The influence of occupant anthropometry and seat position on ejection risk in a rollover.
During rollover crashes, ejection increases an occupant's risk of severe to fatal injury as compared to risks for those retained in the vehicle. The current study examined whether occupant anthropometry might influence ejection risk. Factors such as restraint use/disuse, seating position, vehicle type, and roll direction were also considered in the analysis. The current study examined occupant ejections in 10 years of National Automotive Sampling System (NASS) single-event rollovers of passenger vehicles and light trucks. Statistical analysis of unweighted and weighted ejection data was carried out. No statistically significant differences in ejection rates were found based on occupant height, age, or body mass index. Drivers were ejected significantly more frequently than other occupants: 62 percent of unrestrained drivers were ejected vs. 51 percent unrestrained right front occupants. Second row unrestrained occupants were ejected at rates similar to right front-seated occupants. There were no significant differences in ejection rates for near- vs. far-side occupants. These data suggest that assessment of ejection prevention systems using either a 50th or 5th percentile adult anthropomorphic test dummy (ATD) might provide a reasonable measure of system function for a broad range of occupants. They also support the development of ejection mitigation technologies that extend beyond the first row to protect occupants in rear seat positions. Future studies should consider potential interaction effects (i.e., occupant size and vehicle dimensions) and the influence of occupant size on ejection risk in non-single-event rollovers.


Amphiphilic perylene-calix[4]arene hybrids: synthesis and tunable self-assembly.
The first highly water-soluble perylene-calix[4]arene hybrid with the calixarene scaffold acting as a structure-determining central platform is presented. In this tetrahedrally shaped amphiphilic architecture the hydrophilic and hydrophobic subunits are oriented at the opposite side of the calixarene platform. The hydrophobic part contains the two perylene diimide moieties, which enable strong π-π interactions in self-assembly processes. Two hydrophilic Newkome-type dendrons provide sufficient water solubility at slightly basic conditions. The tetrahedrally shaped amphiphile displays an unprecedented aggregation behavior down to concentrations as low as 10(-7) mol L(-1). The intriguing self-assembly process of the compound in water as well as under changed polarity conditions, achieved by addition of THF, could be monitored by the complemented use of cryogenic transmission electron microscopy (cryo-TEM), UV-vis spectroscopy, and fluorescence spectroscopy. Molecular-dynamics and molecular modeling simulations helped in understanding the interplay of supramolecular and optical behavior.


Effects of second messengers on gap junctional intercellular communication of ovine luteal cells throughout the estrous cycle.
Corpora lutea (CL) from Days 5, 10, and 15 after superovulation were enzymatically dispersed, and a portion of the cells were elutriated to obtain fractions enriched with small or large luteal cells. Mixed, small, and large luteal cell fractions were incubated with no treatment or with agonists or antagonists of cAMP (dbcAMP or Rp-cAMPS), protein kinase C (PKC; TPA or H-7), or calcium (A23187, EGTA, or A23187 + EGTA). The rate of contact-dependent gap junctional intercellular communication (GJIC) was evaluated by laser cytometry. Media were collected for progesterone (P(4)) radioimmunoassay, and luteal cells cultured with no treatment were fixed for immunocytochemistry or frozen for Western blot analysis. Luteal cells from each stage of the estrous cycle exhibited GJIC. The dbcAMP increased (P < 0.05) GJIC for all cell types across the estrous cycle. The Rp-cAMPS decreased (P < 0.05) GJIC for small luteal cells on Day 5 and for all cell types on Days 10 and 15. The TPA inhibited (P < 0.01), but H-7 did not affect, GJIC for all cell types across the estrous cycle. The A23187 decreased (P < 0.05) GJIC for large luteal cells touching only small or only large luteal cells, whereas A23187 + EGTA decreased (P < 0.05) GJIC for all cell types across the estrous cycle. For the mixed and large luteal cell fractions, dbcAMP increased (P < 0.05), but TPA and A23187 + EGTA decreased (P < 0.05), P(4) secretion. The A23187 alone decreased (P < 0.05) P(4) secretion by large, but not by mixed, luteal cells. For all days and cell types, the rate of GJIC and P(4) secretion were correlated (r = 0.113-0.249; P < 0.01). Connexin 43 was detected in cultured luteal cells by immunofluorescence and Western immunoblotting. Thus, intracellular regulators like cAMP, PKC, or calcium appear to regulate GJIC, which probably is an important mechanism for coordinating function of the ovine CL.


Contrast sensitivity and orientation selectivity in lamina IV of the striate cortex of Old World monkeys.
Contrast sensitivity and orientation selectivity were measured for neurons in lamina IV of macaque striate cortex. Contrast sensitivity was determined for a range of spatial frequencies, using a staircase method. The stimuli were at the optimal orientation, direction and speed of drift for each neuron. The assignment of each recording site to a subdivision of lamina IV was made by histological reconstruction of each electrode penetration from sections reacted for cytochrome oxidase and stained for Nissl substance. Neurons in the magnocellular recipient zone of IVc (IVc alpha) have high contrast sensitivities, while those in the parvocellular recipient zone (IVc beta) have low contrast sensitivities. Both of the upper subdivisions of lamina IV (IVa and IVb) contain a mixture of neurons with high and low contrast sensitivities. There were orientation selective neurons within all subdivisions of lamina IV, even in IVc, whereas non-oriented neurons were found only in those subdivisions that receive a direct parvocellular geniculate input (IVa and IVc beta).


Diffusion tensor imaging of dolphin brains reveals direct auditory pathway to temporal lobe.
The brains of odontocetes (toothed whales) look grossly different from their terrestrial relatives. Because of their adaptation to the aquatic environment and their reliance on echolocation, the odontocetes' auditory system is both unique and crucial to their survival. Yet, scant data exist about the functional organization of the cetacean auditory system. A predominant hypothesis is that the primary auditory cortex lies in the suprasylvian gyrus along the vertex of the hemispheres, with this position induced by expansion of 'associative' regions in lateral and caudal directions. However, the precise location of the auditory cortex and its connections are still unknown. Here, we used a novel diffusion tensor imaging (DTI) sequence in archival post-mortem brains of a common dolphin (Delphinus delphis) and a pantropical dolphin (Stenella attenuata) to map their sensory and motor systems. Using thalamic parcellation based on traditionally defined regions for the primary visual (V1) and auditory cortex (A1), we found distinct regions of the thalamus connected to V1 and A1. But in addition to suprasylvian-A1, we report here, for the first time, the auditory cortex also exists in the temporal lobe, in a region near cetacean-A2 and possibly analogous to the primary auditory cortex in related terrestrial mammals (Artiodactyla). Using probabilistic tract tracing, we found a direct pathway from the inferior colliculus to the medial geniculate nucleus to the temporal lobe near the sylvian fissure. Our results demonstrate the feasibility of post-mortem DTI in archival specimens to answer basic questions in comparative neurobiology in a way that has not previously been possible and shows a link between the cetacean auditory system and those of terrestrial mammals. Given that fresh cetacean specimens are relatively rare, the ability to measure connectivity in archival specimens opens up a plethora of possibilities for investigating neuroanatomy in cetaceans and other species.


Seasonal Changes in Soccer Players' Body Composition and Dietary Intake Practices.
Devlin, BL, Kingsley, M, Leveritt, MD, and Belski, R. Seasonal changes in soccer players' body composition and dietary intake practices. J Strength Cond Res 31(12): 3319-3326, 2017-The aims of this study were 2-fold: to determine seasonal changes in dietary intake and body composition in elite soccer players and to evaluate the influence of self-determined individual body composition goals on dietary intake and body composition. This longitudinal, observational study assessed body composition (total mass, fat-free soft tissue mass, and fat mass) using dual-energy x-ray absorptiometry and dietary intake (energy and macronutrients) via multiple-pass 24-hour recalls, at 4 time points over a competitive season in elite soccer players from one professional club in the Australian A-League competition. Self-reported body composition goals were also recorded. Eighteen elite male soccer players took part (25 ± 5 years, 180.5 ± 7.4 cm, 75.6 ± 6.5 kg). Majority (≥67%) reported the goal to maintain weight. Fat-free soft tissue mass increased from the start of preseason (55,278 ± 5,475 g) to the start of competitive season (56,784 ± 5,168 g; p < 0.001), and these gains were maintained until the end of the season. Fat mass decreased over the preseason period (10,072 ± 2,493 g to 8,712 ± 1,432 g; p < 0.001), but increased during the latter part of the competitive season. Dietary intake practices on training days were consistent over time and low compared with sport nutrition recommendations. The self-reported body composition goals did not strongly influence dietary intake practices or changes in body composition. This study has demonstrated that body composition changes over the course of a soccer season are subtle in elite soccer players despite relatively low self-reported intake of energy and carbohydrate.


Nitrate reduction by denitrifying anaerobic methane oxidizing microorganisms can reach a practically useful rate.
Methane in biogas has been proposed to be an electron donor to facilitate complete nitrogen removal using denitrifying anaerobic methane oxidizing (DAMO) microorganisms in an anaerobic ammonium oxidation (anammox) reactor, by reducing the nitrate produced. However, the slow growth and the low activity of DAMO microorganisms cast a serious doubt about the practical usefulness of such a process. In this study, a previously established lab-scale membrane biofilm reactor (MBfR), with biofilms consisting of a coculture of DAMO and anammox microorganisms, was operated to answer if the DAMO reactor can achieve a nitrate reduction rate that can potentially be applied for wastewater treatment. Through progressively increasing nitrate and ammonium loading rates to the reactor, a nitrate removal rate of 684 ± 10 mg-N L(-1) d(-1) was achieved after 453 days of operation. This rate is, to our knowledge, by far the highest reported for DAMO reactors, and far exceeds what is predicted to be required for nitrate removal in a sidestream (5.6-135 mg-N L(-1) d(-1)) or mainstream anammox reactor (3.2-124 mg-N L(-1) d(-1)). Mass balance analysis showed that the nitrite produced by nitrate reduction was jointly reduced by anammox bacteria at a rate of 354 ± 3 mg-N L(-1) d(-1), accompanied by an ammonium removal rate of 268 ± 2 mg-N L(-1) d(-1), and DAMO bacteria at a rate of 330 ± 9 mg-N L(-1) d(-1). This study shows that the nitrate reduction rate achieved by the DAMO process can be high enough for removing nitrate produced by anammox process, which would enable complete nitrogen removal from wastewater.


A hybrid method to recognize 3D object.
A hybrid method using the support vector machine (SVM) correlation filter and the phase-shift interferometry (PSI) holography is proposed to recognize 3D object, which can improve the correct decision rate and resist the distortion of object rotation and noise. The different images of two types of both in-plane and out-of-plane rotated object recorded by digital holography are reconstructed. The reconstructed images of two types are selected to synthesize the SVM correlation filter, respectively. To compare the correct decision rates of the SVM correlation filter with other three ones, it is found that the experimental result is better in rotation resistance and noise tolerance.


Postpartum sterilisation by the Irving technique. A report of 200 cases at Paarl Hospital, CP.
Sterilisation by the Irving procedure accompanying caesarean section was the favoured form of sterilisation at Paarl Hospital from 1971 to 1985. No subsequent pregnancies have been reported from the 200 cases and this success is compared with sterilisation failure rates of 1.35% with the Pomeroy method, 1.27% with the total fimbriectomy method, 0.41% with the Vienna or modified Pritchard method, and 0.89% with the Filshie-clip method: Irving sterilisation is accordingly advised as the method of choice at the time of caesarean section.


Neural correlates of reward processing in schizophrenia--relationship to apathy and depression.
The present study employs a new framework to categorise the heterogeneous findings on the relationship between impaired reward processing and negative and affective symptoms of schizophrenia. Based on previous behavioural and neuroimaging studies we postulate that "wanting" (i.e. anticipation) of a reward is specifically related to apathy, whereas "liking" (i.e. hedonic impact) is related to anhedonia and depression--symptoms commonly observed in schizophrenia. Fifteen patients with schizophrenia or schizoaffective disorder treated with atypical antipsychotic drugs and fifteen healthy controls performed a probabilistic monetary incentive delay task while undergoing functional magnetic resonance imaging. At the group level we found no significant differences between patients and controls in neural activation during anticipation or receipt of a reward. However, in patients with schizophrenia specific relationships between ventral-striatal activation and symptoms were observed. Ventral-striatal activation during reward anticipation was negatively correlated with apathy, while activation during receipt of reward was negatively correlated with severity of depressive symptoms. These results suggest that the link between negative symptoms and reward anticipation might specifically relate to apathy, i.e. a lack of motivation and drive. Impaired hedonic reward processing might contribute to the development of depressive symptoms in patients with schizophrenia, but it is not directly associated with self-rated anhedonia. These results indicate the necessity of more specifically differentiating negative and affective symptoms in schizophrenia in order to understand the role of the reward system in their pathogenesis.


Tet1 in Nucleus Accumbens Opposes Depression- and Anxiety-Like Behaviors.
Depression is a leading cause of disease burden, yet current therapies fully treat <50% of affected individuals. Increasing evidence implicates epigenetic mechanisms in depression and antidepressant action. Here we examined a possible role for the DNA dioxygenase, ten-eleven translocation protein 1 (TET1), in depression-related behavioral abnormalities. We applied chronic social defeat stress, an ethologically validated mouse model of depression-like behaviors, and examined Tet1 expression changes in nucleus accumbens (NAc), a key brain reward region. We show decreased Tet1 expression in NAc in stress-susceptible mice only. Surprisingly, selective knockout of Tet1 in NAc neurons of adult mice produced antidepressant-like effects in several behavioral assays. To identify Tet1 targets that mediate these actions, we performed RNAseq on NAc after conditional deletion of Tet1 and found that immune-related genes are the most highly dysregulated. Moreover, many of these genes are also upregulated in the NAc of resilient mice after chronic social defeat stress. These findings reveal a novel role for TET1, an enzyme important for DNA hydroxymethylation, in the brain's reward circuitry in modulating stress responses in mice. We also identify a subset of genes that are regulated by TET1 in this circuitry. These findings provide new insight into the pathophysiology of depression, which can aid in future antidepressant drug discovery efforts.


Transcranial Direct Current Stimulation over the Parietal Cortex Improves Approximate Numerical Averaging.
The parietal cortex has been implicated in a variety of numerosity and numerical cognition tasks and was proposed to encompass dedicated neural populations that are tuned for analogue magnitudes as well as for symbolic numerals. Nonetheless, it remains unknown whether the parietal cortex plays a role in approximate numerical averaging (rapid, yet coarse computation of numbers' mean)-a process that is fundamental to preference formation and decision-making. To causally investigate the role of the parietal cortex in numerical averaging, we have conducted a transcranial direct current stimulation (tDCS) study, in which participants were presented with rapid sequences of numbers and asked to convey their intuitive estimation of each sequence's average. During the task, the participants underwent anodal (excitatory) tDCS (or sham), applied either on a parietal or a frontal region. We found that, although participants exhibit above-chance accuracy in estimating the average of numerical sequences, they did so with higher precision under parietal stimulation. In a second experiment, we have replicated this finding and confirmed that the effect is number-specific rather than domain-general or attentional. We present a neurocomputational model postulating population-coding underlying rapid numerical averaging to account for our findings. According to this model, stimulation of the parietal cortex elevates neural activity in number-tuned dedicated detectors, leading to increase in the system's signal-to-noise level and thus resulting in more precise estimations.


Suicide and the 2008 economic recession: who is most at risk? Trends in suicide rates in England and Wales 2001-2011.
The negative impacts of previous economic recessions on suicide rates have largely been attributed to rapid rises in unemployment in the context of inadequate social and work protection programmes. We have investigated trends in indicators of the 2008 economic recession and trends in suicide rates in England and Wales in men and women of working age (16-64 years old) for the period 2001-2011, before, during and after the economic recession, our aim was to identify demographic groups whose suicide rates were most affected. We found no clear evidence of an association between trends in female suicide rates and indicators of economic recession. Evidence of a halt in the previous downward trend in suicide rates occurred for men aged 16-34 years in 2006 (95% CI Quarter 3 (Q3) 2004, Q3 2007 for 16-24 year olds & Q1 2005, Q4 2006 for 25-34 year olds), whilst suicide rates in 35-44 year old men reversed from a downward to upward trend in early 2010 (95% CI Q4 2008, Q2 2011). For the younger men (16-34 years) this change preceded the sharp increases in redundancy and unemployment rates of early 2008 and lagged behind rising trends in house repossessions and bankruptcy that began around 2003. An exception were the 35-44 year old men for whom a change in suicide rate trends from downwards to upwards coincided with peaks in redundancies, unemployment and rises in long-term unemployment. Suicide rates across the decade rose monotonically in men aged 45-64 years. Male suicide in the most-to-medium deprived areas showed evidence of decreasing rates across the decade, whilst in the least-deprived areas suicide rates were fairly static but remained much lower than those in the most-deprived areas. There were small post-recession increases in the proportion of suicides in men in higher management/professional, small employer/self-employed occupations and fulltime education. A halt in the downward trend in suicide rates amongst men aged 16-34 years, may have begun before the 2008 economic recession whilst for men aged 35-44 years old increased suicide rates mirrored recession related unemployment. This evidence suggests indicators of economic strain other than unemployment and redundancies, such as personal debt and house repossessions may contribute to increased suicide rates in younger-age men whilst for men aged 35-44 years old job loss and long-term unemployment is a key risk factor.


Bacterial and fungal isolation from face masks under the COVID-19 pandemic.
The COVID-19 pandemic has led people to wear face masks daily in public. Although the effectiveness of face masks against viral transmission has been extensively studied, there have been few reports on potential hygiene issues due to bacteria and fungi attached to the face masks. We aimed to (1) quantify and identify the bacteria and fungi attaching to the masks, and (2) investigate whether the mask-attached microbes could be associated with the types and usage of the masks and individual lifestyles. We surveyed 109 volunteers on their mask usage and lifestyles, and cultured bacteria and fungi from either the face-side or outer-side of their masks. The bacterial colony numbers were greater on the face-side than the outer-side; the fungal colony numbers were fewer on the face-side than the outer-side. A longer mask usage significantly increased the fungal colony numbers but not the bacterial colony numbers. Although most identified microbes were non-pathogenic in humans; Staphylococcus epidermidis, Staphylococcus aureus, and Cladosporium, we found several pathogenic microbes; Bacillus cereus, Staphylococcus saprophyticus, Aspergillus, and Microsporum. We also found no associations of mask-attached microbes with the transportation methods or gargling. We propose that immunocompromised people should avoid repeated use of masks to prevent microbial infection.


IL-17 gene ablation does not impact Treg-mediated suppression of graft-versus-host disease after bone marrow transplantation.
Regulatory T cell (Treg) immunotherapy is a promising strategy for the treatment of graft rejection responses and autoimmune disorders. Our and other laboratories have shown that the transfer of highly purified CD4(+)CD25(+)Foxp3(+) natural Treg can prevent lethal graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation across both major and minor histocompatibility barriers. However, recent evidence suggests that the Treg suppressive phenotype can become unstable, a phenomenon that can culminate in Treg conversion into IL-17-producing cells. We hypothesized that the intense proinflammatory signals released during an ongoing alloreaction might redirect a fraction of the transferred Treg to the Th17 cell fate, thereby losing immunosuppressive potential. We therefore sought to evaluate the impact of Il17 gene ablation on Treg stability and immunosuppressive capacity in a major MHC mismatch model. We show that although Il17 gene ablation results in a mildly enhanced Treg immunosuppressive ability in vitro, such improvement is not observed when IL-17-deficient Treg are used for GVHD suppression in vivo. Similarly, when we selectively blocked IL-1 signaling in Treg, that was shown to be necessary for Th17 conversion, we did not detect any improvement on Treg-mediated GVHD suppressive ability in vivo. Furthermore, upon ex vivo reisolation of transferred wild-type Treg, we detected little or no Treg-mediated IL-17 production upon GVHD induction. Our results indicate that blocking Th17 conversion does not affect the GVHD suppressive ability of highly purified natural Treg in vivo, suggesting that IL-17 targeting is not a valuable strategy to improve Treg immunotherapy after hematopoietic cell transplantation.


Evaluation of clustering and topic modeling methods over health-related tweets and emails.
Internet provides different tools for communicating with patients, such as social media (e.g., Twitter) and email platforms. These platforms provided new data sources to shed lights on patient experiences with health care and improve our understanding of patient-provider communication. Several existing topic modeling and document clustering methods have been adapted to analyze these new free-text data automatically. However, both tweets and emails are often composed of short texts; and existing topic modeling and clustering approaches have suboptimal performance on these short texts. Moreover, research over health-related short texts using these methods has become difficult to reproduce and benchmark, partially due to the absence of a detailed comparison of state-of-the-art topic modeling and clustering methods on these short texts. We trained eight state-of- the-art topic modeling and clustering algorithms on short texts from two health-related datasets (tweets and emails): Latent Semantic Indexing (LSI), Latent Dirichlet Allocation (LDA), LDA with Gibbs Sampling (GibbsLDA), Online LDA, Biterm Model (BTM), Online Twitter LDA, and Gibbs Sampling for Dirichlet Multinomial Mixture (GSDMM), as well as the k-means clustering algorithm with two different feature representations: TF-IDF and Doc2Vec. We used cluster validity indices to evaluate the performance of topic modeling and clustering: two internal indices (i.e. assessing the goodness of a clustering structure without external information) and five external indices (i.e. comparing the results of a cluster analysis to an externally known provided class labels). In overall, for number of clusters (k) from 2 to 50, Online Twitter LDA and GSDMM achieved the best performance in terms of internal indices, while LSI and k-means with TF-IDF had the highest external indices. Also, of all tweets (N = 286, 971; HPV represents 94.6% of tweets and lynch syndrome represents 5.4%), for k = 2, most of the methods could respect this initial clustering distribution. However, we found model performance varies with the source of data and hyper-parameters such as the number of topics and the number of iterations used to train the models. We also conducted an error analysis using the Hamming loss metric, for which the poorest value was obtained by GSDMM on both datasets. Researchers hoping to group or classify health related short-text data can expect to select the most suitable topic modeling and clustering methods for their specific research questions. Therefore, we presented a comparison of the most common used topic modeling and clustering algorithms over two health-related, short-text datasets using both internal and external clustering validation indices. Internal indices suggested Online Twitter LDA and GSDMM as the best, while external indices suggested LSI and k-means with TF-IDF as the best. In summary, our work suggested researchers can improve their analysis of model performance by using a variety of metrics, since there is not a single best metric.


Factors associated with infant feeding practices after hospital discharge.
To assess factors associated with infant feeding practices on the first day at home after hospital discharge. A total of 209 women, who had a child aged four months or less and were living in Itapira, Brazil, were interviewed during the National Immunization Campaign Day in 1999. Statistical analysis was performed using the Chi-square test and a logistic regression model was used for verifying an association between dependent and independent variables. Women aged 25.5 years on average and 18.2% were teenagers. Fifty-three percent of the women delivered vaginally and most vaginal deliveries (78.5%) took place in the public hospital. The prevalence of exclusive breastfeeding on the first day at home was 78.1% and 11.6% of the infants were receiving formula at this time. The only factor associated with EBF on the first day at home was being a teenaged-primiparous mother (OR=9.40; 95% CI: 1.24-71.27). This association remained statistically significant even after controlling for type of delivery and hospital where the birth took place. Feeding formula on the first day at home was only significantly associated with the hospital (i.e., birth at the city hospital was a protective factor (OR=0.33; 95% CI: 0.13-0.86), even after controlling for vaginal delivery. On the first day at home after hospital discharge, teenaged-primiparous mothers were more likely to exclusive breastfeeding as well as those infants born in the municipal public hospital. Further studies are needed from a multidisciplinary approach.


The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase.
Gamma-secretase is a multisubunit aspartyl protease complex that catalyzes intramembrane cleavage of beta-amyloid precursor protein (APP), a substrate key to Alzheimer's disease pathogenesis, and of Notch, a substrate crucial for cell differentiation. How gamma-secretase recognizes and selects substrates is currently barely understood. Recent data suggest that its subunit nicastrin serves as an initial substrate receptor, which might subsequently forward substrates to the active site domain located in its catalytic subunit presenilin (PS), where an additional substrate binding site has been proposed. We now used an active site domain swapping approach of PS1 with its most distant homolog, spermatogenesis defective (SPE-4), to identify sequence determinants in this region. Strikingly, when the active site domain of PS1 was exchanged with that of SPE-4, the chimeric protein, PS1/SPE-4(6/7), supported APP but not Notch processing. In addition, PS1/SPE-4(6/7) was strongly impaired in Caenorhabditis elegans Notch signaling in vivo. Mapping experiments identified a single amino acid at position x of the GxGD motif, which contains one of the two active site aspartates, to be responsible for the observed defect in Notch processing and signaling. Our data thus implicate a role of the GxGD motif in catalytic function and substrate identification of gamma-secretase.


Adult cancer pain.
Pain is a common symptom associated with cancer and its treatment. Pain management is an important aspect of oncologic care, and unrelieved pain significantly comprises overall quality of life. These NCCN Guidelines list the principles of management and acknowledge the range of complex decisions faced in the management oncologic pain. In addition to pain assessment techniques, these guidelines provide principles of use, dosing, management of adverse effects, and safe handling procedures of pharmacologic therapies and discuss a multidisciplinary approach for the management of cancer pain.


Intestinal parasites of endangered orangutans (Pongo pygmaeus) in Central and East Kalimantan, Borneo, Indonesia.
Faecal samples from 163 captive and semi-captive individuals, 61 samples from wild individuals and 38 samples from captive groups of Bornean orangutans (Pongo pygmaeus) in Kalimantan, Indonesia, were collected during one rainy season (November 2005-May 2006) and screened for intestinal parasites using sodium acetate-acetic acid-formalin-concentration (SAFC), sedimentation, flotation, McMaster- and Baermann techniques. We aimed to identify factors influencing infection risk for specific intestinal parasites in wild orangutans and individuals living in captivity. Various genera of Protozoa (including Entamoeba, Endolimax, Iodamoeba, Balantidium, Giardia and Blastocystis), nematodes (such as Strongyloides, Trichuris, Ascaris, Enterobius, Trichostrongylus and hookworms) and one trematode (a dicrocoeliid) were identified. For the first time, the cestode Hymenolepis was detected in orangutans. Highest prevalences were found for Strongyloides (individuals 37%; groups 58%), hookworms (41%; 58%), Balantidium (40%; 61%), Entamoeba coli (29%; 53%) and a trichostrongylid (13%; 32%). In re-introduction centres, infants were at higher risk of infection with Strongyloides than adults. Infection risk for hookworms was significantly higher in wild males compared with females. In groups, the centres themselves had a significant influence on the infection risk for Balantidium. Ranging patterns of wild orangutans, overcrowding in captivity and a shift of age composition in favour of immatures seemed to be the most likely factors leading to these results.


Peptide-based vaccinology: experimental and computational approaches to target hypervariable viruses through the fine characterization of protective epitopes recognized by monoclonal antibodies and the identification of T-cell-activating peptides.
Defining immunogenic domains of viral proteins capable of eliciting a protective immune response is crucial in the development of novel epitope-based prophylactic strategies. This is particularly important for the selective targeting of conserved regions shared among hypervariable viruses. Studying postinfection and postimmunization sera, as well as cloning and characterization of monoclonal antibodies (mAbs), still represents the best approach to identify protective epitopes. In particular, a protective mAb directed against conserved regions can play a key role in immunogen design and in human therapy as well. Experimental approaches aiming to characterize protective mAb epitopes or to identify T-cell-activating peptides are often burdened by technical limitations and can require long time to be correctly addressed. Thus, in the last decade many epitope predictive algorithms have been developed. These algorithms are continually evolving, and their use to address the empirical research is widely increasing. Here, we review several strategies based on experimental techniques alone or addressed by in silico analysis that are frequently used to predict immunogens to be included in novel epitope-based vaccine approaches. We will list the main strategies aiming to design a new vaccine preparation conferring the protection of a neutralizing mAb combined with an effective cell-mediated response.


Recording therapy sessions: an evaluation of patient and therapist reported behaviours, attitudes and preferences.
Audio recording of cognitive behavioural therapy (CBT) sessions has been recommended but not yet widely adopted. It is believed to have positive effects on later recall and reflection by the patient and on supervisory quality and accuracy for therapists. To evaluate self-reported attitudes and behaviour regarding audio recording of therapy sessions in both patients and therapists in a setting where such recording is routinely carried out. In a centre specializing in CBT for anxiety disorders, 72 patients completed a questionnaire at the start of therapy and 31 patients completed a questionnaire at the end of therapy. Fifteen therapists also completed a similar questionnaire. Ninety percent of patients reported listening to recordings between therapy sessions to some extent. The majority reported discussing the recordings with their therapist. Patients typically planned to keep the recordings after therapy ended. Most patients and therapists endorsed positive attitudes towards the use of recordings. Similar advantages (e.g. improving memory for sessions) and disadvantages (e.g. practical issues and feeling self-conscious) of recordings were generated by patients and therapists. Therapists were more likely than patients to express concern about recordings being distressing for patients to listen to. Both patients and therapists regarded the use of recordings for therapist peer supervision purposes favourably. The use of audio recording of sessions as an adjunct to therapy (where patients listen to recordings between sessions) and for therapist supervision is rated as both highly acceptable and useful by both therapists and patients.


Naturopathic care for chronic low back pain: a randomized trial.
Chronic low back pain represents a substantial cost to employers through benefits coverage and days missed due to incapacity. We sought to explore the effectiveness of Naturopathic care on chronic low back pain. This study was a randomized clinical trial. We randomized 75 postal employees with low back pain of longer than six weeks duration to receive Naturopathic care (n = 39) or standardized physiotherapy (n = 36) over a period of 12 weeks. The study was conducted in clinics on-site in postal outlets. Participants in the Naturopathic care group received dietary counseling, deep breathing relaxation techniques and acupuncture. The control intervention received education and instruction on physiotherapy exercises using an approved education booklet. We measured low back pain using the Oswestry disability questionnaire as the primary outcome measure, and quality of life using the SF-36 in addition to low back range of motion, weight loss, and Body Mass Index as secondary outcomes. Sixty-nine participants (92%) completed eight weeks or greater of the trial. Participants in the Naturopathic care group reported significantly lower back pain (-6.89, 95% CI. -9.23 to -3.54, p = <0.0001) as measured by the Oswestry questionnaire. Quality of life was also significantly improved in the group receiving Naturopathic care in all domains except for vitality. Differences for the aggregate physical component of the SF-36 was 8.47 (95% CI, 5.05 to 11.87, p = <0.0001) and for the aggregate mental component was 7.0 (95% CI, 2.25 to 11.75, p = 0.0045). All secondary outcomes were also significantly improved in the group receiving Naturopathic care: spinal flexion (p<0.0001), weight-loss (p = 0.0052) and Body Mass Index (-0.52, 95% CI, -0.96 to -0.08, p = 0.01). Naturopathic care provided significantly greater improvement than physiotherapy advice for patients with chronic low back pain. Controlled-Trials.com ISRCTN41920953.


Intrinsic Control of Axon Regeneration.
A determinant of axon regeneration is the intrinsic growth ability of injured neurons, which dictates a battery of injury responses in axons and cell bodies. While some of these regulatory mechanisms are evolutionarily conserved, others are unique to the mammalian central nervous system (CNS) where spontaneous regeneration usually does not occur. Here we examine our current understanding of these mechanisms at cellular and molecular terms and discuss their potential implications for promoting axon regeneration and functional recovery after nerve injury.


Right ventricular total isovolumic time: Reference value study.
There is lack of noninvasive indices to detail the right side cardiovascular physiology. Total isovolumic time (tIVT) is a sensitive marker of left ventricular electromechanical efficiency and systolic-diastolic interaction. The aim of the study was to evaluate normal reference value of the right ventricular tIVT with increasing age. One hundred and eighty-one healthy volunteers (51% male) underwent transthoracic echocardiography. The population was divided into four categories according to age: A < 30 years; B 30-39 years; C 40-49 years; and C ≥ 50 years old. tIVT was computed in seconds/minutes as: 60 - (tET + tFT). tET and tFT are the total ejection and filling time adjusted by the heart rate, measured, respectively, from the onset to the end of the right ventricle (RV) forward flow through the pulmonary valve and from the onset of the E-wave and the end of the A-wave at the level of the tricuspid valve. The mean RV tIVT was 7 ± 1.1 s/min and increased significantly with age, from a 3.4 to 9.7 s/min(P < 0.0001). Significant correlation was found between tIVT and trans-tricuspid E/E' (P < 0.0001; 0.78 (95% CI: 0.715-0.831) while weaker between tIVT and E/A (P = 0.001; -0.283 95% CI: -0.413 to -0.143). The normal values of RV tIVT increase with age and correlate significantly with Doppler diastolic parameters.


Assessment of flood hazard in a combined sewer system in Reykjavik city centre.
Short-duration precipitation bursts can cause substantial property damage and pose operational risks for wastewater managers. The objective of this study was to assess the present and possible future flood hazard in the combined sewer system in Reykjavik city centre. The catchment is characterised by two hills separated by a plain. A large portion of the pipes in the aging network are smaller than the current minimum diameter of 250 mm. Runoff and sewer flows were modelled using the MIKE URBAN software package incorporating both historical precipitation and synthetic storms derived from annual maximum rainfall data. Results suggest that 3% of public network manholes were vulnerable to flooding during an 11-year long rainfall sequence. A Chicago Design Storm (CDS) incorporating a 10-minute rainfall burst with a 5-year return period predicted twice as many flooded manholes at similar locations. A 20% increase in CDS intensity increased the number of flooded manholes and surface flood volume by 70% and 80%, respectively. The flood volume tripled if rainfall increase were combined with urban re-development, leading to a 20% increase in the runoff coefficient. Results highlight the need for reducing network vulnerabilities, which include decreased pipe diameters and low or drastically varying pipe grades.


Differences between day and nonday workers in exposure to physical and psychosocial work factors in the Danish eldercare sector.
The possible interaction between individual and occupational risk factors, the need for meaningful intervention, and the demand for valid shift work research make the accumulation of adverse exposures at certain times of the day of special relevance with respect to occupational health. The aim of the present study was therefore to examine whether there was a clustering of detrimental work factors among female eldercare workers in fixed evening or fixed night shifts when they are compared with workers in fixed day shifts. This cross-sectional, questionnaire-based study was conducted among 4590 female health care workers in the Danish eldercare sector. The participants worked in nursing homes, in home care, or in both. They answered questions on job demands, job control, and social support, together with questions on physical and psychological violence, physical workload, and passive smoking. We found that-compared with day workers-fixed nonday workers were more exposed to low job control, low support from leaders, physical and psychological violence, and high physical demands. Nonday workers were, however, less exposed to high demands. These differences remained after control for age, job title, and workplace. Exposures in the work environment of Danish eldercare workers varied between shifts. In a research perspective these findings stress the importance of adequate adjustment for work factors when the health effects of shift work are studied. Moreover, the results underscore the need for an increased awareness of work factors of special importance among nonday workers when interventions against shiftwork-related occupational disorders are designed.


The hegemony of empiricism: the opportunity for theoretical science in medicine.
Partly spurred by the rapid emergence of discovery tools, empirical science founded on experimental validation now dominates academic funding, publishing, and recognition while forums for theoretical science have been marginalized. Although this hegemony of empiricism instills useful discipline to the scientific process, it also limits the pace of science to sensor innovation and renders the ontogeny of scientific knowledge path-dependent, concealing potential discontinuities in intellectual trajectories. Theoretical science, founded on intuition, inspiration, and abstraction, can complement empirical science by creating disruptive paradigms that facilitate detection of spurious results and frame new hypotheses. For example, framing the compendium of human diseases as varying manifestations of buffer dysfunctions - insufficient or maladaptive responses to stress - portends new insights into disease mechanisms and treatments. As a specific incarnation of this theory, the "trauma hypothesis" suggests that the coordinated regulation of inflammation, coagulation, vasoconstriction, and fluid retention that evolved as a prehistoric adaptation to predatory stress and environmental injury conspires in modern times to produce acute coronary syndromes, heart failure, renal dysfunction, stroke, and pulmonary embolism. The theory also exposes the paradigmatic flaw behind the half-century detour perfecting balloon-deployed endovascular interventions. As the basis of buffer acquisition shifts from genetic to cognitive, phenoptosis - the theory that adaptive programmed death of organisms yields opportunity to successors - is rendered maladaptive, as an extended lifespan permits more efficient trait acquisition compared with life-death recycling. While forestalling death is a largely unfruitful medical game of "whack-a-mole" today, the recognition that aging and death may be programmed adaptations suggests they may also be amenable to systemic reprogramming. Epitomizing this opportunity are tumor cells, which reprogram themselves to escape their apoptotic fate and assume indefinite persistence. The prevalence and resilience of these cancer cells, and their ability to withstand the protean assaults of toxins, poisons, radiation, and host defenses, presage the potential robustness of life when appropriately programmed. Paradoxical medicine and dynamic range management may represent initial strategies to reprogram the neuroendocrine stress axes to modulate lifespan at the organism level, and many other strategies are anticipated. The key to theoretical science is original insight, but the prevailing pressure to conform to medicine's educational and practice standards dis-incentivizes independent thinking. A scientific future is envisioned when the commoditization of experimental science will enable its outsourcing, liberating health scientists from the tyranny of empiricism to engage in a more balanced process of discovery infused with theoretical considerations.


A Crimean-Congo hemorrhagic fever (CCHF) viral vaccine expressing nucleoprotein is immunogenic but fails to confer protection against lethal disease.
Crimean-Congo Hemorrhagic Fever (CCHF) is a severe tick-borne disease, endemic in many countries in Africa, the Middle East, Eastern Europe and Asia. Between 15-70% of reported cases are fatal with no approved vaccine available. In the present study, the attenuated poxvirus vector, Modified Vaccinia virus Ankara, was used to develop a recombinant candidate vaccine expressing the CCHF virus nucleoprotein. Cellular and humoral immunogenicity was confirmed in 2 mouse strains, including type I interferon receptor knockout mice, which are susceptible to CCHF disease. Despite the immune responses generated post-immunisation, the vaccine failed to protect animals from lethal disease in a challenge model.


Chemical properties, environmental fate, and degradation of seven classes of pollutants.
Industrialism has brought a long series of benefits for modern civilization. Concomitantly, reversible and irreversible changes have been inflicted upon the environment, affecting humans, animals, and whole ecosystems and leading to effects such as declining reproduction in modern human beings, developmental challenges on various species, and destroyed habitats and ecosystems across the globe. In this context, a vast repertoire of modern and older literature is reviewed for a series of pollutants and their status as of 2014. The compound classes covered in this review are polychlorinated biphenyls, halogenated hydrocarbons, estrogen analogues, phthalates, dioxins, perfluorinated compounds, and brominated flame retardants. These groups represent ubiquitous pollutants, of which some have circulated in the environment for more than 60 years. In this context, this review describes the chemical properties, the environmental fate, and the toxicological effects of these classes of pollutants on humans and animals, including an introductory section on the detoxification systems that are triggered in most species upon intoxication. This combined review of in vivo transformation, chemistry, toxicological properties, and structure-activity relationships of pollutants aids in the understanding of the fate, biomagnification, bioaccumulation, and transformation of these compounds, which is essential for toxicologists, environmental scientists, and environmental legislators. The review is concluded with an outlook.


Mobilization of lead from the skeleton during the postnatal period is larger than during pregnancy.
A cohort of 15 immigrant females to Australia and 7 native Australian controls were monitored on a monthly basis with high-precision lead isotopic methods during gestation and for 6 months after pregnancy to determine the extent of lead mobilization from the maternal skeleton. Quarterly environmental samples of house dust, drinking water, urban air, gasoline, and a 6-day duplicate diet were also measured. The geometric mean blood lead concentration for the immigrant females on arrival in Australia was 3.0 microg/dl (range: 1.9 to 20 microg/dl), and for the Australian controls was 3.1 gm/dl (range: 1.9 to 4.3 microg/dl). During gestation and after pregnancy, blood lead concentrations varied, with mean individual changes of -14% to 83%. For the immigrant subjects, the percentage change in blood lead concentration was significantly greater during the postpregnancy period than during the 2nd and 3rd trimesters (p < 0.001). Skeletal contribution to blood lead, based on the isotopic composition for the immigrant subjects, increased in an approximately linear manner during pregnancy. The mean increases for each individual during pregnancy varied from 26% to 99%. Skeletal lead contribution to blood lead was significantly greater (p < 0.001) during the postpregnancy period than during the 2nd and 3rd trimesters. The contribution of skeletal lead to blood lead during the postpregnancy period remained essentially constant at the increased level of lead mobilization, although the duration of breastfeeding varied from 1 week to more than 6 months. The increased contribution of skeletal lead to blood lead during the postpregnancy period is attributed to increased mobilization of lead from maternal skeletal stores during lactation. The increased contribution of skeletal lead both during pregnancy and in the postpregnancy period is consistent with increased bone resorption, and may be associated with an inadequate calcium intake observed in quarterly 6-day duplicate diets. Mobilization of skeletal lead stores represents a potentially important source of perinatal lead intake and accumulation in the developing fetus. Only two subjects consumed dietary supplements for calcium, and their mobilization of lead from the skeleton to the blood was the lowest of all the subjects. These two subjects' use of calcium supplements may have reduced mobilization of skeletal mineral stores to supply the calcium needs of pregnancy and lactation. Calcium supplementation may be an important means of limiting fetal exposure to lead.


Targeting class IA PI3K isoforms selectively impairs cell growth, survival, and migration in glioblastoma.
The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancer and plays a crucial role in glioblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K isoforms as a novel anti-tumor approach in glioblastoma. Consistent expression of the PI3K catalytic isoform PI3K p110α was detected in a panel of glioblastoma patient samples. In contrast, PI3K p110β expression was only rarely detected in glioblastoma patient samples. The expression of a module comprising the epidermal growth factor receptor (EGFR)/PI3K p110α/phosphorylated ribosomal S6 protein (p-S6) was correlated with shorter patient survival. Inhibition of PI3K p110α activity impaired the anchorage-dependent growth of glioblastoma cells and induced tumor regression in vivo. Inhibition of PI3K p110α or PI3K p110β also led to impaired anchorage-independent growth, a decreased migratory capacity of glioblastoma cells, and reduced the activation of the Akt/mTOR pathway. These effects were selective, because targeting of PI3K p110δ did not result in a comparable impairment of glioblastoma tumorigenic properties. Together, our data reveal that drugs targeting PI3K p110α can reduce growth in a subset of glioblastoma tumors characterized by the expression of EGFR/PI3K p110α/p-S6.


Quantum-dot spin-photon entanglement via frequency downconversion to telecom wavelength.
Long-distance quantum teleportation and quantum repeater technologies require entanglement between a single matter quantum bit (qubit) and a telecommunications (telecom)-wavelength photonic qubit. Electron spins in III-V semiconductor quantum dots are among the matter qubits that allow for the fastest spin manipulation and photon emission, but entanglement between a single quantum-dot spin qubit and a flying (propagating) photonic qubit has yet to be demonstrated. Moreover, many quantum dots emit single photons at visible to near-infrared wavelengths, where silica fibre losses are so high that long-distance quantum communication protocols become difficult to implement. Here we demonstrate entanglement between an InAs quantum-dot electron spin qubit and a photonic qubit, by frequency downconversion of a spontaneously emitted photon from a singly charged quantum dot to a wavelength of 1,560 nanometres. The use of sub-10-picosecond pulses at a wavelength of 2.2 micrometres in the frequency downconversion process provides the necessary quantum erasure to eliminate which-path information in the photon energy. Together with previously demonstrated indistinguishable single-photon emission at high repetition rates, the present technique advances the III-V semiconductor quantum-dot spin system as a promising platform for long-distance quantum communication.


Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice.
Inappropriate excess of the steroid hormone aldosterone, which is a mineralocorticoid receptor (MR) agonist, is associated with increased inflammation and risk of cardiovascular disease. MR antagonists are cardioprotective and antiinflammatory in vivo, and evidence suggests that they mediate these effects in part by aldosterone-independent mechanisms. Here we have shown that MR on myeloid cells is necessary for efficient classical macrophage activation by proinflammatory cytokines. Macrophages from mice lacking MR in myeloid cells (referred to herein as MyMRKO mice) exhibited a transcription profile of alternative activation. In vitro, MR deficiency synergized with inducers of alternatively activated macrophages (for example, IL-4 and agonists of PPARgamma and the glucocorticoid receptor) to enhance alternative activation. In vivo, MR deficiency in macrophages mimicked the effects of MR antagonists and protected against cardiac hypertrophy, fibrosis, and vascular damage caused by L-NAME/Ang II. Increased blood pressure and heart rates and decreased circadian variation were observed during treatment of MyMRKO mice with L-NAME/Ang II. We conclude that myeloid MR is an important control point in macrophage polarization and that the function of MR on myeloid cells likely represents a conserved ancestral MR function that is integrated in a transcriptional network with PPARgamma and glucocorticoid receptor. Furthermore, myeloid MR is critical for blood pressure control and for hypertrophic and fibrotic responses in the mouse heart and aorta.


The mediator of cellular immunity. XII. Inhibition of activated T cells by Newcastle disease virus.
Newcastle disease virus (NDV) can interact in at least two ways with rat T cells. By adsorbing to circulating lymphocytes, the virus can transiently deflect the cells from lymph nodes and inflammatory exudates induced in the peritoneal cavity. T cells are affected regardless of age, state of activation, or position in the mitotic cycle. The effect is reversible and is mediated not only by infectious (I)-NDV, but also by UV-NDV which cannot achieve a complete replication cycle in eggs. But I-NDV has another lasting effect on activated T cells. It is revealed in the failure of virus-treated thoracic duct lymphocytes to transfer cellular resistance to Listeria monocytogenes, delayed-type hypersensitivity to soluble antigens of the parasite, and the permanent exclusion of labeled S-phase lymphocytes from inflammatory foci. Activated T cells are inhibited by virus multiplicites which have little if any effect upon the proliferative potential of antigen-sensitive T cells or localization of labeled small lymphocytes in lymph nodes. The underlying mechanism has not been determined; however, there are reasons for thinking that NDV has a lethal effect upon activated T cells, because the latter are permissive for virus replication.


Evaluation of methods for sizing and counting of ultrasound contrast agents.
A precise, accurate and well documented method for the sizing and counting of microbubbles is essential for all aspects of quantitative microbubble-enhanced ultrasound imaging. The efficacy of (a) electro-impedance volumetric zone sensing (ES) also called a Coulter counter/multisizer; (b) optical microscopy (OM); and (c) laser diffraction (LD), for the sizing and counting of microbubbles was assessed. Microspheres with certified mean diameter and number concentration were used to assess sizing and counting reproducibility (precision) and reliability (accuracy) of ES, OM and LD. SonoVue™ was repeatedly (n = 3) sized and counted to validate ES, OM and LD sizing and counting efficacy. Statistical analyses of intra-method variability for the SonoVue™ mean diameter showed that the best microbubble sizing reproducibility was obtained using OM with a mean diameter sizing variability of 1.1%, compared with a variability of 4.3% for ES and 7.1% for LD. The best microbubble counting reproducibility was obtained using ES with a number concentration variability of 8.3%, compared with a variability of 22.4% for OM and 32% for LD. This study showed that no method is fully suited to both sizing and counting of microbubbles.


DTP vaccination and child survival in observational studies with incomplete vaccination data.
Observational studies of diphtheria-tetanus-pertussis (DTP) vaccine from longitudinal study sites have reported divergent effects on child survival, ranging from 10-fold reduction to threefold increased mortality. None of these studies had complete information on DTP vaccinations from both survivors and children who died. We reviewed the data analysis methodology to assess whether methodological differences could explain the divergent results. Studies have used case-control design, survival analysis with interval-fixed vaccination status (landmark approach), and survival analysis with retrospective updating of vaccination status. Seven studies using a case-control design or a landmark approach found a negative effect of DTP on child survival. Eight of nine survival analyses with retrospective updating of vaccination status reported a beneficial effect. This beneficial effect of DTP increased with the length of the interval between data collection visits. Studies with long interval between visits had very high mortality rates among unvaccinated children, low mortality rate ratios for vaccinated compared with unvaccinated children, and strongly beneficial estimates of DTP. The divergent results in observational studies of the impact of DTP on child survival are partly because of methodological differences. To assess the impact on mortality of routine vaccinations, observational study designs which minimize the effect of bias are warranted. Randomized trials should be considered.


Cascaded random distributed feedback Raman fiber laser operating at 1.2 μm.
We demonstrate a CW random distributed feedback Raman fiber laser operating in a 1.2 μm spectral band. The laser generates up to 3.8 W of the quasi-CW radiation at 1175 nm with the narrow spectrum of 1 nm. Conversion efficiency reaches 60%. Up to 1 W is generated at the second Stokes wavelength of 1242 nm. It is shown that the generation spectrum of RDFB Raman fiber laser is much narrower than the spectrum in the system without a weak random feedback.


Impact of community-based health insurance in rural India on self-medication & financial protection of the insured.
The evidence-base of the impact of community-based health insurance (CBHI) on access to healthcare and financial protection in India is weak. We investigated the impact of CBHI in rural Uttar Pradesh and Bihar s0 tates of India on insured households' self-medication and financial position. Data originated from (i) household surveys, and (ii) the Management Information System of each CBHI. Study design was "staggered implementation" cluster randomized controlled trial with enrollment of one-third of the treatment group in each of the years 2011, 2012 and 2013. Around 40-50 per cent of the households that were offered to enroll joined. The benefits-packages covered outpatient care in all three locations and in-patient care in two locations. To overcome self-selection enrollment bias, we constructed comparable control and treatment groups using Kernel Propensity Score Matching (K-PSM). To quantify impact, both difference-in-difference (DiD), and conditional-DiD (combined K-PSM with DiD) were used to assess robustness of results. Post-intervention (2013), self-medication was less practiced by insured HHs. Fewer insured households than uninsured households reported borrowing to finance care for non-hospitalization events. Being insured for two years also improved the HH's location along the income distribution, namely insured HHs were more likely to experience income quintile-upgrade in one location, and less likely to experience a quintile-downgrade in two locations. The realized benefits of insurance included better access to healthcare, reduced financial risks and improved economic mobility, suggesting that in our context health insurance creates welfare gains. These findings have implications for theoretical, ethical, policy and practice considerations.


A telemedicine network to support paediatric care in small hospitals in rural Tanzania.
We reviewed our experience with the Tanzanian Telemedicine Network in supporting paediatric care at 40 small, rural hospitals in the country. The network began operating in 2008. Store and forward telemedicine was provided via the open source software iPath. The 33 volunteer consultants were based in several countries, although most of them had practical experience in Tanzania. During the first three years of network operation there were 533 referrals. There were 159 paediatric cases (median age five years). Three paediatric specialists provided most consultations (64%), but other specialists provided recommendations when required. The response time was usually less than two days (median 6 h; inter-quartile range 2-24 h). A precise recommendation was not always provided, but since all consultants had an intimate knowledge of the state of health services in Tanzania, their advice was usually well adapted to the local circumstances of the hospitals. Referral to a higher level of care was recommended in 26 cases (16%). A simple web-based telemedicine system combined with email alerts is feasible in remote locations in Tanzania, even where fast Internet connections are not available.


Enhancement of toll-like receptor 2-mediated immune responses by AIMP1, a novel cytokine, in mouse dendritic cells.
Aminoacyl tRNA synthetase-interacting protein 1 (AIMP1) is a novel pleiotropic cytokine that was identified initially from Meth A-induced fibrosarcoma. It is expressed in the salivary glands, small intestine and large intestine, and is associated with the innate immune system. Previously, we demonstrated that AIMP1 might function as a regulator of innate immune responses by inducing the maturation and activation of bone-marrow-derived dendritic cells (BM-DCs). Toll-like receptors (TLRs) are major pathogen-recognition receptors that are constitutively expressed on DCs. In this study, we attempted to determine whether AIMP1 is capable of regulating the expression of TLRs, and also capable of affecting the TLR-mediated activation of DCs. Expression of TLR1, -2, -3 and -7 was highly induced by AIMP1 treatment in BM-DCs, whereas the expression of other TLRs was either down-regulated or remained unchanged. In particular, the expression of the TLR2 protein was up-regulated by AIMP1 in a time-dependent and dose-dependent manner, and was suppressed upon the addition of BAY11-7082, an inhibitor of nuclear factor-κB. AIMP1 was also shown to increase nuclear factor-κB binding activity. Importantly, AIMP1 enhanced the production of interleukin-6 and interleukin-12, and the expression of co-stimulatory molecules on BM-DCs when combined with lipoteichoic acid or Pam3Cys, two well-known TLR2 agonists. Collectively, these results demonstrate that the AIMP1 protein enhances TLR2-mediated immune responses via the up-regulation of TLR2 expression.


Surgical outcomes of gastroenterological surgery in Japan: Report of the National Clinical Database 2011-2017.
The Japanese National Clinical Database (NCD) is a large-scale, nationwide, web-based data entry system that is linked to the surgical board certification system and covers almost all surgical cases carried out in Japan. To evaluate outcomes according to the gastroenterological section of the NCD. The 115 surgical procedures stipulated by the "Training Curriculum for Board-Certified Surgeons in Gastroenterology" were registered from 2011 to 2017. The number of surgeries, preoperative comorbidities, and short-term outcomes were compared between registration periods. In total, 3 818 414 cases have been registered. More than 70% of all surgeries were carried out at certified institutions. The annual number of cases has been increasing year after year, and the aged population has also been increasing. Although the rates of preoperative comorbidities and postoperative complications have been increasing, the postoperative mortality rate has remained relatively low; in 2017, the 30-day mortality rate was 1.0% among those who underwent esophagectomy, 0.7% among those who underwent distal gastrectomy, 1.1% among those who underwent total gastrectomy, 1.3% among those who underwent right hemicolectomy, 0.5% among those who underwent low anterior resection, 1.3% among those who underwent hepatectomy, and 1.3% among those who underwent pancreaticoduodenectomy. The annual rate of endoscopic surgery dramatically increased over 7 years between 2011 and 2017, especially for low anterior resection (29.5%-62.6%) and esophagectomy (31.0%-56.1%). This database is expected to ensure the quality of the board-certification system and surgical outcomes in gastroenterological surgery.


Enhanced four-wave-mixing effects by large group indices of one-dimensional silicon photonic crystal waveguides.
Enhanced four-wave-mixing (FWM) effects have been observed with the help of large group-indices near the band edges in one-dimensional (1-D) silicon photonic crystal waveguides (Si PhCWs). A significant increase of the FWM conversion efficiency of about 17 dB was measured near the transmission band edge of the 1-D PhCW through an approximate 3.2 times increase of the group index from 8 to 24 with respect to the central transmission band region despite a large group-velocity dispersion. Numerical analyses based on the coupled-mode equations for the degenerated FWM process describe the experimentally measured results well. Our results indicate that the 1-D PhCWs are good candidates for large group-index enhanced nonlinearity devices even without having any special dispersion engineering.


Family group decision-making for children at risk of abuse or neglect: A systematic review.
Capturing the scale of child maltreatment is difficult, but few would argue that it is anything less than a global problem which can affect victims' health and well-being throughout their life. Systems of detection, investigation and intervention for maltreated children are the subject of continued review and debate. To assess the effectiveness of the formal use of family group decision-making (FGDM) in terms of child safety, permanence (of child's living situation), child and family well-being, and client satisfaction with the decision-making process. Both published and unpublished manuscripts were considered eligible for this review. Library staff from Scholarly Information (Brownless Biomedical Library) University of Melbourne, conducted 14 systematic bibliographic searches. Reviewers also checked the reference lists of all relevant articles obtained, and reference lists from previously published reviews. Researchers also hand-searched 10 relevant journals. Study samples of children and young people, aged 0-18 years, who have been the subject of a child maltreatment investigation, were eligible for this review. Studies had to have used random assignment to create treatment and control groups; or, parallel cohorts in which groups were assessed at the same point in time. Any form of FGDM, used in the course of a child maltreatment investigation or service, was considered an eligible intervention if it involved: a concerted effort to convene family, extended family, and community members; and professionals; and involved a planned meeting with the intention of working collaboratively to develop a plan for the safety well-being of children; with a focus on family-centred decision-making. Two review authors independently extracted the necessary data from each study report, using the software application Covidence. Covidence highlighted discrepancies between data extracted by separate reviewers, further analysis was conducted until a consensus was reached on what data were to be included in the review. Two authors also independently conducted analyses of study bias. Eighteen eligible study reports were found, providing findings from 15 studies, involving 18 study samples. Four were randomised controlled trials (RCTs; N = 941) the remainder employed quasi-experimental designs with parallel cohorts. Three of the quasi-experimental studies used prospective evaluations of nonrandomly assigned comparison groups (N = 4,368); the rest analysed pre-existing survey data, child protection case files or court data (N = 91,786). The total number of children studied was 97,095. The longest postintervention follow-up period was 3 years. Only four studies were conducted outside the United States; two in Canada and one in Sweden and one in the Netherlands. The review authors judged there to be a moderate or high risk of bias, in most of the bias categories considered. Only one study referenced a study protocol. Eleven of the fifteen studies were found to have a high likelihood of selection bias (73%). Baseline imbalance bias was deemed to be unlikely in just two studies, and highly likely in nine (60%). Confounding variables were judged to be highly likely in four studies (27%), and contamination bias was judged highly likely in five studies (33%). Researcher allegiance was rated as a high risk in three studies (20%) where the authors argued for the benefits of FGDM within the article, but without supporting references to an appropriate evidence base. Bias from differential diagnostic activity, and funding source bias, were less evident across the evidence reviewed. This review combines findings for eight FGDM outcome measures. Findings from RCTs were available for four outcomes, but none of these, combined in meta-analysis or otherwise, were statistically significant. Combining findings from the quasi-experimental studies provided one statistically significant finding, for the reunification of families, favouring FGDM. Ten effect sizes, from nine quasi-experimental studies, were synthesised to examine effects on the reunification of children with their family or the effect on maintaining in-home care; in short, the effect FGDM has on keeping families together. There was a high level of heterogeneity between the studies (I 2 = 92%). The overall effect, based on the combination of these studies was positive, small, but statistically significant: odds ratio (OR), 1.69 (confidence interval [CI], 1.03, 2.78). Holinshead's (2017) RCT also measured the maintenance on in-home care and reported a similar result: OR, 1.54 (CI, -0.19, 0.66) not statistically significant. The overall effect for continued maltreatment from meta-analysis of five quasi-experimental studies, favoured the FGDM group, but was not statistically significant: OR, 0.73 (CI, 0.48, 1.11). The overall combined effect for continued maltreatment, reported in RCTs, favoured the control group. But it was not statistically significant: OR, 1.29 (CI, 0.85, 1.98). Five effect sizes, from nonrandomised studies, were synthesised to examine the effect of FGDM on the number of kinship placements. The overall positive effect based on the combination of these studies was negligible: OR, 1.31 (CI, 0.94, 1.82). Meta-analysis was not possible with other outcomes. FGDM's role in expediting case processing and case closures was investigated in six studies, three of which reported findings favouring FGDM, and three which favoured the comparison group. Children's placement stability was reported in two studies: an RCT's findings favoured the control, while a quasi-experimental study's findings favoured FGDM. Three studies reported findings for service user satisfaction: one had only 30 participants, one reported a statistically significant positive effect for FGDM, the other found no difference between FGDM and a control. Engagement with support services was reported in two studies; neither reported statistically significant findings. The current evidence base, in this field, is insufficient to draw conclusions about the effectiveness of FGDM. These models of child protection decision-making may help bring about better outcomes for children at risk, or they may increase the risk of further maltreatment. Further research of rigour, designed to avoid the potential biases of previous evaluations, is needed.


School snacks decrease morbidity in Kenyan schoolchildren: a cluster randomized, controlled feeding intervention trial.
To examine the effects of three different school snacks on morbidity outcomes. Twelve schools were randomized to either one of three feeding groups or a Control group. There were three schools per group in this cluster randomized trial. Children in feeding group schools received school snacks of a local plant-based dish, githeri, with meat, milk or extra oil added. The oil used was later found to be fortified with retinol. Physical status, food intake and morbidity outcomes were assessed longitudinally over two years. Rural Embu District, Kenya, an area with high prevalence of vitamin A deficiency. Standard 1 schoolchildren (n 902; analytic sample) enrolled in two cohorts from the same schools one year apart. The Meat and Plain Githeri (i.e. githeri+oil) groups showed the greatest declines in the probability of a morbidity outcome (PMO) for total and severe illnesses, malaria, poor appetite, reduced activity, fever and chills. The Meat group showed significantly greater declines in PMO for gastroenteritis (mainly diarrhoea) and typhoid compared with the Control group, for jaundice compared with the Plain Githeri group, and for skin infection compared with the Milk group. The Milk group showed the greatest decline in PMO for upper respiratory infection. For nearly all morbidity outcomes the Control group had the highest PMO and the least decline over time. The intervention study showed beneficial effects of both animal source foods and of vitamin A-fortified oil on morbidity status.


PI3Kgamma adaptor subunits define coupling to degranulation and cell motility by distinct PtdIns(3,4,5)P3 pools in mast cells.
Phosphoinositide 3-kinase gamma (PI3Kgamma) plays a major role in chronic inflammation and allergy. It is a heterodimer of a catalytic p110gamma subunit and an adaptor protein, either p101 or the p101 homolog p84 (p87(PIKAP)). It is unclear whether both PI3Kgamma complexes specifically modulate responses such as chemotaxis and degranulation. In mast cells, the p84:p110gamma complex synergizes with immunoglobulin E (IgE)- and antigen-clustered FcepsilonRI receptor signaling and is required to achieve maximal degranulation. During this process, PI3Kgamma is activated by ligands of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs), in particular adenosine receptors, through autocrine and paracrine pathways. Here, we show that p110gamma needs p84 to relay signals from GPCRs to formation of phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)], phosphorylation of Akt, migration of cells, and synergistic adenosine-enforced degranulation. Furthermore, the absence of adaptor subunits could not be compensated for by increased p110gamma abundance. Differentiated, p110gamma null cells also lost adaptor proteins. Complementation of p110gamma null mast cells with p101 and p110gamma restored the activation of Akt and cell migration, but failed to support degranulation. Lack of degranulation was attributed to a change in the spatiotemporal localization of PI3Kgamma-derived PtdIns(3,4,5)P(3); although both p84:p110gamma and p101:p110gamma complexes initially deposited PtdIns(3,4,5)P(3) at the plasma membrane, p101:p110gamma-derived PtdIns(3,4,5)P(3) was rapidly endocytosed to motile, microtubule-associated vesicles. In addition, p84:p110gamma, but not p101:p110gamma signaling was sensitive to disruption of lipid rafts. Our results demonstrate a nonredundant function for the p101 and p84 PI3Kgamma adaptor proteins and show that distinct pools of PtdIns(3,4,5)P(3) at the plasma membrane can elicit specific cell responses.


Cerebrovascular complications and utilization of endovascular techniques following transsphenoidal resection of pituitary adenomas: a study of the Nationwide Inpatient Sample 2001-2010.
Cerebrovascular complications following transsphenoidal resection of pituitary tumors are rare and often evaluated and treated with endovascular techniques. We determined the utilization rate and outcomes of endovascular procedures in transsphenoidal pituitary resection patients using an administrative database. Using the Nationwide Inpatient Sample 2001-2010, patients receiving transsphenoidal resection of benign pituitary tumors were identified. The rate of cerebrovascular complications and utilization of endovascular repair procedures and cerebral angiography were compared between high (≥ 75 procedures/year) and low volume (<75 procedures/year) centers. Chi squared tests were used to compare categorical variables. 70,878 were patients included in this study. ICH/SAH occurred in 0.9 % of patients (652/70,878) and stroke occurred in 0.5 % of patients (327/70,878). Patients treated at high volume centers had significantly lower rates of stroke (0.5 % vs. 1.0 %, P = 0.04), and ICH/SAH (0.5 vs. 1.0 %, P = 0.05) when compared to patients treated at low-volume centers. Overall, 531 patients (0.7 %) received post-operative angiography and 83 patients (0.1 %) received endovascular repair procedures. High volume center patients underwent angiography in 0.4 % of cases compared to 0.9 % for low volume center patients (P = 0.02). There was no significant difference in endovascular repair procedure rates at high and low volume centers (0.1 vs. 0.2 %, P = 0.37). Cerebrovascular surgical complications requiring cerebral angiography and endovascular repair are rare among transsphenoidal pituitary resection patients. These occur with higher frequency at low volume centers and are associated with high mortality rates.


Golden Hour Protocol for Preterm Infants: A Quality Improvement Project.
Preterm infants are a vulnerable patient population, especially during the first hours of life. Hypothermia, hypoglycemia, and early-onset sepsis are common problems related to prematurity. Implementation of a Golden Hour protocol has been shown to improve outcomes for preterm infants. To evaluate the effectiveness of a Golden Hour protocol for infants born at less than 32 weeks' gestation on improving the admission process in a military care facility. Specific aims focused on temperature, time to initiation of intravenous (IV) fluids, time to administration of antibiotics, and time to close of the incubator top. A pre-/postdesign was used to compare outcomes from preimplementation to postimplementation. Predata were collected using electronic health record chart review and postdata were collected from the Neonatal Intensive Care Unit admission worksheet. Although we did not find statistical significance, we found that more infants had a temperature greater than 36.5°C within 1 hour of birth and decrease in time to initiation of IV fluids and antibiotics from preimplementation to postimplementation, which is clinically significant. Time to close of the incubator top remained greater than 1 hour. Implementation of a Golden Hour protocol provides a guide to caring for preterm infants during the first hour of life to improve patient outcomes. Involvement of key stakeholders and staff education are key to successful implementation. Researchers should examine long-term outcomes related to implementation of a Golden Hour protocol in future studies. Future quality improvement projects should include the effectiveness of similar protocols and address possible barriers.


Ludwik Rajchman, international health leader.
Ludwik Rajchman was a man caught up in the whirlwind of international politics. He suffered from the conquest of his country, Poland, by both Nazism and Communism yet managed to rise to eminence as a leader of the Health Organisation of the League of Nations and then of UNICEF.


mRNA Deadenylation Is Coupled to Translation Rates by the Differential Activities of Ccr4-Not Nucleases.
Translation and decay of eukaryotic mRNAs is controlled by shortening of the poly(A) tail and release of the poly(A)-binding protein Pab1/PABP. The Ccr4-Not complex contains two exonucleases-Ccr4 and Caf1/Pop2-that mediate mRNA deadenylation. Here, using a fully reconstituted biochemical system with proteins from the fission yeast Schizosaccharomyces pombe, we show that Pab1 interacts with Ccr4-Not, stimulates deadenylation, and differentiates the roles of the nuclease enzymes. Surprisingly, Pab1 release relies on Ccr4 activity. In agreement with this, in vivo experiments in budding yeast show that Ccr4 is a general deadenylase that acts on all mRNAs. In contrast, Caf1 only trims poly(A) not bound by Pab1. As a consequence, Caf1 is a specialized deadenylase required for the selective deadenylation of transcripts with lower rates of translation elongation and reduced Pab1 occupancy. These findings reveal a coupling between the rates of translation and deadenylation that is dependent on Pab1 and Ccr4-Not.


Yersinia enterocolitica YopT and Clostridium difficile toxin B induce expression of GILZ in epithelial cells.
Glucocorticoid induced-leucine zipper (GILZ) has been shown to be induced in cells by different stimuli such as glucocorticoids, IL-10 or deprivation of IL-2. GILZ has anti-inflammatory properties and may be involved in signalling modulating apoptosis. Herein we demonstrate that wildtype Yersinia enterocolitica which carry the pYV plasmid upregulated GILZ mRNA levels and protein expression in epithelial cells. Infection of HeLa cells with different Yersinia mutant strains revealed that the protease activity of YopT, which cleaves the membrane-bound form of Rho GTPases was sufficient to induce GILZ expression. Similarly, Clostridium difficile toxin B, another bacterial inhibitor of Rho GTPases induced GILZ expression. YopT and toxin B both increased transcriptional activity of the GILZ promoter in HeLa cells. GILZ expression could not be linked to the inactivation of an individual Rho GTPase by these toxins. However, forced expression of RhoA and RhoB decreased basal GILZ promoter activity. Furthermore, MAPK activation proved necessary for profound GILZ induction by toxin B. Promoter studies and gel shift analyses defined binding of upstream stimulatory factor (USF) 1 and 2 to a canonical c-Myc binding site (E-box) in the GILZ promoter as a crucial step of its trans-activation. In addition we could show that USF-1 and USF-2 are essential for basal as well as toxin B induced GILZ expression. These findings define a novel way of GILZ promoter trans-activation mediated by bacterial toxins and differentiate it from those mediated by dexamethasone or deprivation of IL-2.


A predictive model for early mortality after surgical treatment of heart valve or prosthesis infective endocarditis. The EndoSCORE.
The aim of this large retrospective study was to provide a logistic risk model along an additive score to predict early mortality after surgical treatment of patients with heart valve or prosthesis infective endocarditis (IE). From 2000 to 2015, 2715 patients with native valve endocarditis (NVE) or prosthesis valve endocarditis (PVE) were operated on in 26 Italian Cardiac Surgery Centers. The relationship between early mortality and covariates was evaluated with logistic mixed effect models. Fixed effects are parameters associated with the entire population or with certain repeatable levels of experimental factors, while random effects are associated with individual experimental units (centers). Early mortality was 11.0% (298/2715); At mixed effect logistic regression the following variables were found associated with early mortality: age class, female gender, LVEF, preoperative shock, COPD, creatinine value above 2mg/dl, presence of abscess, number of treated valve/prosthesis (with respect to one treated valve/prosthesis) and the isolation of Staphylococcus aureus, Fungus spp., Pseudomonas Aeruginosa and other micro-organisms, while Streptococcus spp., Enterococcus spp. and other Staphylococci did not affect early mortality, as well as no micro-organisms isolation. LVEF was found linearly associated with outcomes while non-linear association between mortality and age was tested and the best model was found with a categorization into four classes (AUC=0.851). The following study provides a logistic risk model to predict early mortality in patients with heart valve or prosthesis infective endocarditis undergoing surgical treatment, called "The EndoSCORE".


Horseshoe bats make adaptive prey-selection decisions, informed by echo cues.
Foragers base their prey-selection decisions on the information acquired by the sensory systems. In bats that use echolocation to find prey in darkness, it is not clear whether the specialized diet, as sometimes found by faecal analysis, is a result of active decision-making or rather of biased sensory information. Here, we tested whether greater horseshoe bats decide economically when to attack a particular prey item and when not. This species is known to recognize different insects based on their wing-beat pattern imprinted in the echoes. We built a simulation of the natural foraging process in the laboratory, where the bats scanned for prey from a perch and, upon reaching the decision to attack, intercepted the prey in flight. To fully control echo information available to the bats and assure its unambiguity, we implemented computer-controlled propellers that produced echoes resembling those from natural insects of differing profitability. The bats monitored prey arrivals to sample the supply of prey categories in the environment and to inform foraging decisions. The bats adjusted selectivity for the more profitable prey to its inter-arrival intervals as predicted by foraging theory (an economic strategy known to benefit fitness). Moreover, unlike in previously studied vertebrates, foraging performance of horseshoe bats was not limited by costly rejections of the profitable prey. This calls for further research into the evolutionary selection pressures that sharpened the species's decision-making capacity.


Uromyces appendiculatus in Honduras: Pathogen Diversity and Host Resistance Screening.
Bean rust, caused by the fungus Uromyces appendiculatus, is a major constraint for common bean production worldwide. Virulence of U. appendiculatus collected from wild and cultivated Phaseolus spp. was examined in 28 locations across Honduras. Host accessions representing wild and domesticated Phaseolus spp. collected at the same sampling locations were evaluated for resistance against U. appendiculatus. In total, 91 pathotypes were identified from 385 U. appendiculatus isolates according to their virulence on each of the 12 host differentials. No significant difference in pathogen total virulence, measured as the mean disease score, was found between locations. However, significant differences were found in pathotype virulence among isolates collected from different Phaseolus spp. within a location. Moreover, when locations were compared on the basis of pathotype occurrence and frequency, differences among locations were evident. No two locations had the same pathotype composition. The most common pathotype was virulent on 9 of the 12 differential lines. A high number of resistant accessions were identified in Phaseolus coccineus and P. lunatus. Although most wild P. vulgaris accessions were highly susceptible, rust resistance was observed in P. vulgaris landraces collected from farmer's fields. Thirty-two (52%) of the accessions screened showed intermediate to high levels of resistance and, of those, 16% were P. coccineus accessions. Our findings support the hypothesis that interaction of U. appendiculatus in host populations composed of diverse Phaseolus spp. and genotypes has favored highly diverse and virulent pathotypes, creating a center for virulence diversity of the pathogen in Honduras. The high percentage of intermediate and highly resistant accessions identified in the present study supports the strategy of collecting plants from the center of diversity of a pathogen or in locations with high incidence of disease and pathogen diversity to maximize the probability of identifying new sources of resistance.


Segregation analysis reveals a major gene effect controlling systolic blood pressure and BMI in an Israeli population.
It has been suggested that genetic factors control blood pressure level at all ages. However, the evidence is limited because of the composite nature of blood pressure and the heterogeneity of the studied samples. The purpose of the present study is to test for genetic influences on systolic blood pressure (SBP) level in a community-based Israeli family study. Segregation analysis was performed on 622 adults from 208 pedigrees. Age, sex, and body mass index (BMI) were significant covariates of SBP. Segregation analysis rejected the environmental transmission model but not the mixed Mendelian transmission model. The best-fitting genetic model was the mixed codominant model, with a heritability of 0.32 and an allele frequency of 0.18 for high SBP level. We further tested whether SBP and BMI shared a common major gene effect. Using bivariate segregation analysis involving two traits and a single locus, we found evidence for a single-locus pleiotropic effect on SBP and BMI. The allele frequency of this major locus was 0.24. The residual genetic correlation resulting from additive polygenes and the environmental correlation between these two traits were not different from zero after taking into account the shared major gene effect. The proportion of phenotypic variation attributable to this major gene effect increased with age for SBP but decreased with age for BMI.


Impact of a school-based and primary care-based multicomponent intervention on HPV vaccination coverage among French adolescents: a cluster randomised controlled trial protocol (the PrevHPV study).
Vaccination is an effective and safe strategy to prevent Human papillomavirus (HPV) infection and related harms. Despite various efforts by French authorities to improve HPV vaccine coverage (VC) these past few years, VC has remained far lower than in most other high-income countries. To improve it, we have coconstructed with stakeholders a school-based and primary care-based multicomponent intervention, and plan to evaluate its effectiveness, efficiency and implementation through a cluster randomised controlled trial (cRCT). This pragmatic cRCT uses an incomplete factorial design to evaluate three components applied alone or in combination: (1) adolescents and parents' education and motivation at school, using eHealth tools and participatory learning; (2) general practitioners' training on HPV using motivational interviewing techniques and provision of a decision aid tool; (3) free-of-charge access to vaccination at school. Eligible municipalities (clusters) are located in one of 14 preselected French school districts and must have only one secondary school which enrols at least 2/3 of inhabitants aged 11-14 years. A randomisation stratified by school district and deprivation index allocated 90 municipalities into 6 groups of 15. The expected overall sample size estimate is 41 940 adolescents aged 11-14 years. The primary endpoint is the HPV VC (≥1 dose) among adolescents aged 11-14 years, at 2 months, at the municipality level (data from routine databases). Secondary endpoints include: HPV VC (≥1 dose at 6 and 12 months; and 2 doses at 2, 6 and 12 months); differences in knowledge, attitudes, behaviours, and intention among adolescents, parents and general practitioners between baseline and 2 months after intervention (self-administered questionnaires); incremental cost-effectiveness ratio. Implementation measures include dose, fidelity, adaptations, reached population and satisfaction (activity reports and self-administered questionnaires). This protocol was approved by the French Ethics Committee 'CPP Sud-Est VI' on 22 December 2020 (ID-RCB: 2020-A02031-38). No individual consent was required for this type of research; all participants were informed of their rights, in particular not to participate or to oppose the collection of data concerning them. Findings will be widely disseminated (conference presentations, reports, factsheets and academic publications). NCT04945655.


Thermal stability, pH dependence and inhibition of four murine kynurenine aminotransferases.
Kynurenine aminotransferase (KAT) catalyzes the transamination of kynunrenine to kynurenic acid (KYNA). KYNA is a neuroactive compound and functions as an antagonist of alpha7-nicotinic acetylcholine receptors and is the only known endogenous antagonist of N-methyl-D-aspartate receptors. Four KAT enzymes, KAT I/glutamine transaminase K/cysteine conjugate beta-lyase 1, KAT II/aminoadipate aminotransferase, KAT III/cysteine conjugate beta-lyase 2, and KAT IV/glutamic-oxaloacetic transaminase 2/mitochondrial aspartate aminotransferase, have been reported in mammalian brains. Because of the substrate overlap of the four KAT enzymes, it is difficult to assay the specific activity of each KAT in animal brains. This study concerns the functional expression and comparative characterization of KAT I, II, III, and IV from mice. At the applied test conditions, equimolar tryptophan with kynurenine significantly inhibited only mouse KAT I and IV, equimolar methionine inhibited only mouse KAT III and equimolar aspartate inhibited only mouse KAT IV. The activity of mouse KAT II was not significantly inhibited by any proteinogenic amino acids at equimolar concentrations. pH optima, temperature preferences of four KATs were also tested in this study. Midpoint temperatures of the protein melting, half life values at 65 degrees C, and pKa values of mouse KAT I, II, III, and IV were 69.8, 65.9, 64.8 and 66.5 degrees C; 69.7, 27.4, 3.9 and 6.5 min; pH 7.6, 5.7, 8.7 and 6.9, respectively. The characteristics reported here could be used to develop specific assay methods for each of the four murine KATs. These specific assays could be used to identify which KAT is affected in mouse models for research and to develop small molecule drugs for prevention and treatment of KAT-involved human diseases.


Review: Assessing fish welfare in research and aquaculture, with a focus on European directives.
The number of farmed fish in the world has increased considerably. Aquaculture is a growing industry that will in the future provide a large portion of fishery products. Moreover, in recent years, the number of teleost fish used as animal models for scientific research in both biomedical and ecological fields has increased. Therefore, it is increasingly important to implement measures designed to enhance the welfare of these animals. Currently, a number of European rules exist as requirements for the establishment, care and accommodation of fish maintained for human purposes. As far as (teleost) fish are concerned, the fact that the number of extant species is much greater than that of all other vertebrates must be considered. Of further importance is that each species has its own specific physical and chemical requirements. These factors make it difficult to provide generalized recommendations or requirements for all fish species. An adequate knowledge is required of the physiology and ecology of each species bred. This paper integrates and discusses, in a single synthesis, the current issues related to fish welfare, considering that teleosts are target species for both aquaculture and experimental models in biological and biomedical research. We first focus on the practical aspects, which must be considered when assessing fish welfare in both research and aquaculture contexts. Next, we address husbandry and the care of fish housed in research laboratories and aquaculture facilities in relation to their physiological and behavioural requirements, as well as in reference to the suggestions provided by European regulations. Finally, to evaluate precisely which parameters described by Directive 2010/63/EU are reported in scientific papers, we analysed 82 articles published by European researchers in 2014 and 2015. This review found that there is a general lack of information related to the optimal environmental conditions that should be provided for the range of species covered by this directive.