Unraveling the Origin of Operational Instability of Quantum Dot Based Light-Emitting Diodes.
We investigate the operational instability of quantum dot (QD)-based light-emitting diodes (QLEDs). Spectroscopic analysis on the QD emissive layer within devices in chorus with the optoelectronic and electrical characteristics of devices discloses that the device efficiency of QLEDs under operation is indeed deteriorated by two main mechanisms. The first is the luminance efficiency drop of the QD emissive layer in the running devices owing to the accumulation of excess electrons in the QDs, which escalates the possibility of nonradiative Auger recombination processes in the QDs. The other is the electron leakage toward hole transport layers (HTLs) that accompanies irreversible physical damage to the HTL by creating nonradiative recombination centers. These processes are distinguishable in terms of the time scale and the reversibility, but both stem from a single origin, the discrepancy between electron versus hole injection rates into QDs. Based on experimental and calculation results, we propose mechanistic models for the operation of QLEDs in individual quantum dot levels and their degradation during operation and offer rational guidelines that promise the realization of high-performance QLEDs with proven operational stability.


Proteins bound to heterogeneous nuclear RNA of simian-virus-40-infected cells.
Heterogeneous nuclear RNA . protein (hnRNA . protein) complexes from simian-virus-40 (SV40)-infected cells late in infection contain 7--10% RNA sequences specific to SV40 DNA. The SV40 nuclear RNA . protein complexes sediment at 60--70 S. The reality and specificity of the RNA-protein association is shown in metrizamide gradients. Protein and RNA lebels of hnRNA . protein-particles in SV40-infected cells follow a parallel pattern with a peak at 1.28 g/cm2 whereas a mixture of ribosomal RNA and soluble cytoplasmic proteins is separated according to the different densities in metrizamide. Analysis of hnRNA . protein from infected cells by two-dimensional gel electrophoresis shows the presence of a number of new proteins. It is demonstrated that three of these proteins are cellular ones induced by the virus infection and hence constitute good candidates to be specific RNA . protein particles for virus nuclear RNA. The presence of actin in hnRNA . protein particles from normal and SV40-infected cells and the presence of the major capsid protein VP1 in hnRNA . protein particles from SV40-infected cells is discussed.


Cardiac computed tomography and myocardial perfusion scintigraphy for risk stratification in asymptomatic individuals without known cardiovascular disease: a position statement of the Working Group on Nuclear Cardiology and Cardiac CT of the European Society of Cardiology.
Cardiovascular events remain one of the most frequent causes of mortality and morbidity worldwide. The majority of cardiac events occur in individuals without known coronary artery disease (CAD) and in low- to intermediate-risk subjects. Thus, the development of improved preventive strategies may substantially benefit from the identification, among apparently intermediate-risk subjects, of those who have a high probability for developing future cardiac events. Cardiac computed tomography and myocardial perfusion scintigraphy (MPS) by single photon emission computed tomography may play a role in this setting. In fact, absence of coronary calcium in cardiac computed tomography and inducible ischaemia in MPS are associated with a very low rate of major cardiac events in the next 3-5 years. Based on current evidence, the evaluation of coronary calcium in primary prevention subjects should be considered in patients classified as intermediate-risk based on traditional risk factors, since high calcium scores identify subjects at high-risk who may benefit from aggressive secondary prevention strategies. In addition, calcium scoring should be considered for asymptomatic type 2 diabetic patients without known CAD to select those in whom further functional testing by MPS or other stress imaging techniques may be considered to identify patients with significant inducible ischaemia. From available data, the use of MPS as first line testing modality for risk stratification is not recommended in any category of primary prevention subjects with the possible exception of first-degree relatives of patients with premature CAD in whom MPS may be considered. However, the Working Group recognizes that neither the use of computed tomography for calcium imaging nor of MPS have been proven to significantly improve clinical outcomes of primary prevention subjects in prospective controlled studies. This information would be crucial to adequately define the role of imaging approaches in cardiovascular preventive strategies.


From dimming to brightening: decadal changes in solar radiation at Earth's surface.
Variations in solar radiation incident at Earth's surface profoundly affect the human and terrestrial environment. A decline in solar radiation at land surfaces has become apparent in many observational records up to 1990, a phenomenon known as global dimming. Newly available surface observations from 1990 to the present, primarily from the Northern Hemisphere, show that the dimming did not persist into the 1990s. Instead, a widespread brightening has been observed since the late 1980s. This reversal is reconcilable with changes in cloudiness and atmospheric transmission and may substantially affect surface climate, the hydrological cycle, glaciers, and ecosystems.


General practitioners' tacit and stated policies in the prescription of lipid lowering agents.
Research into general practitioners' prescribing behaviour with regard to lipid lowering agents has relied on survey methods which presume that doctors have insight into their prescribing behaviour and can describe it accurately. This study set out to measure the tacit policies used by general practitioners in prescribing lipid lowering agents and to compare these with their stated policies. Effects of 13 separate cues on decisions to prescribe were examined. The cues included cholesterol levels and a number of associated risk factors for coronary heart disease. Doctors rated 130 imaginary cases presented by a computer. Thirty five general practitioners in the Plymouth area participated in the study. Their ages ranged from 31 to 55 years and all but four were men. The raw data in each case was a rating of the likelihood that the doctor would prescribe for the patient described. These were converted into statistical weightings by use of multiple linear regression. The pattern of (standardized) weights constituted the tacit policy for each doctor. Stated policies were measured in a subsequent interview by asking doctors to rate the influence of each cue. Both tacit and stated policies diverged widely between different doctors. Most doctors overestimated the number of cues that had actually influenced their decisions, and many believed that they had taken into account associated factors for coronary heart disease when they had not. On lifestyle related risks doctors were generally less likely to treat overweight people and most stated this as their policy. Most were also less likely to treat smokers but some had the opposite policy. Those less likely to treat smokers were also less likely to treat obese patients. There was also considerable variation in the extent to which the doctors took account of the attitude of the patient to receiving treatment. Doctors' policies are highly variable and particularly inconsistent in the treatment of smokers. Relevant risk factors may be ignored--even though they are understood--because the risk assessment involved is too psychologically complex a task to be performed intuitively. Decision aids and clear protocols are needed in this area.


Breastfeeding practice in the Brazilian capital cities and the Federal District: current status and advances.
To present the breastfeeding (BF) indicators obtained in the Second Survey on Prevalence of Breastfeeding in the Brazilian Capitals and the Federal District and to analyze their evolution from 1999 to 2008. A cross-sectional study was conducted in children younger than 1 year old who participated in the second phase of the multivaccination campaign in 2008. We used two-stage cluster sampling. The questionnaire consisted of closed questions, including data on consumption of breast milk, other types of milk, and other foods on the day prior to the survey. We analyzed the prevalence of BF in the first hour of life; exclusive BF in children younger than 6 months; BF in children aged 9 to 12 months; and medians of exclusive BF and BF. The time variation of BF was established by comparing the medians of exclusive BF and BF in 1999 and 2008. We obtained data from 34,366 children. We found that 67.7% (95%CI 66.7-68.8) of the children were breastfed in the first hour of life; the prevalence of exclusive BF in children aged 0 to 6 months was 41% (95%CI 39.7-42.4), while the prevalence of BF in children aged 9 to 12 months was 58.7% (95%CI 56.8-60.7). There was an increase of 30.7 days in the median duration of exclusive BF and 45.7 days in the median of BF. There was a significant improvement in the breastfeeding prevalence in the last decade. However, further efforts are required so that Brazil can reach BF rates compatible with the recommendations of the World Health Organization.


Propensity-matched comparisons of clinical outcomes after transapical or transfemoral transcatheter aortic valve replacement: a placement of aortic transcatheter valves (PARTNER)-I trial substudy.
The higher risk of adverse outcomes after transapical (TA) versus transfemoral (TF) transcatheter aortic valve replacement (TAVR) could be attributable to TA-TAVR being an open surgical procedure or to clinical differences between TA- and TF-TAVR patients. We compared outcomes after neutralizing patient differences using propensity score matching. From April 2007 to February 2012, 1100 Placement of Aortic Transcatheter Valves (PARTNER)-I patients underwent TA-TAVR and 1521 underwent TF-TAVR with Edwards SAPIEN balloon-expandable bioprostheses. Propensity matching based on 111 preprocedural variables, exclusive of femoral access morphology, identified 501 well-matched patient pairs (46% of possible matches), 95% of whom had peripheral arterial disease. Matched TA-TAVR patients experienced more adverse procedural events, longer length of stay (5 versus 8 days; P<0.0001), and slower recovery (New York Heart Association class I, 31% versus 38% at 30 days, equalizing by 6 months at 51% versus 47%); stroke risk was similar (3.4% versus 3.3% at 30 days and 6.0% versus 6.7% at 3 years); mortality was elevated for the first 6 postprocedural months (19% versus 12%; P=0.01); but aortic regurgitation was less (34% versus 52% mild and 8.9% versus 12% moderate to severe at discharge, P=0.001; 36% versus 50% mild and 10% versus 15% moderate to severe at 6 months, P<0.0001). The likelihood of adverse periprocedural events and prolonged recovery is greater after TA-TAVR than TF-TAVR in vasculopathic patients after accounting for differences in cardiovascular risk factors, although stroke risk is equivalent and aortic regurgitation is less. As smaller delivery systems permit TF-TAVR in many of these patients, we recommend a TF-first access strategy for TAVR when anatomically feasible. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894.


Ordering of polystyrene nanoparticles on substrates pre-coated with different polyelectrolyte architectures.
Adjusting the inter-particle distances in ordered nanoparticle arrays can create new nano-devices and is of increasing importance to a number of applications such as nanoelectronics and optical devices. The assembly of negatively charged polystyrene (PS) nanoparticles (NPs) on Poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) brushes, quaternized PDMAEMA brushes and Si/PEI/(PSS/PAH)2, was studied using dip- and spin-coating techniques. By dip-coating, two dimensional (2-D), randomly distributed non-close packed particle arrays were assembled on Si/PEI/(PSS/PAH)2 and PDMAEMA brushes. The inter-particle repulsion leads to lateral mobility of the particles on these surfaces. The 200 nm diameter PS NPs tended to an inter-particle distance of 350 to 400 nm (center to center). On quaternized PDMAEMA brushes, the strong attractive interaction between the NPs and the brush dominated, leading to clustering of the particles on the brush surface. Particle deposition using spin-coating at low spin rates resulted in hexagonal close-packed multilayer structures on Si/PEI/(PSS/PAH)2. Close-packed assemblies with more pronounced defects are also observed on PDMAEMA brushes and QPDMAEMA brushes. In contrast, randomly distributed monolayer NP arrays were achieved at higher spin rates on all polyelectrolyte architectures. The area fraction of the particles decreased with increasing spin rate.


Metabolic rewiring of the hypertensive kidney.
Hypertension is a persistent epidemic across the developed world that is closely associated with kidney disease. Here, we applied a metabolomic, phosphoproteomic, and proteomic strategy to analyze the effect of hypertensive insults on kidneys. Our data revealed the metabolic aspects of hypertension-induced glomerular sclerosis, including lipid breakdown at early disease stages and activation of anaplerotic pathways to regenerate energy equivalents to counter stress. For example, branched-chain amino acids and proline, required for collagen synthesis, were depleted in glomeruli at early time points. Furthermore, indicators of metabolic stress were reflected by low amounts of ATP and NADH and an increased abundance of oxidized lipids derived from lipid breakdown. These processes were specific to kidney glomeruli where metabolic signaling occurred through mTOR and AMPK signaling. Quantitative phosphoproteomics combined with computational modeling suggested that these processes controlled key molecules in glomeruli and specifically podocytes, including cytoskeletal components and GTP-binding proteins, which would be expected to compete for decreasing amounts of GTP at early time points. As a result, glomeruli showed increased expression of metabolic enzymes of central carbon metabolism, amino acid degradation, and lipid oxidation, findings observed in previously published studies from other disease models and patients with glomerular damage. Overall, multilayered omics provides an overview of hypertensive kidney damage and suggests that metabolic or dietary interventions could prevent and treat glomerular disease and hypertension-induced nephropathy.


Impairment of learning and memory in rats caused by oxidative stress and aging, and changes in antioxidative defense systems.
To elucidate the influence of oxidative stress on the brain functions during aging, the cognitive performance ability of rats was assessed by using the water-maze test as an oxidative stress before and after hyperoxia. Young rats showed significantly greater learning ability than both old rats and vitamin-E-deficient rats. Although the memory functions of all rats were Impaired after oxidative stress, the memory retention of young rats was greater than those of other groups. After the stress, none of the rats recovered their learning ability. During aging and through hyperoxia, the release of acetylcholine from nerve terminals was remarkably decreased. Instead, thiobarbituric acid reactive substance (TBARS) contents in rat hippocampus and cebral cortex, and their synaptic membranes, were significantly increased during aging and by oxidative stress. The antioxidative defense system in rat brain was also changed by the stress. These results suggest that oxidative stress may contribute to learning and memory deficits following oxidative brain damage during aging.


Synthesis, spectroscopic, electrochemical and computational studies of rhenium(i) tricarbonyl complexes based on bidentate-coordinated 2,6-di(thiazol-2-yl)pyridine derivatives.
Nine rhenium(i) complexes possessing three carbonyl groups together with a bidentate coordinated 2,6-di(thiazol-2-yl)pyridine derivative were synthesized to examine the impact of structure modification of the triimine ligand on the photophysical, thermal and electrochemical properties of [ReCl(CO)3(4-Rn-dtpy-κ2N)]. The Re(i) complexes were fully characterized using IR, 1H and 13C, HRMS-ESI and single crystal X-ray analysis. Their thermal properties were evaluated using DSC and TGA measurements. Photoluminescence spectra of [ReCl(CO)3(4-Rn-dtpy-κ2N)] were investigated in solution and in the solid state, at 298 and 77 K. Both emission wavelengths and quantum yields of [ReCl(CO)3(4-Rn-dtpy-κ2N)] were found to be structure-related, demonstrating a crucial role of the substituent attached to the 2,6-di(thiazol-2-yl)pyridine skeleton. In order to fully understand the photophysical properties of [ReCl(CO)3(4-Rn-dtpy-κ2N)], density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations were performed. Furthermore, the complexes which showed appropriate solubility in chloroform were tested as an emissive active layer in OLED devices.


Direct and Indirect Effects of Caregiver Social Support on Adolescent Psychological Outcomes in Two South African AIDS-Affected Communities.
Caregiver social support has been shown to be protective for caregiver mental health, parenting and child psychosocial outcomes. This is the first known analysis to quantitatively investigate the relationship between caregiver social support and adolescent psychosocial outcomes in HIV-endemic, resource-scarce Southern African communities. A cross-sectional household survey was conducted over 2009-2010 with 2,477 South African adolescents aged 10-17 and their adult caregivers (18 years or older) in one urban and one rural community in South Africa's KwaZulu-Natal province. Adolescent adjustment was assessed using adult caregiver reports of the Strengths and Difficulties questionnaire (SDQ), which measures peer problems, hyperactivity, conduct problems, emotional symptoms and child prosocial behavior. Hierarchical linear regressions and multiple mediation analyses, using bootstrapping procedures, were conducted to assess for: (a) direct effects of more caregiver social support on better adolescent psychosocial wellbeing; and (b) indirect effects mediated by better parenting and caregiver mental health. Direct associations (p < .001), and indirect associations mediated through better parenting, were found for all adolescent outcomes. Findings reinforce the importance of social support components within parenting interventions but also point to scope for positive intervention on adolescent psychosocial wellbeing through the broader family social network.


Exploring patients' experiences of the whiplash injury-recovery process - a meta-synthesis.
The aim of this study was to conduct a meta-synthesis to analyze qualitative research findings and thereby understand patients' experiences of whiplash-associated disorders (WAD) and the injury-recovery process. A qualitative meta-synthesis, which is an interpretive integration of existing qualitative findings, was performed. The databases PubMed, PsychINFO, Scopus, and Web of Science were searched. The Critical Assessment Skills Programme was used to assess the quality of the included studies. Four studies were included. The synthesis resulted in several codes, 6 categories, and 3 themes (distancing from normalcy, self-efficacy in controlling the life situation after the injury, and readjustment and acceptance) that described the participants' pain beliefs, their WAD-related life situation and their future expectations and acceptance. Changes in self-image were difficult to cope with and likely led to perceived stigmatization. Struggling with feelings of loss of control appeared to lead to low confidence and insecurity. Focusing on increasing knowledge and understanding the pain and its consequences were believed to lead to better strategies for handling the situation. Furthermore, recapturing life roles, including returning to work, was challenging, but an optimistic outlook reinforced symptom improvements and contributed to feelings of happiness. The results of the present study provide a comprehensive understanding of patients' complex, multifaceted experiences of WAD, and the injury-recovery process. The findings can guide us in the development of new ways to evaluate and manage WAD. The results also indicate that a more patient-centered approach is needed to determine the depth and breadth of each patient's problems.


An exploration of flavours in studies of e-cigarettes for smoking cessation: secondary analyses of a systematic review with meta-analyses.
To estimate associations between e-cigarette flavour and smoking cessation and study product use at 6 months or longer. Secondary analysis of data from a living systematic review, with meta-analyses and narrative synthesis, incorporating data up to January 2022. Included studies provided people who smoked combustible cigarettes with nicotine e-cigarettes for the purpose of smoking cessation compared with no treatment or other stop smoking interventions. Measurements included smoking cessation and study product use at 6 months or longer reported as risk ratios (RR) with 95% confidence intervals (CI); and flavour use at any time-points. We included 16 studies (n = 10 336); 14 contributed to subgroup analyses and 10 provided participants with a choice of e-cigarette flavour. We judged nine, five and two studies at high, low and unclear risk of bias, respectively. Subgroup analyses showed no clear associations between flavour and cessation or product use. In all but one analysis, tests for subgroup differences resulted in I2 values between 0 and 35%. In the comparison between nicotine e-cigarettes and nicotine replacement therapy (NRT) (I2 = 65.2% for subgroup differences), studies offering tobacco flavour e-cigarettes showed evidence of a greater proportion of participants still using at 6 months or longer (RR = 3.81; 95% CI = 1.45-10.05; n = 1181; I2 = 84%), whereas there was little evidence for greater 6-month use when studies offered a choice of flavours (RR = 1.44; 95% CI = 0.80-2.56; n = 454; I2 = 82%). However, substantial statistical heterogeneity within subgroups makes interpretation of this result unclear. In the 10 studies where participants had a choice of flavours, and this was tracked over time, some switching between flavours occurred, but there were no clear patterns in flavour preferences. There does not appear to be a clear association between e-cigarette flavours and smoking cessation or longer-term e-cigarette use, possibly due to a paucity of data. There is evidence that people using e-cigarettes to quit smoking switch between e-cigarette flavours.


Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. GW Pharmaceuticals.


Microglia-derived galectin-3 in neuroinflammation; a bittersweet ligand?
Galectins are soluble β-galactoside-binding proteins found in all multicellular organisms. Galectins may act as danger-associated molecular patterns in innate immunity and/or as pattern-recognition receptors that bind to pathogen-associated molecular patterns. Among different galectin family members, galectin-3 has been the focus of studies in neurodegenerative diseases in recent years. This lectin modulates brain innate immune responses, microglia activation patterns in physiological and pathophysiological settings in a context-dependent manner. Galectin-3 is considered as a pivotal tuner of macrophage and microglial activity. Indeed galectin-3 acts as a double edged sword in neuroinflammatory context and this multimodal lectin has diverse roles in physiological and pathophysiological conditions. Better understanding of galectin-3 physiology (its extracellular and intracellular actions) and structure (its C terminus vs. N terminus) is instrumental to design molecules that selectively modulate galectin-3 function toward neuroprotective phenotypes. Several experimental studies using different approaches and methods have demonstrated both protective and deleterious effects of galectin-3 in neuroinflammatory diseases. According to the crucial role of galectin-3 in modulation of innate immune response in brain, it is an attractive target in drug discovery of neurodegenerative diseases. The current insight attempts to provide an updated and balanced discussion on the role of galectin-3 as a complex endogenous immune modulator. This helps to have a better insight into the development of galectin-3 modulators with translational value in different neurological disorders including stroke and neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease and Parkinson's disease.


The phosphotyrosine binding-like domain of talin activates integrins.
Cellular regulation of the ligand binding affinity of integrin adhesion receptors (integrin activation) depends on the integrin beta cytoplasmic domains (tails). The head domain of talin binds to several integrin beta tails and activates integrins. This head domain contains a predicted FERM domain composed of three subdomains (F1, F2, and F3). An integrin-activating talin fragment was predicted to contain the F2 and F3 subdomains. Both isolated subdomains bound specifically to the integrin beta3 tail. However, talin F3 bound the beta3 tail with a 4-fold higher affinity than talin F2. Furthermore, expression of talin F3 (but not F2) in cells led to activation of integrin alpha(IIb)beta3. A molecular model of talin F3 indicated that it resembles a phosphotyrosine-binding (PTB) domain. PTB domains recognize peptide ligands containing beta turns, often formed by NPXY motifs. NPX(Y/F) motifs are highly conserved in integrin beta tails, and mutations that disrupt this motif interfere with both integrin activation and talin binding. Thus, integrin binding to talin resembles the interactions of PTB domains with peptide ligands. These resemblances suggest that the activation of integrins requires the presence of a beta turn at NPX(Y/F) motifs conserved in integrin beta cytoplasmic domains.


Dermoscopy of pigmented skin lesions: results of a consensus meeting via the Internet.
There is a need for better standardization of the dermoscopic terminology in assessing pigmented skin lesions. The virtual Consensus Net Meeting on Dermoscopy was organized to investigate reproducibility and validity of the various features and diagnostic algorithms. Dermoscopic images of 108 lesions were evaluated via the Internet by 40 experienced dermoscopists using a 2-step diagnostic procedure. The first-step algorithm distinguished melanocytic versus nonmelanocytic lesions. The second step in the diagnostic procedure used 4 algorithms (pattern analysis, ABCD rule, Menzies method, and 7-point checklist) to distinguish melanoma versus benign melanocytic lesions. kappa Values, log odds ratios, sensitivity, specificity, and positive likelihood ratios were estimated for all diagnostic algorithms and dermoscopic features. Interobserver agreement was fair to good for all diagnostic methods, but it was poor for the majority of dermoscopic criteria. Intraobserver agreement was good to excellent for all algorithms and features considered. Pattern analysis allowed the best diagnostic performance (positive likelihood ratio: 5.1), whereas alternative algorithms revealed comparable sensitivity but less specificity. Interobserver agreement on management decisions made by dermoscopy was fairly good (mean kappa value: 0.53). The virtual Consensus Net Meeting on Dermoscopy represents a valid tool for better standardization of the dermoscopic terminology and, moreover, opens up a new territory for diagnosing and managing pigmented skin lesions.


The role of zinc and copper in autism spectrum disorders.
Autism spectrum disorders (ASDs) are a group of developmental disabilities that can cause significant social, communication and behavioral challenges. Several studies have suggested a disturbance in the copper (Cu) and zinc (Zn) metabolism in ASDs. Zinc deficiency, excess Cu levels, and low Zn/Cu ratio are common in children diagnosed with an ASD. The literature also suggests that mercury accumulation may occur as a cause or consequence of metallothionein (MT) dysfunction in children diagnosed with an ASD, which may be one of the causes of Zn deficiency. MTs are proteins with important functions in metal metabolism and protection. Zinc and Cu bind to and participate in the control of the synthesis of MT proteins. Studies indicate that the GABAergic system may be involved in ASDs, and that Zn and Cu may play a role in this system.


Microbiology: lessons from a first attempt at Lake Ellsworth.
During the attempt to directly access, measure and sample Subglacial Lake Ellsworth in 2012-2013, we conducted microbiological analyses of the drilling equipment, scientific instrumentation, field camp and natural surroundings. From these studies, a number of lessons can be learned about the cleanliness of deep Antarctic subglacial lake access leading to, in particular, knowledge of the limitations of some of the most basic relevant microbiological principles. Here, we focus on five of the core challenges faced and describe how cleanliness and sterilization were implemented in the field. In the light of our field experiences, we consider how effective these actions were, and what can be learnt for future subglacial exploration missions. The five areas covered are: (i) field camp environment and activities, (ii) the engineering processes surrounding the hot water drilling, (iii) sample handling, including recovery, stability and preservation, (iv) clean access methodologies and removal of sample material, and (v) the biodiversity and distribution of bacteria around the Antarctic. Comparisons are made between the microbiology of the Lake Ellsworth field site and other Antarctic systems, including the lakes on Signy Island, and on the Antarctic Peninsula at Lake Hodgson. Ongoing research to better define and characterize the behaviour of natural and introduced microbial populations in response to deep-ice drilling is also discussed. We recommend that future access programmes: (i) assess each specific local environment in enhanced detail due to the potential for local contamination, (ii) consider the sterility of the access in more detail, specifically focusing on single cell colonization and the introduction of new species through contamination of pre-existing microbial communities, (iii) consider experimental bias in methodological approaches, (iv) undertake in situ biodiversity detection to mitigate risk of non-sample return and post-sample contamination, and (v) address the critical question of how important these microbes are in the functioning of Antarctic ecosystems.


Outcomes of fetuses with lower urinary tract obstruction treated with vesicoamniotic shunt: a single-institution experience.
The purpose of this manuscript was to examine the outcomes of patients with lower urinary tract obstruction (LUTO) treated with vesicoamniotic shunt (VAS) to improve the quality of prenatal consultation and therapy. The medical records of all patients diagnosed with LUTO at our center between January 2004 and March 2012 were reviewed retrospectively. Of 14 male fetuses with LUTO, all with characteristic ultrasound findings, 11 underwent intervention. One patient received vesicocentesis alone, while 10 had VAS. Two fetuses additionally underwent cystoscopy (one with attempted valve ablation), and two had peritoneoamniotic shunts. Of 16 total VAS, 13 were placed successfully, 8 dislodged (median 7 days), and 1 obstructed (84 days). Two fetuses suffered in utero demise, and two have unknown outcomes. LUTO was confirmed in six of eight live-born fetuses. One patient died in the neonatal period, while seven survived. All six available at follow-up (median 3.7 years), had significant genitourinary morbidity. Five patients had chronic kidney disease, but only one has required dialysis and transplant. Three had respiratory insufficiency, and one required a tracheostomy. Despite significant perinatal and long-term morbidity, VAS offers patients faced with a poor prognosis an improved chance of survival. Our results underscore the need for further research into the diagnosis and treatment of LUTO.


Evaluation of WIAMan Technology Demonstrator Biofidelity Relative to Sub-Injurious PMHS Response in Simulated Under-body Blast Events.
Three laboratory simulated sub-injurious under-body blast (UBB) test conditions were conducted with whole-body Post Mortem Human Surrogates (PMHS) and the Warrior Assessment Injury Manikin (WIAMan) Technology Demonstrator (TD) to establish and assess UBB biofidelity of the WIAMan TD. Test conditions included a rigid floor and rigid seat with independently varied pulses. On the floor, peak velocities of 4 m/s and 6 m/s were applied with a 5 ms time to peak (TTP). The seat peak velocity was 4 m/s with varied TTP of 5 and 10 ms. Tests were conducted with and without personal protective equipment (PPE). PMHS response data was compiled into preliminary biofidelity response corridors (BRCs), which served as evaluation metrics for the WIAMan TD. Each WIAMan TD response was evaluated against the PMHS preliminary BRC for the loading and unloading phase of the signal time history using Correlation Analysis (CORA) software to assign a numerical score between 0 and 1. A weighted average of all responses was calculated to determine body region and whole body biofidelity scores for each test condition. The WIAMan TD received UBB biofidelity scores of 0.62 in Condition A, 0.59 in Condition B, and 0.63 in Condition C, putting it in the fair category (0.44-0.65). Body region responses with scores below a rating of good (0.65-0.84) indicate potential focus areas for the next generation of the WIAMan design.


Structures of aromatic inhibitors of influenza virus neuraminidase.
Neuraminidase (NA), a surface glycoprotein of influenza virus, is a potential target for design of antiinfluenza agents. The crystal structure of influenza virus neuraminidase showed that in the active site 11 residues are universally conserved among all strains known so far. Several potent inhibitors based on the carbohydrate compound 2-deoxy-2,3-didehydro-D-N-acetylneuraminic acid (DANA) have been shown to bind to the conserved active site and to reduce virus infection in animals when administered by nasal spray. Inhibitors of this type are, however, rapidly excreted from physiological systems and may not be effective in order to provide long-time protection. A new class of specific NA inhibitors, which are benzoic acid derivatives, has been designed on the basis of the three-dimensional structure of the NA-DANA complex and modeling of derivatives of 4-(acetylamino)benzoic acid in the NA active site. Intermediates were synthesized and were shown to moderately inhibit the NA activity and to bind to the NA active site as predicted. These rudimentary inhibitors, 4-(acetylamino)-3-hydroxy-5-nitrobenzoic acid, 4-(acetylamino)-3-hydroxy-5-aminobenzoic acid, and 4-(acetylamino)-3-aminobenzoic acid, and their X-ray structures in complexes with N2 (A/Tokyo/3/67) and B/Lee/40 neuraminidases have been analyzed. The coordinates of such inhibitors complexed with NA were used as the starting model for further design of more potent benzoic acid inhibitors. Because the active site residues of NA are invariant, the designed aromatic inhibitors have the potential to become an antiviral drug against all strains of influenza virus.


S100B protein, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor in human milk.
Human milk contains a wide variety of nutrients that contribute to the fulfillment of its functions, which include the regulation of newborn development. However, few studies have investigated the concentrations of S100B protein, brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) in human milk. The associations of the concentrations of S100B protein, BDNF, and GDNF with maternal factors are not well explored. To investigate the concentrations of S100B protein, BDNF, and GDNF in human milk and characterize the maternal factors associated with their levels in human milk, human milk samples were collected at days 3, 10, 30, and 90 after parturition. Levels of S100B protein, BDNF, and GDNF, and their mRNAs in the samples were detected. Then, these concentrations were compared with lactation and other maternal factors. S100B protein levels in human milk samples collected at 3, 10, 30, and 90 d after parturition were 1249.79±398.10, 1345.05±539.16, 1481.83±573.30, and 1414.39±621.31 ng/L, respectively. On the other hand, the BDNF concentrations in human milk samples were 10.99±4.55, 13.01±5.88, 13.35±6.43, and 2.83±5.47 µg/L, while those of GDNF were 10.90±1.65, 11.38±1., 11.29±3.10, and 11.40±2.21 g/L for the same time periods. Maternal post-pregnancy body mass index was positively associated with S100B levels in human milk (r = 0.335, P = 0.030<0.05). In addition, there was a significant correlation between the levels of S100B protein and BDNF (z = 2.09, P = 0.037<0.05). Delivery modes were negatively associated with the concentration of GDNF in human milk. S100B protein, BDNF, and GDNF are present in all samples of human milk, and they may be responsible for the long term effects of breast feeding.


Hydrogen Concentration Profiles at the Oxic-Anoxic Interface: a Microsensor Study of the Hindgut of the Wood-Feeding Lower Termite Reticulitermes flavipes (Kollar).
Molecular hydrogen is a key intermediate in lignocellulose degradation by the microbial community of termite hindguts. With polarographic, Clark-type H(inf2) microelectrodes, we determined H(inf2) concentrations at microscale resolution in the gut of the wood-feeding lower termite Reticulitermes flavipes (Kollar). Axial H(inf2) concentration profiles obtained from isolated intestinal tracts embedded in agarose Ringer solution clearly identified the voluminous hindgut paunch as the site of H(inf2) production. The latter was strictly coupled with both a low redox potential (E(infh) = -200 mV) and the absence of oxygen, in agreement with the growth requirements of the cellulolytic, H(inf2)-producing flagellates located in the hindgut paunch. Luminal H(inf2) partial pressures were much higher than expected (ca. 5 kPa) and increased more than threefold when the guts were incubated under a N(inf2) headspace. Radial H(inf2) concentration gradients showed a steep decrease from the gut center towards the periphery, indicating the presence of H(inf2)-consuming activities both within the lumen and at the gut epithelium. Measurements under controlled gas headspace showed that the gut wall was also a sink for externally supplied H(inf2), both under oxic and anoxic conditions. With O(inf2) microelectrodes, we confirmed that the H(inf2) sink below the gut epithelium is located within the microoxic gut periphery, but the H(inf2)-consuming activity itself, at least a substantial part of it, was clearly due to an anaerobic process. These results are in accordance with the recently reported presence of methanogens attached in large numbers to the luminal side of the hindgut epithelium of R. flavipes. If the oxygen partial pressure was increased, O(inf2) penetrated deeper and H(inf2) production was suppressed; it ceased completely as soon as the gut was fully oxic. In experiments with living termites, externally supplied H(inf2) (20 kPa) stimulated methane formation five- to sixfold to 0.93 (mu)mol (g of termite)(sup-1) h(sup-1), indicating that the methanogenic activity in R. flavipes hindguts is not saturated for hydrogen under in situ conditions. This rate was in good agreement with the H(inf2) uptake rates exhibited by isolated hindguts, which would account for more than half of the CH(inf4) formed by living termites under comparable conditions.


A Meta-analysis of the relation between chemokine receptor 5 delta32 polymorphism and multiple sclerosis susceptibility.
The aim of this study was to determine whether the functional chemokine receptor 5 delta32 (CCR5-Δ32) polymorphism is associated with multiple sclerosis (MS) susceptibility. Meta-analysis was conducted to determine the association between the CCR5-Δ32 polymorphism and overall incidence of MS as well frequency of relapsing-remitting (RR), primary progressive (PP), and secondary progressive (SP) MS subtypes. In total, 3869 subjects from eight studies (MS 1666, controls 2203) were considered for meta-analysis. Meta-analysis showed no association between MS and the CCR5-Δ32 allele polymorphism (OR=1.102, 95% CI=0.830-1.462, p=0.502) with a mean frequency of 11.3% in MS patients and 10.4% in controls. Stratification by ethnicity indicated no association between the CCR5-Δ32 allele and MS in Europeans (OR=0.958, 95% CI=0.811-1.132, p=0.618). Meta-analysis by the disease subtype showed no association between RR-MS and the CCR5-Δ32 allele (OR=1.234, 95% CI=0.908-1.677, p=0.178). In addition, no association was found between the CCR5-Δ32 polymorphism and PP or SP-MS. Meta-analysis of 3869 subjects indicates a lack of association between the CCR5-Δ32 polymorphism and MS risk in Europeans.


Desk-based workers' perspectives on using sit-stand workstations: a qualitative analysis of the Stand@Work study.
Prolonged sitting time has been identified as a health risk factor. Sit-stand workstations allow desk workers to alternate between sitting and standing throughout the working day, but not much is known about their acceptability and feasibility. Hence, the aim of this study was to qualitatively evaluate the acceptability, feasibility and perceptions of using sit-stand workstations in a group of desk-based office workers. This article describes the qualitative evaluation of the randomized controlled cross-over Stand@Work pilot trial. Participants were adult employees recruited from a non-government health agency in Sydney, Australia. The intervention involved using an Ergotron Workfit S sit-stand workstation for four weeks. After the four week intervention, participants shared their perceptions and experiences of using the sit-stand workstation in focus group interviews with 4-5 participants. Topics covered in the focus groups included patterns of workstation use, barriers and facilitators to standing while working, effects on work performance, physical impacts, and feasibility in the office. Focus group field notes and transcripts were analysed in an iterative process during and after the data collection period to identify the main concepts and themes. During nine 45-min focus groups, a total of 42 participants were interviewed. Participants were largely intrinsically motivated to try the sit-stand workstation, mostly because of curiosity to try something new, interest in potential health benefits, and the relevance to the participant's own and organisation's work. Most participants used the sit-stand workstation and three common usage patterns were identified: task-based routine, time-based routine, and no particular routine. Common barriers to sit-stand workstation use were working in an open plan office, and issues with sit-stand workstation design. Common facilitators of sit-stand workstation use were a supportive work environment conducive to standing, perceived physical health benefits, and perceived work benefits. When prompted, most participants indicated they were interested in using a sit-stand workstation in the future. The use of a sit-stand workstation in this group of desk-based office workers was generally perceived as acceptable and feasible. Future studies are needed to explore this in different desk-based work populations and settings.


Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering RNA on ovarian cancer cell growth.
Interleukin-8 (IL-8) is a proangiogenic cytokine that is overexpressed in many human cancers. We investigated the clinical and biologic significance of IL-8 in ovarian carcinoma using human samples and orthotopic mouse models. Tumor expression of IL-8 was assessed by immunohistochemistry among ovarian cancer patients (n = 102) with available clinical and survival data. We examined the effect of IL-8 gene silencing with small interfering RNAs incorporated into neutral liposomes (siRNA-DOPCs), alone and in combination with docetaxel, on in vivo tumor growth, angiogenesis (microvessel density), and tumor cell proliferation in mice (n = 10 per treatment group) bearing orthotopic taxane-sensitive (HeyA8 and SKOV3ip1) and taxane-resistant (SKOV3ip2.TR) ovarian tumors. All statistical tests were two-sided. Of the 102 cancer specimens, 43 (42%) had high IL-8 expression and 59 (58%) had low or no IL-8 expression; high IL-8 expression was associated with advanced tumor stage (P = .019), high tumor grade (P = .031), and worse survival (median survival for patients with high vs low IL-8 expression: 1.62 vs 3.79 years; P < .001). Compared with empty liposomes, IL-8 siRNA-DOPC reduced the mean tumor weight by 32% (95% confidence interval [CI] = 14% to 50%; P = .03) and 52% (95% CI = 27% to 78%; P = .03) in the HeyA8 and SKOV3ip1 mouse models, respectively. In all three mouse models, treatment with IL-8 siRNA-DOPC plus the taxane docetaxel reduced tumor growth the most compared with empty liposomes (77% to 98% reduction in tumor growth; P < .01 for all). In the HeyA8 and SKOV3ip1 models, tumors from mice treated with IL-8 siRNA-DOPC alone had lower microvessel density than tumors from mice treated with empty liposomes (HeyA8: 34% lower, 95% CI = 32% to 36% lower [P = .002]; SKOV3ip1: 39% lower, 95% CI = 34% to 44% lower [P = .007]). Compared with empty liposomes, IL-8 siRNA-DOPC plus docetaxel reduced tumor cell proliferation by 35% (95% CI = 25% to 44%; P < .001) and 38% (95% CI = 28% to 48%; P < .001) in the HeyA8 and SKOV3ip1 models, respectively. Increased IL-8 expression is associated with poor clinical outcome in human ovarian carcinoma, and IL-8 gene silencing decreases tumor growth through antiangiogenic mechanisms.


Relevance of inducible nitric oxide synthase for immune control of Mycobacterium avium subspecies paratuberculosis infection in mice.
Mycobacterium avium subspecies paratuberculosis (MAP) causes Johne's disease (JD), an incurable chronic intestinal bowel disease in ruminants. JD occurs worldwide and causes enormous economic burden in dairy industry. Research on JD pathobiology is hampered by its complexity which cannot completely be mimicked by small animal models. As a model the mouse allows dissecting some pathogenicity features of MAP. However, for unknown reasons MAP exhibits reduced growth in granulomas of infected mice compared to other Mycobacterium avium subspecies. Here, we characterized immune reactions of MAP-infected C57BL/6 mice. After infection, mice appeared fully immunocompetent. A strong antigen-specific T cell response was elicited indicated by IFNγ production of splenic T cells re-stimulated with MAP antigens. Function of splenic dendritic cells and proliferation of adoptively transferred antigen-specific CD4+ T cells was unaltered. Isolated splenic myeloid cells from infected mice revealed that MAP resides in CD11b+ macrophages. Importantly, sorted CD11b+CD11c- cells expressed high level of type 2 nitric oxide synthase (NOS2) but only low levels of pro- and anti-inflammatory cytokines. Correspondingly, MAP-infected MAC2 expressing myeloid cells in spleen and liver granuloma displayed strong expression of NOS2. In livers of infected Nos2-/-mice higher bacterial loads, more granuloma and larger areas of tissue damage were observed 5 weeks post infection compared to wild type mice. In vitro, MAP was sensitive to NO released by a NO-donor. Thus, a strong T cell response and concomitant NOS2/NO activity appears to control MAP infection, but allows development of chronicity and pathogen persistence. A similar mechanism might explain persistence of MAP in ruminants.


This Is not Participatory Design - A Critical Analysis of Eight Living Laboratories.
Design of Health Technology for elderly and care personnel has a high priority because of a severe increase of elderly citizens in need of health care combined with a decrease of resources in the health care sector. Desires for maintaining and improving the quality of care while reducing costs has resulted in a search for approaches that support co-operation between technology designers, elderly persons and health care professionals on innovating future care technology. Living laboratories, where areas of a care environment are transformed into a so-called platform for technology innovation, are popular. Expectations for living laboratories are high but examinations of how such laboratories support the intended participatory innovation are few. This paper presents and examines eight living laboratories set up in Danish nursing homes for technology innovation. We present the notion of a living laboratory and explicate the aspirations and expectations of this approach, and discuss why these expectations are hard to meet both on a general level and in the investigated labs. We question the basic assumptions of the possibility of reconciling the different interests of the stakeholders involved. In our analysis we focus on users in the living laboratories. We use guiding principles developed within Participatory Design to reveal the role and participation of the users - the health care professionals and the elderly - in the eight living laboratories. In general, these users played a minor role, in the labs where technical problems turned out to be main activity. We conclude that living laboratories do not nullify different/conflicting interests and that a real-life setting by itself is no guarantee for user participation.


The impact of rheumatoid arthritis on the risk of adverse events following joint replacement: a real-world cohort study.
To assess whether rheumatoid arthritis (RA) is associated with a greater risk of adverse events following total knee replacement (TKR) and total hip replacement (THR) than osteoarthritis (OA). Individuals with a diagnosis of RA or OA were identified using primary care records. TKR and THR following diagnosis were identified using linked hospital records. Myocardial infarction (MI), prosthetic joint infection (PJI), venous thromboembolism (VTE), and death were identified within 90 days following surgery, and revision procedures over 10 years following surgery. The impact of RA compared to OA on the risk for these adverse events was assessed using Cox proportional hazard models. Univariable models, with diagnosis as the only explanatory variable, and multivariable models, with age, gender, and year of surgery first added and then a measure of other comorbidities also included, were estimated. In all 20,763 individuals, with 10,260 TKR and 10,961 THR, were included in the analysis. Compared to those with OA, individuals with a diagnosis of RA had a greater incidence of MI over 90 days following TKR (OA: 0.28%, RA: 0.75%) and revision over 10 years following THR (OA: 5.55%, RA: 8.68%). Both of these differences were statistically significant with, for example, hazard ratios of 3.54 (1.44 to 8.73) for MI and 1.61 (1.06 to 2.46) for revision after controlling for age, gender, year of surgery, and other comorbidities. These findings suggest that, compared to individuals with OA, those with RA have an increased short-term risk of MI following TKR. While risk of MI remains below 1%, this does underline the importance of the management of cardiovascular risk factors for those with RA. RA was also associated with an increased long-term risk of revision following THR, which strengthens the argument for investing in therapies which may prevent the need for joint replacement.


Randomised controlled short-term intervention pilot study on rye bran bread in prostate cancer.
The short-term effects of rye bran bread intake in prostate cancer were investigated. Ten men with conservatively treated prostate cancer were randomised to a daily supplement of 295 g of rye bran bread and eight men to 275 g of wheat bread (control) with similar fibre content for three weeks. Blood samples, ultrasound-guided core biopsies of the prostate, and urine samples were taken. In the rye group, there was a significant increase in plasma enterolactone, and the apoptotic index increased significantly from 2.1% (SD 1.3) to 5.9% (SD 1.8), P<0.005 as measured by a TUNEL index in four cases in the rye group and seven cases in the control group. Besides a significant decrease in weight in both groups, only small changes were observed in plasma concentrations of prostate specific antigen (PSA), circulating sex hormones, excreted oestrogens, insulin-like growth factor (IGF)-I, and in the endothelial fibrinolytical system. High intake of rye bran bread is suggested to increase apoptosis in prostate tumours.


DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), known to be more common in the elderly, who also show more severe symptoms and are at higher risk of hospitalization and death. Here, we show that the expression of the angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 cell receptor, increases during aging in mouse and human lungs. ACE2 expression increases upon telomere shortening or dysfunction in both cultured mammalian cells and in vivo in mice. This increase is controlled at the transcriptional level, and Ace2 promoter activity is DNA damage response (DDR)-dependent. Both pharmacological global DDR inhibition of ATM kinase activity and selective telomeric DDR inhibition by the use of antisense oligonucleotides prevent Ace2 upregulation following telomere damage in cultured cells and in mice. We propose that during aging telomere dysfunction due to telomeric shortening or damage triggers DDR activation and this causes the upregulation of ACE2, the SARS-CoV-2 cell receptor, thus contributing to make the elderly more susceptible to the infection.


Thrombectomy Technique Predicts Outcome in Posterior Circulation Stroke-Insights from the STAR Collaboration.
Randomized controlled trials evaluating mechanical thrombectomy (MT) for acute ischemic stroke predominantly studied anterior circulation patients. Both procedural and clinical predictors of outcome in posterior circulation patients have not been evaluated in large cohort studies. To investigate technical and clinical predictors of functional independence after posterior circulation MT while comparing different frontline thrombectomy techniques. In a retrospective multicenter international study of 3045 patients undergoing MT for stroke between 06/2014 and 12/2018, 345 patients had posterior circulation strokes. MT was performed using aspiration, stent retriever, or combined approach. Functional outcomes were assessed using the 90-d modified Rankin score dichotomized into good (0-2) and poor outcomes (3-6). We included 2700 patients with anterior circulation and 345 patients with posterior circulation strokes. Posterior patients (age: 60 ± 14, 46% females) presented with mainly basilar occlusion (80%) and were treated using contact aspiration or ADAPT (39%), stent retriever (31%) or combined approach (19%). Compared to anterior strokes, posterior strokes had delayed treatment (500 vs 340 min, P < .001), higher national institute of health stroke scale (NIHSS) (17.1 vs 15.7, P < .01) and lower rates of good outcomes (31% vs 43%, P < .01). In posterior MT, diabetes (OR = 0.28, 95%CI: 0.12-0.65), admission NIHSS (OR = 0.9, 95%CI: 0.86-0.94), and use of stent retriever (OR = 0.26, 95%CI: 0.11-0.62) or combined approach (OR = 0.35, 95%CI: 0.12-1.01) vs ADAPT were associated with lower odds of good outcome. Stent retriever use was associated with lower odds of good outcomes compared to ADAPT even when including patients with only basilar occlusion or with successful recanalization only. Despite similar safety profiles, use of ADAPT is associated with higher rates of functional independence after posterior circulation thrombectomy compared to stent retriever or combined approach in large "real-world" retrospective study.


A digital peer-to-peer learning platform for clinical skills development.
Due to constraints in time and resources, medical curricula may not provide adequate opportunities for pre-clerkship students to practice clinical skills. To address this, medical students at the University of Alberta developed a digital peer-to-peer learning initiative. The initiative assessed if students can learn clinical skills from their peers in co-curricular practice objective structured clinical exams (OSCEs). A total of 144 first-year medical students participated. Students wrote case scenarios that were reviewed by physicians. Students enacted the cases in practice OSCEs, acting as the patient, physician, and evaluator. Verbal and electronic evaluations were completed. A digital platform was used to automate the process. Surveys were disseminated to assess student perceptions of their experience. Seventy-five percent of participants said they needed opportunities to practice patient histories and physical exams in addition to those provided in the medical school curriculum. All participants agreed that the co-curricular practice OSCEs met this need. The majority of participants also agreed that the digital platform was efficient and easy to use. Students found the practice OSCEs and digital platform effective for learning clinical skills. Thus, peer-to-peer learning and computer automation can be useful adjuncts to traditional medical curricula.


Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors.
Inhibition of immune regulatory checkpoints, such as CTLA-4 and the PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade. Furthermore, we describe the emerging evidence of how the strong interrelationship between the immune system and the host microbiota can determine responses to cancer therapies, and we introduce a concept by which prior or concomitant modulation of the gut microbiome could optimize therapeutic outcomes upon immune-checkpoint blockade.


Adult consumers' understanding and use of information on food labels: a study among consumers living in the Potchefstroom and Klerksdorp regions, South Africa.
To identify the information that adult consumers use on food labels, the difficulties they experience when using food labels and their reasons for not always using food labels. The relationship between their understanding of the information on the food label and their ability to make informed food choices was also investigated by means of their being required to perform labelling tasks. A cross-sectional and descriptive research approach was followed. Data were collected by means of the administration of questionnaires. Selected supermarkets in Potchefstroom and Klerksdorp in the North West Province, South Africa. Questionnaires were administered to 174 consumers of African descent and Caucasians, ≥18 years of age, who were involved in purchasing household food products. The information that is mostly used on food labels includes the expiry date, the list of ingredients and nutritional information, such as fat and cholesterol content. The difficulties associated with food labels were indicated mainly as being the font size of the print, whereas the reasons for not reading food labels were related to product attributes ('taste and price are more important than is the nutritional content of the food product'), demographic characteristics ('lack of education and nutritional knowledge') and situational factors ('experiencing time constraints'). Results from the present study indicated that the expiry date was the most important information on a food label used by consumers. Scores from the labelling tasks showed that the respondents did not always understand how to use the information on food labels in order to make informed food choices. Barriers to consumer understanding and the use of food labels are highlighted. Improvements on current food labels in South Africa are suggested. Guidelines for consumer education regarding the use of food labels are also provided.


A review of the current knowledge on Zeugodacus cucurbitae (Coquillett) (Diptera, Tephritidae) in Africa, with a list of species included in Zeugodacus.
This paper reviews all available information regarding the occurrence and biology of the melon fly, Zeugodacus cucurbitae (Coquillett), in the Afrotropical Region, including data on invasion history, distribution patterns, population genetics, host range, and interspecific competition. Although limited intraspecific variability has been observed within the region regarding the above mentioned aspects, there seems to be no indication that Zeugodacus cucurbitae represents a species complex. A checklist of all of the species included in Zeugodacus as recently proposed by Virgilio et al. (2015) is provided.


Inpatient cancer rehabilitation: the experience of a national comprehensive cancer center.
Cancer rehabilitation is an important but often underutilized treatment in the comprehensive care of the cancer patient. Cancer patients have varying levels of access to rehabilitation services. Acute inpatient, inpatient consultation-based, and outpatient-based cancer rehabilitation services have been described in the literature. We will discuss acute inpatient cancer rehabilitation and some of its outcomes at the University of Texas MD Anderson Cancer Center in Houston, TX, which is the only national comprehensive cancer center to have its own acute inpatient rehabilitation unit dedicated solely to cancer patients. We retrospectively reviewed the inpatient medical records of consecutive inpatients admitted to the acute inpatient cancer rehabilitation unit from September 2008 to August 2009 for the following information: patient age, sex, primary tumor type, rehabilitation diagnoses, length of stay, discharge destination, and payer source. From September 2008 to August 2009, the physical medicine and rehabilitation service at MD Anderson Cancer Center had 1098 inpatient consultations, of which 427 patients were admitted to the inpatient rehabilitation unit with a mean length of stay of 11 days. Of the 427 patients, 73 (17%) were patients with primary neurologic-based tumor, 71 (16%) were patients with hematologic-based tumors, 48 (11%) were sarcoma patients, 35 (8%) were gastrointestinal tumor patients, 27 (6%) were head and neck tumor patients, 25 (6%) were prostate and bladder cancer patients, 24 (6%) were lung cancer patients, 22 (5%) were melanoma patients, 20 (5%) were breast cancer patients, 15 (4%) were renal cancer patients, 14 (3%) were gynecologic cancer patients, and 53 (12%) were patients with other types of cancer. Of the 427 patients admitted to acute inpatient rehabilitation at MD Anderson Cancer Center, 324 (76%) were discharged home, 72 (17%) went back to acute care service, 15 (4%) were sent to a skilled nursing facility, 9 (2%) were discharged to palliative care, and 5 (1%) were discharged to a long-term acute care facility. An active inpatient rehabilitation unit within a national comprehensive cancer center receives referrals from patients with a wide variety of tumor types and is able to successfully discharge home 76% of its patients.


A novel antiviral formulation inhibits a range of enveloped viruses.
Some free fatty acids derived from milk and vegetable oils are known to have potent antiviral and antibacterial properties. However, therapeutic applications of short- to medium-chain fatty acids are limited by physical characteristics such as immiscibility in aqueous solutions. We evaluated a novel proprietary formulation based on an emulsion of short-chain caprylic acid, ViroSAL, for its ability to inhibit a range of viral infections in vitro and in vivo. In vitro, ViroSAL inhibited the enveloped viruses Epstein-Barr, measles, herpes simplex, Zika and orf parapoxvirus, together with Ebola, Lassa, vesicular stomatitis and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) pseudoviruses, in a concentration- and time-dependent manner. Evaluation of the components of ViroSAL revealed that caprylic acid was the main antiviral component; however, the ViroSAL formulation significantly inhibited viral entry compared with caprylic acid alone. In vivo, ViroSAL significantly inhibited Zika and Semliki Forest virus replication in mice following the inoculation of these viruses into mosquito bite sites. In agreement with studies investigating other free fatty acids, ViroSAL had no effect on norovirus, a non-enveloped virus, indicating that its mechanism of action may be surfactant disruption of the viral envelope. We have identified a novel antiviral formulation that is of great interest for the prevention and/or treatment of a broad range of enveloped viruses, particularly those of the skin and mucosal surfaces.


Evolution of eukaryotic cell cycle regulation: stepwise addition of regulatory kinases and late advent of the CDKs.
Protein kinases regulate a number of critical events in mitosis and meiosis. A study of the evolution of kinases involved in cell cycle control (CCC) might shed light on the evolution of the eukaryotic cell cycle. In particular, applying quantitative phylogenetic methods to key CCC kinases could provide information on the relative timing of gene duplication events. To investigate the evolution of CCC kinases, we constructed phylogenetic trees for the CDC28 family and performed statistical tests of the tree topology. This family includes the cyclin-dependent kinases (CDKs), which are key regulators of the eukaryotic cell cycle, as well as other CCC kinases. We found that CDKs and, in particular, the principal cell cycle regulator Cdc28p, branch off the phylogenetic tree at a late stage, after several other kinases involved in either mitosis or meiosis regulation. On the basis of this tree topology, it is proposed that, at early stages of evolution, the eukaryotic cell cycle was not controlled by CDKs and that only a subset of extant kinases, notably the DNA damage checkpoint kinase Chk1p, were in place. During subsequent evolution, a series of duplications of kinase genes occurred, gradually adding more kinases to the CCC system, the CDKs being among the last major additions.


Dynamic partnership between KCNQ1 and KCNE1 and influence on cardiac IKs current amplitude by KCNE2.
Cardiac slow delayed rectifier (IKs) channel is composed of KCNQ1 (pore-forming) and KCNE1 (auxiliary) subunits. Although KCNE1 is an obligate IKs component that confers the uniquely slow gating kinetics, KCNE2 is also expressed in human heart. In vitro experiments suggest that KCNE2 can associate with the KCNQ1-KCNE1 complex to suppress the current amplitude without altering the slow gating kinetics. Our goal here is to test the role of KCNE2 in cardiac IKs channel function. Pulse-chase experiments in COS-7 cells show that there is a KCNE1 turnover in the KCNQ1-KCNE1 complex, supporting the possibility that KCNE1 in the IKs channel complex can be substituted by KCNE2 when the latter is available. Biotinylation experiments in COS-7 cells show that although KCNE1 relies on KCNQ1 coassembly for more efficient cell surface expression, KCNE2 can independently traffic to the cell surface, thus becoming available for substituting KCNE1 in the IKs channel complex. Injecting vesicles carrying KCNE1 or KCNE2 into KCNQ1-expressing oocytes leads to KCNQ1 modulation in the same manner as KCNQ1+KCNEx (where x=1 or 2) cRNA coinjection. Thus, free KCNEx peptides delivered to the cell membrane can associate with existing KCNQ1 channels to modulate their function. Finally, adenovirus-mediated KCNE2 expression in adult guinea pig ventricular myocytes exhibited colocalization with native KCNQ1 protein and reduces the native IKs current density. We propose that in cardiac myocytes the IKs current amplitude is under dynamic control by the availability of KCNE2 subunits in the cell membrane.


ORCAE-AOCC: A Centralized Portal for the Annotation of African Orphan Crop Genomes.
ORCAE (Online Resource for Community Annotation of Eukaryotes) is a public genome annotation curation resource. ORCAE-AOCC is a branch that is dedicated to the genomes published as part of the African Orphan Crops Consortium (AOCC). The motivation behind the development of the ORCAE platform was to create a knowledge-based website where the research-community can make contributions to improve genome annotations. All changes to any given gene-model or gene description are stored, and the entire annotation history can be retrieved. Genomes can either be set to "public" or "restricted" mode; anonymous users can browse public genomes but cannot make any changes. Aside from providing a user- friendly interface to view genome annotations, the platform also includes tools and information (such as gene expression evidence) that enables authorized users to edit and validate genome annotations. The ORCAE-AOCC platform will enable various stakeholders from around the world to coordinate their efforts to annotate and study underutilized crops.


Tumour formation and insulin secretion by clonal RINm5F cells following repeated subcutaneous transplantation in NEDH rats.
The effects of repeated s.c. transplantation of clonal insulin-secreting RINm5F cells in NEDH rats on tumour morphology, insulin-glucose homeostasis and the function of RINm5F cells re-established in culture were examined after maintenance in vivo for periods of up to 308 days. Transplantation of RINm5F cells for ten consecutive passages consistently produced a single encapsulated vascularized tumour associated with the development in recipient rats of hyperinsulinaemia, hypoglycaemia and eventual neuroglycopenic coma. At the tenth passage, tumour-bearing rats exhibited a markedly enhanced rate of insulin-stimulated glucose uptake by 19 days, with evidence of a large and variable insulin response to i.p. glucose. Survival was 22 +/- 2 days, and resected RINm5F cell tumours exhibited weak immunostaining for insulin in scattered cells, with strands of fibrous tissue separating clusters of tumour cells many of which had distinct polarity. There was no detectable immunostaining for glucagon, somatostatin or pancreatic polypeptide. The insulin content and insulin secretory output of RINm5F cells re-established in culture after 20, 146, 259 or 308 days propagation in vivo were generally enhanced compared with non-passaged RINm5F cells. The magnitude of the effect was not appreciably affected by the duration of maintenance in vivo, but it was critically dependent upon the subsequent period of culture in vitro. Thus, whereas 2-day cultured RINm5F cells from the eighth tumour passage exhibited a greater than 100-fold increment of insulin content and release, with enhanced secretory responsiveness to leucine, arginine, theophylline, K+ (25 mmol/l) or Ca2+ (7.6 mmol/l), RINm5F cells cultured for a further 19 days had almost completely lost the attributes resulting from 259 days of maintenance in vivo. The results indicate substantial enhancement of the functional capabilities of RINm5F cells in vivo, and suggest that the resulting tumours afford a novel model in NEDH rats of responsive trabecular-type insulinomas.


CB 1954: from the Walker tumor to NQO2 and VDEPT.
CB 1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] has been the subject of continued interest for over 30 years. As an anti-cancer agent, it represents one of the very few examples of a compound that shows real anti-tumor selectivity. Unfortunately, for the treatment of human disease, this anti-tumor selectivity was seen only in certain rat tumors. The basis for the anti-tumor selectivity of CB 1954 is that it is a prodrug that is enzymatically activated to generate a difunctional agent, which can form DNA-DNA interstrand crosslinks. The bioactivation of CB 1954 in rat cells involves the aerobic reduction of its 4-nitro group to a 4-hydroxylamine by the enzyme NQO1 (DT-diaphorase). The human form of NQO1 metabolizes CB 1954 much less efficiently than rat NQO1. Thus human tumors are insensitive to CB 1954. In view of the proven success of CB 1954 in the rat system, it would be highly desirable to re-create its anti-tumor activity in man. This has led to the development of CB 1954 analogs and other prodrugs activated by nitroreduction such, as those based on a self-immolative activation mechanism. A gene therapy-based approach for targeting cancer cells and making them sensitive to CB 1954 and related compounds has been developed. VDEPT (gene-directed enzyme prodrug therapy) has been used to express an E. coli nitroreductase in tumor cells and human tumor cells transduced to express this enzyme are very sensitive to prodrugs activated by nitroreduction. CB 1954 is in clinical trial for this application. Recently it has been shown that a latent nitroreductase is present in some human tumors. This is NQO2--an enzyme that requires for activity, the non-biogenic compound dihydronicotinamide riboside (NRH) as a cosubstrate. When active, NQO2 is 3000 times more effective than human DT-diaphorase in the reduction of CB 1954. NRH and reduced pyridinium derivatives that, like NRH, act as co-substrates for NQO2, produce a dramatic increase in the cytotoxicity of CB 1954 against human cell lines in vitro and its anti-tumor activity against certain human xenografts in vivo. NQO2 activity is substantially raised in tumor samples from colorectal and hepatoma patients (up to 14-fold). A phase I clinical trial of an NQO2 co-substrate with CB 1954 is scheduled.


Simultaneous activation of parallel sensory pathways promotes a grooming sequence in Drosophila.
A central model that describes how behavioral sequences are produced features a neural architecture that readies different movements simultaneously, and a mechanism where prioritized suppression between the movements determines their sequential performance. We previously described a model whereby suppression drives a Drosophila grooming sequence that is induced by simultaneous activation of different sensory pathways that each elicit a distinct movement (Seeds et al., 2014). Here, we confirm this model using transgenic expression to identify and optogenetically activate sensory neurons that elicit specific grooming movements. Simultaneous activation of different sensory pathways elicits a grooming sequence that resembles the naturally induced sequence. Moreover, the sequence proceeds after the sensory excitation is terminated, indicating that a persistent trace of this excitation induces the next grooming movement once the previous one is performed. This reveals a mechanism whereby parallel sensory inputs can be integrated and stored to elicit a delayed and sequential grooming response.


Rapid screening of Salmonella enterica serovars Enteritidis, Hadar, Heidelberg and Typhimurium using a serologically-correlative allelotyping PCR targeting the O and H antigen alleles.
Classical Salmonella serotyping is an expensive and time consuming process that requires implementing a battery of O and H antisera to detect 2,541 different Salmonella enterica serovars. For these reasons, we developed a rapid multiplex polymerase chain reaction (PCR)-based typing scheme to screen for the prevalent S. enterica serovars Enteritidis, Hadar, Heidelberg, and Typhimurium. By analyzing the nucleotide sequences of the genes for O-antigen biosynthesis including wba operon and the central variable regions of the H1 and H2 flagellin genes in Salmonella, designated PCR primers for four multiplex PCR reactions were used to detect and differentiate Salmonella serogroups A/D1, B, C1, C2, or E1; H1 antigen types i, g, m, r or z10; and H2 antigen complexes, I: 1,2; 1,5; 1,6; 1,7 or II: e,n,x; e,n,z15. Through the detection of these antigen gene allele combinations, we were able to distinguish among S. enterica serovars Enteritidis, Hadar, Heidelberg, and Typhimurium. The assays were useful in identifying Salmonella with O and H antigen gene alleles representing 43 distinct serovars. While the H2 multiplex could discriminate between unrelated H2 antigens, the PCR could not discern differences within the antigen complexes, 1,2; 1,5; 1,6; 1,7 or e,n,x; e,n,z15, requiring a final confirmatory PCR test in the final serovar reporting of S. enterica. Multiplex PCR assays for detecting specific O and H antigen gene alleles can be a rapid and cost-effective alternative approach to classical serotyping for presumptive identification of S. enterica serovars Enteritidis, Hadar, Heidelberg, and Typhimurium.


Oxidative Stress and Cardiac Remodeling: An Updated Edge.
A common phenotype associated with heart failure is the development of cardiac hypertrophy. Cardiac hypertrophy occurs in response to stress, such as hypertension, coronary vascular disease, or myocardial infarction. The most critical pathophysiological conditions involved may include dilated hypertrophy, fibrosis and contractile malfunction. The intricate pathophysiological mechanisms of cardiac hypertrophy have been the core of several scientific studies, which may help in opening a new avenue in preventive and curative procedures. To our knowledge from the literature, the development of cardiac remodeling and hypertrophy is multifactorial. Thus, in this review, we will focus and summarize the potential role of oxidative stress in cardiac hypertrophy development. Oxidative stress is considered a major stimulant for the signal transduction in cardiac cells pathological conditions, including inflammatory cytokines, and MAP kinase. The understanding of the pathophysiological mechanisms which are involved in cardiac hypertrophy and remodeling process is crucial for the development of new therapeutic plans, especially that the mortality rates related to cardiac remodeling/dysfunction remain high.


Wake-up call for British psychiatry.
The recent drive within the UK National Health Service to improve psychosocial care for people with mental illness is both understandable and welcome: evidence-based psychological and social interventions are extremely important in managing psychiatric illness. Nevertheless, the accompanying downgrading of medical aspects of care has resulted in services that often are better suited to offering non-specific psychosocial support, rather than thorough, broad-based diagnostic assessment leading to specific treatments to optimise well-being and functioning. In part, these changes have been politically driven, but they could not have occurred without the collusion, or at least the acquiescence, of psychiatrists. This creeping devaluation of medicine disadvantages patients and is very damaging to both the standing and the understanding of psychiatry in the minds of the public, fellow professionals and the medical students who will be responsible for the specialty's future. On the 200th birthday of psychiatry, it is fitting to reconsider the specialty's core values and renew efforts to use psychiatric skills for the maximum benefit of patients.


Does sex hormone-binding globulin cause insulin resistance during pubertal growth?
The directional influences between serum sex hormone-binding globulin (SHBG), adiposity and insulin resistance during pubertal growth remain unclear. The aim of this study was to investigate bidirectional associations between SHBG and insulin resistance (HOMA-IR) and adiposity from childhood to early adulthood. Participants were 396 healthy girls measured at baseline (age 11.2 years) and at 1, 2, 4 and 7.5 years. Serum concentrations of estradiol, testosterone and SHBG were determined by ELISA, glucose and insulin by enzymatic photometry, insulin-like growth factor 1 (IGF-1) by time-resolved fluoroimmunoassays, whole-body fat mass by dual-energy X-ray absorptiometry and HOMA-IR were determined by homeostatic model assessment. The associations were examined using cross-lagged path models. In a cross-lagged path model, SHBG predicted HOMA-IR before menarche β = -0.320 (95% CI: -0.552 to -0.089), P = 0.007, independent of adiposity and IGF-1. After menarche, no directional effect was found between SHBG and insulin resistance or adiposity. Our results suggest that in early puberty, decline in SHBG predicts development of insulin resistance, independent of adiposity. However, after menarche, no directional influences between SHBG, adiposity and insulin resistance were found, suggesting that observational associations between SHBG, adiposity and insulin resistance in pubertal children may be subject to confounding. Further research is needed to understand the underlying mechanisms of the associations between SHBG and cardiometabolic risk markers in peripubertal children.


Assessment of left ventricular function by breath-hold cine MR imaging: Comparison of different steady-state free precession sequences.
To compare steady-state free precession (SSFP) sequence protocols with different acquisition times (TA) and temporal resolutions (tRes) due to the implementation of a view sharing technique called shared phases for the assessment of left ventricular (LV) function by breath-hold cine magnetic resonance (MR) imaging. End-diastolic and end-systolic volumes (EDV, ESV) were measured in contiguous short-axis slices with a thickness of 8 mm acquired in 10 healthy male volunteers. The following true fast imaging with steady-state precession (TrueFISP) sequence protocols were compared: protocol A) internal standard of reference, segmented: tRes 34.5 msec, TA 18 beats per slice; protocol B) segmented, shared phases: tRes 34.1 msec, TA 10 beats per slice; and protocol C) real-time, shared phases, parallel acquisition technique: tRes 47.3 msec, TA 24 beats for 12 slices covering the entire left ventricle. Phase sharing leads to a significant decrease in EDV, stroke volume (SV), and ejection fraction (EF) (median difference -7.0 mL [*], -9.6 mL, and -3.4%, respectively, for protocol B; -15.3 mL, -13.3 mL, and -2.4% for protocol C; P = 0.002, *P = 0.021). The observed median difference of real-time EDV and SV estimates is of clinical relevance. Real-time cine MR imaging shows a greater variability of EDV and SV. No relevant differences in ESV were observed. The true cine frame duration of both shared phases sequence protocols exceeds the period of isovolumetric contraction (IVCT) of the left ventricle resulting in a systematic and significant underestimation of EDV and consequently SV and EF. SSFP sequence protocol parameters, particularly tRes and use of view sharing techniques, should therefore be known at follow-up examinations in order to be able to assess LV remodeling in patients with heart failure.


Child maltreatment and hypertension in young adulthood.
Maltreatment during childhood and adolescence has been associated with chronic conditions in adulthood including cardiovascular disease. However, less is known about the effects of childhood maltreatment on cardiovascular risk factors prior to development of cardiovascular disease, or whether these effects are evident in young adulthood. Furthermore, few studies have examined sex differences and most studies have relied on self-reported outcome measures that are subject to misclassification. We examined the relationship between child maltreatment and hypertension in young adulthood in the National Longitudinal Study of Adolescent Health, a nationally representative school-based sample of US adolescents. Participants retrospectively (mean age 29.9, n = 11384) reported on their experiences of child maltreatment prior to the 6th grade (prior to age 11) during follow-up. Child neglect, physical and sexual violence as well as a measure of social services visits to the home were examined. Blood pressure was measured during an in-home visit. Hypertension was defined as measured SBP of at least 140 mmHg or DBP of at least 90 mmHG measured in adulthood, or self-reported use of antihypertensive medications. In adjusted models, women who experienced sexual abuse in early childhood had a higher prevalence of hypertension (Prevalence Ratio (PR) 1.43 95% CI 1.00, 2.05) compared to women who did not experience sexual abuse. Among men, experiencing sexual abuse was not statistically significantly associated with hypertension. Experiencing neglect, physical abuse or having visitations by social services at home during childhood was not associated with hypertension among either women or men. Sexual abuse in early childhood is associated with hypertension in young women.


Differences in fibertract profiles between patients with migraine and those with persistent post-traumatic headache.
Often, persistent post-traumatic headache and migraine are phenotypically similar. However, the similarities and differences in the neuropathological underpinnings of persistent post-traumatic headache and migraine require further understanding. We used diffusion tensor imaging (DTI) and a novel method for detecting subtle changes in fibertract integrity by measuring node-by-node parameters along each tract to compare fibertract profiles between those with migraine and those with persistent post-traumatic headache, and compared both cohorts to a group of controls. Eighteen fibertracts were reconstructed for 131 subjects, including 49 patients with persistent post-traumatic headache attributed to mild traumatic brain injury, 41 with migraine, and 41 controls. Node-by-node diffusion parameters of mean diffusivity and radial diffusivity were calculated along each tract. Mean diffusivity and radial diffusivity measurements were averaged along quartiles of each tract for statistical interpretation and group comparison. Using a post-hoc analysis, correlations between tract quartile measurements and headache frequency were calculated. There were significant differences between migraine and persistent post-traumatic headache cohorts for quartile measurements of mean diffusivity or radial diffusivity in the bilateral anterior thalamic radiations, cingulum (angular bundles and cingulate gyri), inferior longitudinal fasciculi, and uncinate fasciculi, the left corticospinal tract, and the right superior longitudinal fasciculi-parietal portion. For migraine patients, there was a significant positive correlation between headache frequency and forceps major mean diffusivity, whereas for persistent post-traumatic headache there was a positive correlation between headache frequency and cingulum angular bundle mean diffusivity and radial diffusivity. Quartile measurements of radial diffusivity and mean diffusivity indicate unique differences in fibertract profiles between those with migraine vs. persistent post-traumatic headache. Although for both migraine and persistent post-traumatic headache there was a positive relationship between fibertract alterations and headache frequency, there were disease-specific differences between headache frequency and fibertract injury patterns. These findings might suggest potential differences in the neuropathological mechanisms underlying migraine and persistent post-traumatic headache.


Clinical outcome and clinicopathological characteristics of recurrence after laparoscopic gastrectomy for advanced gastric cancer.
Although laparoscopic gastrectomy has been recognized as a treatment of early gastric cancer, the indication for laparoscopic gastrectomy with D2 lymph node dissection has remained controversial. D2 lymph node dissection is considered to be feasible for advanced gastric cancer in some high-volume institutions specifically trained for the laparoscopic procedure. This study was undertaken to determine the clinical outcome and clinicopathological characteristics of patients who showed recurrence following laparoscopic gastrectomy for advanced gastric cancer. From August 1999 through February 2009, among 805 patients who underwent laparoscopic gastrectomy associated with regional lymph node dissection, a total of 209 patients undergoing gastrectomy associated with lymph node dissection who consequently obtained complete resection for advanced gastric cancer were subjected to the retrospective analysis to evaluate clinical outcome. The mean period of postoperative observation was 1,068 days. The final stages of the 209 cases were as follows: 83 in IB, 56 in II, 46 in IIIA, and 24 in IIIB. The 5-year survival rate was 89.1% in stage IB, 93.1% in stage II, 52.5% in stage IIIA, and 46.5% in stage IIIB, respectively. A total of 27 patients (12.9%) had recurrence. Postoperative recurrence of gastric carcinoma occurred in peritoneal dissemination in 13 patients, liver in 7, distant lymph nodes in 6, ovary in 3, lung in 2, skin in 1, and meninges in 1 patient. There were neither port-site metastases nor locoregional recurrence. The characteristics and the rate of postoperative recurrence after laparoscopic gastrectomy for advanced gastric cancer were not greatly different from those of the open conventional procedure. Although further observation is required to finally conclude long-term survival, laparoscopic radical gastrectomy may possibly be indicated for patients with advanced gastric cancer.


Plasmodium falciparum malaria endemicity in Indonesia in 2010.
Malaria control programs require a detailed understanding of the contemporary spatial distribution of infection risk to efficiently allocate resources. We used model based geostatistics (MBG) techniques to generate a contemporary map of Plasmodium falciparum malaria risk in Indonesia in 2010. Plasmodium falciparum Annual Parasite Incidence (PfAPI) data (2006-2008) were used to map limits of P. falciparum transmission. A total of 2,581 community blood surveys of P. falciparum parasite rate (PfPR) were identified (1985-2009). After quality control, 2,516 were included into a national database of age-standardized 2-10 year old PfPR data (PfPR(2-10)) for endemicity mapping. A Bayesian MBG procedure was used to create a predicted surface of PfPR(2-10) endemicity with uncertainty estimates. Population at risk estimates were derived with reference to a 2010 human population count surface. We estimate 132.8 million people in Indonesia, lived at risk of P. falciparum transmission in 2010. Of these, 70.3% inhabited areas of unstable transmission and 29.7% in stable transmission. Among those exposed to stable risk, the vast majority were at low risk (93.39%) with the reminder at intermediate (6.6%) and high risk (0.01%). More people in western Indonesia lived in unstable rather than stable transmission zones. In contrast, fewer people in eastern Indonesia lived in unstable versus stable transmission areas. While further feasibility assessments will be required, the immediate prospects for sustained control are good across much of the archipelago and medium term plans to transition to the pre-elimination phase are not unrealistic for P. falciparum. Endemicity in areas of Papua will clearly present the greatest challenge. This P. falciparum endemicity map allows malaria control agencies and their partners to comprehensively assess the region-specific prospects for reaching pre-elimination, monitor and evaluate the effectiveness of future strategies against this 2010 baseline and ultimately improve their evidence-based malaria control strategies.


Optimization of LiNbO₃ photonic crystals: toward 3D LiNbO₃ micro-components.
We report easy-to-implement techniques to improve the reflectivity of LiNbO₃ photonic crystals within the photonic bandgap. Firstly, we show that widening the channel waveguides confines the optical modes in the vertical direction, which leads to the development of the first 2D-PhCs on Ti-indiffused LiNbO₃ waveguides. We also report the first optical characterization of PhCs implemented on ridge LiNbO₃ waveguides. The reflectivity is measured using a swept-source optical coherence tomography (OCT) system, together with the transmission spectrum. Finally we report 3D-PhCs LiNbO₃ fabricated by Focused Ion Beam milling on the side of ridge waveguides.


Sequence-specific recognition of double helical RNA and RNA.DNA by triple helix formation.
The stabilities of eight triple helical pyrimidine.purine.pyrimidine structures comprised of identical sequence but different RNA (R) or DNA (D) strand combinations were measured by quantitative affinity cleavage titration. The differences in equilibrium binding affinities reveal the importance of strand composition. For the sequences studied here, the stabilities of complexes containing a pyrimidine third strand D or R and purine.pyrimidine double helical DD, DR, RD, and RR decrease in order: D + DD, R + DD, R + DR, D + DR > R + RD, R + RR >> D + RR, D + RD (pH 7.0, 25 degrees C, 100 mM NaCl/1 mM spermine). These findings suggest that RNA and DNA oligonucleotides will be useful for targeting (i) double helical DNA and (ii) RNA.DNA hybrids if the purine Watson-Crick strand is DNA. However, RNA, but not DNA, oligonucleotides will be useful for sequence-specific binding of (i) double helical RNA and (ii) RNA.DNA hybrids if the purine Watson-Crick strand is RNA. This has implications for the design of artificial ligands targeted to specific sequences of double helical RNA and RNA.DNA hybrids.