Movement disorders and nonmotor neuropsychological symptoms in children and adults with classical galactosemia.
Although movement disorders (MDs) are known complications, the exact frequency and severity remains uncertain in patients with classical galactosemia, especially in children. We determined the frequency, classification and severity of MDs in a cohort of pediatric and adult galactosemia patients, and assessed the association with nonmotor neuropsychological symptoms and daily functioning. Patients from seven centers in the United Kingdom and the Netherlands with a confirmed galactosemia diagnosis were invited to participate. A videotaped neurological examination was performed and an expert panel scored the presence, classification and severity of MDs. Disease characteristics, nonmotor neuropsychological symptoms, and daily functioning were evaluated with structured interviews and validated questionnaires (Achenbach, Vineland, Health Assessment Questionnaire, SIP68). We recruited 37 patients; 19 adults (mean age 32.6 years) and 18 children (mean age 10.7 years). Subjective self-reports revealed motor symptoms in 19/37 (51.4%), similar to the objective (video) assessment, with MDs in 18/37 patients (48.6%). The objective severity scores were moderate to severe in one third (6/37). Dystonia was the overall major feature, with additional tremor in adults, and myoclonus in children. Behavioral or psychiatric problems were present in 47.2%, mostly internalizing problems, and associated with MDs. Daily functioning was significantly impaired in the majority of patients. Only one patient received symptomatic treatment for MDs. We show that MDs and nonmotor neuropsychological symptoms are frequent in both children and adults with classical galactosemia.


Contemporary ocean warming and freshwater conditions are related to later sea age at maturity in Atlantic salmon spawning in Norwegian rivers.
Atlantic salmon populations are reported to be declining throughout its range, raising major management concerns. Variation in adult fish abundance may be due to variation in survival, growth, and timing of life history decisions. Given the complex life history, utilizing highly divergent habitats, the reasons for declines may be multiple and difficult to disentangle. Using recreational angling data of two sea age groups, one-sea-winter (1SW) and two-sea-winter (2SW) fish originated from the same smolt year class, we show that sea age at maturity of the returns has increased in 59 Norwegian rivers over the cohorts 1991-2005. By means of linear mixed-effects models we found that the proportion of 1SW fish spawning in Norway has decreased concomitant with the increasing sea surface temperature experienced by the fish in autumn during their first year at sea. Furthermore, the decrease in the proportion of 1SW fish was influenced by freshwater conditions as measured by water discharge during summer months 1 year ahead of seaward migration. These results suggest that part of the variability in age at maturity can be explained by the large-scale changes occurring in the north-eastern Atlantic pelagic food web affecting postsmolt growth, and by differences in river conditions influencing presmolt growth rate and later upstream migration.


Duckling short beak and dwarfism syndrome virus infection activates host innate immune response involving both DNA and RNA sensors.
Duckling short beak and dwarfism syndrome virus (SBDSV), a newly identified goose parvovirus, causes devastating disease in domestic waterfowl and considerable economic losses to Chinese waterfowl industry. The molecular pathogenesis of SBDSV infection, nature and dynamics of host immune responses against SBDSV infection remained elusive. In this study, we systematically explored the relative mRNA expression profiles of major innate immune-related genes in SBDSV infected duck embryo fibroblasts. We found that SBDSV infection effectively activated host innate immune responses and resulted in significant up-regulation of IFN-β and several vital IFN-stimulated genes (ISGs). These up-regulation responses were mainly attributed to viral genomic DNA and dsRNA replication intermediates. Importantly, the expression of cGAS was significantly induced, whereas the expression of other DNA receptors including DDX41, STING, ZBP1, LSM14A and LRRFIP1 have no significant change. Furthermore, SBDSV infection also activates the up-regulation of TLR3 and inhibited the expression of TLR2 and TLR4; however, no effect was observed on the expression of TLR1, TLR5, TLR7, TLR15 and TLR21. Intriguingly, SBDSV infection significantly up-regulated the expression of RNA sensors such as MDA5 and LGP2, and resulted in a delayed but significant up-regulation of RIG-I gene. Taken together, these data indicate that host multiple sensors including DNA sensor (cGAS) and RNA sensors (TLR3, MDA5 and LGP2) are involved in recognizing a variety of different pathogen associated molecular patterns (PAMPs) including viral genomic ssDNA and dsRNA replication intermediates, which trigger an effective antiviral innate immune response.


Prolonged antigen storage endows merocytic dendritic cells with enhanced capacity to prime anti-tumor responses in tumor-bearing mice.
Tumor cell vaccination with irradiated autologous tumor cells is a promising approach to activate tumor-specific T cell responses without the need for tumor Ag identification. However, uptake of dying cells by dendritic cells (DCs) is generally a noninflammatory or tolerizing event to prevent the development of autoreactive immune responses. In this study, we describe the mechanisms that confer the potent T cell priming capacity of a recently identified a population of DCs (merocytic DCs [mcDCs]) that potently primes both CD8(+) and CD4(+) T cells to cell-associated Ags upon uptake of apoptotic cells. mcDCs acquired cell-associated materials through a process of merocytosis that is defined by the uptake of small particles that are stored in nonacidic compartments for prolonged periods, sustained Ag presentation, and the induction of type I IFN. T cells primed by mcDCs to cell-associated Ags exhibit increased primary expansion, enhanced effector function, and increased memory formation. By using transgenic T cell transfer models and endogenous models, we show that treatment of tumor-bearing mice with mcDCs that have been exposed to dying tumor cells results in tumor suppression and increased host survival through the activation of naive tumor-specific CD8(+) T cells as well as the reinvigoration of tumor-specific T cells that had been rendered nonresponsive by the tumor in vivo. The potent capacity of mcDCs to prime both CD4(+) and CD8(+) T cells to cell-associated Ags under immunosuppressive conditions makes this DC subset an attractive target for tumor therapies as well as interventional strategies for autoimmunity and transplantation.


MicroRNA-330-5p as a Putative Modulator of Neoadjuvant Chemoradiotherapy Sensitivity in Oesophageal Adenocarcinoma.
Oesophageal adenocarcinoma (OAC) is the sixth most common cause of cancer deaths worldwide, and the 5-year survival rate for patients diagnosed with the disease is approximately 17%. The standard of care for locally advanced disease is neoadjuvant chemotherapy or, more commonly, combined neoadjuvant chemoradiation therapy (neo-CRT) prior to surgery. Unfortunately, ~60-70% of patients will fail to respond to neo-CRT. Therefore, the identification of biomarkers indicative of patient response to treatment has significant clinical implications in the stratification of patient treatment. Furthermore, understanding the molecular mechanisms underpinning tumour response and resistance to neo-CRT will contribute towards the identification of novel therapeutic targets for enhancing OAC sensitivity to CRT. MicroRNAs (miRNA/miR) function to regulate gene and protein expression and play a causal role in cancer development and progression. MiRNAs have also been identified as modulators of key cellular pathways associated with resistance to CRT. Here, to identify miRNAs associated with resistance to CRT, pre-treatment diagnostic biopsy specimens from patients with OAC were analysed using miRNA-profiling arrays. In pre-treatment biopsies miR-330-5p was the most downregulated miRNA in patients who subsequently failed to respond to neo-CRT. The role of miR-330 as a potential modulator of tumour response and sensitivity to CRT in OAC was further investigated in vitro. Through vector-based overexpression the E2F1/p-AKT survival pathway, as previously described, was confirmed as a target of miR-330 regulation. However, miR-330-mediated alterations to the E2F1/p-AKT pathway were insufficient to significantly alter cellular sensitivity to chemotherapy (cisplatin and 5-flurouracil). In contrast, silencing of miR-330-5p enhanced, albeit subtly, cellular resistance to clinically relevant doses of radiation. This study highlights the need for further investigation into the potential of miR-330-5p as a predictive biomarker of patient sensitivity to neo-CRT and as a novel therapeutic target for manipulating cellular sensitivity to neo-CRT in patients with OAC.


The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: A preliminary randomized, double-blind, placebo-controlled cross-over design study.
Investigate the efficacy of nabilone capsules (NAB) in reducing the frequency and intensity of nightmares in subjects with PTSD. Canadian male military personnel with PTSD, who despite standard treatment continued to experience trauma-related nightmares, received double-blind treatment with 0.5mg NAB or placebo (PBO), and then titrated to the effective dose (nightmare suppression) or reaching a maximum of 3.0mg. Subjects were followed for 7 weeks and then, following a 2-week washout period, were titrated with the other study treatment and followed for an additional 7 weeks. The modified intent-to-treat (mITT) population, which included all treated subjects that met inclusion/exclusion criteria, was analyzed. Ten subjects were included in the mITT population. The mean reduction in nightmares as measured by the CAPS Recurring and Distressing Dream scores were -3.6 ± 2.4 and -1.0 ± 2.1 in the NAB and PBO groups, respectively (p=0.03). Mean global improvement as measured by the Clinical Global Impression of Change (CGI-C) was 1.9 ± 1.1 (i.e. much improved) and 3.2 ± 1.2 (i.e. minimally improved) in the NAB and PBO groups, respectively (p=0.05) Five out of 10 (50%) were much improved on NAB versus 1 out of 9 (11%) on PBO. Results for the General Well Being Questionnaire (WBQ) were 20.8 ± 22 and -0.4 ± 20.6 in the NAB and PBO groups, respectively (p=0.04). The proportion of subjects who experienced a treatment-related occurrence of adverse events was 50% in the NBO group and 60% in the PBO group. No event was severe nor resulted in a drop-out. This study is registered with Health Canada. In this small sample NAB provided significant relief for military personnel with PTSD, indicating that it shows promise as a clinically-relevant treatment for patients with nightmares and a history of non-response to traditional therapies. These findings need to be replicated in a larger cohort. There is a need for further exploration of the effect of nabilone on other symptoms of PTSD such as re-experiencing, hyper vigilance and insomnia.


Higher morale is associated with lower risk of depressive disorders five years later among very old people.
The aim of this study was to investigate whether higher morale, i.e. future-oriented optimism, at baseline was associated with lower risk of depressive disorders five years later among very old people.Methods The Umeå85+/GErontological Regional Database, a population-based study with a longitudinal design, recruited participants in Sweden and Finland aged 85, 90 and ≥95 years. The sample in the present study included 647 individuals (89.1±4.4 years (Mean±SD), range 85-103). After five years, 216 were alive and agreed to a follow-up (92.6±3.4 years, range 90-104). The Philadelphia Geriatric Center Morale Scale (PGCMS) was used to assess morale. The depressive disorder diagnosis was determined according to DSM-IV based on medical records and interview data including assessment scales for depressive disorders. A number of sociodemographic, functional and health-related variables were analysed as possible confounders.Results For those with no depressive disorders at baseline, the only baseline variable significantly associated with depressive disorders five years later was the PGCMS score. A logistic regression model showed lower risk of depressive disorders five years later with higher baseline PGCMS scores (odds ratio 0.779 for one point increase in PGCMS, p<0.001). The association remained after adjusting for social isolation (p<0.1 association with depressive disorders five years later).Conclusion Our results indicate that the higher the morale, the lower the risk of depressive disorders five years later among very old people. The PGCMS seems to identify those very old individuals at increased risk of depressive disorders five years later. Preventive measures could befocused on this group.


From individual behaviour strategies to sustainable food systems: Countering the obesity and non communicable diseases epidemic in New Zealand.
New Zealand is currently facing an obesity and non communicable diseases (NCDs) epidemic. Recent studies have largely attributed these health issues to insufficient food and low-quality diets that cause micronutrient deficiencies. Improving healthy diets requires broader thinking and collaboration, particularly around maintaining sustainable food systems, which signifies a shift from individualistic/behavioural approaches in health promotion. This paper aims to extend solutions addressing increasing rates of obesity and diet-related NCDs in New Zealand while considering diet and human health in concurrence with sustainability. In particular, the three pillars of sustainability-economic, environmental, and social-will be considered, alongside application of a food systems approach to analysing the epidemic and policy developments in New Zealand. Given its proximity to smaller Pacific islands in the region, New Zealand is in a unique position to work multisectorally and be a leader in considering food system approaches to tackling obesity and NCDs in the Pacific.


Numbers to names - restyling the Fusarium incarnatum-equiseti species complex.
The Fusarium incarnatum-equiseti species complex (FIESC) is a phylogenetically species-rich complex that includes over 30 cryptic phylogenetic species, making identification based on phenotypic characters problematic. Several established Fusarium species known to reside in the FIESC lack type material, further complicating the use of Latin binomials for this complex. To overcome this problem, an informal classification system based on a haplotype nomenclature was introduced to improve communication between researchers in various fields. However, some conflicts in the application of this nomenclature system have arisen. To date, 16 phylo-species in the FIESC have been provided with Latin binomials with approximately 18 FIESC phylo-species still lacking Latin binomials, the majority of which reside in the Incarnatum clade. The aim of this study is to introduce Latin binomials for the unnamed FIESC phylo-species based on phylogenetic inference supported by phenotypic characters. The three-gene (calmodulin, RNA polymerase II second largest subunit and translations elongation factor 1-alpha) phylogenetic inference resolved 47 lineages, of which 44 belonged to the FIESC. The F. camptoceras species complex (FCAMSC) is introduced here for three lineages that are distinct from the FIESC. Epitypes are designated for F. compactum, F. incarnatum and F. scirpi, and a neotype for F. camptoceras. Latin binomials are provided for 20 of these newly resolved phylo-species in the FIESC.


National nursing registration in Australia: a way forward for nurse practitioner endorsement.
The move to national registration of health professionals and the creation of the Nursing and Midwifery Board of Australia (NMBA) provides both challenges and opportunities for the regulation of nurse practitioners (NPs) in Australia. National and state health policy documents, accessible on the Internet, concerning the regulation and endorsement processes for NPs in Australia were examined. The similarities between two of the previous jurisdictional NP endorsement processes in New South Wales and Victoria provide a common ground on which to build a robust national system. However, there are also key differences between these two states. These differences were mainly in the evidence required to assess competency of NP applicants and the authority to prescribe medications. All Victorian NP applicants were required to complete an approved medication subject at a master's level. A consistent endorsement process that delivers NPs of the highest standard and allows for efficient use of their skills and expertise is vital. This needs to be performed with the aim of providing high-quality care in a regulatory environment that protects the public and clearly articulates the level of competence expected of all NPs.


Side effects associated with influenza vaccination in healthy working adults. A randomized, placebo-controlled trial.
Concern about side effects is a barrier to influenza vaccination. This randomized, double-blind, placebo-controlled trial assessed side effects following vaccination among healthy working adults. Healthy working adults were recruited during October and November 1994 and were randomized to receive influenza vaccine or placebo injections. Local and systemic symptoms during the week following the injection were evaluated through structured telephone interviews. Of 849 subjects enrolled in the study, 425 received a placebo and 424 received influenza vaccine. Baseline characteristics were similar between the groups, and 99% of subjects completed interviews to assess side effects after the study injection. No differences were seen between the 2 groups for the systemic symptoms of fever, myalgias, fatigue, malaise, or headaches. Overall, 35.2% of placebo and 34.1% of vaccine recipients reported at least 1 of these systemic symptoms (P = .78, chi 2). Vaccine recipients reported a higher rate of arm soreness at the injection site than did placebo recipients (63.8% vs 24.1%, P < .001). Local reactions were mild in both groups and infrequently resulted in decreased use of the arm. After logistic regression, female sex (odds ratio [OR], 1.5;95% confidence interval [CI], 1.1-2.1), age younger than 40 years (OR, 1.6;95% CI, 1.2-2.2), and coincidental upper respiratory tract illness (OR, 4.6; 95% CI, 3.2-6.6) were independently associated with higher rates of systemic symptoms. In the multivariate model, vaccine again was not associated with systemic symptoms (OR, 0.9; 95% CI, 0.7-1.2). Influenza vaccination of healthy working adults is not associated with higher rates of systemic symptoms when compared with placebo injection. These findings should be useful to physicians and other health care providers as they counsel patients to take advantage of an important opportunity for disease prevention and health protection.


Collagen bundle morphometry in skin and scar tissue: a novel distance mapping method provides superior measurements compared to Fourier analysis.
Histopathological evaluations of fibrotic processes require the characterization of collagen morphology in terms of geometrical features such as bundle orientation thickness and spacing. However, there are currently no reliable and valid techniques of measuring bundle thickness and spacing. Hence, two objective methods quantifying the collagen bundle thickness and spacing were tested for their reliability and validity: Fourier first-order maximum analysis and Distance Mapping, with the latter constituting a newly developed morphometric technique. Histological slides were constructed and imaged from 50 scar and 50 healthy human skin biopsies and subsequently analyzed by two observers to determine the interobserver reliability via the intraclass correlation coefficient. An intraclass correlation coefficient larger than 0.7 is considered as representing good reliability. The interobserver reliability for the Fourier first-order maximum and for the Distance Mapping algorithms, respectively, showed an intraclass correlation coefficient above 0.72 and 0.89. Additionally, we performed an assessment of validity in the form of responsiveness, in particular, demonstrating medium to excellent results via a calculation of the effect size, highlighting that both methods are sensitive enough to measure a treatment effect in clinical practice. In summary, two reliable and valid measurement methods were demonstrated for collagen bundle morphometry for the first time. Due to its superior reliability and more useful measures (bundle thickness and bundle spacing), Distance Mapping emerges as the preferred and more practical method. Nevertheless, in the future, both methods can be used for reliable and valid collagen morphometry of skin and scars, whereas further applications evaluating the quantitative microscopy of other fibrotic processes are anticipated.


The popliteal artery, an unusual muscular artery with wall properties similar to the aorta: implications for susceptibility to aneurysm formation?
The popliteal artery is, after the aorta, the most common site for aneurysm formation. Why the popliteal artery is more susceptible than other peripheral muscular arteries is unknown. An important factor may be differences in arterial wall composition as compared with other peripheral muscular arteries, which in turn affect wall properties. These are however unknown. We studied the mechanical wall properties of the popliteal artery in healthy subjects. An ultrasound echo-tracking system was used to measure pulsatile changes in popliteal diameter in 108 healthy subjects (56 female, 52 male; age range, 9-82 years). In combination with blood pressure, stiffness (beta), strain, cross-sectional artery wall compliance coefficient (CC), and distensibility coefficient (DC) were calculated. Intima-media thickness (IMT) was registered with a Philips P700 ultrasound scanner. The popliteal diameter increased with age, and was larger in male subjects than in female subjects (P<.001). Fractional diameter change (strain) decreased with age (P<.001), and strain values were lower in male subjects than in female subjects (P<.01). Accordingly, stiffness increased with age (P<.001), with higher stiffness values in male subjects (P<.01). DC decreased with age (P<.001), with lower DC values in male subjects (P<.01). CC decreased with age, with no difference between genders (P<.001). IMT increased with age (P<.001), with higher IMT values in male subjects (P<.001). The increase in IMT did not affect distensibility. The wall properties of the popliteal artery are affected by age and gender, not only with an increase in diameter, but also with an age-related decrease in distensibility, with male subjects having lower distensibility than in female subjects. This seems not to be the behavior of a true muscular artery, but of a central elastic artery, such as the aorta, and might have implications for susceptibility to arterial dilatation, as well as the association of aneurysm formation between the aorta and the popliteal artery. The popliteal artery is, after the abdominal aorta, the most common location for aneurysm formation in the arterial system. Why it is more susceptible than other arteries is unknown. This study shows that the wall function of the popliteal artery differs from other peripheral arteries, and instead show striking similarities to the abdominal aorta, indicating that the functional arrangement of arterial wall components are similar in the two arteries. This may have implications for the susceptibility to aneurysm formation, as well as the association of dilating disease between the popliteal artery and the abdominal aorta.


What is so frightening about spiders? Self-rated and self-disclosed impact of different characteristics and associations with phobia symptoms.
Spider phobia is a common and impairing mental disorder, yet little is known about what characteristics of spiders that spider phobic individuals find frightening. Using screening data from a clinical trial, we explored which characteristics that spider-fearful individuals (n = 194) rated as having the greatest impact on fear, used factor analysis to group specific characteristics, and explored linear associations with self-reported phobia symptoms. Second, a guided text-mining approach was used to extract the most common words in free-text responses to the question: "What is it about spiders that you find frightening?" Both analysis types suggested that movement-related characteristics of spiders were the most important, followed by appearance characteristics. There were, however, no linear associations with degree of phobia symptoms. Our findings reveal the importance of targeting movement-related fears in in-vivo exposure therapy for spider phobia and using realistically animated spider stimuli in computer-based experimental paradigms and clinical interventions such as Virtual Reality exposure therapy.


The Propionibacterium freudenreichii hemYHBXRL gene cluster, which encodes enzymes and a regulator involved in the biosynthetic pathway from glutamate to protoheme.
A clone that can complement both Escherichia coli hemB and hemL mutations was found among plasmids containing the Propionibacterium freudenreichii hemB gene, which encodes delta-aminolevulinic acid dehydratase. The regions upstream and downstream of the hemB gene were sequenced. Two open-reading frames (ORF1 and -2), which were similar to the hemY gene encoding protoporphyrinogen oxidase and the hemH gene encoding ferrochelatase from Bacillus subtilis, were found upstream of the hemB gene. ORF1 and -2 complemented the E. coli hemG mutation, defective in protoporphyrinogen oxidase, and the hemH gene respectively. Since ORF1 had no homology to hemG, the gene was designated hemY. The hemYHB genes appeared to be within the same transcription unit. Downstream from the hemB gene, three open-reading frames were found. One of these, transcribed in the same direction as the hemB gene, was identical to be the hemL gene, which encodes glutamate-1-semialdehyde 2,1-aminomutase. The other two open-reading frames, located between the hemYHB and hemL genes, were transcribed divergently, and their deduced amino acid sequences showed similarities to a membrane-bound transport protein and a transcriptional regulatory protein respectively. The two genes may thus be involved in hem transport and the regulation of hem gene expression respectively, and were tentatively named hemX and hemR. Although hemX and hemL are unlikely to be part of the same operon, hemYHBXRL are clustered on the P. freudenreichii chromosome.


Structural basis of Deerpox virus-mediated inhibition of apoptosis.
Apoptosis is a key innate defence mechanism to eliminate virally infected cells. To counteract premature host-cell apoptosis, poxviruses have evolved numerous molecular strategies, including the use of Bcl-2 proteins, to ensure their own survival. Here, it is reported that the Deerpox virus inhibitor of apoptosis, DPV022, only engages a highly restricted set of death-inducing Bcl-2 proteins, including Bim, Bax and Bak, with modest affinities. Structural analysis reveals that DPV022 adopts a Bcl-2 fold with a dimeric domain-swapped topology and binds pro-death Bcl-2 proteins via two conserved ligand-binding grooves found on opposite sides of the dimer. Structures of DPV022 bound to Bim, Bak and Bax BH3 domains reveal that a partial obstruction of the binding groove is likely to be responsible for the modest affinities of DPV022 for BH3 domains. These findings reveal that domain-swapped dimeric Bcl-2 folds are not unusual and may be found more widely in viruses. Furthermore, the modest affinities of DPV022 for pro-death Bcl-2 proteins suggest that two distinct classes of anti-apoptotic viral Bcl-2 proteins exist: those that are monomeric and tightly bind a range of death-inducing Bcl-2 proteins, and others such as DPV022 that are dimeric and only bind a very limited number of death-inducing Bcl-2 proteins with modest affinities.


Hepatocellular carcinoma: susceptibility markers.
Genetic polymorphisms of the carcinogen-metabolizing enzymes cytochrome P450 (CYP), glutathione S-transferase (GST) M1 and N-acetyltransferase (NAT2) as well as p53 polymorphisms have been studied experimentally as susceptibility markers for hepatocellular carcinoma development in hepatocellular carcinoma cell lines and in mouse hepatocellular carcinomas. In addition, these susceptibility markers have been studied in hepatocellular carcinoma patients, in the context of coexisting alcohol consumption, smoking and/or HBV infection. To date, there is no clear evidence that susceptibility markers have an overall impact on hepatocarcinogenesis, but in subgroups of individuals, such as smokers, susceptibility markers are emerging indicators for hepatocellular carcinoma risk definition.


Fluorescence lifetime of actin in the familial hypertrophic cardiomyopathy transgenic heart.
Clinical studies have revealed that the D166V mutation in the ventricular myosin regulatory light chain (RLC) can cause a malignant phenotype of familial hypertrophic cardiomyopathy (FHC). It has been proposed that RLC induced FHC in the heart originates at the level of the myosin cross-bridge due to alterations in the rates of cross-bridge cycling. In this report, we examine whether the environment of an active cross-bridge in cardiac myofibrils from transgenic (Tg) mice is altered by the D166V mutation in RLC. The cross-bridge environment was monitored by tracking the fluorescence lifetime (tau) of Alexa488-phalloidin-labeled actin. The fluorescence lifetime is the average rate of decay of a fluorescent species from the excited state, which strongly depends on various environmental factors. We observed that the lifetime was high when cross-bridges were bound to actin and low when they were dissociated from it. The lifetime was measured every 50 ms from the center half of the I-band during 60 s of rigor, relaxation and contraction of muscle. We found no differences between lifetimes of Tg-WT and Tg-D166V muscle during rigor, relaxation and contraction. The duty ratio expressed as a fraction of time that cross-bridges spend attached to the thin filaments during isometric contraction was similar in Tg-WT and Tg-D166V muscles. Since independent measurements showed a large decrease in the cross-bridge turnover rate in Tg-D166V muscle compared to Tg-WT, the fact that the duty cycle remains constant suggests that the D166V mutation of RLC causes a decrease in the rate of cross-bridge attachment to actin.


Musculoskeletal anatomy and feeding performance of pre-feeding engyodontic larvae of the European eel (Anguilla anguilla).
Being part of the elopomorph group of fishes, Anguillidae species show a leptocephalus larval stage. However, due to largely unknown spawning locations and habitats of their earliest life stages, as well as their transparency, these Anguilla larvae are rarely encountered in nature. Therefore, information regarding the early life history of these larvae, including their exogenous feeding strategy and feeding performance, is rather scarce. To better understand the structural basis and functional performance of larval feeding in captivity, the functional morphology of the cranial musculoskeletal system in pre- and first-feeding engyodontic leptocephali of the European eel (Anguilla anguilla) was studied. A 3D reconstruction of the feeding apparatus (head of the leptocephali < 1 mm) was used to visualize and describe the musculoskeletal changes throughout these stages. To analyze the ontogenetic changes in the functionality of the feeding apparatus towards the active feeding phase, 3D data of joints, levers and muscles derived from the reconstructions were used to estimate bite and joint reaction forces (JRFs). Observing a maximum estimated bite force of about 65 μN (and corresponding JRFs of 260 μN), it can be hypothesized that leptocephalus larvae are functionally constrained to feed only on soft food particles. Additionally, potential prey items are size delimited, based on the theoretically estimated average gape of these larvae of about 100 μm. This hypothesis appears to be in line with recent observations of a diet consisting of small and/or gelatinous prey items (Hydrozoa, Thaliacea, Ctenophora, Polycystenia) found in the guts of euryodontic leptocephalus larvae.


Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation.
The etiology and pathogenesis of inflammatory bowel disease (IBD) are unknown. Increasing evidence supports the theory that chronic IBD is the result of dysfunctional immunoregulation manifested by an inappropriate production of mucosal cytokines. The aim of the present study was to test the hypothesis that a specific mucosal imbalance of IL-1 and IL-1 receptor antagonist (IL-1ra) production plays an important role in the perpetuation and chronicity of intestinal inflammation. Total IL-1, IL-1ra, and the IL-1ra/IL-1 ratio were measured in freshly isolated intestinal mucosal cells, as well as in mucosal biopsies obtained from control, Crohn's disease, and ulcerative colitis patients. IL-1 alpha, IL-1 beta, and IL-1 ra were measured by specific non-cross-reacting radioimmunoassays and ELISA. A markedly significant decrease in the intestinal mucosal IL-1ra/IL-1 ratio was found in both Crohn's disease and ulcerative colitis patients when compared with control subjects (p < 0.01). The IL-1ra/IL-1 ratio correlated closely with the clinical severity of disease (r = -0.7846, p < 0.001). Furthermore, the observed decrease in the IL-1ra/IL-1 ratio was specific for IBD because a decreased IL-1ra/IL-1 ratio was not found in patients with self-limiting colitis. These results support the hypothesis that an imbalance between IL-1 and IL-1ra production is of pathogenic importance in chronic inflammatory diseases, including IBD.


Differential modulation of the androgen receptor for prostate cancer therapy depends on the DNA response element.
Androgen receptor (AR) action is a hallmark of prostate cancer (PCa) with androgen deprivation being standard therapy. Yet, resistance arises and aberrant AR signaling promotes disease. We sought compounds that inhibited genes driving cancer but not normal growth and hypothesized that genes with consensus androgen response elements (cAREs) drive proliferation but genes with selective elements (sAREs) promote differentiation. In a high-throughput promoter-dependent drug screen, doxorubicin (dox) exhibited this ability, acting on DNA rather than AR. This dox effect was observed at low doses for multiple AR target genes in multiple PCa cell lines and also occurred in vivo. Transcriptomic analyses revealed that low dox downregulated cell cycle genes while high dox upregulated DNA damage response genes. In chromatin immunoprecipitation (ChIP) assays with low dox, AR binding to sARE-containing enhancers increased, whereas AR was lost from cAREs. Further, ChIP-seq analysis revealed a subset of genes for which AR binding in low dox increased at pre-existing sites that included sites for prostate-specific factors such as FOXA1. AR dependence on cofactors at sAREs may be the basis for differential modulation by dox that preserves expression of genes for survival but not cancer progression. Repurposing of dox may provide unique opportunities for PCa treatment.


Cocoa antioxidants and cardiovascular health.
An increasing body of epidemiologic evidence supports the concept that diets rich in fruits and vegetables can promote health and attenuate, or delay, the onset of various diseases. Epidemiologic data support the idea that these health benefits are causally linked to the consumption of certain flavonoids present in fruit and vegetables. In the context of cardiovascular health, a particular group of flavonoids, namely, the flavan-3-ols (flavanols), has received attention. Flavanol-rich, plant-derived foods and beverages include wine, tea, and various fruits and berries, as well as cocoa and cocoa products. Numerous dietary intervention studies in humans and animals indicate that flavanol-rich foods and beverages might exert cardioprotective effects with respect to vascular function and platelet reactivity. This review discusses the bioactivity of flavanols in the context of cardiovascular health, with respect to their bioavailability, their antioxidant properties, and their vascular effects.


Cognitive burden of anticholinergic medications in psychotic disorders.
Patients with psychotic disorders are often treated with numerous medications, many of which have anticholinergic activity. We assessed cognition in relation to the cumulative anticholinergic burden of multiple drugs included in treatment regimens of participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Clinically stable participants with schizophrenia (n=206), schizoaffective disorder (n=131), and psychotic bipolar disorder (n=146) were examined. Anticholinergic properties of all scheduled drugs were quantified using the Anticholinergic Drug Scale (ADS). ADS scores were summed across individual drugs to create a total ADS burden score for each participant and examined in relation to the Brief Assessment of Cognition in Schizophrenia (BACS). Anticholinergic burden aggregated across all medications was inversely related to cognitive performance starting at ADS scores of 4 in participants with schizophrenia. Those with ADS scores ≥4 had lower composite BACS scores compared to those with ADS<4 (p=0.004). Among BACS subtests, Verbal Memory was the most adversely affected by high anticholinergic burden. Despite similar anticholinergic burden scores across groups, a significant threshold effect of anticholinergic burden was not detected in schizoaffective or psychotic bipolar disorder. We identified an adverse effect threshold of anticholinergic burden on cognition in clinically stable participants with schizophrenia. This relationship was not identified in affective psychoses. Examination of other medications, doses, and clinical measures did not account for these findings. Patients with schizophrenia may have increased cognitive susceptibility to anticholinergic medications and the aggregate effects of one's medication regimen may be important to consider in clinical practice.


Direct comparison of Sn-mesoporphyrin, an inhibitor of bilirubin production, and phototherapy in controlling hyperbilirubinemia in term and near-term newborns.
Sn-mesoporphyrin (SnMP) is a potent inhibitor of bilirubin production. In our previous studies a single dose (6 mumol/kg birth weight) significantly moderated hyperbilirubinemia and reduced phototherapy (PT) time by > 75% when administered within 24 hours of birth to preterm infants. To directly compare the efficacy of SnMP and PT for controlling hyperbilirubinemia in term and near-term infants. Two randomized, sequentially analyzed trials (Study I: male term infants; Study II: infants of both sexes and gestational age [GA] 245-265 days) were conducted. SnMP (6 mumol/kg birth weight) or PT (Phillips F20T12/BB lamps) was administered to paired infants according to strict criteria of plasma bilirubin levels and age. Time of enrollment and closure of cases and crossover, if necessary, of SnMP infants to PT or all infants to exchange transfusion were precisely defined in each pair. SnMP or PT was considered superior if the time between enrollment and closure of the case was reduced by > 24 hours over the alternative treatment or if crossover had occurred. None of the 44 SnMP-treated infants required supplemental PT. Of the 22 pairs of term infants enrolled in Study I, SnMP proved superior to PT in 20 and equal in two. Of the 20 pairs of near-term infants enrolled in Study II, SnMP was superior in 12 and PT in two; six were tied. Two SnMP-treated infants were unpaired. The PT-treated infants in Study I required an average of 33 hours of treatment; those in Study II, 48 hours. None of the enrolled infants required exchange transfusion or interruption of breast-feeding. In both studies, times between case enrollment and closure were reduced by > 30 hours in SnMP compared with PT infants; requirements for additional days of medical observation and bilirubin measurements were also significantly less in SnMP infants. A single dose of SnMP entirely supplanted the need for PT in jaundiced term and near-term newborns and significantly reduced medical resource use to monitor hyperbilirubinemia.


Sunlight-induced transformation of sulfadiazine and sulfamethoxazole in surface waters and wastewater effluents.
Sulfadiazine (SD) and sulfamethoxazole (SMX) are widely used sulfonamide antibiotics, which are present as contaminants in surface waters and are known to undergo phototransformation. This kinetic study was conducted to identify the processes responsible for their phototransformation in sunlit surface waters. Water samples from the Thur River (Switzerland) and from a pilot wastewater treatment plant, as well as aqueous solutions of two well-characterized natural dissolved organic matter (DOM) extracts, namely Suwannee River and Pony Lake fulvic acids (SRFA, PLFA), were examined. Both sulfonamides were found to undergo direct and indirect phototransformation, with contributions of excited triplet states of DOM and of effluent organic matter (EfOM) and possibly of hydroxyl radical and other unidentified reactive species. Under simulated sunlight, SMX mainly reacted through direct phototransformation, with a certain contribution of indirect phototransformation occurring for a wastewater effluent. The behavior of SD was found to be more diverse. For river waters, wastewater effluents and PLFA solutions, indirect phototransformation was predominant, while for SRFA solutions direct phototransformation prevailed. The rates of phototransformation of SD were interpreted as the result of a complex interplay between the photosensitizing and the inhibitory effect of DOM/EfOM, with an additional component related to the nitrite ion as a source of photoproduced hydroxyl radical. For typical conditions found in surface waters comparable to the Thur River, phototransformation half-lives on the order of 3-13 d were estimated for the two studied sulfonamides.


Manic symptoms and impulsivity during bipolar depressive episodes.
In contrast to the extensive literature on the frequent occurrence of depressive symptoms in manic patients, there is little information about manic symptoms in bipolar depressions. Impulsivity is a prominent component of the manic syndrome, so manic features during depressive syndromes may be associated with impulsivity and its consequences, including increased risk of substance abuse and suicidal behavior. Therefore, we investigated the prevalence of manic symptoms and their relationships to impulsivity and clinical characteristics in patients with bipolar depressive episodes. In 56 bipolar I or II depressed subjects, we investigated the presence of manic symptoms, using Mania Rating Scale (MRS) scores from the Schedule for Affective Disorders and Schizophrenia (SADS), and examined its association with other psychiatric symptoms (depression, anxiety, and psychosis), age of onset, history of alcohol and/or other substance abuse and of suicidal behavior, and measures of impulsivity. MRS ranged from 0 to 29 (25th-75th percentile, range 4-13), and correlated significantly with anxiety and psychosis, but not with depression, suggesting the superimposition of a separate psychopathological mechanism. Impulsivity and history of substance abuse, head trauma, or suicide attempt increased with increasing MRS. Receiver-operating curve analysis showed that MRS could divide patients into two groups based on history of alcohol abuse and suicide attempt, with an inflection point corresponding to an MRS score of 6. Even modest manic symptoms during bipolar depressive episodes were associated with greater impulsivity, and with histories of alcohol abuse and suicide attempts. Manic symptoms during depressive episodes suggest the presence of a potentially dangerous combination of depression and impulsivity.


Fluorometric and colorimetric enzymic determination of triglycerides (triacylglycerols) in serum.
We describe two fully enzymic methods, fluorometric and colorimetric, for determination of triglycerides (triacylglycerols) in serum. Samples are incubated with microbial lipase for 10 min, and the glycerol released from the triglycerides is oxidized by NAD+ in the presence of glycerol dehydrogenase. In the fluorometric method, the resulting NADH is in turn oxidized by resazurin as catalyzed by diaphorase to form resorufin, a highly fluorescent compound. In the colorimetric method, the NADH is oxidized by coupling with a tetrazolium salt/diaphorase system to form formazan, a highly colored compound. Calibration curves, constructed by plotting change in fluorescence or absorbance vs concentration of triglycerides, were linear up to 6 and 5 g of triglycerides per liter of serum for the fluorometric and colorimetric methods, respectively. The assays require only 5 and 15 microL of serum for fluorometry and colorimetry, respectively. The CV was 0.59% for the fluorometric method, 0.91% for the colorimetric procedure. The time for analysis for either method is less than 15 min. The results correlate well with those obtained by the Dow Diagnostic Kit method, a colorimetric method in which glycerol kinase and glycerol-1-phosphate dehydrogenase form NADH from ATP and NAD+ in the presence of glycerol and glycerol 1-phosphate.


Protein array autoantibody profiles for insights into systemic lupus erythematosus and incomplete lupus syndromes.
The objective of this study was to investigate the prevalence and clinical significance of a spectrum of autoantibodies in systemic lupus erythematosus and incomplete lupus syndromes using a proteome microarray bearing 70 autoantigens. Microarrays containing candidate autoantigens or control proteins were printed on 16-section slides. These arrays were used to profile 93 serum samples from patients with systemic lupus erythematosus (SLE (n = 33), incomplete LE (ILE; n = 23), first-degree relatives (FDRs) of SLE patients (n = 20) and non-autoimmune controls (NC; n = 17). Data were analysed using the significance analysis of microarray (SAM) and clustering algorithms. Correlations with disease features were determined. Serum from ILE and SLE patients contained high levels of IgG autoantibodies to 50 autoantigens and IgM autoantibodies to 12 autoantigens. Elevated levels of at least one IgG autoantibody were detected in 26% of SLE and 19% of ILE samples; elevated IgM autoantibodies were present in 13% of SLE and 17% of ILE samples. IgG autoantibodies segregated into seven clusters including two specific for DNA and RNA autoantigens that were correlated with the number of lupus criteria. Three IgG autoantibody clusters specific for collagens, DNA and histones, were correlated with renal involvement. Of the four IgM autoantibody clusters, two were correlated negatively with the number of lupus criteria; none were correlated with renal disease. The IgG : IgM autoantibody ratios generally showed a stepwise increase in the groups following disease burden from NC to SLE. Insights derived from the expanded autoantibody profiling made possible with the antigen array suggest differences in autoreactivity in ILE and SLE. Determining whether the IgM aurotreactivity that predominates in ILE represents an early stage prior to IgG switching or is persistent and relatively protective will require further longitudinal studies.


Design, optimisation and evaluation of in situ gelling nanoemulsion formulations of brinzolamide.
The present research work summarises the development of an in situ gelling ophthalmic nanoemulsion of brinzolamide providing sustained release and prolonged therapeutic effect for the treatment of glaucoma. Nanoemulsions were prepared using castor oil, polyoxyl 35 castor oil and polysorbate 80 and with gellan gum as the in situ gelling agent. Formulations were screened based on globule size, Zeta potential, in vitro drug release and stability towards phase separation and sol to gel conversion upon storage. Selected formulations exhibiting a low mean globule diameter (< 160 nm), narrow size distribution (polydispersity index < 0.3), quick in vitro gelling time (< 15 s) and stability for at least 6 months at 25 °C/40% RH and 40 °C/25% RH were evaluated for intraocular pressure (IOP)-lowering efficacy studies using glaucomatous rabbits. Tested nanoemulsion formulations were well tolerated and significantly decreased IOP relative to saline and placebo controls (p < 0.005). Furthermore, an appreciable increase in the area under change in IOP from baseline (ΔIOP) vs. time curve and a longer mean residence time (MRT) was also observed for the test formulations compared with commercially available suspension of brinzolamide (Azopt, Alcon Laboratories, USA). Thus, nanoemulsion formulations containing in situ gelling polymer may serve as improved drug delivery system providing superior therapeutic efficacy and better patient compliance for the treatment of glaucoma. . Graphical abstract.


Surface tension measurement at the microscale by passive resonance of capillary waves.
The properties of fluid interfaces increase in importance as the physical scale decreases and, hence, characterization of surface tension becomes all the more critical. However, there is to date no method to characterize this parameter on microscale surfaces. We propose here a simple method based on the resonance of capillary waves, which are naturally excited by thermal fluctuations, under one-dimensional spatial restrictions using single-beam dynamic light scattering. The principle was verified at methanol/air interfaces in polydimethylsiloxane (PDMS) microchannels having various widths. Characteristic comb-shape power spectra were experimentally obtained. Theoretical analysis showed that the spectral peaks correspond to the first or higher modes of the capillary wave resonance in the restricted space between the parallel channel walls. A useful relation between successive modes was derived to eliminate the effects of damping at the soft PDMS walls. Thus, for methanol, two values were calculated from three successive modes (24.8 and 21.2 mN/m); the literature value is 22.02 mN/m. For acetonitrile, the value obtained was 28.2 ± 5 mN/m, close to the literature value of 28.6 mN/m. Although accuracy and precision require further elucidation, this novel method is expected to become a powerful tool at the micro/nanoscale.


RNA interference-mediated c-MYC inhibition prevents cell growth and decreases sensitivity to radio- and chemotherapy in childhood medulloblastoma cells.
With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to cause anaplasia and correlate with unfavorable prognosis. To study the role of c-MYC in MB biology, we down-regulated c-MYC expression by using small interfering RNA (siRNA) and investigated changes in cellular proliferation, cell cycle analysis, apoptosis, telomere maintenance, and response to ionizing radiation (IR) and chemotherapeutics in a representative panel of human MB cell lines expressing different levels of c-MYC (DAOY wild-type, DAOY transfected with the empty vector, DAOY transfected with c-MYC, D341, and D425). siRNA-mediated c-MYC down-regulation resulted in an inhibition of cellular proliferation and clonogenic growth, inhibition of G1-S phase cell cycle progression, and a decrease in human telomerase reverse transcriptase (hTERT) expression and telomerase activity. On the other hand, down-regulation of c-MYC reduced apoptosis and decreased the sensitivity of human MB cells to IR, cisplatin, and etoposide. This effect was more pronounced in DAOY cells expressing high levels of c-MYC when compared with DAOY wild-type or DAOY cells transfected with the empty vector. In human MB cells, in addition to its roles in growth and proliferation, c-MYC is also a potent inducer of apoptosis. Therefore, targeting c-MYC might be of therapeutic benefit when used sequentially with chemo- and radiotherapy rather than concomitantly.


Functional analysis of myocardial performance in murine hearts overexpressing the human beta 2-adrenergic receptor.
Transgenic mice overexpressing the human beta 2-adrenergic receptor gene were compared with wild mice type in terms of cardiac function, using a modified work-performing isolated murine heart preparation and on-line computer analysis. A preload-dependent experiment was performed, in which venous return was gradually increased in 5 mmHg increments from 5 mmHg to 25 mmHg. At each preload, aortic flow, left atrial pressure and aortic pressure were measured in all hearts, and from these parameters stroke volume, contractility, and cardiac index (cardiac output divided by body weight in g) were calculated and compared between groups. At increasing preload levels, the heart rates ranged from 322 beats/min (+/-29) to 369 beats/min (+/-39) in control mice and from 469 beats/min (+/-36) to 540 beats/min (+/-39) in transgenic mice. Cardiac index increased from 138 microliters/min/g (+/-13) and 48 microliters/min/g (+/-5) for transgenic and control mice, respectively at 5 mmHg preload to 262 microliters/min/g (+/-51) and 167 microliters/min/g (+/-15), respectively at 20 mmHg preload. The contractility in the transgenic mice were significantly increased at lower preload levels compared to control mice (1420 mmHg/s +/- 204 v 1187 mmHg/s +/- 127). An increase in myocardial adrenergic receptor density (100-200 fold) leads to significantly higher indices of cardiac function in transgenic mice compared to control mice. The increased heart rate leading to a positive inotropic effect in the hearts of transgenic mice is, at least in part, due to the overexpression of adrenergic receptors. These findings suggest a possible alternative method of establishing a positive chronotropic and inotropic state without the use of pharmacological agents.


Binary diffractive mask as a beam-shaping element for direct application in large-angle gray scale element fabrication.
The capability of binary gray scale masks in generating beams with a desired lateral intensity profile is extensively studied in order to fabricate large-angle microprisms. Using a recently introduced technique, some samples based on pulsewidth modulation are designed, so that the pulsewidth is changed with different linear rates from a completely clear to a fully dark slit, which results in a different number of gray steps. Then, the influence of the rate on turning an incident plane wave into beams with different specially linear lateral intensity distributions was studied by simulation, experiment, and fabrication of a large-angle microprism. Further, it was shown that the width of the first slit and the increment of gray level have an effective impact on the slope and smoothness of the generated linear intensity profile across the beam. Simulation results are completely verified by experimental data and the fabricated linear gray scale element.


Multiple endocrine neoplasia type IIb: a clinicopathological report.
The clinicopathological findings in a 12-year-old boy with multiple endocrine neoplasia type IIb (MEN-IIb) are presented. He demonstrated the characteristics of a Marfanoid habitus and had mucosal neuromas of the lips, tongue, eyelids, and cornea. The enlarged right thyroid lobe showed an increased thallium-201 chloride uptake, and the serum calcitonin level was markedly raised. A total thyroidectomy was performed. Histopathological examination showed an infiltrating medullary carcinoma of the thyroid (MCT) and metastatic spread to supraclavicular lymph nodes. Special stains, immunocytochemistry, and electron microscopy revealed mucin-containing follicular structures lined by calcitonin-positive and thyroglobulin-negative tumour cells. Ultrastructurally the mucosal neuromas consisted of proliferating perineurial and Schwann cells. The serum calcitonin level fell below 300 pmol/L, and his stools returned to normal postoperatively. Because the incidence of MCT in MEN-IIb is virtually 100%, a total thyroidectomy in high risk patients--even before clinical evidence of malignant tumours--may be the only hope of cure.


Private patient rooms and hospital-acquired methicillin-resistant Staphylococcus aureus: A hospital-level analysis of administrative data from the United States.
To use hospital-level data from the US to determine whether private patient rooms (PPRs) are associated with fewer in hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) infections. We retrospectively analyzed Texas Inpatient Public Use Data with discharges between September 2015 and August 2016 merged with American Hospital Association annual survey data. We used negative binomial regression to estimate the association between the proportion of PPRs within a hospital and the count of discharges with HA-MRSA infections, adjusting for potentially confounding variables. We analyzed data for 340 hospitals and 2,670,855 discharges. HA-MRSA incidence within these hospitals was 386 per 100,000 discharges (95% CI: 379, 393) and, on average, 62.73% (95% CI: 58.99, 66.46) of rooms in these hospitals were PPRs. PPRs were significantly associated with fewer HA-MRSA infections (unadjusted IRR = 0.973, 95% CI: 0.968, 0.979; adjusted IRR = 0.992, 95% CI: 0.991, 0.994; p<0.001 for both); at the hospital level, as the percentage of PPRs increased, HA-MRSA infection rates decreased. This association was non-linear; in hospitals with few PPRs there was a stronger association between PPRs and HA-MRSA infection rate relative to hospitals with many PPRs. We identified 0.8% fewer HA-MRSA infections for each 1% increase in PPRs as a proportion of all rooms, suggesting that private rooms provide substantial protection from HA-MRSA. Small changes may not induce significant improvements in HA-MRSA incidence, and hospitals seeking tangible benefits in HAI reduction likely need to markedly increase the proportion of PPRs through large-scale renovations. The effect of private rooms is disproportionate across hospitals. Hospitals with proportionately fewer PPRs stand to gain the most from adding additional PPRs, while those with an already high proportion of PPRs are unlikely to see large benefits. Our findings enable hospital administrators to consider potential patient safety benefits as they make decisions about facility design and renovation.


Characteristics Associated With Decreased or Increased Mortality Risk From Glycemic Therapy Among Patients With Type 2 Diabetes and High Cardiovascular Risk: Machine Learning Analysis of the ACCORD Trial.
Identifying patients who may experience decreased or increased mortality risk from intensive glycemic therapy for type 2 diabetes remains an important clinical challenge. We sought to identify characteristics of patients at high cardiovascular risk with decreased or increased mortality risk from glycemic therapy for type 2 diabetes using new methods to identify complex combinations of treatment effect modifiers. The machine learning method of gradient forest analysis was applied to understand the variation in all-cause mortality within the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N = 10,251), whose participants were 40-79 years old with type 2 diabetes, hemoglobin A1c (HbA1c) ≥7.5% (58 mmol/mol), cardiovascular disease (CVD) or multiple CVD risk factors, and randomized to target HbA1c <6.0% (42 mmol/mol; intensive) or 7.0-7.9% (53-63 mmol/mol; standard). Covariates included demographics, BMI, hemoglobin glycosylation index (HGI; observed minus expected HbA1c derived from prerandomization fasting plasma glucose), other biomarkers, history, and medications. The analysis identified four groups defined by age, BMI, and HGI with varied risk for mortality under intensive glycemic therapy. The lowest risk group (HGI <0.44, BMI <30 kg/m2, age <61 years) had an absolute mortality risk decrease of 2.3% attributable to intensive therapy (95% CI 0.2 to 4.5, P = 0.038; number needed to treat: 43), whereas the highest risk group (HGI ≥0.44) had an absolute mortality risk increase of 3.7% attributable to intensive therapy (95% CI 1.5 to 6.0; P < 0.001; number needed to harm: 27). Age, BMI, and HGI may help individualize prediction of the benefit and harm from intensive glycemic therapy.


Rheumatic heart disease in pregnancy: Profile of women admitted to a Western Australian tertiary obstetric hospital.
This retrospective study assessed maternal and perinatal outcomes for women with rheumatic heart disease (RHD) admitted to the largest tertiary obstetric hospital in Western Australia from 2009 to 2016. Of 54 women identified, 75.9% were Indigenous, 59.3% lived in rural areas and 40.7% had severe RHD. Heart failure developed in 10% who gave birth. Indigenous women were younger, had higher gravidity (P = 0.0305), were more likely to receive secondary prophylaxis (P = 0.0041) and have sub-optimal antenatal clinic attendance (P = 0.0078). There were no maternal deaths and two perinatal deaths (4.0%), reflecting vigilance in the obstetric management of women with RHD in Western Australia.


Individual and collective exposure to political violence: Palestinian adolescents coping with conflict.
We conducted a survey of Palestinian adolescents in school. We hypothesized that collective and individual exposures to violence would both negatively affect adolescents' mental health. We also anticipated that the negative effect of collective exposures on mental health would be less than that of individual exposures. Our analysis was designed to test these hypotheses. A representative sample of 3415 students of 10th and 11th grades from the Ramallah District of the West Bank participated in the survey. The primary independent variables were scales of individual and collective exposures to trauma/violence (ETV) by the Israeli military and settlers. Factor analysis revealed several sub-scales. Outcome measures were constructed and included: a binary measure of depressive-like states, and emotional, depressive-like state, and somatic scales. Several variables were identified as possible covariates: gender, age, school-type, residence, employment status of father, and identity documents held. Logistic and multiple regression analyses revealed a strong relationship between ETV and adolescents' mental health, with both individual and collective exposures having independent effects. There was a higher prevalence of depressive-like symptoms among girls compared with boys, and in adolescents living in Palestinian refugee camps compared with those living in cities, towns and villages. The findings confirmed our hypothesis that both individual and collective ETV independently affect the mental health of adolescents. Contrary to expectations, individual exposures did not consistently have a greater negative effect on health outcomes than collective exposures, although the sub-scale of direct personal exposures to violence consistently showed the strongest effect among sub-scales. The results emphasize the importance of going beyond individual experiences and including the health outcomes of collective violation when analyzing violent and traumatic contexts.


Inflammation-associated declines in cerebral vasoreactivity and cognition in type 2 diabetes.
The aim of this prospective study was to investigate the relationships between inflammation, cerebral vasoregulation, and cognitive decline in type 2 diabetes mellitus (T2DM) over a 2-year span. Sixty-five participants (aged 66 ± 9.2 years, 35 with T2DM, 33 women) were enrolled for this 2-year prospective study. Continuous arterial spin labeling at 3-tesla MRI was used to measure global and regional cerebral perfusion and vasoreactivity. Neuropsychological measures were evaluated at the beginning and completion of the study. The associations between serum inflammatory markers, regional cerebral vasoreactivity, and cognitive functions were examined using least squares models. After 2 years of follow-up, participants with T2DM had diminished global and regional cerebral vasoreactivity and a decline in multiple cognitive tasks compared with baseline (p < 0.0001-0.012). In the T2DM group, lower cerebral vasoreactivity was associated with a greater decrease in daily living activities score (r(2) adj = 0.35, p = 0.04), and lower global vasodilation was associated with a greater decline in executive function (r(2) adj = 0.6, p = 0.047). Higher serum soluble intercellular and vascular adhesion molecules, higher cortisol, and higher C-reactive protein levels at baseline were associated with greater decreases in cerebral vasoreactivity and vasodilation only in the T2DM group (r(2) adj = 0.16-0.53, p = 0.007-0.048), independent of diabetes control and 24-hour blood pressure. Higher glycated hemoglobin A1c levels were associated with a greater increase in vasoconstriction in the T2DM group. Inflammation may further impair cerebral vasoregulation, which consequently accelerates decline in executive function and daily activities performance in older people with T2DM.


Prevalence and features of ICF-disability in Spain as captured by the 2008 National Disability Survey.
Since 1986, the study of disability in Spain has been mainly addressed by National Disability Surveys (NDSs). While international attempts to frame NDS designs within the International Classification of Functioning, Disability and Health (ICF) have progressed, in general, the ICF has hardly been used in either the NDS or epidemiological studies. This study sought to identify ICF Activity- and Participation-related content in the most recent Spanish NDS, the 2008 Survey on Disabilities, Independence and Dependency Situations (Encuesta sobre discapacidades, autonomía personal y situaciones de Dependencia - EDAD 2008), and estimate the prevalence of such ICF-framed disability. EDAD 2008 methods and questions were perused. Of the 51 EDAD items analysed, 29 were backcoded to specific d2-d7 domains of the ICF Checklist and, by rating the recorded difficulty to perform specific tasks with or without help, these were then taken as performance and capacity respectively. A global ICF score was also derived, albeit lacking data for d1, "Learning and applying knowledge", d8, "Major Life Areas" and d9, "Community, Social and Civic Life". Data were grouped by sex, age, residence and initial positive screening, and prevalence figures were calculated by disability level both for the general population, using the originally designed weights, and for the population that had screened positive to disability. Data for institutionalised persons were processed separately. Crude prevalence of ICF severe/complete and moderate disability among the community-dwelling population aged ≥6 years was 0.9%-2.2% respectively, and that of severe/complete disability among persons living in sheltered accommodation was 0.3%.Prevalence of severe/complete disability was: higher in women than in men, 0.8% vs. 0.4%; increased with age; and was particularly high in domains such as "Domestic Life", 3.4%, "Mobility", 1.8%, and "Self-care", 1.9%, in which prevalence decreased when measured by reference to performance. Moreover, global scores indicated that severe/complete disability in these same domains was frequent among the moderately disabled group. The EDAD 2008 affords an insufficient data set to be ICF-framed when it comes to the Activity and Participation domains. Notwithstanding their unknown validity, ratings for available ICF domains may, however, be suitable for consideration under the ADL model of functional dependency, suggesting that there are approximately 500,000 persons suffering from severe/complete disability and 1,000,000 suffering from moderate disability, with half the latter being severely disabled in domains capable of benefiting from technical or personal aid. Application of EDAD data to the planning of services for regions and other subpopulations means that need for personal help must be assessed, unmet needs ascertained, and knowledge of social participation and support, particularly for the mentally ill, improved. International, WHO-supported co-operation in ICF planning and use of NDSs in Spain and other countries is needed.


Direct observations of field-induced assemblies in magnetite ferrofluids.
Evolution of microstructures in magnetite-based ferrofluids with weak dipolar moments (particle size ≤ 10 nm) is studied with an emphasis on examining the effects of particle concentration (ϕ) and magnetic field strength (H) on the structures. Nanoparticles are dispersed in water at three different concentrations, ϕ = 0.15%, 0.48%, and 0.59% (w/v) [g/ml%] and exposed to uniform magnetic fields in the range of H = 0.05-0.42 T. Cryogenic transmission electron microscopy is employed to provide in-situ observations of the field-induced assemblies in such systems. As the magnetic field increases, the Brownian colloids are observed to form randomly distributed chains aligned in the field direction, followed by head-to-tail chain aggregation and then lateral aggregation of chains termed as zippering. By increasing the field in low concentration samples, the number of chains increases, though their length does not change dramatically. Increasing concentration increases the length of the linear particle assemblies in the presence of a fixed external magnetic field. Thickening of the chains due to zippering is observed at relatively high fields. Through a systematic variation of concentration and magnetic field strength, this study shows that both magnetic field strength and change in concentration can strongly influence formation of microstructures even in weak dipolar systems. Additionally, the results of two commonly used support films on electron microscopy grids, continuous carbon and holey carbon films, are compared. Holey carbon film allows us to create local regions of high concentrations that further assist the development of field-induced assemblies. The experimental observations provide a validation of the zippering effect and can be utilized in the development of models for thermophysical properties such as thermal conductivity.


Angiogenic and anti-inflammatory properties of micro-fragmented fat tissue and its derived mesenchymal stromal cells.
Adipose-derived mesenchymal stromal cells (Ad-MSCs) are a promising tool for advanced cell-based therapies. They are routinely obtained enzymatically from fat lipoaspirate (LP) as SVF, and may undergo prolonged ex vivo expansion, with significant senescence and decline in multipotency. Besides, these techniques have complex regulatory issues, thus incurring in the compelling requirements of GMP guidelines. Hence, availability of a minimally manipulated, autologous adipose tissue would have remarkable biomedical and clinical relevance. For this reason, a new device, named Lipogems® (LG), has been developed. This ready-to-use adipose tissue cell derivate has been shown to have in vivo efficacy upon transplantation for ischemic and inflammatory diseases. To broaden our knowledge, we here investigated the angiogenic and anti-inflammatory properties of LG and its derived MSC (LG-MSCs) population. Human LG samples and their LG-MSCs were analyzed by immunohistochemistry for pericyte, endothelial and mesenchymal stromal cell marker expression. Angiogenesis was investigated testing the conditioned media (CM) of LG (LG-CM) and LG-MSCs (LG-MSCs-CM) on cultured endothelial cells (HUVECs), evaluating proliferation, cord formation, and the expression of the adhesion molecules (AM) VCAM-1 and ICAM-1. The macrophage cell line U937 was used to evaluate the anti-inflammatory properties, such as migration, adhesion on HUVECs, and release of RANTES and MCP-1. Our results indicate that LG contained a very high number of mesenchymal cells expressing NG2 and CD146 (both pericyte markers) together with an abundant microvascular endothelial cell (mEC) population. Substantially, both LG-CM and LG-MSC-CM increased cord formation, inhibited endothelial ICAM-1 and VCAM-1 expression following TNFα stimulation, and slightly improved HUVEC proliferation. The addition of LG-CM and LG-MSC-CM strongly inhibited U937 migration upon stimulation with the chemokine MCP-1, reduced their adhesion on HUVECs and significantly suppressed the release of RANTES and MCP-1. Our data indicate that LG micro-fragmented adipose tissue retains either per se, or in its embedded MSCs content, the capacity to induce vascular stabilization and to inhibit several macrophage functions involved in inflammation.


Evaluation of ergocalciferol or cholecalciferol dosing, 1,600 IU daily or 50,000 IU monthly in older adults.
Whether ergocalciferol (D(2)) and cholecalciferol (D(3)) are equally effective to increase and maintain serum 25-hydroxyvitamin D [25(OH)D] concentration is controversial. The aim of the study was to evaluate the effect of daily and once monthly dosing of D(2) or D(3) on circulating 25(OH)D and serum and urinary calcium. In a university clinical research setting, 64 community dwelling adults age 65+ were randomly assigned to receive daily (1,600 IU) or once-monthly (50,000 IU) D(2) or D(3) for 1 yr. Serum 25(OH)D, serum calcium, and 24-h urinary calcium were measured at months 0, 1, 2, 3, 6, 9, and 12. Serum PTH, bone-specific alkaline phosphatase, and N-telopeptide were measured at months 0, 3, 6, and 12. Serum 25(OH)D was less than 30 ng/ml in 40% of subjects at baseline; after 12 months of vitamin D dosing, levels in 19% of subjects (n = 12, seven receiving daily doses and five monthly doses) remained low, despite compliance of more than 91%. D(2) dosing increased 25(OH)D(2) but produced a decline (P < 0.0001) in 25(OH)D(3). Substantial between-individual variation in 25(OH)D response was observed for both D(2) and D(3). The highest 25(OH)D observed was 72.5 ng/ml. Vitamin D administration did not alter serum calcium, PTH, bone-specific alkaline phosphatase, N-telopeptide, or 24-h urine calcium. Overall, D(3) is slightly, but significantly, more effective than D(2) to increase serum 25(OH)D. One year of D(2) or D(3) dosing (1,600 IU daily or 50,000 IU monthly) does not produce toxicity, and 25(OH)D levels of less than 30 ng/ml persist in approximately 20% of individuals. Substantial between-individual response to administered vitamin D(2) or D(3) is observed.


Psychological Distress among Individuals Whose Partners Have Cancer.
Cancer diagnosis influences both patients and their closest relatives. This cross-sectional study examined psychological distress among individuals whose partners had cancer in a population-based sample. Participants in the survey were citizens residing in Ohsaki City, Miyagi, Japan. Spouse pairs were identified by information of participants' relationship to the householder and address provided by municipality, and we collected self-report information on cancer history and current pain (but not the cause of pain). Psychological distress was evaluated using the Kessler 6 scale (K6). We identified 29,410 potential participants (14,705 couples), of which 23,766 (11,690 men and 12,076 women) were included in the analyses. A total of 1,374 participants (581 male and 793 female participants) had partners with history of cancer. Logistic regression analyses revealed that these participants, regardless of sex, did not show significantly higher risk of psychological distress (K6 score ≥ 13). When stratifying the analysis by partners' current pain, men whose partners had cancer and pain showed greater odds of psychological distress (odds ratio = 1.5, p = 0.04), compared with men whose partners had no cancer and had pain. However, male subjects whose partners had cancer but no pain did not show greater odds of psychological distress compared with men whose partners had no cancer and no pain. By contrast, in women whose partners had cancer, psychological distress was not associated with pain status. In conclusion, men whose partners had cancer and pain have higher risk of psychological distress, and its screening to these individuals may reduce the risk.


Comparison of three transposons for the generation of highly productive recombinant CHO cell pools and cell lines.
Several naturally occurring vertebrate transposable elements have been genetically modified to enable the transposition of recombinant genes in mammalian cells. We compared three transposons-piggyBac, Tol2, and Sleeping Beauty-for their ability to generate cell pools (polyclonal cultures of recombinant cells) and clonal cell lines for the large-scale production of recombinant proteins using Chinese hamster ovary cells (CHO-DG44) as the host. Transfection with each of the dual-vector transposon systems resulted in cell pools with volumetric yields of tumor necrosis factor receptor-Fc fusion protein (TNFR:Fc) that were about ninefold higher than those from cell pools generated by conventional plasmid transfection. On average, the cell pools had 10-12 integrated copies of the transgene per cell. In the absence of selection, the volumetric productivity of the cell pools decreased by 50% over a 2-month cultivation period and then remained constant. The average volumetric TNFR:Fc productivity of clonal cell lines recovered from cell pools was about 25 times higher than that of cell lines generated by conventional transfection. In 14-day fed-batch cultures, TNFR:Fc levels up to 900 mg/L were obtained from polyclonal cell pools and up to 1.5 g/L from clonal cell lines using any of the three transposons. Biotechnol. Bioeng. 2016;113: 1234-1243. © 2015 Wiley Periodicals, Inc.


Updating the minimal important difference for six-minute walk distance in patients with chronic obstructive pulmonary disease.
To establish the minimal important difference (MID) for the six-minute walk distance (6MWD) in persons with chronic obstructive pulmonary disease (COPD). Analysis of data from an observational study using distribution- and anchor-based methods to determine the MID in 6MWD. Outpatient pulmonary rehabilitation program at 2 teaching hospitals. Seventy-five patients with COPD (44 men) in a stable clinical state with mean age 70 years (SD 9 y), forced expiratory volume in one second 52% (SD 21%) predicted and baseline walking distance 359 meters (SD 104 m). Not applicable. Participants completed the six-minute walk test before and after a 7-week pulmonary rehabilitation program. Participants and clinicians completed a global rating of change score while blinded to the change in 6MWD. The mean change in 6MWD in participants who reported themselves to be unchanged was 17.7 meters, compared with 60.2 meters in those who reported small change and 78.4 meters in those who reported substantial change (P=.004). Anchor-based methods identified an MID of 25 meters (95% confidence interval 20-61 m). There was excellent agreement with distribution-based methods (25.5-26.5m, kappa=.95). A change in 6MWD of 14% compared with baseline also represented a clinically important effect; this threshold was less sensitive than for absolute change (sensitivity .70 vs .85). The MID for 6MWD in COPD is 25 meters. Absolute change in 6MWD is a more sensitive indicator than percentage change from baseline. These data support the use of 6MWD as a patient-important outcome in research and clinical practice.


Biochemical mechanisms of aggregation in TGFBI-linked corneal dystrophies.
Transforming growth factor-β-induced protein (TGFBIp), an extracellular matrix protein, is the second most abundant protein in the corneal stroma. In this review, we summarize the current knowledge concerning the expression, molecular structure, binding partners, and functions of human TGFBIp. To date, 74 mutations in the transforming growth factor-β-induced gene (TGFBI) are associated with amyloid and amorphous protein deposition in TGFBI-linked corneal dystrophies. We discuss the current understanding of the biochemical mechanisms of TGFBI-linked corneal dystrophies and propose that mutations leading to granular corneal dystrophy (GCD) decrease the solubility of TGFBIp and affect the interactions between TGFBIp and components of the corneal stroma, whereas mutations associated with lattice corneal dystrophy (LCD) lead to a destabilization of the protein that disrupts proteolytic turnover, especially by the serine protease HtrA1. Future research should focus on TGFBIp function in the cornea, confirmation of the biochemical mechanisms in vivo, and the development of disease models. Future therapies for TGFBI-linked corneal dystrophies might include topical agents that regulate protein aggregation or gene therapy that targets the mutant allele by CRISPR/Cas9 technology.


Abdominal organ transplantation.
The improvement in the success of solid organ transplantation over the past decades is remarkable and well documented. It is now a well-accepted treatment modality for patients with end-stage organ disease. Within the field of transplantation, abdominal organ transplantation is significantly more common than thoracic transplantation. Abdominal organ transplantation includes kidney, liver, pancreas, and combinations of abdominal organs. The most frequently transplanted organs are kidney and liver, which account together for more than 70% of all transplanted organs. For this limited review, it is impossible to cover all organ systems in abdominal transplantation in a comprehensive fashion. Hence, the focus will be on the most commonly performed procedures, namely kidney and liver transplantation. Triggered by the lack of large definitive studies, we intentionally raise controversial points, and some readers may disagree with some of the conclusions. However, these disagreements are a reflection of the paucity of adequate data for some of the discussed topics.


No relevant association of kinematic gait parameters with Health-related Quality of Life in Parkinson's disease.
Health-related Quality of Life (HrQoL) is probably the most important outcome parameter for the evaluation and management of chronic diseases. As this parameter is subjective and prone to bias, there is an urgent need to identify objective surrogate markers. Gait velocity has been shown to be associated with HrQoL in numerous chronic diseases, such as Parkinson's disease (PD). With the development and wide availability of simple-to-use wearable sensors and sophisticated gait algorithms, kinematic gait parameters may soon be implemented in clinical routine management. However, the association of such kinematic gait parameters with HrQoL in PD has not been assessed to date. Kinematic gait parameters from a 20-meter walk from 43 PD patients were extracted using a validated wearable sensor system. They were compared with the Visual Analogue Scale of the Euro-Qol-5D (EQ-5D VAS) by performing a multiple regression analysis, with the International Classification of Functioning, Disability and Health (ICF) model as a framework. Use of assistive gait equipment, but no kinematic gait parameter, was significantly associated with HrQoL. The widely accepted concept of a positive association between gait velocity and HrQoL may, at least in PD, be driven by relatively independent parameters, such as assistive gait equipment.


Dumb and Lazy? A Comparison of Color Learning and Memory Retrieval in Drones and Workers of the Buff-Tailed Bumblebee, Bombus terrestris, by Means of PER Conditioning.
More than 100 years ago, Karl von Frisch showed that honeybee workers learn and discriminate colors. Since then, many studies confirmed the color learning capabilities of females from various hymenopteran species. Yet, little is known about visual learning and memory in males despite the fact that in most bee species males must take care of their own needs and must find rewarding flowers to obtain food. Here we used the proboscis extension response (PER) paradigm to study the color learning capacities of workers and drones of the bumblebee, Bombus terrestris. Light stimuli were paired with sucrose reward delivered to the insects' antennae and inducing a reflexive extension of the proboscis. We evaluated color learning (i.e. conditioned PER to color stimuli) in absolute and differential conditioning protocols and mid-term memory retention was measured two hours after conditioning. Different monochromatic light stimuli in combination with neutral density filters were used to ensure that the bumblebees could only use chromatic and not achromatic (e.g. brightness) information. Furthermore, we tested if bees were able to transfer the learned information from the PER conditioning to a novel discrimination task in a Y-maze. Both workers and drones were capable of learning and discriminating between monochromatic light stimuli and retrieved the learned stimulus after two hours. Drones performed as well as workers during conditioning and in the memory test, but failed in the transfer test in contrast to workers. Our data clearly show that bumblebees can learn to associate a color stimulus with a sugar reward in PER conditioning and that both workers and drones reach similar acquisition and mid-term retention performances. Additionally, we provide evidence that only workers transfer the learned information from a Pavlovian to an operant situation.


Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria.
Cerebral malaria is a leading cause of global morbidity and mortality. Interventions targeting the underlying pathophysiology of cerebral malaria may improve outcomes compared to treatment with antimalarials alone. Microvascular leak plays an important role in the pathogenesis of cerebral malaria. The angiopoietin (Ang)-Tie-2 system is a critical regulator of vascular function. We show that Ang-1 expression and soluble Tie-2 expression were associated with disease severity and outcome in a prospective study of Ugandan children with severe malaria and in a preclinical murine model of experimental cerebral malaria. Ang-1 was necessary for maintenance of vascular integrity and survival in a mouse model of cerebral malaria. Therapeutic administration of Ang-1 preserved blood-brain barrier integrity and, in combination with artesunate treatment, improved survival beyond that with artesunate alone. These data define a role for dysregulation of the Ang-Tie-2 axis in the pathogenesis of cerebral malaria and support the evaluation of Ang-Tie-2-based interventions as potential adjunctive therapies for treating severe malaria.


Overdrinking-induced hyponatraemia in the 2007 London Marathon.
We report a case of overdrinking-induced hyponatraemia from the 2007 London Marathon. The patient was a 37-year-old experienced female marathon runner. She was brought to the emergency room more than 6 h after completing the marathon suffering from diarrhoea, vomiting and confusion, and was unable to recall any detail of the race. An arterial blood sample confirmed hyponatraemia ([Na(+)] 117 mmol.l(-1)) associated with hypokalaemia (serum potassium concentration 3.4 mmol.l(-1)) and respiratory alkalosis (pH 7.62, bicarbonate 16.1 mmol.l(-1) and Pco(2) 2.14 kPa). A diagnosis of uncomplicated exercise-associated hyponatraemia due to voluntary overdrinking was made and the patient was catherised and treated with a slow (1 h) intra-venous infusion of 500 ml of 1.8% sodium chloride (NaCl) solution. The following morning her serum [Na(+)] had normalised at 135 mmol.l(-1) and she was discharged in the afternoon. She has recovered fully without sequelae.


Facilitating return to work through early specialist health-based interventions (FRESH): protocol for a feasibility randomised controlled trial.
Over one million people sustain traumatic brain injury each year in the UK and more than 10 % of these are moderate or severe injuries, resulting in cognitive and psychological problems that affect the ability to work. Returning to work is a primary rehabilitation goal but fewer than half of traumatic brain injury survivors achieve this. Work is a recognised health service outcome, yet UK service provision varies widely and there is little robust evidence to inform rehabilitation practice. A single-centre cohort comparison suggested better work outcomes may be achieved through early occupational therapy targeted at job retention. This study aims to determine whether this intervention can be delivered in three new trauma centres and to conduct a feasibility, randomised controlled trial to determine whether its effects and cost effectiveness can be measured to inform a definitive trial. Mixed methods study, including feasibility randomised controlled trial, embedded qualitative studies and feasibility economic evaluation will recruit 102 people with traumatic brain injury and their nominated carers from three English UK National Health Service (NHS) trauma centres. Participants will be randomised to receive either usual NHS rehabilitation or usual rehabilitation plus early specialist traumatic brain injury vocational rehabilitation delivered by an occupational therapist. The primary objective is to assess the feasibility of conducting a definitive trial; secondary objectives include measurement of protocol integrity (inclusion/exclusion criteria, intervention adherence, reasons for non-adherence) recruitment rate, the proportion of eligible patients recruited, reasons for non-recruitment, spectrum of TBI severity, proportion of and reasons for loss to follow-up, completeness of data collection, gains in face-to-face Vs postal data collection and the most appropriate methods of measuring primary outcomes (return to work, retention) to determine the sample size for a larger trial. To our knowledge, this is the first feasibility randomised controlled trial of a vocational rehabilitation health intervention specific to traumatic brain injury. The results will inform the design of a definitive trial. The trial is registered ISRCTN Number 38581822.


Rationale and design of the coronary artery calcium consortium: A multicenter cohort study.
Although coronary artery calcium (CAC) has been investigated for over two decades, there is very limited data on the association of CAC with cause of death. The CAC Consortium is a large ongoing multi-center observational cohort of individuals who underwent non-contrast cardiac-gated CAC testing and systematic, prospective, long-term follow-up for mortality with ascertainment of cause of death. Four participating institutions from three states within the US (California, Minnesota, and Ohio) have contributed individual-level patient data to the CAC Consortium (spanning years 1991-2010). All CAC scans were clinically indicated and physician-referred in patients without a known history of coronary heart disease. Using strict inclusion and exclusion criteria to minimize missing data and to eliminate non-dedicated CAC scans (i.e. concomitant CT angiography), a sharply defined and well-characterized cohort of 66,636 patients was assembled. Mortality status was ascertained using the Social Security Administration Death Master File and a validated algorithm. In addition, death certificates were obtained from the National Death Index and categorized using ICD (International Classification of Diseases) codes into common causes of death. Mean patient age was 54 ± 11 years and the majority were male (67%). Prevalence of CVD risk factors was similar across sites and 55% had a <5% estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk. Approximately 45% had a Calcium score of 0 and 11% had an Agatston Score ≥400. Over a mean follow-up of 12 ± 4 years, there were 3158 deaths (4.15 per 1000 person-years). The majority of deaths were due to cancer (37%) and CVD (32%). Most CVD deaths were due to CHD (54%) followed by stroke (17%). In general, CAC score distributions were similar across sites, and there were similar cause of death patterns. The CAC Consortium is large and highly generalizable data set that is uniquely positioned to expand the understanding of CAC as a predictor of mortality risk across the spectrum of disease states, allowing innovative modeling of the competing risks of cardiovascular and non-cardiovascular death.


Cloud BioLinux: pre-configured and on-demand bioinformatics computing for the genomics community.
A steep drop in the cost of next-generation sequencing during recent years has made the technology affordable to the majority of researchers, but downstream bioinformatic analysis still poses a resource bottleneck for smaller laboratories and institutes that do not have access to substantial computational resources. Sequencing instruments are typically bundled with only the minimal processing and storage capacity required for data capture during sequencing runs. Given the scale of sequence datasets, scientific value cannot be obtained from acquiring a sequencer unless it is accompanied by an equal investment in informatics infrastructure. Cloud BioLinux is a publicly accessible Virtual Machine (VM) that enables scientists to quickly provision on-demand infrastructures for high-performance bioinformatics computing using cloud platforms. Users have instant access to a range of pre-configured command line and graphical software applications, including a full-featured desktop interface, documentation and over 135 bioinformatics packages for applications including sequence alignment, clustering, assembly, display, editing, and phylogeny. Each tool's functionality is fully described in the documentation directly accessible from the graphical interface of the VM. Besides the Amazon EC2 cloud, we have started instances of Cloud BioLinux on a private Eucalyptus cloud installed at the J. Craig Venter Institute, and demonstrated access to the bioinformatic tools interface through a remote connection to EC2 instances from a local desktop computer. Documentation for using Cloud BioLinux on EC2 is available from our project website, while a Eucalyptus cloud image and VirtualBox Appliance is also publicly available for download and use by researchers with access to private clouds. Cloud BioLinux provides a platform for developing bioinformatics infrastructures on the cloud. An automated and configurable process builds Virtual Machines, allowing the development of highly customized versions from a shared code base. This shared community toolkit enables application specific analysis platforms on the cloud by minimizing the effort required to prepare and maintain them.


Gender differences in couples' division of childcare, work and mental health during COVID-19.
The current COVID-19 crisis, with its associated school and daycare closures as well as social-distancing requirements, has the potential to magnify gender differences both in terms of childcare arrangements within the household and at work. We use data from a nationally representative sample of the United States from the Understanding Coronavirus in America tracking survey to understand gender differences within households on the impact of the COVID-19 crisis. We study how fathers and mothers are coping with this crisis in terms of childcare provision, employment, working arrangements, and psychological distress levels. We find that women have carried a heavier load than men in the provision of childcare during the COVID-19 crisis, even while still working. Mothers' current working situations appear to have a limited influence on their provision of childcare. This division of childcare is, however, associated with a reduction in working hours and an increased probability of transitioning out of employment for working mothers. Finally, we observe a small but new gap in psychological distress that emerged between mothers and women without school-age children in the household in early April. This new gap appears to be driven by higher levels of psychological distress reported by mothers of elementary school-age and younger children.


A study of tinea capitis in Jordan (West Bank).
Between January 1983 and October 1984, 425 cases of tinea capitis were clinically diagnosed in the West Bank of Jordan. These comprised 38% of all dermatophytosis cases seen during the same period. The number of tinea capitis infections varied with season, the highest numbers occurring in winter and spring months and lowest numbers occurring in summer months. Females accounted for about 60% of scalp infections. Specimens from 302 tinea capitis cases were cultured and 217 isolates of dermatophytes were recovered. Trichophyton violaceum was found to be the most common aetiological agent accounting for 49.8% of total isolates. Microsporum canis was the next most common aetiological agent accounting for 31.8%; zoophilic isolates including this species comprised about 38% of all isolates.