An active DNA transposon nDart causing leaf variegation and mutable dwarfism and its related elements in rice.
While characterized mutable alleles caused by DNA transposons have been abundant in maize since the discovery of Dissociation conferring variegation by Barbara McClintock, only a few mutable alleles have been described in rice even though the rice genome contains various transposons. Here, we show that a spontaneous mutable virescent allele, pyl-v, is caused by the disruption of the nuclear-coded essential chloroplast protease gene, OsClpP5, due to insertion of a 607-bp non-autonomous DNA transposon, non-autonomous DNA-based active rice transposon one (nDart1), belonging to the hAT superfamily. The transposition of nDart1 can be induced by crossing with a line containing an autonomous element, aDart, and stabilized by segregating out of aDart. We also identified a novel mutable dwarf allele thl-m caused by an insertion of nDart1. The japonica cultivar Nipponbare carries no aDart, although it contains epigenetically silenced Dart element(s), which can be activated by 5-azacytidine. Nipponbare bears four subgroups of about 3.6-kb Dart-like sequences, three of which contain potential transposase genes, and around 3.6-kb elements without an apparent transposase gene, as well as three subgroups of about 0.6-kb nDart1-related elements that are all internal deletions of the Dart-like sequences. Both nDart1 and 3.6-kb Dart-like elements were also present in indica varieties 93-11 and Kasalath. nDart1 appears to be the most active mutagen among nDart1-related elements contributing to generating natural variations. A candidate for an autonomous element, aDart, and a possible application of nDart1 for transposon tagging are discussed.


Preoperative Score to Predict Postoperative Mortality (POSPOM): Derivation and Validation.
An accurate risk score able to predict in-hospital mortality in patients undergoing surgery may improve both risk communication and clinical decision making. The aim of the study was to develop and validate a surgical risk score based solely on preoperative information, for predicting in-hospital mortality. From January 1, 2010, to December 31, 2010, data related to all surgeries requiring anesthesia were collected from all centers (single hospital or hospitals group) in France performing more than 500 operations in the year on patients aged 18 yr or older (n = 5,507,834). International Statistical Classification of Diseases, 10th revision codes were used to summarize the medical history of patients. From these data, the authors developed a risk score by examining 29 preoperative factors (age, comorbidities, and surgery type) in 2,717,902 patients, and then validated the risk score in a separate cohort of 2,789,932 patients. In the derivation cohort, there were 12,786 in-hospital deaths (0.47%; 95% CI, 0.46 to 0.48%), whereas in the validation cohort there were 14,933 in-hospital deaths (0.54%; 95% CI, 0.53 to 0.55%). Seventeen predictors were identified and included in the PreOperative Score to predict PostOperative Mortality (POSPOM). POSPOM showed good calibration and excellent discrimination for in-hospital mortality, with a c-statistic of 0.944 (95% CI, 0.943 to 0.945) in the development cohort and 0.929 (95% CI, 0.928 to 0.931) in the validation cohort. The authors have developed and validated POSPOM, a simple risk score for the prediction of in-hospital mortality in surgical patients.


Routine Immunization Coverage and Immunization Card Retention in Pakistan: Results From a Cross-sectional National Survey.
Immunization is one of the most successful public health interventions available, saving millions of lives from death and disability each year. Therefore, improving immunization coverage is a high priority for the Government of Pakistan and essential to progress toward universal health coverage. This survey reports the national and provincial/regional coverage and determinants of fully, partially, and not-vaccinated children 12-23 months of age, antigen-wise coverage, percentage of home-based vaccination records (HBR) retention, and reasons for nonretention; dropout, timeliness, and prevalence of missed opportunities for simultaneous vaccination (MOSV). The survey was a descriptive cross-sectional national household survey carried out across Pakistan. The survey included 110,790 children 12-23 months old and their caregivers. A World Health Organization (WHO)-Expanded Program on Immunization (EPI) Survey questionnaire was adapted to collect information. Data were analyzed using the WHO Vaccination Coverage Quality Indicators (VCQI) software and Stata version 17. Nationally excluding Azad Jammu and Kashmir (AJK) and Gilgit Baltistan (GB), the coverage of fully vaccinated children was 76.5%. The likelihood of being fully vaccinated was higher among children of educated parents who belonged to higher wealth quintiles and resided in any province/region other than Balochistan. The main reasons for unimmunization were no faith in immunization, rumors about vaccines, and distance to the facility. About two-thirds (66.2%) of the children had their HBR available, and the main reasons for not having a card were never visiting a health facility and having no awareness about the importance of a card. Dropout was discernible for later doses of vaccines compared with earlier ones. Higher proportions of children received the last doses late by more than two months. Of the 218,002 vaccination visits documented on HBR in the provinces, MOSVs occurred in 17.6% of the visits. The immunization coverage rates provide a direction to strategize the progress to improve the vaccination rates in Pakistan. The country needs to outline the immediate and long-term actions to combat vaccine-preventable diseases, such as escalating integrated immunization campaigns and outreach activities, provision of mobility support, and deploying behavioral interventions as a cross-cutting strategy to improve awareness and reduce misconceptions.


The DDBJ Japanese Genotype-phenotype Archive for genetic and phenotypic human data.
The DNA Data Bank of Japan Center (DDBJ Center; http://www.ddbj.nig.ac.jp) maintains and provides public archival, retrieval and analytical services for biological information. Since October 2013, DDBJ Center has operated the Japanese Genotype-phenotype Archive (JGA) in collaboration with our partner institute, the National Bioscience Database Center (NBDC) of the Japan Science and Technology Agency. DDBJ Center provides the JGA database system which securely stores genotype and phenotype data collected from individuals whose consent agreements authorize data release only for specific research use. NBDC has established guidelines and policies for sharing human-derived data and reviews data submission and usage requests from researchers. In addition to the JGA project, DDBJ Center develops Semantic Web technologies for data integration and sharing in collaboration with the Database Center for Life Science. This paper describes the overview of the JGA project, updates to the DDBJ databases, and services for data retrieval, analysis and integration.


Arthroscopic transtibial posterior cruciate ligament reconstruction with preservation of posterior cruciate ligament fibers: clinical results of minimum 2-year follow-up.
The transtibial technique for posterior cruciate ligament reconstructions can potentially lead to poor clinical outcomes due to the "killer turn" effect. Preserving the original posterior cruciate ligament fibers in the reconstruction will contribute significantly to the posterior stability of the knee joint, healing of the graft, and prevention of graft failure. Case series; Level of evidence, 4. Sixty-one patients (45 men and 16 women; mean age, 30.4 years) underwent transtibial posterior cruciate ligament reconstruction with preservation of the cruciate ligament fibers; they were reviewed at a mean period of 40.8 months. All patients were assessed with the Lysholm knee score, International Knee Documentation Committee subjective and objective evaluations, and KT-2000 arthrometry. Follow-up magnetic resonance imaging was performed in 40 patients; images were assessed for graft continuity, thickness, and signal intensity. Second-look arthroscopy was performed in 42 patients. The mean Lysholm score improved from 65.8 to 92.9. The final International Knee Documentation Committee subjective evaluation rated all patients as normal or nearly normal, and the objective evaluation showed normal or nearly normal in 59 patients (97%) and abnormal in 2 patients (3%). The mean side-to-side difference on the KT-2000 arthrometer was 2.79 mm. All patients showed well-preserved graft continuity on magnetic resonance images. Mean graft thickness was 9.9 mm in the sagittal plane and 12.3 mm in the coronal oblique plane. Images for all patients revealed homogeneously low signal intensity in the distal portion of the graft, with complete healing of the graft and original posterior cruciate ligament fibers as one ligament. Graft loosening or graft tear by the killer turn effect was not detected in any patients. Second-look arthroscopy revealed complete healing and graft integration, with the original posterior cruciate ligament fibers in all patients. In transtibial posterior cruciate ligament reconstructions, poor outcomes from the killer turn effect may be reduced by preserving the original posterior cruciate ligament fibers.


Dystrophin expression in the mdx mouse after localised and systemic administration of a morpholino antisense oligonucleotide.
Duchenne and Becker muscular dystrophies are allelic disorders arising from mutations in the dystrophin gene. Duchenne muscular dystrophy is characterised by an absence of functional protein, while Becker muscular dystrophy is usually caused by in-frame deletions allowing synthesis of some functional protein. Treatment options are limited, and we are investigating the potential of transcript manipulation to overcome disease-causing mutations. Antisense oligonucleotides have been used to induce specific exon removal during processing of the dystrophin primary transcript and thereby by-pass protein-truncating mutations. The antisense oligonucleotide chemistry most widely used to alter pre-mRNA processing is 2'-O-methyl-modified bases on a phosphorothioate backbone. The present studies evaluate 2'-O-methylphosphorothioate, peptide nucleic acid and morpholino antisense oligonucleotides in the mdx mouse model of muscular dystrophy, which has a nonsense mutation in exon 23 of the dystrophin gene. We demonstrate dystrophin expression in mdx mouse tissues after localised and systemic delivery of a morpholino antisense oligonucleotide designed to target the dystrophin exon 23 donor splice site. The stability of the morpholino structural type, and the fact that it can be delivered to muscle in the absence of a delivery reagent, render this compound eminently suitable for consideration for therapeutic exon skipping to address dystrophin mutations.


A prospective cohort study of exposure-response relationship for vibration-induced white finger.
To investigate prospectively the relation between vibration-induced white finger (VWF) and measures of cumulative (lifetime) exposure to hand-transmitted vibration (HTV). Two hundred and forty-nine HTV workers and 138 control men of the same companies participated in a 3-year follow-up study. The diagnosis of VWF (Raynaud's phenomenon in the controls) was based on the medical history, the administration of colour charts and the results of a cold test. Tool vibration magnitudes were expressed as root-mean-square (r.m.s.) acceleration, frequency-weighted according to international standard ISO 5349-1 and also unweighted over the frequency range 6.3-1250 Hz. From the vibration magnitudes and exposure durations, alternative measures of cumulative vibration dose were calculated for each HTV worker, according to the expression: dose = Sigmaa(i)(m)t(i), where a(i) is the acceleration magnitude on tool i, t(i) is the lifetime exposure duration (hours) for tool i, and m = 0, 1, 2 or 4. The incidence of VWF varied from 5 to 6% in the HTV workers versus 0 to 1.5% for Raynaud's phenomenon in the controls. After adjusting for potential confounders, measures of cumulative vibration dose derived from total operating hours and high powers of unweighted acceleration (ie, , with m>1) gave better predictions of the occurrence of VWF than dose measures calculated from frequency-weighted acceleration (ie, ). These findings were observed in the entire sample of HTV workers, in those with no VWF at the initial investigation, and in those with normal cold test results at baseline. This prospective cohort study suggests that measures of cumulative vibration doses constructed from unweighted r.m.s. acceleration perform better for the prediction of VWF than dose measures calculated according to the recommendations of current standards. These findings should contribute to the improvement of the ISO frequency weighting for evaluating the severity of hand-transmitted vibration.


The dependence of the association rate of surface-attached adhesion molecules CD2 and CD48 on separation distance.
The kinetics of bond formation between spherical beads coated with CD48 and CD2-derivatized surfaces was studied with a flow chamber. For a given shear rate, the binding frequency was exquisitively sensitive to the particle velocity. Flow equations were used to derive the particle-to-surface distance from the velocity, thus yielding a relationship between this distance and the binding rate. Numerical values of the binding site densities allowed absolute determination of the rate of association between two individual molecules as a function of the distance between attachment points. In our model, this rate was about 0.03 s-1 at 10 nm separation, and it was inversely proportional to the cube of the distance.


Limited Excessive Voluntary Alcohol Drinking Leads to Liver Dysfunction in Mice.
Liver damage is a serious and sometimes fatal consequence of long-term alcohol intake, which progresses from early-stage fatty liver (steatosis) to later-stage steatohepatitis with inflammation and fibrosis/necrosis. However, very little is known about earlier stages of liver disruption that may occur in problem drinkers, those who drink excessively but are not dependent on alcohol. We examined how repeated binge-like alcohol drinking in C57BL/6 mice altered liver function, as compared with a single binge-intake session and with repeated moderate alcohol consumption. We measured a number of markers associated with early- and later-stage liver disruption, including liver steatosis, measures of liver cytochrome P4502E1 (CYP2E1) and alcohol dehydrogenase (ADH), alcohol metabolism, expression of cytokine mRNA, accumulation of 4-hydroxynonenal (4-HNE) as an indicator of oxidative stress, and alanine transaminase/aspartate transaminase as a measure of hepatocyte injury. Importantly, repeated binge-like alcohol drinking increased triglyceride levels in the liver and plasma, and increased lipid droplets in the liver, indicators of steatosis. In contrast, a single binge-intake session or repeated moderate alcohol consumption did not alter triglyceride levels. In addition, alcohol exposure can increase rates of alcohol metabolism through CYP2E1 and ADH, which can potentially increase oxidative stress and liver dysfunction. Intermittent, excessive alcohol intake increased liver CYP2E1 mRNA, protein, and activity, as well as ADH mRNA and activity. Furthermore, repeated, binge-like drinking, but not a single binge or moderate drinking, increased alcohol metabolism. Finally, repeated, excessive intake transiently elevated mRNA for the proinflammatory cytokine IL-1B and 4-HNE levels, but did not alter markers of later-stage liver hepatocyte injury. Together, we provide data suggesting that even relatively limited binge-like alcohol drinking can lead to disruptions in liver function, which might facilitate the transition to more severe forms of liver damage.


Physical Exercise as a Diagnostic, Rehabilitation, and Preventive Tool: Influence on Neuroplasticity and Motor Recovery after Stroke.
Stroke remains a leading cause of adult motor disabilities in the world and accounts for the greatest number of hospitalizations for neurological disease. Stroke treatments/therapies need to promote neuroplasticity to improve motor function. Physical exercise is considered as a major candidate for ultimately promoting neural plasticity and could be used for different purposes in human and animal experiments. First, acute exercise could be used as a diagnostic tool to understand new neural mechanisms underlying stroke physiopathology. Indeed, better knowledge of stroke mechanisms that affect movements is crucial for enhancing treatment/rehabilitation effectiveness. Secondly, it is well established that physical exercise training is advised as an effective rehabilitation tool. Indeed, it reduces inflammatory processes and apoptotic marker expression, promotes brain angiogenesis and expression of some growth factors, and improves the activation of affected muscles during exercise. Nevertheless, exercise training might also aggravate sensorimotor deficits and brain injury depending on the chosen exercise parameters. For the last few years, physical training has been combined with pharmacological treatments to accentuate and/or accelerate beneficial neural and motor effects. Finally, physical exercise might also be considered as a major nonpharmacological preventive strategy that provides neuroprotective effects reducing adverse effects of brain ischemia. Therefore, prestroke regular physical activity may also decrease the motor outcome severity of stroke.


Maternal territoriality achieved through shaking and lunging: an investigation of patterns in associated behaviors and substrate vibrations in a colonial embiopteran, Antipaluria urichi.
Substrate vibration communication is displayed by a variety of insects that rely on silk for shelter. Such signaling is often associated with territoriality and social interactions. The goal in this study was to explore the use of substrate vibration by subsocial insects of the little-studied order Embioptera (also known as Embiidina). Antipaluria urichi (Saussure) (Embioptera: Clothodidae) from Trinidad and Tobago, a large embiopteran, exhibits maternal care and facultatively colonial behavior. Previous observations suggested that they were aggressive while guarding eggs but gregarious when not. Egg-guarders in particular have been observed shaking and lunging their bodies, but to date these putative signals have not been recorded nor were their contexts known. Staged interactions were conducted in the laboratory using residents that had established silk domiciles enveloping piezo-electric film used to detect vibrations. Predictions from two competing hypotheses, the maternal territoriality hypothesis and the group cohesion hypothesis, were erected to explain the occurrence of signaling. Experiments pitted pre-reproductive and egg-guarding residents against female and male intruders, representing social partners that ranged from potentially threatening to innocuous or even helpful. Behavioral acts were identified and scored along with associated substrate vibrations, which were measured for associated body movements, duration, and frequency spectra. Signals, sorted by the distinct actions used to generate them, were lunge, shake, push up, and snapback. Egg-guarding females produced most signals in response to female intruders, a result that supported the maternal territoriality hypothesis. Female intruders generally responded to such signaling by moving away from egg-guarding residents. In contrast, pre-reproductive residents did not signal much, and intruders settled beside them. Theme software was used to analyze the behavioral event recordings to seek patterns over time and their association with signals. Long patterns of behavioral acts were associated with shakes, lunges, and push-ups, indicating that interactions were occurring between the residents and intruders as would be expected when communication occurs. The value of Theme software, as well as the relationship between signaling by A. urichi and the risks and benefits of coloniality, are discussed.


A Nosocomial Outbreak of Clinical Sepsis in a Neonatal Care Unit (NCU) in Port-Au-Prince Haiti, July 2014 - September 2015.
Between July 2014 and September 2015, a neonatal care unit (NCU) in Port Au Prince, Haiti, experienced an outbreak of sepsis, most probably due to nosocomial transmission of Extended Beta Lactamase (ESBL) producing gram negative bacteria, included Klebsiella pneumoniae. We describe the epidemiological and microbiological activities performed as part of the outbreak investigation and the control measures implemented throughout this period. During the study period 257 cases of sepsis were reported, of which 191 died. The case fatality decreased from 100% in July 2014 to 24% in September 2015 and could be attributed to an improvement in clinical management and strengthened infection prevention and control measures. Risk factors identified to be associated with having late onset sepsis (sepsis onset >48 hours after birth)(n=205/257, 79. included: all categories of birthweight lower than <2500g (p=<0.0001) and all categories of gestational age younger than 36 weeks (p=0.0002). Microbiological investigations confirmed that out of 32 isolates (N=55; 58%) that were positive for gram negative bacteria, 27 (89%) were due to K. pneumoniae and most of these were from single MLST type (ST37). This outbreak highlighted the importance of epidemiological and microbiological surveillance during an outbreak of sepsis in a NCU in a low resource setting, including regular point prevalence surveys.


Coastal Upwelling Drives Intertidal Assemblage Structure and Trophic Ecology.
Similar environmental driving forces can produce similarity among geographically distant ecosystems. Coastal oceanic upwelling, for example, has been associated with elevated biomass and abundance patterns of certain functional groups, e.g., corticated macroalgae. In the upwelling system of Northern Chile, we examined measures of intertidal macrobenthic composition, structure and trophic ecology across eighteen shores varying in their proximity to two coastal upwelling centres, in a hierarchical sampling design (spatial scales of >1 and >10 km). The influence of coastal upwelling on intertidal communities was confirmed by the stable isotope values (δ13C and δ15N) of consumers, including a dominant suspension feeder, grazers, and their putative resources of POM, epilithic biofilm, and macroalgae. We highlight the utility of muscle δ15N from the suspension feeding mussel, Perumytilus purpuratus, as a proxy for upwelling, supported by satellite data and previous studies. Where possible, we used corrections for broader-scale trends, spatial autocorrelation, ontogenetic dietary shifts and spatial baseline isotopic variation prior to analysis. Our results showed macroalgal assemblage composition, and benthic consumer assemblage structure, varied significantly with the intertidal influence of coastal upwelling, especially contrasting bays and coastal headlands. Coastal topography also separated differences in consumer resource use. This suggested that coastal upwelling, itself driven by coastline topography, influences intertidal communities by advecting nearshore phytoplankton populations offshore and cooling coastal water temperatures. We recommend the isotopic values of benthic organisms, specifically long-lived suspension feeders, as in situ alternatives to offshore measurements of upwelling influence.


Predictive Model and Mortality Risk Score during Admission for Ischaemic Stroke with Conservative Treatment.
Stroke is the second cause of mortality worldwide and the first in women. The aim of this study is to develop a predictive model to estimate the risk of mortality in the admission of patients who have not received reperfusion treatment. A retrospective cohort study was conducted of a clinical-administrative database, reflecting all cases of non-reperfused ischaemic stroke admitted to Spanish hospitals during the period 2008-2012. A predictive model based on logistic regression was developed on a training cohort and later validated by the "hold-out" method. Complementary machine learning techniques were also explored. The resulting model had the following nine variables, all readily obtainable during initial care. Age (OR 1.069), female sex (OR 1.202), readmission (OR 2.008), hypertension (OR 0.726), diabetes (OR 1.105), atrial fibrillation (OR 1.537), dyslipidaemia (0.638), heart failure (OR 1.518) and neurological symptoms suggestive of posterior fossa involvement (OR 2.639). The predictability was moderate (AUC 0.742, 95% CI: 0.737-0.747), with good visual calibration; Pearson's chi-square test revealed non-significant calibration. An easily consulted risk score was prepared. It is possible to create a predictive model of mortality for patients with ischaemic stroke from which important advances can be made towards optimising the quality and efficiency of care. The model results are available within a few minutes of admission and would provide a valuable complementary resource for the neurologist.


Lipoprotein(a): An independent, genetic, and causal factor for cardiovascular disease and acute myocardial infarction.
Lipoprotein(a) [Lp(a)] is a circulating lipoprotein, and its level is largely determined by variation in the Lp(a) gene (LPA) locus encoding apo(a). Genetic variation in the LPA gene that increases Lp(a) level also increases coronary artery disease (CAD) risk, suggesting that Lp(a) is a causal factor for CAD risk. Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), a proatherogenic and proinflammatory biomarker. Lp(a) adversely affects endothelial function, inflammation, oxidative stress, fibrinolysis, and plaque stability, leading to accelerated atherothrombosis and premature CAD. The INTER-HEART Study has established the usefulness of Lp(a) in assessing the risk of acute myocardial infarction in ethnically diverse populations with South Asians having the highest risk and population attributable risk. The 2018 Cholesterol Clinical Practice Guideline have recognized elevated Lp(a) as an atherosclerotic cardiovascular disease risk enhancer for initiating or intensifying statin therapy.


Control and prevention of tuberculosis in the United Kingdom: code of practice 2000. Joint Tuberculosis Committee of the British Thoracic Society.
The guidelines on control and prevention of tuberculosis in the United Kingdom have been reviewed and updated. A subcommittee was appointed by the Joint Tuberculosis Committee (JTC) of the British Thoracic Society to revise the guidelines published in 1994 by the JTC, including representatives of the Royal College of Nursing, Public Health Medicine Environmental Group, and Medical Society for Study of Venereal Diseases. In preparing the revised guidelines the authors took account of new published evidence and graded the strength of evidence for their recommendations. The guidelines have been approved by the JTC and the Standards of Care Committee of the British Thoracic Society. Tuberculosis services in each district should have staffing and resources to fulfil both the control and prevention recommendations in this document and to ensure adequate treatment monitoring. Notification of tuberculosis is required for surveillance and to initiate contact tracing (where appropriate). The following areas are discussed and recommendations made where appropriate: (1) public health law in relation to tuberculosis; (2) the organisational requirements for tuberculosis services; (3) measures for control of tuberculosis in hospitals, including segregation of patients; (4) the requirements for health care worker protection, including HIV infected health care workers; (5) measures for control of tuberculosis in prisons; (6) protection for other groups with potential exposure to tuberculosis; (7) awareness of the high rates of tuberculosis in the homeless together with local plans for detection and action; (8) detailed advice on contact tracing; (9) contact tracing required for close contacts of bovine tuberculosis; (10) management of tuberculosis in schools; (11) screening of new immigrants and how this should be performed; (12) outbreak contingency investigation; and (13) BCG vaccination and the management of positive reactors found in the schools programme.


Amended safety assessment of tall oil acid, sodium tallate, potassium tallate, and ammonium tallate.
Tall oil acid is a mixture of oleic and linoleic acids (fatty acids) and rosin acids derived from tall oil, a by-product of pulp from resinous woods, used in cosmetic products as a surfactant at concentrations up to 8%. Ammonium, potassium, and sodium salts also are listed as cosmetic ingredients. In addition to the studies summarized in this report, extensive toxicity, genotoxicity, and carcinogenicity studies in animals are available for oleic, lauric, palmitic, myristic, and stearic fatty acids as published earlier by the Cosmetic Ingredient Review (CIR). These data may be extrapolated to tall oil acid and its salts. There are no reports of current uses or use concentration data for ammonium tallate, nor are use concentration data available for the other salts. The CIR Expert Panel found tall oil acid, ammonium tallate, potassium tallate, and sodium tallate to be safe cosmetic ingredients in the given practices of use and concentration.


Air temperature influences early Covid-19 outbreak as indicated by worldwide mortality.
The Covid-19 outbreak has triggered a global crisis that is challenging governments, health systems and the scientific community worldwide. A central question in the Covid-19 pandemic is whether climatic factors have influenced its progression. To address this question, we used mortality rates during the first three weeks of recorded mortality in 144 countries, during the first wave of the pandemic. We examined the effect of climatic variables, along with the proportion of the population older than 64 years old, the number of beds in hospitals, and the timing and strength of the governmental travel measures to control the spread of the disease. Our first model focuses on air temperature as the central climatic factor and explains 67% of the variation in mortality rate, with 37% explained by the fixed variables considered and 31% explained by country-specific variations. We show that mortality rate is negatively influenced by warmer air temperature. Each additional Celsius degree decreases mortality rate by ~5%. Our second model is centred on the UV Index and follows the same trend as air temperature, explaining 69% of the variation in mortality rate. These results are robust to the exclusion of countries with low incomes, as well as to the exclusion of low- and medium-income countries. We also show that the proportion of vulnerable age classes and access to healthcare are critical factors impacting the mortality rate of this disease. The effects of air temperature at an early stage of the Covid-19 outbreak is a key factor to understand the primary spread of this pandemic, and should be considered in projecting subsequent waves.


Associations between connections to parents and friends and non-suicidal self-injury among adolescents: The mediating role of developmental assets.
We tested a model that incorporated potential developmental assets through which connections to parents and friends reduce the likelihood of engaging in non-suicidal self-injury (NSSI) among adolescents. Data came from the 2016 Minnesota Student Survey, a population-based survey of 8th, 9th, and 11th grade students (N = 119,452). Chi-square test, t-test, and correlations evaluated bivariate relationships between all variables. Indirect effects of three developmental assets (social competency, positive identity, and empowerment) were modeled simultaneously on associations between connections to parents and friends, and past-year NSSI. Bivariate analyses demonstrated protective effects of parent and friend connections on NSSI and that all developmental assets were negatively associated with NSSI. After accounting for demographic variables and associations between developmental assets in a multiple mediator path model, connections to parents showed a stronger, negative direct relationship with NSSI than did connections to friends. Developmental assets, especially positive identity and empowerment, accounted for a greater proportion of the effect of connections to friends on NSSI than the effect of connections to parents. Finally, social competency was no longer significantly related to NSSI in the multiple mediator path model. Clinical efforts to prevent NSSI should focus on enhancing adolescents' sense of positive identity and empowerment, as well as connections to parents and prosocial friends.


Asymptomatic statin-induced rhabdomyolysis after long-term therapy with the hydrophilic drug pravastatin.
A male patient aged 73 years, 165 cm in height, and weighing 78 kg presented to the emergency department with dsypnea. He had undergone heart transplantation 7 years earlier and been receiving daily pravastatin therapy for >3 years without complaining of any symptoms. A physical examination of the patient at admission was unremarkable, except for dyspnea. However, laboratory testing revealed that his serum creative kinase (CK) concentration was substantially above the reference range. Pravastatin was immediately discontinued, and the patient was admitted to the intensive care unit for treatment. CK values declined after 3 days, and they returned to within reference range after 3 weeks. The patient was diagnosed with acute rhabdomyolysis; a score of 6 on the Naranjo adverse drug reaction probability scale indicated that pravastatin was the probable cause. The hydrophilic statin pravastatin is frequently recommended for patients who have undergone heart transplantation due to its favorable tolerability profile. Unlike lipophilic statins, hydrophilic statins such as pravastatin are not metabolized in the liver via the cytochrome P450 system and have little potential for adverse events through interaction with drugs metabolized via this pathway. Based on a search of relevant literature, this report appears to be the first to describe a case of asymptomatic rhabdomyolysis occurring in a patient receiving long-term daily therapy with pravastatin after undergoing heart transplantation and who had no muscular symptoms or history of intense physical exertion. The occurrence of acute statin-induced rhabdomyolysis in this case suggests that even hydrophilic statins may have the potential to damage myocytes. The hydrophilic statin pravastatin appears to have caused asymptomatic rhabdomyolysis, in the absence of physical exertion, in a patient who had undergone heart transplantation and had been receiving the drug for >3 years. Statin therapy should be initiated at the lowest effective dose, especially in patients who have undergone heart transplantation, and should be followed by close monitoring.


Rituximab therapy for refractory orbital inflammation: results of a phase 1/2, dose-ranging, randomized clinical trial.
Orbital inflammation is a potentially blinding and disfiguring disease process that is often treated with systemic corticosteroids and immunosuppression; better treatments are needed. To determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory orbital inflammation. A dose-ranging, randomized, double-masked phase 1/2 clinical trial was conducted at a tertiary referral ophthalmology clinic. Ten individuals with orbital inflammation refractory to systemic corticosteroids and at least 1 other immunosuppressive agent were enrolled from January 2007 to March 2010. Rituximab infusions were administered on study days 1 and 15 at doses of either 500 mg or 1000 mg. Initial responders with recurrent inflammation after week 24 were permitted reinfusion with an additional cycle of 2 open-label 1000-mg rituximab infusions. The primary outcomes were reduction of inflammation measured with a validated orbital disease grading scale and corticosteroid dose reduction by at least 50%. The secondary outcomes were visual acuity, reduction in pain, and participant- and physician-reported global health assessment. Of 10 enrolled patients, 7 demonstrated improvement on the orbital disease grading scale at the 24-week end point with rituximab therapy. Of these 7 individuals, 4 were receiving corticosteroids at study inception and all achieved successful dose reduction. For the secondary outcome measures in the 10 participants, 7 patients and 8 patients improved in self-rated and physician global health scores, respectively, and 7 patients had reduction in pain by 25% or more at 24 weeks. Four patients who were positive responders at the week 24 end point experienced breakthrough inflammation after week 24 and received reinfusions between 24 and 48 weeks. Vision remained stable in all participants. Three of 10 patients had short-term objective or subjective worsening 2 to 8 weeks after receiving rituximab infusions, which was averted in subsequent patients with oral corticosteroids administered during the infusion and did not affect the eventual positive treatment outcome. No significant differences with regard to efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms. Rituximab was safe and effective in 7 of 10 patients with noninfectious orbital disease, although 4 required reinfusion with rituximab to maintain control of orbital inflammation. Substantial toxicity was not noted. Rituximab should be considered in the treatment of refractory orbital inflammation. clinicaltrials.gov Identifier: NCT00415506.


Complex interplays among population dynamics, environmental forcing, and exploitation in fisheries.
The patterns of variations in fisheries time series are known to result from a complex combination of species and fisheries dynamics all coupled with environmental forcing (including climate, trophic interactions, etc.). Disentangling the relative effects of these factors has been a major goal of fisheries science for both conceptual and management reasons. By examining the variability of 169 tuna and billfish time series of catch and catch per unit effort (CPUE) throughout the Atlantic as well as their linkage to the North Atlantic Oscillation (NAO), we find that the importance of these factors differed according to the spatial scale. At the scale of the entire Atlantic the patterns of variations are primarily spatially structured, whereas at a more regional scale the patterns of variations were primarily related to the fishing gear. Furthermore, the NAO appeared to also structure the patterns of variations of tuna time series, especially over the North Atlantic. We conclude that the patterns of variations in fisheries time series of tuna and billfish only poorly reflect the underlying dynamics of these fish populations; they appear to be shaped by several successive embedded processes, each interacting with each other. Our results emphasize the necessity for scientific data when investigating the population dynamics of large pelagic fishes, because CPUE fluctuations are not directly attributable to change in species' abundance.


Syntheses and characterization of dicarbonyl-nitrosyl complexes of technetium(I) and rhenium(I) in aqueous media: spectroscopic, structural, and DFT analyses.
This work describes new synthetic routes to produce mixed carbonyl-nitrosyl complexes of technetium(I) and rhenium(I) in aqueous media. NaNO2, NOHSO4, and NO2(g) have been used to produce in situ nitrous acid as the primary source of NO+. Starting from the organometallic precursor fac-[MX3(CO)3]+, 1 (M = 99Tc, Re; X = Cl, Br), the formation of mixed dicarbonyl-mononitrosyl complexes was observed in aqueous hydrochloric and hydrobromic acid. Time-dependent analyses of the reactions by means of HATR-IR and 99Tc NMR spectroscopy in solution revealed the almost quantitative substitution of one CO ligand by NO+ and, thus, the formation of complexes with facial arrangement of the three pi-acceptor ligands. In the case of technetium, the monomeric complex (NEt4)[TcCl3(CO)2NO] (3a) and the dimeric, chloride-bridged, neutral complex [TcCl(mu-Cl)(CO)2NO]2 (4a) were produced. In the case of rhenium, the monomeric species (NEt4)[ReBr2X(CO)2NO] (X = Br (3b), NO3 (5)) was solely isolated. The X-ray structure of complexes 4a and 5 are discussed. The crystallographic analyses revealed the coordination of the NO+ group trans to the terminal chloride (4a) or the bromide (5), respectively. Crystal data: complex 4a (C4Cl4N2O(6)Tc2), monoclinic, Cc, a = 18.82(3) A, b = 6.103(6) A, c = 12.15(2) A, alpha = 90 degrees , beta = 105.8(2) degrees , gamma = 90 degrees , V = 1343(3) A(3), Z = 4; complex 5 (C10H20N3O(6)Br2Re), orthorhombic, P2(1)2(1)2(1), a = 10.2054(5) A, b = 12.5317(7) A, c = 13.9781(7) A, V = 1787.67(16) A(3), Z = 4. The isolated complexes and their potential facial isomers have been further investigated by density functional theory (DFT) calculations. The energy differences of the isomers are relatively small; however, the calculated energies are consistent with the formation of the observed and isolated compounds. The calculated bond lengths and angles of complex 5 are in good agreement with the data determined by X-ray diffraction. Experiments on the no-carrier-added level starting from fac-[99mTc(H2O)3(CO)3]+ revealed the formation of the complex fac-[99mTcCl(H2O)2(CO)2NO]+ in reasonable good yields. This aqueous-based, synthetic approach will enable the future evaluation of this novel, low-valent metal precursor for potential use in radiopharmacy.


Curcumol induces apoptosis in SPC-A-1 human lung adenocarcinoma cells and displays anti-neoplastic effects in tumor bearing mice.
Curcumol is a sesquiterpene originally isolated from curcuma rhizomes, a component of herbal remedies commonly used in oriental medicine. Its beneficial pharmacological activities have attract significant interest recently. In this study, anti-cancer activity of curcumol was examined with both in vitro and in vivo models. It was found that curcumol exhibited time- and concentration-dependent anti-proliferative effects in SPC-A-1 human lung adenocarcinoma cells with cell cycle arrest in the G0/G1 phase while apoptosis-induction was also confirmed with flow cytometry and morphological analyses. Interestingly, curcumol did not display growth inhibition in MRC-5 human embryonic lung fibroblasts, suggesting the anti-proliferative effects of curcumol were specific to cancer cells. Anti-neoplastic effects of curcumol were also confirmed in tumor bearing mice. Curcumol (60 mg/kg daily) significantly reduced tumor size without causing notable toxicity. In conclusion, curcumol appears a favorable anti-cancer candidate for further development.


Experimental infection of Anopheles farauti with different species of Plasmodium.
Studies were conducted to determine the susceptibility of Anopheles farauti to different species and strains of Plasmodium. Mosquitoes were infected by feeding on animals or cultures infected with different strains of P. vivax, P. falciparum, P. ovale, P. coatneyi, P. gonderi, P. simiovale, P. knowlesi, and P. brasilianum. Infections of P. vivax and P. coatneyi were transmitted via sporozoites from An. farauti to monkeys. Comparative infection studies indicated that An. farauti was less susceptible to infection than An. stephensi, An. gambiae, An. freeborni, and An. dirus with the Salvador I strain of P. vivax, but more susceptible than An. stephensi and An. gambiae to infection with the coindigenous Indonesian XIX strain.


High-Resolution Photoelectron Spectroscopy of Cryogenically Cooled NO3̅.
High-resolution anion photoelectron spectra of cryogenically cooled NO3̅ anions obtained using slow photoelectron velocity-map imaging are presented and provide new insight into the vibronic structure of the corresponding neutral radical. A combination of improved spectral resolution, measurement of energy-dependent intensity effects, temperature control, and comparison to theory allows for full assignment of the vibronic features observed in this spectrum. We obtain a refined electron affinity of 3.9289(14) eV for NO3. Further, the appearance of Franck-Condon forbidden transitions from vibrationally cold anions to neutral states with excitation along the NO3 ν4 mode confirms that these features arise from vibronic coupling with the B̃2E' excited state of NO3 and are not hot bands, as has been suggested. Together, the suite of experimental and simulated results provides clear evidence that the ν3 fundamental of NO3 resides near 1050 cm-1, addressing a long-standing controversy surrounding this vibrational assignment.


An overview of primary care assessment and management of bipolar disorder.
Because patients with major psychiatric illnesses increasingly are treated first--and sometimes exclusively--by primary care physicians, improved diagnostic skills and knowledge of treatment options are essential to improved patient outcomes and quality of life. This article reviews the incidence of bipolar disorder and burdens associated with misdiagnosis of the illness. It also emphasizes the evaluation and recognition of bipolar disorders to assist physicians in making accurate diagnoses, as well as reviewing the pharmacologic options used in treatment.


The Hox11 gene is essential for cell survival during spleen development.
The HOX11 homeobox gene was identified via the translocation t(10;14) in T cell leukaemia. To determine the function of this gene in mice, null mutations were made using homologous recombination in ES cells to incorporate lacZ into the hox11 transcription unit. Production of beta-galactosidase from the recombinant hox11 allele in +/- mutants allowed identification of sites of hox11 expression which included the developing spleen. Newborn hox11 -/- mice exhibit asplenia. Spleen formation commences normally at E11.5 in hox11 -/- mutant embryos but the spleen anlage undergoes rapid and complete resorption between E12.5 and E13.5. Dying spleen cells exhibit molecular features of apoptosis, suggesting that programmed cell death is initiated at this stage of organ development in the absence of hox11 protein. Thus hox11 is not required to initiate spleen development but is essential for the survival of splenic precursors during organogenesis. This function for hox11 suggests that enhanced cell survival may result from the t(10;14) which activates HOX11 in T cell leukaemias, further strengthening the association between oncogene-induced cell survival and tumorigenesis.


Clinical and echocardiographic follow-up of patients following surgical heart valve repair or replacement: a tertiary centre experience.
International best practice guidelines recommend lifelong follow-up of patients that have undergone valve repair or replacement surgery and provide recommendations on the utilization of echocardiography during follow-up. However, such follow-up regimes can vary significantly between different centres and sometimes within the same centre. We undertook this study to determine the patterns of clinical follow-up and use of transthoracic echocardiography (TTE) amongst cardiologists in a large UK tertiary centre. In this retrospective study, we identified patients that underwent heart valve repair or replacement surgery in 2008. We used local postal codes to identify patients within our hospital's follow-up catchment area. We determined the frequency of clinical follow-up and use of transthoracic echocardiography (TTE) during the 9-year follow-up period (2009-2016 inclusive). Of 552 patients that underwent heart valve surgery, 93 (17%) were eligible for local follow-up. Of these, the majority (61/93, 66%) were discharged after their 6-week post-operative check-up with no further follow-up. Of the remaining 32 patients, there was remarkable heterogeneity in follow-up regimes and use of TTE. This variation did not correlate with the prosthesis type. In summary, the frequency of clinical follow-up and use of echocardiography is highly variable in contemporary practice. Many patients are inappropriately discharged back to their family doctor with no plans for hospital follow-up. These data further support the creation of dedicated specialist heart valve clinics to optimize patient care, ensure rational use of TTE and optimize adherence with best practice guidelines.


Problems of Parliamentary accountability in Jamaica: consequences for health administration.
The effective parliamentary democracy implements the policies, programmes, procedures and processes that encourage optimal constituency service, effective departmental performance, thoroughly considered and well-formulated government policies, public responsiveness and accountability. This paper uses a case study of health administration to highlight some of the problems presented in seeking to establish parliamentary accountability in Jamaica. It argues that the ineffectiveness and lack of accountability in and of Parliament have flourished in a context of poor economic growth and deep political and social divides. Accountability requires more than ad-hoc institutional interventions; it depends on social and political change.


Genome-wide insights on gastrointestinal nematode resistance in autochthonous Tunisian sheep.
Gastrointestinal nematode (GIN) infections have negative impacts on animal health, welfare and production. Information from molecular studies can highlight the underlying genetic mechanisms that enhance host resistance to GIN. However, such information often lacks for traditionally managed indigenous livestock. Here, we analysed 600 K single nucleotide polymorphism genotypes of GIN infected and non-infected traditionally managed autochthonous Tunisian sheep grazing communal natural pastures. Population structure analysis did not find genetic differentiation that is consistent with infection status. However, by contrasting the infected versus non-infected cohorts using ROH, LR-GWAS, FST and XP-EHH, we identified 35 candidate regions that overlapped between at least two methods. Nineteen regions harboured QTLs for parasite resistance, immune capacity and disease susceptibility and, ten regions harboured QTLs for production (growth) and meat and carcass (fatness and anatomy) traits. The analysis also revealed candidate regions spanning genes enhancing innate immune defence (SLC22A4, SLC22A5, IL-4, IL-13), intestinal wound healing/repair (IL-4, VIL1, CXCR1, CXCR2) and GIN expulsion (IL-4, IL-13). Our results suggest that traditionally managed indigenous sheep have evolved multiple strategies that evoke and enhance GIN resistance and developmental stability. They confirm the importance of obtaining information from indigenous sheep to investigate genomic regions of functional significance in understanding the architecture of GIN resistance.


Development of polyclonal antibodies specific to ATP-binding cassette transporters human ABCG4 and mouse Abcg4: site-specific expression of mouse Abcg4 in brain.
In our recent study on seeking new mouse ATP-binding cassette (ABC) transporters of the G subfamily, we succeeded in cloning mouse Abcg4 from a cDNA library of mouse brain, and we characterized the tissue-specific expression and chromosomal localization of the mouse Abcg4 gene. To further characterize the physiological function of mouse Abcg4 protein and to compare its function with that of ABCG2, in the present study, we developed polyclonal antibodies against mouse Abcg4 and established the Abcg4-expression system. To raise antibodies, we selected three different epitope peptides that correspond to the amino acid residues of 46-60, 465-479, and 600-613 in mouse Abcg4 protein. The antibody raised against the epitope encoding the amino acids 46-60 was found to be specific to mouse Abcg4, exhibiting a band with molecular weight of 63,000 on immunoblotting, whereas this band was dose-dependently diminished by adding the corresponding epitope peptide into the immunoblot medium. Use of the antibody for immunoblot detection in mouse normal tissues revealed that the Abcg4 protein is expressed in brain, spleen, and testis. Immunohistochemical studies showed that mouse Abcg4 is site-specifically expressed in the cerebral cortex and medulla of mouse brain. These results suggest that mouse Abcg4 plays a certain physiological role in the brain. It is of importance to note that the sequence of amino acids 46-60 is completely identical between mouse Abcg4 and human ABCG4. Thus, this antibody is applicable to the detection of human ABCG4 as well as mouse Abcg4.


NTP Toxicology and Carcinogenesis Studies of Crocidolite Asbestos (CAS No. 12001-28-4) In F344/N Rats (Feed Studies).
Carcinogenesis studies of crocidolite asbestos were conducted with male and female F344/N rats. This form of asbestos was administered at a concentration of 1% in pelleted diet for the lifetime of the rats, starting with the dams of the study animals. The studies were started in January 1978 and ended in December 1980. Group sizes were 118 for male and female controls and 250 for male and female crocidolite asbestos-exposed rats. The offspring from mothers exposed to crocidolite asbestos and the controls were similar in size at birth but were slightly smaller at weaning and remained so throughout their life. Feed consumption and survival were comparable in the exposed and control groups. No overt toxicity was observed in the crocidolite asbestos-exposed animals. There was an elevated (P<0.05) incidence of thyroid gland C-cell adenomas (control, 4/117, 3%, vs. exposed, 23/250, 9%) and of thyroid gland C-cell carcinomas (12/117, 10%, vs. 46/250, 18%) in crocidolite asbestos-exposed female rats relative to concurrent controls. Because these control incidences were low relative to control incidences observed in other contemporary studies at this laboratory (21% for thyroid gland C-cell tumors), this slight increase was not regarded as being biologically important. The data, documents, and pathology materials from the lifetime studies of crocidolite asbestos have been audited. The audit findings show that the conduct of these studies is documented adequately and support the data and results presented in this Technical Report. Conclusions: Under the conditions of these feed studies, crocidolite asbestos was not overtly toxic and did not cause a carcinogenic response when ingested at a concentration of 1% in the diet by male and female F344/N rats for their lifetime. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative


Virulence differences in Toxoplasma mediated by amplification of a family of polymorphic pseudokinases.
The population structure of Toxoplasma gondii includes three highly prevalent clonal lineages referred to as types I, II, and III, which differ greatly in virulence in the mouse model. Previous studies have implicated a family of serine/threonine protein kinases found in rhoptries (ROPs) as important in mediating virulence differences between strain types. Here, we explored the genetic basis of differences in virulence between the highly virulent type I lineage and moderately virulent type II based on successful genetic cross between these lineages. Genome-wide association revealed that a single quantitative trait locus controls the dramatic difference in lethality between these strain types. Neither ROP16 nor ROP18, previously implicated in virulence of T. gondii, was found to contribute to differences between types I and II. Instead, the major virulence locus contained a tandem cluster of polymorphic alleles of ROP5, which showed similar protein expression between strains. ROP5 contains a conserved serine/threonine protein kinase domain that includes only part of the catalytic triad, and hence, all members are considered to be pseudokinases. Genetic disruption of the entire ROP5 locus in the type I lineage led to complete attenuation of acute virulence, and complementation with ROP5 restored lethality to WT levels. These findings reveal that a locus of polymorphic pseudokinases plays an important role in pathogenesis of toxoplasmosis in the mouse model.


Expression of wingless in the Drosophila embryo: a conserved cis-acting element lacking conserved Ci-binding sites is required for patched-mediated repression.
Patterning of the Drosophila embryo depends on the accurate expression of wingless (wg), which encodes a secreted signal required for segmentation and many other processes. Early expression of wg is regulated by the nuclear proteins of the gap and pair-rule gene classes but, after gastrulation, wg transcription is also dependent on cell-cell communication. Signaling to the Wg-producing cells is mediated by the secreted protein, Hedgehog (Hh), and by Cubitus interruptus (Ci), a transcriptional effector of the Hh signal transduction pathway. The transmembrane protein Patched (Ptc) acts as a negative regulator of wg expression; ptc- embryos have ectopic wg expression. According to the current models, Ptc is a receptor for Hh. The default activity of Ptc is to inhibit Ci function; when Ptc binds Hh, this inhibition is released and Ci can control wg transcription. We have investigated cis-acting sequences that regulate wg during the time that wg expression depends on Hh signaling. We show that approximately 4.5 kb immediately upstream of the wg transcription unit can direct expression of the reporter gene lacZ in domains similar to the normal wg pattern in the embryonic ectoderm. Expression of this reporter construct expands in ptc mutants and responds to hh activity. Within this 4.5 kb, a 150 bp element, highly conserved between D. melanogaster and Drosophila virilis, is required to spatially restrict wg transcription. Activity of this element depends on ptc, but it contains no consensus Ci-binding sites. The discovery of an element that is likely to bind a transcriptional repressor was unexpected, since the prevailing model suggests that wg expression is principally controlled by Hh signaling acting through the Ci activator. We show that wg regulatory DNA can drive lacZ in a proper wg-like pattern without any conserved Ci-binding sites and suggest that Ci can not be the sole endpoint of the Hh pathway.


Measurement of a bidirectional reflectance distribution and system achievement based on a hemi-parabolic mirror.
A novel approach is proposed for measuring a surface's bidirectional reflectance distribution function rapidly and accurately. By using a hemi-parabolic mirror, the angular distribution of a surface's reflectance in three-dimensional space can be transformed into a two-dimensional planar image, which is collected by a CCD camera and goes through a followed coordinate mapping. It is shown that, using this method and apparatus, measurement of in plane and out of plane reflectance distributions may be realized within two minutes.


Quantitative analysis of gender stereotypes and information aggregation in a national election.
By analyzing a database of a questionnaire answered by a large majority of candidates and elected in a parliamentary election, we quantitatively verify that (i) female candidates on average present political profiles which are more compassionate and more concerned with social welfare issues than male candidates and (ii) the voting procedure acts as a process of information aggregation. Our results show that information aggregation proceeds with at least two distinct paths. In the first case candidates characterize themselves with a political profile aiming to describe the profile of the majority of voters. This is typically the case of candidates of political parties which are competing for the center of the various political dimensions. In the second case, candidates choose a political profile manifesting a clear difference from opposite political profiles endorsed by candidates of a political party positioned at the opposite extreme of some political dimension.


Defective emotion recognition in early HD is neuropsychologically and anatomically generic.
Huntington's disease (HD) is an inherited neurodegenerative disorder that classically presents with motor, cognitive and psychiatric symptoms. However, other abnormalities also occur in this condition, notably deficient recognition of facial emotional expressions. Deficits in emotion recognition impact significantly on the lives of HD patients and their families and thus it is important to clarify the onset and pattern of impairment. This study investigated facial emotion recognition in a large cohort of early HD patients, and premanifest gene-carriers. We used voxel-based morphometry (VBM) to examine the neuroanatomical correlates of emotion recognition performance. Forty patients with early HD, 21 premanifest gene carriers and 20 controls were assessed using 24 faces from the Ekman Pictures of Facial Affect, and volumetric brain MRI. The HD group was significantly worse than controls at recognising, surprise, disgust, anger and fear, and worse than the premanifest group at recognising disgust and anger. When patient data were expressed as z-scores, recognition of anger was significantly worse than disgust in the early HD group. In the VBM analysis, these deficits were associated with common regional atrophy: impaired recognition of surprise, disgust, anger and fear were all associated with striatal volume loss. Fear was associated with additional atrophy of the right insula and left and right lateral orbitofrontal cortex. Even in early HD there is a wide-ranging impairment in recognition of negative emotions denoting 'threat'. Our findings implicate a generic fronto-subcortical network in the pathogenesis of these emotion recognition deficits.


Nonlinear isochrones in murine left ventricular pressure-volume loops: how well does the time-varying elastance concept hold?
The linear time-varying elastance theory is frequently used to describe the change in ventricular stiffness during the cardiac cycle. The concept assumes that all isochrones (i.e., curves that connect pressure-volume data occurring at the same time) are linear and have a common volume intercept. Of specific interest is the steepest isochrone, the end-systolic pressure-volume relationship (ESPVR), of which the slope serves as an index for cardiac contractile function. Pressure-volume measurements, achieved with a combined pressure-conductance catheter in the left ventricle of 13 open-chest anesthetized mice, showed a marked curvilinearity of the isochrones. We therefore analyzed the shape of the isochrones by using six regression algorithms (two linear, two quadratic, and two logarithmic, each with a fixed or time-varying intercept) and discussed the consequences for the elastance concept. Our main observations were 1) the volume intercept varies considerably with time; 2) isochrones are equally well described by using quadratic or logarithmic regression; 3) linear regression with a fixed intercept shows poor correlation (R(2) < 0.75) during isovolumic relaxation and early filling; and 4) logarithmic regression is superior in estimating the fixed volume intercept of the ESPVR. In conclusion, the linear time-varying elastance fails to provide a sufficiently robust model to account for changes in pressure and volume during the cardiac cycle in the mouse ventricle. A new framework accounting for the nonlinear shape of the isochrones needs to be developed.


Prospective Longitudinal Patient-Reported Satisfaction and Health-Related Quality of Life following DIEP Flap Breast Reconstruction: Relationship with Body Mass Index.
Breast reconstruction plays a significant role in breast cancer treatment recovery. Introduction of the BREAST-Q questionnaire has facilitated quantifying patient-reported quality-of-life measures, promoting improved evidence-based clinical practice. Information regarding the effects of body mass index on patient-reported outcomes and health-related quality of life is significantly lacking. Consecutive deep inferior epigastric perforator (DIEP) flap breast reconstruction patients prospectively completed BREAST-Q questionnaires preoperatively and at two points postoperatively. The first (postoperative time point A) and second (postoperative time point B) postoperative questionnaires were completed 1 month postoperatively and following breast revision, respectively. Postoperative flap and donor-site complications were recorded prospectively. BREAST-Q scores were compared at all time points and stratified by body mass index group (≤25, >25 to 29.9, 30 to 34.9, and ≥35 kg/m). Between July of 2012 and August of 2016, 73 patients underwent 130 DIEP flap breast reconstructions. Breast satisfaction and psychosocial and sexual well-being scores increased significantly postoperatively. Chest and abdominal physical well-being scores returned to baseline levels by postoperative point B. Preoperatively, stratified by body mass index, breast satisfaction and psychosocial well-being scores were significantly lower among patients with body mass index of 35 or higher and of more than 30, respectively. After reconstruction, not only were breast satisfaction, psychosocial, and sexual well-being scores significantly improved in all body mass index groups versus baseline, but also between-body mass index group differences were no longer present. Outcome satisfaction, flap, and donor-site morbidity were similar irrespective of body mass index. Patient-reported outcomes demonstrate significant improvements in breast satisfaction and psychosocial and sexual well-being among patients following DIEP flap reconstruction. Preoperative differences in quality-of-life scores were improved in patients with obesity (body mass index ≥30 kg/m). Risk, II.


The evolutionary history of the catenin gene family during metazoan evolution.
Catenin is a gene family composed of three subfamilies; p120, beta and alpha. Beta and p120 are homologous subfamilies based on sequence and structural comparisons, and are members of the armadillo repeat protein superfamily. Alpha does not appear to be homologous to either beta or p120 based on the lack of sequence and structural similarity, and the alpha subfamily belongs to the vinculin superfamily. Catenins link the transmembrane protein cadherin to the cytoskeleton and thus function in cell-cell adhesion. To date, only the beta subfamily has been evolutionarily analyzed and experimentally studied for its functions in signaling pathways, development and human diseases such as cancer. We present a detailed evolutionary study of the whole catenin family to provide a better understanding of how this family has evolved in metazoans, and by extension, the evolution of cell-cell adhesion. All three catenin subfamilies have been detected in metazoans used in the present study by searching public databases and applying species-specific BLAST searches. Two monophyletic clades are formed between beta and p120 subfamilies using Bayesian phylogenetic inference. Phylogenetic analyses also reveal an array of duplication events throughout metazoan history. Furthermore, numerous annotation issues for the catenin family have been detected by our computational analyses. Delta2/ARVCF catenin in the p120 subfamily, beta catenin in the beta subfamily, and alpha2 catenin in the alpha subfamily are present in all metazoans analyzed. This implies that the last common ancestor of metazoans had these three catenin subfamilies. However, not all members within each subfamily were detected in all metazoan species. Each subfamily has undergone duplications at different levels (species-specific, subphylum-specific or phylum-specific) and to different extents (in the case of the number of homologs). Extensive annotation problems have been resolved in each of the three catenin subfamilies. This resolution provides a more coherent description of catenin evolution.


Filopodia-like protrusions of adjacent somatic cells shape the developmental potential of oocytes.
The oocyte must grow and mature before fertilization, thanks to a close dialogue with the somatic cells that surround it. Part of this communication is through filopodia-like protrusions, called transzonal projections (TZPs), sent by the somatic cells to the oocyte membrane. To investigate the contribution of TZPs to oocyte quality, we impaired their structure by generating a full knockout mouse of the TZP structural component myosin-X (MYO10). Using spinning disk and super-resolution microscopy combined with a machine-learning approach to phenotype oocyte morphology, we show that the lack of Myo10 decreases TZP density during oocyte growth. Reduction in TZPs does not prevent oocyte growth but impairs oocyte-matrix integrity. Importantly, we reveal by transcriptomic analysis that gene expression is altered in TZP-deprived oocytes and that oocyte maturation and subsequent early embryonic development are partially affected, effectively reducing mouse fertility. We propose that TZPs play a role in the structural integrity of the germline-somatic complex, which is essential for regulating gene expression in the oocyte and thus its developmental potential.


Dendritic cells in cord blood transplantation: a review.
Dendritic cells (DCs) are a heterogeneous population of antigen-presenting cells derived from hematopoietic progenitors that bridge the transition between the innate and adaptive immune responses, while maintaining self-tolerance and Th1/Th2 homeostasis, by priming other cells in either an immunogenic or tolerogenic direction. Through their role in both innate and adaptive immunity, DCs play a major part in transplant engraftment and rejection and in graft-versus-host disease (GvHD). Preferentially tolerogenic or immunogenic DC subtypes offer targets for immunotherapy, to optimize transplant success rates and prolong disease-free and overall survival. Cord blood DCs are immature and preferentially tolerogenic, due to maternal-fetal tolerance, leading to better graft acceptance and immune reconstitution and explaining the lower incidence and severity of GvHD in CB transplantation, despite donor-host mismatching. Manipulation of DC maturation and cell loading with tumor-antigens can direct antitumor immunity and target minimal residual disease, as demonstrated for acute myeloid leukemia, optimizing the graft-versus-leukemia effect.


Clinical evaluation of alloderm for root coverage and colour match.
Predictable root coverage and good colour match are the major therapeutic end points in the treatment of gingival recession. Alloderm has been used as a substitute to connective tissue graft, but its colour match in populations with a high degree of melanin pigmentation has not been extensively studied. The aim of this study was to evaluate the effectiveness of an Acellular dermal matrix graft for root coverage procedures and to objectively analyze the post-operative esthetics using a Visual Analog Scale (VAS). Both male and female patients were selected, aged 20-50 years presenting with aesthetic problems due to the exposure of recession defects when smiling. A total of 14 patients contributed to 15 sites, each site falling into Miller's class I or class II gingival recession. A total of 15 sites were treated and a mean coverage of (85.56±21.70 and 83.33±21.82%) was obtained at the end of 3(rd) and 12(th) month respectively. A mean VAS score of 7.93±1.03 and 8.13±0.99 (3(rd) and 12(th) month) and 5.73±0.70 and 6.87±0.83 (3(rd) and 12(th) month) was obtained when the colour match recorded by the patients and an independent observer, respectively. The study showed that acellular dermal matrix graft (alloderm) may be successfully used to treat gingival recession, as adequate root coverage may be predictably obtained. The grafted areas underwent melanization from the 6(th) month onwards and complete blending with the adjacent sites was obtained at 1 year.


Substance use as a longitudinal predictor of the perpetration of teen dating violence.
The prevention of teen dating violence is a major public health priority. However, the dearth of longitudinal studies makes it difficult to develop programs that effectively target salient risk factors. Using a school-based sample of ethnically diverse adolescents, this longitudinal study examined whether substance use (alcohol, marijuana, and hard drugs) and exposure to parental violence predicted the perpetration of physical dating violence over time. 1,042 9th and 10th grade high schools students were recruited and assessed in the spring of 2010, and 93 % of the original sample completed the 1-year follow-up in the spring of 2011. Participants who had begun dating at the initial assessment and who self-identified as African American (n = 263; 32 %), Caucasian (n = 272; 33 %), or Hispanic (n = 293; 35 %) were included in the current analyses (n = 828; 55 % female). Slightly more than half of the adolescents who perpetrated dating violence at baseline reported past year dating violence at follow-up, relative to only 11 % of adolescents who did not report perpetrating dating violence at baseline. Structural equation modeling revealed that the use of alcohol and hard drugs at baseline predicted the future perpetration of physical dating violence, even after accounting for the effects of baseline dating violence and exposure to interparental violence. Despite differences in the prevalence of key variables between males and females, the longitudinal associations did not vary by gender. With respect to race, exposure to mother-to-father violence predicted the perpetration of dating violence among Caucasian adolescents. Findings from the current study indicate that targeting substance use, and potentially youth from violent households, may be viable approaches to preventing the perpetration of teen dating violence.


Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.
Sequencing tests assaying panels of genes or whole exomes are widely available for cancer risk evaluation. However, methods for classification of variants resulting from this testing are not well studied. We evaluated the ability of a variant-classification methodology based on American College of Medical Genetics and Genomics (ACMG) guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG-designated reportable cancer and non-cancer-associated genes, in individuals who met guidelines for hereditary cancer risk evaluation. We performed whole-exome sequencing in 404 individuals in 253 families and classified 1,640 variants. Potentially clinically actionable (likely pathogenic [LP] or pathogenic [P]) versus nonactionable (VUS, likely benign, or benign) calls were 95% concordant with locus-specific databases and Clinvar. LP or P mutations were identified in 12 of 25 breast cancer susceptibility genes in 26 families without identified BRCA1/2 mutations (11%). Evaluation of 84 additional genes associated with autosomal-dominant cancer susceptibility identified LP or P mutations in only two additional families (0.8%). However, individuals from 10 of 253 families (3.9%) had incidental LP or P mutations in 32 non-cancer-associated genes, and 9% of individuals were monoallelic carriers of a rare LP or P mutation in 39 genes associated with autosomal-recessive cancer susceptibility. Furthermore, 95% of individuals had at least one VUS. In summary, these data support the clinical utility of ACMG variant-classification guidelines. Additionally, evaluation of extended panels of cancer-associated genes in breast/ovarian cancer families leads to only an incremental clinical benefit but substantially increases the complexity of the results.


Does climate variability influence the demography of wild primates? Evidence from long-term life-history data in seven species.
Earth's rapidly changing climate creates a growing need to understand how demographic processes in natural populations are affected by climate variability, particularly among organisms threatened by extinction. Long-term, large-scale, and cross-taxon studies of vital rate variation in relation to climate variability can be particularly valuable because they can reveal environmental drivers that affect multiple species over extensive regions. Few such data exist for animals with slow life histories, particularly in the tropics, where climate variation over large-scale space is asynchronous. As our closest relatives, nonhuman primates are especially valuable as a resource to understand the roles of climate variability and climate change in human evolutionary history. Here, we provide the first comprehensive investigation of vital rate variation in relation to climate variability among wild primates. We ask whether primates are sensitive to global changes that are universal (e.g., higher temperature, large-scale climate oscillations) or whether they are more sensitive to global change effects that are local (e.g., more rain in some places), which would complicate predictions of how primates in general will respond to climate change. To address these questions, we use a database of long-term life-history data for natural populations of seven primate species that have been studied for 29-52 years to investigate associations between vital rate variation, local climate variability, and global climate oscillations. Associations between vital rates and climate variability varied among species and depended on the time windows considered, highlighting the importance of temporal scale in detection of such effects. We found strong climate signals in the fertility rates of three species. However, survival, which has a greater impact on population growth, was little affected by climate variability. Thus, we found evidence for demographic buffering of life histories, but also evidence of mechanisms by which climate change could affect the fates of wild primates.


Reduced Fading of Visual Afterimages after Transcranial Magnetic Stimulation over Early Visual Cortex.
In the complete absence of small transients in visual inputs (e.g., by experimentally stabilizing an image on the retina or in everyday life during intent staring), information perceived by the eyes will fade from the perceptual experience. Although the mechanisms of visual fading remain poorly understood, one possibility is that higher level brain regions actively suppress the stable visual signals via targeted feedback onto early visual cortex (EVC). Here, we used positive afterimages and multisensory conflict to induce gestalt-like fading of participants' own hands. In two separate experiments, participants rated the perceived quality of their hands both before and after transcranial magnetic stimulation (TMS) was applied over EVC. In a first experiment, triple-pulse TMS was able to make a faded hand appear less faded after the pulses were applied, compared with placebo pulses. A second experiment demonstrated that this was because triple-pulse TMS slowed down fading of the removed hand that otherwise occurs naturally over time. Interestingly, TMS similarly affected the left and right hands, despite being applied only over the right EVC. Together, our results suggest that TMS over EVC attenuates the effects of visual fading in positive afterimages, and it might do so by crossing transcollosal connections or via multimodal integration sites in which both hands are represented.


Intracellular labile iron pools as direct targets of iron chelators: a fluorescence study of chelator action in living cells.
The primary targets of iron chelators used for treating transfusional iron overload are prevention of iron ingress into tissues and its intracellular scavenging. The present study was aimed at elucidating the capacity of clinically important iron chelators such as deferiprone (DFP), desferrioxamine, and ICL670 to (a) gain direct access to intracellular iron pools of key cells of iron accumulation (macrophages, hepatocytes, and cardiomyocyte cell lines); (b) chelate the labile iron present in discrete cell compartments/organelles; and (c) prevent labile iron involvement in the generation of reactive oxidant species. Chelation of cytosolic and organellar cell iron was visualized dynamically and quantitatively in living cells by fluorescence microscopic imaging of fluorescent metallosensors (used as iron-quenched complexes of calceins) targeted to either cytosol, endosome-lysosomes, or mitochondria. The rate and extent of fluorescence recovery provided an in situ measure of the accessibility of chelators to particular cell sites/organelles. Complementary, fluorogenic redox probes associated with cell compartments enabled identification of chelator-sensitive, localized reactive oxidant production. Our studies indicate that chelation by desferrioxamine is slow and is enhanced in cells with relatively high endocytic activities, while ICL670 and DFP readily enter most cells and efficiently reach the major intracellular sites of iron accumulation.


Genetic diversity and differentiation among Lagopus lagopus populations in Scandinavia and Scotland: evolutionary significant units confirmed by SNP markers.
Single Nucleotide Polymorphism in four Scandinavian populations of willow grouse (Lagopus lagopus) and two Scottish populations of red grouse (Lagopus lagopus scoticus) were assessed at 13 protein-coding loci. We found high levels of diversity, with one substitution every 55 bp as an average and a total of 76 unlinked parsimony informative SNPs. Different estimators of genetic diversity such as: number of synonymous and non-synonymous sites, average number of alleles, number and percentage of polymorphic loci, mean nucleotide diversity (pi(s), pi(a)) and gene diversity at synonymous and non-synonymous sites showed higher diversity in the northern populations compared to southern ones. Strong levels of purifying selection found in all the populations together with neutrality tests conforming to neutral expectations agree with large effective population sizes. Assignment tests reported a clear distinction between Scandinavian and Scottish grouse suggesting the existence of two different evolutionary significant units. The divergence time between willow and red grouse ranging between 12 500 and 125 000 years, in conjunction with the presence of 'specific' markers for each subspecies prompt a reassessment of the taxonomical status of the Scottish red grouse.


Covariance mapping: a correlation method applied to multiphoton multiple ionization.
In some cases there are hidden correlations in a highly fluctuating signal, but these are lost in a conventional averaging procedure. Covariance mapping allows these correlations to be revealed unambiguously. As an example of the applicability of this technique, the dynamics of fragmentation of molecules ionized by an intense picosecond laser are analyzed.


[The emerging role of three-dimensional transesophageal echocardiography in guiding the MitraClip procedure].
Percutaneous edge-to-edge mitral valve repair with the MitraClip device has been shown to be a safe and effective procedure in selected patients with moderate-to-severe mitral regurgitation. Two-dimensional transesophageal echocardiography (2D TEE) is the primary imaging modality for guidance of the procedure. Real-time three-dimensional (3D) TEE has recently been used as additional imaging modality during the MitraClip procedure. In comparison with 2D TEE, 3D TEE provides additional information in several steps of the procedure, including precise positioning of the clip delivery system into the left atrium, correct alignment of the clip arms perpendicular to the coaptation line and confirmation of the correct grasping location. This review describes the relevant role of 3D TEE imaging during the procedure, but also its limitations.


Prophylactic milrinone for the prevention of low cardiac output syndrome and mortality in children undergoing surgery for congenital heart disease.
Children with congenital heart disease often undergo heart surgery at a young age. They are at risk for postoperative low cardiac output syndrome (LCOS) or death. Milrinone may be used to provide inotropic and vasodilatory support during the immediate postoperative period. This review examines the effectiveness of prophylactic postoperative use of milrinone to prevent LCOS or death in children having undergone surgery for congenital heart disease. Electronic and manual literature searches were performed to identify randomised controlled trials. We searched CENTRAL, MEDLINE, EMBASE and Web of Science in February 2014 and conducted a top-up search in September 2014 as well as clinical trial registries and reference lists of published studies. We did not apply any language restrictions. Only randomised controlled trials were selected for analysis. We considered studies with newborn infants, infants, toddlers, and children up to 12 years of age. Two review authors independently extracted data according to a pre-defined protocol. We obtained additional information from all study authors. Three of the five included studies compared milrinone versus levosimendan, one study compared milrinone with placebo, and one compared milrinone verus dobutamine, with 101, 242, and 50 participants, respectively. Three trials were at low risk of bias while two were at higher risk of bias. The number and definitions of outcomes were non-uniform as well. In one study comparing two doses of milrinone and placebo, there was some evidence in an overall comparison of milrinone versus placebo that milrinone lowered risk for LCOS (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.28 to 0.96; 227 participants). The results from two small studies do not provide enough information to determine whether milrinone increases the risk of LCOS when compared to levosimendan (RR 1.22, 95% CI 0.32 to 4.65; 59 participants). Mortality rates in the studies were low, and there was insufficient evidence to draw conclusions on the effect of milrinone compared to placebo or levosimendan or dobutamine regarding mortality, the duration of intensive care stay, hospital stay, mechanical ventilation, or maximum inotrope score (where available). Numbers of patients requiring mechanical cardiac support were also low and did not allow a comparison between studies, and none of the participants of any study received a heart transplantation up to the end of the respective follow-up period. Time to death within three months was not reported in any of the included studies. A number of adverse events was examined, but differences between the treatment groups could not be proven for hypotension, intraventricular haemorrhage, hypokalaemia, bronchospasm, elevated serum levels of liver enzymes, or a reduced left ventricular ejection fraction < 50% or reduced left ventricular fraction of shortening < 28%. Our analysis did not prove an increased risk of arrhythmias in patients treated prophylactically with milrinone compared with placebo (RR 3.59, 95% CI 0.83 to 15.42; 238 participants), a decreased risk of pleural effusions (RR 1.78, 95% CI 0.92 to 3.42; 231 participants), or a difference in risk of thrombocytopenia on milrinone compared with placebo (RR 0.86, 95% CI 0.39 to 1.88; 238 participants). Comparisons of milrinone with levosimendan or with dobutamine, respectively, did not clarify the risk of arrhythmia and were not possible for pleural effusions or thrombocytopenia. There is insufficient evidence of the effectiveness of prophylactic milrinone in preventing death or low cardiac output syndrome in children undergoing surgery for congenital heart disease, compared to placebo. So far, no differences have been shown between milrinone and other inodilators, such as levosimendan or dobutamine, in the immediate postoperative period, in reducing the risk of LCOS or death. The existing data on the prophylactic use of milrinone has to be viewed cautiously due to the small number of small trials and their risk of bias.


Channel density regulation of firing patterns in a cortical neuron model.
Modifying the density and distribution of ion channels in a neuron (by natural up- and downregulation or by pharmacological intervention or by spontaneous mutations) changes its activity pattern. In this investigation we analyzed how the impulse patterns are regulated by the density of voltage-gated channels in a neuron model based on voltage-clamp measurements of hippocampal interneurons. At least three distinct oscillatory patterns, associated with three distinct regions in the Na-K channel density plane, were found. A stability analysis showed that the different regions are characterized by saddle-node, double-orbit, and Hopf-bifurcation threshold dynamics, respectively. Single, strongly graded action potentials occur in an area outside the oscillatory regions, but less graded action potentials occur together with repetitive firing over a considerable range of channel densities. The relationship found here between channel densities and oscillatory behavior may partly explain the difference between the principal spiking patterns previously described for crab axons (class 1 and 2) and cortical neurons (regular firing and fast spiking).


Validity and reliability problems with patient global as a component of the ACR/EULAR remission criteria as used in clinical practice.
To investigate what factors influence patient global health assessment (PtGlobal), and how those factors and the reliability of PtGlobal affect the rate, reliability, and validity of recently published American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) rheumatoid arthritis (RA) remission criteria when used in clinical practice. We examined consecutive patients with RA in clinical practice and identified 77 who met ACR/EULAR joint criteria for remission (≤ 1 swollen joint and ≤ 1 tender joint). We evaluated factors associated with a PtGlobal > 1, because a PtGlobal ≤ 1 defined ACR/EULAR remission in this group of patients who had already met ACR/EULAR joint criteria. Of the 77 patients examined, only 17 (22.1%) had PtGlobal ≤ 1 and thus fully satisfied ACR/EULAR criteria. A large proportion of patients not in remission by ACR/EULAR criteria had high PtGlobal related to noninflammatory issues, including low back pain, fatigue, and functional limitations, and a number of patients clustered in the range of PtGlobal > 1 and ≤ 2. However, the minimal detectable difference for PtGlobal was 2.3. In addition, compared with a PtGlobal severity score, a PtGlobal activity score was 3.3% less likely to be abnormal (> 1). Noninflammatory factors contribute to the level of PtGlobal and result in the exclusion of many patients who would otherwise be in "true" remission according to the ACR/EULAR definition. Reliability problems associated with PtGlobal can also result in misclassification, and may explain the observation of low longterm remission rates in RA. As currently constituted, the use of the ACR/EULAR remission criteria in clinical practice appears to be problematic.


Green synthesis as a simple and rapid route to protein modified magnetic nanoparticles for use in the development of a fluorometric molecularly imprinted polymer-based assay for detection of myoglobin.
We have developed a low-cost molecularly imprinted polymer (MIP)-based fluorometric assay to directly quantify myoglobin in a biological sample. The assay uses a previously unreported method for the development of microwave-assisted rapid synthesis of aldehyde functionalized magnetic nanoparticles, in just 20 min. The aldehyde functionalized nanoparticles have an average size of 7.5 nm ± 1.8 and saturation magnetizations of 31.8 emu g-1 with near-closed magnetization loops, confirming their superparamagnetic properties. We have subsequently shown that protein tethering was possible to the aldehyde particles, with 0.25 ± 0.013 mg of myoglobin adsorbed to 20 mg of the nanomaterial. Myoglobin-specific fluorescently tagged MIP (F-MIP) particles were synthesized and used within the assay to capture myoglobin from a test sample. Excess F-MIP was removed from the sample using protein functionalized magnetic nanoparticles (Mb-SPION), with the remaining sample analyzed using fluorescence spectroscopy. The obtained calibration plot of myoglobin showed a linear correlation ranging from 60 pg ml-1 to 6 mg ml-1 with the limit of detection of 60 pg ml-1. This method was successfully used to detect myoglobin in spiked fetal calf serum, with a recovery rate of more than 93%.


Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS Program.
This study compared initiation of insulin and other antihyperglycaemic agents (AHAs) with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year, fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs. 16%), insulin (3% vs. 9%) or any non-insulin AHA (5% vs. 12%) (P < .001 for all); overall AHA initiation rates increased over time but were consistently lower with canagliflozin compared with placebo. During the study, the likelihood of initiating insulin was 2.7 times lower for participants treated with canagliflozin compared with placebo (hazard ratio, 0.37; 95% CI: 0.31, 0.43; P < .001). The time difference between 10% of patients in the canagliflozin and placebo groups being initiated on insulin from the beginning of the trial was about 2 years. Time to initiation of other AHAs, including metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sulphonylureas, was also delayed for canagliflozin versus placebo (P < .001 for each). Compared with placebo, canagliflozin delayed the need for initiation of other AHAs and delayed time to insulin therapy, an outcome that is important to many people with diabetes.


Relationship between periodontal infections and systemic disease.
Oral conditions such as gingivitis and chronic periodontitis are found worldwide and are among the most prevalent microbial diseases of mankind. The cause of these common inflammatory conditions is the complex microbiota found as dental plaque, a complex microbial biofilm. Despite 3000 years of history demonstrating the influence of oral status on general health, it is only in recent decades that the association between periodontal diseases and systemic conditions such as coronary heart disease and stroke, and a higher risk of preterm low birth-weight babies, has been realised. Similarly, recognition of the threats posed by periodontal diseases to individuals with chronic diseases such as diabetes, respiratory diseases and osteoporosis is relatively recent. Despite these epidemiological associations, the mechanisms for the various relationships remain unknown. Nevertheless, a number of hypotheses have been postulated, including common susceptibility, systemic inflammation with increased circulating cytokines and mediators, direct infection and cross-reactivity or molecular mimicry between bacterial antigens and self-antigens. With respect to the latter, cross-reactive antibodies and T-cells between self heat-shock proteins (HSPs) and Porphyromonas gingivalis GroEL have been demonstrated in the peripheral blood of patients with atherosclerosis as well as in the atherosclerotic plaques themselves. In addition, P. gingivalis infection has been shown to enhance the development and progression of atherosclerosis in apoE-deficient mice. From these data, it is clear that oral infection may represent a significant risk-factor for systemic diseases, and hence the control of oral disease is essential in the prevention and management of these systemic conditions.


Irrational Beliefs and Psychological Distress: A Meta-Analysis.
Since the cognitive revolution of the early 1950s, cognitions have been discussed as central components in the understanding and treatment of mental illnesses. Even though there is an extensive literature on the association between therapy-related cognitions such as irrational beliefs and psychological distress over the past 60 years, there is little meta-analytical knowledge about the nature of this association. The relationship between irrational beliefs and distress was examined based on a systematic review that included 100 independent samples, gathered in 83 primary studies, using a random-effect model. The overall effects as well as potential moderators were examined: (a) distress measure, (b) irrational belief measure, (c) irrational belief type, (d) method of assessment of distress, (e) nature of irrational beliefs, (f) time lag between irrational beliefs and distress assessment, (g) nature of stressful events, (h) sample characteristics (i.e. age, gender, income, and educational, marital, occupational and clinical status), (i) developer/validator status of the author(s), and (k) publication year and country. Overall, irrational beliefs were positively associated with various types of distress, such as general distress, anxiety, depression, anger, and guilt (omnibus: r = 0.38). The following variables were significant moderators of the relationship between the intensity of irrational beliefs and the level of distress: irrational belief measure and type, stressful event, age, educational and clinical status, and developer/validator status of the author. Irrational beliefs and distress are moderately connected to each other; this relationship remains significant even after controlling for several potential covariates.