Promoting sunscreen use and skin self-examination to improve early detection and prevent skin cancer: quasi-experimental trial of an adolescent psycho-educational intervention.
Skin cancer rates are increasing. Interventions to increase adolescent sunscreen use and skin self-examination (SSE) are required. Quasi-experimental design; 1 control and 4 intervention group schools in Scotland, UK. Participants were 15-16 year old students on the school register. The intervention was a theoretically-informed (Common-Sense Model and Health Action Process Approach) 50-min presentation, delivered by a skin cancer specialist nurse and young adult skin cancer survivor, to students in a classroom, supplemented by a home-based assignment. Outcome variables were sunscreen use intention, SSE intention/behaviour, planning, illness perceptions and skin cancer communication behaviour, measured 2 weeks pre- and 4 weeks post- intervention using self-completed pen and paper survey. School attendance records were used to record intervention up-take; students self-reported completion of the home-based assignment. Pearson's chi-square test, analysis of variance, and non-parametric Wilcoxon Signed Ranks Test were used to measure outcomes and associations between variables. Focus groups elicited students' (n = 29) views on the intervention. Qualitative data were analysed thematically. Five of 37 invited schools participated. 639 (81%) students in intervention schools received the intervention; 33.8% completed the home-based assignment. 627 (69.6%) of students on the school register in intervention and control schools completed a questionnaire at baseline; data for 455 (72.6%) students were available at baseline and follow-up. Focus groups identified four themes - personal experiences of skin cancer, distaste for sunscreen, relevance of SSE in adolescence, and skin cancer conversations. Statistically significant (p < 0.05) changes were observed for sunscreen use, SSE, planning, and talk about skin cancer in intervention schools but not the control. Significant associations were found between sunscreen use, planning and 2 illness perceptions (identity and consequence) and between SSE, planning and 3 illness perceptions (timeline, causes, control). It is feasible to promote sunscreen use and SSE in the context of an adolescent school-based psychoeducation intention. Further research is required to improve study uptake, intervention adherence and effectiveness. ISRCTN11141528.


Assessment tool for pharmacy drug-drug interaction software.
To assess the performance of pharmacy clinical decision support (CDS) systems for drug-drug interaction (DDI) detection and to identify approaches for improving the ability to recognize important DDIs. Pharmacists rely on CDS systems to assist in the identification of DDIs, and research suggests that these systems perform suboptimally. The software evaluation tool described here may be used in all pharmacy settings that use electronic decision support to detect potential DDIs, including large and small community chain pharmacies, community independent pharmacies, hospital pharmacies, and governmental facility pharmacies. A tool is provided to determine the ability of pharmacy CDS systems to identify established DDIs. It can be adapted to evaluate potential DDIs that reflect local practice patterns and patient safety priorities. Beyond assessing software performance, going through the evaluation processes creates the opportunity to evaluate inadequacies in policies, procedures, workflow, and training of all pharmacy staff relating to pharmacy information systems and DDIs. The DDI evaluation tool can be used to assess pharmacy information systems' ability to recognize relevant DDIs. Suggestions for improvement include determining whether the software allows for customization, creating standard policies for handling specific interactions, and ensuring that drug knowledge database updates occur frequently.


Polymorphism and expression of isoflavone synthase genes from soybean cultivars.
Isoflavones are synthesized by isoflavone synthases via the phenylpropanoid pathway in legumes. We have cloned two isoflavone synthase genes, IFS1 and IFS2, from a total of 18 soybean cultivars. The amino acid residues of the proteins that differed between cultivars were dispersed over the entire coding region. However, amino acid sequence variation did not occur in conserved domains such as the ERR triad region, except that one conserved amino acid was changed in the IFS2 protein of the GS12 cultivar (R374G) and the IFS1 proteins of the 99M06 and Soja99s65 cultivars (A109T, F105I). In three cultivars (99M06, 99M116, and Simheukpi), most of amino acid changes were such that the difference between the amino acid sequences of IFS1 and IFS2 was reduced. The expression profiles of three enzymes that convert naringenin to the isoflavone, genistein, chalcone isomerase (CHI), isoflavone synthase (IFS) and flavanone 3-hydroxylase (F3H) were examined. In general, IFS mRNA was more abundant in etiolated seedlings than mature plants whereas the levels of CHI and F3H mRNAs were similar in the two stages. During seed development, IFS was expressed a little later than CHI and F3H but expression of these three genes was barely detectable, if at all, during later seed hardening. In addition, we found that the levels of CHI, F3H, and IFS mRNAs were under circadian control. We also showed that IFS was induced by wounding and by application of methyl jasmonate to etiolated soybean seedlings.


Origin of Cryptococcus neoformans var. neoformans diploid strains.
The basidiomycetous yeast Cryptococcus neoformans is an important human fungal pathogen. Two varieties, C. neoformans var. neoformans and C. neoformans var. gattii, have been identified. Both are heterothallic with two mating types, MATa and MATalpha. Some rare isolates are self-fertile and are considered occasional diploid or aneuploid strains. In the present study, 133 isolates, mostly from Italian patients, were investigated to detect the presence of diploid strains in the Igiene Università Milano culture collection. All of the diploid isolates were further investigated by different methods to elucidate their origins. Forty-nine diploid strains were identified by flow cytometry. PCR fingerprinting using the (GACA)(4) primer showed that the diploid state was associated with two specific genotypes identified as VN3 and VN4. Determination of mating type on V8 juice medium confirmed that the majority of the strains were sterile. PCR and dot blotting using the two pheromone genes (MFa and MFalpha) as probes identified 36 of the 49 diploid isolates as MATa/alpha. The results of pheromone gene sequencing showed that two allelic MFalpha genes exist and are distinct for serotypes A and D. In contrast, the MFa gene sequence was conserved in both serotype alleles. Amplification of serotype-specific STE20 alleles demonstrated that the diploid strains contained one mating locus inherited from a serotype A parent and one inherited from a serotype D parent. The present results suggest that diploid isolates may be common among the C. neoformans population and that in Italy and other European countries serotype A and D populations are not genetically isolated but are able to recombine by sexual reproduction.


Uncertain impacts on economic growth when stabilizing global temperatures at 1.5°C or 2°C warming.
Empirical evidence suggests that variations in climate affect economic growth across countries over time. However, little is known about the relative impacts of climate change on economic outcomes when global mean surface temperature (GMST) is stabilized at 1.5°C or 2°C warming relative to pre-industrial levels. Here we use a new set of climate simulations under 1.5°C and 2°C warming from the 'Half a degree Additional warming, Prognosis and Projected Impacts' (HAPPI) project to assess changes in economic growth using empirical estimates of climate impacts in a global panel dataset. Panel estimation results that are robust to outliers and breaks suggest that within-year variability of monthly temperatures and precipitation has little effect on economic growth beyond global nonlinear temperature effects. While expected temperature changes under a GMST increase of 1.5°C lead to proportionally higher warming in the Northern Hemisphere, the projected impact on economic growth is larger in the Tropics and Southern Hemisphere. Accounting for econometric estimation and climate uncertainty, the projected impacts on economic growth of 1.5°C warming are close to indistinguishable from current climate conditions, while 2°C warming suggests statistically lower economic growth for a large set of countries (median projected annual growth up to 2% lower). Level projections of gross domestic product (GDP) per capita exhibit high uncertainties, with median projected global average GDP per capita approximately 5% lower at the end of the century under 2°C warming relative to 1.5°C. The correlation between climate-induced reductions in per capita GDP growth and national income levels is significant at the p < 0.001 level, with lower-income countries experiencing greater losses, which may increase economic inequality between countries and is relevant to discussions of loss and damage under the United Nations Framework Convention on Climate Change.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.


The risk of respiratory symptoms on allergen exposure increases with increasing specific IgE levels.
The relation between IgE sensitization and allergic respiratory symptoms has usually been evaluated by dichotomizing specific IgE levels. The aim of this study was to evaluate the association between specific IgE levels and risk of symptoms on allergen-related exposure, with special reference to allergen-related asthma-rhinitis comorbidity. We considered 6391 subjects enrolled within the European Community Respiratory Health Survey 2, having information on cat/grass/D. pteronyssinus IgE levels and symptoms on exposure to animals/pollen/dust. The risk of oculonasal/asthmalike/both symptoms was evaluated by a multinomial logistic model. A clear positive association was observed between specific IgE levels to cat/grass/mite and the risk of symptoms on each allergen-related exposure (test for trend with P < 0.001). This trend was particularly pronounced when considering the coexistence of asthmalike and oculonasal symptoms. Compared to non-sensitized subjects, subjects with specific IgE to cat >= 3.5 kU/l presented relative risk ratios of 11.4 (95% CI 6.7-19.2), 18.8 (8.2-42.8), and 55.3 (30.5-100.2) when considering, respectively, only oculonasal symptoms, only asthmalike symptoms, or both. A similar pattern was observed when considering specific IgE to grass/mite and symptoms on exposure to pollen/dust. Also the proportion of people using inhaled medicines or visiting a general practitioner for breathing problems in the previous year increased with increasing sum of specific IgE to cat/grass/mite. Specific IgE level is the most important predictor of allergen-related symptoms. The risk of both oculonasal/asthmalike symptoms increases with specific IgE levels, suggesting that specific IgE contributes to the 'united airways disease'.


Characterization of cardiac-resident progenitor cells expressing high aldehyde dehydrogenase activity.
High aldehyde dehydrogenase (ALDH) activity has been associated with stem and progenitor cells in various tissues. Human cord blood and bone marrow ALDH-bright (ALDH(br)) cells have displayed angiogenic activity in preclinical studies and have been shown to be safe in clinical trials in patients with ischemic cardiovascular disease. The presence of ALDH(br) cells in the heart has not been evaluated so far. We have characterized ALDH(br) cells isolated from mouse hearts. One percent of nonmyocytic cells from neonatal and adult hearts were ALDH(br). ALDH(very-br) cells were more frequent in neonatal hearts than adult. ALDH(br) cells were more frequent in atria than ventricles. Expression of ALDH1A1 isozyme transcripts was highest in ALDH(very-br) cells, intermediate in ALDH(br) cells, and lowest in ALDH(dim) cells. ALDH1A2 expression was highest in ALDH(very-br) cells, intermediate in ALDH(dim) cells, and lowest in ALDH(br) cells. ALDH1A3 and ALDH2 expression was detectable in ALDH(very-br) and ALDH(br) cells, unlike ALDH(dim) cells, albeit at lower levels compared with ALDH1A1 and ALDH1A2. Freshly isolated ALDH(br) cells were enriched for cells expressing stem cell antigen-1, CD34, CD90, CD44, and CD106. ALDH(br) cells, unlike ALDH(dim) cells, could be grown in culture for more than 40 passages. They expressed sarcomeric α -actinin and could be differentiated along multiple mesenchymal lineages. However, the proportion of ALDH(br) cells declined with cell passage. In conclusion, the cardiac-derived ALDH(br) population is enriched for progenitor cells that exhibit mesenchymal progenitor-like characteristics and can be expanded in culture. The regenerative potential of cardiac-derived ALDH(br) cells remains to be evaluated.


Hepatocyte ploidy and pathological mutations in hepatocellular carcinoma: impact on oncogenesis and therapeutics.
Hepatocellular carcinoma (HCC) occurs in the chronic liver inflammation such as viral hepatitis, alcoholic and non-alcoholic steatohepatitis. While anti-viral treatment has been significantly improved, the prevalence of HCC remains high and treatment is still challenging. The continuation of hepatocyte death, inflammation, and fibrosis leads to the accumulation of gene alterations, which may trigger carcinogenesis. Hepatocytes are a unique cell type having more than one complete set of 23 chromosomes, termed polyploidy. Due to gene redundancy, hepatocytes may tolerate lethal mutations. Next generation sequencing technology has revealed gene alterations in HCC related to telomere maintenance, Wnt/β-catenin pathway, p53 cell-cycle pathway, epigenetic modifiers, oxidative stress pathway, PI3K/AKT/mTOR, and RAS/RAF/MAPK pathway with or without a chromosomal instability. Some type of driver gene mutations accumulates in hepatocytes and breaks the orchestration of excessive copies of chromosomes, which may lead to unfavorable gene expressions and fuel tumorigenesis. Recently, molecular targeted drugs, developed with the aim of interfering with these signaling pathways, are being used for HCC patients in the clinics. Therefore, a deeper understanding of hepatocyte ploidy and genetic or epigenetic alterations is indispensable for the establishment of novel therapeutic strategies against HCC.


Structure of rotavirus outer-layer protein VP7 bound with a neutralizing Fab.
Rotavirus outer-layer protein VP7 is a principal target of protective antibodies. Removal of free calcium ions (Ca2+) dissociates VP7 trimers into monomers, releasing VP7 from the virion, and initiates penetration-inducing conformational changes in the other outer-layer protein, VP4. We report the crystal structure at 3.4 angstrom resolution of VP7 bound with the Fab fragment of a neutralizing monoclonal antibody. The Fab binds across the outer surface of the intersubunit contact, which contains two Ca2+ sites. Mutations that escape neutralization by other antibodies suggest that the same region bears the epitopes of most neutralizing antibodies. The monovalent Fab is sufficient to neutralize infectivity. We propose that neutralizing antibodies against VP7 act by stabilizing the trimer, thereby inhibiting the uncoating trigger for VP4 rearrangement. A disulfide-linked trimer is a potential subunit immunogen.


Mycobacterium fortuitum infection arising in a new tattoo.
We report an uncommon case of a cutaneous infection with Mycobacterium fortuitum arising in a new tattoo. A 29-year-old man presented with a several month history of a non-pruritic papular eruption within a tattoo; the papules developed 1-to-2 weeks after the tattoo procedure. He denied similar symptoms with previous tattoos. He had been treated unsuccessfully with cephalexin. Histopathologic examination revealed perifollicular chronic and granulomatous inflammation, consistent with chronic folliculitis. Acid-fast bacilli culture identified Mycobacterium fortuitum complex. The patient was treated with a 2-month course of oral trimethoprim-sulfamethoxazole (160mg/800mg twice daily) and ciprofloxacin (250 mg twice daily), with clinical improvement at follow up after three weeks of the antibiotic regimen. Rapidly growing mycobacteria have emerged as a cause of tattoo-associated cutaneous infection in recent years. Diagnosis and treatment can be difficult without clinical suspicion. M. fortuitum and other rapidly growing mycobacteria should be considered in the differential diagnosis of tattoo-associated dermatologic complications.


Fall incidence in frail older women after individualized visual feedback-based balance training.
The knowledge concerning balance training actually lowering fall rates among frail older persons is limited. The aim of this study was to examine the effects of a 4-week individualized visual feedback-based balance training on the fall incidence during 1-year follow-up among frail older women living in residential care. Twenty-seven older women from 2 residential care homes were randomized into exercise (n = 20) and control (n = 7) groups. Balance measurements were carried out before and after a 4-week training period and falls were monitored by monthly diaries for 1 year. An interview about fear of falling and physical activity was completed before and after the intervention and after the 1-year follow-up. A positive effect of balance training on fall incidence was found. A dynamic Poisson regression model showed that during the follow-up the monthly risk of falling was decreased in the exercise group compared to controls (risk ratio 0.398, 95% CI 0.174-0.911, p = 0.029). In addition, the exercise group reported a reduced fear of falling and increased physical activity after a training period but these changes declined during the follow-up period. Individualized visual feedback-based balance training was shown to be a promising method for fall prevention among frail older women. High compliance (97.5%) with the training program showed that carefully targeted training programs can be carried out among older people with health limitations.


Alterations in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure.
We sought to assess the distribution of collagen deposits and collagen degradation in hypertensive patients with either systolic heart failure (SHF) or diastolic heart failure (DHF). Increased collagen synthesis and deposition have been described in the myocardium of heart failure (HF) hypertensive patients. We studied 39 HF hypertensive patients subdivided into two groups: 16 with SHF and 23 with DHF. Endomyocardial biopsies were performed to quantify mysial (i.e., perimysial plus endomysial) and perivascular and scar-related collagen volume fraction (CVF). Matrix metalloproteinase (MMP)-1 and its tissue inhibitor matrix metalloproteinase (TIMP)-1 were analyzed in cardiac samples by Western blot and immunohistochemistry, and in blood samples by enzyme-linked immunosorbent assay. Mysial CVF was lower in SHF hypertensive patients than in normotensive (p < 0.05) and DHF hypertensive patients (p < 0.01). Perivascular and scar-related CVF was higher (p < 0.05) in the two groups of hypertensive patients than in normotensive subjects, and in SHF hypertensive compared with DHF hypertensive patients. The MMP-1:TIMP-1 ratio was increased (p < 0.05) in tissue and serum samples from the SHF hypertensive group compared with the other two groups of subjects. The MMP-1 expression was increased (p < 0.01) in the interstitium and cardiomyocytes of SHF hypertensive patients compared with DHF hypertensive and normotensive subjects. The serum MMP-1:TIMP-1 ratio was inversely correlated with ejection fraction (r = -0.510, p < 0.001) and directly correlated with left ventricular end-diastolic diameter (r = 0.549, p < 0.001) in all subjects. These findings show that the pattern of collagen deposits and the balance of the MMP-1/TIMP-1 system are different in the myocardium of SHF and DHF hypertensive patients. It is proposed that excessive degradation of mysial collagen may be related to the compromise of systolic function in HF hypertensive patients.


Smoking cessation interventions and cessation rates in the oncology population: an updated systematic review and meta-analysis.
To evaluate tobacco smoking cessation interventions and cessation rates in the oncology population through a systematic review and meta-analysis. The literature was searched using PubMed, Google Scholar, Medline, EMBASE, and the Cochrane Library (inception to October 2012) by 3 independent review authors. Studies were included if they were randomized controlled trials (RCTs) or prospective cohort (PCs) studies evaluating tobacco smoking cessation interventions with patients assigned to a usual care or an intervention group. The primary outcome measure was smoking cessation rates. Two authors extracted data independently for each study. When applicable, disagreements were resolved by consensus. The systematic review identified 10 RCTs and 3 PCs. Statistical analysis was conducted using StatsDirect software (Cheshire, UK). Pooled odds ratios (ORs) for smoking cessation interventions were calculated in 2 groups based on follow-up duration. The therapeutic interventions included counseling, nicotine replacement therapy, buproprion, and varenicline. Smoking cessation interventions had a pooled odds ratio of 1.54 (95% confidence interval [CI], 0.909-2.64) for patients in the shorter follow-up group and 1.31 (95% CI, 0.931-1.84) in the longer follow-up group. Smoking cessation interventions in the perioperative period had a pooled odds ratio of 2.31 (95% CI, 1.32-4.07). Our systematic review and meta-analysis demonstrate that tobacco cessation interventions in the oncology population, in both the short-term and long-term follow-up groups, do not significantly affect cessation rates. The perioperative period, though, may represent an important teachable moment with regard to smoking cessation.


Cough headache: a study of 83 consecutive patients.
To delineate the differences in clinical characteristics and evaluate the outcome between primary and secondary cough headache, 83 consecutive patients (59M/24F, mean age 61.5 +/- 17.7 years) with cough headache (1.2%) out of 7100 patients in a headache clinic were studied. All of them received brain imaging studies. Most did not have relevant brain lesions (n = 74, 89.2%, primary group) except for nine patients (10.8%, the secondary group). Most of the intracranial lesions were located in the posterior fossa (n = 6, 67%), including only two patients with Chiari malformation. The primary group had a higher response rate to indomethacin than the secondary group (72.7% vs. 37.5 %, P = 0.046). Mild to moderate headache intensity and age onset < 50 years predicted a favourable response. At a mean follow-up of 51.4 months, 83.9% of patients with primary cough headache completely remitted. Inconsistent with the proposed International Classification of Headache Disorders, 2nd edn criteria, 10.8% of patients with primary cough headache had headache duration of > 30 min. Clinical features, neurological examinations and drug response could not safely differentiate primary from secondary cough headache. Neuroimaging studies are required in each patient.


Drosophila homologs of two mammalian intracellular Ca(2+)-release channels: identification and expression patterns of the inositol 1,4,5-triphosphate and the ryanodine receptor genes.
We have identified and cloned portions of two Drosophila genes homologous to two classes of mammalian intracellular Ca(2+)-release channels, the ryanodine receptor and the inositol 1,4,5-triphosphate (IP3) receptor. The Drosophila ryanodine receptor gene (dry) encodes an approx. 15 kb mRNA. It is expressed in the mesoderm of early stage-9 embryos and subsequently in somatic muscles and their precursor cells. In adults, dry mRNA was detected in tubular muscles and at a lower level in neuronal tissues. Embryonic expression of the Drosophila IP3 receptor gene (dip) appears more dynamic and is associated with developing anterior sense organs. In adults, dip expression occurs in several tissues, and relatively high levels of dip mRNA in adult antennae suggest a role for this gene product during olfactory transduction.


Changes in functional status related to health maintenance visits to family physicians.
Physicians do not provide preventive care at the level recommended by national organizations. This may be because of physicians' lack of training or low level of confidence or because of patients' fears, beliefs, and lack of health knowledge. We used an observational prospective cohort study in an academic family practice office to investigate changes in patients' functional status associated with receiving recommendations to change behavior from family physicians. Patients 18 years and older presenting for health maintenance visits to family physicians completed a functional status instrument and a brief intake questionnaire by telephone before their visit. After the visit patients were randomized to a debriefing interview or an observation-only group. The interview included the Patient/Doctor Interaction Scale and an assessment of whether patients received a recommendation to change behavior. One hundred thirty-two patients were randomized to the debriefing group, and of those, 92% completed assessments at 3 months. Patients reporting recommendations to change behavior had lower scores at 1 and 3 months for mental health, social health, and self-esteem and higher anxiety and depression scores than patients not receiving these recommendations. There are declines in social and emotional functional status in patients presenting to family practice clinicians for health maintenance visits during which recommendations for behavioral change were made. Such declines may inhibit physicians from making recommendations for behavioral change or patients from accepting them.


Use of carboxymethyl cellulose and collagen carrier with equine bone lyophilisate suggests late onset bone regenerative effect in a humerus drill defect - a pilot study in six sheep.
We assessed the use of a filler compound together with the osteoinductive demineralized bone matrix (DBM), Colloss E. The filler was comprised of carboxymethyl-cellulose and collagen type 1. The purpose of the study was to see if the filler compound would enhance the bone formation and distribute the osteoinductive stimulus throughout the bone defect. Six sheep underwent a bilateral humerus drill defect. The drill hole was filled with a compound consisting of 100 mg CMC, 100 mg collagen powder, and 1 ccm autologous full blood in one side, and a combination of this filler compound and 20 mg Colloss E in the other. The animals were divided into three groups of two animals and observed for 8, 12 and 16 weeks. Drill holes was evaluated using quantitative computed tomography (QCT), micro computed tomography (microCT) and histomorphometry. Mean total bone mineral density (BMD) of each implantation site was calculated with both QCT and microCT. Bone volume to total volume (BV/TV) was analyzed using microCT and histomorphometry. Although not statistically significant, results showed increased bone BMD after 16 weeks in microCT data and an increased BV/TV after 16 weeks in both microCT and histology. Correlation between QCT and microCT was R(2) = 0.804. Correlation between histomorphometry and microCT BV/TV data was R(2) = 0.8935 and with an average overrepresentation of 8.2% in histomorphometry. In conclusion the CMC-Collagen + Colloss E filler seems like a viable osteogenic bone filler mid- to long term. A correlation was found between the analytical methods used in this study.


Racial differences in treatment and survival in older patients with diffuse large B-cell lymphoma (DLBCL).
Diffuse large B-cell lymphoma (DLBCL) comprises 31% of lymphomas in the United States. Although it is an aggressive type of lymphoma, 40% to 50% of patients are cured with treatment. The study objectives were to identify patient factors associated with treatment and survival in DLBCL. Using Surveillance, Epidemiology, and End Results (SEER) registry data linked to Medicare claims, we identified 7,048 patients diagnosed with DLBCL between January 1, 2001 and December 31, 2005. Patients were followed from diagnosis until the end of their claims history (maximum December 31, 2007) or death. Medicare claims were used to characterize the first infused chemo-immunotherapy (C-I therapy) regimen and to identify radiation. Multivariate analyses were performed to identify patient demographic, socioeconomic, and clinical factors associated with treatment and with survival. Outcomes variables in the survival analysis were all-cause mortality, non-Hodgkin's lymphoma (NHL) mortality, and other/unknown cause mortality. Overall, 84% (n = 5,887) received C-I therapy or radiation treatment during the observation period: both, 26%; C-I therapy alone, 53%; and radiation alone, 5%. Median age at diagnosis was 77 years, 54% were female, 88% were white, and 43% had Stage III or IV disease at diagnosis. The median time to first treatment was 42 days, and 92% of these patients had received their first treatment by day 180 following diagnosis. In multivariate analysis, the treatment rate was significantly lower among patients ≥ 80 years old, blacks versus whites, those living in a census tract with ≥ 12% poverty, and extra-nodal disease. Blacks had a lower treatment rate overall (Hazard Ratio [HR] 0.77; P < 0.001), and were less likely to receive treatment within 180 days of diagnosis (Odds Ratio [OR] 0.63; P = 0.002) than whites. In multivariate survival analysis, black race was associated with higher all-cause mortality (HR 1.24; P = 0.01) and other/unknown cause mortality (HR 1.35; P = 0.01), but not mortality due to NHL (HR 1.16; P = 0.19). In elderly patients diagnosed with DLBCL, there are large differences in treatment access and survival between blacks and whites.


Revisited anti-inflammatory activity of matricine in vitro: Comparison with chamazulene.
The proazulene matricine (1) is present in chamomile flower heads and has been proven to exhibit strong in vivo anti-inflammatory activity. In contrast to other secondary metabolites in chamomile preparations like its degradation product chamazulene (2), no plausible targets have been found to explain this activity. Therefore we revisited 1 regarding its in vitro anti-inflammatory activity in cellular and molecular studies. Using ICAM-1 as a marker for NF-κB activation, it was shown that ICAM-1 protein expression induced by TNF-α and LPS, but not by IFN-γ, was remarkably inhibited by 1 in endothelial cells (HMEC-1). Inhibition was concentration-dependent in a micromolar range (10-75 μM) and did not involve cytotoxic effects. At 75 μM expression of the adhesion molecule ICAM-1 was down to 52.7 ± 3.3% and 20.4 ± 1.8% of control in TNF-α and LPS-stimulated HMEC-1, respectively. In contrast, 2 showed no activity. Quantitative RT-PCR experiments revealed that TNF-α-induced expression of the ICAM-1 gene was also reduced by 1 in a concentration-dependent manner, reaching 32.3 ± 6.2% of control at 100 μM matricine. Additional functional assays (NF-κB promotor activity and cytoplasm to nucleus translocation) confirmed the inhibitory effect of 1 on NF-κB signaling. Despite the fact that 1 lacks an α,β-unsaturated carbonyl and is thus not able to act via a Michael reaction with electron rich SH groups of functional biological molecules, data gave strong evidence that 1 inhibits NF-κB transcriptional activity in endothelial cells by an hitherto unknown mechanism and this may contribute to its well-known anti-inflammatory activity in vivo.


Implementation of a structured paediatric admission record for district hospitals in Kenya--results of a pilot study.
The structured admission form is an apparently simple measure to improve data quality. Poor motivation, lack of supervision, lack of resources and other factors are conceivably major barriers to their successful use in a Kenyan public hospital setting. Here we have examined the feasibility and acceptability of a structured paediatric admission record (PAR) for district hospitals as a means of improving documentation of illness. The PAR was primarily based on symptoms and signs included in the Integrated Management of Childhood Illness (IMCI) diagnostic algorithms. It was introduced with a three-hour training session, repeated subsequently for those absent, aiming for complete coverage of admitting clinical staff. Data from consecutive records before (n = 163) and from a 60% random sample of dates after intervention (n = 705) were then collected to evaluate record quality. The post-intervention period was further divided into four 2-month blocks by open, feedback meetings for hospital staff on the uptake and completeness of the PAR. The frequency of use of the PAR increased from 50% in the first 2 months to 84% in the final 2 months, although there was significant variation in use among clinicians. The quality of documentation also improved considerably over time. For example documentation of skin turgor in cases of diarrhoea improved from 2% pre-intervention to 83% in the final 2 months of observation. Even in the area of preventive care documentation of immunization status improved from 1% of children before intervention to 21% in the final 2 months. The PAR was well accepted by most clinicians and greatly improved documentation of features recommended by IMCI for identifying and classifying severity of common diseases. The PAR could provide a useful platform for implementing standard referral care treatment guidelines.


Hyperbaric Oxygen Therapy for Second-Degree Burn Healing: An Experimental Study in Rabbits.
The wound healing process includes inflammation, proliferation, and remodelling phases, the main features of which are inflammation, neoangiogenesis, and epithelialization. Hyperbaric oxygen therapy (HBOT) is one modality postulated to improve wound healing. The objective of this study was to determine whether HBOT could improve selected features of burn wound healing in an experimental rabbit model. Researchers conducted an experimental study with 36 rabbits given second-degree burns. Subjects were separated into two groups: a control group (n = 18) and an intervention group that was given HBOT at 2.4 atmospheres absolute for 6 days (n = 18). The main outcome measure was wound healing. Compared with the control group, the HBOT group showed more robust inflammatory cells (P = .025) and epithelialization (P = .024), but no significant difference in angiogenesis (P = .442). The authors conclude that HBOT may improve second-degree burn healing by increasing inflammatory cell migration and re-epithelialization.


Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline.
The objective is to formulate clinical practice guidelines for treating Cushing's syndrome. Participants include an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. The European Society for Endocrinology co-sponsored the guideline. The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews and used the best available evidence from other published systematic reviews and individual studies. The Task Force achieved consensus through one group meeting, several conference calls, and numerous e-mail communications. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Treatment of Cushing's syndrome is essential to reduce mortality and associated comorbidities. Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities via directly treating the cause of Cushing's syndrome and by adjunctive treatments (eg, antihypertensives). Surgical resection of the causal lesion(s) is generally the first-line approach. The choice of second-line treatments, including medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors), must be individualized to each patient.


Variation in lung cancer risk by smoky coal subtype in Xuanwei, China.
Lung cancer rates in Xuanwei County have been among the highest in China for both males and females and have been causally associated with exposure to indoor smoky (bituminous) coal emissions that contain very high levels of polycyclic aromatic hydrocarbons. There are numerous coal mines across the County. Although lung cancer risk is strongly associated with the use of smoky coal as a whole, variation in risk by smoky coal subtype has not been characterized as yet. We conducted a population-based case-control study of 498 lung cancer cases and 498 controls, individually matched to case subjects on age (+/-2 years) and sex to examine risk by coal subtype. Odds ratios (ORs) and 95% confidence intervals (CIs) for coal subtype were calculated by conditional logistic regression, adjusting for potential confounders. Overall, smoky coal use was positively and statistically significantly associated with lung cancer risk, when compared with the use of smokeless coal or wood (OR = 7.7, 95% CI = 4.5-13.3). Furthermore, there was a marked heterogeneity in risk estimates for specific subtypes of smoky coal (test for heterogeneity: p = 5.17 x 10(-10)). Estimates were highest for coal of the Laibin (OR = 24.8, 95% CI = 12.4-49.6) and Longtan (OR = 11.6, 95% CI = 5.0-27.2) coal types and lower for coal from other subtypes. These findings strongly suggest that in Xuanwei and elsewhere, the carcinogenic potential of coal combustion products can exhibit substantial local variation by specific coal source.


Probing the breadth of macrolide glycosyltransferases: in vitro remodeling of a polyketide antibiotic creates active bacterial uptake and enhances potency.
The glycan portion of macrolide antibiotics modulates their efficacy. High-level expression of three macrolide GTs and kinetic analysis has revealed a highly selective synthetic "tool kit" with such plasticity that 12 glycan-modified macrolide antibiotics have been readily created. One of these (1-Gal) is enhanced over its parent oleandomycin (1) by "glycotargeting", allowing higher uptake through active internalization by virtue of the attachment of a glycan (Gal) not normally found on 1. Subsequent release of the targeting glycan by endogenous galactosidase activity releases 1.


Public housing and healthcare use: an investigation using linked administrative data.
This study investigated whether a move to public housing affects people's use of healthcare services. Using administrative data from Manitoba, the number of hospitalizations, general practitioner (GP), specialist and emergency department (ED) visits, and prescription drugs dispensed in the years before and after the housing move-in date (2012/2013) were measured for a public housing and matched cohort. Generalized linear models with generalized estimating equations tested for differences between the cohorts in utilization trends. The data were modeled using Poisson (rate ratio, RR), negative binomial (incident rate ratio, IRR), and binomial (odds ratio, OR) distributions. GP visits (IRR = 1.04, 95% CI 1.01-1.06) and prescriptions (IRR = 1.04, 95% CI 1.02-1.05) increased, while ED visits (RR = 0.90, 95% CI 0.82-1.00) and hospitalizations (OR = 0.95, 95% CI 0.93-0.96) decreased over time. The public housing cohort had a significantly higher rate of GP visits (IRR = 1.08, 95% CI 1.04-1.13), ED visits (RR = 1.18, 95% CI 1.01-1.37), and prescriptions (IRR = 1.09, 95% CI 1.05-1.13), and was more likely to be hospitalized (OR = 1.39, 95% CI 1.21-1.61) compared to the matched cohort. The rate of inpatient days significantly decreased for the public housing cohort, but did not change for the matched cohort. Healthcare use changed similarly over time (except inpatient days) for the two cohorts. Public housing provides a basic need to a population who has a high burden of disease and who may not be able to obtain and maintain housing in the private market.


Fragment analysis of single-molecule conduction.
In the tight-binding source and sink potential model of transmission in single-molecule pi-conjugated conductors, vanishing of the opacity polynomial defines a necessary condition for zero conductance at a given energy. Theorems are given for calculating opacity polynomials of composite devices in terms of opacity and characteristic polynomials of the subunits. These relations rationalize the positions and shapes of zeros in transmission curves for devices consisting of molecules with side chains or of units assembled in series and take an especially simple form for polymeric molecules with identical repeat units.


Extinct New Zealand megafauna were not in decline before human colonization.
The extinction of New Zealand's moa (Aves: Dinornithiformes) followed the arrival of humans in the late 13th century and was the final event of the prehistoric Late Quaternary megafauna extinctions. Determining the state of the moa populations in the pre-extinction period is fundamental to understanding the causes of the event. We sampled 281 moa individuals and combined radiocarbon dating with ancient DNA analyses to help resolve the extinction debate and gain insights into moa biology. The samples, which were predominantly from the last 4,000 years preceding the extinction, represent four sympatric moa species excavated from five adjacent fossil deposits. We characterized the moa assemblage using mitochondrial DNA and nuclear microsatellite markers developed specifically for moa. Although genetic diversity differed significantly among the four species, we found that the millennia preceding the extinction were characterized by a remarkable degree of genetic stability in all species, with no loss of heterozygosity and no shifts in allele frequencies over time. The extinction event itself was too rapid to be manifested in the moa gene pools. Contradicting previous claims of a decline in moa before Polynesian settlement in New Zealand, our findings indicate that the populations were large and stable before suddenly disappearing. This interpretation is supported by approximate Bayesian computation analyses. Our analyses consolidate the disappearance of moa as the most rapid, human-facilitated megafauna extinction documented to date.


Pax9 and Jagged1 act downstream of Gli3 in vertebrate limb development.
From early in limb development the transcription factor Gli3 acts to define boundaries of gene expression along the anterior-posterior (AP) axis, establishing asymmetric patterns required to provide positional information. As limb development proceeds, posterior mesenchyme expression of Sonic hedgehog (Shh) regulates Gli3 transcription and post-translational processing to specify digit number and identity. The molecular cascades dependent on Gli3 at later stages of limb development, which link early patterning events with final digit morphogenesis, remain poorly characterised. By analysing the transcriptional consequences of loss of Gli3 in the anterior margin of the E11.5 and E12.5 limb bud in the polydactylous mouse mutant extra-toes (Gli3(Xt/Xt)), we have identified a number of known and novel transcripts dependent on Gli3 in the limb. In particular, we demonstrated that the genes encoding the paired box transcription factor Pax9, the Notch ligand Jagged1 and the cell surface receptor Cdo are dependent on Gli3 for correct expression in the anterior limb mesenchyme. Analysis of expression in compound Shh;Gli3 mutant mouse embryos and in both in vitro and in vivo Shh signaling assays, further defined the importance of Shh regulated processing of Gli3 in controlling gene expression. In particular Pax9 regulation by Shh and Gli3 was shown to be context dependent, with major differences between the limb and somite revealed by Shh bead implantation experiments in the chick. Jagged1 was shown to be induced by Shh in the chick limb and in a C3H10T1/2 cell based signaling assay, with Shh;Gli3 mutant analysis indicating that expression is dependent on Gli3 derepression. Our data have also revealed that perturbation of early patterning events within the Gli3(Xt/Xt) limb culminates in a specific delay of anterior chondrogenesis which is subsequently realised as extra digits.


School-based management of the child with an acute asthma episode.
Asthma is a chronic inflammatory disorder of the airways that affects 5 million American children. In the past decade, asthma morbidity has dramatically increased. This increase is particularly apparent in poor minority inner-city children. School-based health centers offer a conveniently located setting for the acute treatment and long-term management of childhood asthma. Treatment of asthma using the most recent management guidelines offered in a school setting should result in a decrease in the morbidity and mortality associated with pediatric asthma.


Assessing the Collective Population Representativeness of Related Type 2 Diabetes Trials by Combining Public Data from ClinicalTrials.gov and NHANES.
Randomized controlled trials generate high-quality medical evidence. However, the use of unjustified inclusion/exclusion criteria may compromise the external validity of a study. We have introduced a method to assess the population representativeness of related clinical trials using electronic health record (EHR) data. As EHR data may not perfectly represent the real-world patient population, in this work, we further validated the method and its results using the National Health and Nutrition Examination Survey (NHANES) data. We visualized and quantified the differences in the distributions of age, HbA1c, and BMI among the target population of Type 2 diabetes trials, diabetics in NHANES databases, and a convenience sample of patients enrolled in selected Type 2 diabetes trials. The results are consistent with the previous study.


Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis.
Objective To assess the impact of incretin based treatment on all cause mortality in patients with type 2 diabetes.Design Systematic review and meta-analysis of randomised trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov.Eligibility criteria Randomised controlled trials that compared glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors with placebo or active anti-diabetic drugs in patients with type 2 diabetes.Data collection and analysis Paired reviewers independently screened citations, assessed risk of bias of included studies, and extracted data. Peto's method was used as the primary approach to pool effect estimates from trials, sensitivity analyses were carried out with other statistical approaches, and meta-regression was applied for six prespecified hypotheses to explore heterogeneity. The GRADE approach was used to rate the quality of evidence.Results 189 randomised controlled trials (n=155 145) were included, all of which were at low to moderate risk of bias; 77 reported no events of death and 112 reported 3888 deaths among 151 614 patients. Meta-analysis of 189 trials showed no difference in all cause mortality between incretin drugs versus control (1925/84 136 v 1963/67 478; odds ratio 0.96, 95% confidence interval 0.90 to 1.02, I2=0%; risk difference 3 fewer events (95% confidence interval 7 fewer to 1 more) per 1000 patients over five years; moderate quality evidence). Results suggested the possibility of a mortality benefit with GLP-1 agonists but not DPP-4 inhibitors, but the subgroup hypothesis had low credibility. Sensitivity analyses showed no important differences in the estimates of effects.Conclusions Current evidence does not support the suggestion that incretin based treatment increases all cause mortality in patients with type 2 diabetes. Further studies are warranted to examine if the effect differs between GLP-1 agonists versus DPP-4 inhibitors.


Patterns of sociocognitive stratification and perinatal risk in the child brain.
The expanding behavioral repertoire of the developing brain during childhood and adolescence is shaped by complex brain-environment interactions and flavored by unique life experiences. The transition into young adulthood offers opportunities for adaptation and growth but also increased susceptibility to environmental perturbations, such as the characteristics of social relationships, family environment, quality of schools and activities, financial security, urbanization and pollution, drugs, cultural practices, and values, that all act in concert with our genetic architecture and biology. Our multivariate brain-behavior mapping in 7,577 children aged 9 to 11 y across 585 brain imaging phenotypes and 617 cognitive, behavioral, psychosocial, and socioeconomic measures revealed three population modes of brain covariation, which were robust as assessed by cross-validation and permutation testing, taking into account siblings and twins, identified using genetic data. The first mode revealed traces of perinatal complications, including preterm and twin birth, eclampsia and toxemia, shorter period of breastfeeding, and lower cognitive scores, with higher cortical thickness and lower cortical areas and volumes. The second mode reflected a pattern of sociocognitive stratification, linking lower cognitive ability and socioeconomic status to lower cortical thickness, area, and volumes. The third mode captured a pattern related to urbanicity, with particulate matter pollution (PM25) inversely related to home value, walkability, and population density, associated with diffusion properties of white matter tracts. These results underscore the importance of a multidimensional and interdisciplinary understanding, integrating social, psychological, and biological sciences, to map the constituents of healthy development and to identify factors that may precede maladjustment and mental illness.


Identified obstacles and prerequisites in telenurses' work environment - a modified Delphi study.
Telenursing is an expanding part of healthcare, staffed with registered nurses whose work environment is typical of a call centre. Work-related stress has been shown to be a major problem in nurses' work environments and of importance to the outcome of care, patient safety, nurse job satisfaction and burnout. Today, however, we have a limited understanding of and knowledge about the work environment for telenurses. The aim of the present study is to explore and reach consensus on perceived important obstacles and prerequisites in telenurses' work environment. A modified Delphi design, using qualitative as well as quantitative data sequentially through three phases, was taken. Data were initially collected via semi-structured interviews (Phase I) and later using a web survey (Phase II-III) between March 2015 and March 2016. The findings present a consensus view of telenurses' experiences of important obstacles and prerequisites in their work environment. Central to the findings are the aspects of telenurses having a demanding work, cognitive fatigue and having no opportunity for recovery during the work shift was ranked as important obstacles. Highly ranked prerequisites for managing were being able to focus on one caller at a time, working in a calm and pleasant environment and having technical support 24/7. Managers need to enable telenurses to experience control in their work, provided with possibilities to control their work and to recover during work; shortening work time could improve their work environment. Limited possibilities to perform work might contribute to feelings of stress and inability to perform work.


De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders.
Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study. We identified four unrelated individuals with damaging de novo variants in MYRF (P = 5.3x10(-8)), including one likely gene-disrupting (LGD) and three deleterious missense (D-mis) variants. Eight additional individuals with de novo LGD or missense variants were identified from our other genetic studies or from the literature. Common phenotypes of MYRF de novo variant carriers include CDH, congenital heart disease and genitourinary abnormalities, suggesting that it represents a novel syndrome. MYRF is a membrane associated transcriptional factor highly expressed in developing diaphragm and is depleted of LGD variants in the general population. All de novo missense variants aggregated in two functional protein domains. Analyzing the transcriptome of patient-derived diaphragm fibroblast cells suggest that disease associated variants abolish the transcription factor activity. Furthermore, we showed that the remaining genes with damaging variants in CDH significantly overlap with genes implicated in other developmental disorders. Gene expression patterns and patient phenotypes support pleiotropic effects of damaging variants in these genes on CDH and other developmental disorders. Finally, functional enrichment analysis implicates the disruption of regulation of gene expression, kinase activities, intra-cellular signaling, and cytoskeleton organization as pathogenic mechanisms in CDH.


Binding of anti-GRP78 autoantibodies to cell surface GRP78 increases tissue factor procoagulant activity via the release of calcium from endoplasmic reticulum stores.
The increased risk of venous thromboembolism in cancer patients has been attributed to enhanced tissue factor (TF) procoagulant activity (PCA) on the surface of cancer cells. Recent studies have shown that TF PCA can be modulated by GRP78, an endoplasmic reticulum (ER)-resident molecular chaperone. In this study, we investigated the role of cell surface GRP78 in modulating TF PCA in several human cancer cell lines. Although both GRP78 and TF are present on the cell surface of cancer cells, there was no evidence of a stable interaction between recombinant human GRP78 and TF, nor was there any effect of exogenously added recombinant GRP78 on cell surface TF PCA. Treatment of cells with the ER stress-inducing agent thapsigargin, an inhibitor of the sarco(endo)plasmic reticulum Ca(2+) pump that causes Ca(2+) efflux from ER stores, increased cytosolic [Ca(2+)] and induced TF PCA. Consistent with these findings, anti-GRP78 autoantibodies that were isolated from the serum of patients with prostate cancer and bind to a specific N-terminal epitope (Leu(98)-Leu(115)) on cell surface GRP78, caused a dose-dependent increase in cytosolic [Ca(2+)] and enhanced TF PCA. The ability to interfere with cell surface GRP78 binding, block phospholipase C activity, sequester ER Ca(2+), or prevent plasma membrane phosphatidylserine exposure resulted in a significant decrease in the TF PCA induced by anti-GRP78 autoantibodies. Taken together, these findings provide evidence that engagement of the anti-GRP78 autoantibodies with cell surface GRP78 increases TF PCA through a mechanism that involves the release of Ca(2+) from ER stores. Furthermore, blocking GRP78 signaling on the surface of cancer cells attenuates TF PCA and has the potential to reduce the risk of cancer-related venous thromboembolism.


Potato consumption and risk of cardio-metabolic diseases: evidence mapping of observational studies.
Recent systematic review of clinical trials concluded that there was no convincing evidence to suggest an association between potatoes and risk of cardio-metabolic diseases. Summarize observational study data related to potato intake and cardio-metabolic health outcomes in adults using evidence mapping to assess the need for a future systematic review. We searched MEDLINE®, Commonwealth Agricultural Bureau, and bibliographies for eligible observational studies published between 1946 and July 2020. Included studies evaluated potato intake in any form or as part of a dietary pattern with risk for cardio-metabolic diseases. Outcomes of interest included cardiovascular disease (CVD), cerebrovascular diseases, diabetes, hypertension, blood lipids, and body composition. Of 121 eligible studies, 51 reported two different methods to quantify potato intake (30 studies quantified intake as either grams or serving; 20 studies reported times per week; one reported both methods) and 70 reported potato as part of a dietary pattern and compared higher vs. lower intake, linear change, or difference in potato intake among cases and controls. Studies that quantified potato intake as either grams or serving reported the following outcomes: diabetes (8 studies); cerebrovascular stroke (6 studies); five studies each for CVD, systolic and diastolic blood pressure, and hypertension; three studies each for body mass index, body weight, CVD mortality; two studies for myocardial infarction; and one study each for blood glucose, HOMA-IR, and blood lipids. Higher potato intake was associated with an increased risk for blood pressure and body weight, and the results of all other outcomes observed no association. Potato consumption as part of dietary pattern studies reported a negative association between fried form of potato and all or most cardio-metabolic risk factors and diseases. Evidence mapping found sufficient data on the association between potato intake and cardio-metabolic disease risk factors to warrant for a systematic review/meta-analysis of observational studies.


Grape seed polyphenol extract and cognitive function in healthy young adults: a randomised, placebo-controlled, parallel-groups acute-on-chronic trial.
Grapes are polyphenol-rich, and grape juice intake has shown cognitive benefits in middle-aged females and older adults with mild cognitive impairment. Extracts obtained from grape seeds have similarly been associated with cognitive benefits in older adults. The aim of this research was to investigate whether a highly purified grape seed-derived polyphenol extract was associated with cognitive benefits in healthy young adults following a single acute dose, and chronically following repeated daily dosage over 12 weeks. Following an acute-on-chronic, parallel groups, randomised, double-blind, placebo-controlled design, sixty adults aged 18-30 consumed either a 400 mg grape seed polyphenol extract (GSPE, n = 30) or a placebo (n = 30). Cognitive function was assessed acutely at baseline and 2, 4 and 6 h post consumption, and chronically at 6 and 12 twelve weeks with a computerised battery of multiple cognitive tests. Mood was assessed with the Positive and Negative Affect Schedule. Linear marginal model analysis with baseline included as a covariate did not reveal a consistent pattern of cognitive benefits following the GSPE relative to the placebo either acutely or chronically when considering all outcome measures. GSPE was associated with some improvements in reaction time (acutely) and psychomotor skill (chronically), however the placebo was also associated with some benefits to reaction time and memory. Therefore, a 400 mg GSPE did not consistently improve cognitive function in healthy young adults. These findings suggest that younger, healthy populations are perhaps less sensitive to polyphenol extract doses <400mg relative to older, or cognitively compromised populations.


Lack of evidence for a fine-scale magnetic map sense for fall migratory Eastern North American monarch butterflies (Danaus plexippus).
How first-time animal migrants find specific destinations remains an intriguing ecological question. Migratory marine species use geomagnetic map cues acquired as juveniles to aide long-distance migration, but less is known for long-distance migrants in other taxa. We test the hypothesis that naïve Eastern North American fall migratory monarch butterflies (Danaus plexippus), a species that possesses a magnetic sense, locate their overwintering sites in Central Mexico using inherited geomagnetic map cues. We examined whether overwintering locations and the abundance of monarchs changed with the natural shift of Earth's magnetic field from 2004 to 2018. We found that migratory monarchs continued to overwinter at established sites in similar abundance despite significant shifts in the geomagnetic field, which is inconsistent with monarchs using fine-scale geomagnetic map cues to find overwintering sites. It is more likely that monarchs use geomagnetic cues to assess migratory direction rather than location and use other cues to locate overwintering sites.


Exploring the Loci Responsible for Awn Development in Rice through Comparative Analysis of All AA Genome Species.
Wild rice species have long awns at their seed tips, but this trait has been lost through rice domestication. Awn loss mitigates harvest and seed storage; further, awnlessness increases the grain number and, subsequently, improves grain yield in Asian cultivated rice, highlighting the contribution of the loss of awn to modern rice agriculture. Therefore, identifying the genes regulating awn development would facilitate the elucidation of a part of the domestication process in rice and increase our understanding of the complex mechanism in awn morphogenesis. To identify the novel loci regulating awn development and understand the conservation of genes in other wild rice relatives belonging to the AA genome group, we analyzed the chromosome segment substitution lines (CSSL). In this study, we compared a number of CSSL sets derived by crossing wild rice species in the AA genome group with the cultivated species Oryza sativa ssp. japonica. Two loci on chromosomes 7 and 11 were newly discovered to be responsible for awn development. We also found wild relatives that were used as donor parents of the CSSLs carrying the functional alleles responsible for awn elongation, REGULATOR OF AWN ELONGATION 1 (RAE1) and RAE2. To understand the conserveness of RAE1 and RAE2 in wild rice relatives, we analyzed RAE1 and RAE2 sequences of 175 accessions among diverse AA genome species retrieved from the sequence read archive (SRA) database. Comparative sequence analysis demonstrated that most wild rice AA genome species maintained functional RAE1 and RAE2, whereas most Asian rice cultivars have lost either or both functions. In addition, some different loss-of-function alleles of RAE1 and RAE2 were found in Asian cultivated species. These findings suggest that different combinations of dysfunctional alleles of RAE1 and RAE2 were selected after the speciation of O. sativa, and that two-step loss of function in RAE1 and RAE2 contributed to awnlessness in Asian cultivated rice.


Osteoclasts degrade bone and cartilage knee joint compartments through different resorption processes.
Osteoclasts have been strongly implicated in osteoarthritic cartilage degradation, at least indirectly via bone resorption, and have been shown to degrade cartilage in vitro. The osteoclast resorption processes required to degrade subchondral bone and cartilage-the remodeling of which is important in the osteoarthritic disease process-have not been previously described, although cathepsin K has been indicated to participate. In this study we profile osteoclast-mediated degradation of bovine knee joint compartments in a novel in vitro model using biomarkers of extracellular matrix (ECM) degradation to assess the potential of osteoclast-derived resorption processes to degrade different knee joint compartments. Mature human osteoclasts were cultured on ECMs isolated from bovine knees-articular cartilage, cortical bone, and osteochondral junction ECM (a subchondral bone-calcified cartilage mixture)-in the presence of inhibitors: the cystein protease inhibitor E-64, the matrix metalloproteinase (MMP) inhibitor GM6001, or the vacuolar-type H+-ATPase (V-ATPase) inhibitor diphyllin. Biomarkers of bone (calcium and C-terminal type I collagen (CTX-I)) and cartilage (C2M) degradation were measured in the culture supernatants. Cultures without osteoclasts were used as background samples. Background-subtracted biomarker levels were normalized to the vehicle condition and were analyzed using analysis of variance with Tukey or Dunnett's T3 post hoc test, as applicable. Osteochondral CTX-I release was inhibited by E-64 (19% of vehicle, p = 0.0008), GM6001 (51% of vehicle, p = 0.013), and E-64/GM6001 combined (4% of vehicle, p = 0.0007)-similarly to bone CTX-I release. Diphyllin also inhibited osteochondral CTX-I release (48% of vehicle, p = 0.014), albeit less than on bone (4% of vehicle, p < 0.0001). Osteochondral C2M release was only inhibited by E-64 (49% of vehicle, p = 0.07) and GM6001 (14% of vehicle, p = 0.006), with complete abrogation when combined (0% of vehicle, p = 0.004). Cartilage C2M release was non-significantly inhibited by E-64 (69% of vehicle, p = 0.98) and was completely abrogated by GM6001 (0% of vehicle, p = 0.16). Our study supports that osteoclasts can resorb non-calcified and calcified cartilage independently of acidification. We demonstrated both MMP-mediated and cysteine protease-mediated resorption of calcified cartilage. Osteoclast functionality was highly dependent on the resorbed substrate, as different ECMs required different osteoclast processes for degradation. Our novel culture system has potential to facilitate drug and biomarker development aimed at rheumatic diseases, e.g. osteoarthritis, where pathological osteoclast processes in specific joint compartments may contribute to the disease process.


Doctoring: University of California, Los Angeles.
The Doctoring curriculum at the University of California, Los Angeles, UCLA School of Medicine covers all four years of medical school. Its goal is to train physicians to give care that is compassionate, humanistic, high-quality, and evidence-based through a longitudinal, interdisciplinary curriculum with integration of learning experiences within and between years and with more emphasis on certain topics that had been previously neglected (e.g., advanced physical diagnosis, nutrition, public health, ethics). The curriculum operates alongside the traditional one, but strong attempts are made to link the two curricula. The authors describe the gradual introduction of the Doctoring curriculum, the sometimes formidable barriers that were encountered and in some cases still exist (e.g., some faculty and student resistance, need to find funds, faculty recruitment and retention). Active, interested faculty are essential, and intensive faculty development is needed. A detailed description of each year's courses and teaching approaches is given. Year one focuses on interpersonal communication, the medical interview, human development and behavior, and the role of the community in health care; year two, on clinical reasoning, physical diagnosis skills, population medicine, and ethics; year three, on clinical problem solving, health services, professionalization issues, and prevention; and year four (which is elective), on medical education and leadership. The methods of evaluating students, faculty, and the curriculum itself are described and assessed. The authors conclude with a review of plans, prospects, and ongoing problems.


The regulation of Ostertagia ostertagi populations in calves: the effect of past and current experience of infection on proportional establishment and parasite survival.
A mathematical model of the parasitic phase of the life-cycle of Ostertagia ostertagi in calves is described. The model is used in the re-analysis of previously published data from a long-term trickle infection experiment in which groups of calves were infected daily with graded doses of 3rd-stage (L3) larvae. The results of the analysis are consistent with the hypothesis that the observed changes in the intensity of infection in the calves were the result of a decline in the proportional establishment of ingested L3 larvae, and a rise in the death rate of the 5th-stage worms as the duration of exposure to infection increased. The proportion of ingested L3 larvae that become established in the mucosa can be described as an exponential decay function of the duration of the infection. Within the range of trickle intensities investigated, the function appears to vary independently of the level of exposure to infection. In contrast, the rate of mortality of the 5th-stage worms appears to be an increasing linear function of the total cumulative number of 3rd-stage larvae administered.


Adnexal Tumors of Skin: An Experience at a Tertiary Care Center at Delhi.
Adnexal skin tumors are a heterogeneous group of uncommon tumors usually misdiagnosed clinically due to a huge variety of types and their variants. Histopathology usually helps in establishing the diagnosis. The study was undertaken to analyze the morphological, clinical, and histological features of adnexal tumors (ATs) of the skin at our center over a period of 4 years. retrospective study was conducted over a period of 4 years (April 2010-March 2014), comprising 25 ATs of skin diagnosed in the Department of Pathology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi. All the consecutively reported AT cases were reviewed and reclassified as AT arising from sebaceous glands, hair follicles, or sweat glands. The concordance of clinical and histopathological diagnosis was also assessed. Most of the ATs were benign (24/25) with head and neck being the most common location (72%). Nearly 56% of the tumors exhibited sweat gland differentiation, 28% hair follicle differentiation, and sebaceous gland tumors accounted for 16%. The most common varieties of tumors encountered in the present study included hidradenoma papilliferum and pilomatricoma. The concordance between clinical and histopathological diagnosis was found to be 50% approximately. ATs of the skin are rare neoplasms with benign tumors being far more common. They are often misdiagnosed clinically, so histopathology remains the gold standard for establishing an accurate diagnosis of skin ATs.


Accuracy of visual assessment by school teachers in school eye screening program in delhi.
Although school eye screening is a major activity of the National Program for Control of Blindness, inadequate evidence exists about accuracy of school teachers in screening. Compare quality of referral for subnormal vision by school teachers and primary eye care workers (PECW) in school children and to establish appropriate cutoff for identification of subnormal vision in school going children. This was a cross-sectional study involving school children studying in classes 1 to 9 in different schools of Delhi evaluated for sub-normal vision. Vision was recorded by the teacher and a primary eye care worker especially trained for the study using the optotypes of Early treatment Diabetic Retinopathy Survey (ETDRS) vision chart with standard lighting. The total number of children enlisted in the 20 selected schools was 10,114. Of these, 9838 (97.3%) children were examined in the study. The mean age of children enrolled in the study was 11.6 ± 2.19 years with 6752 (66.9%) males. The sensitivity and specificity of teachers in comparison to PECW using 6/9.5 vision level as cutoff for referral was 79.2% and 93.3%, respectively compared to 77.0% and 97.1%, respectively on using the 6/12 optotype. The results showed significantly higher sensitivity and lower specificity for private schools against government schools and for older against younger children. Our results show that the use of teachers and shift to use of the 6/12 sized "E" for the school eye screening (SES) program is appropriate and would substantially reduce the work of eye care providers while improving its overall efficiency.


Complications of type 1 diabetes: new molecular findings.
Interventions targeting the treatment of diabetic complications have not been nearly as successful as initially estimated, despite a marked improvement in therapeutic options for diabetes. The need for understanding why some very promising interventions have failed demands a closer look at the pathomechanisms of the complications. Great strides have been made in understanding the pathology, and several important hypotheses have emerged in recent years. On this basis, Brownlee and coworkers suggested a unifying hypothesis integrating various mechanisms discussed in past years with an overproduction of reactive oxygen species as an initiating cause. This hypothesis and further hypotheses, as well as mechanisms, are highlighted in this article. The field of pathomechanisms of diabetic complications is very wide, and any attempt to completely cover it within a single article is unrealistic. Therefore, our purpose is to present the most relevant concepts underlying diabetic complications in an attempt to contribute to a better understanding and pinpoint areas that warrant further research.


5-hydroxymethylcytosine but not MTAP methylation status can stratify malignant pleural mesothelioma based on the lineage of origin.
Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis, mainly associated with work or environmental exposure to asbestos. MPM's molecular profile is largerly unexplored and effective therapies are still lacking. MPM rarely harbours those somatic genetic lesions that usually characterize solid epithelial-derived tumors. On this basis, our study aims at investigating MPM epigenetic profile. We here assessed through immunohistochemistry, FISH and methylation specific PCR, the expression of 5-hydroxymethylcytosine (5- hmC) - an epigenetic marker and an important regulator of embryonic development and carcinogenesis - and the methylation status of the promoter of the MTAP gene - encoding for an enzyme involved in the rescue process of methionine and adenine - in two relevant series of FF-PE MPM samples derived from MPM thoracoscopic biopsies. Tissue sampling was performed at diagnosis. Within the limitations of the study cohort, the 5-hmC immunophenotype was different among the histological MPM types analysed. In fact, 18% of the epithelial MPMs were negative, 47% weakly positive, and 35% of the cases showed an intense expression of 5-hmC. Sarcomatoid and biphasic MPMs showed intense 5-hmC expression pattern (positive and weakly positive in more than 80% of cases). Among MPM featuring epithelial lineage, none showed methylation of MTAP promoter. Mesothelial sarcomatoid tumors featured a methylation profile characterized by a permanent gene silencing. Epithelial MPM methylation profile was in-between that of sarcomatoid MPM and the one of epithelial-derived tumors. MTAP promoter methylation level cannot be considered a suitable biomarker of epithelial MPM arousal.


Mechanically tunable optofluidic distributed feedback dye laser.
A continuously tunable optofluidic distributed feedback (DFB) dye laser was demonstrated on a monolithic replica molded poly(dimethylsiloxane) (PDMS) chip. The optical feedback was provided by a phase-shifted higher order Bragg grating embedded in the liquid core of a single mode buried channel waveguide. Due to the soft elastomeric nature of PDMS, the laser frequency could be tuned by mechanically stretching the grating period. In principle, the mechanical tuning range is only limited by the gain bandwidth. A tuning range of nearly 60 nm was demonstrated from a single dye laser chip by combining two common dye molecules Rhodamine 6G and Rhodamine 101. Single-mode operation was maintained with less than 0.1 nm linewidth. Because of the higher order grating, a single laser, when operated with different dye solutions, can provide tunable light output covering the entire spectrum from near UV to near IR in which efficient laser dyes are available. An array of five DFB dye lasers with different grating periods was also demonstrated on a chip. Such tunable integrated laser arrays are expected to become key components in inexpensive advanced spectroscopy chips.


Preliminary Associations Between Brain-Derived Neurotrophic Factor, Memory Impairment, Functional Cognition, and Depressive Symptoms Following Severe TBI.
Background Traumatic brain injury (TBI) often leads to mood and cognitive complications, affecting functional recovery. Understanding neurobiological alterations common in post-TBI depression (PTD) and cognition may identify novel biomarkers for TBI complications. Brain-derived neurotrophic factor (BDNF) is a likely target based on evidence of reduced BDNF signaling in experimental TBI and depression models and its role in learning and memory. Objective To evaluate BDNF as a biomarker for PTD, cognitive impairment, and functional cognition in a prospective cohort with severe TBI. Methods Participants with TBI (n = 113) were evaluated for PTD (Patient Health Questionnaire-9 [PHQ-9]), cognitive impairment (cognitive composite score), and functional cognition (Functional Independence Measure-Cognition, FIM-Cog). BDNF levels were measured in cerebrospinal fluid and serum at 0 to 6 days postinjury and in serum at 6 and 12 months postinjury. Serum BDNF was reduced after TBI versus controls at all time points. Acute serum BDNF positively correlated with memory composites (6 months: r = 0.43, P = .019, n = 30; 12 months: r = 0.53, P = .005, n = 26) and FIM-Memory scores (6 months: r = 0.35, P = .019, n = 45; 12 months: r = 0.38, P = .018, n = 38). Acute serum BDNF negatively correlated with 12-month PHQ-9 scores (r = -0.38; P = .044; n = 29). At 12 months, chronic serum BDNF tended to be lower in participants with PTD (P = .07) and correlated with PHQ-9 scores (r = -0.41; P = .019; n = 32). Conclusions Acute BDNF associations with memory recovery may implicate hippocampal damage/degeneration. Comparatively, BDNF associations with PTD status were not as strong as associations with PTD severity. Further investigation may delineate longitudinal BDNF patterns, and BDNF responsive treatments, reflecting mood and cognitive recovery following TBI.


Pollination syndromes ignored: importance of non-ornithophilous flowers to Neotropical savanna hummingbirds.
Generalization prevails in flower-animal interactions, and although animal visitors are not equally effective pollinators, most interactions likely represent an important energy intake for the animal visitor. Hummingbirds are nectar-feeding specialists, and many tropical plants are specialized toward hummingbird-pollination. In spite of this, especially in dry and seasonal tropical habitats, hummingbirds may often rely on non-ornithophilous plants to meet their energy requirements. However, quantitative studies evaluating the relative importance of ornithophilous vs. non-ornithophilous plants for hummingbirds in these areas are scarce. We here studied the availability and use of floral resources by hummingbirds in two different areas of the Cerrado, the seasonal savannas in Central Brazil. Roughly half the hummingbird visited plant species were non-ornithophilous, and these contributed greatly to increase the overall nectar availability. We showed that mean nectar offer, at the transect scale, was the only parameter related to hummingbird visitation frequency, more so than nectar offer at single flowers and at the plant scale, or pollination syndrome. Centrality indices, calculated using hummingbird-plant networks, showed that ornithophilous and non-ornithophilous plants have similar importance for network cohesion. How this foraging behaviour affects reproduction of non-ornithophilous plants remains largely unexplored and is probably case specific, however, we suggest that the additional energy provided by non-ornithophilous plants may facilitate reproduction of truly ornithophilous flowers by attracting and maintaining hummingbirds in the area. This may promote asymmetric hummingbird-plant associations, i.e., pollination depends on floral traits adapted to hummingbird morphology, but hummingbird visitation is determined more by the energetic "reward" than by pollination syndromes.


Cognitive and functional deterioration in patients with severe COPD.
The objective of this study was to examine the association among the duration of COPD, degree of hypoxemia, and neurological abnormalities including cognitive functioning. Fifty-four patients with severe COPD and 24 age- and sex-matched controls, were included in the study. All patients and controls were administered pulmonary function tests, standardized Mini-mental State Examination (MMSE), Blessed Dementia Scale (BDS), Physical Self-maintenance Scale (PSMS), Modified Activities of Daily Living scale (MADL), Instrumental Activities of Daily Living scale (IADL), Cornell Scale for Depression in Dementia (CSDD), Global Deterioration Scale (GDS) and Clinical Dementia Rating (CDR). In addition, detailed physical and neurological examinations were performed. Sixty-four percent of patients with COPD showed abnormalities in MMSE, predominantly in recent memory, construction, attention, language, and orientation domains. Functional abnormalities were correlated with cognitive abnormalities. Although COPD patients did not show significant depression compared to controls, 77.7%. of the patients showed subjective and objective cognitive disturbance and 72.2% of the patients were classified as questionable or mild dementia. In conclusion, patients with COPD show significant cognitive and functional impairments that cannot be explained just by coincidence or by depression.


Rheumatoid Arthritis and Coronary Artery Disease: Genetic Analyses Do Not Support a Causal Relation.
Inflammatory diseases, specifically rheumatoid arthritis (RA), are assumed to increase the risk of coronary artery disease (CAD). More recently, multiple single-nucleotide polymorphisms (SNP) associated with RA risk were identified. If causal mechanisms affecting risks of RA and CAD are overlapping, risk alleles for RA might also increase the risk of CAD. Sixty-one SNP associating with RA in genome-wide significant analyses were tested for association with CAD in CARDIoGRAM (Coronary ARtery DIsease Genome wide Replication and Meta-analysis), a metaanalysis including genome-wide association data (22,233 CAD cases, 64,762 controls). In parallel, a set of SNP being associated with low-density lipoprotein cholesterol (LDL-C) was tested as a positive control. Twenty-nine RA-associated SNP displayed a directionality-consistent association with CAD (OR range 1.002-1.073), whereas 32 RA-associated SNP were not associated with CAD (OR range 0.96-0.99 per RA risk-increasing allele). The proportion (48%) of directionality-consistent associated SNP equaled the proportion expected by chance (50%, p = 0.09). Of only 5 RA-associated SNP showing p values for CAD < 0.05, 4 loci (C5orf30, IL-6R, PTPN22, and RAD51B) showed directionality-consistent effects on CAD, and 1 (rs10774624, locus SH2B3) reached study-wide significance (p = 7.29E-06). By contrast, and as a proof of concept, 46 (74%) out of 62 LDL-C-associated SNP displayed a directionality-consistent association with CAD, a proportion that was significantly different from 50% (p = 5.9E-05). We found no evidence that RA-associated SNP as a group are associated with CAD. Even though we were not able to study potential effects of all genetic variants individually, shared nongenetic factors may more plausibly explain the observed coincidence of the 2 conditions.


Development of a bioaffinity SPR immunosensor based on functionalized graphene oxide for the detection of pregnancy-associated plasma protein A2 in human plasma.
Graphene-like material such as functionalized carboxyl-graphene oxide (carboxyl-GO) can be intelligently tuned to achieve particular properties for biological and chemical sensing applications. In this study, we propose a method to improve interference of non-specific proteins for use in human plasma assays. The highly specific interactions between molecules are an advantage of carboxyl-GO-based surface plasmon resonance (SPR) immunoassays, and this can be applied to spiked plasma samples with pregnancy-associated plasma protein A2 (PAPPA2). The experiment results showed that carboxyl-GO could be used to modulate the plasmon resonance energy, work function and conductivity properties. In addition, carboxyl groups could be used to enhance the conduction of electrons between carboxyl-GO and Au electrodes due to the excellent conductivity and electron transfer rate. The carboxyl-GO-based SPR chip exhibited high sensitivity based on the electric field amplification effects of the composite dielectric material. Therefore, the surface electric field could be enhanced by electron transfer, thereby greatly improving the sensitivity of the sensing system. Enhanced electric field intensity was generated around the carboxyl-GO of 63.58 V/m, and the measured work function was 4.95 eV. The results showed that the carboxyl-GO-based SPR biosensor had high sensitivity, affinity and selective ability for PAPPA2 protein with a high association rate constant (ka) of 3.1 ×109 M-1 S-1 and a limit of detection of 0.01 pg/mL in spiked human plasma. The results showed a detection accuracy of protein in spiked plasma of >90% compared to PBS buffer, suggesting that the carboxyl-GO-based SPR biosensor could be used in assays of human plasma for early and late gynecological diseases. The future of this technology will be useful for the diagnosis and evaluation of the risk of early maternal preeclampsia and potentially in clinical applications for gestational diseases.


Fractional Fourier transform of truncated elliptical Gaussian beams.
Based on the fact that a hard-edged elliptical aperture can be expanded approximately as a finite sum of complex Gaussian functions in tensor form, an analytical expression for an elliptical Gaussian beam (EGB) truncated by an elliptical aperture and passing through a fractional Fourier transform system is derived by use of vector integration. The approximate analytical results provide more convenience for studying the propagation and transformation of truncated EGBs than the usual way by using the integral formula directly, and the efficiency of numerical calculation is significantly improved.


Overexpression and mutation of p53 in epithelial ovarian cancer.
We examined p53 expression in 107 epithelial ovarian cancers with immunohistochemical techniques using monoclonal antibody PAb1801. High level expression of nuclear p53 protein was detected in the malignant epithelium in 54 (50%) of these cancers. Expression of p53 protein was undetectable in 13 benign gynecological tissues. p53 mRNA from three cancers that overexpressed the protein were sequenced and point mutations which altered the coding sequence of the highly conserved region of the gene were found in each case. Three cancers with undetectable protein levels also were sequenced and were found to be wild-type through the same region of the gene. As in other cancers, overexpression of the p53 protein in ovarian cancer appears to correlate closely with the presence of mutation in the p53 gene. p53 overexpression did not correlate with stage, histological grade, or the ability to perform optimal cytoreductive surgery. A significant correlation (P = 0.04) was observed between p53 overexpression and aneuploidy in advanced stage (III/IV) disease. There was no significant relationship between overall survival and p53 expression. Since mutation and overexpression of p53 are common in epithelial ovarian cancers, further studies are warranted to clarify the role of p53 in ovarian tumorigenesis.


Prevalence of adverse childhood experiences (ACE) in the Czech Republic.
A cross-sectional survey was undertaken to estimate the prevalence of child maltreatment and adverse childhood experiences in the Czech Republic, as data on these is scarce. The survey was conducted among 1760 randomly selected students from five Czech universities. Participants filled in the adverse childhood experiences survey instrument. The results showed that the prevalence of child maltreatment and other adverse childhood experiences is high: emotional abuse was reported by 20.7%, physical abuse by 17.1%, sexual abuse by 6.4%, and physical neglect by 8.0%. Household dysfunction was also high, with household street drug use reported by 4.9%, alcohol misuse by 15.3%, mental disorder by 13.4%, parental violence by 22.1% and parental separation by 23%. Thirty-eight per cent had not experienced any adverse childhood experience, while 9.9% reported experiencing four or more types of adverse childhood experiences. There was a significant association between adverse childhood experiences and health-harming behaviours such as suicide attempt, drug use, risky sexual behaviour and tobacco use. The findings suggest that there is a need to invest in prevention programmes.


High diversity of invasive Haemophilus influenzae isolates in France and the emergence of resistance to third generation cephalosporins by alteration of ftsI gene.
Invasive infections due to Haemophilus influenzae are infrequent following the implementation of vaccination against H. influenzae of serotype b. However, their changing epidemiology may not be clear due to a lack of appropriate genotyping methods combined with antibiotic susceptibility analyses which do not discriminate invasive and non-invasive isolates. We aimed to describe recent epidemiological trends of invasive H. influenzae infections in France and explore the microbiological characteristics of invasive versus non-invasive isolates. All culture- and PCR-confirmed cases due to H. influenzae isolated from a sterile site, that were received at the French national reference centre for H. influenzae during the year 2017 (n = 138) were characterized by whole genome sequencing (WGS), serotyping and antibiotic susceptibility testing. We also included 100 isolates that were received from non-invasive infections. Most of the non-invasive isolates were non-typeable (99%) and this proportion was significantly less among invasive isolates 75%, p < 0.0001). Serotype f was the most frequently observed but serotypes b and a were also present among invasive isolates. WGS analysis suggested a serotype b to a capsule switching event. Non-typeable isolates showed extensive heterogeneity. Antibiotic susceptibility testing indicated that 24% of the invasive isolates were resistant to ampicillin but this percentage was significantly higher (51%, p < 0.001) among the non-invasive isolates. Moreover, the proportion of beta-lactamase negative ampicillin resistant isolates (BLNAR) was significantly higher among non-invasive isolates compared to that of invasive isolates (24% versus 7%, p < 0.001). BLNAR isolates were linked to modification in the ftsI gene encoding the penicillin binding protein 3 (PBP3). In particular, ftsI alleles that harboured the mutations D350N, S357N, M377I and S385T were resistant to ampicillin and third generation cephalosporins. These isolates were more frequent among non-invasive isolates. Our data suggest that invasive H. influenzae isolates differed phenotypically and genotypically from non-invasive isolates. The high proportion of ampicillin resistance by mutation in ftsI among non-invasive isolates may suggest a biological cost of these mutations on the function of PBP3 that can lead to lower bacterial invasiveness. WGS should be used routinely for the characterization of H. influenzae isolates in order to reliably follow the emergence, spread and mechanism of antibiotic resistance.


Impairment of Nitric Oxide Pathway by Intravascular Hemolysis Plays a Major Role in Mice Esophageal Hypercontractility: Reversion by Soluble Guanylyl Cyclase Stimulator.
Paroxysmal nocturnal hemoglobinuria (PNH) patients display exaggerated intravascular hemolysis and esophageal disorders. Since excess hemoglobin in the plasma causes reduced nitric oxide (NO) bioavailability and oxidative stress, we hypothesized that esophageal contraction may be impaired by intravascular hemolysis. This study aimed to analyze the alterations of the esophagus contractile mechanisms in a murine model of exaggerated intravascular hemolysis induced by phenylhydrazine (PHZ). For comparative purposes, sickle cell disease (SCD) mice were also studied, a less severe intravascular hemolysis model. Esophagus rings were dissected free and placed in organ baths. Plasma hemoglobin was higher in PHZ compared with SCD mice, as expected. The contractile responses produced by carbachol (CCh), KCl, and electrical-field stimulation (EFS) were superior in PHZ esophagi compared with control but remained unchanged in SCD mice. Preincubation with the NO-independent soluble guanylate cyclase stimulator 3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (BAY 41-2272; 1 μM) completely reversed the increased contractile responses to CCh, KCl, and EFS in PHZ mice, but responses remained unchanged with prior treatment with NO donor sodium nitroprusside (300 μM). Protein expression of 3-nitrotyrosine and 4-hydroxynonenal increased in esophagi from PHZ mice, suggesting a state of oxidative stress. In endothelial nitric oxide synthase gene-deficient mice, the contractile responses elicited by KCl and CCh were increased in the esophagus but remained unchanged with the intravascular hemolysis induced by PHZ. In conclusion, our results show that esophagus hypercontractile state occurs in association with lower NO bioavailability due to exaggerated hemolysis intravascular and oxidative stress. Moreover, our study supports the hypothesis that esophageal disorders in PNH patients are secondary to intravascular hemolysis affecting the NO-cGMP pathway.


Evaluation and interconversion of various indicator PCB schemes for ∑PCB and dioxin-like PCB toxic equivalent levels in fish.
Polychlorinated biphenyls (PCBs) remain chemicals of concern more than three decades after the ban on their production. Technical mixture-based total PCB measurements are unreliable due to weathering and degradation, while detailed full congener specific measurements can be time-consuming and costly for large studies. Measurements using a subset of indicator PCBs (iPCBs) have been considered appropriate; however, inclusion of different PCB congeners in various iPCB schemes makes it challenging to readily compare data. Here, using an extensive data set, we examine the performance of existing iPCB3 (PCB 138, 153, and 180), iPCB6 (iPCB3 plus 28, 52, and 101) and iPCB7 (iPCB6 plus 118) schemes, and new iPCB schemes in estimating total of PCB congeners (∑PCB) and dioxin-like PCB toxic equivalent (dlPCB-TEQ) concentrations in sport fish fillets and the whole body of juvenile fish. The coefficients of determination (R(2)) for regressions conducted using logarithmically transformed data suggest that inclusion of an increased number of PCBs in an iPCB improves relationship with ∑PCB but not dlPCB-TEQs. Overall, novel iPCB3 (PCB 95, 118, and 153), iPCB4 (iPCB3 plus 138) and iPCB5 (iPCB4 plus 110) presented in this study and existing iPCB6 and iPCB7 are the most optimal indicators, while the current iPCB3 should be avoided. Measurement of ∑PCB based on a more detailed analysis (50+ congeners) is also overall a good approach for assessing PCB contamination and to track PCB origin in fish. Relationships among the existing and new iPCB schemes have been presented to facilitate their interconversion. The iPCB6 equiv levels for the 6.5 and 10 pg/g benchmarks of dlPCB-TEQ05 are about 50 and 120 ng/g ww, respectively, which are lower than the corresponding iPCB6 limits of 125 and 300 ng/g ww set by the European Union.


Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization.
Post-COVID cognitive deficits, including 'brain fog', are clinically complex, with both objective and subjective components. They are common and debilitating, and can affect the ability to work, yet their biological underpinnings remain unknown. In this prospective cohort study of 1,837 adults hospitalized with COVID-19, we identified two distinct biomarker profiles measured during the acute admission, which predict cognitive outcomes 6 and 12 months after COVID-19. A first profile links elevated fibrinogen relative to C-reactive protein with both objective and subjective cognitive deficits. A second profile links elevated D-dimer relative to C-reactive protein with subjective cognitive deficits and occupational impact. This second profile was mediated by fatigue and shortness of breath. Neither profile was significantly mediated by depression or anxiety. Results were robust across secondary analyses. They were replicated, and their specificity to COVID-19 tested, in a large-scale electronic health records dataset. These findings provide insights into the heterogeneous biology of post-COVID cognitive deficits.


Dopamine D1 receptor associations within and between dopaminergic pathways in younger and elderly adults: links to cognitive performance.
Age-related dopamine (DA) losses have been extensively demonstrated for the D2 receptor subtype. Comparatively little is known about adult age changes regarding D1 receptors. In this study, we demonstrate marked age-related D1 receptor losses in striatal, limbic, and cortical areas using positron emission tomography and the radioligand [(11)C]SCH23390 in humans. Interregional correlations of binding potential (BP) values were high for areas within DA pathways in younger and elderly adults alike. Furthermore, interregional correlations in D1 BP between DA pathways were uniformly high in younger adults, indicating that D1 receptor densities in striatal, limbic, and cortical areas are not regulated independently, despite dopaminergic innervation from different midbrain areas. For elderly adults, between-pathway correlations of D1 receptor densities were preserved only between mesolimbic and mesocortical areas, whereas striatal BPs were weakly related to those in limbic and neocortical regions. Importantly, weak between-pathway correlations in elderly adults were found only for the slower half of the sample when BP was estimated during a cognitive interference task. These results suggest that D1 receptor densities in different pathways are not regulated independently in younger adults, but segregate in older age, and that this segregation of D1 receptor systems may be related to age-related cognitive slowing.