under identical process conditions. Nitrification rate testing that was conducted to obtain insight into the biomass activity demonstrated that IFAS consistently had improved nitrification kinetics despite lower mixed liquor volatile suspended solids levels thereby demonstrating the contribution of the biofilm to nitrification. Increased transformation of atenolol (ATEN; ranging from 10-60%) and trimethoprim (TRIM; ranging from 30-50%) in the IFAS equipped reactors relative to their respective activated sludge (AS) controls was observed under all experimental conditions. Negligible transformation of carbamazepine was observed in both reactors under all conditions investigated. More than 99% of acetaminophen was transformed in both configurations under all conditions. There was no correspondence between nitrification activity and TRIM removal in the control AS while conditions that stimulated nitrification in the control AS also resulted in enhanced removal of ATEN. The results of this study indicate that the integration of biofilms in AS processes enhances transformation of some PCs.


The rapid and direct determination of ATPase activity by ion exchange chromatography and the application to the activity of heat shock protein-90.
Adenosine nucleotides are involved as substrates or co-factors in several biochemical reactions, catalyzed by enzymes, which modulate energy production, signal transduction and cell proliferation. We here report the development and optimization of an ion exchange liquid chromatography (LC) method for the determination of ATP, ADP and AMP. This method is specifically aimed at the determination of the ATP-ase activity of human heat shock protein 90 (Hsp90), a molecular chaperone that has emerged as target enzyme in cancer therapy. Separation of the three nucleotides was achieved in a 15-min run by using a disk shaped monolithic ethylene diamine stationary phase of small dimensions (2mm×6mm i.d.), under a three-solvent gradient elution mode and UV detection at 256nm. The described direct LC method resulted highly specific as a consequence of the baseline separation of the three adenosine nucleotides and could be applied to the determination of the enzymatic activity of ADP/ATP generating or consuming enzymes (such as kinases). Furthermore, comparison of the LOD and LOQ values of the LC method with those obtained with the malachite green assay, which is one of the most used indirect screening methodologies for ATP-ase activity, showed that the LC method has a similar range of application without presenting the drawbacks related to contamination by inorganic phosphate ions and glycerol, which are present in Hsp90 commercial samples.


L-2-Oxothiazolidine-4-carboxylic acid reverses endothelial dysfunction in patients with coronary artery disease.
The effective action of endothelium-derived nitric oxide (EDNO) is impaired in patients with atherosclerosis. This impairment has been attributed in part to increased vascular oxidative stress. EDNO action is improved by administration of ascorbic acid, a water-soluble antioxidant. Ascorbic acid is a potent free-radical scavenger in plasma, and also regulates intracellular redox state in part by sparing cellular glutathione. We specifically investigated the role of intracellular redox state in EDNO action by examining the effect of L-2-oxo-4-thiazolidine carboxylate (OTC) on EDNO-dependent, flow-mediated dilation in a randomized double-blind placebo-controlled study of patients with angiographically proven coronary artery disease. OTC augments intracellular glutathione by providing substrate cysteine for glutathione synthesis. Brachial artery flow-mediated dilation was examined with high-resolution ultrasound before and after oral administration of 4.5 g of OTC or placebo in 48 subjects with angiographically documented coronary artery disease. Placebo treatment produced no change in flow-mediated dilation (7.0+/-3.9% vs. 7.2+/-3.7%), whereas OTC treatment was associated with a significant improvement in flow-mediated dilation (6.6+/-4.4% vs. 11.0+/-6.3%; P = 0.005). OTC had no effect on arterial dilation to nitroglycerin, systemic blood pressure, heart rate, or reactive hyperemia. These data suggest that augmenting cellular glutathione levels improves EDNO action in human atherosclerosis. Cellular redox state may be an important regulator of EDNO action, and is a potential target for therapy in patients with coronary artery disease.


Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB).
Advantages to combining childhood vaccines include reducing the number of visits, injections and patient discomfort, increasing compliance and optimising prevention. The World Health Organization (WHO) recommends that routine infant immunisation programmes include a vaccination against Haemophilus influenzae (H. influenzae) type B (HIB) in the combined diphtheria-tetanus-pertussis (DTP)-hepatitis B virus (HBV) vaccination. The effectiveness and safety of the combined vaccine should be carefully and systematically assessed to ensure its acceptability by the community. To compare the effectiveness of combined DTP-HBV-HIB vaccines versus combined DTP-HBV and separate HIB vaccinations. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (January 1966 to week 1, November 2011), EMBASE (January 1990 to November 2011) and www.clinicaltrials.gov (up to April 2011). Randomised controlled trials (RCTs) or quasi-RCTs comparing vaccination with any combined DTP-HBV-HIB vaccine, with or without three types of inactivated polio virus (IPV) or concomitant oral polio vaccine (OPV) in any dose, preparation or time schedule, compared with separate vaccines or placebo, administered to infants up to two years old. Two review authors independently inspected references identified by the searches and evaluated them against the inclusion criteria, extracted data and assessed the methodological quality of included trials. Data for the primary outcome (prevention of disease) were lacking. We performed a meta-analysis to pool the results of 20 studies with 5874 participants in an immunogenicity analysis and 5232 participants in the reactogenicity analysis. There were no data on clinical outcomes for the primary outcome (prevention of disease) and all studies used immunogenicity and reactogenicity (adverse events). The number of vaccine doses differed significantly between the studies. Heterogeneous interventions, study location, healthcare environment and combining research across disparate geographical locations, may have lead to bias. The risk of bias was unclear across most of the included studies. Comparisons found little heterogeneity. In two immunological responses the combined vaccine achieved lower responses than the separate vaccines for HIB and tetanus. No significant differences in immunogenicity were found for pertussis, diphtheria, polio and hepatitis B. Serious adverse events were comparable with mainly hospitalisation and acute bronchiolitis cases. Minor adverse events such as pain and redness were more common in children given the combined vaccine. Overall, the direction shown by the results is in favour of the DTPw (diptheria-tetanus-whole cell pertussis)-HBV-HIB vaccine rather than the DTPa (diptheria-tetanus-acellular pertussis)-HBV-HIB vaccine when compared to the separate vaccines (size of effect: risk ratio (RR) 1.43; 95% confidence interval (CI) 0.98 to 2.10, for 5269 participants). We could not conclude that the immune responses elicited by the combined vaccine were different from or equivalent to the separate vaccines. There was significantly less immunological response for HIB and tetanus and more local reactions in the combined injections. However, these differences rely mostly on one study each. Studies did not use an intention-to-treat (ITT) analysis and we were uncertain about the risk of bias in many of the studies. These results are therefore inconclusive. Studies addressing clinical end points whenever possible, using correct methodology and a large enough sample size should be conducted.


What is the strength of a mask in visual metacontrast masking?
After more than a century of research, the mechanisms underlying visual masking are still hotly debated. One key characteristic of masking is that variations in the stimulus onset asynchrony (SOA) between the target and the mask can lead to either monotonic reductions in the effect of the mask on the target (A-type masking) or an increase in masking for intermediate SOAs and then a decrease in masking for longer SOAs (B-type masking). Past experimental and theoretical work suggested that the type of the masking function depends on the strength of the mask relative to the target. Usually, mask strength is related to energy (stimulus intensity x duration). Here, we show that the overall spatial layout of the mask is a much stronger factor than classical energy to explain the type of masking function.


Growth-supporting activity for Legionella pneumophila in tap water cultures and implication of hartmannellid amoebae as growth factors.
Photosynthetic cyanobacteria, heterotrophic bacteria, free-living amoebae, and ciliated protozoa may support growth of Legionella pneumophila. Studies were done with two tap water cultures (WS1 and WS2) containing L. pneumophila and associated microbiota to characterize growth-supporting activity and assess the relative importance of the microbiota in supporting multiplication of L. pneumophila. The water cultures were incubated in the dark at 35 degrees C. The growth-supporting factor(s) was separated from each culture by filtration through 1-micron-pore-size membrane filters. The retentate was then suspended in sterile tap water. Multiplication of L. pneumophila occurred when both the retentate suspension and the filtrate from either culture were inoculated into sterile tap water. L. pneumophila did not multiply in tap water inoculated with only the filtrate, even though filtration did not reduce the concentration of L. pneumophila or heterotrophic bacteria in either culture. Growth-supporting activity of the retentate suspension from WS1 was inactivated at 60 degrees C but unaffected at 0, 25, and 45 degrees C after 30-min incubations. Filtration experiments indicated that the growth-supporting factor(s) in WS1 was 2 to 5 micron in diameter. Ciliated protozoa were not detected in either culture. Hartmannellid amoebae were conclusively demonstrated in WS2 but not in WS1. L. pneumophila multiplied in tap water inoculated with the amoebae (10(3)/ml) and the 1-micron filtrate of WS2. No multiplication occurred in tap water inoculated with the filtrate only. Growth-supporting activity for L. pneumophila may be present in plumbing systems; hartmannellid amoebae appear to be important determinants of multiplication of L. pneumophila in some tap water cultures.


Contactless conductivity detector for microchip capillary electrophoresis.
A microfabricated electrophoresis chip with an integrated contactless conductivity detection system is described. The new contactless conductivity microchip detector is based on placing two planar sensing aluminum film electrodes on the outer side of a poly(methyl methacrylate) (PMMA) microchip (without contacting the solution) and measuring the impedance of the solution in the separation channel. The contactless route obviates problems (e.g., fouling, unwanted reactions) associated with the electrode-solution contact, offers isolation of the detection system from high separation fields, does not compromise the separation efficiency, and greatly simplifies the detector fabrication. Relevant experimental variables, such as the frequency and amplitude of the applied ac voltage or the separation voltage, were examined and optimized. The detector performance was illustrated by the separation of potassium, sodium, barium, and lithium cations and the chloride, sulfate, fluoride, acetate, and phosphate anions. The response was linear (over the 20 microM-7 mM range) and reproducible (RSD = 3.4-4.9%; n = 10), with detection limits of 2.8 and 6.4 microM (for potassium and chloride, respectively). The advantages associated with the contactless conductivity detection, along with the low cost of the integrated PMMA chip/detection system, should enhance the power and scope of microfluidic analytical devices.


Gestational Age and the Cord Blood Lipidomic Profile in Late Preterm and Term Infants.
Lipid metabolism is vital to fetal development and cardiometabolic health and the final weeks of gestation are known to be a time of intense metabolic activity. New techniques such as lipidomics allow investigation of a complex lipidomic profile in infants. This research aimed to (1) describe variations in lipidomic profile in late preterm and term infants and (2) compare variations to an adult lipidomic profile with known clinical implications. The Barwon Infant Study (n = 1,074) is a population-derived pre-birth cohort study. The lipidomic profile of cord blood was measured by liquid chromatography-mass spectrometry in 225 participants and the association between gestational age and lipidomic profile was investigated using multiple linear regression adjusting for birth weight, exposure to labour, and infant sex. Patterns of association with gestational age across the lipidomic profile were compared with associations between body mass index (BMI) and lipidomic profile observed among adults in the San Antonia Family Heart Study (n = 994). Gestational age was independently associated with the abundances of 39% of lipid species. Variations in the lipidomic profile with increasing gestational age were comparable to some variations observed in association with increasing BMI among adults. There is a strong relationship between gestational age and the cord blood lipid profile at birth, providing further evidence for the importance of metabolic changes of late gestation. A number of the variations in the lipid profile with increasing gestational age are analogous to differences observed in the adult lipid profile with an increasing BMI.


Driving the usage of tuberculosis diagnostic data through capacity building in low- and middle-income countries.
Connectivity platforms collect a wealth of data from connected GeneXpert instruments, with the potential to provide valuable insights into the burden of disease and effectiveness of tuberculosis programmes. The challenge faced by many countries is a lack of training, analytical skills, and resources required to understand and translate this data into patient management and programme improvement. We describe a novel training programme, the tuberculosis Data Fellowship, designed to build capacity in low- and middle- income countries for tuberculosis data analytics. The programme consisted of classroom and remote training plus mentorship over a 12-month period. The focus was on skills development in Tableau software, followed by training in exploration, analysis, and interpretation of GeneXpert tuberculosis data across five key programme areas: patient services, programme monitoring, quality of testing, inventory management, and disease burden. The programme was piloted in six countries (Bangladesh, Ethiopia, Ghana, Malawi, Mozambique) in July 2018 and Nigeria in September 2018; 20 participants completed the training. A number of key outputs have been achieved, such as improved instrument utilisation rates, decreased error rates, and improved instrument management. The training programme empowers local tuberculosis programme staff to discover and fix critical inefficiencies, provides high-level technical and operational support to the tuberculosis programme, and provides a platform for continued sharing of insights and best practices between countries. It supports the notion that connectivity can increase efficiencies and clinical benefits with better data for decision making, if coupled with commensurate capacity building in data analysis and interpretation.


Activation of Human Peroxisome Proliferator-Activated Nuclear Receptors (PPARγ1) by Semi-Volatile Compounds (SVOCs) and Chemical Mixtures in Indoor Dust.
Recently, we reported that several semi-volatile compounds (SVOCs) were competitive ligands for human peroxisome proliferator-activated nuclear receptor gamma (PPARγ1). We also observed significant binding from chemicals extracted from house dust at a concentration of 3 mg dust/mL in the dosing medium. To follow up on this study, a commercially available reporter gene assay (GeneBLAzer PPARγ1 non-DA Assay, Invitrogen) was used to investigate the PPARγ1 activation by 30 common SVOCs (e.g., brominated flame retardants, organophosphates, and phthalates) and in house dust extracts. Twenty-eight SVOCs or their metabolites were either confirmed or for the first time were found to be weak or moderate PPARγ1 agonists. We also observed activation in 15 of 25 dust extracts examined. In some cases, activation was as high as 50% of the activation of the positive control (rosiglitazone). Furthermore, there was a significant and positive correlation (r = 0.7, p < 0.003) between data collected from this reporter assay and our previous ligand binding assay tested on the same dust extracts. Our results suggest that many SVOCs ubiquitous in house dust, or their metabolites, are possible PPARγ1 agonists. Also, chemical mixtures present in house dust at environmentally relevant levels can activate human PPARγ1 in a transfected cell culture system, and further research is needed to identify the primary chemical(s) driving this activity.


Non-Fouling Biodegradable Poly(ϵ-caprolactone) Nanofibers for Tissue Engineering.
Poly(ϵ-caprolactone) (PCL) nanofibers are very attractive materials for tissue engineering (TE) due to their degradability and structural similarity to the extracellular matrix (ECM). However, upon exposure to biological media, their surface is rapidly fouled by proteins and cells, which may lead to inflammation and foreign body reaction. In this study, an approach for the modification of PCL nanofibers to prevent protein fouling from biological fluids and subsequent cell adhesion is introduced. A biomimetic polydopamine (PDA) layer was deposited on the surface of the PCL nanofibers and four types of antifouling polymer brushes were grown by surface-initiated atom transfer radical polymerization (SI-ATRP) from initiator moieties covalently attached to the PDA layer. Cell adhesion was assessed with mouse embryonic fibroblasts (MEFs). MEFs rapidly adhered and formed cell-matrix adhesions (CMAs) with PCL and PCL-PDA nanofibers. Importantly, the nanofibers modified with antifouling polymer brushes were able to suppress non-specific protein adsorption and thereby cell adhesion.


Comparison of the characteristics, morbidity, and mortality of COVID-19 and seasonal influenza: a nationwide, population-based retrospective cohort study.
To date, influenza epidemics have been considered suitable for use as a model for the COVID-19 epidemic, given that they are respiratory diseases with similar modes of transmission. However, data directly comparing the two diseases are scarce. We did a nationwide retrospective cohort study using the French national administrative database (PMSI), which includes discharge summaries for all hospital admissions in France. All patients hospitalised for COVID-19 from March 1 to April 30, 2020, and all patients hospitalised for influenza between Dec 1, 2018, and Feb 28, 2019, were included. The diagnosis of COVID-19 (International Classification of Diseases [10th edition] codes U07.10, U07.11, U07.12, U07.14, or U07.15) or influenza (J09, J10, or J11) comprised primary, related, or associated diagnosis. Comparisons of risk factors, clinical characteristics, and outcomes between patients hospitalised for COVID-19 and influenza were done, with data also stratified by age group. 89 530 patients with COVID-19 and 45 819 patients with influenza were hospitalised in France during the respective study periods. The median age of patients was 68 years (IQR 52-82) for COVID-19 and 71 years (34-84) for influenza. Patients with COVID-19 were more frequently obese or overweight, and more frequently had diabetes, hypertension, and dyslipidaemia than patients with influenza, whereas those with influenza more frequently had heart failure, chronic respiratory disease, cirrhosis, and deficiency anaemia. Patients admitted to hospital with COVID-19 more frequently developed acute respiratory failure, pulmonary embolism, septic shock, or haemorrhagic stroke than patients with influenza, but less frequently developed myocardial infarction or atrial fibrillation. In-hospital mortality was higher in patients with COVID-19 than in patients with influenza (15 104 [16·9%] of 89 530 vs 2640 [5·8%] of 45 819), with a relative risk of death of 2·9 (95% CI 2·8-3·0) and an age-standardised mortality ratio of 2·82. Of the patients hospitalised, the proportion of paediatric patients (<18 years) was smaller for COVID-19 than for influenza (1227 [1·4%] vs 8942 [19·5%]), but a larger proportion of patients younger than 5 years needed intensive care support for COVID-19 than for influenza (14 [2·3%] of 613 vs 65 [0·9%] of 6973). In adolescents (11-17 years), the in-hospital mortality was ten-times higher for COVID-19 than for influenza (five [1·1% of 458 vs one [0·1%] of 804), and patients with COVID-19 were more frequently obese or overweight. The presentation of patients with COVID-19 and seasonal influenza requiring hospitalisation differs considerably. Severe acute respiratory syndrome coronavirus 2 is likely to have a higher potential for respiratory pathogenicity, leading to more respiratory complications and to higher mortality. In children, although the rate of hospitalisation for COVID-19 appears to be lower than for influenza, in-hospital mortality is higher; however, low patient numbers limit this finding. These findings highlight the importance of appropriate preventive measures for COVID-19, as well as the need for a specific vaccine and treatment. French National Research Agency.


Components of the hematopoietic compartments in tumor stroma and tumor-bearing mice.
Solid tumors are composed of cancerous cells and non-cancerous stroma. A better understanding of the tumor stroma could lead to new therapeutic applications. However, the exact compositions and functions of the tumor stroma are still largely unknown. Here, using a Lewis lung carcinoma implantation mouse model, we examined the hematopoietic compartments in tumor stroma and tumor-bearing mice. Different lineages of differentiated hematopoietic cells existed in tumor stroma with the percentage of myeloid cells increasing and the percentage of lymphoid and erythroid cells decreasing over time. Using bone marrow reconstitution analysis, we showed that the tumor stroma also contained functional hematopoietic stem cells. All hematopoietic cells in the tumor stroma originated from bone marrow. In the bone marrow and peripheral blood of tumor-bearing mice, myeloid populations increased and lymphoid and erythroid populations decreased and numbers of hematopoietic stem cells markedly increased with time. To investigate the function of hematopoietic cells in tumor stroma, we co-implanted various types of hematopoietic cells with cancer cells. We found that total hematopoietic cells in the tumor stroma promoted tumor development. Furthermore, the growth of the primary implanted Lewis lung carcinomas and their metastasis were significantly decreased in mice reconstituted with IGF type I receptor-deficient hematopoietic stem cells, indicating that IGF signaling in the hematopoietic tumor stroma supports tumor outgrowth. These results reveal that hematopoietic cells in the tumor stroma regulate tumor development and that tumor progression significantly alters the host hematopoietic compartment.


High efficiency, resonantly diode pumped, double-clad, Er:YAG-core, waveguide laser.
We report on the highly efficient, resonantly diode-pumped Er:YAG-core, double-clad, all-crystalline eye-safe waveguide laser. A 500 × 500 μm Er(3+)(1%):YAG single-crystalline core with an ultra low numerical aperture (NA) of ~0.02 was surrounded by a 700 × 700 μm undoped single-crystalline YAG cladding. The entire Er:YAG/YAG core/clad structure was over-clad by transparent magnesium aluminum spinel (MgAl(2)O(4)) ceramic. The waveguide was continuously (CW) clad-pumped by a spectrally-narrowed, fiber-coupled InGaAsP/InP laser diode module at ~1532 nm. We achieved 25.4 W of output power at 1645 nm with a beam quality of M2 ~2.6. The achieved 56.6% slope efficiency with respect to the absorbed pump was derived by factoring out scattering loss of the pump light in the inner cladding. With a wavelength-selective cavity, the waveguide laser delivered ~8 W of output power at 1616.6 nm. To the best of our knowledge, it is the first reported laser experiment with a crystalline Er(3+):YAG-core and a truly double-clad crystalline waveguide structure.


Flow regulation of vascular tone. Its sensitivity to changes in sodium and calcium.
Our hypothesis is that flow-through hydraulic drag or shear stresses the extracellular elements in the vascular wall. When the endothelium is intact, this results in the release of endothelium-derived relaxing factor and other substances, eg, prostanoids, from the endothelium. As in some reports, after inhibition of nitric oxide synthase, flow effects are still observed although diminished; the shear effect is extended mechanically to the subendothelial tissues. Shear causes conformational changes in the glycosaminoglycans by extending them from a randomly coiled aggregated state to a more elongated condition along the line of flow. This elongation and the consequent exposure of an increased number of cationic binding sites on the glycosaminoglycans lead to changes in sodium binding. The extent of the conformational change is influenced by the concentration of calcium, an ion that not only competes with sodium at specific binding sites but possibly cross-links the polysaccharide chains of the protein saccharide complex. These complex interactions might account for the cooperative, nonantagonistic interaction of sodium and calcium over the physiological concentration range. Sodium binding is influenced by changes in external sodium concentration, and this presumably accounts for the sodium sensitivity of the flow response. Although glycosaminoglycans are possibly the most studied in this regard, they are not the only candidates. Other extracellular proteins, either in conjunction with glycosaminoglycans or independently, might be involved. By mechanisms not yet identified, these changes are signaled to the cell. We have proposed that in part, at any rate, this may be related to the sodium concentration gradient.


Mechanotransduction of ultrasound is frequency dependent below the cavitation threshold.
This study provides evidence that low-intensity ultrasound directly affects nuclear processes, and the magnitude of the effect varies with frequency. In particular, we show that the transcriptional induction of first load-inducible genes, which is independent of new protein synthesis, is frequency dependent. Bovine chondrocytes were exposed to low-intensity (below the cavitational threshold) ultrasound at 2, 5 and 8 MHz. Ultrasound elevated the expression of early response genes c-Fos, c-Jun and c-Myc, maximized at 5 MHz. The phosphorylated ERK inhibitor PD98059 abrogated any increase in c-series gene expression, suggesting that signaling occurs via the MAPPK/ERK pathway. However, phosphorylated ERK levels did not change with ultrasound frequency, indicating that processes downstream of ERK phosphorylation (such as nuclear transport and chromatin reorganization) respond to ultrasound with frequency dependence. A quantitative, biphasic mathematical model based on Biot theory predicted that cytoplasmic and nuclear stress is maximized at 5.2 ± 0.8 MHz for a chondrocyte, confirming experimental measurements.


Reconstruction of fluorescence/bioluminescence sources in biological medium with spatial filter.
We propose a new method for reconstruction of emitting source distributions by use of a spatial filter and a successive updating process of the forward model for fluorescence/bioluminescence diffuse optical tomography. The spatial filter transforms a set of the measurement data to a single source strength at a position of interest, and the forward model is updated by use of the estimated source strengths. This updating process ignores the dispensable source positions from reconstruction according to the reconstructed source distribution, and the spatial resolution of the reconstructed image is improved. The estimated sources are also used for the reduction of artifacts induced by noises based on the singular value decomposition. Some numerical experiments show the advantages of the proposed method by comparing the present results with those obtained by the conventional methods of the least squares method nd Algebraic Reconstruction Technique. Finally the criteria for practical use of the method are quantitatively presented by the simulations for 2D and 3D geometries.


The longitudinal impact of patient navigation on equity in colorectal cancer screening in a large primary care network.
The long-term effects of interventions to improve colorectal (CRC) screening in vulnerable populations are uncertain. The authors evaluated the impact of patient navigation (PN) on the equity of CRC prevention over a 5-year period. A culturally tailored CRC screening PN program was implemented in 1 community health center (CHC) in 2007. In a primary care network, CRC screening rates from 2006 to 2010 among eligible patients from the CHC with PN were compared with the rates from other practices without PN. Multivariable logistic regression models for repeated measures were used to assess differences over time. Differences in CRC screening rates diminished among patients at the CHC with PN and at other practices between 2006 (49.2% vs 62.5%, respectively; P < .001) and 2010 (69.2% vs 73.6%, respectively; P < .001). The adjusted rate of increase over time was higher at the CHC versus other practices (5% vs 3.4% per year; P < .001). Among Latino patients at the CHC compared with other practices, lower CRC screening rates in 2006 (47.5% vs 52.1%, respectively; P = .02) were higher by 2010 (73.5% vs 67.3%, respectively; P < .001). Similar CRC screening rates among non-English speakers at the CHC and at other practices in 2006 (44.3% vs 44.7%, respectively; P = .79) were higher at the CHC by 2010 (70.6% vs 58.6%, respectively; P < .001). Adjusted screening rates increased more over time for Latino and non-English speakers at the CHC compared with other practices (both P < .001). A PN program increased CRC screening rates in a CHC and improved equity in vulnerable patients. Long-term funding of PN programs has the potential to reduce cancer screening disparities.


Association between Contrast Sensitivity and Reading with Macular Pathology.
Comparison between the role of spatial and temporal contrast sensitivities in the association with reading may provide insight into how visual tasks (such as reading) are related to primary optical or neural (or both) effects. More insight into primary visual factors influencing reading is important for understanding reading problems. The aim of this study was to gain insight into the association between optical and neural components of contrast sensitivity (CS), operationalized as spatial CS (optical and neural) or temporal CS (solely neural), and reading speed in a clinical sample of participants with macular pathologies. The precision and agreement were also investigated. The Mars test and temporal CS implementation of the C-Quant device were used to measure spatial CS and temporal CS, respectively. Tests were performed with 47 participants: mean age, 77 years (range, 52 to 92 years). Associations were investigated with correlations and linear regression models. Precision was defined by coefficients of repeatability. The 95% limits of agreement between spatial CS and temporal CS values were assessed. Reading speed correlated with both spatial CS (r = 0.35, P = .015) and temporal CS (r = 0.66, P < .001). After correction for visual acuity, central loss, and education level, the association between temporal CS and reading speed was not significant anymore. The coefficients of repeatability and reproducibility were 0.20 and 0.28 log unit (spatial CS) and 0.33 and 0.35 log unit (temporal CS), respectively. The values for temporal CS were 0.08 and 0.13 log unit higher than those for spatial CS. For spatial CS and temporal CS, moderate to strong correlations were found, respectively, with reading speed in patients with maculopathies. The stronger association between temporal CS and reading speed is suggested to reflect a high sensitivity for neural integrity of temporal CS. The differences in coefficients of repeatability and reproducibility could be explained by the psychometrical differences between methods.


The design of a five-degree-of-freedom powered orthosis for the upper limb.
In response to the need for a sophisticated powered upper-limb orthosis for use by people with disabilities and/or limb weakness or injury, the MULOS (motorized upper-limb orthotic system) has been developed. This is a five-degree-of-freedom electrically powered device having three degrees of freedom at the shoulder, one at the elbow and one to provide pronation/supination. The shoulder mechanism consists of a serial linkage having an equivalent centre of rotation close to that of the anatomical shoulder; this is a self-contained module in which power transmission is provided by tensioned cables. The elbow and pronation/supination modules are also self-contained. The system has been designed to operate under three modes of control: 1. As an assistive robot attached directly to the arm to provide controlled movements for people with severe disability. In this case, it can be operated by a variety of control interfaces, including a specially designed five-degree-of-freedom joystick. 2. Continuous passive motion for the therapy of joints after injury. The trajectory of the joints is selected by 'walk-through' programming and can be replayed for a given number of cycles at a chosen speed. 3. As an exercise device to provide strengthening exercises for elderly people or those recovering from injury or surgery. This mode has not been fully implemented at this stage. In assistive mode, prototype testing has demonstrated that the system can provide the movements required for a range of simple tasks and, in continuous passive motion (CPM) mode, the programming system has been successfully implemented. Great attention has been paid to all aspects of safety. Future work is required to identify problems of operation, and to develop new control interfaces.


Effects of deletion and duplication in a patient with a 46,XX,der(7)t(7;17)(q36;p13)mat karyotype.
Exact breakpoint determination by DNA-array has dramatically improved the analysis of genotype-phenotype correlations in chromosome aberrations. It allows a more exact definition of the most relevant genes and particularly their isolated or combined impact on the phenotype in an unbalanced state. Here, we report on a 21-year-old female with severe growth retardation, severe intellectual disability, hypoplasia of the corpus callosum, unilateral sacral hypoplasia, tethered cord, various minor facial dysmorphisms, and a telomeric deletion of about 4.4 Mb in 7q36.2->qter combined with a telomeric duplication of about 8 Mb in 17pter->p13.1. Fine mapping was achieved with the Illumina® Infinium HumanOmni1-Quad v1.0 BeadChip. Most of the major clinical features correspond to the well-known effects of haploinsufficiency of the MNX1 and SHH genes. In addition, review of the literature suggests an association of the 17p duplication with specific facial dysmorphic features and skeletal anomalies, but also an aggravating effect of the duplication-deletion for severe growth retardation as well as sacral and corpus callosum hypoplasia by one or more genes located on the proximal half of the segmental 17p duplication could be elaborated by comparison with other patients from the literature carrying either the deletion or the duplication found in our patient.


Analytic validation and clinical evaluation of the STA LIATEST immunoturbidimetric D-dimer assay for the diagnosis of disseminated intravascular coagulation.
To evaluate the diagnostic performance of a quantitative, immunoturbidimetric D-dimer assay and compare it with other components of the proposed International Society on Thrombosis and Haemostasis disseminated intravascular coagulation (DIC) diagnostic algorithm, we retrospectively analyzed the D-dimer, platelet count, prothrombin time, and fibrinogen results for all eligible hospitalized patients (n = 241) who had a D-dimer assay ordered during a 12-month period. A receiver operating characteristic (ROC) curve constructed from the maximum D-dimer measurement for all patients was significant (P < .001) with an area under the curve (AUC) of 0.94. The ROC curves of the other tests were each significant (P < .001), but the AUCs of the prothrombin time (0.74), fibrinogen level (0.70), and platelet count (0.67) did not approach that of the D-dimer. A D-dimer cutoff of 8.2 microg/mL (8,200 microg/L) optimized sensitivity and negative predictive value for the total population and patients with a predisposing condition. Validation against 286 additional patients in a separate analysis verified the diagnostic performance of the aforementioned cutoff. A sensitive, immunoturbidimetric D-dimer assay, by itself provides excellent sensitivity and negative predictive value for the diagnosis of DIC.


Inexplicable or simply unexplained? The management of maize seed in Mexico.
Farmer management of plant germplasm pre-dates crop domestication, but humans' role in crop evolution and diversity remains largely undocumented and often contested. Seemingly inexplicable practices observed throughout agricultural history, such as exchanging or replacing seed, continue to structure crop populations across the developing world. Seed management practices can be construed as events in the life history of crops and management data used to model crop demography, but this requires suitable quantitative data. As a prerequisite to addressing the causes and implications of maize seed management, we describe its patterns of variation across Mexico by drawing from the literature and new analysis. We find that rates of seed replacement, introduction and diffusion differ significantly across regions and altitudinal zones, but interactions among explanatory factors can obscure patterns of variation. The type, source, geographic origin and ownership of seed help explain observed rates. Yet, controlling for the characteristics of germplasm barely reduces interregional differences vastly exceeding variation across elevations. With few exceptions, monotonic altitudinal trends are absent. Causal relationships between management practices and the physical environment could determine farmers' wellbeing and crop conservation in the face of climate change. Scarce and inconsistent data on management nevertheless could prevent an understanding of these relationships. Current conceptions on the management and dynamics of maize diversity are founded on a patchwork of observations in surprisingly few and dissimilar environments. Our estimates of management practices should shed light on differences in maize population dynamics across Mexico. Consistency with previous studies spanning over a decade suggests that common sets of forces are present within large areas, but causal associations remain unknown. The next step in explaining crop diversity should address variation in seed management across space and time simultaneously while identifying farmers' values and motivations as underlying forces.


Situated food safety behavior.
Previous studies indicate that many consumers eat rare hamburgers and that information about microbiological hazards related to undercooked meat does not necessarily lead to changed behavior. With this study we aim to investigate whether consumers' willingness to eat hamburgers, both risky and safe, depends on the situation where they are confronted with the food. A representative sample of 1046 Norwegian consumers participated in a web experiment. Participants were randomly divided into four groups. Each group was told to imagine a specific eating situation (at their friend's place, at home, at a restaurant abroad, at a domestic restaurant). Four pictures of hamburgers (rare, medium rare, medium, well-done) were presented in randomized order, and participants rated their intentions to eat each hamburger. Situated risk perception was measured as the stated likelihood of food poisoning from consuming hamburgers in eight different situations. The results show that both risk perception and risk taking vary depending on the situation. In general, participants perceive their own home to be the safest place to consume a hamburger, but they are significantly more likely to consume an undercooked hamburger when at a friend's place. These findings indicate that situations play an important role for consumers' likelihood of eating unsafe food, and that risk taking does not always follow risk perception. That risk taking is elevated in situations that may have social consequences should be taken into consideration when developing food safety strategies.


Assessment of requests for assisted suicide by a Swiss right-to-die society.
Non-physician volunteers of Exit, the largest right-to-die organization in Switzerland, play an important role in assisted suicide. They conduct assessments and deliver lethal medications for a member to self-administer. This study analyses the content of 114 intake sheets (checklists) of Exit members whose requests for assisted suicide were granted in an effort to examine the frequency of depression and whether their relatives agreed with the member's decision to commit suicide (2 questions that can help increase the likelihood that the member's decision was both informed and voluntary). Exit's paperwork indicated that depression was found to exist in 27% of the cases, was more common among those under 65, and relatives explicitly disagreed with the member's decision in 5% of the cases.


Hemodialysis delivery, dialysis dose achievement, and vascular access types in hemodialysis patients from the Gulf Cooperation Council countries enrolled in the dialysis outcomes and practice patterns study phase 5 (2012-2015).
The prospective observational Dialysis Outcomes and Practice Patterns Study (DOPPS) was initiated in late 2012 in national samples of hemodialysis (HD) units (n = 41 study sites) in all six Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates). For many years, guidelines have recommended single pool Kt/V ≥1.2 as the minimum adequate dose for chronic HD patients. Here, we report initial DOPPS results regarding HD practices related to dialysis dose achievement in the GCC. A total of 928 adult HD patients were included in this analysis from 41 centers representing all six GCC countries. Baseline descriptive statistics (e.g., mean, standard deviation, median, interquartile range, or percentage) were calculated for the study sample. Results were weighted according to the fraction of HD patients sampled within each participating study site. Mean age varied between 51 years in Bahrain, Oman, and Saudi Arabia, 55 years in the United Arab Emirates (UAE) and Kuwait, and 62 years in Qatar. Mean body mass index (BMI) was the lowest in Oman patients (23.9 kg/m 2 , but the remaining GCC countries had mean BMIs of 25.7-28.9 kg/m 2 and substantial fractions of overweight patients. Median dialysis vintage ranged from 1.52 years in Kuwait to 3.52 years in Oman. Mean treatment time per session varied from 202 min in Saudi Arabia to 230 min in Qatar while mean blood flow rate (BFR) ranged between 267 mL/min in Oman and 310 mL/min in Saudi Arabia. Interdialytic weight gain varied considerably among GCC countries between 3.1 and 4.0 kg. Central venous catheter use was high among GCC countries, ranging from 29% in Oman to 56% in Kuwait, with other countries averaging 30-40% catheter use. Data were available only for 50-76% of patients in four GCC countries (Kuwait, Qatar, Saudi Arabia, and UAE) for calculating single pool Kt/V to indicate dialysis adequacy. When calculated for patients with vintage >1 year and dialyzing three times per week, mean single pool Kt/V was highest in Qatar and the UAE (1.50-1.51), intermediate in Kuwait (1.35), and lowest in Saudi Arabia (1.29). A higher risk of mortality was observed for patients having a single pool Kt/V <1.2 (vs. ≥1.2) [hazard ratio (HR) = 1.71, 95% confidence interval [CI]: 1.01-2.92]. Achievement of Kt/V in the GCC, although lower than in other DOPPS regions such as Europe/ANZ and North America, was similar to that in Japan. Japan and the GCC also share the practice of having a lower blood volume filtered per HD session per kg body weight. These findings suggest that increasing mean BFR and treatment time in the GCC, along with reducing catheter use, would substantially increase overall achievement of Kt/V >1.2 in the GCC, and hence, may improve survival. These mortality findings will need to be confirmed with up-coming GCC-DOPPS 6 analysis.


Spectrum of musculoskeletal disorders in Nigerians with types 2 diabetes mellitus: prevalence and predictors.
Musculoskeletal (MSK) conditions are more frequently found among patients with diabetes mellitus (DM) than in the non-diabetics. Despite several reports outside Africa, they have been under-studied among Africans. This study aimed to assess the overall prevalence and predictors of MSK conditions in Nigerian with types 2 diabetes mellitus (T2DM). A total of 268 adult with T2DM and 268 non-diabetic controls were recruited. All study subjects had their socio-demographics and clinical parameters obtained using interviewer-administered questionnaire. Musculoskeletal conditions among study subjects were classified using validated criteria and case definitions. Musculoskeletal disorders (MSKD) were significantly more frequent amongst subjects with DM (56% vs 22%, OR=4.5 p=0.001). Osteoarthritis (9.3% vs 4.1%, p=0.016), lumbosacral spondylosis (5.6% vs 2.2%, p=0.045), limited joint mobility (13.8% vs 5.6%, p-0.001), adhesive capsulitis (4.5% vs 1.5%, p-0.042) and rotator cuff tendinitis (3.7% vs 0.4%, p=0.006) were more frequent in DM subjects than in controls. Logistic regression showed that age (OR=2.1, CI=1.5-2.6) and waist circumference (OR=3.0, CI=2.6- 3.4) are independent predictors of MSKD among patients with diabetes. This study found higher prevalence of MSKD among diabetic subjects. It also identified certain factors associated with MSKD among patients with diabetes mellitus.


Efficient systemic delivery of siRNA by using high-density lipoprotein-mimicking peptide lipid nanoparticles.
The main challenge for RNAi therapeutics lies in systemic delivery of siRNA to the correct tissues and transporting them into the cytoplasm of targeted cells, at safe, therapeutic levels. Recently, we developed a high-density lipoprotein-mimicking peptide-phospholipid scaffold (HPPS) and demonstrated its direct cytosolic delivery of siRNA in vitro, thereby bypassing endosomal trapping. We investigate the in vivo implementation of HPPS for siRNA delivery. After systemic administration in KB tumor-bearing mice, HPPS prolonged the blood circulation time of cholesterol-modified siRNA (chol-siRNA) by a factor of four, improved its biodistribution and facilitated its uptake in scavenger receptor class B type I overexpressed tumors. For therapeutic targeting to the bcl-2 gene, the HPPS-chol-si-bcl-2 nanoparticles downregulated Bcl-2 protein, induced enhanced apoptosis (2.5-fold) in tumors when compared with controls (saline, HPPS, HPPS-chol-si-scramble and chol-si-bcl-2) and significantly inhibited tumor growth with no adverse effect. HPPS is a safe, efficient nanocarrier for RNAi therapeutics in vivo.


Recovery from chronic fatigue syndrome after treatments given in the PACE trial.
A multi-centre, four-arm trial (the PACE trial) found that rehabilitative cognitive behaviour therapy (CBT) and graded exercise therapy (GET) were more effective treatments for chronic fatigue syndrome (CFS) than specialist medical care (SMC) alone, when each was added to SMC, and more effective than adaptive pacing therapy (APT) when added to SMC. In this study we compared how many participants recovered after each treatment. We defined recovery operationally using multiple criteria, and compared the proportions of participants meeting each individual criterion along with two composite criteria, defined as (a) recovery in the context of the trial and (b) clinical recovery from the current episode of the illness, however defined, 52 weeks after randomization. We used logistic regression modelling to compare treatments. The percentages (number/total) meeting trial criteria for recovery were 22% (32/143) after CBT, 22% (32/143) after GET, 8% (12/149) after APT and 7% (11/150) after SMC. Similar proportions met criteria for clinical recovery. The odds ratio (OR) for trial recovery after CBT was 3.36 [95% confidence interval (CI) 1.64–6.88] and for GET 3.38 (95% CI 1.65–6.93), when compared to APT, and after CBT 3.69 (95% CI 1.77–7.69) and GET 3.71 (95% CI 1.78–7.74), when compared to SMC (p values < or =0.001 for all comparisons). There was no significant difference between APT and SMC. Similar proportions recovered in trial subgroups meeting different definitions of the illness. This study confirms that recovery from CFS is possible, and that CBT and GET are the therapies most likely to lead to recovery.


Mother-to-child transmission of human immunodeficiency virus type 1: influence of parity and mode of delivery. Paediatric AIDS Group of Switzerland.
In a national prospective study of risk factors for mother-to-child transmission of human immunodeficiency virus (HIV), 316 children of HIV-positive mothers were followed up for at least 6 months. Infection status was determined in 254 of them and 46 were found to be infected giving a transmission rate of 18.1%. Univariate analysis of potential risk factors for mother-to-child transmission showed an association between primiparity and increased transmission rate: odds ratio 2.2, 95% confidence interval (CI) 1.1-4.6, P < 0.05. Analysis by logistic regression confirmed this association (adjusted odds ratio 2.4) and showed, in addition, a negative association between transmission rate and elective Caesarean section (adjusted odds ratio 0.36, 95% CI 0.13-0.97, P < 0.05). The effect of primiparity was less pronounced in combination with elective Caesarean section (odds ratio 1.7) than with other delivery modes (odds ratio 2.5, difference not significant). HIV-infected children were less likely to experience the birth of a younger sibling during the observation period than their uninfected counterparts (2 of 46 vs 27 of 208, P < 0.05 by logrank test). Primiparous women appear to transmit HIV to their children at a higher rate. This could be explained by increased intrapartum transmission because of longer and more complicated labour in primiparas and/or by a self-selection of women with lower risk of transmission among those deciding to have additional children.


Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition-induced expression of miR-15a, miR-16, or miR-29b in primary CLL cells was associated with declines in the levels of Mcl-1, but not Bcl-2, mitochondrial dysfunction, and induction of cell death. Therefore, our results show that HDACs aberrantly silence the expression of the critical tumor suppressors miR-15a, miR-16, and miR-29b in CLL. Deacetylase inhibition may be a therapeutic strategy that restores the expression of these miRs to antagonize Mcl-1, an important survival protein in these cells. Consequently, CLL patients who exhibit such epigenetic silencing may benefit from HDAC inhibitor-based therapy.


Stem cell therapy and its potential role in pituitary disorders.
The pituitary gland is one of the key components of the endocrine system. Congenital or acquired alterations can mediate destruction of cells in the gland leading to hormonal dysfunction. Even though pharmacological treatment for pituitary disorders is available, exogenous hormone replacement is neither curative nor sustainable. Thus, alternative therapies to optimize management and improve quality of life are desired. An alternative modality to re-establish pituitary function is to promote endocrine cell regeneration through stem cells that can be obtained from the pituitary parenchyma or pluripotent cells. Stem cell therapy has been successfully applied to a plethora of other disorders, and is a promising alternative to hormonal supplementation for resumption of normal hormone homeostasis. In this review, we describe the common causes for pituitary deficiencies and the advances in cellular therapy to restore the physiological pituitary function.


National trends in the utilization of partial nephrectomy before and after the establishment of AUA guidelines for the management of renal masses.
To assess the impact of the American Urological Association (AUA) guidelines advocating partial nephrectomy for T1 tumors guidelines on the likelihood of undergoing partial nephrectomy. We analyzed the Nationwide Inpatient Sample (NIS), a dataset encompassing 20% of all United States inpatient hospitalizations, from 2007 through 2010. Our dependent variable was receipt of radical vs partial nephrectomy (55.50, 55.51, 55.52, and 55.54 vs 55.4) for a renal mass (International Classification of Disease, 9th Revision [ICD-9] code 189.0). The independent variable of interest was time of surgery (before or after the establishment of AUA guidelines); covariates included a diagnosis of chronic kidney disease (CKD), overall comorbidity, age, race, gender, geographic region, income, and hospital characteristics. Bivariate and multivariable adjusted logistic regression was used to determine the association between receipt of partial nephrectomy and time of guideline establishment. We identified 26,165 patients with renal tumors who underwent surgery. Before the guidelines, 4031 patients (27%) underwent partial nephrectomy compared to 3559 (32%) after. On multivariable analysis, undergoing surgery after the establishment of guidelines (odds ratio [OR] 1.20, 95% confidence interval [CI] 1.08-1.32, P <.01) was an independent predictor of partial nephrectomy. Other factors associated with partial nephrectomy were urban location, surgery at a teaching hospital, large hospital bed size, Northeast location, and Black race. Female gender and CKD were not associated with partial nephrectomy. Although adoption of partial nephrectomy increased after establishment of new guidelines on renal masses, partial nephrectomy remains an underutilized procedure. Future research must focus on barriers to adoption of partial nephrectomy and how to overcome them.


Raman microscopy-based cytochemical investigations of potential niche-forming inhomogeneities present in human embryonic stem cell colonies.
Measuring spatial and temporal patterns of cytochemical variation in human embryonic stem cell (hESC) colonies is necessary for understanding the role of cellular communication in spontaneous differentiation, the mechanisms of biological niche creation, and structure-generating developmental processes. Such insights will ultimately facilitate directed differentiation and therewith promote advances in tissue engineering and regenerative medicine. However, the patterns of cytochemical inhomogeneities of hESC colonies are not well studied and their causes are not fully understood. We used Raman spectroscopic mapping to contrast supracellular variations in cytochemical composition across pluripotent and partly differentiated hESC colonies to gain a better understanding of the early-stage (i.e., 5 days) effects of the differentiation process on the nature and evolution of these patterns. Higher protein-to-nucleic acid ratios, a differentiation status indicator observed previously using Raman spectroscopy, confirmed reported results that spontaneous differentiation is more pronounced on the edges of a colony than elsewhere. In addition, pluripotent and partly differentiated colonies also showed higher lipid concentrations relative to nucleic acids at colony edges in contrast to relative glycogen concentrations, which were up to 400% more pronounced in the colony centers compared to their edges. Pluripotent and partly differentiated colonies differed, with the latter having higher average protein-to-nucleic acid and lipid-to-nucleic acid ratios but a lower glycogen-to-nucleic acid ratio. In both cases, cell density, pluripotency, and high glycogen appeared to vary in tandem. Spatial variations in glycogen- and protein-to-nucleic acid ratios have features on the order of 100 μm and larger. These dimensions are consistent with those reported for stem cell niches and suggest that cytochemical inhomogeneities may provide colony-level information about niches and niche formation. These results demonstrate Raman mapping to be a potentially useful technique for revealing the complexities in the spatial organization of hESC cultures and thus for monitoring the evolution of engineered hESC niches.


Impact of ocean warming and ocean acidification on larval development and calcification in the sea urchin Tripneustes gratilla.
As the oceans simultaneously warm, acidify and increase in P(CO2), prospects for marine biota are of concern. Calcifying species may find it difficult to produce their skeleton because ocean acidification decreases calcium carbonate saturation and accompanying hypercapnia suppresses metabolism. However, this may be buffered by enhanced growth and metabolism due to warming. We examined the interactive effects of near-future ocean warming and increased acidification/P(CO2) on larval development in the tropical sea urchin Tripneustes gratilla. Larvae were reared in multifactorial experiments in flow-through conditions in all combinations of three temperature and three pH/P(CO2) treatments. Experiments were placed in the setting of projected near future conditions for SE Australia, a global change hot spot. Increased acidity/P(CO2) and decreased carbonate mineral saturation significantly reduced larval growth resulting in decreased skeletal length. Increased temperature (+3 degrees C) stimulated growth, producing significantly bigger larvae across all pH/P(CO2) treatments up to a thermal threshold (+6 degrees C). Increased acidity (-0.3-0.5 pH units) and hypercapnia significantly reduced larval calcification. A +3 degrees C warming diminished the negative effects of acidification and hypercapnia on larval growth. This study of the effects of ocean warming and CO(2) driven acidification on development and calcification of marine invertebrate larvae reared in experimental conditions from the outset of development (fertilization) shows the positive and negative effects of these stressors. In simultaneous exposure to stressors the dwarfing effects of acidification were dominant. Reduction in size of sea urchin larvae in a high P(CO2) ocean would likely impair their performance with negative consequent effects for benthic adult populations.


SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer prodrug that cross-links DNA and exerts highly potent antitumor activity.
The pyrrolobenzodiazepines (PBD) are naturally occurring antitumor antibiotics, and a PBD dimer (SJG-136, SG2000) is in phase II trials. Many potent PBDs contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring. The novel compound SG2202 is a PBD dimer containing this motif. SG2285 is a water-soluble prodrug of SG2202 in which two bisulfite groups inactivate the PBD N10-C11 imines. Once the bisulfites are eliminated, the imine moieties can bind covalently in the DNA minor groove, forming an interstrand cross-link. The mean in vitro cytotoxic potency of SG2285 against human tumor cell lines is GI(50) 20 pmol/L. SG2285 is highly efficient at producing DNA interstrand cross-links in cells, but they form more slowly than those produced by SG2202. Cellular sensitivity to SG2285 was primarily dependent on ERCC1 and homologous recombination repair. In primary B-cell chronic lymphocytic leukemia samples, the mean LD(50) was significantly lower than in normal age-matched B and T lymphocytes. Antitumor activity was shown in several human tumor xenograft models, including ovarian, non-small cell lung, prostate, pancreatic, and melanoma, with cures obtained in the latter model with a single dose. Further, in an advanced-stage colon model, SG2285 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. Our findings define SG2285 as a highly active cytotoxic compound with antitumor properties desirable for further development.


Short- and long-term benefits of cognitive training.
Does cognitive training work? There are numerous commercial training interventions claiming to improve general mental capacity; however, the scientific evidence for such claims is sparse. Nevertheless, there is accumulating evidence that certain cognitive interventions are effective. Here we provide evidence for the effectiveness of cognitive (often called "brain") training. However, we demonstrate that there are important individual differences that determine training and transfer. We trained elementary and middle school children by means of a videogame-like working memory task. We found that only children who considerably improved on the training task showed a performance increase on untrained fluid intelligence tasks. This improvement was larger than the improvement of a control group who trained on a knowledge-based task that did not engage working memory; further, this differential pattern remained intact even after a 3-mo hiatus from training. We conclude that cognitive training can be effective and long-lasting, but that there are limiting factors that must be considered to evaluate the effects of this training, one of which is individual differences in training performance. We propose that future research should not investigate whether cognitive training works, but rather should determine what training regimens and what training conditions result in the best transfer effects, investigate the underlying neural and cognitive mechanisms, and finally, investigate for whom cognitive training is most useful.


Label-free fluorescence detection of DNA methylation and methyltransferase activity based on restriction endonuclease HpaII and exonuclease III.
Strategies to detect the methylation of site specific DNA and assay of M.SssI methyltransferase (M.SssI MTase) activity are important in determining human cancers due to aberrant methylation linked to cancer initiation and progression. Herein, we report a label-free fluorescence detection method for DNA methylation and MTase activity based on restriction endonuclease HpaII and exonuclease III (Exo III). A label-free probe DNA was designed, which hybridized with target DNA (one 32-mer DNA from the exon 8 promoter region of the Homo sapiens p53 gene) to form double stranded DNA (dsDNA). Upon the cleavage action of HpaII and degradation reaction of Exo III, dsDNA changed to single stranded DNA (ssDNA) and the fluorescence intensity of thiazole orange (TO) is weak. After the resulting dsDNA was methylated by M.SssI MTase, the action of HpaII and Exo III was prevented, then TO intercalates into the dsDNA and emits strong fluorescence. This method can determine DNA methylation at the site of CpG and distinguish a one-base mismatched target sequence. The fluorescence intensity has a linear relationship with M.SssI MTase activities in the range of 1-10 U mL(-1) with a detection limit of 0.16 U mL(-1) in terms of 3 times deviation of the blank sample. The methylation of DNA by a hydroxyl radical triggered by DMSO and CH3CHO was also measured. These results show that the proposed method can specifically and selectively detect DNA methylation and M.SssI MTase activity. Human serum has no obvious effects on the assay performance, indicating that the method has great potential for further application in complex samples.


New production regulates export stoichiometry in the ocean.
The proportion in which carbon and growth-limiting nutrients are exported from the oceans' productive surface layer to the deep sea is a crucial parameter in models of the biological carbon pump. Based on >400 vertical flux observations of particulate organic carbon (POC) and nitrogen (PON) from the European Arctic Ocean we show the common assumption of constant C:N stoichiometry not to be met. Exported POC:PON ratios exceeded the classical Redfield atomic ratio of 6.625 in the entire region, with the largest deviation in the deep Central Arctic Ocean. In this part the mean exported POC:PON ratio of 9.7 (a:a) implies c. 40% higher carbon export compared to Redfield-based estimates. When spatially integrated, the potential POC export in the European Arctic was 10-30% higher than suggested by calculations based on constant POC:PON ratios. We further demonstrate that the exported POC:PON ratio varies regionally in relation to nitrate-based new production over geographical scales that range from the Arctic to the subtropics, being highest in the least productive oligotrophic Central Arctic Ocean and subtropical gyres. Accounting for variations in export stoichiometry among systems of different productivity will improve the ability of models to resolve regional patterns in carbon export and, hence, the oceans' contribution to the global carbon cycle will be predicted more accurately.


Bone marrow transplantation for patients with chronic myeloid leukaemia: T-cell depletion with Campath-1 reduces the incidence of graft-versus-host disease but may increase the risk of leukaemic relapse.
Between December 1983 and November 1985 we treated 39 patients with chronic myeloid leukaemia by chemoradiotherapy and transplantation from HLA-identical sibling donors using bone marrow that had been depleted of T cells ex vivo with the rat monoclonal antibody Campath-1. Twenty-eight of the patients were in the chronic phase (good-risk group) and 11 patients were in more advanced phases of the disease (accelerated phase or blastic transformation; poor-risk group). Of the patients of good risk 23 (82%) survive; the median duration of follow-up is 461 (range 111-776) days; of the 11 patients of poor risk four survive; the median duration of follow-up is 280 (range 189-658) days. Acute graft-versus-host disease (GVHD) of grade II or greater occurred in three (11%) of the patients of good risk and in six (55%) of the patients of poor risk. In the patients of good risk haematological evidence of relapse was seen in four and cytogenetic evidence of persisting or relapsed leukaemia (based on the finding of Philadelphia-chromosome-positive marrow metaphases more than 6 months after transplant) was seen in three other patients. In comparison with the patients of good risk transplanted with untreated marrow between February 1981 and December 1983, the incidence of acute GVHD was reduced significantly (P less than 0.001) but the risk of leukaemic relapse (including patients with only cytogenetic evidence of relapse) was increased (P less than 0.005). We conclude that T-cell depletion used in this manner may be associated with an increased risk of leukaemic relapse.


Temporal profile of the induction of heat shock protein 70 and heat shock cognate protein 70 mRNAs after transient ischemia in gerbil brain.
Distributions of heat shock protein (HSP) 70 and heat shock cognate protein (HSC) 70 mRNAs after 2, 5 and 15 min of transient global ischemia in gerbil forebrain were investigated by in situ hybridization using cloned cDNA probes selective for each mRNA species. Morphological studies were also performed at the dorsal hippocampal level of coronal sections from the identical brains until 7 days after the reperfusion. Following 2 min of ischemia, HSP70 and HSC70 mRNAs were induced together in hippocampal dentate granule cells at 1 and 3 h of the reperfusion. No histological change was observed in brain cells. Following 5 min of ischemia, HSP70 and HSC70 mRNAs were induced in all hippocampal cells. The induction of HSP70 mRNA in hippocampal CA1 cells sustained until 2 days, while that of HSC70 mRNA declined gradually. Only CA1 cells were lost at 7 days of the reperfusion. Following 15 min of ischemia, the mRNAs were induced in more extensive brain regions including neocortex and thalamic nuclei. In hippocampal CA1 cells, inductions of HSP70 and HSC70 mRNAs diminished by 2 days corresponding with the neuronal damage. HSC70 mRNA induction was not so much as HSP70 mRNA induction especially in hippocampal CA1 and thalamic cells. Our results showed that HSP70 and HSC70 mRNAs were generally induced together after transient ischemia, but that the inductions were spatially and chronologically different after different periods of ischemia. The dissociation of the induction was also found in cells severely injured after 5 and 15 min of ischemia.


Outcomes After Hip Fracture Surgery Compared With Elective Total Hip Replacement.
Patients undergoing surgery for a hip fracture have a higher risk of mortality and major complications compared with patients undergoing an elective total hip replacement (THR) operation. The effect of older age and comorbidities associated with hip fracture on this increased perioperative risk is unknown. To determine if there was a difference in hospital mortality among patients who underwent hip fracture surgery relative to an elective THR, after adjustment for age, sex, and preoperative comorbidities. Using the French National Hospital Discharge Database from January 2010 to December 2013, patients older than 45 years undergoing hip surgery at French hospitals were included. The International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10), codes were used to determine patients' comorbidities and complications after surgery. A population matched for age, sex, and preoperative comorbidities of patients who underwent elective THR or hip fracture surgery was created using a multivariable logistic model and a greedy matching algorithm with a 1:1 ratio. Hip fracture. Postoperative in-hospital mortality. A total of 690,995 eligible patients were included from 864 centers in France. Patients undergoing elective THR surgery (n = 371,191) were younger, more commonly men, and had less comorbidity compared with patients undergoing hip fracture surgery. Following hip fracture surgery (n = 319,804), 10,931 patients (3.42%) died before hospital discharge and 669 patients (0.18%) died after elective THR. Multivariable analysis of the matched populations (n = 234,314) demonstrated a higher risk of mortality (1.82% for hip fracture surgery vs 0.31% for elective THR; absolute risk increase, 1.51% [95% CI, 1.46%-1.55%]; relative risk [RR], 5.88 [95% CI, 5.26-6.58]; P < .001) and of major postoperative complications (5.88% for hip fracture surgery vs 2.34% for elective THR; absolute risk increase, 3.54% [95% CI, 3.50%-3.59%]; RR, 2.50 [95% CI, 2.40-2.62]; P < .001) among patients undergoing hip fracture surgery. In a large cohort of French patients, hip fracture surgery compared with elective THR was associated with a higher risk of in-hospital mortality after adjustment for age, sex, and measured comorbidities. Further studies are needed to define the causes for these differences.


Water and a Borohydride/Hydronium Intermediate in the Borane-Catalyzed Hydrogenation of Carbonyl Compounds with H2 in Wet Ether: A Computational Study.
We have computationally evaluated water as an active Lewis base (LB) and introduced the borohydride/hydronium intermediate in the mechanism of B(C6F5)3-catalyzed hydrogenation of carbonyl compounds with H2 in wet/moist ether. Our calculations extend the known frustrated Lewis pair mechanism of this reaction toward the inclusion of water as the active participant in all steps. Although the definition of the zero-energy point interweaves in comparison of the scenarios with and without water, we will be able to show that (i) water (hydrogen bonded to its molecular environment) can, in principle, act as a reasonably viable LB in cooperation with the borane Lewis acid such as B(C6F5)3 but relatively a strong borane-water complexation can be the hindering factor; (ii) the herein-proposed borohydride/hydronium intermediates with the hydronium cation having three OH···ether hydrogen bonds or a combination of the OH···ether/OH···ketone hydrogen bonds appear to be as valid as the previously considered borohydride/oxonium or borohydride/oxocarbenium intermediates; (iii) the proton-coupled hydride transfer from the borohydride/hydronium to a ketone (acetone) has a reasonably low barrier. Our findings could be useful for better mechanistic understanding and further development of the aforementioned reaction.


Theoretical Analysis of the Relative Significance of Thermodynamic and Kinetic Dispersion in the dc and ac Voltammetry of Surface-Confined Molecules.
Commonly, significant discrepancies are reported in theoretical and experimental comparisons of dc voltammograms derived from a monolayer or close to monolayer coverage of redox-active surface-confined molecules. For example, broader-than-predicted voltammetric wave shapes are attributed to the thermodynamic or kinetic dispersion derived from distributions in reversible potentials (E(0)) and electrode kinetics (k(0)), respectively. The recent availability of experimentally estimated distributions of E(0) and k(0) values derived from the analysis of data for small numbers of surface-confined modified azurin metalloprotein molecules now allows more realistic modeling to be undertaken, assuming the same distributions apply under conditions of high surface coverage relevant to voltammetric experiments. In this work, modeling based on conventional and stochastic kinetic theory is considered, and the computationally far more efficient conventional model is shown to be equivalent to the stochastic one when large numbers of molecules are present. Perhaps unexpectedly, when experimentally determined distributions of E(0) and k(0) are input into the model, thermodynamic dispersion is found to be unimportant and only kinetic dispersion contributes significantly to the broadening of dc voltammograms. Simulations of ac voltammetric experiments lead to the conclusion that the ac method, particularly when the analysis of kinetically very sensitive higher-order harmonics is undertaken, are far more sensitive to kinetic dispersion than the dc method. ac methods are therefore concluded to provide a potentially superior strategy for addressing the inverse problem of determining the k(0) distribution that could give rise to the apparent anomalies in surface-confined voltammetry.


The heritability of the expression of two stress-regulated gene fragments in pigs.
Pigs reared in commercial production units sometimes encounter stressors that significantly decrease growth performance. It is hypothesized that response to stress challenges could potentially be used as selection criteria. This study aimed to investigate, in a commercial setting, the heritability of two target genes previously shown to be induced in response to stress, and related to growth performance, in an experimental situation. Blood samples (n = 2,392) were collected from three separate breeding lines of pedigreed and performance-tested boars between 24 to 25 wk of age. The expression levels of a novel fragment, '29a,' and the calcitonin receptor gene (CTR) were quantified using quantitative real-time PCR (qRT-PCR) on a subset (n = 709) of the blood samples. Gene expression levels were corrected for the efficiency of PCR reactions and also computed directly from threshold cycle (Ct) values. Resulting data showed a skewed nonnormal distribution of expression levels for the target genes relative to the endogenous control, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and were highly variable. Analyses were subsequently performed using untransformed and log-transformed data, with outliers identified and deleted in edited data sets. Regardless of the transformation or editing procedures for outliers applied, there was negligible genetic variation for the expression of target genes relative to GAPDH. In contrast, repeatabilities of replicate samples were generally high (between 0.54 and 0.67). Absolute expression levels for GAPDH and 29a were lowly heritable (h2 of about 0.04), although estimates did not exceed their SE. Subsetting the data according to whether the target gene had a higher or lower level of expression than GAPDH was then performed using the relevant Ct values. In the subset where the target gene was more highly expressed than GAPDH, a moderate estimate of heritability (0.18 +/- 0.10) for the log-transformed absolute expression level of 29a was obtained, whereas the estimate for its expression relative to GAPDH was lower (0.09 +/- 0.07). Estimates of heritability did not increase in the subset of low expression data. The limitations of using gene expression measures as potential selection criteria in commercial situations are discussed.