Radial versus right internal thoracic artery as a second arterial conduit for coronary surgery: early and midterm outcomes.
We sought to compare early and midterm clinical outcomes in patients receiving a right internal thoracic artery or a radial artery as the second arterial conduit for myocardial revascularization. Data prospectively collected for all patients who underwent coronary artery bypass surgery between April 1996 and May 2001 and who received both a left internal thoracic artery graft and either a right internal thoracic artery (n = 336) or a radial artery graft (n = 325) were analyzed. Patients in the radial artery group were older, with a greater body mass index, poorer ejection fraction, greater prevalence of diabetes, and higher New York Heart Association class than those in the right internal thoracic artery group. Odds ratios for perioperative myocardial infarction, atrial fibrillation, postoperative transfusion, and intensive care unit stay all showed a statistically significant benefit in the radial artery group compared with results in the right internal thoracic artery group (P <or=.05). Survival estimates at 18 months for patients who received right internal thoracic artery and radial artery grafts were 98.4% and 99.7%, respectively (hazard ratio, 0.25; 95% confidence interval, 0.06-1.10; P =.07). Estimates for survival free from any cardiac-related event or death in the right internal thoracic artery and radial artery groups were 92.3% and 97.8%, respectively (hazard ratio, 0.37; 95% confidence interval, 0.16-0.84; P =.02). A multivariate Cox regression model showed a stronger protective effect of a radial artery graft (hazard ratio, 0.25; 95% confidence interval, 0.12-0.51; P <.0001). Early and midterm outcomes of myocardial revascularization with 2 arterial grafts are better if the radial artery is used for the second graft rather than the right internal thoracic artery, assuming that the left internal thoracic artery is used for the first arterial graft.


Enhanced oxygen-release/storage properties of Pd-loaded Sr3Fe2O7-δ.
This study proves that a small amount of Pd loading (1 wt%) on Sr3Fe2O7-δ can dramatically enhance the oxygen-storage properties of Sr3Fe2O7-δ. The topotactic oxygen intake and release between Sr3Fe2O6.75 and Sr3Fe2O6 takes place in response to gas switching between an O2 flow and H2 flow, regardless of the presence or absence of Pd loading. The effect of Pd loading is significant for the oxygen-release process under H2 atmosphere; that is, highly dispersed Pd metal nanoparticles sized less than 1 nm formed on Pd/Sr3Fe2O7-δ to promote H2 dissociation, resulting in the improvement of the oxygen-release temperature and rate. Pd/Sr3Fe2O7-δ with a layered perovskite structure has a higher oxygen-release property at lower temperature than Pd/SrFeO3-δ with a perovskite phase without the layered structure. These facts indicate that the surface reaction as well as the crystal structure are responsible for the oxide ion mobility in perovskite structure, and also provide guidelines for designing novel oxygen-storage materials.


Analysis of the metal requirement of 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase from Escherichia coli.
The three isozymes of 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase from Escherichia coli were overproduced, purified, and characterized with respect to their requirement for metal cofactor. The isolated isozymes contained 0.2-0.3 mol of iron/mol of enzyme monomer, variable amounts of zinc, and traces of copper. Enzymatic activity of the native enzymes was stimulated 3-4-fold by the addition of Fe2+ ions to the reaction mixture and was eliminated by treatment of the enzymes with EDTA. The chelated enzymes were reactivated by a variety of divalent metal ions, including Ca2+, Cd2+, Co2+, Cu2+, Fe2+, Mn2+, Ni2+, and Zn2+. The specific activities of the reactivated enzymes varied widely with the different metals as follows: Mn2+ greater than Cd2+, Fe2+ greater than Co2+ greater than Ni2+, Cu2+, Zn2+ much greater than Ca2+. Steady state kinetic analysis of the Mn2+, Fe2+, Co2+, and Zn2+ forms of the phenylalanine-sensitive isozyme (DAHPS(Phe)) revealed that metal variation significantly affected the apparent affinity for the substrate, erythrose 4-phosphate, but not for the second substrate, phosphoenolpyruvate, or for the feedback inhibitor, L-phenylalanine. The tetrameric DAHPS(Phe) exhibited positive homotropic cooperativity with respect to erythrose 4-phosphate, phophoenolpyruvate, and phenylalanine in the presence of all metals tested.


Fiber-based polarization-sensitive OCT of the human retina with correction of system polarization distortions.
In polarization-sensitive optical coherence tomography (PS-OCT) the use of single-mode fibers causes unpredictable polarization distortions which can result in increased noise levels and erroneous changes in calculated polarization parameters. In the current paper this problem is addressed by a new Jones matrix analysis method that measures and corrects system polarization distortions as a function of wavenumber by spectral analysis of the sample surface polarization state and deeper located birefringent tissue structures. This method was implemented on a passive-component depth-multiplexed swept-source PS-OCT system at 1040 nm which was theoretically modeled using Jones matrix calculus. High-resolution B-scan images are presented of the double-pass phase retardation, diattenuation, and relative optic axis orientation to show the benefits of the new analysis method for in vivo imaging of the human retina. The correction of system polarization distortions yielded reduced phase retardation noise, and better estimates of the diattenuation and the relative optic axis orientation in weakly birefringent tissues. The clinical potential of the system is shown by en face visualization of the phase retardation and optic axis orientation of the retinal nerve fiber layer in a healthy volunteer and a glaucoma patient with nerve fiber loss.


Reduction of cingulate gray matter density in poor outcome bipolar illness.
Structural brain abnormalities are associated with poor outcome unipolar depressive disorder. Gray matter density can be assessed with an automated, operator independent analysis (SPM99). We thus compared 11 poor outcome bipolar patients with 15 age-, sex- and IQ-matched healthy volunteers with a standard neuropsychological examination and an Elscint 2.0 Tesla MRI scanner. At the time of examination, patients were neither hypomanic nor significantly depressed, but were significantly impaired on the McGlashan scale. Their memory function was characterized by reduced performance in the California verbal learning and digit-symbol substitution tests. Statistical parametric mapping revealed abnormal gray matter density, mainly in fronto-limbic cortex, but particularly widespread in cingulate cortex. Although causality of these changes is difficult to resolve, the results offer useful insights into the neural correlates of severe bipolar disorder.


Policymaker experiences with rapid response briefs to address health-system and technology questions in Uganda.
Health service and systems researchers have developed knowledge translation strategies to facilitate the use of reliable evidence for policy, including rapid response briefs as timely and responsive tools supporting decision making. However, little is known about users' experience with these newer formats for presenting evidence. We sought to explore Ugandan policymakers' experience with rapid response briefs in order to develop a format acceptable for policymakers. We used existing research regarding evidence formats for policymakers to inform the initial version of rapid response brief format. We conducted user testing with healthcare policymakers at various levels of decision making in Uganda, employing a concurrent think-aloud method, collecting data on elements including usability, usefulness, understandability, desirability, credibility and value of the document. We modified the rapid response briefs format based on the results of the user testing and sought feedback on the new format. The participants generally found the format of the rapid response briefs usable, credible, desirable and of value. Participants expressed frustrations regarding several aspects of the document, including the absence of recommendations, lack of clarity about the type of document and its potential uses (especially for first time users), and a crowded front page. Participants offered conflicting feedback on preferred length of the briefs and use and placement of partner logos. Users had divided preferences for the older and newer formats. Although the rapid response briefs were generally found to be of value, there are major and minor frustrations impeding an optimal user experience. Areas requiring further research include how to address policymakers' expectations of recommendations in these briefs and their optimal length.


Use of ecallantide in pediatric hereditary angioedema.
Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare autosomal dominant disease that manifests as sudden unpredictable attacks of subcutaneous or submucosal edema affecting the skin, intestine, and upper airway. Ecallantide is a plasma kallikrein inhibitor indicated for treatment of HAE attacks in patients aged 16 years and older. This analysis examines safety and efficacy of ecallantide for treatment of HAE attacks in patients <18 years of age. Data for patients aged 9 to 17 years treated subcutaneously with 30 mg ecallantide or placebo were pooled from 4 clinical studies (2 double-blind, placebo-controlled and 2 open-label). Efficacy end points included 2 HAE-specific patient-reported outcome measures: mean symptom complex severity (MSCS) score and treatment outcome score (TOS). Times to initial improvement, sustained improvement, and complete or near-complete symptom resolution were calculated. Treatment-emergent adverse events were examined. Overall, 29 pediatric patients were included; 25 of them received ecallantide for 62 total HAE attacks, and 10 received placebo for 10 total attacks. Ecallantide-treated attacks revealed clinically relevant reduction in symptom severity at 4 hours postdosing based on mean change in MSCS score (-1.4 ± 0.9 ecallantide versus -0.9 ± 0.6 placebo) and TOS (73.9 ± 35.50 ecallantide versus 45.0 ± 43.78 placebo). Patients treated with ecallantide showed rapid improvement in symptoms (median time to complete or near-complete symptom resolution: 181 minutes). No serious adverse events related to treatment were observed. Ecallantide appears effective for HAE attacks in adolescents, with rapid symptom improvement. No unexpected safety issues were identified.


Effects of acute and 14-day coenzyme Q10 supplementation on exercise performance in both trained and untrained individuals.
To determine whether acute (single dose) and/or chronic (14-days) supplementation of CoQ10 will improve anaerobic and/or aerobic exercise performance by increasing plasma and muscle CoQ10 concentrations within trained and untrained individuals. Twenty-two aerobically trained and nineteen untrained male and female subjects (26.1 +/- 7.6 yrs, 172 +/- 8.7 cm, 73.5 +/- 17 kg, and 21.2 +/- 7.0%) were randomized to ingest in a double-blind manner either 100 mg of a dextrose placebo (CON) or a fast-melt CoQ10 supplement (CoQ10) twice a day for 14-days. On the first day of supplementation, subjects donated fasting blood samples and a muscle biopsy. Subjects were then given 200 mg of the placebo or the CoQ10 supplement. Sixty minutes following supplement ingestion, subjects completed an isokinetic knee extension endurance test, a 30-second wingate anaerobic capacity test, and a maximal cardiopulmonary graded exercise test interspersed with 30-minutes of recovery. Additional blood samples were taken immediately following each exercise test and a second muscle biopsy sample was taken following the final exercise test. Subjects consumed twice daily (morning and night), 100 mg of either supplement for a period of 14-days, and then returned to the lab to complete the same battery of tests. Data was analyzed using repeated measures ANOVA with an alpha of 0.05. Plasma CoQ10 levels were significantly increased following 2 weeks of CoQ10 supplementation (p < 0.001); while a trend for higher muscle CoQ10 levels was observed after acute CoQ10 ingestion (p = 0.098). A trend for lower serum superoxide dismutase (SOD) was observed following acute supplementation with CoQ10 (p = 0.06), whereas serum malondialdehyde (MDA) tended to be significantly higher (p < 0.05). Following acute ingestion of CoQ10, plasma CoQ10 levels were significantly correlated to muscle CoQ10 levels; maximal oxygen consumption; and treadmill time to exhaustion. A trend for increased time to exhaustion was observed following 2 weeks of CoQ10 supplementation (p = 0.06). Acute supplementation with CoQ10 resulted in higher muscle CoQ10 concentration, lower serum SOD oxidative stress, and higher MDA levels during and following exercise. Chronic CoQ10 supplementation increased plasma CoQ10 concentrations and tended to increase time to exhaustion. Results indicate that acute and chronic supplementation of CoQ10 may affect acute and/or chronic responses to various types of exercise.


A health systems resilience research agenda: moving from concept to practice.
Health system resilience, known as the ability for health systems to absorb, adapt or transform to maintain essential functions when stressed or shocked, has quickly gained popularity following shocks like COVID-19. The concept is relatively new in health policy and systems research and the existing research remains mostly theoretical. Research to date has viewed resilience as an outcome that can be measured through performance outcomes, as an ability of complex adaptive systems that is derived from dynamic behaviour and interactions, or as both. However, there is little congruence on the theory and the existing frameworks have not been widely used, which as diluted the research applications for health system resilience. A global group of health system researchers were convened in March 2021 to discuss and identify priorities for health system resilience research and implementation based on lessons from COVID-19 and other health emergencies. Five research priority areas were identified: (1) measuring and managing systems dynamic performance, (2) the linkages between societal resilience and health system resilience, (3) the effect of governance on the capacity for resilience, (4) creating legitimacy and (5) the influence of the private sector on health system resilience. A key to filling these research gaps will be longitudinal and comparative case studies that use cocreation and coproduction approaches that go beyond researchers to include policy-makers, practitioners and the public.


Membranes Are Decisive for Maximum Freezing Efficiency of Bacterial Ice Nucleators.
Ice-nucleating proteins (INPs) from Pseudomonas syringae are among the most active ice nucleators known, enabling ice formation at temperatures close to the melting point of water. The working mechanisms of INPs remain elusive, but their ice nucleation activity has been proposed to depend on the ability to form large INP aggregates. Here, we provide experimental evidence that INPs alone are not sufficient to achieve maximum freezing efficiency and that intact membranes are critical. Ice nucleation measurements of phospholipids and lipopolysaccharides show that these membrane components are not part of the active nucleation site but rather enable INP assembly. Substantially improved ice nucleation by INP assemblies is observed for deuterated water, indicating stabilization of assemblies by the stronger hydrogen bonds of D2O. Together, these results show that the degree of order/disorder and the assembly size are critically important in determining the extent to which bacterial INPs can facilitate ice nucleation.


Effect of Linagliptin on Cognitive Performance in Patients With Type 2 Diabetes and Cardiorenal Comorbidities: The CARMELINA Randomized Trial.
Type 2 diabetes is associated with cognitive dysfunction and an increased dementia risk, particularly in individuals with concomitant cardiovascular and/or kidney disease. Incretin therapies may modulate this risk via glycemic and nonglycemic pathways. We explored if the dipeptidyl peptidase 4 inhibitor linagliptin could prevent cognitive decline in people with type 2 diabetes with cardiorenal disease. The CArdiovascular and Renal Microvascular outcomE study with LINAgliptin (CARMELINA)-COG substudy was an integral part of CARMELINA (NCT01897532) that randomized participants with cardiorenal disease to linagliptin 5 mg or placebo once daily (1:1), in addition to standard of care. The primary cognitive outcome was the occurrence of accelerated cognitive decline at the end of treatment, defined as a regression-based index score ≤16th percentile on the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning and analyzed in participants with a baseline MMSE ≥24. Effects across subgroups by baseline factors, as well as absolute cognitive changes, were also assessed. Of the 6,979 participants in CARMELINA, CARMELINA-COG included 1,545 (mean ± SD age, 68 ± 8 years; MMSE, 28.3 ± 1.7; estimated glomerular filtration rate, 52 ± 23 mL/min/1.73 m2; and HbA1c, 7.8 ± 0.9% [61.4 ± 10.1 mmol/mol]). Over a median treatment duration of 2.5 years, accelerated cognitive decline occurred in 28.4% (linagliptin) vs. 29.3% (placebo) (odds ratio 0.96 [95% CI 0.77, 1.19]). Consistent effects were observed across subgroups by baseline characteristics. Absolute cognitive performance changes were also similar between treatment groups. In a large international cardiovascular outcome trial in people with type 2 diabetes and cardiorenal disease, linagliptin did not modulate cognitive decline over 2.5 years.


"Do your homework…and then hope for the best": the challenges that medical tourism poses to Canadian family physicians' support of patients' informed decision-making.
Medical tourism-the practice where patients travel internationally to privately access medical care-may limit patients' regular physicians' abilities to contribute to the informed decision-making process. We address this issue by examining ways in which Canadian family doctors' typical involvement in patients' informed decision-making is challenged when their patients engage in medical tourism. Focus groups were held with family physicians practicing in British Columbia, Canada. After receiving ethics approval, letters of invitation were faxed to family physicians in six cities. 22 physicians agreed to participate and focus groups ranged from two to six participants. Questions explored participants' perceptions of and experiences with medical tourism. A coding scheme was created using inductive and deductive codes that captured issues central to analytic themes identified by the investigators. Extracts of the coded data that dealt with informed decision-making were shared among the investigators in order to identify themes. Four themes were identified, all of which dealt with the challenges that medical tourism poses to family physicians' abilities to support medical tourists' informed decision-making. Findings relevant to each theme were contrasted against the existing medical tourism literature so as to assist in understanding their significance. Four key challenges were identified: 1) confusion and tensions related to the regular domestic physician's role in decision-making; 2) tendency to shift responsibility related to healthcare outcomes onto the patient because of the regular domestic physician's reduced role in shared decision-making; 3) strains on the patient-physician relationship and corresponding concern around the responsibility of the foreign physician; and 4) regular domestic physicians' concerns that treatments sought abroad may not be based on the best available medical evidence on treatment efficacy. Medical tourism is creating new challenges for Canadian family physicians who now find themselves needing to carefully negotiate their roles and responsibilities in the informed decision-making process of their patients who decide to seek private treatment abroad as medical tourists. These physicians can and should be educated to enable their patients to look critically at the information available about medical tourism providers and to ask critical questions of patients deciding to access care abroad.


The innate immune rheostat: influence on lung inflammatory disease and secondary bacterial pneumonia.
The activity of innate immunity is not simply dictated by the presence of an antigen but also by the balance between negative regulatory and immune potentiator pathways. Even in the absence of antigen, innate immunity can 'inflame' if negative regulators are absent. This resting state is adaptable and dictated by environmental influences, host genetics and past infection history. A return to homoeostasis post inflammation may therefore not leave the tissue in an identical state to that prior to the inflammatory event. This adaptability makes us all unique and also explains the variable outcome experienced by a diverse population to the same inflammatory stimulus. Using murine models we have identified that influenza virus causes a long-term modification of the lung microenvironment by a de-sensitization to bacterial products and an increase in the myeloid negative regulator CD200R (CD200 receptor). These two events prevent subsequent inflammatory damage while the lung is healing, but also they may predispose to bacterial colonization of the lower respiratory tract should regulatory mechanisms overshoot. In the extreme, this leads to bacterial pneumonia, sepsis and death. A deeper understanding of the consequences arising from innate immune cell alteration during influenza infection and the subsequent development of bacterial complications has important implications for future drug development.


Cellular senescence and aging: the role of B-MYB.
Cellular senescence is a stable cell cycle arrest, caused by insults, such as: telomere erosion, oncogene activation, irradiation, DNA damage, oxidative stress, and viral infection. Extrinsic stimuli such as cell culture stress can also trigger this growth arrest. Senescence is thought to have evolved as an example of antagonistic pleiotropy, as it acts as a tumor suppressor mechanism during the reproductive age, but can promote organismal aging by disrupting tissue renewal, repair, and regeneration later in life. The mechanisms underlying the senescence growth arrest are broadly considered to involve p16(INK4A) -pRB and p53-p21(CIP1/WAF1/SDI1) tumor suppressor pathways; but it is not known what makes the senescence arrest stable and what the critical downstream targets are, as they are likely to be key to the establishment and maintenance of the senescent state. MYB-related protein B (B-MYB/MYBL2), a member of the myeloblastosis family of transcription factors, has recently emerged as a potential candidate for regulating entry into senescence. Here, we review the evidence which indicates that loss of B-MYB expression has an important role in causing senescence growth arrest. We discuss how B-MYB acts, as the gatekeeper, to coordinate transit through the cell cycle, in conjunction with the multivulval class B (MuvB) complex and FOXM1 transcription factors. We also evaluate the evidence connecting B-MYB to the mTOR nutrient signaling pathway and suggest that inhibition of this pathway leading to an extension of healthspan may involve activation of B-MYB.


T-cell responses to autoantigens in IDDM. The search for the Holy Grail.
IDDM (type I diabetes) is generally believed to result from T-cell-mediated autoimmune destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans. In the last few years, considerable progress has been made with regard to the identification and characterization of candidate autoantigens recognized by autoantibodies; several of these candidate autoantigens are recognized by T-cells, including insulin, GAD65 and GAD67, heat-shock protein 65 (hsp65), and islet-cell antigen 69 (ICA69). In addition to these, a number of unidentified beta-cell antigens, including insulin-secretory granule membrane proteins and a 38-kDa protein, have been shown to stimulate T-cells of IDDM patients. However, T-cell autoreactivity to islet antigens is not specific for IDDM, and the T-cell target antigens are not specific for beta-cells. Moreover, the autoantigens involved in the initiation of the insulitis must be defined, and the mechanism of the T-cell-dependent beta-cell destruction remains to be unraveled. This review focuses on T-cell autoreactivity in IDDM in humans and the implications of the present knowledge for immunointervention and monitoring of immunotherapeutic trials.


Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities.
Considerable evidence is available in support of an independent association between obstructive sleep apnoea syndrome (OSAS) and cardiovascular disease, which is particularly strong for systemic arterial hypertension and growing for ischaemic heart disease, stroke, heart failure, atrial fibrillation and cardiac sudden death. The pathogenesis of cardiovascular disease in OSAS is not completely understood but likely to be multifactorial, involving a diverse range of mechanisms including sympathetic nervous system overactivity, selective activation of inflammatory molecular pathways, endothelial dysfunction, abnormal coagulation and metabolic dysregulation, the latter particularly involving insulin resistance and disordered lipid metabolism. The present report, which arose out of a European Union Cooperation in the field of Scientific and Technical Research (COST) action on OSAS (COST B26), reviews the current evidence for an independent association and proposes research priorities to identify the underlying mechanisms involved, with a view to identifying novel therapeutic strategies. Large-scale collaborative studies of carefully defined patient populations with obstructive sleep apnoea syndrome, adequately controlled for potential confounders, are needed. Such studies carry the prospect of evaluating potential interactions between different basic mechanisms operating in obstructive sleep apnoea syndrome and cardiovascular disease, and interactions with other related disorders, such as obesity, diabetes and dyslipidaemia. Furthermore, translational studies involving cell culture and animal models linked to studies of obstructive sleep apnoea syndrome patients are necessary to integrate basic mechanisms with the clinical disorder.


Effect of magnification on locating the MB2 canal in maxillary molars.
The purpose of this study was to determine if the surgical operating microscope and/or dental loupes could enhance the practitioner's ability to locate the second mesiobuccal canal (MB2) canal of maxillary molars in an in vivo, clinical setting. The participating endodontists documented 312 cases of root canal therapy on maxillary first and second molars. Participants that used the microscope or dental loupes located the MB2 canal with a frequency of 57.4% and 55.3%, respectively. Those using no magnification located the MB2 canal with a frequency of 18.2%. When no magnification was used, significantly fewer MB2 canals were located based by Chi-square analysis at p < 0.01. There was no significant difference between the use of the microscope and dental loupes in the frequency of locating the MB2 canal. When the maxillary first molars were considered separately, the frequency of MB2 canal detection for the microscope, dental loupes, and no magnification groups was 71.1%, 62.5%, and 17.2%, respectively. The results of this study show that the use of magnification in combined groups leads to a MB2 detection rate approximately three times that of the nonmagnification group and that the use of no magnification results in the location of significantly fewer MB2 canals. Based on these results, more emphasis should be placed on the importance of using magnification for locating the MB2 canal.


Contemporary epidemiological overview of malaria in Madagascar: operational utility of reported routine case data for malaria control planning.
Malaria remains a major public health problem in Madagascar. Widespread scale-up of intervention coverage has led to substantial reductions in case numbers since 2000. However, political instability since 2009 has disrupted these efforts, and a resurgence of malaria has since followed. This paper re-visits the sub-national stratification of malaria transmission across Madagascar to propose a contemporary update, and evaluates the reported routine case data reported at this sub-national scale. Two independent malariometrics were evaluated to re-examine the status of malaria across Madagascar. First, modelled maps of Plasmodium falciparum infection prevalence (PfPR) from the Malaria Atlas Project were used to update the sub-national stratification into 'ecozones' based on transmission intensity. Second, routine reports of case data from health facilities were synthesized from 2010 to 2015 to compare the sub-national epidemiology across the updated ecozones over time. Proxy indicators of data completeness are investigated. The epidemiology of malaria is highly diverse across the island's ecological regions, with eight contiguous ecozones emerging from the transmission intensity PfPR map. East and west coastal areas have highest transmission year-round, contrasting with the central highlands and desert south where trends appear more closely associated with epidemic outbreak events. Ecozones have shown steady increases in reported malaria cases since 2010, with a near doubling of raw reported case numbers from 2014 to 2015. Gauges of data completeness suggest that interpretation of raw reported case numbers will underestimate true caseload as only approximately 60-75 % of health facility data are reported to the central level each month. A sub-national perspective is essential when monitoring the epidemiology of malaria in Madagascar and assessing local control needs. A robust assessment of the status of malaria at a time when intervention coverage efforts are being scaled up provides a platform from which to guide intervention preparedness and assess change in future periods of transmission.


Towards measurement of the Healthy Ageing Phenotype in lifestyle-based intervention studies.
Given the biological complexity of the ageing process, there is no single, simple and reliable measure of how healthily someone is ageing. Intervention studies need a panel of measures which capture key features of healthy ageing. To help guide our research in this area, we have adopted the concept of the "Healthy Ageing Phenotype" (HAP) and this study aimed to (i) identify the most important features of the HAP and (ii) identify/develop tools for measurement of those features. After a comprehensive assessment of the literature we selected the following domains: physiological and metabolic health, physical capability, cognitive function, social wellbeing, and psychological wellbeing which we hoped would provide a reasonably holistic characterisation of the HAP. We reviewed the literature and identified systematic reviews and/or meta-analysis of cohort studies, and clinical guidelines on outcome measures of these domains relevant to the HAP. Selection criteria for these measures included: frequent use in longitudinal studies of ageing; expected to change with age; evidence for strong association with/prediction of ageing-related phenotypes such as morbidity, mortality and lifespan; whenever possible, focus on studies measuring these outcomes in populations rather than on individuals selected on the basis of a particular disease; (bio)markers that respond to (lifestyle-based) intervention. Proposed markers were exposed to critique in a Workshop held in Newcastle, UK in October 2012. We have selected a tentative panel of (bio)markers of physiological and metabolic health, physical capability, cognitive function, social wellbeing, and psychological wellbeing which we propose may be useful in characterising the HAP and which may have utility as outcome measures in intervention studies. In addition, we have identified a number of tools which could be applied in community-based intervention studies designed to enhance healthy ageing. We have proposed, tentatively, a panel of outcome measures which could be deployed in community-based, lifestyle intervention studies. The evidence base for selection of measurement domains is less well developed in some areas e.g. social wellbeing (where the definition of the concept itself remains elusive) and this has implications for the identification of appropriate tools. Although we have developed this panel as potential outcomes for intervention studies, we recognise that broader agreement on the concept of the HAP and on tools for its measurement could have wider utility and e.g. could facilitate comparisons of healthy ageing across diverse study designs and populations.


Alignment-independent bilinear multivariate modelling (AIBIMM) for global analyses of 16S rRNA gene phylogeny.
Alignment-independent phylogenetic methods have interesting properties for global phylogenetic reconstructions, particularly with respect to speed and accuracy. Here, we present a novel multimer-based alignment-independent bilinear mathematical modelling (AIBIMM) approach for global 16S rRNA gene phylogenetic analyses. In AIBIMM, jackknife cross-validated principal component analyses (PCA) are used to explain the variance in nucleotide n-mer frequency data. We compared AIBIMM with alignment-based distance, maximum-parsimony and maximum-likelihood phylogenetic methods, analysing taxa belonging to the Proteobacteria (n=82), Actinobacteria (n=30) and Archaea (n=7). These analyses indicated an attraction between the Actinobacteria and Archaea for the traditional methods, with the two taxa Acidimicrobium and Rubrobacter at the root of the tree. AIBIMM, on the other hand, showed that the Actinobacteria was tightly clustered, with Acidimicrobium and Rubrobacter within a distinct subgroup of the Actinobacteria. The application of AIBIMM was further evaluated, analysing full-length 16S rRNA gene sequences for 2818 taxa representing the prokaryotic domains. We obtained a highly structured description of the prokaryote diversity. Sample-to-model (Si) distances were also determined for taxa included in our work. We determined Si distances for models of the six major subgroups of taxa detected in the global analyses, in addition to nested subgroups within the Alphaproteobacteria. The Si-distance evaluation showed a very good separation of the taxa within the models from those outside. We conclude that AIBIMM represents a novel phylogenetic framework suitable for accommodating the current exponential growth of 16S rRNA gene sequences in the public domain.


Ultrasound detection of vascular decompression bubbles: the influence of new technology and considerations on bubble load.
Diving often causes the formation of 'silent' bubbles upon decompression. If the bubble load is high, then the risk of decompression sickness (DCS) and the number of bubbles that could cross to the arterial circulation via a pulmonary shunt or patent foramen ovale increase. Bubbles can be monitored aurally, with Doppler ultrasound, or visually, with two dimensional (2D) ultrasound imaging. Doppler grades and imaging grades can be compared with good agreement. Early 2D imaging units did not provide such comprehensive observations as Doppler, but advances in technology have allowed development of improved, portable, relatively inexpensive units. Most now employ harmonic technology; it was suggested that this could allow previously undetectable bubbles to be observed. This paper provides a review of current methods of bubble measurement and how new technology may be changing our perceptions of the potential relationship of these measurements to decompression illness. Secondly, 69 paired ultrasound images were made using conventional 2D ultrasound imaging and harmonic imaging. Images were graded on the Eftedal-Brubakk (EB) scale and the percentage agreement of the images calculated. The distribution of mismatched grades was analysed. Fifty-four of the 69 paired images had matching grades. There was no significant difference in the distribution of high or low EB grades for the mismatched pairs. Given the good level of agreement between pairs observed, it seems unlikely that harmonic technology is responsible for any perceived increase in observed bubble loads, but it is probable that our increasing use of 2D ultrasound to assess dive profiles is changing our perception of 'normal' venous and arterial bubble loads. Methods to accurately investigate the load and size of bubbles developed will be helpful in the future in determining DCS risk.


Marital status and HIV prevalence among women in Nigeria: Ingredients for evidence-based programming.
To assess the influence of marital status and other correlates on HIV infection among women in Nigeria. Data were extracted from the 2012 Nigerian population-based HIV/AIDS and reproductive health survey. The survey determined the HIV status of consenting women using standard procedures. Data were weighted and analyzed using descriptive statistics and logistic regression at the 5% significance level. HIV prevalence among currently married and never married women was 3.4%, but was 5.9% among formerly married women. The odds of HIV infection were found to be 1.8 times higher among formerly married women compared with currently married women (odds ratio (OR) 1.8, 95% confidence interval (CI) 1.3-2.5) and never married women (OR 1.8, 95% CI 1.2-2.6). Also, the odds of HIV infection were 1.5 times higher among women who had made their sexual debut before the age of 15 years (adjusted OR 1.5, 95% CI 1.1-2.1) compared with women who delayed it. The odds of HIV infection were 1.4 times higher among women who had recently had transactional sex (adjusted OR 1.4, 95% CI 1.1-2.0) compared with others. Being formerly married, under 15 years of age at first sex, and having engaged in transactional sex were found to be the strongest HIV risk factors among women. Besides empowering formerly married women and providing better social security, these women should be targeted in HIV programming and policies.


End-of-Life Cancer Care: Temporal Association between Homecare Nursing and Hospitalizations.
Most cancer patients want to die at home, but scaleable models to achieve this are not well researched. Our objective was to investigate the temporal association of homecare nursing, especially by generalist nurses, with reduced end-of-life hospitalizations. We conducted a retrospective Canadian cohort study of end-of-life cancer decedents during 2004-2009 in Ontario (ON), Nova Scotia (NS), and British Columbia (BC), which have homecare systems that use generalist nurses to provide end-of-life care. Each province linked administrative databases to examine the association during the last six months of life between the homecare nursing rate and the hospitalization rate in the subsequent week, using standardized definitions and controlling for other covariates. We dichotomized nursing into standard and end-of-life care intent. Our cohort included 83,827 cancer decedents. Approximately 55% of decedents were older than 70 and the most common cancer was lung. Nearly 85% of the cohort had at least one hospital admission. Receiving end-of-life compared to standard homecare nursing significantly reduced a patient's hospitalization rate by 34%, 33%, and 17% in ON, BC, and NS. In the last month of life patients having a standard nursing rate of greater than five hours compared to one hour per week had a significantly lower hospitalization rate (relative reduction of 15%-23%) across the three provinces. Our study showed a protective effect of nursing with an end-of-life intent on hospitalization across the last six months of life and of standard nursing in the last month. This finding's generalizability is strengthened, since the trends were similar across three different homecare systems.


Maternal depression, antidepressant use and placental oxytocin receptor DNA methylation: Findings from the MPEWS study.
The aim of this study was to investigate placental DNA methylation of the oxytocin receptor gene (OXTR) in women with depression in pregnancy. We also explored the role of antidepressant medication in pregnancy on placental OXTR methylation. Data were obtained from 239 women in the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS), a selected pregnancy cohort. Current depressive disorders were diagnosed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID-IV). Depressive symptoms were measured during the third trimester in pregnancy using the Edinburgh Postnatal Depression Scale (EPDS). Plasma levels of antidepressant drugs were measured in maternal and cord blood obtained at delivery. OXTR DNA methylation was measured in placenta samples. Depressive symptoms in pregnancy were not associated with significant changes in DNA methylation of OXTR in the placenta. Cord plasma antidepressant levels were more strongly associated than maternal antidepressant dose or circulating blood antidepressant levels with increased DNA methylation of a specific unit within the promotor region of OXTR. This study provides preliminary data to suggest that antidepressant use during pregnancy can alter OXTR methylation in placental tissue. Our findings also indicate that the way exposures are measured in pregnancy can influence the direction and strength of findings. Future studies should investigate whether altered OXTR methylation might mediate the impacts of maternal antidepressant treatment on pregnancy and offspring outcomes.


Angiogenesis correlates with macrophage and mast cell infiltration in lung tissue of animals exposed to fluoro-edenite fibers.
Angiogenesis plays a crucial role in progression of pleural malignant mesothelioma. A significantly increased incidence of pleural mesothelioma has been attributed to exposure to fluoro-edenite, a fibrous amphibole extracted from a local stone quarry. In this study, we have investigated the expression of CD68-positive macrophages, tryptase-positive mast cells and CD31 positive areas, as expression of microvascular density, in lung tissue of sheeps exposed to fluoro-edenite fibers vs controls, by immunohistochemical, morphometric and Western blot analysis. The result have evidenced a significant increase in the expression of CD68-positive macrophages, tryptase-positive mast cells as well as a significant increase in microvascular density evaluated as CD31 positive areas in lung tissue of of sheeps exposed to fluoro-edenite fibers vs controls. These data confirmed the important role played by tumor microenvironment components, including macrophages and mast cells, in favour of angiogenesis in pleural mesothelioma induced by fluoro-edenite exposure.


Exposing racial discrimination: implicit & explicit measures--the My Body, My Story study of 1005 US-born black & white community health center members.
To date, research on racial discrimination and health typically has employed explicit self-report measures, despite their potentially being affected by what people are able and willing to say. We accordingly employed an Implicit Association Test (IAT) for racial discrimination, first developed and used in two recent published studies, and measured associations of the explicit and implicit discrimination measures with each other, socioeconomic and psychosocial variables, and smoking. Among the 504 black and 501 white US-born participants, age 35-64, randomly recruited in 2008-2010 from 4 community health centers in Boston, MA, black participants were over 1.5 times more likely (p<0.05) to be worse off economically (e.g., for poverty and low education) and have higher social desirability scores (43.8 vs. 28.2); their explicit discrimination exposure was also 2.5 to 3.7 times higher (p<0.05) depending on the measure used, with over 60% reporting exposure in 3 or more domains and within the last year. Higher IAT scores for target vs. perpetrator of discrimination occurred for the black versus white participants: for "black person vs. white person": 0.26 vs. 0.13; and for "me vs. them": 0.24 vs. 0.19. In both groups, only low non-significant correlations existed between the implicit and explicit discrimination measures; social desirability was significantly associated with the explicit but not implicit measures. Although neither the explicit nor implicit discrimination measures were associated with odds of being a current smoker, the excess risk for black participants (controlling for age and gender) rose in models that also controlled for the racial discrimination and psychosocial variables; additional control for socioeconomic position sharply reduced and rendered the association null. Implicit and explicit measures of racial discrimination are not equivalent and both warrant use in research on racial discrimination and health, along with data on socioeconomic position and social desirability.


Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline.
Cognitive decline following surgery in older individuals is a major clinical problem of uncertain mechanism; a similar cognitive decline also follows severe infection, chemotherapy, or trauma and is currently without effective therapy. A variety of mechanisms have been proposed, and exploring the role of inflammation, we recently reported the role of IL-1β in the hippocampus after surgery in mice with postoperative cognitive dysfunction. Here, we show that TNF-α is upstream of IL-1 and provokes its production in the brain. Peripheral blockade of TNF-α is able to limit the release of IL-1 and prevent neuroinflammation and cognitive decline in a mouse model of surgery-induced cognitive decline. TNF-α appears to synergize with MyD88, the IL-1/TLR superfamily common signaling pathway, to sustain postoperative cognitive decline. Taken together, our results suggest a unique therapeutic potential for preemptive treatment with anti-TNF antibody to prevent surgery-induced cognitive decline.


SHANK3 Regulates Intestinal Barrier Function Through Modulating ZO-1 Expression Through the PKCε-dependent Pathway.
The integrity of the gut barrier in patients with inflammatory bowel disease is known to be impaired but the exact mechanisms remain mostly unknown. SHANK3 mutations are associated with autism, and patients with autism are known to have higher proportions of inflammatory bowel disease. Here, we explore the role of SHANK3 in inflammatory bowel disease, both in vivo and in vitro. Dextran sulfate sodium colitis was induced in SHANK3 knockout mice. Transepithelial electrical resistance, paracellular permeability, and Salmonella invasion assays were used to evaluate epithelial barrier function, in vitro and in vivo. Expression of tight junction proteins, protein kinases, and MAP kinase phosphorylation changes were analyzed by immunoblotting after overexpression or knockdown of SHANK3 expression. SHANK3 expression in intestinal tissue from patients with Crohn's disease was analyzed by quantitative polymerase chain reaction and immunohistochemistry. SHANK3 knockout mice were more susceptible to dextran sulfate sodium. SHANK3 knockout resulted in a leaky epithelial barrier phenotype, as demonstrated by decreased transepithelial electrical resistance, increased paracellular permeability, and increased Salmonella invasion. Overexpression of SHANK3 enhanced ZO-1 expression, and knockdown of SHANK3 resulted in decreased expression of ZO-1. Regulation of ZO-1 expression by SHANK3 seems to be mediated through a PKCε-dependent pathway. SHANK3 expression correlated with ZO-1 and PKCε in colonic tissue of patients with Crohn's disease. The expression level of SHANK3 affects ZO-1 expression and the barrier function in intestinal epithelial cells. This may provide novel insights in Crohn's disease pathogenesis and treatment.


In vivo assessment of basal and drug-induced dopamine release in cortical and subcortical regions of the anesthetized primate.
There is an acute interest in studying the functional characteristics of dopamine systems in the cortex of primates. In particular, the prefrontal cortical dopamine projections have received a great deal of attention. This system is essential for proper functioning of the prefrontal cortex, and dysfunction within the system may be involved in some psychiatric and neurological illnesses. In vivo assessments of cortical dopamine in the primate have been scarce. This has been due, in part, to technical difficulties associated with these studies and with quantifying the relatively low levels of dopamine found in cortical regions. In the present study, intracerebral microdialysis was utilized to assess the extracellular concentration of dopamine in cortical and subcortical areas of the pentobarbital-anesthetized rhesus monkey. Basal extracellular dopamine levels were consistently detected in the medial prefrontal cortex, premotor cortex, and caudate-putamen. The basal extracellular concentration of dopamine in the dorsolateral prefrontal cortex was reliably detected in 1 of 4 animals. Intravenous administration of amphetamine (1 mg/kg) enhanced extracellular dopamine levels in the caudate-putamen area by more than 20-fold. In cortical areas, amphetamine's effect was less profound: An increase of 400-500 percent over basal extracellular dopamine levels was observed in each region. These studies demonstrate the feasibility of microdialysis for detecting extracellular fluxes of dopamine in the cortex of nonhuman primates. They further provide direct evidence that the dopamine released within the prefrontal cortex and the premotor cortex of nonhuman primates responds to pharmacological manipulation.


Dynamic and ligand-selective interactions of vitamin D receptor with retinoid X receptor and cofactors in living cells.
The vitamin D receptor (VDR) mediates vitamin D signaling in numerous physiological and pharmacological processes, including bone and calcium metabolism, cellular growth and differentiation, immunity, and cardiovascular function. Although transcriptional regulation by VDR has been investigated intensively, an understanding of ligand-selective dynamic VDR conformations remains elusive. Here, we examined ligand-dependent dynamic interactions of VDR with retinoid X receptor (RXR), steroid receptor coactivator 1 (SRC-1), and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) in cells using fluorescence resonance energy transfer (FRET) and chromatin immunoprecipitation (ChIP) assays. We compared the effects of 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], lithocholic acid (LCA), and (25R)-25-adamantyl-1α,25-dihydroxy-2-methylene-22,23-didehydro-19,26,27-trinor-20-epivitamin D(3) (ADTT), a partial agonist/antagonist vitamin D derivative. In the absence of ligand, VDR homodimers were preferred to RXR heterodimers and were associated with SMRT. 1,25(OH)(2)D(3) induced heterodimerization with RXR, dissociation of SMRT, and association of SRC-1. LCA and ADTT induced those effects to a lesser extent at concentrations that did not induce expression of the VDR target gene CYP24A1 in human embryonic kidney (HEK) 293 cells. Unlike in HEK293 cells, ADTT increased CYP24A1 expression in HCT116 cells and increased the association of VDR and SMRT on the CYP24A1 promoter. The results indicate that ligand-selective conformation may lead to unique cofactor complex formation in a cell context-dependent manner. The combination of FRET and ChIP assays is a powerful tool useful in understanding ligand-selective dynamic VDR conformations and the development of selective VDR modulators.


CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence.
Multiple early gastric cancers (EGCs) may develop in 6-14% of patients even after achieving curative endoscopic submucosal dissection (ESD); however, a useful biomarker for predicting recurrence is not available. The present study investigated whether the expression of CD44 variant 9 (CD44v9), a functional cancer stem cell marker, in the primary gastric cancer tissue represents an indicator of recurrence. Eighty-eight patients who underwent ESD for EGC from 2008 to 2010 were enrolled and monitored for recurrence for 3 years. The expression levels of CD44v9 in the tissue of initial EGCs were evaluated by immunohistochemistry, and the recurrence rate was compared between CD44v9-positive and CD44v9-negative groups. The mucin phenotype and expression of microRNA-21 (miR-21) and programmed cell death protein 4 (PDCD4) were also analysed. The recurrence rate of EGC was significantly higher in the CD44v9-positive group than in the CD44v9-negative group (hazard ratio (HR), 21.8; 95% confidence interval (CI), 5.71-83.1). However, mucin phenotypes and the expression of miR-21 and PDCD4 did not predict recurrence after ESD. Meanwhile, grade of gastric atrophy was also identified as a significant marker of multiple recurrence (HR, 4.95; 95% CI, 1.30-18.8). CD44 variant 9 expression represents a potential predictive marker for recurrence in EGC.


Photoreceptor rhodopsin: structural and conformational study of its chromophore 11-cis retinal in oriented membranes by deuterium solid state NMR.
Rhodopsin is the retinal photoreceptor responsible for visual signal transduction. To determine the orientation and conformation of retinal within the binding pocket of this membrane bound receptor, an ab initio solid state 2H NMR approach was used. Bovine rhodopsin containing 11-cis retinal, specifically deuterated at its methyl groups at the C19 or C20 position, was uniaxially oriented in DMPC bilayers. Integrity of the membranes and quality of alignment were monitored by 31P NMR. Analysis of the obtained 2H NMR spectra provided angles for the individual labelled chemical bond vectors leading to an overall picture for the three dimensional structure of the polyene chain of the chromophore in the protein binding pocket around the Schiff base attachment site.


Combining transcription factor binding affinities with open-chromatin data for accurate gene expression prediction.
The binding and contribution of transcription factors (TF) to cell specific gene expression is often deduced from open-chromatin measurements to avoid costly TF ChIP-seq assays. Thus, it is important to develop computational methods for accurate TF binding prediction in open-chromatin regions (OCRs). Here, we report a novel segmentation-based method, TEPIC, to predict TF binding by combining sets of OCRs with position weight matrices. TEPIC can be applied to various open-chromatin data, e.g. DNaseI-seq and NOMe-seq. Additionally, Histone-Marks (HMs) can be used to identify candidate TF binding sites. TEPIC computes TF affinities and uses open-chromatin/HM signal intensity as quantitative measures of TF binding strength. Using machine learning, we find low affinity binding sites to improve our ability to explain gene expression variability compared to the standard presence/absence classification of binding sites. Further, we show that both footprints and peaks capture essential TF binding events and lead to a good prediction performance. In our application, gene-based scores computed by TEPIC with one open-chromatin assay nearly reach the quality of several TF ChIP-seq data sets. Finally, these scores correctly predict known transcriptional regulators as illustrated by the application to novel DNaseI-seq and NOMe-seq data for primary human hepatocytes and CD4+ T-cells, respectively.


Patient-reported quality of life and toxicity in unilateral and bilateral radiotherapy for early-stage human papillomavirus associated tonsillar carcinoma.
The purpose of this study was to compare self-reported health-related quality of life (QoL) and symptom burden in early stage tonsillar carcinoma patients treated with unilateral (URT) and bilateral radiotherapy (BRT). This is a secondary analysis of a larger study assessing patient reported outcomes in human papillomavirus (HPV) oropharyngeal cancer (OPC) patients. Recruited patients were ≥12 months from completion of radiotherapy. This analysis included only patients with T1-2, N1-2b tonsil cancer and excluded patients with base of tongue involvement or recurrent disease. QoL and patient reported toxicity was measured using the EORTC QLQ-C30 module and the MDASI-HN. Patients were enrolled from November 2018 to May 2019. Of the 136 patients recruited to the main study, 43 were eligible for this substudy (22 URT, 21 BRT), with a median age and follow up of 58.2 and 3.0 years respectively. The two groups were balanced with respect to patient, tumor and treatment factors with the exception of higher rates of T2 disease (27% v 71%, p = 0.006) and more extensive GTV nodal volumes (11.0 v 25.5cc, p = 0.006) in the BRT group.BRT patients had lower global health status/QoL (84 v 69, p = 0.0005) and social functioning scores (93 vs 78, p = 0.033) on the EORTC QLQ-C30, and higher symptom severity (0.6 vs. 2.0, p = 0.001) and symptom interference scores (0.8 vs. 2.0, p = 0.010) on the MDASI-HN. Four of the six largest differences observed on MDASI-HN items were attributable to radiotherapy technique (dry mouth, mucous, difficulty swallowing/chewing and taste), with corresponding dose differences to the respective organs (contralateral parotid, oral cavity and pharyngeal constrictors). In every instance, severity of symptoms was worse on average for patients treated with BRT. In the highly conformal radiotherapy era, BRT in early HPV tonsillar cancer survivors has an enduring impact on long-term QoL and toxicity.


Whole-Blood Gene Expression Profiles in Large-Scale Epidemiological Studies: What Do They Tell?
In nutrigenomics, gene expression profiling is used to investigate transcriptional mechanisms associated with nutrients and diet. Blood samples collected in the framework of dietary interventions and epidemiological studies allow the use of humans as the model system, as opposed to using cell lines or animal models. Here, we review recent publications in the field of gene expression profiling, based on a systematic literature search focusing on studies from the last 5 years and including studies that investigated either single nutrients, foods, food groups, or dietary patterns. Findings highlight the role of inflammatory processes as key mediators of the association between diet and disease and point to the relevance of using blood as the target tissue in nutrigenomics. However, recurring challenges include study design issues, practical and statistical challenges, and biological interpretation of the results. Many of the published studies have small sample size, and given the nature of gene expression data, their conclusions have limited impact. These challenges should be addressed by future nutrigenomics studies in order to increase their relevance and validity.


Improved contact predictions using the recognition of protein like contact patterns.
Given sufficient large protein families, and using a global statistical inference approach, it is possible to obtain sufficient accuracy in protein residue contact predictions to predict the structure of many proteins. However, these approaches do not consider the fact that the contacts in a protein are neither randomly, nor independently distributed, but actually follow precise rules governed by the structure of the protein and thus are interdependent. Here, we present PconsC2, a novel method that uses a deep learning approach to identify protein-like contact patterns to improve contact predictions. A substantial enhancement can be seen for all contacts independently on the number of aligned sequences, residue separation or secondary structure type, but is largest for β-sheet containing proteins. In addition to being superior to earlier methods based on statistical inferences, in comparison to state of the art methods using machine learning, PconsC2 is superior for families with more than 100 effective sequence homologs. The improved contact prediction enables improved structure prediction.


Improving the surface biocompatibility with the use of mixed zwitterionic self-assembled monolayers prepared by a proper solvent.
In this study, the mixed self-assembled monolayers (SAMs) containing the mixture of long-chain alkanethiol, SH(CH(2))(11)NH(2) and SH(CH(2))(10)SO(3)H, was prepared as a model surface to examine the interaction between the biological environment and artificial surface. The 10% (v/v) NH(4)OH ethanolic solution and DMSO were chosen as the solvents for the preparation of these mixed SAMs and the "solvent effect" was discussed. X-ray photoelectron spectroscopy (XPS) has indicated that -SO(3)H/-NH(2) mixed SAMs formed from 10% (v/v) NH(4)OH ethanolic solution were surface "-SO(3)H poor", while a nearly equivalent amount of surface -SO(3)H functionality was presented on the mixed SAMs formed from DMSO. This has resulted from the different solvation capability between solvent molecules and the alkanethiol. Such solvent effects were also reflected in various surface properties such as surface wettability and surface zeta potential. The mixed SAMs formed from DMSO were more surface hydrophilic and less negatively surface charged than from 10% (v/v) NH(4)OH ethanolic solution. In addition, these mixed SAMs formed from DMSO exhibited the least amount of protein adsorbed as well as a better platelet compatibility than its counterpart from 10% (v/v) NH(4)OH ethanolic solution. These findings indicated that choosing a proper solvent for mixed zwitterionic SAM can greatly affect its surface properties and biocompatibility, such as to form a surface with near neutrality for reducing protein adsorption and subsequent platelet adhesion and activation.


Frequent positive staining with NKI/C3 in normal and neoplastic tissues limits its usefulness in the diagnosis of cellular neurothekeoma.
NKI/C3 originally was described as a marker for melanoma. Recently, it resurfaced as a marker to separate cellular neurothekeoma from other dermal tumors in the differential diagnosis. To determine the sensitivity and specificity of NKI/C3, we evaluated its staining pattern in 709 normal and neoplastic tissues, including 92 dermal tumors, using tissue microarrays and conventional sections. We found that although NKI/C3 is positive in only a few normal tissues, it stains a broad spectrum of neoplastic tissues. NKI/C3 is also positive in many dermal tumors of possible histiocytic origin, including juvenile xanthogranuloma (6/10), atypical fibroxanthoma (4/12), cellular fibrous histiocytoma (5/10), reticulohistiocytoma (3/6), and xanthoma (8/10). However, it is negative in epithelioid cell histiocytomas (0/7) and Langerhans cell histiocytosis (0/9). Given the wide spectrum of positive staining in morphologic mimics of cellular neurothekeomas, pathologists should be cautious when making this diagnosis based solely on positive staining with NKI/C3.


Yeast silent mating type loci form heterochromatic clusters through silencer protein-dependent long-range interactions.
The organization of eukaryotic genomes is characterized by the presence of distinct euchromatic and heterochromatic sub-nuclear compartments. In Saccharomyces cerevisiae heterochromatic loci, including telomeres and silent mating type loci, form clusters at the nuclear periphery. We have employed live cell 3-D imaging and chromosome conformation capture (3C) to determine the contribution of nuclear positioning and heterochromatic factors in mediating associations of the silent mating type loci. We identify specific long-range interactions between HML and HMR that are dependent upon silencing proteins Sir2p, Sir3p, and Sir4p as well as Sir1p and Esc2p, two proteins involved in establishment of silencing. Although clustering of these loci frequently occurs near the nuclear periphery, colocalization can occur equally at more internal positions and is not affected in strains deleted for membrane anchoring proteins yKu70p and Esc1p. In addition, appropriate nucleosome assembly plays a role, as deletion of ASF1 or combined disruption of the CAF-1 and HIR complexes abolishes the HML-HMR interaction. Further, silencer proteins are required for clustering, but complete loss of clustering in asf1 and esc2 mutants had only minor effects on silencing. Our results indicate that formation of heterochromatic clusters depends on correctly assembled heterochromatin at the silent loci and, in addition, identify an Asf1p-, Esc2p-, and Sir1p-dependent step in heterochromatin formation that is not essential for gene silencing but is required for long-range interactions.


Composites of ZnO nanoparticles and biomass based activated carbon: adsorption, photocatalytic and antibacterial capacities.
Composite material (AC-ZnO) was prepared by growing ZnO nanoparticles during the production of biomass based-activated carbon (AC) via the incorporation of zinc acetate in the process. Comprehensive analyses confirmed the presence of ZnO nanoparticles over the AC surface and described the particular nature of the composite adsorbent. Methylene blue (MB) equilibrium data fitted the Dubinin-Radushkevich model. The MB adsorption capacity was higher for the bare activated carbons (197.9-188.7 mg/g) than the activated carbons with ZnO nanoparticles (137.6-149.7 mg/g). The adsorption of the MB on the adsorbents is physical because the mean adsorption energy (E) is between 1.76 and 2.00 kJ/mol. Experiments that combine adsorption and photocatalysis were carried out with different loads of adsorbents and with and without UV-light exposure. Photocatalytic activity was identified mostly at the first stage of the adsorption process and, in the case of experiments with less load of the composite AC-ZnO, because the light obstruction effect of the activated carbon is more for higher loads. The ZnO grown over AC improves the adsorption of cations such as Pb, Al and Fe in aqueous phase (polluted river water) and provides antibacterial capacity against Escherichia coli and Salmonella typhimurium.


The seasonal natural history of the ant, Dolichoderus mariae, in Northern Florida.
Dolichoderus mariae Forel, (Hymenoptera: Formicidae) is an uncommon, monomorphic but locally abundant, reddish-brown ant of peculiar nesting habits, whose range includes most of the eastern USA. In north Florida the ant excavates soil under wiregrass clumps or other plants with fibrous roots to form a single, large, shallow, conical or ovoid chamber broadly open to the surface around the plant base. Colonies are highly polygyne and, during the warm season, inhabit multiple nests connected only by above ground trails, over which nests exchange workers. Although monomorphic, worker size may differ significantly between colonies. The colony cycle is dominated by strong seasonal polydomy. From one or two over-wintering nests, the colonies expanded to occupy up to 60 nests by late summer, then retract once more to one or two nests by mid-winter. The worker-to-queen ratio changed greatly during this cycle, with over two thousand workers per queen during fall and winter, dropping to a low of about 300 during midsummer. Most of these summer queens probably die during the fall. Colonies reoccupy roughly the same area year to year even though they contract down to one or two nests in winter. Observation of fights in the contact zone between colonies suggested that the colonies are territorial. The ants subsist by tending aphids and scale insects for honeydew and scavenging for dead insects within their territories.


Identification of a gene within the tandem array of red and green color pigment genes.
The tandem array of color pigment genes on chromosome Xq28 contains nested exons of a distinct gene. This gene (termed TEX28) is composed of five exons that span almost the entire distance between the protein-coding regions of the color pigment genes and a transketolase-related gene. Although most of the TEX28 gene is repeated within the color pigment gene array, the exclusion of exon 1 from the array is predicted to restrict transcription to a single copy of the gene. The TEX28 gene encodes a polypeptide of 410 amino acid residues. This polypeptide does not display significant homology with any known proteins in public databases. Transcripts of the gene (1.8 kb) were detected in testes, but not in any other tissue examined. Color vision disorders that result from the deletion of color pigment genes should be reappraised for associated phenotypes that may derive from disruption of the TEX28 gene.


Discriminating autism and language impairment and specific language impairment through acuity of musical imagery.
Deficits in auditory short-term memory have been widely reported in children with Specific Language Impairment (SLI), and recent evidence suggests that children with Autism Spectrum Disorder and co-morbid language impairment (ALI) experience similar difficulties. Music, like language relies on auditory memory and the aim of the study was to extend work investigating the impact of auditory short-term memory impairments to musical perception in children with neurodevelopmental disorders. Groups of children with SLI and ALI were matched on chronological age (CA), receptive vocabulary, non-verbal intelligence and digit span, and compared with CA matched typically developing (TD) controls, on tests of pitch and temporal acuity within a voluntary musical imagery paradigm. The SLI participants performed at significantly lower levels than the ALI and TD groups on both conditions of the task and their musical imagery and digit span scores were positively correlated. In contrast ALI participants performed as well as TD controls on the tempo condition and better than TD controls on the pitch condition of the task. Whilst auditory short-term memory and receptive vocabulary impairments were similar across ALI and SLI groups, these were not associated with a deficit in voluntary musical imagery performance in the ALI group.


Mechanistic Insights into the Directed Assembly of Hydrogel Blocks Mediated by Polyelectrolytes or Microgels.
In this study, we report the directed assembly of hydrogel blocks mediated by electrostatic interactions. We compared two different assembly mechanisms, one mediated by microgel particles and another mediated by direct interaction between oppositely charged blocks. The system consisted of hydrogel blocks made of an interpenetrated network of (hydroxyethyl)methacrylate-poly(ethylene glycol)dimethacrylate (HEMA-PEGDMA) and either positively charged polyethylenimine (PEI) or negatively charged hyaluronic acid (HA). Positively charged hydrogel blocks were pretreated with negatively charged microgel particles (MG) made of N-isopropylacrylamide-methacrylic acid. Both systems (PEI/HA and PEI/MG) demonstrated spontaneous directed assembly, meaning that positive blocks were systematically found in contact with oppositely charged blocks. Directed assembly in water of PEI/HA blocks resulted in large and open aggregates, while PEI/MG blocks exhibited more compact aggregates. Effects of salt and pH were also assessed for both systems. Inhibition of blocks aggregation was found to appear above a critical salt concentration (CSalt*) which was significantly higher for the PEI/HA system (80 mM) compared to the PEI/MG system (5-20 mM). The observed difference was interpreted in terms of the nanostructure of the contact area between blocks. Blocks aggregation was also found to be controlled by the content of negatively charged groups in the microgels as well as the concentration of MG in the suspension (CMG) used to treat the hydrogel block surfaces. Our results shine light on the subtle differences underlying the adhesion mechanisms between hydrogel blocks and suggest new routes toward the design of innovative complex soft materials.


Requirement for Shh and Fox family genes at different stages in sweat gland development.
Sweat glands play a fundamental role in thermal regulation in man, but the molecular mechanism of their development remains unknown. To initiate analyses, we compared the model of Eda mutant Tabby mice, in which sweat glands were not formed, with wild-type (WT) mice. We inferred developmental stages and critical genes based on observations at seven time points spanning embryonic, postnatal and adult life. In WT footpads, sweat gland germs were detected at E17.5. The coiling of secretory portions started at postnatal day 1 (P1), and sweat gland formation was essentially completed by P5. Consistent with a controlled morphological progression, expression profiling revealed stage-specific gene expression changes. Similar to the development of hair follicles-the other major skin appendage controlled by EDA-sweat gland induction and initial progression were accompanied by Eda-dependent up-regulation of the Shh pathway. During the further development of sweat gland secretory portions, Foxa1 and Foxi1, not at all expressed in hair follicles, were progressively up-regulated in WT but not in Tabby footpads. Upon completion of WT development, Shh declined to Tabby levels, but Fox family genes remained at elevated levels in mature sweat glands. The results provide a framework for the further analysis of phased down-stream regulation of gene action, possibly by a signaling cascade, in response to Eda.


[Publish & Perish; research on research and researchers].
In the last years many people have questioned the reliability of research results and the societal relevance of much of today's clinical research; they are critical too about the current publication culture in which scientists are judged according to the number of articles they have published, impact factors and citations.
 AIM: To make a close study of the publication culture that now prevails in the Dutch biomedical sciences.
 METHOD: Discussion of results described in the thesis entitled 'Publish and Perish; research on research and researchers'.
 RESULTS: To investigate what 'pressure to publish' is, we designed the Publication Pressure Questionnaire. In addition, in a group of 437 professors, we found a relationship between 'pressure to publish' and burnout; about 25% of the professors reported having suffered from severe burnout. We used focus groups to discover the factors that scientists consider are harmful in today's publication culture. They mentioned aspects such as impact factors, problems with research funding, authorship of articles, publication bias, emphasis on quantity rather than quality and 'domineering egos'. Next, we sought the views of 400 Dutch psychiatrists on the influence of pharmaceutical sponsorship on clinical trials. The psychiatrists seem to overlook the effects that pharmaceutical sponsoring might have on research results, but were more critical of results that appeared to be 'too good to be true'. A character study of more than 500 biomedical professionals revealed a link between scientific misconduct and pressure to publish; Machiavellian characteristics seemed to be associated with this misconduct. Finally, the author of the thesis (with 'tongue in cheek') describes a new psychiatric disorder which he calls 'publiphilia impactfactorius', defined as a disorder affecting biomedical professionals characterised by narcissistic, psychopathic, manipulative and emotionally unstable traits, whose egos are focused primarily on publication and high citation scores.
 CONCLUSION: The thesis demonstrates that on the one hand scientists should look critically at new research so that they can assess its value, but on the other hand they must be ready to support new research, even though most results are likely to require later revision and updating. In spite of the shortcomings of many published research results, they are after all, the best we have at a particular moment.


Hemimegalencephaly with intractable epilepsy: A case report.
Isolated Hemimegalencephaly (iHME) is a rare form of congenital malformation of cortical development.It is characterized by enlargement of all or part of one cerebral hemisphere. It typically presents with intractable seizures, mental retardation, developmental delay, contralateral hemiparesis and hemianopia. The patient was a five and half month's old baby girl who presented first with focal seizures at 10th day of life. No other physical or behavioral abnormality was noted. However, Initial EEG showed excessive sharp EEG transients more over the right hemisphere, repeated EEG showed spikes, polyspikes, sharps and slow wave discharges predominately over right hemisphere. MRI brain showed asymmetric enlargement of the right cerebral hemisphere, suggestive of hemimegalencephaly. Initial treatment with anti-epileptics was successful in controlling the seizures but later on the seizures became intractable even on polytherapy. Identification of this and similar cases of iHME can help us better understand this disorder and its associated symptoms and eventually help us develop better treatment options for it.


Duration of airborne-manganese exposure in rhesus monkeys is associated with brain regional changes in biomarkers of neurotoxicity.
Juvenile (20-24-month-old) rhesus monkeys were exposed to airborne-manganese sulfate (MnSO(4)) 1.5 mg Mn/m(3) (6h/day, 5 days/week) for 15 or 33 days, or for 65 days followed by a 45 or 90 days post-exposure recovery period, or air. We assessed biochemical endpoints indicative of oxidative stress and excitotoxicity in the cerebellum, frontal cortex, caudate, globus pallidus, olfactory cortex, and putamen. Glutamine synthetase (GS), glutamate transporters (GLT-1 and GLAST) and tyrosine hydroxylase (TH) protein levels, metallothionein (MT), GLT-1, GLAST, TH and GS mRNA levels, and total glutathione (GSH) levels were determined for all brain regions. Exposure to Mn significantly decreased MT mRNA in the caudate (vs. air-exposed controls). This depression persisted at least 90 days post-exposure. In contrast, putamen MT mRNA levels were unaffected by Mn exposure. GLT-1 and GLAST were relatively unaffected by short term Mn exposure, except in the globus pallidus where exposure for 33 days led to decreased protein levels, which persisted after 45 days of recovery for both proteins and 90 days of recovery in the case of GLAST. Exposure to 1.5 mg Mn/m(3) caused a significant decrease in GSH levels in the caudate and increased GSH levels in the putamen of monkey exposed for 15 and 33 days with both effects persisting at least 90 days post-exposure. Finally, TH protein levels were significantly lowered in the globus pallidus of the monkeys exposed for 33 days but mRNA levels were significantly increased in this same region. Overall, the nonhuman primate brain responds to airborne Mn in a heterogeneous manner and most alterations in these biomarkers of neurotoxicity are reversible upon cessation of Mn exposure.


Common variation at 1q24.1 (ALDH9A1) is a potential risk factor for renal cancer.
So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation.


Interaction between yeast RNA polymerase III and transcription factor TFIIIC via ABC10alpha and tau131 subunits.
Yeast TFIIIC mediates transcription of class III genes by promoting the assembly of a stable TFIIIB-DNA complex that is sufficient for RNA polymerase III recruitment and function. Unexpectedly, we found an interaction in vivo and in vitro between the TFIIIB-recruiting subunit of TFIIIC, tau131, and ABC10alpha, a small essential subunit common to the three forms of nuclear RNA polymerases. This interaction was mapped to the C-terminal region of ABC10alpha. A thermosensitive mutation in the C terminus region of ABC10alpha (rpc10-30) was found to be selectively suppressed by overexpression of a mutant form of tau131 (tau131-DeltaTPR2) that lacks the second TPR repeat. Remarkably, the rpc10-30 mutation weakened the ABC10alpha-tau131 interaction, and the suppressive mutation, tau131-DeltaTPR2 increased the interaction between the two proteins in the two-hybrid assay. These results point to the potential importance of a functional contact between TFIIIC and RNA polymerase III.


Is being in school better? The impact of school on children's BMI when starting age is endogenous.
In this paper, we investigate the impact of attending school on body weight and obesity using a regression-discontinuity design. As is the case with academic outcomes, school exposure is related to unobserved determinants of weight outcomes because some families choose to have their child start school late (or early). If one does not account for this endogeneity, it appears that an additional year of school exposure results in a greater BMI and a higher probability of being overweight or obese. When we compare the weight outcomes of similar age children with one versus two years of school exposure due to regulations on school starting age, the significant positive effects disappear, and most point estimates become negative, but insignificant. However, additional school exposure appears to improve weight outcomes of children for whom the transition to elementary school represents a more dramatic change in environment (those who spent less time in childcare prior to kindergarten).


Competition between DNA Methylation, Nucleotide Synthesis, and Antioxidation in Cancer versus Normal Tissues.
Global DNA hypomethylation occurs in many cancer types, but there is no explanation for its differential occurrence or possible impact on cancer cell physiology. Here we address these issues with a computational study of genome-scale DNA methylation in 16 cancer types. Specifically, we identified (i) a possible determinant for global DNA methylation in cancer cells and (ii) a relationship between levels of DNA methylation, nucleotide synthesis, and intracellular oxidative stress in cells. We developed a system of kinetic equations to capture the metabolic relations among DNA methylation, nucleotide synthesis, and antioxidative stress response, including their competitions for methyl and sulfur groups, based on known information about one-carbon metabolism and trans-sulfuration pathways. We observed a kinetic-based regulatory mechanism that controls reaction rates of the three competing processes when their shared resources are limited, particularly when the nucleotide synthesis rates or oxidative states are high. The combination of this regulatory mechanism and the need for rapid nucleotide synthesis, as well as high production of glutathione dictated by cancer-driving forces, led to the nearly universal observations of reduced global DNA methylation in cancer. Our model provides a natural explanation for differential global DNA methylation levels across cancer types and supports the observation that more malignant cancers tend to exhibit reduced DNA methylation levels. Insights obtained from this work provide useful information about the complexities of cancer due to interplays among competing, dynamic biological processes. Cancer Res; 77(15); 4185-95. ©2017 AACR.


Contaminant removal in septage treatment with vertical flow constructed wetlands operated under batch flow conditions.
Individual septic tanks are the most common means of on-site sanitation in Malaysia, but they result in a significant volume of septage. A two-staged vertical flow constructed wetlands (VFCWs) system for the treatment of septage was constructed and studied in Sarawak, Malaysia. Raw septage was treated in the first stage wetlands, and the resulting percolate was fed onto the second stage wetlands for further treatment. Here, the effects of a batch loading regime on the contaminant removal efficiency at the second stage wetlands, which included palm kernel shell within their filter substrate, are presented. The batch loading regime with pond:rest (P:R) period of 1:1, 2:2 and 3:3 (day:day) was studied. The improvement of the effluent redox condition was evident with P:R = 3:3, resulting in excellent organic matters (chemical oxygen demand and biochemical oxygen demand) and nitrogen reduction. The bed operated with P:R = 1:1 experienced constant clogging, with a water layer observed on the bed surface. For the P:R = 3:3 regime, the dissolved oxygen profile was not found to decay drastically after 24 hours of ponding, suggesting that the biodegradation mainly occurred during the first day. The study results indicate that a suitable application regime with an adequate rest period is important in VFCWs to ensure efficient operation.


Complex patterns of metabolic and Ca²⁺ entrainment in pancreatic islets by oscillatory glucose.
Glucose-stimulated insulin secretion is pulsatile and driven by intrinsic oscillations in metabolism, electrical activity, and Ca(2+) in pancreatic islets. Periodic variations in glucose can entrain islet Ca(2+) and insulin secretion, possibly promoting interislet synchronization. Here, we used fluorescence microscopy to demonstrate that glucose oscillations can induce distinct 1:1 and 1:2 entrainment of oscillations (one and two oscillations for each period of exogenous stimulus, respectively) in islet Ca(2+), NAD(P)H, and mitochondrial membrane potential. To our knowledge, this is the first demonstration of metabolic entrainment in islets, and we found that entrainment of metabolic oscillations requires voltage-gated Ca(2+) influx. We identified diverse patterns of 1:2 entrainment and showed that islet synchronization during entrainment involves adjustments of both oscillatory phase and period. All experimental findings could be recapitulated by our recently developed mathematical model, and simulations suggested that interislet variability in 1:2 entrainment patterns reflects differences in their glucose sensitivity. Finally, our simulations and recordings showed that a heterogeneous group of islets synchronized during 1:2 entrainment, resulting in a clear oscillatory response from the collective. In summary, we demonstrate that oscillatory glucose can induce complex modes of entrainment of metabolically driven oscillations in islets, and provide additional support for the notion that entrainment promotes interislet synchrony in the pancreas.


Lesion load may predict long-term cognitive dysfunction in multiple sclerosis patients.
Magnetic Resonance Imaging (MRI) techniques provided evidences into the understanding of cognitive impairment (CIm) in Multiple Sclerosis (MS). To investigate the role of white matter (WM) and gray matter (GM) in predicting long-term CIm in a cohort of MS patients. 303 out of 597 patients participating in a previous multicenter clinical-MRI study were enrolled (49.4% were lost at follow-up). The following MRI parameters, expressed as fraction (f) of intracranial volume, were evaluated: cerebrospinal fluid (CSF-f), WM-f, GM-f and abnormal WM (AWM-f), a measure of lesion load. Nine years later, cognitive status was assessed in 241 patients using the Symbol Digit Modalities Test (SDMT), the Semantically Related Word List Test (SRWL), the Modified Card Sorting Test (MCST), and the Paced Auditory Serial Addition Test (PASAT). In particular, being SRWL a memory test, both immediate recall and delayed recall were evaluated. MCST scoring was calculated based on the number of categories, number of perseverative and non-perseverative errors. AWM-f was predictive of an impaired performance 9 years ahead in SDMT (OR 1.49, CI 1.12-1.97 p = 0.006), PASAT (OR 1.43, CI 1.14-1.80 p = 0.002), SRWL-immediate recall (OR 1.72 CI 1.35-2.20 p<0.001), SRWL-delayed recall (OR 1.61 CI 1.28-2.03 p<0.001), MCST-category (OR 1.52, CI 1.2-1.9 p<0.001), MCST-perseverative error(OR 1.51 CI 1.2-1.9 p = 0.001), MCST-non perseverative error (OR 1.26 CI 1.02-1.55 p = 0.032). In our large MS cohort, focal WM damage appeared to be the most relevant predictor of the long-term cognitive outcome.


Avatars mirroring the actual self versus projecting the ideal self: the effects of self-priming on interactivity and immersion in an exergame, Wii Fit.
As exergames are increasingly being used as an interventional tool to fight the obesity epidemic in clinical studies, society is absorbing their impact to a more intense degree. Interactivity and immersion are key factors that attract exergame consumers. This research asks, What are the effects of priming the actual self versus the ideal self on users' perceived interactivity and immersion in avatar-based exergame playing? and What are important moderators that play a role in exergame users' self-concept perception? To answer these research questions, this study leveraged the Wii's avatar-creating function (Mii Channel) and exergame feature (Wii Fit) in a controlled, randomized experimental design (N = 126). The results of a 2 x 2 factorial design experiment demonstrated the significant main effect of self-priming on interactivity and the moderating role of the actual-ideal self-concept discrepancy in influencing immersion during exergame playing. Game players who created an avatar reflecting the ideal self reported greater perceived interactivity than those who created a replica avatar mirroring the actual self. A two-way ANOVA demonstrated the moderating role of the actual-ideal self-concept discrepancy in determining the effects of the primed regulatory focus on immersion in the exergame play. The underlying theoretical mechanism is derived from and explained by Higgins's self-concept discrepancy perspective. Practical implications for game developers and managerial implications for the exergame industry are discussed.


Role of beta-adrenergic receptors in the hyperphagic and hypermetabolic responses to dietary methionine restriction.
Dietary methionine restriction (MR) limits fat deposition and decreases plasma leptin, while increasing food consumption, total energy expenditure (EE), plasma adiponectin, and expression of uncoupling protein 1 (UCP1) in brown and white adipose tissue (BAT and WAT). beta-adrenergic receptors (beta-AR) serve as conduits for sympathetic input to adipose tissue, but their role in mediating the effects of MR on energy homeostasis is unclear. Energy intake, weight, and adiposity were modestly higher in beta(3)-AR(-/-) mice on the Control diet compared with wild-type (WT) mice, but the hyperphagic response to the MR diet and the reduction in fat deposition did not differ between the genotypes. The absence of beta(3)-ARs also did not diminish the ability of MR to increase total EE and plasma adiponectin or decrease leptin mRNA, but it did block the MR-dependent increase in UCP1 mRNA in BAT but not WAT. In a further study, propranolol was used to antagonize remaining beta-adrenergic input (beta(1)- and beta(2)-ARs) in beta(3)-AR(-/-) mice, and this treatment blocked >50% of the MR-induced increase in total EE and UCP1 induction in both BAT and WAT. We conclude that signaling through beta-adrenergic receptors is a component of the mechanism used by dietary MR to increase EE, and that beta(1)- and beta(2)-ARs are able to substitute for beta(3)-ARs in mediating the effect of dietary MR on EE. These findings are consistent with the involvement of both UCP1-dependent and -independent mechanisms in the physiological responses affecting energy balance that are produced by dietary MR.


Cost Comparison of Genetic Testing Strategies in Women With Epithelial Ovarian Cancer.
The advent of multigene panels has increased genetic testing options for women with epithelial ovarian cancer (EOC). We designed a decision model to compare costs and probabilities of identifying a deleterious mutation or variant of uncertain significance (VUS) using different genetic testing strategies. A decision model was developed to compare costs and outcomes of two testing strategies for women with EOC: multigene testing (MGT) versus single-gene testing for BRCA1/2. Outcomes were mean cost and number of deleterious mutations and VUSs identified. Model inputs were obtained from published genetic testing data in EOC. One-way sensitivity analyses and Monte Carlo probabilistic sensitivity analyses were performed. No family history model: MGT cost $1,160 more on average than BRCA1/2 testing and identified an additional 3.8 deleterious mutations for every 100 women tested. For each additional deleterious mutation identified, MGT cost $30,812 and identified 5.4 additional VUSs. Family history model: MGT cost $654 more on average and identified an additional 7.0 deleterious mutations for every 100 women tested. For each additional deleterious mutation identified, MGT cost $9,909 and identified 2.6 additional VUSs. MGT was associated with a higher additional cost per deleterious mutation identified and a higher ratio of VUS burden to actionable information in women with no family history as compared with women with a family history. Family history should be considered when determining an initial genetic testing platform in women with EOC.


Bronchopulmonary dysplasia.
In the absence of effective interventions to prevent preterm births, improved survival of infants who are born at the biological limits of viability has relied on advances in perinatal care over the past 50 years. Except for extremely preterm infants with suboptimal perinatal care or major antenatal events that cause severe respiratory failure at birth, most extremely preterm infants now survive, but they often develop chronic lung dysfunction termed bronchopulmonary dysplasia (BPD; also known as chronic lung disease). Despite major efforts to minimize injurious but often life-saving postnatal interventions (such as oxygen, mechanical ventilation and corticosteroids), BPD remains the most frequent complication of extreme preterm birth. BPD is now recognized as the result of an aberrant reparative response to both antenatal injury and repetitive postnatal injury to the developing lungs. Consequently, lung development is markedly impaired, which leads to persistent airway and pulmonary vascular disease that can affect adult lung function. Greater insights into the pathobiology of BPD will provide a better understanding of disease mechanisms and lung repair and regeneration, which will enable the discovery of novel therapeutic targets. In parallel, clinical and translational studies that improve the classification of disease phenotypes and enable early identification of at-risk preterm infants should improve trial design and individualized care to enhance outcomes in preterm infants.


Relative Pitch Perception and the Detection of Deviant Tone Patterns.
Most people are able to recognise familiar tunes even when played in a different key. It is assumed that this depends on a general capacity for relative pitch perception; the ability to recognise the pattern of inter-note intervals that characterises the tune. However, when healthy adults are required to detect rare deviant melodic patterns in a sequence of randomly transposed standard patterns they perform close to chance. Musically experienced participants perform better than naïve participants, but even they find the task difficult, despite the fact that musical education includes training in interval recognition.To understand the source of this difficulty we designed an experiment to explore the relative influence of the size of within-pattern intervals and between-pattern transpositions on detecting deviant melodic patterns. We found that task difficulty increases when patterns contain large intervals (5-7 semitones) rather than small intervals (1-3 semitones). While task difficulty increases substantially when transpositions are introduced, the effect of transposition size (large vs small) is weaker. Increasing the range of permissible intervals to be used also makes the task more difficult. Furthermore, providing an initial exact repetition followed by subsequent transpositions does not improve performance. Although musical training correlates with task performance, we find no evidence that violations to musical intervals important in Western music (i.e. the perfect fifth or fourth) are more easily detected. In summary, relative pitch perception does not appear to be conducive to simple explanations based exclusively on invariant physical ratios.