Substance use disorders in association with attention-deficit/hyperactivity disorder, co-morbid mental disorders, and medication in a nationwide sample.
The association of substance use disorders (SUD) with attention-deficit disorder (ADHD), co-morbid mental disorders, and medication has only been studied in isolation and in rather small samples. Data were based on four Danish national registers covering a total of 20,742 patients with ADHD, their dispensed medications, co-morbid mental disorders, and associated SUD between 1994 and 2010. The analyses considered the risk of various medications (methylphenidate only, antidepressants only, antipsychotic only, mixed medication) in comparison to a control group of non-medicated patients with ADHD, various co-morbid disorders, duration of medication, age at diagnosis, year of birth, and sex for developing SUD. The observation period of the cohort ranged between 2.25 and 66.21 years and the prevalence for SUD was 9.51%. The SUD rates were significantly higher prior to, compared to following the onset of medication in the methylphenidate and the mixed medication subgroup, whereas they were significantly higher following onset of medication in the antidepressants and the antipsychotics subgroups. However, the SUD rates were significantly higher in all drug conditions except for methylphenidate after onset of medication compared to the non-medicated subgroup. Risk factors obtained by regression analysis did not include methylphenidate but did include antidepressants, antipsychotics, and mixed medications, in combination with co-morbid mood, anxiety, personality, and conduct disorders, and older age at diagnosis. Longer duration of medication and female sex were protective factors. This representative study based on a large nationwide psychiatric sample provides solid evidence into the patterns of SUD in patients with ADHD based on medication use and co-morbidities.


Sodium ions as blocking agents and charge carriers in the potassium channel of the squid giant axon.
Instantaneous K channel current-voltage (I-V) relations were determined by using internally perfused squid axons. When K was the only internal cation, the I-V relation was linear for outward currents at membrane potentials up to +240 mV inside. With 25-200 mM Na plus 300 mM K in the internal solution, an N-shaped I-V curve was seen. Voltage-dependent blocking of the K channels by Na produces a region of negative slope in the I-V plot (F. Bezanilla and C. M. Armstrong. 1972. J. Gen Physiol, 60: 588). At higher voltages (greater than or equal to 160 mV) we observed a second region of increasing current and a decrease in the fraction of the K conductance blocked by Na. Internal tetraethylammonium (TEA) ions blocked currents over the whole voltage range. In a second series of experiments with K-free, Na-containing internal solutions, the I-V curve turned sharply upward about +160 mV. The current at high voltages increased with increasing internal Na concentration was largely blocked by internal TEA. These data suggest that the K channel becomes substantially more permeable to Na at high voltages. This change is apparently responsible for the relief, at high transmembrane voltages, of the blocking effect seen in axons perfused with Na plus K mixtures. Each time a Na ion passed through, vacating the blocking site, the channel would transiently allow K ions to pass through freely.


Motor patterns for two distinct rhythmic behaviors evoked by excitatory amino acid agonists in the Xenopus embryo spinal cord.
1. Mechanisms underlying the selective expression of different motor patterns in vertebrates are poorly understood. Immobilized, spinal Xenopus embryos are used here to examine the motor patterns evoked by various concentrations of excitatory amino acids. 2. Relatively low concentrations of N-methyl-D-aspartate (NMDA) (40-60 microM), kainate (7-8 microM), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) (5 microM) evoked motor root discharge characteristic of swimming. Brief applications of higher concentrations of kainate (20-40 microM), AMPA (25-30 microM), quisqualate (5 microM), and glutamate (1-4 mM) evoked sequences of a different motor pattern: struggling. This is characterized by a longer cycle period, increased burst duration, and a reversed longitudinal pattern of motor root discharge. The struggling pattern was never evoked by higher concentrations of NMDA (300-500 microM), but was evoked by 30 microM AMPA or 5 microM quisqualate in the presence of 50 microM D-2-amino-5-phosphonopentanoic acid. 3. Intracellular recordings from presumed spinal motoneurons showed different patterns of activity during agonist-evoked swimming and struggling. The patterns were like those described previously during sensory-evoked behavior. 4. Caudal applications of excitatory amino acids that produced struggling discharge did so only at caudal motor roots, whereas caudal applications of NMDA evoked swimming activity throughout the spinal cord. 5. During excitatory-amino-acid-evoked struggling, sensory Rohon-Beard neurons depolarized up to 7 mV, but did not fire. 6. The results show that expression of the struggling pattern, like swimming, is not critically dependent on sensory discharge. The results are also consistent with the idea that expression of the two very different motor patterns for swimming or struggling in this simple vertebrate preparation can be controlled by the level of excitation within the spinal motor circuitry, and need not involve the activity of a specific external neuromodulator.


FGF binding and FGF receptor activation by synthetic heparan-derived di- and trisaccharides.
Fibroblast growth factors (FGFs) require a polysaccharide cofactor, heparin or heparan sulfate (HS), for receptor binding and activation. To probe the molecular mechanism by which heparin or HS (heparin/HS) activates FGF, small nonsulfated oligosaccharides found within heparin/HS were assayed for activity. These synthetic and isomerically pure compounds can activate the FGF signaling pathway. The crystal structures of complexes between FGF and these heparin/HS oligosaccharides reveal several binding sites on FGF and constrain possible mechanisms by which heparin/HS can activate the FGF receptor. These studies establish a framework for the molecular design of compounds capable of modulating FGF activity.


Enrichment of Phosphorylated Peptides with Metal-Organic Framework Nanosheets for Serum Profiling of Diabetes and Phosphoproteomics Analysis.
Capturing phosphopeptides from complicated biological samples is essential for the discovery of new post-translational modification sites and disease diagnostics. Although several two-dimensional (2-D) materials have been used for phosphopeptides capturing, metal-organic framework (MOF) nanosheets have not been reported. The Ti-based MOF nanosheets have well-defined 2-D morphology, high density of active sites, large surface area, and an ultrathin structure. Phosphopeptides can be efficiently extracted and superior detection limits of 0.1 fmol μL-1 can be achieved even for an extremely low molar ratio of phosphoprotein/nonphosphoprotein (1:10000) mixtures. The selectivity over nonphosphopeptides can be enhanced further by pretreatment with a 10 mM salt solution (β-glycerophosphate disodium, NaCl, or KCl). The performance of 2-D Ti-based MOF nanosheets is much better than Zr-based MOF (Zr-BTB) nanosheets or any other Ti-based 3-D MOF counterpart, such as MIL-125 and NH2-MIL-125. The nanosheets were used for in situ isotope labeling for abnormally regulated phosphopeptides analysis from serum samples of type 2 diabetes patients. The relative quantitative results showed that three of the phosphorylated fibrinogen peptides A (FPA, DpSGEGDFLAEGGGV, DpSGEGDFLAEGGGVR, and ADpSGEGDFLAEGGGVR) were down-regulated, while the other isoform (ADpSGEGDFLAEGGGV) was up-regulated in the serum samples of type 2 diabetes patients compared with those of healthy volunteers. Finally, proteomics analysis showed selective enrichment of phosphopeptides with 2-D Ti-based MOF nanosheets from real samples, including tryptic digests of mouse brain neocortex lysate, mouse spinal cord lysate, and mouse testis lysate, followed by LC-MS/MS analysis. Total numbers of 2601, 3208, and 2866 phosphopeptides were successfully identified from the three samples, respectively. The 2-D Ti-based MOF nanosheets significantly improved sample preparation for mass spectrometric analysis in phosphopeptides and phosphoproteomics research.


NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis.
IκB kinase/nuclear [corrected] factor κB (IKK/NF-κB) signaling exhibits important yet opposing functions in hepatocarcinogenesis. Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer. Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice. Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMO(LPC-KO) mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1. Collectively, these results show that NEMO prevents hepatocarcinogenesis by inhibiting RIPK1 kinase activity-driven hepatocyte apoptosis through NF-κB-dependent and -independent functions.


Novel bifunctional nucleases, OmBBD and AtBBD1, are involved in abscisic acid-mediated callose deposition in Arabidopsis.
Screening of the expressed sequence tag library of the wild rice species Oryza minuta revealed an unknown gene that was rapidly and strongly induced in response to attack by a rice fungal pathogen (Magnaporthe oryzae) and an insect (Nilaparvata lugens) and by wounding, abscisic acid (ABA), and methyl jasmonate treatments. Its recombinant protein was identified as a bifunctional nuclease with both RNase and DNase activities in vitro. This gene was designated OmBBD (for O. minuta bifunctional nuclease in basal defense response). Overexpression of OmBBD in an Arabidopsis (Arabidopsis thaliana) model system caused the constitutive expression of the PDF1.2, ABA1, and AtSAC1 genes, which are involved in priming ABA-mediated callose deposition. This activation of defense responses led to an increased resistance against Botrytis cinerea. atbbd1, the knockout mutant of the Arabidopsis ortholog AtBBD1, was susceptible to attack by B. cinerea and had deficient callose deposition. Overexpression of either OmBBD or AtBBD1 in atbbd1 plants complemented the susceptible phenotype of atbbd1 against B. cinerea as well as the deficiency of callose deposition. We suggest that OmBBD and AtBBD1 have a novel regulatory role in ABA-mediated callose deposition.


Light induced cytosolic drug delivery from liposomes with gold nanoparticles.
Externally triggered drug release at defined targets allows site- and time-controlled drug treatment regimens. We have developed liposomal drug carriers with encapsulated gold nanoparticles for triggered drug release. Light energy is converted to heat in the gold nanoparticles and released to the lipid bilayers. Localized temperature increase renders liposomal bilayers to be leaky and triggers drug release. The aim of this study was to develop a drug releasing system capable of releasing its cargo to cell cytosol upon triggering with visible and near infrared light signals. The liposomes were formulated using either heat-sensitive or heat- and pH-sensitive lipid compositions with star or rod shaped gold nanoparticles. Encapsulated fluorescent probe, calcein, was released from the liposomes after exposure to the light. In addition, the pH-sensitive formulations showed a faster drug release in acidic conditions than in neutral conditions. The liposomes were internalized into human retinal pigment epithelial cells (ARPE-19) and human umbilical vein endothelial cells (HUVECs) and did not show any cellular toxicity. The light induced cytosolic delivery of calcein from the gold nanoparticle containing liposomes was shown, whereas no cytosolic release was seen without light induction or without gold nanoparticles in the liposomes. The light activated liposome formulations showed a controlled content release to the cellular cytosol at a specific location and time. Triggering with visual and near infrared light allows good tissue penetration and safety, and the pH-sensitive liposomes may enable selective drug release in the intracellular acidic compartments (endosomes, lysosomes). Thus, light activated liposomes with gold nanoparticles are an attractive option for time- and site-specific drug delivery into the target cells.


Bone mineral density and lifestyle among female students aged 16-24 years.
The objective of the study was to investigate bone mineral density and bone turnover among female students aged 16-24 years in relation to lifestyle factors, such as dietary habits and physical activity, as well as physiological factors, such as age, body weight, and menstrual pattern. Female college and university students (n = 218) were given a validated questionnaire with 34 questions concerning diet, recreational physical activity, alcohol, smoking, menstrual pattern, weight gain and loss. Bone mineral density (BMD) measurements were performed using a heel bone scanner (DEXA). Deoxypyridinoline (DPD) levels were measured in urine samples. The data were analyzed by linear regression and multiple regression analysis. The mean BMD was 0.568 g/cm2. Multiple regression showed that hormonal age was a better predictor of high BMD and low bone mineral turnover than chronological age. The best model predicting high BMD was composed of physical activity, regular menstruation, hormonal age and body weight. Smoking, alcohol consumption and current calcium intake did not contribute to the model. A negative association between BMD and DPD was found, indicating an enhanced bone remodeling. A correlation was found between DPD and hormonal age, chronological age, sugar intake and time with irregular menses. In multiple regression analysis, hormonal age, high sugar intake and weight loss were the factors best predicting DPD. BMD was positively influenced by a healthy lifestyle, including a physically active life and healthy dietary habits without dieting. Our study shows that hormonal age is a stronger BMD predictor than chronological age. Menstrual disturbances might be an indication of a risk for low BMD and might therefore be a reason for measuring BMD among young females.


Position of the academy of nutrition and dietetics: total diet approach to healthy eating.
It is the position of the Academy of Nutrition and Dietetics that the total diet or overall pattern of food eaten is the most important focus of healthy eating. All foods can fit within this pattern if consumed in moderation with appropriate portion size and combined with physical activity. The Academy strives to communicate healthy eating messages that emphasize a balance of food and beverages within energy needs, rather than any one food or meal. Public policies and dietary patterns that support the total diet approach include the 2010 Dietary Guidelines for Americans, DASH (Dietary Approaches to Stop Hypertension) Diet, MyPlate, Let's Move, Nutrition Facts labels, Healthy People 2020, and the Dietary Reference Intakes. In contrast to the total diet approach, classification of specific foods as good or bad is overly simplistic and can foster unhealthy eating behaviors. Alternative approaches are necessary in some situations. Eating practices are dynamic and influenced by many factors, including taste and food preferences, weight concerns, physiology, time and convenience, environment, abundance of foods, economics, media/marketing, perceived product safety, culture, and attitudes/beliefs. To increase the effectiveness of nutrition education in promoting sensible food choices, skilled food and nutrition practitioners utilize appropriate behavioral theory and evidence-based strategies. Focusing on variety, moderation, and proportionality in the context of a healthy lifestyle, rather than targeting specific nutrients or foods, can help reduce consumer confusion and prevent unnecessary reliance on supplements. Proactive, empowering, and practical messages that emphasize the total diet approach promote positive lifestyle changes.


Co-existence of tuberculous meningitis and pulmonary tuberculosis in a denim sandblaster.
Silicosis is a well-known occupational lung disease that was discovered by the ancient Greeks and Romans. In 2001, it has emerged again in an unexpected occupation: denim sandblasting. Exposure to crystalline silica, with or without clinical disease, is one of the most important predisposing factors for the development of tuberculosis; however, there has been no previous report of tuberculosis among cases of silicosis due to denim sandblasting. Herein, we report the first case of a denim sandblaster with silicosis who developed both pulmonary tuberculosis and tuberculous meningitis.


The effects of type 2 diabetes on lipoprotein composition and arterial stiffness in male youth.
Recent studies suggest HDL exists as numerous subpopulations with distinct protein/lipid compositions that are not reflected in the HDL cholesterol (HDL-C) number. In this study, we sought to evaluate HDL subpopulations in adolescents with type 2 diabetes (T2D) to determine if changes in HDL composition are associated with early vascular disease. T2D (n = 10), lean (n = 9), and obese (n = 11) youth were recruited. Plasma was fractionated using gel-filtration chromatography, and lipid-associated proteins were identified using mass spectrometry. Concurrently, vascular stiffness was assessed using pulse wave velocity (PWV). We found youth with T2D exhibited decreased phospholipid content in fractions containing large HDL particles that was inversely associated with PWV (P < 0.001). No association was noted between HDL-C and PWV. Proteomic analysis revealed changes in 7 of 45 identified proteins in the T2D group, including apolipoprotein (apo) A-II, apoE, and paraoxonase-1 (P < 0.05). Our data demonstrate early changes in the lipid and protein compositions of specific HDL subspecies in adolescents with T2D that are related to early markers of arterial disease. These findings suggest that analyzing the composition of HDL, rather than HDL-C, may be useful in assessing cardiovascular risk in this population.


Sympathetic overactivity in ischaemic heart disease.
The efficacy of pharmacological beta-blockade in decreasing cardiac death in patients after myocardial infarction suggests the existence of sympathetic overactivity and indicates the importance of assessing its magnitude. The paper by Graham and co-workers in this issue of Clinical Science has attempted to address this issue by measuring muscle sympathetic nerve activity (MSNA) in various groups of patients and control subjects. It was found that, after myocardial infarction, there was sympathetic overactivity, which was more marked and more long-lasting than after unstable angina, whereas, in the presence of simple coronary artery disease, sympathetic activity did not differ from that in control subjects. Clear signs of sympathetic overactivity lasting for months after an acute myocardial infarction have already been reported using quite different methodology, i.e. spectral analysis of heart period and systolic arterial pressure variability. The soundest hypothesis to explain such a sympathetic overactivity appears to be based on the well-demonstrated finding that the ischaemic heart is a powerful site of origin of both excitatory and/or inhibitory reflexes, which may be of paramount clinical importance.


Impact of trained champions of comprehensive school physical activity programs on school physical activity offerings, youth physical activity and sedentary behaviors.
A quasi-experimental cluster-controlled design was used to test the impact of comprehensive school physical activity program (CSPAP) professional development on changes in school physical activity (PA) offerings, moderate-to-vigorous physical activity (MVPA) and sedentary behaviors of 9-14 year-old children during school. Two groups of Louisiana elementary and middle school physical education teachers (N=129) attended a CSPAP summer workshop (95 in 2012=intervention, 34 in 2013=control) and were assessed on school PA offerings (teacher-reported; pre, mid, and post). During the 2012-2013 school year, intervention teachers received CSPAP support while implementing new school PA programs. MVPA and sedentary behaviors were assessed (accelerometry; baseline and post) on a sample of 231 intervention, 120 control students from 16 different schools. Multivariate analysis of covariance indicated that intervention teachers reported significantly more PA offerings during school (3.35 vs. 2.37) and that involve staff (1.43 vs. 0.90). Three-level, mixed model regressions (stratified by sex) indicated that students overall spent less time in MVPA and more time being sedentary during school, but the effects were significantly blunted among intervention students, especially boys. This study provides preliminary evidence for CSPAP professional development programs to influence school-level PA offerings and offset student-level declines in MVPA and increases in sedentary behavior.


Influence of the menstrual cycle on the oral microbial flora in women: a case-control study including men as control subjects.
Changes in the levels of female sex hormones during the menstrual cycle may cause cyclic differences in subgingival bacterial colonization patterns. The purpose of the present study was to test the hypothesis that hormonal changes in the menstrual cycle cause changes in the oral microbiota. Bacterial plaque samples were collected in 20 systemically and periodontally healthy women using no hormonal contraceptives (test group) over a period of 6 weeks. Twenty age-matched systemically and periodontally healthy men were assigned to the control group. Samples were processed by checkerboard DNA-DNA hybridization assay, and 74 species were analyzed. No cyclic pattern of bacterial colonization was identified for any of the 74 species studied in women not using hormonal contraceptives. Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) (Y4) was common at the beginning of menstruation (mean: 32%) and increased during the following 2 weeks (36%) in women (P <0.05). No cyclic differences in bacterial presence were found among the men (P values varied between 0.14 and 0.98). Men presented with significantly higher bacterial counts for 40 of 74 species (P <0.001), including Staphylococcus aureus and Pseudomonas aeruginosa but not Porphyromonas gingivalis (P = 0.15) or Tannerella forsythia (previously T. forsythensis) (P = 0.42). During a menstruation period, cyclic variation in the subgingival microbiota of periodontally healthy women of child-bearing age who were not using oral hormonal contraceptives could not be confirmed. Male control subjects presented with higher levels of many species but also without a cyclic pattern.


Essential variables for reporting research studies on fetal growth restriction: a Delphi consensus.
To determine, by expert consensus using a Delphi procedure, a minimum reporting set of study variables for fetal growth restriction (FGR) research studies. A panel of experts, identified based on their publication record as lead or senior author of studies on FGR, was asked to select a set of essential reporting study parameters from a literature-based list of variables, utilizing the Delphi consensus methodology. Responses were collected in four consecutive rounds by online questionnaires presented to the panelists through a unique token-secured link for each round. The experts were asked to rate the importance of each parameter on a five-point Likert scale. Variables were selected in the three first rounds based on a 70% threshold for agreement on the Likert-scale scoring. In the final round, retained parameters were categorized as essential (to be reported in all FGR studies) or recommended (important but not mandatory). Of the 100 invited experts, 87 agreed to participate and of these 62 (71%) completed all four rounds. Agreement was reached for 16 essential and 30 recommended parameters including maternal characteristics, prenatal investigations, prenatal management and pregnancy/neonatal outcomes. Essential parameters included hypertensive complication in the current pregnancy, smoking, parity, maternal age, fetal abdominal circumference, estimated fetal weight, umbilical artery Doppler (pulsatility index and end-diastolic flow), fetal middle cerebral artery Doppler, indications for intervention, pregnancy outcome (live birth, stillbirth or neonatal death), gestational age at delivery, birth weight, birth-weight centile, mode of delivery and 5-min Apgar score. We present a list of essential and recommended parameters that characterize FGR independent of study hypotheses. Uniform reporting of these variables in prospective clinical research is expected to improve data quality, study consistency and ultimately our understanding of FGR. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.


DNA-Biofunctionalization of CTAC-Capped Gold Nanocubes.
Clinical diagnostics and disease control are fields that strongly depend on technologies for rapid, sensitive, and selective detection of biological or chemical analytes. Nanoparticles have become an integral part in various biomedical detection devices and nanotherapeutics. An increasing focus is laid on gold nanoparticles as they express less cytotoxicity, high stability, and hold unique optical properties with the ability of signal transduction of biological recognition events with enhanced analytical performance. Strong electromagnetic field enhancements can be found in close proximity to the nanoparticle that can be exploited to enhance signals for e.g., metal-enhanced fluorescence or Raman spectroscopy. Even stronger field enhancements can be achieved with sharp-edged nanoparticles, which are synthesized with the help of facet blocking agents, such as cetyltrimethylammonium bromide/chloride (CTAB/CTAC). However, chemical modification of the nanoparticle surface is necessary to reduce the particle's cytotoxicity, stabilize it against aggregation, and to bioconjugate it with biomolecules to increase its biocompatibility and/or specificity for analytical applications. Here, a reliable two-step protocol following a ligand exchange with bis (p-sulfonatophenyl) phenyl phosphine (BSPP) as the intermediate capping-agent is demonstrated, which results in the reliable biofunctionalization of CTAC-capped gold nanocubes with thiol-modified DNA. The functionalized nanocubes have been characterized regarding their electric potential, plasmonic properties, and stability against high concentrations of NaCl and MgCl2.


Detached and attached Arabidopsis leaf assays reveal distinctive defense responses against hemibiotrophic Colletotrichum spp.
The agriculturally important genus Colletotrichum is an emerging model pathogen for studying defense in Arabidopsis. During the process of screening for novel pathogenic Colletotrichum isolates on Arabidopsis, we found significant differences in defense responses between detached and attached leaf assays. A near-adapted isolate Colletotrichum linicola A1 could launch a typical infection only on detached, but not attached, Arabidopsis leaves. Remarkably, resistance gene-like locus RCH1-mediated resistance in intact plants also was compromised in detached leaves during the attacks with the virulent reference isolate C. higginsianum. The differences in symptom development between the detached leaf and intact plant assays were further confirmed on defense-defective mutants following inoculation with C. higginsianum, where the greatest inconsistency occurred on ethylene-insensitive mutants. In intact Arabidopsis plants, both the salicylic acid- and ethylene-dependent pathways were required for resistance to C. higginsianum and were associated with induced expression of pathogenesis-related genes PR1 and PDF1.2. In contrast, disease symptom development in detached leaves appeared to be uncoupled from these defense pathways and more closely associated with senescence: an observation substantiated by coordinated gene expression analysis and disease symptom development, and chemically and genetically mimicking senescence.


Chemical Composition, Antioxidant and Anti-inflammatory Activity Evaluation of the Lebanese Propolis Extract.
Propolis is a resinous substance produced by bees and known to possess antioxidant, antimicrobial, antiproliferative and anti-inflammatory activities. This study is aimed at evaluating the in vivo and in vitro anti-inflammatory potential of the Crude Ethanolic Extract (CE) of Lebanese propolis and its Ethyl Acetate Fraction (EAF). Chemical content of propolis was characterized using high-performance liquid chromatography and LC-MS/MS. COX-2 and iNOS protein expression, nitric oxide (NO) and prostaglandin (PGE2) release in LPS-activated RAW monocytes were achieved respectively by western blot and spectrophotometry. Antioxidant activity was evaluated by DPPH free radical scavenging assay. Measurement of paw thickness in carrageenan-induced paw edema in mice and pathologic assessment of inflammation in paw sections were used to judge the anti-inflammatory properties of propolis. Pathology analysis revealed in the treated group significant reduction of immune cell infiltration and edema. Both extract and ethyl acetate fraction showed significant anti-inflammatory and antioxidant effects in LPS-treated RAW cells characterized by the inhibition of COX-2 and iNOS protein expression, as well as PGE2 and NO release. Chemical analysis of the crude extract and its ethyl acetate fraction identified 28 different compounds of which two phenolic acids and nine other flavonoids were also quantified. Ferulic acid, caffeic acid, chrysin, galangin, quercetin, and pinocembrin were among the most representative compounds. Lebanese propolis is rich in a various amount of flavonoids which showed promising antiinflammatory and antioxidant properties. Additionally, chemical analysis showed unique chemical compositions with the potential of identifying ingredients with interesting anti-inflammatory activities.


Nutritional Status in Nocturnal Hemodialysis Patients - A Systematic Review with Meta-Analysis.
Hemodialysis patients experience an elevated risk of malnutrition associated with increased morbidity and mortality. Nocturnal hemodialysis (NHD) results in more effective removal of waste products and fluids. Therefore, diet and fluid restrictions are less restricted in NHD patients. However, it is ambiguous whether transition from conventional hemodialysis (CHD) to NHD leads to improved intake and nutritional status. We studied the effect of NHD on protein intake, laboratory indices of nutritional status, and body composition. Systematic review with meta-analysis. NHD patients. Systematic literature search from databases, Medline, Cinahl, EMBASE and The Cochrane Library, to identify studies reporting on nutritional status post-transition from CHD to NHD. Transition from CHD to NHD. Albumin, normalized protein catabolic rate (nPCR), dry body weight (DBW), body mass index (BMI), phase angle, protein intake, and energy intake. Systematic literature search revealed 13 studies comprising 282 patients that made the transition from CHD to NHD. Meta-analysis included nine studies in 229 patients. In control group controlled studies (n = 4), serum albumin increased significantly from baseline to 4-6 months in NHD patients compared with patients that remained on CHD (mean difference 1.3 g/l, 95% CI 0.02; 2.58, p = 0.05). In baseline controlled studies, from baseline to 4-6 months of NHD treatment, significant increases were ascertained in serum albumin (mean difference (MD) 1.63 g/l, 95% CI 0.73-2.53, p<0.001); nPCR (MD 0.16 g/kg/day; 95% CI 0.04-0.29, p = 0.01); protein intake (MD 18.9 g, 95% CI 9.7-28.2, p<0.001); and energy intake (MD 183.2 kcal, 95% CI 16.8-349.7, p = 0.03). Homogeneity was rejected only for nPCR (baseline versus 4-6 months). DBW, BMI, and phase angle did not significantly change. Similar results were obtained for comparison between baseline and 8-12 months of NHD treatment. Most studies had moderate sample sizes; some had incomplete dietary records and relatively brief follow-up period. Studies markedly differed with regard to study design. NHD is associated with significantly higher protein and energy intake as well as increases in serum albumin and nPCR. However, the data on body composition are inconclusive.


De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.
Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.


A predictive model for the diffusion of a highly non-ideal ternary system.
Diffusion plays a central part in many unit operations. The Maxwell-Stefan model is the dominant model for both gaseous and liquid diffusion. However, it was developed from the kinetic theory of gases, raising the question of whether it can be extended to non-ideal liquid systems. The dynamic fluctuation model is an alternative model based on the Cussler theory and predicts a smaller thermodynamic influence relative to the linear influence of the Maxwell-Stefan model due to dynamic concentration fluctuations. Since the dynamic fluctuation model, which uses the scaling factor α, had improved performance relative to the Maxwell-Stefan model for a wide range of binary systems, it is postulated that this improved performance should also be observed for a ternary system. In this work, the dynamic molecular fluctuation model was extended to a highly non-ideal ternary system, using the same scaling factor α, through matrix manipulation. Using self-diffusion data measured by NMR, mutual diffusion predictions of the developed model and the Maxwell-Stefan model were compared to experimental mutual diffusion data of the partially miscible system ethanol/toluene/n-decane. It is demonstrated that the dynamic fluctuation model gives improved predictions relative to the Maxwell-Stefan approach, consistent with previous observations on binary systems, showing that the reduced thermodynamic influence of the dynamic fluctuation model is an improvement. In addition, we show that the use of local mole fractions, to account for molecular association, in both the dynamic fluctuation and Maxwell-Stefan models, results in improved diffusion predictions for the ternary system. The results confirm that the dynamic fluctuation model improves predictions of mutual diffusion in liquid mixtures, suggesting a non-linear correction to the thermodynamic correction factor. The results also suggest that that the key assumptions in the Maxwell-Stefan model and its derivation, rooted in the kinetic theory of gases, are not entirely accurate for highly non-ideal liquid systems. The optimum α for the ternary system studied here is approximately 0.45, similarly to the optimum α of 0.40 to 0.80 for a range of binary systems previously studied, suggesting that the use of the α scaling factor, which is grounded in scaling laws theory, is of general validity.


HIV Testing Among Young People Aged 16-24 in South Africa: Impact of Mass Media Communication Programs.
Knowing one's serostatus is critical in the HIV prevention, care and treatment continuum. This study examines the impact of communication programs on HIV testing in South Africa. Data came from 2204 young men and women aged 16-24 who reported to be sexually active in a population based survey. Structural equation modeling was used to test the directions and causal pathways between communication program exposure, HIV testing discussion, and having a test in the last 12 months. Bivariate and multivariate probit regressions provided evidence of exogeneity of communication exposure and the two HIV-related outcomes. One in three sampled individuals had been tested in the last 12 months. Communication program exposure only had an indirect effect on getting tested by encouraging young people to talk about testing. The study suggests that communication programs may create an environment that supports open HIV-related discussions and may have a long-term impact on behavior change.


Effect of timing of eccentric hamstring strengthening exercises during soccer training: implications for muscle fatigability.
The purpose of this study was to examine the effects of a field-based injury prevention exercise on eccentric hamstring strength during simulated soccer match play. Sixteen semiprofessional soccer players (age 21.3 +/- 2.9 years; height 185.0 +/- 8.7 cm; body mass 81.6 +/- 6.7 kg) completed the Soccer-specific Aerobic Field Test (SAFT90), a multidirectional 90-minute exercise protocol representative of soccer match play. Subjects performed 3 maximal dominant-limb isokinetic contractions at 120 degrees x s(-1) for concentric knee extensors (conQ) and flexors (conH), and eccentric knee flexors (eccH) before SAFT90 (t0), at half-time (t45), and immediately after the SAFT90 (t105). After baseline testing, subjects were divided into 2 groups, either performing Nordic hamstring eccentric strengthening exercises during the cool-down (CD) or warm-up (WU) of twice-weekly training sessions. After an 8-week intervention program, the baseline testing was repeated. The WU group displayed a significant increase postintervention in eccH gravity-corrected peak torque (PT) and the functional eccH:conQ ratio at t0 (p < 0.01), a significantly greater improvement compared with CD group (p < 0.05). Conversely, the CD group displayed a significant increase in both eccH PT and the functional eccH:conQ ratio postintervention at t45 (p < 0.05) and at t105 (p < 0.05), which were significantly greater increases compared with the WU group (p < 0.05). These findings indicate that the training intervention had a time-dependent beneficial effect on eccentric hamstring strength and that strength training conducted posttraining significantly reduced the negative influence of fatigue.


Fabrication of photoactive heterostructures based on quantum dots decorated with Au nanoparticles.
Silica based multifunctional heterostructures, exhibiting near infrared (NIR) absorption (650-1200 nm) and luminescence in the visible region, represent innovative nanosystems useful for diagnostic or theranostic applications. Herein, colloidal synthetic procedures are applied to design a photoactive multifunctional nanosystem. Luminescent silica (SiO2) coated quantum dots (QDs) have been used as versatile nanoplatforms to assemble on their surface gold (Au) seeds, further grown into Au spackled structures. The synthesized nanostructures combine the QD emission in the visible region, and, concomitantly, the distinctive NIR absorption of Au nanodomains. The possibility of having multiple QDs in a single heterostructure, the SiO2 shell thickness, and the extent of Au deposition onto SiO2 surface have been carefully controlled. The work shows that a single QD entrapped in 16 nm thick SiO2 shell, coated with Au speckles, represents the most suitable geometry to preserve the QD emission in the visible region and to generate NIR absorption from metal NPs. The resulting architectures present a biomedical potential as an effective optical multimodal probes and as promising therapeutic agents due to the Au NP mediated photothermal effect.


Glucose Lowering Effect of Basil Leaves in Diabetic Rats.
The incidence of diabetes and its complications has risen since the last decades, and it has been predicted that the prevalence of diabetes will be double in the coming year. Chronic hyperglycemia marked as elevated advanced glycation end products plays an important role in complications of diabetes. Basil leaves (Ocimum basilicum) originating from India and commonly found in Southeast Asia, is widely used empirically to decrease the blood sugar in diabetic patients. The purpose of the study was to investigate the effect of extract ethanol of Basil leaves in diabetic rats. This is an experimental study; Streptozotocin was used to induce type 2 diabetic rats. Thirty Wistar male rats were divided into six groups (normal group, group treated with metformin 45 mg/kg body weight, group treated with Basil leaves 100 mg/kg body weight, 200 mg/kg body weight, 400 mg/kg body weight, control diabetic group). The blood glucose level was measured before induction and after treatment at week 1 and 4. Advanced glycation end products were measured in all groups at week 4. Extract ethanol of basil leaves 100, 200, 400 mg/body weight all showed significant lowering blood glucose level (p < 0.001) compared to diabetic group without treatment, but did not show superior to metformin group (p = 0.17), advanced glycation end products did not show statistical significance between group with normal rats and group of diabetic rats treated with basil leaves 100 mg/kg, 200 mg/kg, 400 mg/kg (p = 0.12, p = 0.33, p = 0.26). Extract ethanol of basil leaves showed good results in lowering blood glucose and advanced glycation end products in diabetic rats.


U1 snRNP is mislocalized in ALS patient fibroblasts bearing NLS mutations in FUS and is required for motor neuron outgrowth in zebrafish.
Mutations in FUS cause amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to neurodegeneration remain obscure. We previously found that U1 snRNP is the most abundant FUS interactor. Here, we report that components of the U1 snRNP core particle (Sm proteins and U1 snRNA), but not the mature U1 snRNP-specific proteins (U1-70K, U1A and U1C), co-mislocalize with FUS to the cytoplasm in ALS patient fibroblasts harboring mutations in the FUS nuclear localization signal (NLS). Similar results were obtained in HeLa cells expressing the ALS-causing FUS R495X NLS mutation, and mislocalization of Sm proteins is RRM-dependent. Moreover, as observed with FUS, knockdown of any of the U1 snRNP-specific proteins results in a dramatic loss of SMN-containing Gems. Significantly, knockdown of U1 snRNP in zebrafish results in motor axon truncations, a phenotype also observed with FUS, SMN and TDP-43 knockdowns. Our observations linking U1 snRNP to ALS patient cells with FUS mutations, SMN-containing Gems, and motor neurons indicate that U1 snRNP is a component of a molecular pathway associated with motor neuron disease. Linking an essential canonical splicing factor (U1 snRNP) to this pathway provides strong new evidence that splicing defects may be involved in pathogenesis and that this pathway is a potential therapeutic target.


Altered synaptic plasticity in Drosophila memory mutants with a defective cyclic AMP cascade.
Synaptic transmission was examined in Drosophila mutants deficient in memory function. These mutants, dunce and rutabaga, are defective in different steps of the cyclic adenosine 3',5'-monophosphate (cAMP) cascade. In both dunce and rutabaga larvae, voltage-clamp analysis of neuromuscular transmission revealed impaired synaptic facilitation and post-tetanic potentiation as well as abnormal responses to direct application of dibutyryl cAMP. In addition, the calcium dependence of transmitter release was shifted in dunce. The results suggest that the cAMP cascade plays a role in synaptic facilitation and potentiation and indicate that synaptic plasticity is altered in Drosophila memory mutants.


Causes and Predictors of 30-Day Readmission in Patients With Syncope/Collapse: A Nationwide Cohort Study.
Background Syncope accounts for 0.6% to 1.5% of hospitalizations in the United States. We sought to determine the causes and predictors of 30-day readmission in patients with syncope. Methods and Results We identified 323 250 encounters with a primary diagnosis of syncope/collapse in the 2013-2014 Nationwide Readmissions Database. We excluded patients younger than 18 years, those discharged in December, those who died during hospitalization, hospital transfers, and those whose length of stay was missing. We used multivariable logistic regression analysis to evaluate the association between baseline characteristics and 30-day readmission. A total of 282 311 syncope admissions were included. The median age was 72 years (interquartile range, 58-83), 53.9% were women, and 9.3% had 30-day readmission. The most common cause of 30-day readmissions was syncope/collapse, followed by cardiac, neurological, and infectious causes. Characteristics associated with 30-day readmissions were age 65 years and older (odds ratio [OR], 0.7; 95% confidence interval [ CI ], 0.6-0.7), female sex (OR, 0.9; 95% CI, 0.8-0.9), congestive heart failure (OR, 1.5; 95% CI, 1.2-1.9), atrial fibrillation/flutter (OR, 1.3; 95% CI, 1.3-1.4), diabetes mellitus (OR, 1.2; 95% CI, 1.2-1.3), coronary artery disease (OR, 1.2; 95% CI, 1.2-1.3), anemia (OR, 1.4; 95% CI, 1.4-1.5), chronic obstructive pulmonary disease (OR, 1.4; 95% CI, 1.3-1.4), home with home healthcare disposition (OR, 1.5; 95% CI, 1.5-1.6), leaving against medical advice (OR, 1.7; 95% CI, 1.6-1.9), length of stay of 3 to 5 days (OR, 1.5; 95% CI, 1.4-1.6) or >5 days (OR, 2; 95% CI, 1.8-2), and having private insurance (OR, 0.6; 95% CI, 0.6-0.7). Conclusions The 30-day readmission rate after syncope/collapse was 9.3%. We identified causes and risk factors associated with readmission. Future prospective studies are needed to derive risk-stratification models to reduce the high burden of readmissions.


Clinicopathological Characteristics of Mitotically-active Cellular Fibroma of the Ovary: A Single-institutional Experience.
Mitotically-active cellular fibroma (MACF) is a rare form of ovarian fibromatous tumor. Although it is generally acknowledged to have indolent biological behavior, its rarity and overlapping histopathological features with more common and aggressive entities make MACF prone to misdiagnosis and overtreatment. The clinicopathological characteristics of ovarian MACF have not been clearly established. Our 10-year review of cellular fibromatous tumors of the ovary diagnosed at a single institution revealed four cases of cellular fibroma (CF) and three cases of MACF. The mean age of patients with MACF was 46 years (range=20-71 years). Patients presented with symptoms related to pelvic masses, such as abdominal pain and discomfort and flank pain. Serum levels of cancer antigen 125 was increased in two patients with MACF. All cases of MACF were a single unilateral tumor. Magnetic resonance imaging revealed solid or mixed solid and cystic ovarian masses with diameters of 7.3-14.9 cm. The radiological impressions included benign stromal tumor, benign epithelial tumor, and borderline epithelial tumor. Grossly, MACFs exhibited yellow-to-tan fleshy cut surfaces, without necrosis or hemorrhage. Extensive hyaline degeneration, resulting in a fibrotic cut surface, was observed in one case. Histologically, MACF displayed frequent mitotic figures, as well as increased cellularity and mild cytological atypia. The mean mitotic count was 8.7 per 10 high-power fields. MACF is a newly-recognized subtype of ovarian cellular fibromatous tumor. Pathologists and clinicians should be aware of this rare entity to prevent misdiagnosis of MACF as fibrosarcoma or adult granulosa cell tumor and resultant overtreatment.


Calcium dependence of large dense-cored vesicle exocytosis evoked by calcium influx in bovine adrenal chromaffin cells.
We used the perforated-patch technique to examine the relationship between Ca2+ entry and exocytosis of large dense-cored vesicles in bovine adrenal chromaffin cells. Exocytosis evoked by single-step depolarizations was monitored by capacitance detection. Ca2+ entry was varied by changing external calcium concentration, stepping to different test potentials, depolarizing for different durations, or applying blockers of specific calcium channel subtypes. Regardless of protocol, the amount of exocytosis was strictly related to the integral of the voltage-clamped calcium current, raised to a power of approximately 1.5. Thus, despite the complexities of transient and nonuniform changes in submembrane calcium concentration produced by voltage-gated calcium entry, the calcium dependence of large dense-cored vesicle fusion under conditions of minimal stimulation is well approximated by a simple transfer function of summed calcium entry.


Allele *1 of HS1.2 enhancer associates with selective IgA deficiency and IgM concentration.
Selective IgA deficiency (IGAD) is the most common primary immunodeficiency, yet its pathogenesis is elusive. The IG (heavy) H chain human 3' Regulatory Region harbors three enhancers and has an important role in Ig synthesis. HS1.2 is the only polymorphic enhancer of the 3' RRs. We therefore evaluated HS1.2 allelic frequencies in 88 IGAD patients and 101 controls. Our data show that IGAD patients have a highly significant increase of homozygousity of the allele *1 (39% in the IGAD patients and 15% in controls), with an increase of 2.6-fold. Allele *4 has a similar trend of allele *2, both showing a significant decrease of frequency in IGAD. No relationship was observed between allele *1 frequencies and serum levels of IgG. However, allele *1 was associated in IGAD patients with relatively low IgM levels (within the 30th lowest percentile of patients). The HS1.2 polymorphism influences Ig seric production, but not IgG switch, in fact 30th lowest or highest percentile of IgG in patients did not associate to different frequencies of HS1.2 alleles. The control on normal healthy subjects did not correlate high or low levels of IgM or IgG with HS1.2 allelic frequence variation. Overall our candidate gene approach confirms that the study of polymorphisms in human diseases is a valid tool to investigate the function of these Regulatory Regions that confers multiple immune features.


Measures of overweight and obesity and risk of cardiovascular disease: a population-based study.
Although overweight and obesity are associated with cardiovascular disease (CVD), it is unclear which clinical measure of overweight and obesity is the strongest predictor of CVD, and it is unclear whether the various measures of overweight and obesity are indeed independent predictors of CVD. This study was a prospective population-based study of 2493 Danish men and women, age 41-72 years, without major CVD at baseline. At baseline, body mass index, waist circumference, hip circumference, waist-to-hip ratio (WHR), and traditional and new risk factors were recorded. Over a median follow-up of 12.6 years, the incidence of a combined CV event (CV death, nonfatal ischemic heart disease, and nonfatal stroke) amounted to 328 cases. Of the various measures of overweight and obesity, in Cox-proportional hazard models, adjusted for age, only WHR was significantly associated with incident CVD with a hazard ratio (95% confidence interval) in women of 2.22 (1.31-3.77; P=0.0032) in the highest compared with the lowest quartile, and a hazard ratio in men of 1.73 (1.12-2.66; P=0.014) in the highest compared with the lowest quartile. However, when adjustments were made for the presence of diabetes, dyslipidemia, hypertension, hyperinsulinemia, and inflammation, WHR was no longer significantly (P>0.41) associated with incident CVD. In this study, of the various measures of overweight and obesity, WHR was the only significant predictor of incident CVD, and the relationship between WHR and risk of CVD was mediated by well-known risk factors of CVD.


Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-beta2 signaling.
During human embryogenesis, neural crest cells migrate to the anterior chamber of the eye and then differentiate into the inner layers of the cornea, the iridocorneal angle, and the anterior portion of the iris. When proper development does not occur, this causes iridocorneal angle dysgenesis and intraocular pressure (IOP) elevation, which ultimately results in developmental glaucoma. Here, we show that heparan sulfate (HS) deficiency in mouse neural crest cells causes anterior chamber dysgenesis, including corneal endothelium defects, corneal stroma hypoplasia, and iridocorneal angle dysgenesis. These dysfunctions are phenotypes of the human developmental glaucoma, Peters anomaly. In the neural crest cells of mice embryos, disruption of the gene encoding exostosin 1 (Ext1), which is an indispensable enzyme for HS synthesis, resulted in disturbed TGF-beta2 signaling. This led to reduced phosphorylation of Smad2 and downregulated expression of forkhead box C1 (Foxc1) and paired-like homeodomain transcription factor 2 (Pitx2), transcription factors that have been identified as the causative genes for developmental glaucoma. Furthermore, impaired interactions between HS and TGF-beta2 induced developmental glaucoma, which was manifested as an IOP elevation caused by iridocorneal angle dysgenesis. These findings suggest that HS is necessary for neural crest cells to form the anterior chamber via TGF-beta2 signaling. Disturbances of HS synthesis might therefore contribute to the pathology of developmental glaucoma.


The stroboscopic Pulfrich effect is not evidence for the joint encoding of motion and depth.
In the Pulfrich effect, an illusion of depth is produced by introducing differences in the times at which a moving object is presented to the two eyes. In the classic form of the illusion, there is a simple explanation for the depth percept: the interocular delay introduces a spatial disparity into the stimulus. However, when the moving object is viewed stroboscopically, this simple explanation no longer holds. In recent years, depth perception in the stroboscopic Pulfrich effect has been explained by invoking neurons that are sensitive both to stereo disparity and to direction of motion. With such joint motion/disparity encoders, interocular delay causes a perception of depth by causing a shift in each neuron's preferred disparity. This model has been implemented by N. Qian and R. A. Andersen (1997). Here we show that this model's predictions for perceived disparity are quantitatively at odds with psychophysical measures. The joint-encoding model predicts that the perceived disparity is the virtual disparity implied by the apparent motion; in fact, the perceived disparity is smaller. We show that the percept can be quantitatively explained on the basis of spatial disparities present in the stimulus, which could be extracted from pure disparity sensors. These results suggest that joint encoding of motion and depth is not the dominant neuronal basis of depth perception in this stimulus.


Pan-specific and partially selective dye-labeled peptidic inhibitors of the polycomb paralog proteins.
Epigenetic regulation of gene expression is in part controlled by post-translational modifications on histone proteins. Histone methylation is a key epigenetic mark that controls gene transcription and repression. There are five human polycomb paralog proteins (Cbx2/4/6/7/8) that use their chromodomains to recognize trimethylated lysine 27 on histone 3 (H3K27me3). Recognition of the methyllysine side chain is achieved through multiple cation-pi interactions within an 'aromatic cage' motif. Despite high structural similarity within the chromodomains of this protein family, they each have unique functional roles and are linked to different cancers. Selective inhibition of different CBX proteins is desirable for both fundamental studies and potential therapeutic applications. We report here on a series of peptidic inhibitors that target certain polycomb paralogs. We have identified peptidic scaffolds with sub-micromolar potency, and will report examples that are pan-specific and that are partially selective for individual members within the family. These results highlight important structure-activity relationships that allow for differential binding to be achieved through interactions outside of the methyllysine-binding aromatic cage motif.


Selecting specialist registrars by station interview.
Appointments to the specialist registrar (SpR) grade depend almost entirely on performance at interview, yet standard panel interviews do not directly assess the competences required of a medical trainee. In this study, station interviews were used to select neurology SpRs. Eighteen candidates were assessed in three interviews, each involving three stations: a curriculum vitae (CV)-based interview, an interview with a simulated patient, and a discussion of scenarios based upon teaching, audit and research. Two or three assessors at each station ranked candidates independently before discussing the pooled rankings and reading written references. The CV-based interview rankings (resembling a traditional panel interview) correlated less well with the overall rankings (r=0.54) than did research (r=0.83), information giving (r=0.75), audit (r=0.70) or teaching presentation (r=0.59). Station interviews appear fairer (providing more time, more independent examiners, fresh starts at each station), although they require more planning and expense. Competency-based assessments should be more widely used in selecting medical trainees.


Estimated impact of the GST on tobacco products in India.
To examine the potential impact of the goods and services tax (GST) on price, consumption and tax revenue from tobacco products in India and across states. Data on prices, tax rates and tax revenue are used to estimate a benchmark scenario prior to the GST implementation in 2017-2018. Using own-price elasticity of demand for tobacco products, we estimate the impact of GST at the state level and the aggregate state-wise impact to obtain the national level impact. We predict that the statutory GST rate of 28% plus compensation cess will increase the price of cigarettes, bidi and smokeless tobacco by 0.18%, 8.8% and 6%, respectively, and, as a result, it will reduce the weighted average consumption by 0.3%, 10% and 6% and increase tax revenue by 0.17%, 35% and 4.7%, respectively. Most states will experience a fall in tax revenue from tobacco products by more than 50% compared with the value-added tax revenue they collected pre-GST. The GST compensation cess will have to be used to compensate states' revenue shortfalls. The GST has increased the complexity of the tax system for tobacco products. In particular, for cigarettes, the specific cess constitutes the majority of tax revenue, and therefore, it must be revised regularly to protect revenue and keep real prices from falling. In addition, India should reintroduce excise taxation on all tobacco products, at least in part, on top of the GST, to make them less affordable and to smooth the transition after the expiration of the compensation cess.


Population-based study of bronchopulmonary dysplasia in very low birth weight infants in Switzerland.
In Switzerland, data are collected prospectively by collaborators from all nine neonatal intensive care units and their affiliated paediatric units caring for neonates, to determine survival and (pulmonary) outcome of infants with birth weights ranging from 501 to 1500 g. To assess the pulmonary outcome of very low birth weight (VLBW) infants in Switzerland in 1996 and 2000, factors associated with bronchopulmonary dysplasia (BPD) were identified and compared with pulmonary outcomes from the Vermont Oxford Network data. BPD was defined as a requirement for supplemental oxygen at 36 weeks postmenstrual age. Complete data were available for 600 and 636 VLBW infants in 1996 and in 2000, respectively. Mortality rates in Switzerland were significantly higher (1996: 19.2%, 2000: 20.8%) than in the Vermont Oxford Network (1996: 14%, 2000: 14%). Expressed as percentage of infants still hospitalised at 36 weeks postmenstrual age, 16.7% and 13.2% of Swiss VLBW infants were diagnosed with BPD in 1996 and 2000, respectively. These rates were significantly lower than in the Vermont Oxford Network (1996: 28%, 2000: 35%). Infants exposed to factors previously shown to be associated with BPD were investigated: in Switzerland, infants with a history of surfactant replacement therapy and/or mechanical ventilation had a significantly higher rate of BPD in both cohorts. Infants with postnatal transport, sepsis proven by positive blood culture and patent ductus arteriosus had a higher BPD rate only in the 1996 cohort. Between 1996 and 2000, mortality rates and incidence of BPD in VLBW infants remained unchanged in Switzerland. BPD rates in Switzerland are lower than those found in the Vermont Oxford Network whereas a mortality rate comparison displays an inverted picture. We suspect that these effects are interrelated and may be due in part to a selective approach of Swiss neonatologists to resuscitation of infants in the smallest birth weight stratum. The factors listed above have apparently become less important in the context of bronchopulmonary dysplasia and other influences, including prenatal conditions, will need to be investigated.


Comparison of femoral blood gases and muscle near-infrared spectroscopy at exercise onset in humans.
We hypothesized that near-infrared spectroscopy (NIRS) measures of hemoglobin and/or myoglobin O2 saturation (IR-SO2) in the vascular bed of exercising muscle would parallel changes in femoral venous O2 saturation (SfvO2) at the onset of leg-kicking exercise in humans. Six healthy subjects performed transitions from rest to 48 +/- 3 (SE)-W two-legged kicking exercise while breathing 14, 21, or 70% inspired O2. IR-SO2 was measured over the vastus lateralis muscle continuously during all tests, and femoral venous and radial artery blood samples were drawn simultaneously during rest and during 5 min of exercise. In all gas-breathing conditions, there was a rapid decrease in both IR-SO2 and SfvO2 at the onset of moderate-intensity leg-kicking exercise. Although SfvO2 remained at low levels throughout exercise, IR-SO2 increased significantly after the first minute of exercise in both normoxia and hyperoxia. Contrary to the hypothesis, these data show that NIRS does not provide a reliable estimate of hemoglobin and/or O2 saturation as reflected by direct femoral vein sampling.


Serum levels of soluble CD26 and CD30 in patients on hemodialysis.
Various abnormalities of the immune system have been demonstrated in patients on hemodialysis (HD). We hypothesize that the imbalance between type 1 helper T (Th1) cells and type 2 helper T (Th2) cells in patients on HD contributes to these abnormalities. Furthermore, we investigate the relationship between the Th1/Th2 imbalance and HD duration. We measured the serum levels of soluble CD26 (sCD26) and soluble CD30 (sCD30) in 47 patients on HD and in 13 patients with chronic renal failure not on HD and analyzed the effect of HD duration on the serum levels of sCD26 and sCD30. The serum level of sCD26 in the HD group was significantly lower than that in the control group. On the other hand, the serum levels of sCD30 in the HD group and in the CRF group were significantly higher than in the control group. In the short-term HD group (<1 year), the serum levels of sCD26 were lower and the sCD30 levels higher than those in middle-term HD group (1-10 years). In the HD group, the Th1/Th2 balance may shift towards Th2 dominance. It is possible that this imbalance contributes to the abnormality of the immune system in HD patients.


[Antiproliferative effect of curcumin combined with cyclophosmide on the growth of human lymphoma cell line HT/CTX with drug resistance and its relation with FA/BRCA pathway].
The aim of this study was to investigate the antiproliferative effect of curcumin combined with cyclophosmide on the growth of human lymphoma cell line HT/CTX with drug resistance and its relation with FA/BRCA pathway. The inhibitory effects of the drugs on the growth of HT/CTX cells were determined by MTT assay. Cell cycle phase and apoptosis were analyzed by flow cytometry. The expression of FANCD2 protein in FA/BRCA pathway was determined by Western blot. The results indicated that the combination of curcumin with CTX had an additional synergistic inhibitory effects on the proliferation and cell cycle distribution of HT/CTX cells. The curcumin could enhance toxicity of CTX on HT/CTX cells through inhibition of FA/BRCA pathway which was realized by suppression of FANCD2 monoubiquitination. The curcumin combined with CTX could increase apoptosis inducing effect on HT/CTX cells, while the curcumin or CTX alone did not showed this effect, and without inhibition of FA/BRCA pahtway. It is concluded that combination of curcumin and CTX produces synergistic effects and reverses multiple drug resistance of HT/CTX cells effectively. The prevention of cells from entering the next cell cycle and down regulation of FANCD2 protein monoubiquitination may be involved in the mechanism.


Longevity of class 2 direct restorations in root-filled teeth: A retrospective clinical study.
To evaluate retrospectively the longevity of endodontically treated teeth restored with direct resin composite without cusp coverage, with or without the insertion of fibre posts. The null hypothesis was that direct restorations with fibre posts perform better than those without fibre posts. Patients recruited for this study were treated in the Department of Cariology and Operative Dentistry, University of Turin, between 2008 and 2011. In total, 247 patients with 376 root treated posterior teeth, restored with direct resin composite, were recalled for a control visit. Only second-class cavities were considered. Two groups were defined based on the absence (Group A) or presence (Group B) of fibre post. Failures and complications, such as periodontal failure, endodontic failure, tooth extraction, root fracture, post fracture, post debonding, replacement of restoration, crown displacement, and coronal-tooth fracture, were noted. Functional restoration quality was evaluated following the modified USPHS criteria. Data were evaluated statistically with ANOVA. Group A consisted of 128 patients with 178 restorations (88 premolars, 90 molars) with a median follow-up of 34.44 months. Group B consisted of 119 patients with 198 teeth (92 premolars, 106 molars) with a median follow-up of 35.37 months. Direct restorations with fibre posts were statistically significantly more functional (95.12% success) than those without fibre posts (80% success) because of less marginal discolouration, better marginal integrity, and higher restoration integrity. The null hypothesis was accepted because direct post-endodontic restorations with fibre posts performed better than restorations without posts after 3 years of masticatory function. An evaluation of the longevity of post endodontic direct restoration would seem to enhance the fiber post insertion within a composite restoration to reduce clinical failures.


Compared perspectives of Arab patients in Palestine and Israel on the role of complementary medicine in cancer care.
Complementary medicine (CM) is extensively used by patients with cancer across the Middle East. We aimed to compare the perspectives of two Arab populations residing in diverse socioeconomic-cultural settings in Palestine and Israel regarding the role of CM in supportive cancer care. A 27-item questionnaire was constructed and administered to a convenience sample of Arab patients receiving cancer care in four oncology centers in northern Israel and Palestine. Each of the two groups had 324 respondents and was equally distributed by age and marital status. Compared with the Israeli-Arab group, Palestinian participants reported significantly higher CM use for cancer-related outcomes (63.5% vs. 39.6%, P < 0.001), which included more herbal use (97.6% vs. 87.9%, P = 0.001) and significantly lower use of dietary supplements, acupuncture, mind-body and manual therapies, and homeopathy. Most respondents in both groups stated that they would consult CM providers if CM was integrated in oncology departments. Related to this theoretical integrative scenario, Palestinian respondents expressed fewer expectations from their oncologists to actively participate in building their CM treatment plan. Treatment expectations in both groups focused on improving quality of life (QOL), whereas Palestinian respondents had fewer expectations for CM to improve fatigue, emotional concerns, sleep, and daily functioning. Arab patients with cancer from Palestine and Israel highly support CM integration within their oncology institutions aiming to improve QOL. Nevertheless, respondents differed in their perceived model of CM integration, its treatment objectives, and their oncologists' role in CM integration.


Steerable optical tweezers for ultracold atom studies.
We report on the implementation of an optical tweezer system for controlled transport of ultracold atoms along a narrow, static confinement channel. The tweezer system is based on high-efficiency acousto-optic deflectors and offers two-dimensional control over beam position. This opens up the possibility for tracking the transport channel when shuttling atomic clouds along it, forestalling atom spilling. Multiple clouds can be tracked independently by time-shared tweezer beams addressing individual sites in the channel. The deflectors are controlled using a multichannel direct digital synthesizer, which receives instructions on a submicrosecond time scale from a field-programmable gate array. Using the tweezer system, we demonstrate sequential binary splitting of an ultracold 87Rb cloud into 2(5) clouds.


Inner Ear Gene Therapies Take Off: Current Promises and Future Challenges.
Hearing impairment is the most frequent sensory deficit in humans of all age groups, from children (1/500) to the elderly (more than 50% of the over-75 s). Over 50% of congenital deafness are hereditary in nature. The other major causes of deafness, which also may have genetic predisposition, are aging, acoustic trauma, ototoxic drugs such as aminoglycosides, and noise exposure. Over the last two decades, the study of inherited deafness forms and related animal models has been instrumental in deciphering the molecular, cellular, and physiological mechanisms of disease. However, there is still no curative treatment for sensorineural deafness. Hearing loss is currently palliated by rehabilitation methods: conventional hearing aids, and for more severe forms, cochlear implants. Efforts are continuing to improve these devices to help users to understand speech in noisy environments and to appreciate music. However, neither approach can mediate a full recovery of hearing sensitivity and/or restoration of the native inner ear sensory epithelia. New therapeutic approaches based on gene transfer and gene editing tools are being developed in animal models. In this review, we focus on the successful restoration of auditory and vestibular functions in certain inner ear conditions, paving the way for future clinical applications.


Extraocular sebaceous carcinoma in a patient with Muir-Torre syndrome.
Sebaceous carcinoma is a rare, aggressive neoplasm that arises from the adnexal epithelium of sebaceous glands and is commonly associated with Muir-Torre syndrome. The metastatic potential of extraocular sebaceous carcinoma warrants a thorough evaluation to establish the extent of disease. We describe a 55-year-old man who presented with an asymptomatic abdominal wall mass 3 years after definitive diagnosis of Muir-Torre syndrome. A biopsy of the surgical specimen revealed sebaceous carcinoma. Dermatologists are crucial to the early recognition and diagnosis of extraocular sebaceous carcinoma. In our patient with documented Muir-Torre syndrome, continued surveillance allowed for prompt recognition and treatment of this associated cutaneous malignancy.


Play seriously: Effectiveness of serious games and their features in motor rehabilitation. A meta-analysis.
Evidence for the effectiveness of serious games (SGs) and their various features is inconsistent in the motor rehabilitation field, which makes evidence based development of SGs a rare practice. To investigate the effectiveness of SGs in motor rehabilitation for upper limb and movement/balance and to test the potential moderating role of SGs features like feedback, activities, characters and background. We ran a meta-analysis including 61 studies reporting randomized controlled trials (RCTs), controlled trials (CTs) or case series designs in which at least one intervention for motor rehabilitation included the use of SGs as standalone or in combination. There was an overall moderate effect of SGs on motor indices, d = 0.59, [95% CI, 0.48, 0.71], p < 0.001. Regarding the game features, only two out of 17 moderators were statistically different in terms of effect sizes: type of activity (combination of group with individual activities had the highest effects), and realism of the scenario (fantasy scenarios had the highest effects). While we showed that SGs are more effective in improving motor upper limb and movement/balance functions compared to conventional rehabilitation, there were no consistent differences between various game features in their contribution to effects. Further research should systematically investigate SGs features that might have added value in improving effectiveness.


Noninvasive oxygenation strategies in adult patients with acute respiratory failure: a protocol for a systematic review and network meta-analysis.
Acute hypoxemic respiratory failure is one of the leading causes of intensive care unit admission and is associated with high mortality. Noninvasive oxygenation strategies such as high-flow nasal cannula, standard oxygen therapy, and noninvasive ventilation (delivered by either face mask or helmet interface) are widely available interventions applied in these patients. It remains unclear which of these interventions are more effective in decreasing rates of invasive mechanical ventilation and mortality. The primary objective of this network meta-analysis is to summarize the evidence and compare the effect of noninvasive oxygenation strategies on mortality and need for invasive mechanical ventilation in patients with acute hypoxemic respiratory failure. We will search key databases for randomized controlled trials assessing the effect of noninvasive oxygenation strategies in adult patients with acute hypoxemic respiratory failure. We will exclude studies in which the primary focus is either acute exacerbations of chronic obstructive pulmonary disease or cardiogenic pulmonary edema. The primary outcome will be all-cause mortality (longest available up to 90 days). The secondary outcomes will be receipt of invasive mechanical ventilation (longest available up to 30 days). We will assess the risk of bias for each of the outcomes using the Cochrane Risk of Bias Tool. Bayesian network meta-analyses will be conducted to obtain pooled estimates of head-to-head comparisons. We will report pairwise and network meta-analysis treatment effect estimates as risk ratios and 95% credible intervals. Subgroup analyses will be conducted examining key populations including immunocompromised hosts. Sensitivity analyses will be conducted by excluding those studies with high risk of bias and different etiologies of acute respiratory failure. We will assess certainty in effect estimates using GRADE methodology. This study will help to guide clinical decision-making when caring for adult patients with acute hypoxemic respiratory failure and improve our understanding of the limitations of the available literature assessing noninvasive oxygenation strategies in acute hypoxemic respiratory failure. PROSPERO CRD42019121755.


Lifestyle changes in heart transplant recipients.
The purpose of this study was to understand the lifestyle; examine the relationships among lifestyle, medical factors, and stress status; and determine the predictors of better lifestyle in heart transplant recipients in Taiwan. A prospective design with convenience sampling was used. Data were collected through the Health-Promoting Lifestyle Profile-II and demographic questionnaires, which included personal information, stress status, and medical information. Pearson correlations, 1-way analysis of variance, independent t tests, paired t tests, and hierarchical regression were used to analyze the factors related to better lifestyle. A total of 80 heart transplant recipients participated. The mean score for lifestyle decreased from baseline to 3 months and was even lower at 6 months. Nevertheless, the trend for some participants was the opposite-their lifestyle improved over the 6-month period after baseline. Notably, the trend for each of the 6 subscales was not consistent with the mean of the total score. Stress status accounted for 12.8% of lifestyle. When stress status was combined with family income and creatinine, the 3 factors accounted for 32.2% of lifestyle. This study demonstrated that maintenance of a healthy lifestyle fluctuates after transplantation. Demographic factors and stress status can help to identify people who are more likely to have a poor lifestyle.


The effects of a multicomponent dyadic intervention on the mood, behavior, and physical health of people with dementia: a randomized controlled trial.
The effects of a multicomponent dyadic intervention on the mood, behavior, and physical health of people with dementia living in the community were evaluated in a randomized controlled trial. This multicomponent dyadic intervention is a translated and adapted version of an intervention that has been shown to be effective for people with dementia in the US. People with dementia living in the community and their family caregivers (N=111 caregiver-care recipient dyads) were randomly assigned to the intervention and comparison group. The intervention group received home-based physical exercise training, psycho-education, communication skills training, and pleasant activities training during 3 months directed at both the person with dementia and the caregiver. Mood, behavior, and physical health were measured at baseline, 3 months, and 6 months. The effects of the study were determined by using generalized estimating equations based on an intention-to-treat analysis. Analyses showed no beneficial effects over time on any of the outcome measures. This study showed no effects. The negative results in this study compared to the study that has been carried out in the US might be explained by the translation, adaptation, and shortening of the intervention used in the US, and a different social context. In addition, the results might be explained by the lack of room for improvement and by experiencing the intervention as too much of a burden. Furthermore, improving physical health might only be effective if the physical exercises are of moderate-to-high-intensity and are tailored in accordance with participants' preferences and needs. For future studies, because dyads often commented positively about the pleasure and support they received, it might also be valuable to measure quality of life outcomes such as relationship quality, pleasure, and self-esteem in dyadic focused interventions.


Maternal screening for early postnatal vulnerability.
Research has highlighted the wide impact of maternal mental health problems during and beyond the postpartum period and the public health role of community health professionals in early detection of women who may be at risk. This paper aims to describe, explore and test an a priori hypothesised conceptual model of postnatal experience, identifying the relationships between postnatal mental vulnerability and postnatal adjustment to maternal roles and attitudes, marital/partner-relationship and sense of coherence. Three validated self-report questionnaires (WAST, MAMA, SOC) measuring the variables of the encompassing framework and EPDS were administered in random order. The conceptual models were tested using the software IBM SPSS Statistics and LISREL and the tests performed were: Student's ttest, chi-square tests, Explanatory factor analysis using a Varimax rotation Principal Components Method, Confirmatory analysis -known as structural equation modelling- of principal components. Psychometric scores indicate high correlation between WAST, MAMA, SOC and EPDS. An exploratory factor analysis confirmed the role of SOC, specific MAMA subscales (maternal roles and attitudes, body image, sex, breasts, nausea) and WAST (relationship tension and emotional and physical abuse) subscales (KMO measure of sampling adequacy=0.735 and Bartlett's test of sphericity=184,786, df=36, p<0.0005). The latent variables confirmed with SEM were marital relationship, maternity experience and self-efficacy (Chi-square=28.45, df=24, P-value=0.24, RMSEA=0.046 p<0.05). Marital Relationship (Factor I: Eigenvalue=3.066) concerning lack of or disappointment with partner support, poor marital relationship and emotional/physical abuse has been associated with high levels of postpartum anxiety and depression. Maternity Experience (Factor II: Eigenvalue=1.280) representing postnatal roles and attitudes towards their infant can be as useful as mood changes for evaluation of mothers. Self-Efficacy (Factor III: Eigen- value=3.144) and especially attitudes regarding body image, sex and coping resources and options of dealing with the stressor, has been demonstrated that serve as a mediator or buffer for psychological distress. The results of this study have implications for the prevention and intervention of postnatal adjustment difficulties both of which need to be intensified in order to minimise perinatal mental vulnerability.


The respiratory chain of a newly isolated Methylomonas Pl1.
1. Whole cells of Methylomonas Pl1 contained ubiquinone, identified as ubiquinone-8. No naphthaquinone was detected. Ubiquinone was located predominantly in the particulate fraction, which also contained most of the NADH oxidase activity. 2. Aerobic incubation of cells with formaldehyde or methanol resulted in about 20% reduction of ubiquinone, irrespective of the presence or absence of dinitrophenol. On inhibition of the respiration by cyanide, ubiquinone became partly reduced by endogenous substrates (15--25%), and a further reduction occurred only in the presence of formaldehyde (up to 60%). When endogenous substrates were completely exhausted, then 44 and 23% of ubiquinone was reduced by formaldehyde or methanol respectively. 3. The difference spectra at room and liquid-N2 temperatures revealed the presence of cytochrome b and two cytochromes c (c-552.5 and c-549) all tightly bound to the membrane. Cytochrome c-552.5 was also found in the soluble fraction. 4. Redox changes of cytochromes b and c, with methanol or formaldehyde as substrates, respond to the aerobic and anaerobic states of the cell and to KCN inhibition in a manner characteristic of the electron carriers of the respiratory chain. 5. The merging point for electron transport from NADH dehydrogenase and formaldehyde dehydrogenase is suggested to be at the level of ubiquinone.


Ascertaining infectious disease burden through primary care clinic attendance among young Aboriginal children living in four remote communities in Western Australia.
Infectious diseases contribute a substantial burden of ill-health in Australia's Aboriginal children. Skin infections have been shown to be common in remote Aboriginal communities, particularly in the Northern Territory, Australia. However, primary care data on skin and other infectious diseases among Aboriginal children living in remote areas of Western Australia are limited. We conducted a retrospective review of clinic presentations of all children aged 0 to 5 years presenting to four clinics located in the Western Desert region of Western Australia between 2007 and 2012 to determine this burden at a local level. Infectious diseases accounted for almost 50% of all clinic presentations. Skin infections (sores, scabies and fungal infections) were the largest proportion (16%), with ear infections (15%) and upper respiratory infections (13%) also high. Skin infections remained high in all age groups; 72% of children presented at least once with skin infections. Scabies accounted for only 2% of all presentations, although one-quarter of children presented during the study for management of scabies. Skin sores accounted for 75% of the overall burden of skin infections. Improved public health measures targeting bacterial skin infections are needed to reduce this high burden of skin infections in Western Australia.


Diastolic properties of the normal left ventricle during supine exercise.
Diastolic function in response to dynamic exercise was studied by biplane left ventriculography and by measuring left ventricular pressure with a high fidelity micromanometer tipped catheter at rest and during supine bicycle exercise in nine normal subjects. During exercise there was a fall in end systolic volume, in the time constant of left ventricular isovolumic pressure decay, and in the lowest diastolic pressure. Stroke volume, peak filling rate, mean passive filling rate, and the volume at the lowest diastolic pressure increased. There was an increase in the number of time constants that had elapsed before the lowest diastolic pressure was reached and the slope of the pressure-volume curves during passive filling (delta P/delta V) increased without changes in end diastolic pressure and volume. These results show that during exercise elastic recoil is enhanced and left ventricular relaxation is faster and more complete. Both phenomena reduce the lowest diastolic filling pressure. The observed increase in chamber stiffness from rest to exercise is probably related to increased resistance of the left ventricular wall caused by higher passive filling rates. The enhanced early diastolic pressure decay during exercise allows stroke volume to increase despite an increase in diastolic viscoelastic resistance and chamber stiffness.


Dithionite-supported hydroxylation of palmitic acid by cytochrome P450BM-3.
The ability of dithionite, an inexpensive reducing agent routinely used to produce the ferrous-carbonyl form of P450, to support P450BM-3-catalyzed hydroxylation of palmitate was studied. The hydroxylation products in the presence of dithionite were 15, 14, and 13-hydroxyhexadecanoate, with relative distributions similar to those observed with NADPH. The hydroxylation reaction was carried out in two separate steps, anaerobic reduction and subsequent oxidation of P450BM-3 by oxygen bubbling. The reduction step was much slower than the oxidation step, thus limiting the overall rate of hydroxylation. Upon addition of dithionite, the reductase domain of P450BM-3 seemed to be reduced before significant reduction of the heme domain occurred. The discovery of new reducing agents for P450-catalyzed reaction raises the possibility of replacing NADPH in specialty chemical hydroxylation catalyzed by P450s, especially catalytically self-sufficient P450s, such as P450BM-3 or recombinant fusion proteins of P450 covalently linked to a reductase.


Reduced DNA repair capacity for removing tobacco carcinogen-induced DNA adducts contributes to risk of head and neck cancer but not tumor characteristics.
Although cigarette smoking and alcohol use are known risk factors for squamous cell carcinoma of head and neck (SCCHN), only a few exposed individuals develop this disease, suggesting an individual susceptibility. In this study, we investigated the associations between genetically determined DNA repair capacity (DRC) for removing tobacco-induced DNA adducts and risk of SCCHN and tumor characteristics. We measured DRC in cultured T lymphocytes using the host-cell reactivation assay in a hospital-based case-control study of 744 SCCHN patients and 753 age-, sex-, and ethnicity-matched cancer-free controls recruited from The University of Texas M.D. Anderson Cancer Center. Patients with SCCHN had significantly lower mean DRC (8.84% +/- 2.68%) than controls (9.97% +/- 2.61%; P < 0.0001), and the difference accounted for approximately 2-fold increased risk of SCCHN [adjusted odds ratio (OR), 1.91; 95% confidence interval (CI), 1.52-2.40] after adjustment for other covariates. Compared with the highest DRC quartile of controls, this increased risk was dose dependent (second highest quartile: OR, 1.40; 95% CI, 0.99-1.98; third quartile: OR, 1.87; 95% CI, 1.34-2.62; and fourth quartile: OR, 2.76; 95% CI, 1.98-3.84, respectively; P(trend) < 0.0001). We also assessed the performance of DRC in risk prediction models by calculating the area of under the receiver operating characteristic curve. The addition of DRC to the model significantly improved the sensitivity of the expanded model. However, we did not find the association between DRC and tumor sites and stages. DRC is an independent susceptibility biomarker for SCCHN risk but not a tumor marker.


The impact of COVID-19 related regulations and restrictions on mobility and potential for sustained climate mitigation across the Netherlands, Sweden and the UK: a data-based commentary.
Human behaviour change is necessary to meet targets set by the Paris Agreement to mitigate climate change. Restrictions and regulations put in place globally to mitigate the spread of COVID-19 during 2020 have had a substantial impact on everyday life, including many carbon-intensive behaviours such as transportation. Changes to transportation behaviour may reduce carbon emissions. Behaviour change theory can offer perspective on the drivers and influences of behaviour and shape recommendations for how policy-makers can capitalise on any observed behaviour changes that may mitigate climate change. For this commentary, we aimed to describe changes in data relating to transportation behaviours concerning working from home during the COVID-19 pandemic across the Netherlands, Sweden and the UK. We display these identified changes in a concept map, suggesting links between the changes in behaviour and levels of carbon emissions. We consider these changes in relation to a comprehensive and easy to understand model of behaviour, the Opportunity, Motivation Behaviour (COM-B) model, to understand the capabilities, opportunities and behaviours related to the observed behaviour changes and potential policy to mitigate climate change. There is now an opportunity for policy-makers to increase the likelihood of maintaining pro-environmental behaviour changes by providing opportunities, improving capabilities and maintaining motivation for these behaviours.


Detection of viruses via statistical gene expression analysis.
We develop a new bayesian construction of the elastic net (ENet), with variational bayesian analysis. This modeling framework is motivated by analysis of gene expression data for viruses, with a focus on H3N2 and H1N1 influenza, as well as Rhino virus and RSV (respiratory syncytial virus). Our objective is to understand the biological pathways responsible for the host response to such viruses, with the ultimate objective of developing a clinical test to distinguish subjects infected by such viruses from subjects with other symptom causes (e.g., bacteria). In addition to analyzing these new datasets, we provide a detailed analysis of the bayesian ENet and compare it to related models.


Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas.
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.


Could human coronavirus OC43 have co-evolved with early humans?
This paper reports on an investigation of the role of codon usage evolution on the suggested bovine-to-human spillover of Bovine coronavirus (BCoV), an enteric/respiratory virus of cattle, resulting in the emergence of the exclusively respiratory Human coronavirus OC43 (HCoV-OC43). Analyses based on full genomes of BCoV and HCoV-OC43 and on both human and bovine mRNAs sequences of cholecystokinin (CCK) and surfactant protein 1 A (SFTP1-A), representing the enteric and respiratory tract codon usage, respectively, have shown natural selection leading to optimization or deoptimization of viral codon usage to the human enteric and respiratory tracts depending on the virus genes under consideration. A higher correlation was found for the nucleotide distance at the 3rd nucleotide position of codons and codon usage optimization to the human respiratory tract when BCoV and HCoV-OC43 were compared. An MCC tree based on relative synonymous codon usage (RSCU) data integrating data from both viruses and hosts into a same analysis indicated three putative host/virus contact dates ranging from 1.54E8 to 2.44E5 years ago, suggesting that an ancestor coronavirus might have followed human evolution.


Risk factors for acute myocardial infarction in Latin America: the INTERHEART Latin American study.
Current knowledge of the impact of cardiovascular risk factors in Latin America is limited. As part of the INTERHEART study, 1237 cases of first acute myocardial infarction and 1888 age-, sex-, and center-matched controls were enrolled from Argentina, Brazil, Colombia, Chile, Guatemala, and Mexico. History of smoking, hypertension, diabetes mellitus, diet, physical activity, alcohol consumption, psychosocial factors, anthropometry, and blood pressure were recorded. Nonfasting blood samples were analyzed for apolipoproteins A-1 and B-100. Logistic regression was used to estimate multivariate adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). Persistent psychosocial stress (OR, 2.81; 95% CI, 2.07 to 3.82), history of hypertension (OR, 2.81; 95% CI, 2.39 to 3.31), diabetes mellitus (OR, 2.59; 95% CI, 2.09 to 3.22), current smoking (OR, 2.31; 95% CI, 1.97 to 2.71), increased waist-to-hip ratio (OR for first versus third tertile, 2.49; 95% CI, 1.97 to 3.14), and increased ratio of apolipoprotein B to A-1 (OR for first versus third tertile, 2.31; 95% CI, 1.83 to 2.94) were associated with higher risk of acute myocardial infarction. Daily consumption of fruits or vegetables (OR, 0.63; 95% CI, 0.51 to 0.78) and regular exercise (OR, 0.67; 95% CI, 0.55 to 0.82) reduced the risk of acute myocardial infarction. Abdominal obesity, abnormal lipids, and smoking were associated with high population-attributable risks of 48.5%, 40.8%, and 38.4%, respectively. Collectively, these risk factors accounted for 88% of the population-attributable risk. Interventions aimed at decreasing behavioral risk factors, lowering blood pressure, and modifying lipids could have a large impact on the risk of acute myocardial infarction among Latin Americans.


Computed tomographic coronary artery calcium assessment for evaluating chest pain in the emergency department: long-term outcome of a prospective blind study.
To determine the long-term outcome of computed tomographic (CT) quantification of coronary artery calcium (CAC) used as a triage tool for patients presenting with chest pain to an emergency department (ED). Patients (men aged 30-62 years and women aged 30-65 years) with chest pain and low-to-moderate probability of coronary artery disease underwent both conventional ED chest pain evaluation and CT CAC assessment prospectively. Patients' physicians were blinded to the CAC results. The results of the conventional evaluation were compared with CAC findings on CT, and the long-term outcome in patients undergoing CT CAC assessment was established. Primary end points (acute coronary syndrome, death, fatal or nonfatal non-ST-segment elevation myocardial infarction, fatal or nonfatal ST-segment elevation myocardial infarction) and secondary outcomes (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, coronary stenting, or a combination thereof) were obtained when the patient was dismissed from the ED or hospital and then at 30 days, 1 year, and 5 years. Of the 263 study patients, 133 (51%) had a CAC score of zero. This absence of CAC correlated strongly with the likelihood of noncardiac chest pain. Among 133 patients with a CAC score of zero, only 1 (<1%) had cardiac chest pain. Conversely, of the 31 patients shown to have cardiac chest pain, 30 (97%) had evidence of CAC on CT. When a CAC cutoff score of 36 was used, as suggested by receiver operating characteristic analysis, sensitivity was 90%; specificity, 85%; positive predictive value, 44%; and negative predictive value, 99%. During long-term follow-up, patients without CAC experienced no cardiac events at 30 days, 1 year, and 5 years. Findings suggest that CT CAC assessment is a powerful adjunct in chest pain evaluation for the population at low-to-intermediate risk. Absent or minimal CAC in this population makes cardiac chest pain extremely unlikely. The absence of CAC suggests an excellent long-term (5-year) prognosis, with no primary or secondary cardiac outcomes occurring in study patients at 5-year follow-up.