Nanoscale Patterning of Extracellular Matrix Alters Endothelial Function under Shear Stress.
The role of nanotopographical extracellular matrix (ECM) cues in vascular endothelial cell (EC) organization and function is not well-understood, despite the composition of nano- to microscale fibrillar ECMs within blood vessels. Instead, the predominant modulator of EC organization and function is traditionally thought to be hemodynamic shear stress, in which uniform shear stress induces parallel-alignment of ECs with anti-inflammatory function, whereas disturbed flow induces a disorganized configuration with pro-inflammatory function. Since shear stress acts on ECs by applying a mechanical force concomitant with inducing spatial patterning of the cells, we sought to decouple the effects of shear stress using parallel-aligned nanofibrillar collagen films that induce parallel EC alignment prior to stimulation with disturbed flow resulting from spatial wall shear stress gradients. Using real time live-cell imaging, we tracked the alignment, migration trajectories, proliferation, and anti-inflammatory behavior of ECs when they were cultured on parallel-aligned or randomly oriented nanofibrillar films. Intriguingly, ECs cultured on aligned nanofibrillar films remained well-aligned and migrated predominantly along the direction of aligned nanofibrils, despite exposure to shear stress orthogonal to the direction of the aligned nanofibrils. Furthermore, in stark contrast to ECs cultured on randomly oriented films, ECs on aligned nanofibrillar films exposed to disturbed flow had significantly reduced inflammation and proliferation, while maintaining intact intercellular junctions. This work reveals fundamental insights into the importance of nanoscale ECM interactions in the maintenance of endothelial function. Importantly, it provides new insight into how ECs respond to opposing cues derived from nanotopography and mechanical shear force and has strong implications in the design of polymeric conduits and bioengineered tissues.


Evaluation of nonradioactive, colored microspheres for measurement of regional myocardial blood flow in dogs.
Measurement of regional myocardial blood flow (RMBF) is crucial in experimental studies of myocardial ischemia and reperfusion in dogs. The standard measurement technique uses radioactive microspheres; however, not all institutions are able to dispose of radioactive waste and therefore cannot make use of this method. We tested a new, nonradioactive microsphere, labeled with colors instead of nuclides. Simultaneous blood flow measurements with two nuclide-labeled and two colored microspheres were performed after coronary occlusion in dogs. Both techniques show a within-method correlation of r greater than 0.98. Duplicate variability for paired RMBF values in 80 samples was 8.7 +/- 0.1% when computed with radioactive microspheres and 13.2 +/- 1.8% when computed with colored microspheres. There was a good correlation in the measurement of RMBF between the radioactive- and colored-microsphere methods (r = 0.98). The best-fitting linear regression line was expressed by the formula: Colored-microsphere RMBF = 1.11 (radioactive-microsphere RMBF)-0.02. When measured by colored microspheres, RMBF was approximately 8% higher than when computed with radioactive microspheres for blood flow values of 0-2 ml/min/g. When blood flow was increased pharmacologically to levels of 2-7.5 ml/min/g, colored microspheres yielded blood flow values 39% higher than the values computed by radioactive microspheres. We conclude that the nonradioactive, colored-microsphere method correlates with the radioactive technique, but at high flows, it yields values greater than those obtained with radioactive microspheres.


Weed risk assessment for aquatic plants: modification of a New Zealand system for the United States.
We tested the accuracy of an invasive aquatic plant risk assessment system in the United States that we modified from a system originally developed by New Zealand's Biosecurity Program. The US system is comprised of 38 questions that address biological, historical, and environmental tolerance traits. Values associated with each response are summed to produce a total score for each species that indicates its risk of invasion. To calibrate and test this risk assessment, we identified 39 aquatic plant species that are major invaders in the continental US, 31 species that have naturalized but have no documented impacts (minor invaders), and 60 that have been introduced but have not established. These species represent 55 families and span all aquatic plant growth forms. We found sufficient information to assess all but three of these species. When the results are compared to the known invasiveness of the species, major invaders are distinguished from minor and non-invaders with 91% accuracy. Using this approach, the US aquatic weed risk assessment correctly identifies major invaders 85%, and non-invaders 98%, of the time. Model validation using an additional 10 non-invaders and 10 invaders resulted in 100% accuracy for the former, and 80% accuracy for the latter group. Accuracy was further improved to an average of 91% for all groups when the 17% of species with scores of 31-39 required further evaluation prior to risk classification. The high accuracy with which we can distinguish non-invaders from harmful invaders suggests that this tool provides a feasible, pro-active system for pre-import screening of aquatic plants in the US, and may have additional utility for prioritizing management efforts of established species.


The Chlamydia type III secretion system C-ring engages a chaperone-effector protein complex.
In Gram-negative bacterial pathogens, specialized chaperones bind to secreted effector proteins and maintain them in a partially unfolded form competent for translocation by type III secretion systems/injectisomes. How diverse sets of effector-chaperone complexes are recognized by injectisomes is unclear. Here we describe a new mechanism of effector-chaperone recognition by the Chlamydia injectisome, a unique and ancestral line of these evolutionarily conserved secretion systems. By yeast two-hybrid analysis we identified networks of Chlamydia-specific proteins that interacted with the basal structure of the injectisome, including two hubs of protein-protein interactions that linked known secreted effector proteins to CdsQ, the putative cytoplasmic C-ring component of the secretion apparatus. One of these protein-interaction hubs is defined by Ct260/Mcsc (Multiple cargo secretion chaperone). Mcsc binds to and stabilizes at least two secreted hydrophobic proteins, Cap1 and Ct618, that localize to the membrane of the pathogenic vacuole ("inclusion"). The resulting complexes bind to CdsQ, suggesting that in Chlamydia, the C-ring of the injectisome mediates the recognition of a subset of inclusion membrane proteins in complex with their chaperone. The selective recognition of inclusion membrane proteins by chaperones may provide a mechanism to co-ordinate the translocation of subsets of inclusion membrane proteins at different stages in infection.


Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors.
HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8-11.1] months. In HER2-mutant non-small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1-14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors. SIGNIFICANCE: T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627.


The predictive value of high sensitivity-troponin velocity within the first 6h of presentation for cardiac outcomes regardless of acute coronary syndrome diagnosis.
Low-range troponin elevations without clear coronary manifestations remain a major diagnostic challenge. We sought to determine if troponin velocity could allow for early identification of patients without an obvious cardiac diagnosis and who are at increased risk for cardiac-specific events. All patients presenting to South Australian public hospitals between 1 September 2011 and 30 September 2012, with at least two troponin measurements during the first 6h after ED presentation were included. Diagnoses were classified as 'coronary', 'non-coronary cardiac', and 'non-cardiac' using the International Classification of Diseases 10 codes. The relationship between troponin velocity and cardiac-specific mortality and combined cardiac outcome (death and myocardial infarction) was assessed using Fine and Gray competing risk models in patients with an initial troponin <52 ng/L. Sensitivity analyses were performed using different initial and maximum troponin cut-off values. In total, 7300 patients were identified. A troponin velocity of 2.5 ng/L/h or greater in the non-cardiac (n=2793) patient group was significantly associated with an increased risk for 12-month cardiac mortality (sub-hazard ratio [SHR] 2.90, 95% CI 1.33-6.34) and combined cardiac outcome (SHR 2.08, 95% CI 1.01-4.27). This association was consistent for coronary (n=3835) and non-coronary cardiac (n=672) patient groups, and remained after sensitivity analyses. The significant association observed across all patient groups suggests that troponin velocity could be used for early risk stratification of patients with low-range troponin elevations without clear cardiac symptoms. These results may help guide future clinical trials aimed at assessing the utility of cardiac-targeted interventions in this challenging patient population.


Overexpression of the 78-kDa glucose-regulated protein/immunoglobulin-binding protein (GRP78/BiP) inhibits tissue factor procoagulant activity.
Previous studies have demonstrated that overexpression of GRP78/BiP, an endoplasmic reticulum (ER)-resident molecular chaperone, in mammalian cells inhibits the secretion of specific coagulation factors. However, the effects of GRP78/BiP on activation of the coagulation cascade leading to thrombin generation are not known. In this study, we examined whether GRP78/BiP overexpression mediates cell surface thrombin generation in a human bladder cancer cell line T24/83 having prothrombotic characteristics. We report here that cells overexpressing GRP78/BiP exhibited significant decreases in cell surface-mediated thrombin generation, prothrombin consumption and the formation of thrombin-inhibitor complexes, compared with wild-type or vector-transfected cells. This effect was attributed to the ability of GRP78/BiP to inhibit cell surface tissue factor (TF) procoagulant activity (PCA) because conversion of factor X to Xa and factor VII to VIIa were significantly lower on the surface of GRP78/BiP-overexpressing cells. The additional findings that (i) cell surface factor Xa generation was inhibited in the absence of factor VIIa and (ii) TF PCA was inhibited by a neutralizing antibody to human TF suggests that thrombin generation is mediated exclusively by TF. GRP78/BiP overexpression did not decrease cell surface levels of TF, suggesting that the inhibition in TF PCA does not result from retention of TF in the ER by GRP78/BiP. The additional observations that both adenovirus-mediated and stable GRP78/BiP overexpression attenuated TF PCA stimulated by ionomycin or hydrogen peroxide suggest that GRP78/BiP indirectly alters TF PCA through a mechanism involving cellular Ca(2+) and/or oxidative stress. Similar results were also observed in human aortic smooth muscle cells transfected with the GRP78/BiP adenovirus. Taken together, these findings demonstrate that overexpression of GRP78/BiP decreases thrombin generation by inhibiting cell surface TF PCA, thereby suppressing the prothrombotic potential of cells.


Death from uveal melanoma. Number of epithelioid cells and inverse SD of nucleolar area as prognostic factors.
Criteria for the Callender classification of uveal melanoma are subjective and lead to variations among observers of the same tumor. Two other measures for cell type-the number of epithelioid cells per high-power field (Epi/HPF) and the inverse SD of nucleolar area (ISDNA)-were evaluated as prognostic factors for survival following enucleation for uveal melanoma in 232 patients. Variables significantly related to the number of Epi/HPF were related to ISDNA. Larger, more anteriorly located tumors had a high number of Epi/HPF and a low ISDNA. The two measures were also correlated. Using Kaplan-Meier survival analysis, both measures were related to tumor deaths. Worse prognosis was associated with a higher number of Epi/HPF and a lower ISDNA. Considered together in Cox' proportional hazards analysis, both measures independently predicted outcome. Separately, each measure predicted uveal melanoma-related deaths, in combination with largest tumor dimension, invasion of tumor to the line of transection, and location of the anterior tumor margin. Although ISDNA is the more objective measure of cell type, its practicality compared with other measures of cell type must also be considered.


The apical ectodermal ridge of the mouse model of ectrodactyly Dlx5;Dlx6-/- shows altered stratification and cell polarity, which are restored by exogenous Wnt5a ligand.
The congenital malformation split hand/foot (SHFM) is characterized by missing central fingers and dysmorphology or fusion of the remaining ones. Type-1 SHFM is linked to deletions/rearrangements of the DLX5-DLX6 locus and point mutations in the DLX5 gene. The ectrodactyly phenotype is reproduced in mice by the double knockout (DKO) of Dlx5 and Dlx6. During limb development, the apical ectodermal ridge (AER) is a key-signaling center responsible for early proximal-distal growth and patterning. In Dlx5;6 DKO hindlimbs, the central wedge of the AER loses multilayered organization and shows down-regulation of FGF8 and Dlx2. In search for the mechanism, we examined the non-canonical Wnt signaling, considering that Dwnt-5 is a target of distalless in Drosophila and the knockout of Wnt5, Ryk, Ror2 and Vangl2 in the mouse causes severe limb malformations. We found that in Dlx5;6 DKO limbs, the AER expresses lower levels of Wnt5a, shows scattered β-catenin responsive cells and altered basolateral and planar cell polarity (PCP). The addition of Wnt5a to cultured embryonic limbs restored the expression of AER markers and its stratification. Conversely, the inhibition of the PCP molecule c-jun N-terminal kinase caused a loss of AER marker expression. In vitro, the addition of Wnt5a on mixed primary cultures of embryonic ectoderm and mesenchyme was able to confer re-polarization. We conclude that the Dlx-related ectrodactyly defect is associated with the loss of basoapical and PCP, due to reduced Wnt5a expression and that the restoration of the Wnt5a level is sufficient to partially reverts AER misorganization and dysmorphology.


Neisseria meningitis GNA1030 is a ubiquinone-8 binding protein.
Bexsero, a new vaccine against Neisseria meningitidis serogroup B (MenB), is composed of 3 main recombinant proteins and an outer membrane vesicle component. One of the main bactericidal antigens, neisseria heparin binding antigen (NHBA), is present as a fusion protein with the accessory protein genome-derived neisserial antigen (GNA) 1030 to further increase its immunogenicity. The gene encoding for GNA1030 is present and highly conserved in all Neisseria strains, and although orthologs are present in numerous species, its biologic function is unknown. Native mass spectrometry was used to demonstrate that GNA1030 forms a homodimer associated with 2 molecules of ubiquinone-8 (Ub8), a cofactor mainly involved in the electron transport chain and with antioxidant properties. Disc diffusion assays on the wild-type and knockout mutant of GNA1030, in the presence of various compounds, suggested that GNA1030 is not involved in oxidative stress or electron chain transport per se, although it contributes to constitutive refilling of the inner membrane with Ub8. These studies shed light on an accessory protein present in Bexsero and reveal functional insights into the family of related proteins. On the basis of our findings, we propose to name the protein neisseria ubiquinone binding protein (NUbp).


Anti-Tumour Necrosis Factor Therapy for Inflammatory Bowel Diseases Do Not Impact Serious Infections after Arthroplasty.
There is a paucity of data on the safety of joint replacement surgery in patients with inflammatory bowel disease [IBD], including those on tumour necrosis factor-alpha inhibitors [anti-TNF]. We explored the risk of serious infections in this population. A retrospective case-control study [2006-2014] was performed using the MarketScan Database. All patients aged 18-64 years with an International Classification of Diseases code for IBD and an IBD-specific medication, with ≥ 6 months of enrollment prior to hip, knee or shoulder replacement surgery, were included. Ten non-IBD controls were frequency-matched to each case on length of enrollment, year and the joint replaced. Primary outcome was serious infection [composite of joint infection, surgical site infection, pneumonia, sepsis] within 90 days of the operation. Cox proportional hazards models were used to assess the association of IBD and IBD medications with serious infection. More patients with IBD [N = 1455] had serious infections than controls [3.2% vs 2.3%, p = 0.04], but not after controlling for comorbidities (hazard ratio [HR], 1.3; 95% confidence interval [CI], 0.95-1.76). Among IBD patients, corticosteroids were associated with increased risk of serious infection [HR, 4.6; 95% CI, 2.2-9.8; p < 0.01] while anti-TNFs were not. Opioids were also associated with increased risk of infection [HR, 1.5; 95% CI, 1.2-1.8; p < 0.01]. After controlling for comorbidities, IBD patients were not at increased risk of serious infection following joint replacement. Corticosteroids, but not anti-TNFs or immunomodulators, were associated with increased risk of serious infections in IBD patients.


The effects of delayed puberty on the growth plate.
Many athletes are beginning intense training before puberty, a time of increased bone accrual when up to 25% of total bone mineral accrual occurs. Female athletes experiencing late or delayed pubertal onset may have open epiphyseal plates that are vulnerable to injury. This investigation's purpose was to determine whether a delay in puberty (primary amenorrhea) affects the growth plate immediately postpuberty and at maturity. Forty-eight female Sprague-Dawley rats (23 d old) were randomly assigned to 4 groups (n=12); short-term control (C-ST), long-term control (C-LT), short-term GnRH antagonist (G-ST), and long-term GnRH antagonist (G-LT). At 25 days of age, daily gonadotropin-releasing hormone antagonist (GnRH-a) injections were administered delaying pubertal onset. Left tibias were analyzed. Stained frontal slices of proximal tibia (5 µm thick) were analyzed in hypertrophic, proliferative, and reserve zones for total height, zone height, and cell/column counts. All procedures were approved by Institutional Animal Care and Use Committee at Brooklyn College. Growth plate height was 19.7% wider in delayed puberty (G-ST) group and at maturity was 27.9% greater in G-LT group compared with control (C-LT) (P<0.05). No significant differences were found in short-term or long-term growth plate zone heights or cell/column counts between groups (P>0.05). Growth plate zone height normalized to total height resulted in 28.7% larger reserve zone in the short-term GnRH-a group but the proliferative zone was 8.5% larger in the long-term group compared with the control group (P<0.05). Normalized to growth plate height a significant decrease was found in column counts in proliferative zones of the short-term and long-term GnRH-a groups. Current data illustrate that delayed puberty using GnRH-a injections results in significant growth plate height and decreases proliferative column counts and zone height, thus potentially contributing to decreases in bone mass at maturity. Growth plate height increases indicate increased potential for growth and bone accrual. However, previous models report decreased bone volume following delayed puberty via GnRH-a injections that may have detrimental effects in the long term.


The carbon footprint of behavioural support services for smoking cessation.
To estimate the carbon footprint of behavioural support services for smoking cessation: text message support, telephone counselling, group counselling and individual counselling. Carbon footprint analysis. Publicly available data on National Health Service Stop Smoking Services and per unit carbon emissions; published effectiveness data from the txt2stop trial and systematic reviews of smoking cessation services. Carbon dioxide equivalents (CO2e) per 1000 smokers, per lifetime quitter, and per quality-adjusted life year gained, and cost-effectiveness, including social cost of carbon, of smoking cessation services. Emissions per 1000 participants were 8143 kg CO2e for text message support, 8619 kg CO2e for telephone counselling, 16 114 kg CO2e for group counselling and 16 372 kg CO2e for individual counselling. Emissions per intervention lifetime quitter were 636 (95% CI 455 to 958) kg CO2e for text message support, 1051 (95% CI 560 to 2873) kg CO2e for telephone counselling, 1143 (95% CI 695 to 2270) kg CO2e for group counselling and 2823 (95% CI 1688 to 6549) kg CO2e for individual counselling. Text message, telephone and group counselling remained cost-effective when cost-effectiveness analysis was revised to include the environmental and economic cost of damage from carbon emissions. All smoking cessation services had low emissions compared to the health gains produced. Text message support had the lowest emissions of the services evaluated. Smoking cessation services have small carbon footprints and were cost-effective after accounting for the societal costs of greenhouse gas emissions.


Pathogens in the middle ear effusion of children with persistent otitis media: implications of drug resistance and complications.
Acute otitis media (AOM) is the most common disease for which pediatricians prescribe antimicrobial agents. Middle ear fluid were collected from 243 children with AOM that failed to respond to a previous course of antimicrobial therapy and who had then received myringotomy from September 1997 through August 1999. Bacterial cultures were done and antimicrobial susceptibilities were analyzed. Streptococcus pneumoniae (21.8%) was the most common causative organism, followed by Haemophilus influenzae (10.2%), Staphylococcus aureus (7%), and Pseudomonas aeruginosa (1.8%), while Moraxella catarrhalis (0.7%) and group A beta-hemolytic streptococcus (0.2%) were rarely isolated. In patients whose condition failed to improve after a course of antibiotic treatment, drug resistance became a serious problem. Fourteen percent of the patients in this series had complications, which included recurrent AOM, persistent middle ear effusion necessitating ventilation tube insertion, hearing impairment, mastoiditis, meningitis, chronic otitis media, brain abscess, and sepsis. Possible risk factors such as young age, male sex, underlying diseases, and a culture of S. pneumoniae or H. influenzae were not significantly associated with an increased incidence of complications. More stringent diagnosis and the correct choice of antibiotic treatment combined with the introduction of potential virus and bacterial vaccines are promising ways to reduce the morbidity of AOM in children.


[A retrospective study of clinical and pathological spectrum in 91 patients with chronic severe hepatitis B].
In China, liver failure is also termed as severe hepatitis in whom chronic severe hepatitis B (CSHB) is most common. The aim of this study was to assess whether CSHB based on different liver injury extent can meet the international definition of acute-on-chronic liver failure(ACLF)criteria, according by their clinical and pathological feature. A total of 91 patients with CSHB were involved in the study. The clinical findings, laboratory data and liver pathology features were retrospectively analyzed and grouped by hepatitis virus B carrier state (HBC), chronic hepatitis B (CHB) or liver cirrhosis (LC) before they started liver failure. 74 out of the 91 patients were male and 17 were female, the mean age was 40.6+/-11.2 years. 9.9%, 7.7% and 82.4% of the patients were based on HBC, CHB and LC respectively. The ages of HBC group were youngest. The mean age of HBC group (years) (25.8+/-6.6) was significantly lower than that of CHB group (36.9+/-9.0) and LC group (42.0+/-10.5)with P values of 0.032 and 0.001 respectively. Most cases presented with sub-acute liver failure characterized by high icterus and ascites. Predisposing factors included exertion, superinfection, virus variation, drugs or alcoholic injury. No difference found between PTA (F = 0.906, P = 0.408) and TBil (F = 0.839, P = 0.436) among the above three groups. The Alb and CHE levels in LC group were (30.3+/-5.1) g/L and (2926.8+/-1471.1) U/L respectively, which were lower than both HBC group [Alb (35.6+/-5.1) g/L, CHE (4363.5+/-2063.2) U/L] and CHB group [Alb (37.4+/-5.0) g/L, CHE (5167.1+/-1522.1) U/L] (F = 9.450; F = 9.297; P value less than 0.01).The level of CHO (1.8+/-1.0) mmol/L in LC group was lower than that of HBC group (2.9+/-1.0mmol/L, P = 0.034), while serum HBV DNA level of HBC group [(6.8+/-1.7) log10copies/ml] was higher than that of LC group [(4.2+/-2.6) log10copies/ml]. The liver tissue in HBC and CHB group showed massive or submassive necrosis which distribute evenly in different parts of liver and similarly in slides, most like acute/subacute severe hepatitis. The chronic lesion was easily covered by extensive necrosis in CSHB based on CHB, with portal fibrosis can be seen by masson stain. Characteristic picture of LC group were massive or submassive necrosis with some nodules were intact or only patchy necrosis of the parenchyma, disparity of extent and stage of necrosis existed in slides, which were the major difference in histopathological change in HBC and CHB group. Most of CSHB cases were based on liver cirrhosis, which match with the international definition of ACLF, while small part of CSHB cases based on HBC and CHB are identical to acute/subacute liver failure.


Effect of bentonite characteristics on the elemental composition of wine.
Physical, chemical, and mineralogical characteristics of six bentonites were assessed and related to their elemental release to wine. Extraction essays of bentonites in wine at three pH levels were carried out. The multielemental analysis of bentonites and wines was performed by atomic absorption spectrometry (AAS) and inductively coupled plasma mass spectrometry (ICP-MS). Bentonite addition resulted in significantly higher concentrations of Li, Be, Na, Mg, Al, Ca, Sc, V, Mn, Fe, Co, Ni, Ga, Ge, As, Sr, Y, Zr, Nb, Mo, Cd, Sn, Sb, Ba, W, Tl, Bi, and W. In contrast, the concentrations of B, K, Cu, Zn, and Rb significantly decreased. A strong correlation between Na concentrations of treated wines and its content in bentonite exchange complex was observed. Al and Fe contents reflected bentonite extractable aluminous and ferruginous constituents, while Be, Mg, Ca, V, Mn, Ni, Ge, Zr, Nb, Mo, Sn, Sb, Tl, Pb, and U concentrations reflected the elemental composition of bentonites. Several nonconformances with OIV specifications demonstrated the need for an effective control.


Effects of the cytokines on the proliferation of and collagen synthesis by human cataract lens epithelial cells.
To assess the effects of the cytokines, interleukin-1 (IL-1), IL-1 receptor antagonist (IL-1ra), transforming growth factor-beta 2 (TGF-beta 2) and basic fibroblast growth factor (b-FGF), on the mitosis of and collagen synthesis by lens epithelial cells (LECs) of human cataracts. The anterior lens capsule with attached LECs was obtained by capsulotomy during cataract surgery and cultured. The cultures at 2 to 3 weeks before confluency were used for the experiments. To quantify the mitosis and collagen synthesis, the incorporation of 3H-thymidine and 3H-proline, respectively, into the LECs was measured by a scintillation counter at 48 hours and 24 hours, respectively, after addition of the cytokine at various concentrations into the incubation medium. IL-1 and b-FGF increased the mitosis and collagen synthesis significantly, but IL-1ra significantly decreased the mitosis while leaving the collagen synthesis intact. TGF-beta 2 decreased the mitosis significantly, but increased the collagen synthesis significantly. These cytokines may play an important role in an autocrine or paracrine pathway in the proliferation of residual LECs after cataract surgery. Elucidation of the role of these cytokines may lead to the development of new therapies for the prevention of secondary cataract.


Multi-attribute preference functions. Health Utilities Index.
Multi-attribute utility theory, an extension of conventional utility theory, can be applied to model preference scores for health states defined by multi-attribute health status classification systems. The type of preference independence among the attributes determines the type of preference function required: additive, multiplicative or multilinear. In addition, the type of measurement instrument used determines the type of preference score obtained: value or utility. Multi-attribute utility theory has been applied to 2 recently developed multi-attribute health status classification systems, the Health Utilities Index (HUI) Mark II and Mark III systems. Results are presented for the Mark II system, and ongoing research is described for the Mark III system. The theory is also discussed in the context of other well known multi-attribute systems. The HUI system is an efficient method of determining a general public-based utility score for a specified health outcome or for the health status of an individual. In clinical populations, the scores can be used to provide a single summary measure of health-related quality of life. In cost-utility analyses, the scores can be used as quality weights for calculating quality-adjusted life years. In general populations, the measure can be used as quality weights for determining population health expectancy.


Metal nanomaterials: Immune effects and implications of physicochemical properties on sensitization, elicitation, and exacerbation of allergic disease.
The recent surge in incorporation of metallic and metal oxide nanomaterials into consumer products and their corresponding use in occupational settings have raised concerns over the potential for metals to induce size-specific adverse toxicological effects. Although nano-metals have been shown to induce greater lung injury and inflammation than their larger metal counterparts, their size-related effects on the immune system and allergic disease remain largely unknown. This knowledge gap is particularly concerning since metals are historically recognized as common inducers of allergic contact dermatitis, occupational asthma, and allergic adjuvancy. The investigation into the potential for adverse immune effects following exposure to metal nanomaterials is becoming an area of scientific interest since these characteristically lightweight materials are easily aerosolized and inhaled, and their small size may allow for penetration of the skin, which may promote unique size-specific immune effects with implications for allergic disease. Additionally, alterations in physicochemical properties of metals in the nano-scale greatly influence their interactions with components of biological systems, potentially leading to implications for inducing or exacerbating allergic disease. Although some research has been directed toward addressing these concerns, many aspects of metal nanomaterial-induced immune effects remain unclear. Overall, more scientific knowledge exists in regards to the potential for metal nanomaterials to exacerbate allergic disease than to their potential to induce allergic disease. Furthermore, effects of metal nanomaterial exposure on respiratory allergy have been more thoroughly-characterized than their potential influence on dermal allergy. Current knowledge regarding metal nanomaterials and their potential to induce/exacerbate dermal and respiratory allergy are summarized in this review. In addition, an examination of several remaining knowledge gaps and considerations for future studies is provided.


Environmental effects on WHODAS 2.0 among patients with stroke with a focus on ICF category e120.
To explore the environmental effects on the disabilities of people post stroke and to search for the best probabilistic cut-off value of the WHO Disability Assessment Schedule second edition (WHODAS 2.0) scores to predict people post stroke experiencing an access barrier to the International Classification of Functioning, Disability and Health category e120 products and technology for personal indoor and outdoor mobility and transportation (PMT). We analyzed data of 162 younger (aged 18-64 years) and 202 older (aged ≥65 years) people post stroke from the databank of persons with disability between June 1, 2011 and February 29, 2012. All participants rated each WHODAS 2.0 item with environmental intervention (performance score) and without any intervention (capacity score). We used the paired capacity-performance score difference to assess the whole environmental effects on the participants' disability, evaluated each participant's access barrier to PMT (negative PMT), and used a receiver-operating characteristic curve to predict patients having a negative PMT. The whole environment acted as a barrier on mobility and self-care in >10 % of older people post stroke. Older patients having a summary index performance score of ≥78.8 points and younger patients having an index of ≥56.0 points were likely to experience a negative PMT. Older patients who have an access to PMT were possible to improve their daily activities performance, and younger patients could report less disability. An environmental support to improve the PMT accessibility is important for people post stroke to reduce their disability.


Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.
Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes, and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension. We assessed the effects of the routine administration of an angiotensin converting enzyme (ACE) inhibitor-diuretic combination on serious vascular events in patients with diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs. The trial was done by 215 collaborating centres in 20 countries. After a 6-week active run-in period, 11 140 patients with type 2 diabetes were randomised to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. The primary endpoints were composites of major macrovascular and microvascular events, defined as death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction, and new or worsening renal or diabetic eye disease, and analysis was by intention-to-treat. The macrovascular and microvascular composites were analysed jointly and separately. This trial is registered with ClinicalTrials.gov, number NCT00145925. After a mean of 4.3 years of follow-up, 73% of those assigned active treatment and 74% of those assigned control remained on randomised treatment. Compared with patients assigned placebo, those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg. The relative risk of a major macrovascular or microvascular event was reduced by 9% (861 [15.5%] active vs 938 [16.8%] placebo; hazard ratio 0.91, 95% CI 0.83-1.00, p=0.04). The separate reductions in macrovascular and microvascular events were similar but were not independently significant (macrovascular 0.92; 0.81-1.04, p=0.16; microvascular 0.91; 0.80-1.04, p=0.16). The relative risk of death from cardiovascular disease was reduced by 18% (211 [3.8%] active vs 257 [4.6%] placebo; 0.82, 0.68-0.98, p=0.03) and death from any cause was reduced by 14% (408 [7.3%] active vs 471 [8.5%] placebo; 0.86, 0.75-0.98, p=0.03). There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline. Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death. Although the confidence limits were wide, the results suggest that over 5 years, one death due to any cause would be averted among every 79 patients assigned active therapy.


The Dry Season Shuffle: Gorges Provide Refugia for Animal Communities in Tropical Savannah Ecosystems.
In the wet-dry tropics, animal species face the major challenges of acquiring food, water or shelter during an extended dry season. Although large and conspicuous animals such as ungulates and waterfowl migrate to wetter areas during this time, little is known of how smaller and more cryptic animal species with less mobility meet these challenges. We fenced off the entire entrance of a gorge in the Australian tropical savanna, offering the unique opportunity to determine the composition and seasonal movement patterns of the small vertebrate community. The 1.7 km-long fence was converted to a trapline that was deployed for 18-21 days during the early dry season in each of two years, and paired traps on both sides of the fence allowed us to detect the direction of animal movements. We predicted that semi-aquatic species (e.g., frogs and turtles) would move upstream into the wetter gorge during the dry season, while more terrestrial species (e.g., lizards, snakes, mammals) would not. The trapline captured 1590 individual vertebrates comprising 60 species. There was a significant bias for captures on the outside of the fence compared to the inside for all species combined (outside/inside = 5.2, CI = 3.7-7.2), for all vertebrate classes, and for specific taxonomic groups. The opposite bias (inside/outside = 7.3, N= 25) for turtles during the early wet season suggested return migration heading into the wet season. Our study revealed that the small vertebrate community uses the gorge as a dry season refuge. The generality of this unreplicated finding could be tested by extending this type of survey to tropical savannahs worldwide. A better understanding of how small animals use the landscape is needed to reveal the size of buffer zones around wetlands required to protect both semi-aquatic and terrestrial fauna in gorges in tropical savannah woodland, and thus in ecosystems in general.


Spray bacteriotherapy decreases middle ear fluid in children with secretory otitis media.
Secretory otitis media (SOM) is characterised by persistent fluid in the middle ear cavity, but the cause is unknown. We investigated the clinical, bacteriological and immunological effects of treatment with probiotic bacteria on SOM. In this double-blind pilot/preliminary study, 60 children with long-standing SOM (median 6 months) who were scheduled for insertion of tympanostomy tubes were randomised to nasal spray treatment with Streptococcus sanguinis, Lactobacillus rhamnosus or placebo for 10 days before surgery. Clinical evaluation was carried out after 10 days of treatment. Middle ear fluid (MEF) was collected during surgery for quantification of cytokines and detection of bacteria by culture and polymerase chain reaction (PCR). Nasopharyngeal swabs were obtained before treatment and at surgery. Complete or significant clinical recovery occurred in 7/19 patients treated with S sanguinis compared to 1/17 patients in the placebo group (p<0.05). In the L rhamnosus treatment group, 3/18 patients were cured or much better (p = 0.60 compared with placebo). Spray treatment did not alter the composition of the nasopharyngeal flora or the cytokine pattern observed in the nasopharynx or MEF, except for a higher level of IL-8 found in the nasopharynx of L rhamnosus treated children. This study shows that spray treatment with S sanguinis may be effective against SOM. The mechanism for the effect remains to be investigated.


Tin doping speeds up hole transfer during light-driven water oxidation at hematite photoanodes.
Numerous studies have shown that the performance of hematite photoanodes for light-driven water splitting is improved substantially by doping with various metals, including tin. Although the enhanced performance has commonly been attributed to bulk effects such as increased conductivity, recent studies have noted an impact of doping on the efficiency of the interfacial transfer of holes involved in the oxygen evolution reaction. However, the methods used were not able to elucidate the origin of this improved efficiency, which could originate from passivation of surface electron-hole recombination or catalysis of the oxygen evolution reaction. The present study used intensity-modulated photocurrent spectroscopy (IMPS), which is a powerful small amplitude perturbation technique that can de-convolute the rate constants for charge transfer and recombination at illuminated semiconductor electrodes. The method was applied to examine the kinetics of water oxidation on thin solution-processed hematite model photoanodes, which can be Sn-doped without morphological change. We observed a significant increase in photocurrent upon Sn-doping, which is attributed to a higher transfer efficiency. The kinetic data obtained using IMPS show that Sn-doping brings about a more than tenfold increase in the rate constant for water oxidation by photogenerated holes. This result provides the first demonstration that Sn-doping speeds up water oxidation on hematite by increasing the rate constant for hole transfer.


The recovery patterns of back pain among workers with compensated occupational back injuries.
To investigate the longitudinal patterns of recovery among workers with compensated occupational back injuries. A longitudinal cohort study, with one-year follow-up via structured telephone interviews, among respondents off work because of "new" back injuries. Self-reported pain intensity was recorded at baseline and at four follow-up time points over the course of one year. Workers who answered the questionnaire on at least three occasions (n = 678) were classified into clusters according to their patterns of pain intensity over time using a two-step cluster analysis. Four pain recovery patterns were identified: workers with high levels of pain intensity showing no improvement over time (43%); those experiencing recovery in the first four months with no further improvement or possibly even some deterioration, in the second half year (33%); those experiencing a slow consistent recovery but still with considerable back pain at the end of the follow-up (12%); and those quickly progressing to low level of pain or resolution (12%). Trajectories of average Roland-Morris Disability scores and SF-36 Role of Physical scores for above clusters mapped consistently with the corresponding patterns in pain. However, individuals with fluctuating, recurrent pain patterns showed the shortest cumulative duration on 100% benefit and the earliest return-to-work among other clusters. Four clinically sensible patterns were identified in this cohort of injured workers, suggesting inter-individual differences in back pain recovery. The results confirm that recurrent or chronic back pain is a typical condition in respondents with new back injuries. Pain intensity and disability scores are good measures of recovery of back pain at the individual level. After initial return-to-work, or cessation of benefits, administrative measures of percentage of respondents back at work, or no longer on benefits, may not accurately reflect an individual's condition of back pain.


Clinical Outcomes of Inadequate Calorie Delivery and Protein Deficit in Surgical Intensive Care Patients.
Adequate nutritional therapy in critically ill patients is integral to optimal outcome. To evaluate the association between cumulative macronutrient deficit and overall morbidity in surgical intensive care unit patients. Adult patients receiving enteral nutrition for more than 72 hours were included if they had no previous admission to the surgical intensive care unit, had received no enteral feedings before admission, had no intestinal obstruction or ileus, and survived 72 hours or more after admission. Data on demographics, outcomes, and nutritional intake during the unit stay were collected for up to 14 days until oral intake began, discharge, or death. Outcome variables included lengths of stay in the hospital and intensive care unit, days with no mechanical ventilation, complications, and mortality. Of 94 participants, 71% were men, mean age was 63 years, and mean score on the Acute Physiology and Chronic Health Evaluation II was 14. Patients with high cumulative calorie deficit (≥ 6000 cal) and high protein deficit (≥ 300 g) had significantly fewer days with no mechanical ventilation (P < .001), longer unit stays (P < .001), longer hospital stays (P = .007), more total complications (P = .007), and more infectious complications (P = .009) than other participants. These associations remained significant in multivariable models after adjustments for age, sex, reason for admission, and propensity score of deficit. In-hospital and 30-day mortality did not differ. Cumulative macronutrient deficits have important clinical outcomes in surgical intensive care patients.


The uptake of iron-55 by marine sediment, macroalgae, and biota following discharge from a nuclear power station.
Significant quantities of 55Fe, an activation product of stable iron, have been released into the environment following the atmospheric testing of nuclear weapons (mainly in the 1950s and 1960s) as well as through authorized discharges of radioactivity from nuclear power and reprocessing sites. Although some studies have been performed on the behavior of weapons' fallout-derived 55Fe in the environment and subsequent impact on humans, little has been published on the behavior of 55Fe released as a point source discharge from nuclear sites. This study presents data on the concentration and temporal variation of 55Fe in fucoid seaweeds, shellfish, crab, and lobster collected from Weymouth Bay and adjacent coastal areas, southern England. These areas have received authorized discharges of radionuclides originating from the operation of a now-decommissioned steam-generating, heavy water-type reactor at AEE Winfrith. The highest activities of 55Fe are found associated with marine sediments collected near the discharge pipeline and a rapid decline occurs away from the pipeline. This is consistent with rapid sorption of 55Fe by the sediment, and the data show there is only limited reworking and remobilization. Activities of 55Fe in biota generally decreased over time, due to a reduction in the amount of 55Fe discharged. The variation of 55Fe activity, revealed from the monthly sampling of seaweed, does not reflect the short-term fluctuations seen in the patterns of discharged 55Fe activity. Although discharges of 55Fe from AEE Winfrith exceeded other radionuclides, the radiological impact on local seafood consumers is considerably less than for other key radionuclides such as 60Co and 65Zn but of comparable magnitude to the global average population dose arising from fallout-derived 55Fe.


Metabolic Dysfunction in Parkinson's Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism.
The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of protein inclusions (Lewy bodies) are the pathological hallmarks of Parkinson's disease (PD). PD is triggered by genetic alterations, environmental/occupational exposures and aging. However, the exact molecular mechanisms linking these PD risk factors to neuronal dysfunction are still unclear. Alterations in redox homeostasis and bioenergetics (energy failure) are thought to be central components of neurodegeneration that contribute to the impairment of important homeostatic processes in dopaminergic cells such as protein quality control mechanisms, neurotransmitter release/metabolism, axonal transport of vesicles and cell survival. Importantly, both bioenergetics and redox homeostasis are coupled to neuro-glial central carbon metabolism. We and others have recently established a link between the alterations in central carbon metabolism induced by PD risk factors, redox homeostasis and bioenergetics and their contribution to the survival/death of dopaminergic cells. In this review, we focus on the link between metabolic dysfunction, energy failure and redox imbalance in PD, making an emphasis in the contribution of central carbon (glucose) metabolism. The evidence summarized here strongly supports the consideration of PD as a disorder of cell metabolism.


Identification of a male with fragile X syndrome through newborn screening.
A pilot newborn screening (NBS) study for fragile X syndrome was recently conducted at the University of California, Davis Medical Center. The screening study identified a case of a male with the full mutation completely methylated and no detectable expression of the fragile X mental retardation-1 (FMR1) gene. The patient was initially seen in clinic at the MIND Institute, for medical follow-up and a genetic counseling session at the chronological age of 3 months. Since then, he has been seen in clinic every six months for follow up, medical examination and developmental assessments. Longitudinally administered developmental testing of the infant has revealed persistent delays in development, consistent with fragile X syndrome. Cascade testing revealed that the patient's mother and two siblings also have the full mutation. The patient has been receiving speech and language therapy, combined with physical and occupational therapies on a weekly basis since the age of one year. He is currently being treated with 2.5 mg of sertraline, which has been demonstrated to be helpful for improving language in young children with the syndrome.


Bayesian adaptive regression splines for hierarchical data.
This article considers methodology for hierarchical functional data analysis, motivated by studies of reproductive hormone profiles in the menstrual cycle. Current methods standardize the cycle lengths and ignore the timing of ovulation within the cycle, both of which are biologically informative. Methods are needed that avoid standardization, while flexibly incorporating information on covariates and the timing of reference events, such as ovulation and onset of menses. In addition, it is necessary to account for within-woman dependency when data are collected for multiple cycles. We propose an approach based on a hierarchical generalization of Bayesian multivariate adaptive regression splines. Our formulation allows for an unknown set of basis functions characterizing the population-averaged and woman-specific trajectories in relation to covariates. A reversible jump Markov chain Monte Carlo algorithm is developed for posterior computation. Applying the methods to data from the North Carolina Early Pregnancy Study, we investigate differences in urinary progesterone profiles between conception and nonconception cycles.


Survival and Causes of Death Among People With Clinically Diagnosed Synucleinopathies With Parkinsonism: A Population-Based Study.
To our knowledge, a comprehensive study of the survival and causes of death of persons with synucleinopathies compared with the general population has not been conducted. Understanding the long-term outcomes of these conditions may inform patients and caregivers of the expected disease duration and may help with care planning. To compare survival rates and causes of death among patients with incident, clinically diagnosed synucleinopathies and age- and sex-matched referent participants. This population-based study used the Rochester Epidemiology Project medical records-linkage system to identify all residents in Olmsted County, Minnesota, who received a diagnostic code of parkinsonism from 1991 through 2010. A movement-disorders specialist reviewed the medical records of each individual to confirm the presence of parkinsonism and determine the type of synucleinopathy. For each confirmed patient, an age- and sex-matched Olmsted County resident without parkinsonism was also identified. We determined the age- and sex-adjusted risk of death for each type of synucleinopathy, the median time from diagnosis to death, and the causes of death. Of the 461 patients with synucleinopathies, 279 (60.5%) were men, and of the 452 referent participants, 272 (60.2%) were men. From 1991 through 2010, 461 individuals received a diagnosis of a synucleinopathy (309 [67%] of Parkinson disease, 81 [17.6%] of dementia with Lewy bodies, 55 [11.9%] of Parkinson disease dementia, and 16 [3.5%] of multiple system atrophy with parkinsonism). During follow-up, 68.6% (n = 316) of the patients with synucleinopathies and 48.7% (n = 220) of the referent participants died. Patients with any synucleinopathy died a median of 2 years earlier than referent participants. Patients with multiple system atrophy with parkinsonism (hazard ratio, 10.51; 95% CI, 2.92-37.82) had the highest risk of death compared with referent participants, followed by those with dementia with Lewy bodies (hazard ratio, 3.94; 95% CI, 2.61-5.94), Parkinson disease with dementia (hazard ratio, 3.86; 95% CI, 2.36-6.30), and Parkinson disease (hazard ratio, 1.75; 95% CI, 1.39-2.21). Neurodegenerative disease was the most frequent cause of death listed on the death certificate for patients, and cardiovascular disease was the most frequent cause of death among referent participants. Individuals with multiple system atrophy with parkinsonism, dementia with Lewy bodies, and Parkinson disease dementia have increased mortality compared with the general population. The mortality among persons with Parkinson disease is only moderately increased compared with the general population.


Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions.
Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10(-07)), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 × 10(-05)). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.


Smoking in pregnancy and development into early adulthood.
Follow up analyses of data on the 1958 cohort from the national child development study have shown that the association of smoking in pregnancy with physical and intellectual development diverges between the sexes at age 16, no longer being significantly associated with height in girls. These studies, however, have emphasised that the differences in outcome are small and may be explained by other factors. The analyses have taken account of birth weight and have therefore examined the effects of smoking on subsequent development in addition to this variable. To assess the importance of smoking on development in early adult life and whether the effect is independent of birth weight data from the 1958 cohort at age 23 were analysed. Only weak evidence for a relation between smoking in pregnancy and self reported height of the offspring was apparent once social class, size of family, mothers' height, and birth weight for gestational age were taken into account. After omission of birth weight from the analyses, however, the average difference in height between subjects whose mothers smoked 20 cigarettes a day or more during the second half of pregnancy and those whose mothers did not was 0.93 cm in men and 1.83 cm in women. A strong association was also evident with the highest qualification achieved by subjects at this age, suggesting a long term relation between smoking in pregnancy and the intellectual development of the offspring.


fMRI data predict individual differences of behavioral effects of nicotine: a partial least square analysis.
Reorienting of visuospatial attention can be investigated by comparing reaction times to validly and invalidly cued targets ("validity effect"). The cholinergic agonist nicotine reduces the validity effect and neural activity in the posterior parietal cortex. Behavioral effects of nicotine in nonsmokers are weak and it has been suggested that differences in baseline behavior before nicotine exposure may influence the effect of nicotine. This study investigates whether individual differences in reorienting-related neural activity under placebo may be used to predict individual nicotine effects. Individual nicotine effects are defined as the behavioral effects under nicotine that cannot be predicted by the behavioral data under placebo. Fifteen nonsmoking subjects were given either placebo or nicotine gum (2 mg) prior to performing a cued target detection task inside a magnetic resonance imaging scanner. The results of a partial least square analysis suggest that neural data under placebo can be used to predict individual behavioral effects of nicotine. Neural activity in the left posterior cingulate cortex, the right superior parietal cortex, the right dorsal medial prefrontal cortex, and the left ventral medial prefrontal cortex significantly contributes to that prediction. We conclude that nicotine effects on reorienting attention depend on individual differences in reorienting-related neural activity under placebo and suggest that functional magnetic resonance imaging data can contribute to the prediction of individual drug effects.


Methplotlib: analysis of modified nucleotides from nanopore sequencing.
Modified nucleotides play a crucial role in gene expression regulation. Here, we describe methplotlib, a tool developed for the visualization of modified nucleotides detected from Oxford Nanopore Technologies sequencing platforms, together with additional scripts for statistical analysis of allele-specific modification within-subjects and differential modification frequency across subjects. The methplotlib command-line tool is written in Python3, is compatible with Linux, Mac OS and the MS Windows 10 Subsystem for Linux and released under the MIT license. The source code can be found at https://github.com/wdecoster/methplotlib and can be installed from PyPI and bioconda. Our repository includes test data, and the tool is continuously tested at travis-ci.com. Supplementary data are available at Bioinformatics online.


Increased familial risk and genomewide significant linkage for Alzheimer's disease with psychosis.
Psychotic symptoms are common in Alzheimer's disease (AD) and are associated with increased cognitive impairment and earlier institutionalization. One study has suggested that they are genetically modified and two genome screens have been performed to search for susceptibility loci for AD with psychosis (AD + P). The aim of this study was to further investigate the familial aggregation of AD + P and perform a genome screen for AD, conditioning on the presence or absence of psychotic symptoms. Samples from the UK and US were combined, providing data from 374 families in which at least two members met criteria for AD and had complete data regarding psychotic symptoms. Generalized estimating equations (GEE) were used to assess the relationship of psychotic symptoms between siblings. A total of 321 affected relative pairs (ARPs) were genotyped for linkage. There was a significant association between proband psychosis status and the occurrence of AD + P in siblings in the UK (OR = 4.17, P = 0.002) and US (OR = 3.2, P < 0.001) samples. Chromosomewide and genomewide significant linkage peaks were observed on chromosomes 7 (LOD = 2.84) and 15 (LOD = 3.16), respectively, with the strongest evidence coming from pairs concordant for AD without psychosis. A LOD score of 2.98 was observed close to a previously reported AD + P linkage region on chromosome 6, however the increase in LOD attributable to psychosis was not significant. These findings support the hypothesis that psychotic symptoms in AD are genetically modified and that a gene/s implicated in their aetiology may be located on chromosome 7 and 15.


Modeling the impact of Medicare Advantage payment cuts on ambulatory care sensitive and elective hospitalizations.
To assess relationships between changes in Medicare Advantage (MA) payment rates and Medicare beneficiary hospitalizations and to simulate the effects of scheduled payment cuts on ambulatory care sensitive (ACS) and elective hospitalization rates. State Inpatient Database discharge abstracts from Arizona, Florida, and New York merged with administrative Medicare enrollment and MA payment data. Retrospective, fixed effect regression analysis of the relationship between MA payment rates and rates of ACS and elective hospitalizations among Medicare beneficiaries in counties with at least 10,000 Medicare beneficiaries and 3 percent MA penetration from 1999 to 2005. MA payment rates were negatively related to rates of ACS admissions. Simulations suggest that payment cuts could be associated with higher rates of ACS admissions. No relationship between MA payments and rates of elective hospitalizations was found. Reductions in MA payment rates may result in a small increase in ACS admissions. Trends in ACS admissions among chronically ill Medicare beneficiaries should be tracked following MA payment cuts.


Representing glycophenotypes: semantic unification of glycobiology resources for disease discovery.
While abnormalities related to carbohydrates (glycans) are frequent for patients with rare and undiagnosed diseases as well as in many common diseases, these glycan-related phenotypes (glycophenotypes) are not well represented in knowledge bases (KBs). If glycan-related diseases were more robustly represented and curated with glycophenotypes, these could be used for molecular phenotyping to help to realize the goals of precision medicine. Diagnosis of rare diseases by computational cross-species comparison of genotype-phenotype data has been facilitated by leveraging ontological representations of clinical phenotypes, using Human Phenotype Ontology (HPO), and model organism ontologies such as Mammalian Phenotype Ontology (MP) in the context of the Monarch Initiative. In this article, we discuss the importance and complexity of glycobiology and review the structure of glycan-related content from existing KBs and biological ontologies. We show how semantically structuring knowledge about the annotation of glycophenotypes could enhance disease diagnosis, and propose a solution to integrate glycophenotypes and related diseases into the Unified Phenotype Ontology (uPheno), HPO, Monarch and other KBs. We encourage the community to practice good identifier hygiene for glycans in support of semantic analysis, and clinicians to add glycomics to their diagnostic analyses of rare diseases.


Influence of Statins and Cholesterol on Mortality Among Patients With Pancreatic Cancer.
Recent studies have suggested associations between statins and enhanced survival among patients with pancreatic ductal adenocarcinoma (PDAC). However, the relationship between statins, cholesterol, and survival remains unclear. We conducted a retrospective cohort study on 2142 PDAC patients in a regional integrated healthcare system from 2006 to 2014. Electronic pharmacy records were used to abstract information on the type, length, and dosage of statin exposures starting in the year prior to diagnosis. The cumulative and individual effects of simvastatin, lovastatin, atorvastatin, pravastatin, and rosuvastatin on mortality were assessed using Cox proportional hazards regression. Statins were evaluated as any use (pre- and postdiagnosis as a time-dependent variable) and baseline use (prediagnosis only). We also evaluated whether low-density lipoprotein (LDL) cholesterol, measured at various time windows prior to diagnosis, had an independent influence on survival. Additional analyses were performed to examine whether cholesterol mediated the relationship between statins and mortality. All models included age, race, stage, surgery, gemcitabine-based chemotherapy, and the Charlson comorbidity index as covariates. Any (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.79 to 0.97) and baseline (HR = 0.88, 95% CI = 0.79 to 0.98) statin use were both associated with a decreased risk in mortality. When assessing individual statins, we found reduced mortality among simvastatin (HR = 0.87, 95% CI = 0.77 to 0.98) and atorvastatin (HR = 0.58, 95% CI = 0.46 to 0.72) users. Cholesterol was not associated with mortality and did not mediate any relationships between statins and survival. Statin use rather than cholesterol level was associated with lower mortality risk in patients with pancreatic cancer. Statins appear to improve survival through a lipid-independent mechanism.


Validation of the PDPAR as an adolescent diary: effect of accelerometer cut points.
To evaluate the validity of the Previous Day Physical Activity Recall (PDPAR) as a physical activity diary in adolescents using two accelerometer intensity classifications. One hundred eighth graders (47 boys, 53 girls) used the PDPAR as a daily diary and wore MTI accelerometers for four consecutive days. Measured time spent in moderate (> or = 3 METs) and vigorous (> or = 6 METs) activity was based on two published MTI cut-point limits (that of Freedson et al./Trost et al. and that of Puyau et al.). Spearman rank order correlations and Bland-Altman plots were used to examine agreement between MTI and PDPAR diary estimates of activity. MTI estimates of mean minutes per day of total moderate to vigorous physical activity (MVPA) were 65.2 (+/-43.2) using the Freedson et al./Trost et al. cutoffs and 17.5 (+/-18.5) using those of Puyau et al., while students self-reported 105.1 (+/-80.1) min.d(-1). Significant relationships were observed between the diary and MTI for total MVPA using either the Freedson et al./Trost et al. (r = 0.42) or Puyau et al. (r = 0.41) cutoff as well as raw counts (r = 0.44). Plots showed reasonable agreement between the diary and Freedson et al./Trost et al. MTI estimates of MVPA for daily totals of < or = 60 min, but the Puyau et al. estimates were consistently lower. Diaries overestimated activity as time increased when compared to either MTI cut point, especially on vigorous activity. Time estimates of MVPA differed by assessment tool, but diary estimates showed adequate association with the MTI. Diaries reflected intensity-specific activity, corresponding most closely with the Freedson et al./Trost et al. classification of moderate, but substantially overestimated vigorous activity regardless of cut-point method. This is likely due to the measurement characteristics of the PDPAR, which classifies activities in 30-min blocks, as well as the nature of common activities in which high levels of intensity are not sustained.


Homozygosity at the Candida albicans MTL locus associated with azole resistance.
Antifungal drug resistance in the pathogenic fungus Candida albicans is a serious threat to the growing population of immunocompromised patients. This study describes a significant correlation between loss of heterozygosity at the C. albicans mating-type-like (MTL) locus and resistance to azole antifungals. A pool of 96 clinical isolates consisting of 50 azole-resistant or susceptible dose-dependent isolates and 46 azole-susceptible isolates was screened by PCR for the presence of MTLa1 and MTLalpha1. These genes were used as markers for the MTLa and MTLalpha loci. Both loci were present in 84 of the isolates. Six isolates failed to amplify MTLa1 and six failed to amplify MTLalpha1. Further PCR analysis demonstrated that loss of the MTLa1 and MTLalpha1 genes corresponded to loss of all of the loci-specific genes, resulting in homozygosity at the MTL locus. Southern analysis and single nucleotide polymorphism (SNP) analysis were used to determine that this loss of heterogeneity was due to replacement of one of the MTL loci with a duplicate of the other locus resulting in two homozygous copies of the MTL locus. Of the 12 homozygous isolates, one isolate was sensitive to azole drugs. Statistical analysis of the data demonstrates a strong correlation between homozygosity at the MTL locus and azole resistance (P<0 small middle dot003). In a set of serial isolates, an increase in azole resistance correlated with the loss of heterozygosity at the MTL locus, lending further strength to the correlation. Gene disruptions of the MTL loci were found to have no effect on azole susceptibility.


Herbal medicine use among patients with chronic diseases.
Complementary and alternative medicine (CAM) is commonly used all over the world, and herbal medicines are the most preferred ways of CAM. The aim of this study was to determine the frequency of herbal medicine use among patients with chronic diseases. A cross-sectional descriptive study was conducted from April 2014 to December 2014 among patients who had been diagnosed with diabetes mellitus (DM), hypertension (HT), and hyperlipidemia (HL) in Family Medicine Department of Dışkapı Yıldırım Beyazıt Training and Research Hospital, in Ankara. A questionnaire about herbal drug use was applied by face to face interview to the participants. A total of 217 patients were included in this study. The mean age of the participants was 56.6 ± 9.7 years (55 male and 162 female). The rate of herbal medicine use was 29%. Herbal medicine use among female gender was significantly higher (P = 0.040). Conventional medication use was found to be lower among herbal medicine consumers. There was no relationship between herbal medicine use and type of chronic disease, living area, and occupation or education level. Most frequently used herbs were lemon (39.6%) and garlic (11.1%) for HT, cinnamon (12.7%) for DM, and walnut (6.3%) for HL. In this study, herbal medicine use was found to be higher among patients who had been diagnosed with chronic diseases. Therefore, physicians should be aware of herbal medicine usage of their patients and inform them about the effectivity and side effects of herbal medicines.


Transmission of SEN virus from mothers to their babies.
Sera from 30 women at high risk for infection, one half of which were SEN virus positive (SENV(+)), were collected at delivery to study SENV mother-to child transmission. Thirteen of their babies were positive for at least one SENV strain: one baby was SENV(+) at birth, eight became positive within 6 months from delivery, and four became positive in the following months. Our data indicate that vertical transmission of SENV does occur, presumably, at delivery, but it may not induce persistent viremia. This is supported by the fact that, generally, SENV is not detected at birth, by the high SENV homology in the sequences found in the mothers and in their children, by a lack of other risk factors for infection of the babies, and by the irregular detection of SENV in the follow-up. No clinical events surely linked to SENV infection were found, but transient elevations of alanine aminotransferase were observed in babies followed for a long period of time.


Intron-dependent recruitment of pre-mRNA splicing factors to sites of transcription.
We have examined the nuclear localization of transiently and stably expressed nascent RNA transcripts containing or lacking introns in order to determine if the spatial association of RNA transcripts and pre-mRNA splicing factors in nuclei is random or functionally significant. Our findings show that the association between nascent RNA and splicing factors in the nucleus is intron-dependent when the RNAs are either transiently or stably expressed. Furthermore, our data indicate that splicing factors are recruited to the transcription sites. The presence of both pre-and mRNA at these locations suggest that pre-mRNA splicing occurs at these sites of transcription. In addition, electron microscopic examination of the highly active transcription sites has revealed a granular appearance which closely resembles, but is functionally different from, interchromatin granule clusters. Our findings demonstrate that the nucleus is highly organized and dynamic with regard to the functions of the transcription and pre-mRNA splicing.


Antibiotics in IBD: Still a Role in the Biological Era?
Despite compelling evidence pointing to a critical role of gut microflora in inflammatory bowel disease (IBD) pathogenesis, the role of antibiotics in clinical practice remains limited, largely due to heterogeneous trials with often conflicting evidence. In this review, we revisit previous randomized controlled trials and high-quality uncontrolled studies in an effort to better elucidate the role of antibiotics in contemporary treatment algorithms. The most established role of antibiotics is in perianal Crohn's disease (CD), utilizing ciprofloxacin with or without metronidazole often as an adjunct to biological therapy. Evidence also points to a likely modest role of various antibiotic classes in mild to moderate luminal CD, including ciprofloxacin, metronidazole, azithromycin, and rifaximin. The benefit of metronidazole in preventing postoperative recurrence in CD is well reported; however, the long-term benefit of this intervention remains uncertain. The use of antibiotics in ulcerative colitis (UC) is even more controversial, but studies using broad-spectrum oral antibiotic cocktails have reported a possible role in acute severe colitis and chronic persistent UC. Similarly, the role of oral vancomycin and gentamicin in very early-onset IBD has interesting preliminary results. Adverse events of antibiotics, the resulting alterations in the microbiome with its associated unknown long-term sequela, and the emergence of antibiotic-resistant strains must be carefully balanced. Therefore, although antibiotics may be underused in the treatment of IBD, their integration into clinical practice must be approached judiciously and individually.


Patients' reasons for not presenting emotional problems in general practice consultations.
Patients commonly do not mention emotional problems in consultations, and this is a factor in general practitioners' (GPs') difficulty in identifying psychological morbidity. To investigate patients' self-reported reasons for not disclosing psychological problems in consultations with GPs. From nine general practices, a sample of patients with high General Health Questionnaire scores, who planned to present only somatic symptoms to the GP, were interviewed after their consultation with the GP. The interview covered their reasons for not mentioning emotional problems. A patient satisfaction questionnaire was administered. A total of 83 patients were interviewed. Sixty-four patients confirmed that they had not mentioned emotional problems in the consultation; 23 (36%) of these gave primarily realistic reasons for not presenting emotional problems (e.g. able to cope with distress), 29 (45%) gave reasons related to psychological embarrassment or hesitation to trouble the GP, and 12 (19%) were mainly deterred by the doctors' interview behaviours. The latter group had significantly lower satisfaction scores than patients in the other two groups. In addition, patients in all groups commonly reported perceptions of lack of time (48%) and that there is nothing doctors can do to help (39%) as barriers to mentioning emotional problems. An understanding of patients' reasons for not disclosing emotional problems can assist in identifying subgroups of patients with different management needs.


Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico.
Oral antiplatelet drugs are a key to modern pharmacotherapy in cardiovascular atherothrombotic diseases. Clopidogrel (CLO) constitutes the main preventive treatment of atherothrombosis. However, a considerable inter-individual variation in CLO response has been documented, resulting in suboptimal therapy and an increased risk of recurrent adverse effects in some patients. The enzyme CYP2C19 has been reported to be the CYP isoform that activates CLO to its active metabolite. Several single nucleotide polymorphisms in the CYP2C19 gene have been identified as strong predictors of CLO-impaired pharmacological response. At least 16 variants have been associated with changes in CYP2C19 activity. The following research was composed of a total of 102 subjects with high cardiovascular risk in the northeast of Mexico, with a maintenance dose of 75 mg of CLO per day. The platelet reactivity was measured with VerifyNow P2Y12 assay, while the presence of CYP2C19*2 was identified by real-time polymerase chain reaction. Patients were categorized by CYP2C19 metabolizer status based on *2 genotypes using the common consensus star allele nomenclature as normal metabolizer (G/G), intermediate metabolizer (G/A), and poor metabolizer (A/A), respectively. The phenotype frequency for CYP2C19*2 was 74.5% (G/G), 21.6% (G/A), and 3.9% (A/A). The subjects with the A allele presented ≥235 P2Y12 reaction unit levels, classifying them how poor metabolizer. The prevalence of reduced CLO effectiveness was associated with the presence of CYP2C19*2 polymorphism among Mexican patients. The presence of the CYP2C19*2 allele is related to resistance to the antiplatelet effect of CLO (p = 0.003).


Evaluation of a microarray-hybridization based method applicable for discovery of single nucleotide polymorphisms (SNPs) in the Pseudomonas aeruginosa genome.
Whole genome sequencing techniques have added a new dimension to studies on bacterial adaptation, evolution and diversity in chronic infections. By using this powerful approach it was demonstrated that Pseudomonas aeruginosa undergoes intense genetic adaptation processes, crucial in the development of persistent disease. The challenge ahead is to identify universal infection relevant adaptive bacterial traits as potential targets for the development of alternative treatment strategies. We developed a microarray-based method applicable for discovery of single nucleotide polymorphisms (SNPs) in P. aeruginosa as an easy and economical alternative to whole genome sequencing. About 50% of all SNPs theoretically covered by the array could be detected in a comparative hybridization of PAO1 and PA14 genomes at high specificity (> 0.996). Variations larger than SNPs were detected at much higher sensitivities, reaching nearly 100% for genetic differences affecting multiple consecutive probe oligonucleotides. The detailed comparison of the in silico alignment with experimental hybridization data lead to the identification of various factors influencing sensitivity and specificity in SNP detection and to the identification of strain specific features such as a large deletion within the PA4684 and PA4685 genes in the Washington Genome Center PAO1. The application of the genome array as a tool to identify adaptive mutations, to depict genome organizations, and to identify global regulons by the "ChIP-on-chip" technique will expand our knowledge on P. aeruginosa adaptation, evolution and regulatory mechanisms of persistence on a global scale and thus advance the development of effective therapies to overcome persistent disease.


Effect of delivery method on the efficacy of Salmonella vaccination in chickens.
To investigate whether the efficacy of live vaccines is influenced by the mode of vaccine delivery, a widely-used UK live commercial Salmonella Enteritidis vaccine was delivered to pullet chicks either by spray, in drinking water, or in combination with a bivalent vaccine containing inactivated Salmonella Enteritidis and Salmonella Typhimurium. The birds were subsequently challenged with 10(2) or 10(8) colony-forming units (cfu) of Salmonella Enteritidis through drinking water at either six or 20 weeks of age. Ten days after the challenge, the birds were euthanased and their caecal contents cultured for Salmonella. All of the vaccinated groups contained fewer Salmonella Enteritidis-positive birds than the unvaccinated groups. The 'spray-vaccinated' group contained significantly fewer Salmonella Enteritidis-positive birds than the 'water-vaccinated' group after challenge with 10(8) cfu at 20 weeks. However, there was little or no difference at the other challenge time points between the groups that received vaccine through different modes of delivery.


Sensitive tear screening of diabetic retinopathy with dual biomarkers enabled using a rapid electrokinetic patterning platform.
Bead-based immunosensors have intrigued the scientific community over the past decades due to their rapid and multiplexed capabilities in the detection of various biological targets. Nevertheless, their use in the detection of low-abundance analytes remains a continuing challenge because of their limited number of active enrichment approaches. To this end, our research presents a delicate microbead enrichment technique using an optoelectrokinetic platform, followed by the detection of dual biomarkers for the sensitive screening of an eye disease termed diabetic retinopathy (DR). In this study, microbeads turned fluorescent as their surfaces formed sandwiched immunocomplexes in the presence of target antigens. The tiny fluorescent dots were then concentrated using the optoelectrokinetic platform for the enhancement of their signals. The signal rapidly escalated in 10 s, and the optimal limit of detection was nearly 100 pg mL-1. For practical DR screening, two biomarkers, lipocalin 1 (LCN1) and vascular endothelial growth factor (VEGF), were used. Approximately 20 μL of analytes were collected from the tear samples of the tested patients. The concentrations of both biomarkers showed escalating trends with the severity of DR. Two concentration thresholds of LCN1 and VEGF that indicate proliferative DR were determined out of 24 clinical samples based on the receiver operating characteristic curves. For verification, a single-blind test was conducted with additional clinical tear samples from five random subjects. The final outcome of this evaluation showed an accuracy of >80%. This non-invasive screening provides a potential means for the early diagnosis of DR and may increase the screening rate among the high-risk diabetic population in the future.


Destabilization of the HIV-1 reverse transcriptase dimer upon interaction with N-acyl hydrazone inhibitors.
N-(4-tert-butylbenzoyl)-2-hydroxy-1-naphthaldehyde hydrazone (BBNH) inhibits both the DNA polymerase and ribonuclease H (RNase H) activities of the human immunodeficiency virus type 1 reverse transcriptase. In this study, we show that BBNH binding impacts on the stability of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) heterodimer. The Gibbs free energy of dimer dissociation of HIV-1 RT is decreased in the presence of increasing concentrations of BBNH, resulting in a loss in stability of 3.8 kcal mol(-1). To evaluate whether this observed phenomenon was mediated by BBNH binding to one or more sites in RT, we synthesized a variety of BBNH analogs and identified (4-t-butylbenzoyl)-2-hydroxy-1-salicylyl hydrazone (BBSH) and (4,N,N-dimethylaminobenzoyl)-2-hydroxy-1-naphthyl hydrazone as specific inhibitors of RT DNA polymerase or RT RNase H activity, respectively. Interestingly, only BBSH provided significant destabilization of the HIV-1 RT dimer. The identification of these specific inhibitors, in combination with other biochemical data, suggests a model in which two molecules of BBNH bind per RT heterodimer. In this regard, only the binding of hydrazone molecules in the DNA polymerase domain activity elicits the observed destabilization of the HIV-1 RT heterodimer.


Non-surgical versus surgical treatment for oesophageal cancer.
Oesophageal cancer is the sixth most common cause of cancer-related mortality in the world. Currently surgery is the recommended treatment modality when possible. However, it is unclear whether non-surgical treatment options is equivalent to oesophagectomy in terms of survival. To assess the benefits and harms of non-surgical treatment versus oesophagectomy for people with oesophageal cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to 4th March 2016. We also screened reference lists of included studies. Two review authors independently screened all titles and abstracts of articles obtained from the literature searches and selected references for further assessment. For these selected references, we based trial inclusion on assessment of the full-text articles. Two review authors independently extracted study data. We calculated the risk ratio (RR) with 95% confidence interval (CI) for binary outcomes, the mean difference (MD) or the standardised mean difference (SMD) with 95% CI for continuous outcomes, and the hazard ratio (HR) for time-to-event outcomes. We performed meta-analyses where it was meaningful. Eight trials, which included 1132 participants in total, met the inclusion criteria of this Cochrane review. These trials were at high risk of bias trials. One trial (which included five participants) did not contribute any data to this Cochrane review, and we excluded 13 participants in the remaining trials after randomisation; this left a total of 1114 participants, 510 randomised to non-surgical treatment and 604 to surgical treatment for analysis. The non-surgical treatment was definitive chemoradiotherapy in five trials and definitive radiotherapy in three trials. All participants were suitable for major surgery. Most of the data were from trials that compared chemoradiotherapy with surgery. There was no difference in long-term mortality between chemoradiotherapy and surgery (HR 0.88, 95% CI 0.76 to 1.03; 602 participants; four studies; low quality evidence). The long-term mortality was higher in radiotherapy than surgery (HR 1.39, 95% CI 1.18 to 1.64; 512 participants; three studies; very low quality evidence). There was no difference in long-term recurrence between non-surgical treatment and surgery (HR 0.96, 95% CI 0.80 to 1.16; 349 participants; two studies; low quality evidence). The difference between non-surgical and surgical treatments was imprecise for short-term mortality (RR 0.39, 95% CI 0.11 to 1.35; 689 participants; five studies; very low quality evidence), the proportion of participants with serious adverse in three months (RR 0.61, 95% CI 0.25 to 1.47; 80 participants; one study; very low quality evidence), and proportion of people with local recurrence at maximal follow-up (RR 0.89, 95% CI 0.70 to 1.12; 449 participants; three studies; very low quality evidence). The health-related quality of life was higher in non-surgical treatment between four weeks and three months after treatment (Spitzer Quality of Life Index; MD 0.93, 95% CI 0.24 to 1.62; 165 participants; one study; very low quality evidence). The difference between non-surgical and surgical treatments was imprecise for medium-term health-related quality of life (three months to two years after treatment) (Spitzer Quality of Life Index; MD -0.95, 95% CI -2.10 to 0.20; 62 participants; one study; very low quality of evidence). The proportion of people with dysphagia at the last follow-up visit prior to death was higher with definitive chemoradiotherapy compared to surgical treatment (RR 1.48, 95% CI 1.01 to 2.19; 139 participants; one study; very low quality evidence). Based on low quality evidence, chemoradiotherapy appears to be at least equivalent to surgery in terms of short-term and long-term survival in people with oesophageal cancer (squamous cell carcinoma type) who are fit for surgery and are responsive to induction chemoradiotherapy. However, there is uncertainty in the comparison of definitive chemoradiotherapy versus surgery for oesophageal cancer (adenocarcinoma type) and we cannot rule out significant benefits or harms of definitive chemoradiotherapy versus surgery. Based on very low quality evidence, the proportion of people with dysphagia at the last follow-up visit prior to death was higher with definitive chemoradiotherapy compared to surgery. Based on very low quality evidence, radiotherapy results in less long-term survival than surgery in people with oesophageal cancer who are fit for surgery. However, there is a risk of bias and random errors in these results, although the risk of bias in the studies included in this systematic review is likely to be lower than in non-randomised studies.Further trials at low risk of bias are necessary. Such trials need to compare endoscopic treatment with surgical treatment in early stage oesophageal cancer (carcinoma in situ and Stage Ia), and definitive chemoradiotherapy with surgical treatments in other stages of oesophageal cancer, and should measure and report patient-oriented outcomes. Early identification of responders to chemoradiotherapy and better second-line treatment for non-responders will also increase the need and acceptability of trials that compare definitive chemoradiotherapy with surgery.


Construct validity of the Beck Hopelessness Scale (BHS) among university students: A multitrait-multimethod approach.
There is considerable debate about the underlying factor structure of the Beck Hopelessness Scale (BHS) in the literature. An established view is that it reflects a unitary or bidimensional construct in nonclinical samples. There are, however, reasons to reconsider this conceptualization. Based on previous factor analytic findings from both clinical and nonclinical studies, the aim of the present study was to compare 16 competing models of the BHS in a large university student sample (N = 1, 733). Sixteen distinct factor models were specified and tested using conventional confirmatory factor analytic techniques, along with confirmatory bifactor modeling. A 3-factor solution with 2 method effects (i.e., a multitrait-multimethod model) provided the best fit to the data. The reliability of this conceptualization was supported by McDonald's coefficient omega and the differential relationships exhibited between the 3 hopelessness factors ("feelings about the future," "loss of motivation," and "future expectations") and measures of goal disengagement, brooding rumination, suicide ideation, and suicide attempt history. The results provide statistical support for a 3-trait and 2-method factor model, and hence the 3 dimensions of hopelessness theorized by Beck. The theoretical and methodological implications of these findings are discussed. (PsycINFO Database Record


Determining the clinical knowledge and practice of Australian podiatrists on children with developmental coordination disorder: a cross-sectional survey.
Developmental coordination disorder (DCD) is a common condition in children affecting motor coordination. This impacts on academic performance, and activities of daily living. Literature surrounding interventions for DCD has focused mostly on physical and occupational therapies. However, it is known that children with DCD present to podiatrists as these children often also have abnormalities in lower limb functioning associated with the condition. This study aimed to determine current knowledge of Australian podiatrists regarding presentation, assessment, and management of children with developmental coordination disorder. A single-round survey, developed using SurveyMonkey®, was completed by a sample of Australian podiatrists. Data were collected through either online or paper means. Participants were asked about their familiarity with DCD and depending on their response, were directed via skip logic to questions on presentation, assessment and management strategies of DCD in children. Participants were also asked about their willingness and preferences for further education on DCD. Descriptive statistics were used to describe the data. There were 365 Australian podiatrists who completed the survey. There were 30% (n = 109) who reported being familiar with DCD as a diagnosis, while a further 37% (n = 134) reported familiarity with alternate or outdated terminology associated with the DCD diagnosis. Participants who were familiar with DCD or terminology relating to DCD, showed good knowledge of signs and symptoms associated with DCD. Both familiar and unfamiliar participants favoured referral to other health professionals over completing assessments. Common podiatric management strategies such as footwear advice, orthoses, and strength training were the most frequently chosen by both groups, despite current evidence only supporting strength training as an intervention. Participants were willing to receive education on DCD through a range of both online and in-person mediums. The majority of Australian podiatrists were unfamiliar with DCD, despite its prevalence and symptomology falling within the podiatric scope. However, participants did overwhelmingly show willingness to receive further education on DCD. Further research should consider understanding the role of podiatrists in the assessment and management of children with DCD and the impact of the type of treatment strategies that may be provided.


Social inequalities in childhood dental caries: the convergent roles of stress, bacteria and disadvantage.
The studies reported here examines stress-related psychobiological processes that might account for the high, disproportionate rates of dental caries, the most common chronic disease of childhood, among children growing up in low socioeconomic status (SES) families. In two 2004-2006 studies of kindergarten children from varying socioeconomic backgrounds in the San Francisco Bay Area of California (Ns = 94 and 38), we performed detailed dental examinations to count decayed, missing or filled dental surfaces and microtomography to assess the thickness and density of microanatomic dental compartments in exfoliated, deciduous teeth (i.e., the shed, primary dentition). Cross-sectional, multivariate associations were examined between these measures and SES-related risk factors, including household education, financial stressors, basal and reactive salivary cortisol secretion, and the number of oral cariogenic bacteria. We hypothesized that family stressors and stress-related changes in oral biology might explain, fully or in part, the known socioeconomic disparities in dental health. We found that nearly half of the five-year-old children studied had dental caries. Low SES, higher basal salivary cortisol secretion, and larger numbers of cariogenic bacteria were each significantly and independently associated with caries, and higher salivary cortisol reactivity was associated with thinner, softer enamel surfaces in exfoliated teeth. The highest rates of dental pathology were found among children with the combination of elevated salivary cortisol expression and high counts of cariogenic bacteria. The socioeconomic partitioning of childhood dental caries may thus involve social and psychobiological pathways through which lower SES is associated with higher numbers of cariogenic bacteria and higher levels of stress-associated salivary cortisol. This convergence of psychosocial, infectious and stress-related biological processes appears to be implicated in the production of greater cariogenic bacterial growth and in the conferral of an increased physical vulnerability of the developing dentition.