Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates.
Epidemiological and transgenic animal studies have implicated apo C-III as a major determinant of plasma triglyceride metabolism. Since fibrates are very efficient in lowering triglycerides, it was investigated whether fibrates regulate apo C-III gene expression. Different fibrates lowered rat liver apo C-III mRNA levels up to 90% in a dose- and time-dependent manner, whereas intestinal apo C-III mRNA remained constant. This decrease in liver apo C-III mRNA was rapid (1 d) and reversible, since it was restored to control levels within 1 wk after cessation of treatment. In addition, fenofibrate treatment abolished the developmental rise of hepatic apo C-III mRNA observed during the suckling-weaning period. Administration of fibrates to rats induced liver and intestinal expression of the acyl CoA oxidase gene, the rate-limiting enzyme for peroxisomal beta-oxidation of fatty acids. In primary cultures of rat and human hepatocytes, fenofibric acid lowered apo C-III mRNA in a time- and dose-dependent manner. This reduction in apo C-III mRNA levels was accompanied by a decreased secretion of apo C-III in the culture medium of human hepatocytes. In rat hepatocytes fenofibric acid induced acyl CoA oxidase gene expression, whereas acyl CoA oxidase mRNA remained unchanged in human hepatocytes. Nuclear run-on and transient transfection experiments of a reporter construct driven by the human apo C-III gene promoter indicated that fibrates downregulate apo C-III gene expression at the transcriptional level. In conclusion, these studies demonstrate that fibrates decrease rat and human liver apo C-III gene expression. In humans the mechanisms appears to be independent of the induction of peroxisomal enzymes. This downregulation of liver apo C-III gene expression by fibrates may contribute to the hypotriglyceridemic action of these drugs.


Low-fouling, mixed-charge poly-l-lysine polymers with anionic oligopeptide side-chains.
Biosensors and biomedical devices require antifouling surfaces to prevent the non-specific adhesion of proteins or cells, for example, when aiming to detect circulating cancer biomarkers in complex natural media (e.g., in blood plasma or serum). A mixed-charge polymer was prepared by the coupling of a cationic polyelectrolyte and an anionic oligopeptide through a modified "grafting-to" method. The poly-l-lysine (PLL) backbone was modified with different percentages (y%) of maleimide-NHS ester chains (PLL-mal(y%), from 13% to 26%), to produce cationic polymers with specific grafting densities, obtaining a mixed-charge polymer. The anionic oligopeptide structure (CEEEEE) included one cysteine (C) and five glutamic acid (E) units, which were attached to the PLL-mal(y%) polymers, preadsorbed on gold substrates, through the thiol-maleimide Michael-type addition. Contact angle and PM-IRRAS data confirmed monolayer formation of the modified PLLs. Antifouling properties of peptide-PLL surfaces were assessed in adsorption studies using quartz crystal microbalance with dissipation (QCM-D) and surface plasmon resonance imaging (SPRI) techniques. PLL-mal(26%)-CEEEEE showed the best antifouling performance in single-protein solutions, and the nonspecific adsorption of proteins was 46 ng cm-2 using diluted human plasma samples. The new PLL-mal(26%)-CEEEEE polymer offers a prominent low-fouling activity in complex media, with rapid and simple procedures for the synthesis and functionalization of the surface compared to conventional non-fouling materials.


Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances.
Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism.


Basal LAT-diacylglycerol-RasGRP1 signals in T cells maintain TCRα gene expression.
In contrast to the well-characterized T cell receptor (TCR) signaling pathways that induce genes that drive T cell development or polarization of naïve CD4 T cells into the diverse T(H)1, T(H)2, T(H)17 and T(reg) lineages, it is unclear what signals maintain specific gene expression in mature resting T cells. Resting T cells residing in peripheral lymphoid organs exhibit low-level constitutive signaling. Whereas tonic signals in B cells are known to be critical for survival, the roles of tonic signals in peripheral T cells are unknown. Here we demonstrate that constitutive signals in Jurkat T cell lines are transduced via the adapter molecule LAT and the Ras exchange factor RasGRP1 to maintain expression of TCRα mRNA and surface expression of the TCR/CD3 complex. Independent approaches of reducing basal activity through the LAT-diacylglycerol-RasGRP pathway led to reduced constitutive Ras-MEK-ERK signals and decreased TCRα mRNA and surface TCR expression in Jurkat cells. However, loss of TCR expression takes several days in these cell line experiments. In agreement with these in vitro approaches, inducible deletion of Lat in vivo results in reduced TCRα mRNA- and surface TCR-expression in a delayed temporal manner as well. Lastly, we demonstrate that loss of basal LAT-RasGRP signals appears to lead to silencing or repression of TCRα transcription. We postulate that basal LAT-diacylglycerol-RasGRP signals fulfill a regulatory function in peripheral T lymphocytes by maintaining proper gene expression programs.


Prostate cancer chemoprevention by silibinin: bench to bedside.
Prostate cancer (PCA) is the most invasive malignancy and second leading cause of cancer deaths in American males. One approach to reduce PCA incidence, growth and metastasis is prevention and intervention targeted towards mitogenic and survival signaling and cell-cycle regulation. This approach is based on the rationale that overexpression of receptor tyrosine kinases (RTKs) and/or non-receptor tyrosine kinases leads to persistent autocrine stimulation of malignant cells for deregulated cell-cycle progression and uncontrolled growth. PCA progression has also been associated with transition from a paracrine to an autocrine relationship between receptors and growth ligands as this malignancy progresses to an advanced androgen-independent aggressive stage. Together, these studies suggest that targeting RTK-mediated signaling pathways along with cell-cycle regulators could be a practical and translational approach for PCA prevention and intervention. Here, we provide evidence that a naturally occurring nontoxic flavanoid, silibinin, targets the epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R) and NF-kappaB (nuclear factor-kappa B) pathways in PCA. Furthermore, it modulates cell-cycle regulators, including cyclin-dependent kinases (CDKs), Cip/Kip and cyclins for its anticancer efficacy against PCA. Silibinin inhibits growth of PCA cells from human, mouse, and rat origins, and also suppresses human prostate tumor xenograft growth in nude mice. Silibinin also inhibits PCA growth in the transgenic adenocarcinoma of mouse prostate (TRAMP) mouse model. Now, silibinin has been entered into phase I/II clinical trials in human PCA patients where preliminary observations were suggestive of its further study in a larger base of the patient population.


The Safety and Feasibility of Image-Guided BrainPath-Mediated Transsulcul Hematoma Evacuation: A Multicenter Study.
Subcortical injury resulting from conventional surgical management of intracranial hemorrhage may counteract the potential benefits of hematoma evacuation. To evaluate the safety and potential benefits of a novel, minimally invasive approach for clot evacuation in a multicenter study. The integrated approach incorporates 5 competencies: (1) image interpretation and trajectory planning, (2) dynamic navigation, (3) atraumatic access system (BrainPath, NICO Corp, Indianapolis, Indiana), (4) extracorporeal optics, and (5) automated atraumatic resection. Twelve neurosurgeons from 11 centers were trained to use this approach through a continuing medical education-accredited course. Demographical, clinical, and radiological data of patients treated over 2 years were analyzed retrospectively. Thirty-nine consecutive patients were identified. The median Glasgow Coma Scale (GCS) score at presentation was 10 (range, 5-15). The thalamus/basal ganglion regions were involved in 46% of the cases. The median hematoma volume and depth were 36 mL (interquartile range [IQR], 27-65 mL) and 1.4 cm (IQR, 0.3-2.9 cm), respectively. The median time from ictus to surgery was 24.5 hours (IQR, 16-66 hours). The degree of hematoma evacuation was ≥90%, 75% to 89%, and 50% to 74% in 72%, 23%, and 5.0% of the patients, respectively. The median GCS score at discharge was 14 (range, 8-15). The improvement in GCS score was statistically significant ( P < .001). Modified Rankin Scale data were available for 35 patients. Fifty-two percent of those patients had a modified Rankin Scale score of ≤2. There were no mortalities. The approach was safely performed in all patients with a relatively high rate of clot evacuation and functional independence.


Trait Mindfulness and Progression to Injection Use in Youth With Opioid Addiction.
Many youth initiate opioid misuse with prescription opioids and transition over time to more severe substance-using behaviors, including injection. Trait mindfulness is a potentially protective factor. This is a cross-sectional study characterizing a sample of opioid-using youth by level of mindfulness and examines the potential effect modification of emotion regulation on the relationship between mindfulness and progression to injection opioid use. A convenience sample of 112 youth (ages 14-24) was recruited during an episode of inpatient detoxification and residential treatment for opioid use disorders. We examined emotion regulation (Difficulties in Emotion Regulation Scale), mindfulness (Child Acceptance and Mindfulness Measure), and opioid use. We completed multivariable regressions stratified by degree of emotion regulation looking at relationship of mindfulness on time to injection use from age of first prescription opioid. Youth had difficulties in emotion regulation (m = 104.2; SD = 2.41) and low mindfulness (m = 19.1;SD = 0.59). While we found overall that mindfulness was associated with time to progression to injection opioid use, there was significant effect modification. Among youth with high levels of difficulty in emotion regulation, those with high mindfulness trait had quicker progressions to injection (-1.31 years; p =.003). In contrast, youth with normal emotion regulation and high mindfulness trait had a slower progression to injection (1.67 years; p =.041). Conclusion/Importance: Our study showed a majority of youth presenting with opioid use disorders have impairments in emotion regulation and deficits in trait mindfulness. The relationship between mindfulness and opioid use is impacted by emotion regulation capacity. More research is needed to understand the various facets of mindfulness and how they interact with emotion regulation in youth.


STAT3 NH2-terminal acetylation is activated by the hepatic acute-phase response and required for IL-6 induction of angiotensinogen.
The signal transducers and activators of transcription (STATs) are cytoplasmic transcription factors mediating acute-phase response (APR) of the human angiotensinogen (hAGT) gene in hepatocytes. The mechanisms of how STAT3 activates target genes are unknown. Here we analyzed the biochemistry of STAT3 activation by interleukin (IL)-6 in hepatocellular carcinoma HepG2 and Balb/C mice. Immunoprecipitation-Western assays and Matrix Assisted Laser Desorption-Time of Flight mass spectrometry determined sites of STAT3 acetylation by the 300-kilodalton target of E1A (p300) co-activator. The subcellular localization of acetylation-deficient STAT3 molecules were studied by microscopic imaging, effects on DNA binding measured by gel shift and chromatin immunoprecipitation (ChIP) assays, and gene transactivation by Northern blot and reporter assays. Two Lys residues at amino acids 49 and 87 in the STAT3 NH2 terminus are acetylated by p300. Lys-to-Arg point mutations (STAT3 K49R/K87R) had no effect on inducible DNA binding, but blocked p300-mediated acetyl(Ac)-STAT3 formation and abrogated IL-6-induced hAGT activation. Although STAT3 K49R/K87R rapidly translocated into the nucleus, it did not bind p300 and had delayed cytoplasmic redistribution. ChIP assays show IL-6-inducible acetylated STAT3 and p300 binding to the native hAGT promoter. Activation of the APR in mice induces nuclear Tyr phosphorylated and acetylated STAT3 in hepatic nuclei. We also observed that STAT3 interacts with histone deacetylases (HDACs), specifically HDAC 1, that down-regulate IL-6-induced hAGT transactivation. IL-6-induced target gene activation requires p300-mediated STAT3 acetylation, and HDACs are involved in the termination of STAT3 action. These studies indicate the acetylation-deacetylation reaction as a novel signaling mechanism controlling the IL-6-STAT3 pathway in the hepatic APR.


Characterizing Real-World Use Of Tiotropium In Asthma In The USA.
Tiotropium bromide (TIO) is a long-acting muscarinic antagonist recommended as an add-on therapy option for patients with uncontrolled asthma on inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA). However, real-world data on TIO use in asthma remains limited. To identify unmet needs, this study explored the use of TIO in US patients with asthma. This retrospective cohort study used IQVIATM Health Plan Claims Data (October 1, 2014─December 31, 2016). Patients with asthma diagnoses initiating TIO 1.25 or 2.5 mcg after September 16, 2015 (first dispensing on index date) with ≥6 and ≥3 months continuous enrollment pre- and post-index, respectively, were identified. Patients with COPD diagnoses were excluded. Baseline characteristics, healthcare resource utilization and costs, and treatment patterns before and following TIO initiation were described for TIO cohorts and subgroups classified by concomitant medications received during the 30-day period after initiation. The study included 766 TIO 1.25 mcg and 1055 TIO 2.5 mcg users. In the TIO 1.25 mcg cohort, 16% (126/766) used TIO monotherapy while 61% (465/766) used TIO+ICS/LABA± leukotriene receptor antagonists (triple therapy). In TIO 1.25 mcg monotherapy and triple therapy subgroups, 39% and 49% were treated by allergists/pulmonologists, 27% and 48% experienced a moderate/severe asthma exacerbation, and 50% and 68% used rescue oral corticosteroids during the baseline period, respectively. Following triple therapy initiation, 44% of patients discontinued ICS within 6 months. The TIO 2.5 mcg cohort demonstrated similar trends. This study provided insights into real-world US use of TIO in asthma. Overall, 16-19% of patients received TIO monotherapy and had high baseline exacerbation rates, suggesting that additional ICS-containing medication may be beneficial. Patients initiating triple therapy were among the most severe, with high baseline exacerbation rates and rescue medication use, and had high post-treatment ICS discontinuation rates, suggesting unmet needs in this population.


In vitro and in vivo evaluation of chitosan buccal films of ondansetron hydrochloride.
Buccal films of ondanstron hydrochloride were fabricated from mucoadhesive polymer, chitosan, and polyvinyl pyrrolidone (PVP K30) for the purpose of prolonging drug release and improving its bioavailability. All fabricated film formulations prepared were smooth and translucent, with good flexibility. The weight and thickness of all the formulations were found to be uniform. Drug content in the films ranged from 98 - 99%, indicating favorable drug loading and uniformity. The inclusion of PVP K30, a hydrophilic polymer, significantly reduced the bioadhesive strength and in vitro mucoadhesion time of the films, although the degree of swelling increased. In vitro drug release studies in simulated saliva showed a prolonged release of over five to six hours for all formulations, except C4, with 99.98% release in 1.5 hours. Kinetic analysis of the release data indicated that the best fit model with the highest correlation coefficient for all formulations was the Peppas model. In vivo studies, on selected films in rabbits, were conducted, to determine the pharmacokinetic parameters such as C(max), T(max), and AUC(0-∞), using model-independent methods with nonlinear least-squares regression analysis. The AUC and values of C(max) of ondansetron hydrochloride were found to be significantly greater (P < 0.005) than the selected films C2 and C3, as compared to those from the oral solution, thereby confirming improved bioavailability via the buccal route. The T(max) values were also significantly greater (P < 0.005), indicating the slower release of the drug from buccal films, thereby, providing prolonged effects. Good in vitro-in vivo correlation was observed with R(2) values exceeding 0.98, when the percentage of drug released was correlated with the percentage of drug absorbed.


Genetics against race: Science, politics and affirmative action in Brazil.
This article analyses interrelations between genetic ancestry research, political conflict and social identity. It focuses on the debate on race-based affirmative action policies, which have been implemented in Brazil since the turn of the century. Genetic evidence of high levels of admixture in the Brazilian population has become a key element of arguments that question the validity of the category of race for the development of public policies. In response, members of Brazil's black movement have dismissed the relevance of genetics by arguing, first, that in Brazil race functions as a social--rather than a biological--category, and, second, that racial classification and discrimination in this country are based on appearance, rather than on genotype. This article highlights the importance of power relations and political interests in shaping public engagements with genetic research and their social consequences.


The prospective association between health anxiety and cancer detection: A cohort study linking the Hordaland Health Study (HUSK) with the Norwegian Cancer Registry.
Health anxiety is associated with distress and disability, and overutilization of health services, but it is not known whether high levels of health anxiety may lead to increased detection of severe diseases such as cancer. By linking a large population based health study with the national cancer registry, the aim of the study was to investigate a potential prospective association between health anxiety in men and women and later cancer detection and tumour metastasis at the time of diagnosis. A longitudinal study with a 13.2 year follow-up linking the population-based Hordaland Health Study (HUSK) and the Cancer Registry of Norway (CRN) was conducted. Health anxiety was measured with the Whiteley Index. Associations were examined through gender stratified Cox regression analyses adjusted for relevant covariates. No association was found between baseline health anxiety and cancer detection for women (adjusted HR: 1.21, 95% CI: 0.42-3.50), but a positive association was found between health anxiety at baseline and cancer detection for men (adjusted HR: 1.76, 95% CI: 1.06-2.91). No statistically significant association was demonstrated between health anxiety and cancer metastasis for either gender. An increased level of health anxiety in men may be advantageous, as it may motivate to self-examination and healthcare seeking when disturbing symptoms arise. Research is needed to investigate whether health anxiety has a protective effect on cancer metastasis at the time of detection, or whether health anxiety increases the risk of over-diagnosis and overtreatment.


Carbohydrate-Derived Polytriazole Nanoparticles Enhance the Anti-Inflammatory Activity of Cilostazol.
Poly(amide-triazole) and poly(ester-triazole) synthesized from d-galactose as a renewable resource were applied for the synthesis of nanoparticles (NPs) by the emulsification/solvent evaporation method. The NPs were characterized as stable, spherical particles, and none of their components, including the stabilizer poly(vinyl alcohol), were cytotoxic for normal rat kidney cells. These NPs proved to be useful for the efficient encapsulation of cilostazol (CLZ), an antiplatelet and vasodilator drug currently used for the treatment of intermittent claudication, which is associated with undesired side-effects. In this context, the nanoencapsulation of CLZ was expected to improve its therapeutic administration. The carbohydrate-derived polymeric NPs were designed taking into account that the triazole rings of the polymer backbone could have attractive interactions with the tetrazole ring of CLZ. The activity of the nanoencapsulated CLZ was measured using a matrix metalloproteinase model in a lipopolysaccharide-induced inflammation system. Interestingly, the encapsulated drug exhibited enhanced anti-inflammatory activity in comparison with the free drug. The results are very promising since the stable, noncytotoxic NP systems efficiently reduced the inflammation response at low CLZ doses. In summary, the NPs were obtained through an innovative methodology that combines a carbohydrate-derived synthetic polymer, designed to interact with the drug, ease of preparation, adequate biological performance, and environmentally friendly production.


Antiarthritic activity of a standardized, multiherbal, Ayurvedic formulation containing Boswellia serrata: in vitro studies on knee cartilage from osteoarthritis patients.
A validated in vitro model of cartilage damage and published data were used showing that this model measures the chondroprotective and antiinflammatory effects of different antiarthritic drugs. In this report, this model was used to evaluate the effects of a new antiarthritic Ayurvedic formulation containing Zingiber officinale root, Tinospora cordifolia stem, Phyllanthus emblica fruit and oleoresin of Boswellia serrata. Glucosamine sulphate was used as a positive control in the study. Aqueous extracts of each drug were tested on explant cultures of knee cartilage obtained from osteoarthritis patients undergoing knee replacement surgery. The new formulation caused a sustained and statistically significant inhibition in the release of glycosaminoglycans and aggrecan by cartilage explants from these patients. This formulation also induced a transient antiinflammatory effect as measured by a reduction in the levels of nitric oxide released by explants. Furthermore, the data strongly suggest that oleoresin of B. serrata plays a crucial role in the chondroprotective and antiinflammatory activity of this formulation. In summary, this report provides the first, direct, in vitro biochemical evidence of anti-arthritic activity a new Ayurvedic formulation. This formulation significantly reduced damage of articular knee cartilage from chronic osteoarthritis patients.


Effect of left atrial filling pressure on the activity of specific myosin isozymes in rat heart.
One of the fundamental properties of cardiac muscle is the increase in force generated and work performed with a rise in the resting length of the tissue. There are data to indicate that length-dependent responses of electromechanical coupling and calcium binding by troponin are part of the basis for the pressure-volume relation in the heart. In this study, the contribution of changes in the functional properties of the contractile proteins independent of modification in electromechanical coupling has been examined. Isolated working hearts containing either a mixture of myosin heavy chain (MHC) isozymes (alpha[fast] and beta [slow]) or exclusively the fast MHC have been subjected to left atrial filling pressures (LAPs) between 5 and 20 cm H2O. After 40 minutes at a given LAP, the heart was quickly frozen. The relative activities of calcium- and actin-activated ATPase of V1 and V3 myosin, containing alpha- and beta-MHC, were measured in cryostatic sections of the heart by quantitative histochemistry under conditions for which the concentration of calcium would not be limiting. In hearts containing both isozymes of myosin, the relative enzymatic activity of each isozyme of myosin varied with LAP. At low LAP, V1 was primarily responsible for the enzymatic activity, but as LAP increased the relative contribution of V1 decreased and that of V3 increased. The change in the calcium- and actin-activated activities of the enzyme with change in LAP occurred within 5 minutes and was reversible. In spite of the apparent substitution of enzymatic activity of V3 for V1, total myosin ATPase activity did not decline, but instead remained constant.(ABSTRACT TRUNCATED AT 250 WORDS)


Inflammatory and metabolic response of the myocardium during aortic valve surgery on the beating heart.
This study has been conducted in an effort to establish metabolic and inflammatory responses of the myocardium during aortic valve surgery on the beating heart with CPB and continuous coronary sinus perfusion with normothermic blood. Twenty patients, divided into two groups, participated in this study. Conventional aortic valvular operations were performed on first 10 patients, while the second group, consisting of 10 patients as well, was subjected to the operations with CPB on the beating heart with continuously perfusion with blood through coronary sinus. There were total of 14 biological and 6 mechanical valves implanted in aortic position. In this study, cardiac markers and inflammatory mediators IL-8 and TNF, were measured preoperatively and postoperatively. Metabolic changes were documented based on the levels of CK-MB, troponin I, myoglobin and LDH. Inflammatory factors we measured through IL-8 and TNF. All measurements were taken in 6 hour intervals during the initial 48 hours following the operations. The patients of "the beating heart" group had significantly lower dose of markers and cytokines in comparison to those who had undergone the conventional valvular operation. The elimination of the adverse effects of global ischemia produced from reperfusion injury and the similarity to the physiological condition, suggests that the revival of the beating heart procedure is more reasonable. This procedure of valvular surgery on the beating heart can be one of the good surgical options for the high-risk valvular patients.


Parvovirus B19 may have a role in the pathogenesis of juvenile idiopathic arthritis.
To determine the prevalence of human parvovirus B19 infection in patients with juvenile idiopathic arthritis (JIA) by detection of specific IgM, IgG, and viral DNA. Serum samples of 50 patients with diagnosis of JIA and 39 healthy controls were analyzed by ELISA to detect IgG and IgM anti-B19-specific antibodies. The parvovirus B19 genome was detected by nested polymerase chain reaction (PCR). The average age of the patients was 9.6 years (2-14 yrs); 30 were female (60%) and 20 male (40%). The definitive diagnoses of these patients corresponded to 19 systemic forms (38%), 11 to the oligoarticular variety (22%) and 20 to the polyarticular (40%). The average age of the control group was 7.8 years (2-16 yrs); the distribution by sex was 25 females (64%) and 14 males (36%). IgM against parvovirus B19 was detected in 20% of the cases (10 patients) and B19 DNA genome by PCR in 48% (24 patients); in 10% of the cases (5 patients), both markers were detected. IgG was found in 32% (16 patients). In the control group neither IgM nor the viral genome was detected. However, 43.5% of the controls (17/39) had IgG against parvovirus B19, indicating past infection by the virus. Our study confirms recent observations regarding a high prevalence of viral DNA in JIA patients and a possible role of this viral infection in JIA pathogenesis.


Valpha24-JalphaQ-independent, CD1d-restricted recognition of alpha-galactosylceramide by human CD4(+) and CD8alphabeta(+) T lymphocytes.
Human CD1d molecules present an unknown ligand, mimicked by the synthetic glycosphingolipid alpha-galactosylceramide (alphaGC), to a highly conserved NKT cell subset expressing an invariant TCR Valpha24-JalphaQ paired with Vbeta11 chain (Valpha24(+)Vbeta11(+) invariant NK T cell (NKT(inv))). The developmental pathway of Valpha24(+)Vbeta11(+)NKT(inv) is still unclear, but recent studies in mice were consistent with a TCR instructive, rather than a stochastic, model of differentiation. Using CD1d-alphaGC-tetramers, we demonstrate that in humans, TCR variable domains other than Valpha24 and Vbeta11 can mediate specific recognition of CD1d-alphaGC. In contrast to Valpha24(+)Vbeta11(+)NKT(inv) cells, Valpha24(-)/CD1d-alphaGC-specific T cells express either CD8alphabeta or CD4 molecules, but they are never CD4 CD8 double negative. We show that CD8alphabeta(+)Valpha24(-)/CD1d-alphaGC-specific T cells exhibit CD8-dependent specific cytotoxicity and have lower affinity TCRs than Valpha24(+)/CD1d-alphaGC-specific T cells. In conclusion, our results demonstrate that, contrary to the currently held view, recognition of CD1d-alphaGC complex in humans is not uniformly restricted to the Valpha24-JalphaQ/Vbeta11 NKT cell subset, but can be mediated by a diverse range of Valpha and Vbeta domains. The existence of a diverse repertoire of CD1d-alphaGC-specific T cells in humans strongly supports their Ag-driven selection.


Targeting Cyclin-Dependent Kinases in Synovial Sarcoma: Palbociclib as a Potential Treatment for Synovial Sarcoma Patients.
In synovial sarcomas alterations in the cyclin D1-CDK4/6-Rb axis have been described. Also, β-catenin, a cyclin D1 regulator, is often overexpressed. Additionally, studies have shown that the t(X;18) translocation influences tumor behavior partly through cyclin D1 activation. We investigated how alterations in the cyclin D1-CDK4/6-Rb axis impact prognosis and studied effects of targeting this axis with the CDK4/6 inhibitor palbociclib. Synovial sarcoma samples (n = 43) were immunohistochemically stained for β-catenin, cyclin D1, p16, p21, p27, Rb, and phospho-Rb. Fluorescent in situ hybridization (FISH) was performed to detect CCND1 amplification or translocation. In 4 synovial sarcoma cell lines sensitivity to palbociclib was investigated using cell viability assays, and effects on the sensitive cell lines were evaluated on protein level and by cell cycle arrest. Expression of nuclear phospho-Rb and nuclear β-catenin in the patient samples was associated with poor survival. FISH showed a sporadic translocation of CCND1 in a subset of tumors. An 8-fold CCND1 amplification was found in 1 cell line, but not in the patient samples investigated. Palbociclib effectively inhibited Rb-phosphorylation in 3 cell lines, resulting in an induction of a G1 arrest and proliferation block. In this series nuclear phospho-Rb and nuclear β-catenin expression were negative prognostic factors. In vitro data suggest that palbociclib may be a potential treatment for a subset of synovial sarcoma patients. Whether this effect can be enhanced by combination treatment deserves further preclinical investigations.


Purification and characterization of a soybean root nodule phosphatase expressed in Pichia pastoris.
Soybean root nodules possess a developmentally regulated acid phosphatase (ACP) that exhibits the highest specificity for purine 5'-nucleoside monophosphates. The enzyme is a glycosylated dimer of 28- and 31-kDa subunits, which appear to be products of the same gene but differ in posttranslational modifications. In order to perform directed mutagenesis and more extensive biochemical characterization, a means of producing recombinant ACP was needed. Several attempts were made to express ACP in Escherichia coli, but all conditions employed resulted in protein that was found entirely in inclusion bodies, and resolubilization experiments were unsuccessful. Therefore, the methyltrophic yeast Pichia pastoris was chosen as a eukaryotic expression host. The coding sequence of ACP was cloned into the pPIC9 vector to create a fusion with the yeast alpha mating factor secretion signal. The ACP:pPIC9 construct was integrated into P. pastoris strain GS115. Expression of ACP was under the control of an alcohol oxidase methanol-inducible promoter. Methanol induction resulted in secretion of ACP to a level of 10 mg/L. The recombinant ACP was purified 550-fold to homogeneity by phenyl-Sepharose, hydroxyapatite, and MonoS chromatography. The purified enzyme had Km values of 0.08 and 0.12 for 5'-AMP and 5'-GMP. These values were similar to those obtained for the native ACP heterodimer purified from soybean (0.08 and 0.15 mM for 5'-AMP and 5'-GMP). The specific activity of the recombinant enzyme for all substrates tested was 1.6- to 1.8-fold higher than the values for the purified soybean heterodimer.


Fatal hyperammonemia and carbamoyl phosphate synthetase 1 (CPS1) deficiency following high-dose chemotherapy and autologous hematopoietic stem cell transplantation.
Fatal hyperammonemia secondary to chemotherapy for hematological malignancies or following bone marrow transplantation has been described in few patients so far. In these, the pathogenesis of hyperammonemia remained unclear and was suggested to be multifactorial. We observed severe hyperammonemia (maximum 475 μmol/L) in a 2-year-old male patient, who underwent high-dose chemotherapy with carboplatin, etoposide and melphalan, and autologous hematopoietic stem cell transplantation for a neuroblastoma stage IV. Despite intensive care treatment, hyperammonemia persisted and the patient died due to cerebral edema. The biochemical profile with elevations of ammonia and glutamine (maximum 1757 μmol/L) suggested urea cycle dysfunction. In liver homogenates, enzymatic activity and protein expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) were virtually absent. However, no mutation was found in CPS1 cDNA from liver and CPS1 mRNA expression was only slightly decreased. We therefore hypothesized that the acute onset of hyperammonemia was due to an acquired, chemotherapy-induced (posttranscriptional) CPS1 deficiency. This was further supported by in vitro experiments in HepG2 cells treated with carboplatin and etoposide showing a dose-dependent decrease in CPS1 protein expression. Due to severe hyperlactatemia, we analysed oxidative phosphorylation complexes in liver tissue and found reduced activities of complexes I and V, which suggested a more general mitochondrial dysfunction. This study adds to the understanding of chemotherapy-induced hyperammonemia as drug-induced CPS1 deficiency is suggested. Moreover, we highlight the need for urgent diagnostic and therapeutic strategies addressing a possible secondary urea cycle failure in future patients with hyperammonemia during chemotherapy and stem cell transplantation.


Daily functioning profile of children with attention deficit hyperactive disorder: A pilot study using an ecological assessment.
Children with attention-deficit hyperactivity disorder (ADHD) often present with activities of daily living (ADL) performance deficits. This study aimed to compare the performance characteristics of children with ADHD to those of controls based on the Do-Eat assessment tool, and to establish the tool's validity. Participants were 23 children with ADHD and 24 matched controls, aged 6-9 years. In addition to the Do-Eat, the Children Activity Scale-Parent (ChAS-P) and the Behavioral Rating Inventory of Executive Function (BRIEF) were used to measure sensorimotor abilities and executive function (EF). Significant differences were found in the Do-Eat scores between children with ADHD and controls. Significant moderate correlations were found between the Do-Eat sensorimotor scores, the ChAS-P and the BRIEF scores in the ADHD group. Significant correlations were found between performance on the Do-Eat and the ChAS-P questionnaire scores, verifying the tool's ecological validity. A single discriminant function described primarily by four Do-Eat variables, correctly classified 95.5% of the study participants into their respective study groups, establishing the tool's predictive validity within this population. These preliminary findings indicate that the Do-Eat may serve as a reliable and valid tool that provides insight into the daily functioning characteristics of children with ADHD. However, further research on larger samples is indicated.


Isolation and culture of motor neurons from the newborn mouse spinal cord.
A protocol for the isolation and culture of motor neurons from postnatal day 1 mouse spinal cord is described. After 72 h in culture, phase contrast microscopy reveals healthy cells with motor neuronal morphology and extensive neuritic processes. These neurons express the 75-kDa low-affinity neurotrophin receptor (p75NTR) and choline acetyltransferase (ChAT), both proteins are specifically expressed by neonatal and embryonic motor neurons in vivo. This protocol can be adapted for various postnatal motor neuron assays.


Development and Validation of a Risk Prediction Model for Esophageal Squamous Cell Carcinoma Using Cohort Studies.
Esophageal squamous cell carcinoma (ESCC) carries a poor prognosis, but earlier tumor detection would improve survival. We aimed to develop and externally validate a risk prediction model based on exposure to readily available risk factors to identify high-risk individuals of ESCC. Competing risk regression modeling was used to develop a risk prediction model. Individuals' absolute risk of ESCC during follow-up was computed with the cumulative incidence function. We used prospectively collected data from the Nord-Trøndelag Health Study (HUNT) for model derivation and the UK Biobank cohort for validation. Candidate predictors were age, sex, tobacco smoking, alcohol consumption, body mass index (BMI), education, cohabitation, physical exercise, and employment. Model performance was validated internally and externally by evaluating model discrimination using the area under the receiver-operating characteristic curve (AUC) and model calibration. The developed risk prediction model included age, sex, smoking, alcohol, and BMI. The AUC for 5-year risk of ESCC was 0.76 (95% confidence interval [CI], 0.58-0.93) in the derivation cohort and 0.70 (95% CI, 0.64-0.75) in the validation cohort. The calibration showed close agreement between the predicted cumulative risk and observed probabilities of developing ESCC. Higher net benefit was observed when applying the risk prediction model than considering all participants as being at high risk, indicating good clinical usefulness. A web tool for risk calculation was developed: https://sites.google.com/view/escc-ugis-ki. This ESCC risk prediction model showed good discrimination and calibration and validated well in an independent cohort. This readily available model can help select high-risk individuals for preventive interventions.


Leucobacter soli sp. nov., from soil amended with humic acid.
A Gram-positive, non-spore-forming actinobacterium (IMT-300T) was isolated from soil amended with humic acid in Malvern, AL, USA. This soil has been used for 50+years for the cultivation of earthworms for use as fish bait. Based on 16S rRNA gene sequence similarity studies, strain IMT-300T was shown to belong to the genus Leucobacter and was closely related to the type strain of 'Leucobacter margaritiformis' L1T (97.8%). Similarity to all other type strains of Leucobacter species was lower than 97.2 %. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between the IMT-300T genome assembly and those of the closest relative Leucobacter type strain were 81.4 and 23.3 % (Leucobacter chironomi), respectively. The peptidoglycan of strain IMT-300T contained l-2,4-diaminobutyric acid as the diagnostic diamino acid. In addition, glycine, d- and l-alanine and d-glutamic acid were found. The peptidoglycan type represents a variant of B2δ (B11). The major quinones were menaquinones MK-10 and MK-11. The polar lipid profile consisted of the major lipids diphosphatidylglycerol, phosphatidylglycerol and moderate to minor amounts of two unidentified phospholipids, two unidentified glycolipids and an unidentified aminophospholipid. The polyamine pattern contained major amounts of spermidine and spermine. Strain IMT-300T contained the major fatty acids C15 : 0 anteiso, C16 : 0 iso and C17 : 0 anteiso, like other members of the genus Leucobacter. The results of ANI and dDDH analyses and physiological and biochemical tests allowed a genotypic and phenotypic differentiation of strain IMT-300T from the most closely related Leucobacter species. Strain IMT-300T represents a novel Leucobacter species, for which we propose the name Leucobacter soli sp. nov., with the type strain IMT-300T (CIP 111803T=DSM 110505T=CCM 9020T=LMG 31600T).


Modulation Spectra Capture EEG Responses to Speech Signals and Drive Distinct Temporal Response Functions.
Speech signals have a unique shape of long-term modulation spectrum that is distinct from environmental noise, music, and non-speech vocalizations. Does the human auditory system adapt to the speech long-term modulation spectrum and efficiently extract critical information from speech signals? To answer this question, we tested whether neural responses to speech signals can be captured by specific modulation spectra of non-speech acoustic stimuli. We generated amplitude modulated (AM) noise with the speech modulation spectrum and 1/f modulation spectra of different exponents to imitate temporal dynamics of different natural sounds. We presented these AM stimuli and a 10-min piece of natural speech to 19 human participants undergoing electroencephalography (EEG) recording. We derived temporal response functions (TRFs) to the AM stimuli of different spectrum shapes and found distinct neural dynamics for each type of TRFs. We then used the TRFs of AM stimuli to predict neural responses to the speech signals, and found that (1) the TRFs of AM modulation spectra of exponents 1, 1.5, and 2 preferably captured EEG responses to speech signals in the δ band and (2) the θ neural band of speech neural responses can be captured by the AM stimuli of an exponent of 0.75. Our results suggest that the human auditory system shows specificity to the long-term modulation spectrum and is equipped with characteristic neural algorithms tailored to extract critical acoustic information from speech signals.


Isotonic solutions of mannitol, sorbitol and glycine and distilled water as irrigating fluids during transurethral resection of the prostate and calculation of irrigating fluid influx.
The aim of the study was to evaluate the clinical properties of some irrigating fluids used in transurethral resection of the prostate, to study humoral changes and disposition of the various fluids and solutes on intravenous absorption and, finally, to draw conclusions concerning a suitable composition of irrigation fluid. 60 patients undergoing transurethral resection of the prostate were included in the study. Plasma concentrations of mannitol, sorbitol and glycine were determined (during and after operation) as indicators of intravenous irrigation fluid influx. The serum concentration of prostatic acid phosphatase and, in patients irrigated with distilled water, the postoperative increase in plasma haemoglobin and the serum lactate dehydrogenase increase were used as semiquantitative estimates of fluid influx. A wide-ranging series of biochemical analyses was performed on blood in all cases before, during and after the resection (inter alia, sodium, albumin, haptoglobin in serum). The half-lives in plasma were estimated for mannitol, sorbitol and glycine. Fluid absorption was calculated in several ways. Haemodilution occurred with all iso-osmolar solutions on absorption but not with distilled water. The dilution effect of glycine solution was the most pronounced. Calculation of absorbed fluid volumes gave values up to 3.0 litres. Plasma osmolality was unchanged with all irrigating fluids used. The half-life in plasma for sorbitol was about 30 min, for glycine about 90 min and for mannitol about 120 min. Glycine entered muscle cells and changed the amino acid pattern. There was an increase in the serine and ammonia concentrations in plasma postoperatively. On absorption of distilled water there was an increase in the concentration of plasma haemoglobin and in erythrocyte-derived enzymes. The immediate postoperative concentration of glycine, mannitol and sorbitol in plasma was used to calculate fluid absorption. These concentrations showed good correlation with the immediate postoperative decrease in serum sodium concentration. The serum sodium decrease can be used for calculations of the absorbed fluid volume. On absorption of large volumes of water with haemolysis products, kidney damage is possible. The osmotic diuretic effect of mannitol gives a tendency to low postoperative blood pressure if combined with an intravenous diuretic. Water as an irrigating fluid can be recommended for diagnostic purposes and for general bladder surgery.(ABSTRACT TRUNCATED AT 400 WORDS)


An environmental scan of quality improvement and patient safety activities in emergency medicine in Canada.
We conducted an environmental scan of quality improvement and patient safety (QIPS) infrastructure and activities in academic emergency medicine (EM) programs and departments across Canada. We developed 2 electronic surveys through expert panel consensus to assess important themes identified by the CAEP QIPS Committee. "Survey 1" was sent by email to all 17 Canadian medical school affiliated EM department Chairs and Academic Hospitals department Chiefs; "Survey 2" to 12 identified QIPS leads in these hospitals. This was followed by 2 monthly email reminders to participate in the survey. 22/70 (31.4%) Department Chairs/Chiefs completed Survey 1. Most (81.8%) reported formal positions dedicated to QIPS activities within their groups, with a mixed funding model. Less than half of these positions have dedicated logistical support. 11/12 (91.7%) local QIPS leads completed Survey 2. Two-thirds (63.6%) reported explicit QIPS topics within residency curricula, but only 9.1% described QIPS training for staff physicians. Many described successful academic scholarship output, with the total number of peer-reviewed QIPS-related publications per centre ranging from 1-10 over the past 5 years. Few respondents reported access to academic supports: methodologists (27.3%), administrative personnel (27.3%), and statisticians (9.1%). This environmental scan provides a snapshot of QIPS activities in EM across academic centres in Canada. We found significant local educational and academic efforts, although there is a discrepancy between the level of formal support/infrastructure and such activities. There remains opportunity to further advance QIPS efforts on a national level, as well as advocating and supporting local QIPS activities.


Improving lanthanide nanocrystal colloidal stability in competitive aqueous buffer solutions using multivalent PEG-phosphonate ligands.
The range of properties available in the lanthanide series has inspired research into the use of lanthanide nanoparticles for numerous applications. We aim to use NaLnF(4) nanoparticles for isotopic tags in mass cytometry. This application requires nanoparticles of narrow size distribution, diameters preferably less than 15 nm, and robust surface chemistry to avoid nonspecific interactions and to facilitate bioconjugation. Nanoparticles (NaHoF(4), NaEuF(4), NaGdF(4), and NaTbF(4)) were synthesized with diameters from 9 to 11 nm with oleic acid surface stabilization. The surface ligands were replaced by a series of mono-, di-, and tetraphosphonate PEG ligands, whose synthesis is reported here. The colloidal stability of the resulting particles was monitored over a range of pH values and in phosphate containing solutions. All of the PEG-phosphonate ligands were found to produce non-aggregated colloidally stable suspensions of the nanoparticles in water as judged by DLS and TEM measurements. However, in more aggressive solutions, at high pH and in phosphate buffers, the mono- and diphosphonate PEG ligands did not stabilize the particles and aggregation as well as flocculation was observed. However, the tetraphosphonate ligand was able to stabilize the particles at high pH and in phosphate buffers for extended periods of time.


School-Age Outcomes of Early Intervention for Preterm Infants and Their Parents: A Randomized Trial.
To examine the child and parental outcomes at school age of a randomized controlled trial of a home-based early preventative care program for infants born very preterm and their caregivers. At term-equivalent age, 120 infants born at a gestational age of <30 weeks were randomly allocated to intervention (n = 61) or standard care (n = 59) groups. The intervention included 9 home visits over the first year of life focusing on infant development, parental mental health, and the parent-infant relationship. At 8 years' corrected age, children's cognitive, behavioral, and motor functioning and parental mental health were assessed. Analysis was by intention to treat. One hundred children, including 13 sets of twins, attended follow-up (85% follow-up of survivors). Children in the intervention group were less likely to have mathematics difficulties (odds ratio, 0.42; 95% confidence interval [CI], 0.18 to 0.98; P = .045) than children in the standard care group, but there was no evidence of an effect on other developmental outcomes. Parents in the intervention group reported fewer symptoms of depression (mean difference, -2.7; 95% CI, -4.0 to -1.4; P < .001) and had reduced odds for mild to severe depression (odds ratio, 0.14; 95% CI, 0.03 to 0.68; P = .0152) than parents in the standard care group. An early preventive care program for very preterm infants and their parents had minimal long-term effects on child neurodevelopmental outcomes at the 8-year follow-up, whereas primary caregivers in the intervention group reported less depression.


Two-dimensional polarimeter with a charge-coupled-device image sensor and a piezoelastic modulator.
We present the first measurements and scientific observations of the solar photosphere obtained with a new two-dimensional polarimeter based on piezoelastic modulators and synchronous demodulation in a CCD imager. This instrument, which is developed for precision solar-vector polarimetry, contains a specially masked CCD that has every second row covered with an opaque mask. During exposure the charges are shifted back and forth between covered and light-sensitive rows synchronized with the modulation. In this way Stokes I and one of the other Stokes parameters can be recorded. Since the charge shifting is performed at frequencies well above the seeing frequencies and both polarization states are measured with the same pixel, highly sensitive and accurate polarimetry is achieved. We have tested the instrument in laboratory conditions as well as at three solar telescopes.


The Influence of Omega-3 Fatty Acids on Skeletal Muscle Protein Turnover in Health, Disuse, and Disease.
Ingestion of omega-3 fatty acids is known to exert favorable health effects on a number of biological processes such as improved immune profile, enhanced cognition, and optimized neuromuscular function. Recently, data have emerged demonstrating a positive influence of omega-3 fatty acid intake on skeletal muscle. For instance, there are reports of clinically-relevant gains in muscle size and strength in healthy older persons with omega-3 fatty acid intake as well as evidence that omega-3 fatty acid ingestion alleviates the loss of muscle mass and prevents decrements in mitochondrial respiration during periods of muscle-disuse. Cancer cachexia that is characterized by a rapid involuntary loss of lean mass may also be attenuated by omega-3 fatty acid provision. The primary means by which omega-3 fatty acids positively impact skeletal muscle mass is via incorporation of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) into membrane phospholipids of the sarcolemma and intracellular organelles. Enrichment of EPA and DHA in these membrane phospholipids is linked to enhanced rates of muscle protein synthesis, decreased expression of factors that regulate muscle protein breakdown, and improved mitochondrial respiration kinetics. However, exactly how incorporation of EPA and DHA into phospholipid membranes alters these processes remains unknown. In this review, we discuss the interaction between omega-3 fatty acid ingestion and skeletal muscle protein turnover in response to nutrient provision in younger and older adults. Additionally, we examine the role of omega-3 fatty acid supplementation in protecting muscle loss during muscle-disuse and in cancer cachexia, and critically evaluate the molecular mechanisms that underpin the phenotypic changes observed in skeletal muscle with omega-3 fatty acid intake.


Lung remodeling and pulmonary hypertension after myocardial infarction: pathogenic role of reduced caveolin expression.
Pulmonary hypertension (PH) and lung structural remodeling are frequent complications of congestive heart failure (CHF). Yet, the molecular mechanisms involved in CHF-induced PH and lung remodeling remain unknown. Caveolins (Cav-1, -2 and -3) are the principal structural proteins of the vesicular invaginations of the plasma membrane, termed caveolae. Mice with homozygous deletion of the caveolin-1 gene (Cav-1(-/-)) have been shown to develop dilated cardiomyopathy, PH and lung structural remodeling, characterized by hypercellularity and thickening of the alveolar septa. However, the physiological relevance of these observations for the pathogenesis of PH and lung remodeling remains to be determined. Here, we investigate the natural behavior of the endogenous caveolin proteins during the development of PH and lung structural remodeling, using a rat model of myocardial infarction (MI). MI was induced in male Wistar rats by ligating the left anterior coronary artery. Two weeks post-MI, rats were anesthetized and hemodynamic and morphometric measurements were obtained. Rats subjected to MI developed marked PH, lung structural remodeling and right ventricular hypertrophy (RVH). Both immunoblot analysis and immunohistochemistry dramatically show that Cav-1 and Cav-2 expression is downregulated to almost undetectable levels in the lungs of post-MI rats. Mechanistically, the reduced expression of caveolins was associated with the increased tyrosine-phosphorylation of the signal transducer and activator of transcription-3 (STAT3) and the upregulation of cyclin D1 and D3 expression. We also show that STAT3 is hyperphosphorylated, and cyclin D1 and D3 levels are dramatically upregulated, in lung tissue samples derived from Cav-1 (-/-)- and Cav-2 (-/-)-deficient mice. Thus, down-modulation of pulmonary Cav-1 and Cav-2 expression in rats subjected to MI may represent an initiating mechanism leading to the activation of the STAT3/Cyclins pathway and, ultimately, to the development of PH and lung structural remodeling.


Assessing the Effects of the New Cooperative Medical Scheme on Alleviating the Health Payment-Induced Poverty in Shaanxi Province, China.
Disease has become one of the key causes of falling into poverty in rural China. The poor households are even more likely to suffer. The New Cooperative Medical Scheme (NCMS) has been implemented to provide rural residents financial protection against health risks. This study aims to assess the effect of the NCMS on alleviating health payment-induced poverty in the Shaanxi Province of China. The data was drawn from the 5th National Health Service Survey of Shaanxi Province, conducted in 2013. In total, 41,037 individuals covered by NCMS were selected. Poverty headcount ratio (HCR), poverty gap and mean positive poverty gap were used for measuring the incidence, depth and intensity of poverty, respectively. The differences on poverty measures pre- and post- insurance reimbursement indicate the effectiveness of alleviating health payment-induced poverty under NCMS. For the general insured, 5.81% of households fell below the national poverty line owing to the health payment; this HCR dropped to 4.84% after insurance reimbursement. The poverty HCRs for the insured that had hospitalization in the past year dropped from 7.50% to 2.09% after reimbursement. With the NCMS compensation, the poverty gap declined from 42.90 Yuan to 34.49 Yuan (19.60% decreased) for the general insured and from 57.48 Yuan to 10.01 Yuan (82.59% decreased) for the hospital admission insured. The mean positive poverty gap declined 3.56% and 37.40% for two samples, respectively. The NCMS could alleviate the health payment-induced poverty. The effectiveness of alleviating health payment-induced poverty is greater for hospital admission insured than for general insured, mainly because NCMS compensates for serious diseases. Our study suggests that a more comprehensive insurance benefit package design could further improve the effectiveness of poverty alleviation.


Validation of EN ISO method 10273 - Detection of pathogenic Yersinia enterocolitica in foods.
EN ISO 10273 method for the detection of pathogenic Yersinia enterocolitica in foods was validated in the project Mandate M/381 funded by European Commission. A total of 14 laboratories from five European countries participated in the interlaboratory study (ILS) organized during 2013 and 2014. Before the ILS, the method was revised by an international group of experts and the performance of the revised method was assessed in an ILS study. The results are published as a part of the standard EN ISO 10273 revision. The study included three rounds with different sample types; raw milk, iceberg lettuce and minced meat, inoculated with a low and high level of pathogenic Y. enterocolitica strains representing major pathogenic bioserotypes 4/O:3 and 2/O:9. The homogeneity and stability of the samples were verified before dispatching them to the laboratories. The results demonstrated the method sensitivity of 96% in raw milk, 97% in minced meat, and 98% in lettuce at high inoculation level of pathogenic Y. enterocolitica. The specificity was 100% in raw milk, 96% in minced meat, and 98% in lettuce. The level of detection, LOD50, varied between study rounds, being 9.4 CFU/25 ml in raw milk, 9.9 CFU/25 g in minced meat and 63 CFU/25 g in lettuce samples. During the study, confirmation by using real-time PCR method ISO/TS 18867 together with pyrazinamidase testing was also validated, as alternative to conventional biochemical confirmation. When comparing different isolation steps used in the revised method during the study rounds, PSB enrichment and plating on CIN after alkaline (KOH) treatment showed the highest sensitivity (52-92%) in raw milk and minced meat samples. In lettuce samples, however, ITC with KOH treatment before plating on CIN showed higher sensitivity (64% at low level; 82% at high level) than plating on CIN from PSB with KOH treatment (44% at low level; 74% at high level). Statistical analysis of different isolation steps supported the use of two enrichment media, PSB and ITC, in the revised method. Recovery of pathogenic Y. enterocolitica on CIN was most efficient after KOH treatment and, based on the analysis, plating on CIN agar without KOH treatment could be left as optional procedure in the method.


Exploring strategies for protein trapping in Drosophila.
The use of fluorescent protein tags has had a huge impact on cell biological studies in virtually every experimental system. Incorporation of coding sequence for fluorescent proteins such as green fluorescent protein (GFP) into genes at their endogenous chromosomal position is especially useful for generating GFP-fusion proteins that provide accurate cellular and subcellular expression data. We tested modifications of a transposon-based protein trap screening procedure in Drosophila to optimize the rate of recovering useful protein traps and their analysis. Transposons carrying the GFP-coding sequence flanked by splice acceptor and donor sequences were mobilized, and new insertions that resulted in production of GFP were captured using an automated embryo sorter. Individual stocks were established, GFP expression was analyzed during oogenesis, and insertion sites were determined by sequencing genomic DNA flanking the insertions. The resulting collection includes lines with protein traps in which GFP was spliced into mRNAs and embedded within endogenous proteins or enhancer traps in which GFP expression depended on splicing into transposon-derived RNA. We report a total of 335 genes associated with protein or enhancer traps and a web-accessible database for viewing molecular information and expression data for these genes.


Mnemonics usage and cognitive decline in age-associated memory impairment.
To determine predictors of cognitive deterioration, the authors performed baseline and 1- to 5-year follow-up (mean +/- SD = 2.5 +/- 1.2 years) neuropsychological assessments on 36 persons (mean age +/- SD = 62.1 +/- 8.0; range = 50 to 81 years) with age-associated memory impairment. Subjects were recruited from a larger group of volunteers, had minimal medical comorbidity, and 25 of them had a family history of Alzheimer's disease. Baseline age and a subjective memory measure indicating reported frequency of mnemonics usage were significant decline predictors. Subjects reporting more frequent mnemonics use at baseline were more likely to show objective cognitive decline at follow-up. Baseline full-scale IQ, educational level, and family history of Alzheimer's disease failed to predict decline. These findings suggest that although age is the strongest decline predictor in some people with age-associated memory impairment, self-perception of memory function may also predict subsequent cognitive loss.


Learning to Hash With Optimized Anchor Embedding for Scalable Retrieval.
Sparse representation and image hashing are powerful tools for data representation and image retrieval respectively. The combinations of these two tools for scalable image retrieval, i.e., sparse hashing (SH) methods, have been proposed in recent years and the preliminary results are promising. The core of those methods is a scheme that can efficiently embed the (high-dimensional) image features into a low-dimensional Hamming space, while preserving the similarity between features. Existing SH methods mostly focus on finding better sparse representations of images in the hash space. We argue that the anchor set utilized in sparse representation is also crucial, which was unfortunately underestimated by the prior art. To this end, we propose a novel SH method that optimizes the integration of the anchors, such that the features can be better embedded and binarized, termed as Sparse Hashing with Optimized Anchor Embedding. The central idea is to push the anchors far from the axis while preserving their relative positions so as to generate similar hashcodes for neighboring features. We formulate this idea as an orthogonality constrained maximization problem and an efficient and novel optimization framework is systematically exploited. Extensive experiments on five benchmark image data sets demonstrate that our method outperforms several state-of-the-art related methods.


Infant stranger fear trajectories predict anxious behaviors and diurnal cortisol rhythm during childhood.
Although a robust literature has linked stable, high levels of fear across childhood to increased risk for anxiety problems, less is known about alternative pathways to anxiety. We tested two putatively normative developmental pathways of early fearfulness for their distinct associations with behavioral (anxiety-related behaviors and symptoms) and biological (diurnal cortisol) markers of anxiety risk in middle childhood in a community-based sample (n = 107). Steeper increases in fear from 6 to 36 months predicted more parent-reported anxiety symptoms at age 8 years. In addition, children who exhibited steep increases in fear during infancy were overrepresented among children with diagnoses of separation anxiety disorder at age 8 years. Finally, we showed that steeper increases in fearfulness in infancy predicted flatter slopes of diurnal cortisol at age 8 years for girls. Thus, differences in stranger fear across infancy may indicate varying degrees of risk for anxious behaviors in later childhood.


Factors enabling advanced practice nursing role integration in Canada.
Although advanced practice nurses (APNs) have existed in Canada for over 40 years and there is abundant evidence of their safety and effectiveness, their full integration into our healthcare system has not been fully realized. For this paper, we drew on pertinent sections of a scoping review of the Canadian literature from 1990 onward and interviews or focus groups with 81 key informants conducted for a decision support synthesis on advanced practice nursing to identify the factors that enable role development and implementation across the three types of APNs: clinical nurse specialists, primary healthcare nurse practitioners and acute care nurse practitioners. For development of advanced practice nursing roles, many of the enabling factors occur at the federal/provincial/territorial (F/P/T) level. They include utilization of a pan-Canadian approach, provision of high-quality education, and development of appropriate legislative and regulatory mechanisms. Systematic planning to guide role development is needed at both the F/P/T and organizational levels. For implementation of advanced practice nursing roles, some of the enabling factors require action at the F/P/T level. They include recruitment and retention, role funding, intra-professional relations between clinical nurse specialists and nurse practitioners, public awareness, national leadership support and role evaluation. Factors requiring action at the level of the organization include role clarity, healthcare setting support, implementation of all role components and continuing education. Finally, inter-professional relations require action at both the F/P/T and organizational levels. A multidisciplinary roundtable formulated policy and practice recommendations based on the synthesis findings, and these are summarized in this paper.


Simulation of tsunamis from great earthquakes on the cascadia subduction zone.
Large earthquakes occur episodically in the Cascadia subduction zone. A numerical model has been used to simulate and assess the hazards of a tsunami generated by a hypothetical earthquake of magnitude 8.5 associated with rupture of the northern sections of the subduction zone. Wave amplitudes on the outer coast are closely related to the magnitude of sea-bottom displacement (5.0 meters). Some amplification, up to a factor of 3, may occur in some coastal embayments. Wave amplitudes in the protected waters of Puget Sound and the Strait of Georgia are predicted to be only about one fifth of those estmated on the outer coast.


Comparative effects of whey protein versus L-leucine on skeletal muscle protein synthesis and markers of ribosome biogenesis following resistance exercise.
We compared immediate post-exercise whey protein (WP, 500 mg) versus L-leucine (LEU, 54 mg) feedings on skeletal muscle protein synthesis (MPS) mechanisms and ribosome biogenesis markers 3 h following unilateral plantarflexor resistance exercise in male, Wistar rats (~250 g). Additionally, in vitro experiments were performed on differentiated C2C12 myotubes to compare nutrient (i.e., WP, LEU) and 'exercise-like' treatments (i.e., caffeine, hydrogen peroxide, and AICAR) on ribosome biogenesis markers. LEU and WP significantly increased phosphorylated-rpS6 (Ser235/236) in the exercised (EX) leg 2.4-fold (P < 0.01) and 2.7-fold (P < 0.001) compared to the non-EX leg, respectively, whereas vehicle-fed control (CTL) did not (+65 %, P > 0.05). Compared to the non-EX leg, MPS levels increased 32 % and 52 % in the EX leg of CTL (P < 0.01) and WP rats (P < 0.001), respectively, but not in LEU rats (+15 %, P > 0.05). Several genes associated with ribosome biogenesis robustly increased in the EX versus non-EX legs of all treatments; specifically, c-Myc mRNA, Nop56 mRNA, Bop1 mRNA, Ncl mRNA, Npm1 mRNA, Fb1 mRNA, and Xpo-5 mRNA. However, only LEU significantly increased 45S pre-rRNA levels in the EX leg (63 %, P < 0.001). In vitro findings confirmed that 'exercise-like' treatments similarly altered markers of ribosome biogenesis, but only LEU increased 47S pre-rRNA levels (P < 0.01). Collectively, our data suggests that resistance exercise, as well as 'exercise-like' signals in vitro, acutely increase the expression of genes associated with ribosome biogenesis independent of nutrient provision. Moreover, while EX with or without WP appears superior for enhancing translational efficiency (i.e., increasing MPS per unit of RNA), LEU administration (or co-administration) may further enhance ribosome biogenesis over prolonged periods with resistance exercise.


Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression.
Several recent papers have now provided compelling experimental evidence that the progression of tumours towards a malignant phenotype does not depend exclusively on the cell-autonomous properties of cancer cells themselves but is also deeply influenced by tumour stroma reactivity, thereby undergoing a strict environmental control. Tumour microenvironmental elements include structural components such as the extracellular matrix or hypoxia as well as stromal cells, either resident cells or recruited from circulating precursors, as macrophages and other inflammatory cells, endothelial cells and cancer-associated fibroblasts (CAFs). All these elements synergistically play a specific role in cancer progression. This review summarizes our current knowledge on the role of CAFs in tumour progression, with a particular focus on the biunivocal interplay between CAFs and cancer cells leading to the activation of the epithelial-mesenchymal transition programme and the achievement of stem cell traits, as well as to the metabolic reprogramming of both stromal and cancer cells. Recent advances on the role of CAFs in the preparation of metastatic niche, as well as the controversial origin of CAFs, are discussed in light of the new emerging therapeutic implications of targeting CAFs.


Should children be in the room when the mother is screened for partner violence?
The goal of our study was to understand the important issues to consider when screening women for intimate partner violence in front of their children. Interviews and focus groups were conducted with experienced family physicians and pediatricians and family violence experts (child psychologists, social workers, and domestic violence agency directors). Session transcripts were coded and categorized. Experts disagreed on the appropriateness of general screening for intimate partner violence in front of children older than 2 to 3 years. The majority thought that general questions were appropriate, if the in-depth questioning of the abused parent was done in private. Screening for child abuse when domestic violence is identified (and for domestic violence when child abuse is discovered) was recommended. Documentation about intimate partner violence in the child's medical chart raises questions about confidentiality, since the person committing the abuse may have access, if he or she is a legal guardian. Physicians need more education on the symptoms of children who are exposed to violence between adults. More research is needed to understand appropriate questions and methods of screening for intimate partner violence in front of children. The tension is between practical recommendations for routine screening and preserving the safety of the parent and the children. Intimate partner violence screening by physicians is important. Interrupting the cycle of violence may give a child a better chance at maturing into a healthy adult.


Police officers' views of their encounters with people with personality disorder.
In Australia, people experiencing personality disorder have featured little in policing studies and policy or mental health policy and legislation, and in the absence of specific guidance their behaviours represent an ongoing challenge for police. This paper presents police officers' accounts from a qualitative research project that explored police encounters with people experiencing mental illness. The officers singled out people with personality disorder and expressed frustration, anger, powerlessness and resignation with their referrals of this group to health services. Officers reported that emergency departments were reluctant to assess people with personality disorder and when they did assess them stated that the person did not meet criteria for admission to mental health services, or if admitted, they were quickly discharged. People with personality disorder were reported to take up considerable police resources. When police were told by mental health professionals that there was nothing they could do about people experiencing personality disorder, then the question from police was what was to be done with them. While pockets of collaborative practice exist between police and mental health services, much change is required to demonstrate that the needs of the person with personality disorder are being met.


Role of interleukin 2 (IL 2) and hemopoietin-1 (H-1) in the generation of mouse natural killer (NK) cells from primitive bone marrow precursors.
The development of natural killer (NK) cells from bone marrow (BM) precursors was studied. Recombinant interleukin 2 (IL 2) was able to induce the in vitro development of NK cells when added to cultures of mouse BM cells. Treatment of donor mice with 5-fluorouracil (150 mg/kg i.v.), which eliminates more differentiated cells but spares less differentiated cells, appears to augment NK cell development. The "NK stem cell" was found to be asialo GM1-, Thy-1+, Lyt-2-, and Lyt-1-. The cells generated in vitro had a typical phenotype of NK cells, being asialo GM1+, Lyt-5+, Thy-1+, Lyt-2-, and Lyt-1-. These effector cells also had specificity characteristics of NK cells lysing the NK-susceptible YAC-1 and K562 targets, but not the NK-resistant EL/4 or allogeneic and syngeneic blasts. Hemopoietin-1 (H-1), a factor which acts on very primitive multipotent BM cells, was able to cooperate with IL 2, increasing the development of NK cells. In contrast, other factors such as interleukin 3 or colony-stimulating factor did not cause induction of NK activity when added to cultures of BM cells, indicating that this effect, i.e., induction of NK cell development, is peculiar to IL 2. These results indicate that IL 2 can act as a differentiation as well as growth factor for NK cells, and that H-1 can promote the development of functional activity in a lymphocyte subpopulation as well as affect the differentiation of myelomonocytic and other cell lineages. This experimental system appears quite useful for characterization of BM precursors for NK cells, and should help to better understand the relationship of the NK cell lineage to the T cell or other lineages.


The association between dietary protein intake, energy intake and physical frailty: results from the Rotterdam Study.
Sufficient protein intake has been suggested to be important for preventing physical frailty, but studies show conflicting results which may be explained because not all studies address protein source and intake of other macronutrients and total energy. Therefore, we studied 2504 subjects with data on diet and physical frailty, participating in a large population-based prospective cohort among subjects aged 45+ years (the Rotterdam Study). Dietary intake was assessed with a FFQ. Frailty was defined according to the frailty phenotype as the presence of at least three out of the following five symptoms: weight loss, low physical activity, weakness, slowness and fatigue. We used multinomial logistic regression models to evaluate the independent association between protein intake and frailty using two methods: nutrient residual models and energy decomposition models. With every increase in 10 g total, plant or animal protein per d, the odds to be frail were 1·06 (95 % CI 0·98, 1·15), 0·87 (95 % CI 0·71, 1·07) and 1·07 (95 % CI 0·99, 1·15), respectively, using the nutrient residual method. Using the energy partition model, we observed that the odds to be frail were lower with higher vegetable protein intake (OR per 418·4 kJ (100 kcal): 0·61, 95 % CI 0·39, 0·97), however, results disappeared when adjusting for physical activity. For energy intake from any source we observed that with every 418·4 kJ (100 kcal) increase, the odds to be frail were 5 % lower (OR: 0·95, 95 % CI 0·93, 0·97). Our results suggest that energy intake, but not protein specifically, is associated with less frailty. Considering other macronutrients, physical activity and diet quality seems to be essential for future studies on protein and frailty.


Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants.
Acute intermittent porphyria (AIP) is a disorder of the haem biosynthetic pathway caused by mutations in the hydroxymethylbilane synthase (HMBS) gene. Knowledge of the spectrum of mutations present in South Africa is limited. This study presents the molecular profile of 20 South African patients with AIP, and the kinetic analysis of one novel expressed mutated HMBS enzyme and a previously identified mutation at the same position. Genomic DNA was isolated from affected probands and selected family members, the HMBS gene amplified and mutations characterised by direct sequencing and restriction enzyme analysis. One of the novel mutations (p.Lys98Glu), a previously characterised mutation at the same position (p.Lys98Arg), and the wild-type enzyme were expressed, purified and subjected to partial kinetic characterisation. Four new mutations, p.Lys98Glu, p.Asp230Aspfs*20, c.161-1G>A and c.422+3_6delAAGT, are described. Seven previously described mutations were found, while four patients revealed no mutations. Mutation analysis of five offspring of one of the probands carrying the p.Trp283X mutation revealed two asymptomatic carriers. Kinetic analysis showed that the p.Lys98Glu mutation results in loss of substrate affinity, whereas the previously described p.Lys98Arg mutation causes the loss of binding between the enzyme and its dipyrromethane cofactor, rendering the enzyme inactive. This study comprises the most comprehensive characterisation of HMBS gene mutations in patients with AIP in South Africa. The biochemical characterisation of expressed HMBS mutants reveals insight into the mechanism of catalytic activity loss, which may inspire investigation into individualised therapy based on the molecular lesion identified.


Does experience matter? A comparison of the practice of attendings and residents.
To compare the utilization of health care resources and patterns of chronic disease care by patients of medical residents and patients of their attending physicians. This study involved a longitudinal cohort of 14,554 patients seen over a 1-year period by 149 residents and 36 attendings located in an urban academic medical center. Data were acquired prospectively through a practice management system used to order tests, write prescriptions, and code ambulatory visits. We assessed resource utilization by measuring the total direct costs of care over a 1-year period, including ambulatory and inpatient costs, and the numbers and types of resources used. Residents' patients were similar to attendings' patients in age and gender, but residents' patients were more likely to have Medicaid or Medicare and to have a higher burden of comorbidity. Total annual ambulatory care costs were almost 60% higher for residents' patients than for attendings' patients in unadjusted analyses, and 30% higher in analyses adjusted for differences in case mix (adjusted mean 888 dollars vs 750 dollars; P=.0001). The primary cost drivers on the outpatient side were consultations and radiological procedures. Total inpatient costs were almost twice as high for residents' patients compared to attendings' patients in unadjusted analyses, but virtually identical in analyses adjusted for case mix differences (adjusted mean of 849 dollars vs 860 dollars). Admission rates were almost double for residents' patients. Total adjusted costs for residents' patients were slightly, but not significantly, higher than for attendings' patients (adjusted mean 1,651 dollars vs 1,540 dollars; P>.05). Residents' and attendings' patients generally did not differ in the patterns of care for diabetes, asthma/chronic obstructive pulmonary disease (COPD), congestive heart failure, ischemic heart disease, and depression, except that residents' patients with asthma/COPD, ischemic heart disease, and diabetes were admitted more frequently than attendings' patients. Our results indicate that residents' patients had higher costs than attendings' patients, but the differences would have been seriously overestimated without adjustment. We conclude that it costs about 7% more for residents to manage patients than for attendings. On the ambulatory side, the larger number of procedures and consults ordered for residents' patients appears to drive the higher costs.


Mediterranean diet and non enzymatic antioxidant capacity in the PREDIMED study: evidence for a mechanism of antioxidant tuning.
The intake of antioxidant-rich foods may increase the blood levels of non enzymatic antioxidant capacity (NEAC). NEAC takes into account all antioxidants from food and synergistic effects between them. We examined the effect of a 1-year intervention with Mediterranean diet on plasma NEAC and assessed whether it was related to baseline NEAC levels. Five hundred sixty-four participants at high cardiovascular risk were randomly selected from the PREDIMED (Prevención con DIeta MEDiterránea) Study, a large 3-arm randomized clinical trial. Blood NEAC levels were measured at baseline and after 1-year of dietary intervention with 1) a Mediterranean diet supplemented with virgin olive oil (MED + VOO); 2) a Mediterranean diet supplemented with nuts (MED + nuts), or 3) a control low-fat diet. Plasma NEAC was analyzed using FRAP (ferric reducing antioxidant potential) and TRAP (total radical-trapping antioxidant parameter) assays. Plasma FRAP levels increased after 1-year of intervention with MED + VOO [72.0 μmol/L (95% CI, 34.2-109.9)] and MED + nuts [48.9 μmol/L (24.3-73.5)], but not after the control low-fat diet [13.9 μmol/L (-11.9 to 39.8)]. Participants in the lowest quartile of plasma FRAP at baseline significantly increased their levels after any intervention, while those in the highest quartile decreased. Similar results occurred with TRAP levels. This study shows that a 1-year of MED diet intervention increases plasma TAC level in subjects at high risk for cardiovascular disease. Moreover, the effectiveness of dietary supplementation with antioxidants may be related to baseline levels of plasma NEAC.


Response to infliximab in SAPHO syndrome.
Infliximab has become increasingly important in the treatment of SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome. There is, however, little experience with this biological agent, and treatment protocols usually follow the regimens for spondylarthropathies. We report a patient with a highly unusual and severe clinical presentation of SAPHO syndrome including widespread bone and skin disease, and collagenous colitis. Infliximab treatment (5 mg/kg) given at weeks 0, 2 and 6 and every 8 weeks thereafter, induced rapid remission of the osteoarticular symptoms, although the skin lesions improved only partially, and after 10 months continuous therapy with infliximab a bone scan even uncovered new active bone lesions. Collagenous colitis is unresponsive to tumour necrosis factor α (TNFα) blocking agents. This moderate response to infliximab may indicate that a more aggressive treatment protocol is mandatory. We further believe that remission of osteoarticular complaints should be routinely confirmed by scintigraphic findings to verify treatment response.


The Association between the Perceived Adequacy of Workplace Infection Control Procedures and Personal Protective Equipment with Mental Health Symptoms: A Cross-sectional Survey of Canadian Health-care Workers during the COVID-19 Pandemic: L'association entre le caractère adéquat perçu des procédures de contrôle des infections au travail et de l'équipement de protection personnel pour les symptômes de santé mentale. Un sondage transversal des travailleurs de la santé canadiens durant la pandémie COVID-19.
To examine the relationship between perceived adequacy of personal protective equipment (PPE) and workplace-based infection control procedures (ICP) and mental health symptoms among a sample of health-care workers in Canada within the context of the current COVID-19 pandemic. A convenience-based internet survey of health-care workers in Canada was facilitated through various labor organizations between April 7 and May 13, 2020. A total of 7,298 respondents started the survey, of which 5,988 reported information on the main exposures and outcomes. Anxiety symptoms were assessed using the Generalized Anxiety Disorder (GAD-2) screener, and depression symptoms using the Patient Health Questionnaire (PHQ-2) screener. We assessed the perceived need and adequacy of 8 types of PPE and 10 different ICP. Regression analyses examined the proportion of GAD-2 and PHQ-2 scores of 3 and higher across levels of PPE and ICP, adjusted for a range of demographic, occupation, workplace, and COVID-19-specific measures. A total of 54.8% (95% confidence interval [CI], 53.5% to 56.1%) of the sample had GAD-2 scores of 3 and higher, and 42.3% (95% CI, 41.0% to 43.6%) of the sample had PHQ-2 scores of 3 and higher. Absolute differences of 18% (95% CI, 12% to 23%) and 17% (95% CI, 12% to 22%) were observed in the prevalence of GAD-2 scores of 3 and higher between workers whose perceived PPE needs and ICP needs were met compared to those who needs were not met. Differences of between 11% (95% CI, 6% to 17%) and 19% (95% CI, 14% to 24%) were observed in PHQ-2 scores of 3 and higher across these same PPE and ICP categories. Our results suggest strengthening employer-based infection control strategies likely has important implications for the mental health symptoms among health-care workers in Canada.


Anti-apoptotic BCL-2 family proteins in acute neural injury.
Cells under stress activate cell survival and cell death signaling pathways. Cell death signaling frequently converges on mitochondria, a process that is controlled by the activities of pro- and anti-apoptotic B-cell lymphoma 2 (BCL-2) proteins. In this review, we summarize current knowledge on the control of neuronal survival, development and injury by anti-apoptotic BCL-2 family proteins. We discuss overlapping and differential effects of the individual family members BCL-2, BCL-extra long (BCL-XL), myeloid cell leukemia 1 (MCL-1), and BCL2-like 2 (BCL-W) in the control of survival during development and pathophysiological processes such as trophic factor withdrawal, ischemic injury, excitotoxicity, oxidative stress and energy stress. Finally we discuss recent evidence that several anti-apoptotic BCL-2 proteins influence mitochondrial bioenergetics and control neuronal Ca(2+) homeostasis independent of their classical role in cell death signaling.


The Interaction between Lockdown-Specific Conditions and Family-Specific Variables Explains the Presence of Child Insomnia during COVID-19: A Key Response to the Current Debate.
It is still debated whether lockdown conditions in response to the coronavirus disease 2019 (COVID-19) health crisis seriously affected children's sleep. For young children, some studies identified more insomnia, while others only transient disturbances, or even no effect. Based on the premise of mother-child synchrony, a well-known dynamic established in child development research, we hypothesized that principally, the children whose mothers perceived the lockdown as stressful and/or responded maladaptively, suffered sleep disturbances. The main objective of this study was to identify the family profiles, variables, and lockdown responses most linked to insomnia in young children. The sample consisted of 165 mothers, French vs. Swiss origin (accounting for different lockdown severities), of children 6 months to 5 years old. Validated sleep, stress, and behavior scales were used. Multiple regression, age-matched clustering, and structural equation modeling analyses provided evidence that insomnia in young children is indeed strongly linked to the mother's reaction to the pandemic and lockdown. Specifically, reactions such as COVID-19 fear/anxiety and obsessive COVID-19 information seeking coincide with heightened vigilance, cascading into reduced child social contact, outings, and increased screen viewing, ultimately culminating in child insomnia and behavioral problems. Mother education level and child day care quality (e.g., home-schooling) were also identified as strong insomnia predictors.


Health impact assessment of cycling network expansions in European cities.
We conducted a health impact assessment (HIA) of cycling network expansions in seven European cities. We modeled the association between cycling network length and cycling mode share and estimated health impacts of the expansion of cycling networks. First, we performed a non-linear least square regression to assess the relationship between cycling network length and cycling mode share for 167 European cities. Second, we conducted a quantitative HIA for the seven cities of different scenarios (S) assessing how an expansion of the cycling network [i.e. 10% (S1); 50% (S2); 100% (S3), and all-streets (S4)] would lead to an increase in cycling mode share and estimated mortality impacts thereof. We quantified mortality impacts for changes in physical activity, air pollution and traffic incidents. Third, we conducted a cost-benefit analysis. The cycling network length was associated with a cycling mode share of up to 24.7% in European cities. The all-streets scenario (S4) produced greatest benefits through increases in cycling for London with 1,210 premature deaths (95% CI: 447-1,972) avoidable annually, followed by Rome (433; 95% CI: 170-695), Barcelona (248; 95% CI: 86-410), Vienna (146; 95% CI: 40-252), Zurich (58; 95% CI: 16-100) and Antwerp (7; 95% CI: 3-11). The largest cost-benefit ratios were found for the 10% increase in cycling networks (S1). If all 167 European cities achieved a cycling mode share of 24.7% over 10,000 premature deaths could be avoided annually. In European cities, expansions of cycling networks were associated with increases in cycling and estimated to provide health and economic benefits.


CT-Screening for lung cancer does not increase the use of anxiolytic or antidepressant medication.
CT screening for lung cancer has recently been shown to reduce lung cancer mortality, but screening may have adverse mental health effects. We calculated risk ratios for prescription of anti-depressive (AD) or anxiolytic (AX) medication redeemed at Danish pharmacies for participants in The Danish Lung Cancer Screening Trial (DLCST). The DLCST was a randomized clinical trial which comprised 4,104 former or present smokers who were randomized from 12 May 2004 to 20 June 2006 to either CT scan of the chest, lung-function test and filling in questionnaires annually for five years in the period 1 April 2006-31 March 2010 (n = 2,052), or to a control group (n = 2,052) receiving similar procedures except CT scan. We used CT scan intervention group versus control group status as exposure. The follow-up period for use of AD or AX was three years. Baseline data on civil status, socioeconomic status, and co-morbidity as well as outcome data on AD and AX were obtained by linkage to national registries. The intervention and the control groups did not differ by age, gender, civil status, socio-economic position, co-morbidity index or former use of AD or AX. The adjusted risk ratio for at least one recipe of AD or AX in the CT intervention group during follow-up was not increased when adjusting for previous use of AD or AX, HR 1.00, 95 % CI (0.90-1.12). Similar results were seen when excluding subjects using AD or AX in a four-month or two-year period before baseline, when analyzing AD and AX separately, or requiring at least two recipes. We found no indications that participation in a lung cancer CT-screening program increases the risk of specific adverse mental health outcomes. Clinical Trials.gov Protocol Registration System (NCT00496977).


Modulation of Theta-Band Local Field Potential Oscillations Across Brain Networks With Central Thalamic Deep Brain Stimulation to Enhance Spatial Working Memory.
Deep brain stimulation (DBS) is a well-established technique for the treatment of movement and psychiatric disorders through the modulation of neural oscillatory activity and synaptic plasticity. The central thalamus (CT) has been indicated as a potential target for stimulation to enhance memory. However, the mechanisms underlying local field potential (LFP) oscillations and memory enhancement by CT-DBS remain unknown. In this study, we used CT-DBS to investigate the mechanisms underlying the changes in oscillatory communication between the CT and hippocampus, both of which are involved in spatial working memory. Local field potentials (LFPs) were recorded from microelectrode array implanted in the CT, dentate gyrus, cornu ammonis (CA) region 1, and CA region 3. Functional connectivity (FC) strength was assessed by LFP-LFP coherence calculations for these brain regions. In addition, a T-maze behavioral task using a rat model was performed to assess the performance of spatial working memory. In DBS group, our results revealed that theta oscillations significantly increased in the CT and hippocampus compared with that in sham controls. As indicated by coherence, the FC between the CT and hippocampus significantly increased in the theta band after CT-DBS. Moreover, Western blotting showed that the protein expressions of the dopamine D1 and α4-nicotinic acetylcholine receptors were enhanced, whereas that of the dopamine D2 receptor decreased in the DBS group. In conclusion, the use of CT-DBS resulted in elevated theta oscillations, increased FC between the CT and hippocampus, and altered synaptic plasticity in the hippocampus, suggesting that CT-DBS is an effective approach for improving spatial working memory.


Updates in Management and Timing of Dialysis in Acute Kidney Injury.
Acute kidney injury (AKI) is a common complication in hospitalized patients and is associated with mortality, prolonged hospital length of stay, and increased healthcare costs. This paper reviews several areas of controversy in the identification and management of AKI. Serum creatinine and urine output are used to identify and stage AKI by severity. Although standardized definitions of AKI are used in research settings, these definitions do not account for individual patient factors or clinical context which are necessary components in the assessment of AKI. After treatment of reversible causes of AKI, patients with AKI should receive adequate volume resuscitation with crystalloid solutions. Balanced crystalloid solutions generally prevent severe hyperchloremia and could potentially reduce the risk of AKI, but additional studies are needed to demonstrate a clinical benefit. Intravenous albumin may be beneficial in patients with chronic liver disease either to prevent or attenuate the severity of AKI; otherwise, the use of albumin or other colloids (eg, hydroxyethyl starch) is not recommended. Diuretics should be used to treat volume overload, but they do not facilitate AKI recovery or reduce mortality. Nutrition consultation may be helpful to ensure that patients receive adequate, but not excessive, dietary protein intake, as the latter can lead to azotemia and electrolyte disturbances disproportionate to the patient's kidney failure. The optimal timing of dialysis initiation in AKI remains controversial, with conflicting results from two randomized controlled trials.