Temporal lobe epilepsy with a contralateral parietal seizure-onset zone.
Achieving sustained seizure freedom following epilepsy surgery remains a challenge in some patients. Lesional temporal lobe epilepsy (TLE), for example, in patients with mesial temporal sclerosis or other MRI abnormalities, carries a good prognosis for seizure freedom compared to significantly lower chances of seizure freedom in patients with non-lesional epilepsy. However, even in some lesional TLE cases, persistent post-operative seizures suggest seizure onset from a brain region that is clinically and electrographically silent but manifests only after propagation to the temporal lobe. A notable example of such a brain region is the parietal lobe, which has extensive connectivity to various brain regions. While certain seizure semiologies, for example, sensory seizures, suggest parietal lobe onset, some medial parietal seizures may be semiologically indistinguishable from temporal lobe seizures. Here, we report a patient with focal impaired awareness seizures that manifested semiologically and electrographically as left TLE but proved to originate from the contralateral medial parietal lobe. We discuss putative seizure propagation pathways.


Morphology of depletant-induced erythrocyte aggregates.
Red blood cells suspended in quiescent plasma tend to aggregate into multicellular assemblages, including linearly stacked columnar rouleaux, which can reversibly form more complex clusters or branching networks. While these aggregates play an essential role in establishing hemorheological and pathological properties, the biophysics behind their self-assembly into dynamic mesoscopic structures remains under-explored. We employ coarse-grained molecular simulations to model low-hematocrit erythrocytes subject to short-range implicit depletion forces, and demonstrate not only that depletion interactions are sufficient to account for a sudden dispersion-aggregate transition, but also that the volume fraction of depletant macromolecules controls small aggregate morphology. We observe a sudden transition from a dispersion to a linear column rouleau, followed by a slow emergence of disorderly amorphous clusters of many short rouleaux at larger volume fractions. This work demonstrates how discocyte topology and short-range, non-specific, physical interactions are sufficient to self-assemble erythrocytes into various aggregate structures, with markedly different morphologies and biomedical consequences.


Elevation of iron storage in humans attenuates the pulmonary vascular response to hypoxia.
Sustained hypoxia over several hours induces a progressive rise in pulmonary artery systolic pressure (PASP). Administration of intravenous iron immediately prior to the hypoxia exposure abrogates this effect, suggesting that manipulation of iron stores may modify hypoxia-induced pulmonary hypertension. Iron (ferric carboxymaltose) administered intravenously has a plasma half-life of 7-12 h. Thus any therapeutic use of intravenous iron would require its effect on PASP to persist long after the iron-sugar complex has been cleared from the blood. To examine this, we studied PASP during sustained (6 h) hypoxia on 4 separate days (days 0, 1, 8, and 43) in 22 participants. On day 0, the rise in PASP with hypoxia was well matched between the iron and saline groups. On day 1, each participant received either 1 g of ferric carboxymaltose or saline in a double-blind manner. After administration of intravenous iron, the rise in PASP with hypoxia was attenuated by ∼50%, and this response remained suppressed on both days 8 and 43 (P < 0.001). Following administration of intravenous iron, values for ferritin concentration, transferrin saturation, and hepcidin concentration rose significantly (P < 0.001, P < 0.005, and P < 0.001, respectively), and values for transferrin concentration fell significantly (P < 0.001). These changes remained significant at day 43 We conclude that the attenuation of the pulmonary vascular response to hypoxia by elevation of iron stores persists long after the artificial iron-sugar complex has been eliminated from the blood. The persistence of this effect suggests that intravenous iron may be of benefit in some forms of pulmonary hypertension.


Expression patterns of transmembrane and released forms of neuregulin during spinal cord and neuromuscular synapse development.
We mapped the distribution of neuregulin and its transmembrane precursor in developing, embryonic chick and mouse spinal cord. Neuregulin mRNA and protein were expressed in motor and sensory neurons shortly after their birth and levels steadily increased during development. Expression of the neuregulin precursor was highest in motor and sensory neuron cell bodies and axons, while soluble, released neuregulin accumulated along early motor and sensory axons, radial glia, spinal axonal tracts and neuroepithelial cells through associations with heparan sulfate proteoglycans. Neuregulin accumulation in the synaptic basal lamina of neuromuscular junctions occurred significantly later, coincident with a reorganization of muscle extracellular matrix resulting in a relative concentration of heparan sulfate proteoglycans at endplates. These results demonstrate an early axonal presence of neuregulin and its transmembrane precursor at developing synapses and a role for heparan sulfate proteoglycans in regulating the temporal and spatial sites of soluble neuregulin accumulation during development.


Spontaneous activity does not predict morphological type in cerebellar interneurons.
The effort to determine morphological and anatomically defined neuronal characteristics from extracellularly recorded physiological signatures has been attempted with varying success in different brain areas. Recent studies have attempted such classification of cerebellar interneurons (CINs) based on statistical measures of spontaneous activity. Previously, such efforts in different brain areas have used supervised clustering methods based on standard parameterizations of spontaneous interspike interval (ISI) histograms. We worried that this might bias researchers toward positive identification results and decided to take a different approach. We recorded CINs from anesthetized cats. We used unsupervised clustering methods applied to a nonparametric representation of the ISI histograms to identify groups of CINs with similar spontaneous activity and then asked how these groups map onto different cell types. Our approach was a fuzzy C-means clustering algorithm applied to the Kullbach-Leibler distances between ISI histograms. We found that there is, in fact, a natural clustering of the spontaneous activity of CINs into six groups but that there was no relationship between this clustering and the standard morphologically defined cell types. These results proved robust when generalization was tested to completely new datasets, including datasets recorded under different anesthesia conditions and in different laboratories and different species (rats). Our results suggest the importance of an unsupervised approach in categorizing neurons according to their extracellular activity. Indeed, a reexamination of such categorization efforts throughout the brain may be necessary. One important open question is that of functional differences of our six spontaneously defined clusters during actual behavior.


Validation of capillary zone electrophoresis and capillary isoelectric focusing separations optimized for the characterization of two recombinant products of the birch pollen allergen Bet v 1a.
CZE and CIEF separation systems, both developed previously for a quality control of two recombinant products of the major birch pollen allergen Bet v 1a of Betula verrucosa, were validated including aspects of the International Conference on Harmonization. One product contained carbamylated variants as impurities. Linearity of response was confirmed by Mandel's fitting test between 0.028 and 1.90 mg/mL for CZE and between 0.016 and 0.26 mg/mL for CIEF. Repeatability and intermediate precision were evaluated for the effective mobility (mu(eff)) in CZE, for relative mobilization time in CIEF and the peak area ratio of Bet v 1a. LOQ for Bet v 1a was between 10 and 23 microg/mL for both methods. Evaluation of robustness for CZE revealed susceptibility of micro(eff) of Bet v 1a to alterations in of buffer pH and separation temperature. Selectivity was impaired by an increase in temperature, pH, and buffer concentration. In addition, pH variations influenced the separation profile of impurities. For CIEF, the ratio of narrow pH range carrier ampholytes is the critical parameter to retain robustness. Results demonstrate the suitability of both separation systems to discriminate between nonmodified Bet v 1a and carbamylated variants in the selected recombinant allergen products.


Antivenom Treatment Is Associated with Fewer Patients using Opioids after Copperhead Envenomation.
Copperhead envenomation causes local tissue destruction, leading people to seek treatment for the pain and swelling. First-line treatment for the pain is opioid medications. There is rising concern that an initial opioid prescription from the emergency department (ED) can lead to long-term addiction. This analysis sought to determine whether use of Fab antivenom (FabAV) for copperhead envenomation affected opioid use. We performed a secondary analysis using data from a randomized clinical trial designed to determine the effect of FabAV on limb injury recovery following mild to moderate copperhead envenomation. Opioid use was a defined secondary outcome in the parent trial. Patients were contacted after discharge, and data were obtained regarding medications used for pain and the patients' functional status. This analysis describes the proportion of patients in each treatment group reporting opioid use at each time point. It also assesses the interaction between functional status and use of opioids. We enrolled 74 patients in the parent trial (45 received FabAV, 29 placebo), of whom 72 were included in this secondary analysis. Thirty-five reported use of any opioids after hospital discharge. A smaller proportion of patients treated with FabAV reported opioid use: 40.9% vs 60.7% of those in the placebo group. The proportion of patients using opioids remained smaller in the FabAV group at each follow-up time point. Controlling for confounders and interactions between variables, the model estimated that the odds ratio of using opioids after hospital discharge among those who received placebo was 5.67 times that of those who received FabAV. Patients who reported higher baseline pain, those with moderate as opposed to mild envenomation, and females were more likely to report opioid use at follow-up. Patients with ongoing limitations to functional status had an increased probability of opioid use, with a stronger association over time. Opioid use corresponded with the trial's predefined criteria for full recovery, with only two patients reporting opioid use in the 24 hours prior to achieving full limb recovery and no patients in either group reporting opioid use after full limb recovery. In this study population, the proportion of patients using opioids for pain related to envenomation was smaller in the FabAV treatment group at all follow-up time points.


Animal ethics and welfare education in wet-lab training can foster residents' ethical values toward life.
Live animals are used in surgical skills training in wet lab, which has undeniable effectiveness for the development of future surgeons. However, where such training is provided, animal welfare is a major consideration. Increasingly, institutions that offer wet-lab training are incorporating animal ethics and welfare-related content into their training courses, but the effectiveness of such animal ethics education has yet to be evaluated quantitatively. We investigated whether the animal ethics content of a training course affected trainees by measuring increase in ethical awareness using visual analog scale questionnaires before and after training. Our results demonstrated a significant and positive increase in awareness of animal ethics (significance level of 5%; 0.0380≤P≤0.0016).


Sex bias in studies selected for clinical guidelines.
To determine the proportions of female participants in research studies selected to inform the development of national clinical guidelines and to assess these against the proportions of women affected by the conditions. We assessed 392 published articles, involving a total of 5.2 million participants, cited as references in five influential clinical guidelines addressing the use of antiarrhythmics, chronic fatigue, depression, diabetes, and colorectal cancer. For each article, we extracted the number of female participants to determine any discrepancies in the sex of participants and if the proportion of female participants as research subjects reflected the sex distribution of patients affected by the condition. The overall and median percentages (per study) of females per guideline were: use of antiarrhythmics (35%, median 38%), chronic fatigue (70%, median 73%), colorectal cancer (67%, median 46%), depression (66%, median 66%), and diabetes (63%, median 50%). The baseline prevalence rates used for comparison purposes were (percentage female): antiarrhythmics (60% of patients 75(+) years); chronic fatigue (66%), colorectal cancer (46%), depression (66%), and diabetes (46%). The colorectal cancer, depression, and chronic fatigue guidelines were based on research populations that accurately reflected the sex distribution of the condition in the general population. Women were slightly overrepresented in the research studies supporting the diabetes guidelines and were significantly underrepresented in the research studies supporting the guidelines on the use of antiarrhythmics. Guideline developers should be aware of and comment on the potential impact of sex. Where the evidence base is lacking, guideline developers should highlight this and, where necessary, limit their specific conclusions to populations on whom the research was performed.


Interactions of hydroxyapatite surfaces: conditioning films of human whole saliva.
Hydroxyapatite is a very interesting material given that it is the main component in tooth enamel and because of its uses in bone implant applications. Therefore, not only the characterization of its surface is of high relevance but also designing reliable methods to study the interfacial properties of films adsorbed onto it. In this paper we apply the colloidal probe atomic force microscopy method to investigate the surface properties of commercially available hydroxyapatite surfaces (both microscopic particles and macroscopic discs) in terms of interfacial and frictional forces. In this way, we find that hydroxyapatite surfaces at physiological relevant conditions are slightly negatively charged. The surfaces were then exposed to human whole saliva, and the surface properties were re-evaluated. A thick film was formed that was very resistant to mechanical stress. The frictional measurements demonstrated that the film was indeed highly lubricating, supporting the argument that this system may prove to be a relevant model for evaluating dental and implant systems.


Effect of Health-Promoting Agents on Exclusion-Zone Size.
It is now well-confirmed that hydrophilic surfaces including those within the cell generate structural changes in water. This interfacial water is ordered and acquires features different from the bulk. Amongst those features is the exclusion of colloidal and molecular solutes from extensive regions next to the hydrophilic surface, thereby earning it the label of "exclusion zone" (EZ) water. The transition of ordered EZ water to bulk serves as an important trigger of many cellular physiological functions, and in turn cellular health. We tested physiological doses of half a dozen agents generally identified to restore or build health on the extent to which they build EZs. All agents known to enhance biological function resulted in EZ expansion. On the other hand, the weed killer, glyphosate, considerably diminished EZ size. While the expansion effect of the health-promoting agents was observed over a wide range of concentrations, excessive doses ultimately reduced EZ size. We hypothesize that EZ buildup may be a mechanistic feature underlying many health-promoting agents, while agents that impair health may act by diminishing the amount of EZ water.


Systemic inflammation is negatively associated with early post discharge growth following acute illness among severely malnourished children - a pilot study.
Background: Rapid growth should occur among children with severe malnutrition (SM) when medically and nutritionally treated. Systemic inflammation (SI) is associated with death among children with SM and is negatively associated with linear growth. However, the relationship between SI and weight gain during therapeutic feeding following acute illness is unknown. We hypothesised that growth in the first 60 days post-hospital discharge is associated with SI among children with SM. Methods: We conducted secondary analysis of data from HIV-uninfected children with SM (n=98) who survived and were not readmitted to hospital during one year of follow up. We examined the relationship between changes in absolute deficits in weight and mid-upper-arm circumference (MUAC) from enrolment at stabilisation to 60 days later and untargeted plasma proteome, targeted cytokines/chemokines, leptin, and soluble CD14 (sCD14) using multivariate regularized linear regression. Results: The mean change in absolute deficit in weight and MUAC was -0.50kg (standard deviation; SD±0.69) and -1.20cm (SD±0.89), respectively, from enrolment to 60 days later. During the same period, mean weight and MUAC gain was 3.3g/kg/day (SD±2.4) and 0.22mm/day (SD±0.2), respectively. Enrolment inflammatory cytokines interleukin 17 alpha (IL17α), interleukin 2 (IL2), and serum amyloid P (SAP) were negatively associated with weight and MUAC gain. Lipopolysaccharide binding protein (LBP) and complement component 2 were negatively associated with weight gain only. Leptin was positively associated with weight gain. sCD14, beta-2 microglobulin (β2M), and macrophage inflammatory protein 1 beta (MIP1β) were negatively associated with MUAC gain only. Conclusions: Early post-hospital discharge weight and MUAC gain were rapid and comparable to children with uncomplicated SM treated with similar diet in the community. Higher concentrations of SI markers were associated with less weight and MUAC gain, suggesting inflammation negatively impacts recovery from wasting. This finding warrants further research on the role of inflammation on growth among children with SM.


Imatinib mesylate enhances therapeutic effects of gemcitabine in human malignant mesothelioma xenografts.
Platelet-derived growth factor receptor beta (PDGFRbeta), frequently activated in malignant mesothelioma, is a promising cancer therapeutic target. Imatinib mesylate (STI571; Glivec) is a selective inhibitor of tyrosine kinases as bcr-abl, c-kit, c-fms, and PDGFRbeta and enhances tumor drug uptake by reducing the interstitial fluid pressure. We previously showed that imatinib mesylate synergizes with gemcitabine and pemetrexed in PDGFRbeta-positive mesothelioma cells. Here, we aimed at investigating these combined treatments in a novel mesothelioma model. REN mesothelioma cells, infected with a lentiviral vector carrying the luciferase gene, were injected in the peritoneum of severe combined immunodeficient mice. This model allowed imaging of live animals treated with pemetrexed or gemcitabine chemotherapeutics, or with imatinib mesylate alone, as well as with a combination of gemcitabine and imatinib mesylate. We show here that, consistent with our previous in vitro studies, gemcitabine inhibited tumor growth, whereas pemetrexed was ineffective, even at the highest dosage tested. Compared with monotreatment, the combination of gemcitabine with imatinib mesylate led to a further tumor growth inhibition and improved mice survival, by a decrease rate of tumor cell proliferation and an increase in number of apoptotic tumor cells. Imatinib mesylate enhances the therapeutic response to gemcitabine, in accordance with our previous in vitro data. These in vivo results validate imatinib mesylate and gemcitabine as a combination treatment of malignant mesothelioma, also in view of its known positive effects on tumor drug uptake. These evidences provide the rationale for the currently ongoing clinical trials.


Automated detection of cerebral microbleeds on MR images using knowledge distillation framework.
Cerebral microbleeds (CMBs) are associated with white matter damage, and various neurodegenerative and cerebrovascular diseases. CMBs occur as small, circular hypointense lesions on T2*-weighted gradient recalled echo (GRE) and susceptibility-weighted imaging (SWI) images, and hyperintense on quantitative susceptibility mapping (QSM) images due to their paramagnetic nature. Accurate automated detection of CMBs would help to determine quantitative imaging biomarkers (e.g., CMB count) on large datasets. In this work, we propose a fully automated, deep learning-based, 3-step algorithm, using structural and anatomical properties of CMBs from any single input image modality (e.g., GRE/SWI/QSM) for their accurate detections. In our method, the first step consists of an initial candidate detection step that detects CMBs with high sensitivity. In the second step, candidate discrimination step is performed using a knowledge distillation framework, with a multi-tasking teacher network that guides the student network to classify CMB and non-CMB instances in an offline manner. Finally, a morphological clean-up step further reduces false positives using anatomical constraints. We used four datasets consisting of different modalities specified above, acquired using various protocols and with a variety of pathological and demographic characteristics. On cross-validation within datasets, our method achieved a cluster-wise true positive rate (TPR) of over 90% with an average of <2 false positives per subject. The knowledge distillation framework improves the cluster-wise TPR of the student model by 15%. Our method is flexible in terms of the input modality and provides comparable cluster-wise TPR and better cluster-wise precision compared to existing state-of-the-art methods. When evaluating across different datasets, our method showed good generalizability with a cluster-wise TPR >80 % with different modalities. The python implementation of the proposed method is openly available.


Anatomical risk factors for phonological dyslexia.
Successful behavioral genetic studies require precise definition of a homogenous phenotype. This study searched for anatomical markers that might restrict variability in the reading disability phenotype. The subjects were 15 college students (8 male/7 female) diagnosed with a reading disability (RD) and 15 controls (8 males/7 females). All subjects completed a cognitive and reading battery. Only 11 of the RD subjects had a phonological deficit [phonological dyslexia (PD): pseudo word decoding scores < 90 (27th percentile)]. Thirteen RD (9 PD) and 15 controls received a volumetric MRI scan. Four anatomical measures differentiated the PD group from the remainder of the subjects: (i) marked rightward cerebral asymmetry, (ii) marked leftward asymmetry of the anterior lobe of the cerebellum, (ii) combined leftward asymmetry of the planum and posterior ascending ramus of the sylvian fissure, and (iv) a large duplication of Heschl's gyrus on the left. When these four measures were normalized and summed, the resulting variable predicted short- and long-term phonological memory. By contrast, oral and written comprehension skills were predicted by a different anatomical variable: low cerebral volume. These findings provide neurobiological support for an RD phenotype characterized by phonological deficits in the presence of normal or superior comprehension. The study of individual variation in cortical structure may provide a useful link between genotype and behavior.


Impacts of COVID-19 on at-sea data collection and regulatory activities and fisheries catches off Namibia.
This study was undertaken to: (i) comprehend the observers' perceptions of COVID-19 and identify its impacts on the observation of harvesting, handling, and processing of marine resources, and biological data collection during commercial fishing, (ii) assess the risk of contracting COVID-19 onboard the fishing vessels, (iii) compare fishery catches for the pre-COVID-19 (2018 and 2019) and COVID-19 (2020 and 2021) years, and (iv) suggest possible ways to mitigate the impacts of COVID-19 on the activities of at sea-observations and data collection. Thus, 45 Namibian fisheries observers were interviewed by telephone to capture their perceptions of COVID-19 on the sea-observations and biological data collection. Messrooms were the riskiest places (45.7%) onboard the fishing vessel where observers perceived likely to contract COVID-19. For at-sea observations, 57.1% of the respondents felt that COVID-19 has negatively impacted observations as fisheries observers were risk-averse, especially in the processing factories. Half of the participants purported a negative impact on the collection of biological data, as on some vessels fisheries observers were not permitted to sample the fish supposedly for fear of cross-contamination. Analysis of fisheries observation data and fisheries catch data showed a significant difference in the total number of fishing trips made between 2018 and 2021 (X 2 = 145 . 34 , df = 3, p < 0.05), with a notable reduction in 2020 fishing trips. Similarly, the number of observed fishing trips between 2018 and 2021 differed significantly (X 2 = 136 . 80 , df = 3, p < 0.05). Fishing catches were lowest in 2020, possibly reflecting severe impacts of COVID-19 in that year. Understanding the impact of COVID-19 on at-sea observation and data collection can inform decision makers to improve management of marine resources during COVID-19 pandemic. Findings from this study can also serve as a lesson for nations that use observer data for stock assessment.


Ligand-induced Epitope Masking: DISSOCIATION OF INTEGRIN α5β1-FIBRONECTIN COMPLEXES ONLY BY MONOCLONAL ANTIBODIES WITH AN ALLOSTERIC MODE OF ACTION.
We previously demonstrated that Arg-Gly-Asp (RGD)-containing ligand-mimetic inhibitors of integrins are unable to dissociate pre-formed integrin-fibronectin complexes (IFCs). These observations suggested that amino acid residues involved in integrin-fibronectin binding become obscured in the ligand-occupied state. Because the epitopes of some function-blocking anti-integrin monoclonal antibodies (mAbs) lie near the ligand-binding pocket, it follows that the epitopes of these mAbs may become shielded in the ligand-occupied state. Here, we tested whether function-blocking mAbs directed against α5β1 can interact with the integrin after it forms a complex with an RGD-containing fragment of fibronectin. We showed that the anti-α5 subunit mAbs JBS5, SNAKA52, 16, and P1D6 failed to disrupt IFCs and hence appeared unable to bind to the ligand-occupied state. In contrast, the allosteric anti-β1 subunit mAbs 13, 4B4, and AIIB2 could dissociate IFCs and therefore were able to interact with the ligand-bound state. However, another class of function-blocking anti-β1 mAbs, exemplified by Lia1/2, could not disrupt IFCs. This second class of mAbs was also distinguished from 13, 4B4, and AIIB2 by their ability to induce homotypic cell aggregation. Although the epitope of Lia1/2 was closely overlapping with those of 13, 4B4, and AIIB2, it appeared to lie closer to the ligand-binding pocket. A new model of the α5β1-fibronectin complex supports our hypothesis that the epitopes of mAbs that fail to bind to the ligand-occupied state lie within, or very close to, the integrin-fibronectin interface. Importantly, our findings imply that the efficacy of some therapeutic anti-integrin mAbs could be limited by epitope masking.


Intergenerational learning about keeping health: a qualitative regional Australian study.
Understanding the conditions under which families try to influence members' health-related practices can provide information to build concepts adding to models of health promotion. This paper reports on an exploratory qualitative study examining the influences of intergenerational relationships in shaping beliefs, knowledge and practices about health and illness in a regional Australian city. We conducted semi-structured interviews with 27 adults with family members of other generations living in the city, all of whom had experience of asthma. We found that overall people's experience of health and illness, particularly in childhood, was taken for granted and not reflected upon. It was in the face of serious illness or death of a family member that objective knowledge about health and illness was sought and integrated within the family leading, in most cases, to significant lifestyle changes or 'doing things differently'. We drew on Bourdieu's concept of the three forms of theoretical knowledge in analysing our findings. We found the concept of knowledge as 'primary taken-for-granted experience', and the concept of praxeological knowledge as the knowledge created by the dialectical relationships between an individual subject and objectives structures were helpful. To influence individual health practices, we need to acknowledge how the family context confirms the taken-for-granted health practices of an individual and the family circumstances that might lead families to seek objective knowledge and make lifestyle changes to promote health.


Long-Term Modeling and Monitoring of Neuromusculoskeletal System Performance Using Tattoo-Like EMG Sensors.
This paper introduces stretchable, long-term wearable, tattoo-like dry surface electrodes for highly repeatable electromyography (EMG). The tattoo-like sensors are hair thin, skin compliant and can be laminated on human skin just like a temporary transfer tattoo, which enables multi-day noninvasive but intimate contact with the skin even under severe skin deformation. The new electrodes were used to facilitate a system-based approach to tracking of long-term fatiguing and recovery processes in a human neuromusculoskeletal (NMS) system, which was based on establishing an autoregressive moving average model with exogenous inputs (ARMAX model) relating signatures extracted from the surface electromyogram (sEMG) signals collected using the tattoo-like sensors, and the corresponding hand grip force (HGF) serving as the model output. Performance degradation of the relevant NMS system was evaluated by tracking the evolution of the errors of the ARMAX model established using the data corresponding to the rested (fresh) state of any given subject. Results from several exercise sessions clearly showed repeated patterns of fatiguing and resting, with a notable point that these patterns could now be quantified via dynamic models relating the relevant muscle signatures and NMS outputs.


Active approach to recognising asthma in general practice.
The general practice medical records of 214 children born in 1977 were scrutinised for a diagnosis of asthma. In 18 (8%) of these a diagnosis of asthma had been entered. Using a scoring system based on the medical record a further group of children who were thought likely to have undiagnosed asthma was exercise tested. Twelve children (6%) had demonstrable exercise induced asthma. In addition, seven children (3%) had both frequent respiratory symptoms and borderline exercise test results, indicating that they too had clinically important airways obstruction. As expected, histories of atopic eczema, nocturnal cough, persistent cough (more than one week), and wheezing appeared often in the medical records of the children with asthma. In combinations these diagnostic clues were more than 50% predictive of asthma. A more active approach in general practice to the diagnosis of asthma in children is both necessary and possible.


DNA topoisomerase I: customs officer at the border between DNA and RNA worlds?
DNA topoisomerase I is required for the normal development of multicellular organisms, probably because it plays a role in controlling gene activity, in addition to its function in relieving tortional stress during DNA replication and transcription. The discovery of DNA topoisomerase I as a specific kinase that phosphorylates serine-arginine rich (SR) splicing factors may provide new insights into their precise function in regulating gene expression. It is clear that the splicing factors phosphorylated by DNA topoisomerase I can modulate gene expression by changing the splicing pattern of structural genes. Studies of the splicing mechanism suggest that the phosphorylation of serine residues of SR proteins contribute to their activity. As this phosphorylation can be accomplished by several kinases, it remains to be determined whether phosphorylation by DNA topoisomerase I protein kinase is the limiting step in regulating this process. The availability of specific inhibitors of DNA topoisomerase I, structurally related to the alkaloid camptothecin, have made it possible to address this question experimentally. These inhibitors, which hold great promise as antineoplastic drugs, lead to specific inhibition of SR protein phosphorylation in cultured cells. This observation will hopefully lead to improved understanding of the mechanism by which these drugs act at cellular level.


Biosynthesis, Synthesis, and Activities of Barnesin A, a NRPS-PKS Hybrid Produced by an Anaerobic Epsilonproteobacterium.
Despite the wealth of physiological knowledge and plentiful genomes available, only few natural products of anaerobic bacteria have been identified until today and even less have been linked to their biosynthetic gene cluster. Here, we analyzed a unique NRPS-PKS hybrid gene cluster from an anaerobic Epsilonproteobacterium ( Sulfurospirillum barnesii). Phylogenetic analysis of key biosynthetic genes, gene expression studies, and comparative metabolomics resulted in the identification of the first anoxically biosynthesized NRPS-PKS hybrid metabolite: a lipo-dipeptide with a vinylogous side chain, called barnesin A. The absolute structure was verified by a modular total synthesis, and barnesin and derivatives were found to have antimicrobial activity, as well as selective and nanomolar inhibitory activity, against pharmacological important cysteine proteases, such as cathepsin B.


Determinants of Malaria Protective Immunity in Mice Immunized with Live Sporozoites during Trimethoprim-Sulfamethoxazole Prophylaxis.
HIV and malaria geographically overlap. Trimethoprim-sulfamethoxazole (TMP-SMX) is a drug widely used in HIV-exposed uninfected and infected children in malaria-endemic areas, and is known to have antimalarial effects. Further study in terms of antimalarial impact and effect on development of malaria-specific immunity is therefore essential. Using rodent malaria models, we previously showed that repeated Plasmodium exposure during TMP-SMX administration, or chemoprophylaxis vaccination (CVac), induces CD8 T-cell-dependent preerythrocytic immunity. However, humoral immune responses have been shown to be important in models of preerythrocytic immunity. Herein, we demonstrate that antibody-mediated responses contribute to protective immunity induced by CVac immune sera using TMP-SMX in models of homologous, but not heterologous, parasite species. Clinical studies must account for potential anti-Plasmodium antibody induced during TMP-SMX prophylaxis.


[Intervention of Tibetan medicine--twenty wei chenxiang pill on elevation of hypoxic pulmonary arterial pressure in rats].
To investigate the role of Tibetan medicine-Twenty Wei Chenxiang Pill interfering with serum ET-1 level, in order to confirm that ET-1 is involved to the pathogenesis of hypoxic pulmonary hypertension. 165 Wistar rats were randomly divided into high altitude control group,Tibetan medicine-Twenty Wei Chenxiang Pill group and plain control group. The physiological signal acquisition system was used to record pulmonary arterial pressure, and RV/(LV + S) ratio were caculated. Serum HIF-1alpha and ET-1 protein levels were determined by the method of ELISA, and ETA protein levels in lung tissue were determined by Western Blot method. Compared with the high altitude group,in the rats of Tibetan medicine-Twenty Wei Chenxiang Pill group,the pulmonary arterial pressure decreased significantly from the seventh day and the seventh day (P < 0.01), the RV/(LV + S) ratio and serum HIF-1alpha levels decreased significantly from the third day (P < 0.05 or P < 0.01), the serum ET-1 levels decreased significantly from the third day (P < 0.05 or P < 0.01), and the expression of ETA protein decreased significantly from the beginning (P < 0.01 or P < 0.001). ET-1 is one of the important factors causing pulmonary artery pressure increasing and right ventricular wall thickening, which plays a role in hypoxic pulmonary artery only involved in the early period hypoxia, but not in the later period. Tibetan medicine--twenty Wei Chenxiang Pill can prevent the pulmonary artery hypertension and the right ventricular wall thickening in rats, and its mechanism may be related to the direct inhibition of ET-1 and protein levels of ETA or the indirect downregulation of ET-1 level and ETA through inhibition of HIF-la level.


Pathways towards chronic care-focused healthcare systems: evidence from Spain.
Increasing healthcare expenditure is a matter of concern in many countries, particularly in relation to the underlying drivers of such escalation that include ageing, medical innovation, and changes in the burden of disease, such as the growing prevalence of chronic diseases. Most healthcare systems in developed countries have been designed to 'cure' acute episodes, rather than to 'manage' chronic conditions, and therefore they are not suitably or efficiently organized to respond to the changing needs and preferences of users. New models of chronic care provision have been developed to respond to the changing burden of disease and there is already considerable practical experience in several different countries showing their advantages but also the difficulties associated with their implementation. In this paper, we focus on the Spanish experience in terms of policy changes and pilot studies focused on testing the feasibility of moving towards chronic care models. In particular, we discuss a framework that identifies and analyses ten key prerequisites to achieving high performing chronic care-based healthcare systems and apply it to the current Spanish National Health System (NHS). We find that the design of the Spanish NHS already meets some of these pre-requisites. However, other features are still in their early stages of development or are being applied only in limited geographical and clinical contexts. We outline the policies that are being implemented and the pathway that the Spanish NHS is taking to address the crucial challenge of the transition towards an optimal health system focused on chronic care. Given the current evidence and trends, we expect that the pathway for developing a chronicity strategy being followed by the Spanish NHS will significantly transform its current healthcare delivery model in the next few years.


Multisite-specific tRNA:m5C-methyltransferase (Trm4) in yeast Saccharomyces cerevisiae: identification of the gene and substrate specificity of the enzyme.
Several genes encoding putative RNA:5-methylcytidine-transferases (m5C-transferases) from different organisms, including yeast, have been identified by sequence homology with the recently identified 16S rRNA:m5C967-methyltransferase (gene SUN) from Escherichia coli. One of the yeast ORFs (YBL024w) was amplified by PCR, inserted in the expression vector pET28b, and the corresponding protein was hyperexpressed in E. coli BL21 (DE3). The resulting N-terminally His6-tagged recombinant Ybl024p was purified to apparent homogeneity by one-step affinity chromatography on Ni2+-NTA-agarose column. The activity and substrate specificity of the purified Ybl024p were tested in vitro using T7 transcripts of different yeast tRNAs as substrates and S-adenosyl-L-methionine as a donor of the methyl groups. The results indicate that yeast ORF YBL024w encodes S-adenosyl-L-methionine-dependent tRNA: m5C-methyltransferase that is capable of methylating cytosine to m5C at several positions in different yeast tRNAs and pre-tRNAs containing intron. Modification of tRNA occurs at all four positions (34, 40, 48, and 49) at which m5C has been found in yeast tRNAs sequenced so far. Disruption of the ORF YBL024w leads to the complete absence of m5C in total yeast tRNA. Moreover no tRNA:m5C-methyltransferase activity towards all potential m5C methylation sites was detected in the extract of the disrupted yeast strain. These results demonstrate that the protein product of a single gene is responsible for complete m5C methylation of yeast tRNA. Because this newly characterized multisite-specific modification enzyme Ybl024p is the fourth tRNA-specific methyltransferase identified in yeast, we suggest designating it as TRM4, the gene corresponding to ORF YBL024w.


Work Activities and Compensation of Male and Female Cardiologists.
Much remains unknown about experiences, including working activities and pay, of women in cardiology, which is a predominantly male specialty. The goal of this study was to describe the working activities and pay of female cardiologists compared with their male colleagues and to determine whether sex differences in compensation exist after accounting for differences in work activities and other characteristics. The personal, job, and practice characteristics of a national sample of practicing cardiologists were described according to sex. We applied the Peters-Belson technique and multivariate regression analysis to evaluate whether gender differences in compensation existed after accounting for differences in other measured characteristics. The study used 2013 data reported by practice administrators to MedAxiom, a subscription-based service provider to cardiology practices. Data regarding cardiologists from 161 U.S. practices were included, and the study sample included 2,679 subjects (229 women and 2,450 men). Women were more likely to be specialized in general/noninvasive cardiology (53.1% vs. 28.2%), and a lower proportion (11.4% vs. 39.3%) reported an interventional subspecialty compared with men. Job characteristics that differed according to sex included the proportion working full-time (79.9% vs. 90.9%; p < 0.001), the mean number of half-days worked (387 vs. 406 days; p = 0.001), and mean work relative value units generated (7,404 vs. 9,497; p < 0.001) for women and men, respectively. Peters-Belson analysis revealed that based on measured job and productivity characteristics, the women in this sample would have been expected to have a mean salary that was $31,749 (95% confidence interval: $16,303 to $48,028) higher than that actually observed. Multivariate analysis confirmed the direction and magnitude of the independent association between sex and salary. Men and women practicing cardiology in this national sample had different job activities and salaries. Substantial sex-based salary differences existed even after adjusting for measures of personal, job, and practice characteristics.


Global modeling of complex data series using the term-ranking approach and its application to voice synthesis.
A term-ranking approach is proposed to globally model the underlying dynamics of a chaotic series. The basic idea of this approach is to rank candidate bases before they are used to construct the global model. The ranked bases are involved in the global model one by one in a sequence from high to low until the best model is found. Simulations show that the model obtained by the term-ranking approach has a much longer prediction time, but fewer coefficients, than the widely used standard model. The proposed approach is also successfully applied to coding and synthesis of chaoslike voice data, showing promise for its use with truly noisy experimental data.


Differential expression of homing-associated adhesion molecules by T cell subsets in man.
The ability of lymphocyte populations to recognize and bind high endothelial venules during homing into lymphoid tissues and sites of chronic inflammation is critically dependent on their expression of certain homing-associated adhesion molecules known as homing receptors (HR). In animal models, certain lymphocyte populations, particularly subsets of memory or previously activated lymphocytes, demonstrate tissue-selective homing behavior, and it has been hypothesized that differential expression of HR accounts for this selective migration. In this study, we analyzed expression of human HR--the Dreg 56/Leu 8-defined peripheral lymph node (PLN) HR (also known as LECAM-1), H-CAM (CD44), and alpha 4-integrins (CD49d; VLA-4)--among subsets of thymocytes and peripheral blood T cells to identify populations with differential homing potential. In the thymus, these three HR classes are differentially regulated relative to phenotypically defined maturational stages, but are all expressed on the mature, surface CD3high subset. In the peripheral blood, virgin T cells (LFA-3/CD58low) show uniform high expression of the PLN HR, uniform relatively low expression of H-CAM and alpha 4-integrin, and lack markers of tissue association--the mucosal and cutaneous lymphocyte associated Ag (MLA and CLA Ags) defined by mAb Ber ACT8 and HECA-452, respectively. In contrast, circulating memory T cells (LFA-3/CD58high) are bimodal with respect to PLN HR expression, show uniform high expression of H-CAM and alpha 4-integrin, and contain essentially all the CLA and MLA Ag-bearing T cells. The circulating skin-associated T cell subset (CLA Ag+; 10 to 15% of total T cells) is predominantly PLN HR+, and shows high levels of both the alpha 4- and beta 1-integrin chains. The distinct mucosa-associated T cell subset (MLA Ag+; 1 to 3% of peripheral blood T cells) is predominantly PLN HR-; and is alpha 4high, but beta 1low. These findings indicate the independent regulation of homing-associated adhesion molecules among populations of memory/previously activated T cells, and suggest that the expression patterns of these molecules contribute to, or perhaps determine, the tissue distribution of these subsets.


Do walking strategies to increase physical activity reduce reported sitting in workplaces: a randomized control trial.
Interventions designed to increase workplace physical activity may not automatically reduce high volumes of sitting, a behaviour independently linked to chronic diseases such as obesity and type II diabetes. This study compared the impact two different walking strategies had on step counts and reported sitting times. Participants were white-collar university employees (n = 179; age 41.3 +/- 10.1 years; 141 women), who volunteered and undertook a standardised ten-week intervention at three sites. Pre-intervention step counts (Yamax SW-200) and self-reported sitting times were measured over five consecutive workdays. Using pre-intervention step counts, employees at each site were randomly allocated to a control group (n = 60; maintain normal behaviour), a route-based walking group (n = 60; at least 10 minutes sustained walking each workday) or an incidental walking group (n = 59; walking in workday tasks). Workday step counts and reported sitting times were re-assessed at the beginning, mid- and endpoint of intervention and group mean+/- SD steps/day and reported sitting times for pre-intervention and intervention measurement points compared using a mixed factorial ANOVA; paired sample-t-tests were used for follow-up, simple effect analyses. A significant interactive effect (F = 3.5; p < 0.003) was found between group and step counts. Daily steps for controls decreased over the intervention period (-391 steps/day) and increased for route (968 steps/day; t = 3.9, p < 0.000) and incidental (699 steps/day; t = 2.5, p < 0.014) groups. There were no significant changes for reported sitting times, but average values did decrease relative to the control (routes group = 7 minutes/day; incidental group = 15 minutes/day). Reductions were most evident for the incidental group in the first week of intervention, where reported sitting decreased by an average of 21 minutes/day (t = 1.9; p < 0.057). Compared to controls, both route and incidental walking increased physical activity in white-collar employees. Our data suggests that workplace walking, particularly through incidental movement, also has the potential to decrease employee sitting times, but there is a need for on-going research using concurrent and objective measures of sitting, standing and walking.


The human carotid body: expression of oxygen sensing and signaling genes of relevance for anesthesia.
Hypoxia is a common cause of adverse events in the postoperative period, where respiratory depression due to residual effects of drugs used in anesthesia is an important underlying factor. General anesthetics and neuromuscular blocking agents reduce the human ventilatory response to hypoxia. Although the carotid body (CB) is the major oxygen sensor in humans, critical oxygen sensing and signaling pathways have been investigated only in animals so far. Thus, the aim of this study was to characterize the expression of key genes and localization of their products involved in the human oxygen sensing and signaling pathways with a focus on receptor systems and ion channels of relevance in anesthesia. Six CBs were removed unilaterally from patients undergoing radical neck dissection. The gene expression and cell-specific protein localization in the CBs were investigated with DNA microarrays, real-time polymerase chain reaction, and immunohistochemistry. We found gene expression of the oxygen-sensing pathway, heme oxygenase 2, and the K channels TASK (TWIK-related acid sensitive K channel)-1 and BK (large-conductance potassium channel). In addition, we show the expression of critical receptor subunits such as γ-aminobutyric acid A (α2, β3, and γ2), nicotinic acetylcholine receptors (α3, α7, and β2), purinoceptors (A2A and P2X2), and the dopamine D2 receptor. In unique samples of the human CB, we here demonstrate presence of critical proteins in the oxygen-sensing and signaling cascade. Our findings demonstrate similarities to, but also important differences from, established animal models. In addition, our work establishes an essential platform for studying the interaction between anesthetic drugs and human CB chemoreception.


Risk factors and prevention among patients with hospital-acquired and pre-existing pressure ulcers in an acute care hospital.
This study aimed to describe and identify risk factors associated with hospital-acquired pressure ulcers among adults in an acute care hospital compared with patients with pre-existing pressure ulcers present on admission. A further aim was to identify the preventive measures performed with both groups respectively. Pressure ulcers occur most often in older and immobile persons with severe acute illness and neurological deficits. However, few studies have addressed risk factors that are associated with hospital-acquired pressure ulcers compared with patients with pre-existing pressure ulcers. A point prevalence study with a cross-sectional survey design was conducted at a Swedish university hospital. Data on 535 patients were recorded using a modified version of the protocol developed and tested by the European Pressure Ulcer Advisory Panel, including the Braden scale for risk assessment. The prevalence of pressure ulcers was 27% (95% confidence interval, 23-31%). Higher age and a total Braden score below 17 were significantly associated with the presence of pressure ulcers. Among individual risk factors higher age, limited activity level and friction and shear while seated or lying down were associated with hospital-acquired pressure ulcers, whereas only higher age and friction and shear were associated with the presence of pressure ulcers in the overall sample. There was an overall sparse use of preventive measures to relieve pressure. The findings of the present study revealed that pressure ulcers and the insufficient use of preventive measure to relieve pressure is still a problem in acute care settings. A continued focus must be placed on staff training in identifying patients at risk for pressure ulcers development. Increasing the ability to identify patients who are at risk for pressure ulcer development can assist in preventing unnecessary complications and suffering as well as reduce costs.


The role of striatal tonically active neurons in reward prediction error signaling during instrumental task performance.
The detection of differences between predictions and actual outcomes is important for associative learning and for selecting actions according to their potential future reward. There are reports that tonically active neurons (TANs) in the primate striatum may carry information about errors in the prediction of rewards. However, this property seems to be expressed in classical conditioning tasks but not during performance of an instrumental task. To address this issue, we recorded the activity of TANs in the putamen of two monkeys performing an instrumental task in which probabilistic rewarding outcomes were contingent on an action in block-design experiments. Behavioral evidence suggests that animals adjusted their performance according to the level of probability for reward on each trial block. We found that the TAN response to reward was stronger as the reward probability decreased; this effect was especially prominent on the late component of the pause-rebound pattern of typical response seen in these neurons. The responsiveness to reward omission was also increased with increasing reward probability, whereas there were no detectable effects on responses to the stimulus that triggered the movement. Overall, the modulation of TAN responses by reward probability appeared relatively weak compared with that observed previously in a probabilistic classical conditioning task using the same block design. These data indicate that instrumental conditioning was less effective at demonstrating prediction error signaling in TANs. We conclude that the sensitivity of the TAN system to reward probability depends on the specific learning situation in which animals experienced the stimulus-reward associations.


The potential of human allogeneic juvenile chondrocytes for restoration of articular cartilage.
Donor-site morbidity, limited numbers of cells, loss of phenotype during ex vivo expansion, and age-related decline in chondrogenic activity present critical obstacles to the use of autologous chondrocyte implantation for cartilage repair. Chondrocytes from juvenile cadaveric donors may represent an alternative to autologous cells. Hypothesis/ The authors hypothesized that juvenile chondrocyte would show stronger and more stable chondrogenic activity than adult cells in vitro and that juvenile cells pose little risk of immunologic incompatibility in adult hosts. Controlled laboratory study. Cartilage samples were from juvenile (<13 years old) and adult (>13 years old) donors. The chondrogenic activity of freshly isolated human articular chondrocytes and of expanded cells after monolayer culture was measured by proteoglycan assay, gene expression analysis, and histology. Lymphocyte proliferation assays were used to assess immunogenic activity. Proteoglycan content in neocartilage produced by juvenile chondrocytes was 100-fold higher than in neocartilage produced by adult cells. Collagen type II and type IX mRNA in fresh juvenile chondrocytes were 100- and 700-fold higher, respectively, than in adult chondrocytes. The distributions of collagens II and IX were similar in native juvenile cartilage and in neocartilage made by juvenile cells. Juvenile cells grew significantly faster in monolayer cultures than adult cells (P = .002) and proteoglycan levels produced in agarose culture was significantly higher in juvenile cells than in adult cells after multiple passages (P < .001). Juvenile chondrocytes did not stimulate lymphocyte proliferation. These results document a dramatic age-related decline in human chondrocyte chondrogenic potential and show that allogeneic juvenile chondrocytes do not stimulate an immunologic response in vivo. Juvenile human chondrocytes have greater potential to restore articular cartilage than adult cells, and may be transplanted without the fear of rejection, suggesting a new allogeneic approach to restoring articular cartilage in older individuals.


[The Autism-Spectrum Quotient (AQ) Japanese version: evidence from high-functioning clinical group and normal adults].
Baron-Cohen, Wheelwright, Skinner, Martin, and Clubley (2001) constructed brief, self-administered instruments named the Autism-Spectrum Quotient (AQ), for measuring the degree to which an adult with normal intelligence has the traits associated with the autistic spectrum. In this paper, we report on a Japanese version of this new instrument. Three groups of Japanese subjects were assessed. Group 1 (n = 57) consisted of adults with Asperger Syndrome (AS) or high-functioning autism (HFA). The other two groups were control groups. Subjects of Group 2 (n = 194) were normal adults and those of Group 3 (n = 1 050) were students selected from five Universities in Tokyo and Chiba. The adults with AS/HFA had a mean AQ score of 37.9 (SD = 5.31), which was significantly higher than the two control groups (Group 2: X = 18.5, SD = 6.21, and Group 3: X = 20.7, SD = 6.38). While eighty-eight percent of the adults with AS/HFA scored more than 33 points, only 3% of subjects in the two control groups indicated those points. Among the controls, males scored slightly but significantly higher than females. The reliability of the AQ in both test-retest and inter-rater measures were significantly high.


Effect of Dimethyl Sulfoxide on Bond Strength of a Self-Etch Primer and an Etch and Rinse Adhesive to Surface and Deep Dentin.
Composite bond to dentin is crucial in many clinical conditions particularly in deep cavities without enamel margins due to insufficient penetration of adhesive into demineralized dentin. The aim of this study was to assess the shear bond strength (SBS) of a methacrylate-based and a silorane-based composite resin to surface and deep dentin after pretreatment with dimethyl sulfoxide (DMSO). Eighty extracted human premolars were randomly divided into two groups of flat occlusal dentin with different cuts as A: surface group (sections just below the dentinoenamel junction (DEJ) and B: deep group (2 mm below DEJ). Each group was randomly assigned to 4 subgroups and their samples were restored with Adper Single bond (ASB) and Filtek Z350 or Silorane system Adhesive (SA) and Filtek P90 composite resins, using a 3×3mm cylindrical plastic mold. following these steps , the subgroups were assigned as SubgroupA1: surface dentin+ Silorane System Primer (SSP)+ Silorane System Bonding (SSB)+ P90; Subgroup A2: surface dentin+ 37% etchant (E37%) + Adper Single Bond (ASB)+ Z350; Subgroup A3: surface dentin+ DMSO+ SSP+ SSB+ P90; Subgroup A4: surface dentin+ E37%+ DMSO+ ASB+ Z350; Subgroup B1: deep dentin+ SSP+ SSB+ P90; Subgroup B2: deep dentin+ E37%+ ASB+ Z350; Subgroup B3: deep dentin+ DMSO+ SSP+ SSB+ P90; Subgroup B4:dentin +E37% +DMSO +ASB +Z350. The specimens were thermocycled at 5± 2/55± 2°C for 1000 cycles and then tested for SBS. Using DMSO as dentin conditioner increased SBS of ASB to deep dentin (p< 0.001) and SBS of SA to surface dentin (p= 0.003) but had no effect on SBS of SA to deep dentin (p= 1.00). The ability of DMSO to increase SBS of ASB to deep dentin provides a basis for improving bonding of this composite resin in deep cavities.


Using an agent-based model to simulate children's active travel to school.
Despite the multiple advantages of active travel to school, only a small percentage of US children and adolescents walk or bicycle to school. Intervention studies are in a relatively early stage and evidence of their effectiveness over long periods is limited. The purpose of this study was to illustrate the utility of agent-based models in exploring how various policies may influence children's active travel to school. An agent-based model was developed to simulate children's school travel behavior within a hypothetical city. The model was used to explore the plausible implications of policies targeting two established barriers to active school travel: long distance to school and traffic safety. The percent of children who walk to school was compared for various scenarios. To maximize the percent of children who walk to school the school locations should be evenly distributed over space and children should be assigned to the closest school. In the case of interventions to improve traffic safety, targeting a smaller area around the school with greater intensity may be more effective than targeting a larger area with less intensity. Despite the challenges they present, agent based models are a useful complement to other analytical strategies in studying the plausible impact of various policies on active travel to school.


Assessing Coastal Plain Risk Indices for Subsurface Phosphorus Loss.
Phosphorus (P) Index evaluations are critical to advancing nutrient management planning in the United States. However, most assessments until now have focused on the risks of P losses in surface runoff. In artificially drained agroecosystems of the Atlantic Coastal Plain, subsurface flow is the predominant mode of P transport, but its representation in most P Indices is often inadequate. We explored methods to evaluate the subsurface P risk routines of five P Indices from Delaware, Maryland (two), Virginia, and North Carolina using available water quality and soils datasets. Relationships between subsurface P risk scores and published dissolved P loads in leachate (Delaware, Maryland, and North Carolina) and ditch drainage (Maryland) were directionally correct and often statistically significant, yet the brevity of the observation periods (weeks to several years) and the limited number of sampling locations precluded a more robust assessment of each P Index. Given the paucity of measured P loss data, we then showed that soil water extractable P concentrations at depths corresponding with the seasonal high water table (WEP) could serve as a realistic proxy for subsurface P losses in ditch drainage. The associations between WEP and subsurface P risk ratings reasonably mirrored those obtained with sparser water quality data. As such, WEP is seen as a valuable metric that offers interim insight into the directionality of subsurface P risk scores when water quality data are inaccessible. In the long term, improved monitoring and modeling of subsurface P losses clearly should enhance the rigor of future P Index appraisals.


Public views on health care rationing: a group discussion study.
This small-scale study develops a new methodology for investigating which ethical principles of health care rationing the public support after discussion and deliberation. In ten groups of about six people, members of the public are asked to discuss a hypothetical rationing choice, concerning four identified patients who are described in general terms but without detailed information. It is explained to respondents that the purpose of the exercise is to find out what general ethical principles they support. Discussions are chaired by an academic specialising in health policy, whose role is to encourage debate but not actively to participate. On the basis of an innovative qualitative data analysis, which translates what people say into ethical principles identified in the theoretical literature, the public appear to support three main rationing principles: (1) a broad 'rule of rescue' that gives priority to those in immediate need, (2) health maximisation and (3) equalisation of lifetime health. To our knowledge, this pluralistic viewpoint on rationing has never been developed into a coherent theoretical position, nor into a quantifiable model that health care managers can use for guidance.


Dupuytren's disease: a localised and accessible human fibrotic disorder.
We review the biology of Dupuytren's disease (DD), a common localised fibrotic disorder of the hand. The disease develops through a complex interplay of genetic and environmental factors, and epigenetic signalling. The early-stage disease nodules comprise a complex milieu of stromal and immune cells which interact to promote disease development. Recently, inhibition of tumour necrosis factor (TNF) locally resulted in softening and a decrease in nodule size, potentially controlling disease progression. Unlike fibrotic disorders of the visceral organs, the easy access to tissue in DD patients enables dissection of the cellular landscape and molecular signalling pathways. In addition, the study of DD may have wider benefits in enhancing our understanding of less-accessible fibrotic tissues.


Extracellular guanosine increases astrocyte cAMP: inhibition by adenosine A2 antagonists.
Both extracellular guanosine and adenosine stimulated astrocyte proliferation in vitro and increased intracellular cAMP 6-fold within 2 min. The effects of both guanosine and adenosine on proliferation and cAMP levels were inhibited by antagonists of adenosine A2 receptors but augmented by A1 receptor antagonists. The correlation between cAMP accumulation and stimulation of cell proliferation by adenosine and guanosine indicates that increased intracellular cAMP may be one of the second messengers involved in these effects. Guanosine is not an adenosine A2 receptor agonist and does not activate adenylate cyclase. It may exert its effects indirectly by increasing the endogenous extracellular adenosine concentration.


Deriving the optimal number of events for an event-related fMRI study based on the spatial extent of activation.
Event-related fMRI is a powerful tool for localising psychological functions to specific brain areas. However, the number of events required to produce stable activation maps is a poorly investigated and understood problem. Huettel and McCarthy [Huettel, S.A., McCarthy, G., 2001. The effects of single-trial averaging upon the spatial extent of fMRI activation. NeuroReport 12, 2411-2416] have shown that the spatial extent of activation increases monotonically with the number of events in an analysis. In the present paper, this result is replicated and shown to be a consequence of the cross-correlation technique used to determine active voxels and does not hold, for example, for a GLM analysis. Another analysis technique, that does not depend on goodness-of-fit to the data, is also proposed. This technique calculates an impulse response function (IRF) for each voxel, finds the best fitting haemodynamic shape to the IRF and returns an area-under-the-curve (%AUC) activation measure. Using spatial extent as a measure, asymptotic behaviour is evident after as few as 25 events for the %AUC analysis technique in a finger-tapping task with non-overlapping haemodynamic responses and for both the GLM and %AUC techniques in a similar task that allows responses to overlap. The experimental validity of the %AUC technique to identify active brain regions while minimising false positive levels is demonstrated in a group study with 25 participants.


Population-based case-control association studies.
This unit provides an overview of the design and analysis of population-based case-control studies of genetic risk factors for complex disease. Considerations specific to genetic studies are emphasized. The unit reviews basic study designs differentiating case-control studies from others, presents different genetic association strategies (candidate gene, genome-wide association, and high-throughput sequencing), introduces basic methods of statistical analysis for case-control data and approaches to combining case-control studies, and discusses measures of association and impact. Admixed populations, controlling for confounding (including population stratification), consideration of multiple loci and environmental risk factors, and complementary analyses of haplotypes, genes, and pathways are briefly discussed. Readers are referred to basic texts on epidemiology for more details on general conduct of case-control studies.


Challenges of providing confidential care to adolescents in urban primary care: clinician perspectives.
Clinician time alone with an adolescent has a major impact on disclosure of risk behavior. This study sought to describe primary care clinicians' patterns of delivering time alone, decision making about introducing time alone to adolescents and their parents, and experiences delivering confidential services. We undertook qualitative interviews with 18 primary care clinicians in urban health centers staffed by specialists in pediatrics, family medicine, and adolescent medicine. The annual preventive care visit is the primary context for provision of time alone with adolescents; clinicians consider the parent-child dynamic and the nature of the chief complaint for including time alone during visits for other than preventive care. Time constraints are a major barrier to offering time alone more frequently. Clinicians perceive that parental discomfort with time alone is rare. Many clinicians wrestle with internal conflict about providing confidential services to adolescents with serious health threats and regard their role as facilitating adolescent-parent communication. Health systems factors can interfere with delivery of confidential services, such as inconsistent procedures for determining whether unaccompanied youth would be seen. Despite competing time demands, clinicians report commitment to offering time alone during preventive care visits and infrequently offer it at other times. Experienced clinicians can gain skills in the art of managing complex relationships between adolescents and their parents. Office systems should be developed that enhance the consistency of delivery of confidential services.


A systematic review of studies utilizing hair glucocorticoids as a measure of stress suggests the marker is more appropriate for quantifying short-term stressors.
Quantitating glucocorticoids (GCs) in hairs is a popular method for assessing chronic stress in studies of humans and animals alike. The cause-and-effect relationship between stress and elevated GC levels in hairs, sampled weeks later, is however hard to prove. This systematic review evaluated the evidence supporting hair glucocorticoids (hGCs) as a biomarker of stress. Only a relatively small number of controlled studies employing hGC analyses have been published, and the quality of the evidence is compromised by unchecked sources of bias. Subjects exposed to stress mostly demonstrate elevated levels of hGCs, and these concentrations correlate significantly with GC concentrations in serum, saliva and feces. This supports hGCs as a biomarker of stress, but the dataset provided no evidence that hGCs are a marker of stress outside of the immediate past. Only in cases where the stressor persisted at the time of hair sampling could a clear link between stress and hGCs be established.


Plasma activity of prolyl endopeptidase in relation to psychopathology during immunotherapy with IFN-alpha in patients with renal cell carcinoma.
Abnormal activity in peripheral blood of the cytosolic enzyme prolyl endopeptidase (PEP, EC 22.214.171.124, post prolyl cleaving enzyme, prolyl oligopeptidase) has been found in patients with a variety of psychiatric disorders, most consistently in mood disorders. Mood disturbance is a well-known side effect of immunotherapy with interferon-alpha (IFN-alpha). Earlier, we documented a decrease in serum PEP activity in the first 4 weeks of treatment with IFN-alpha. In 24 patients (16 men, 8 women, median age 60.5 years, range 47-72 years) with metastatic renal cell carcinoma (RCC), psychiatric assessment and blood sampling were performed before and at 4 and 8 weeks and at 6 months after initiation of treatment with IFN-alpha. No episodes of depression were observed, and the sum score and the scores on the subscales for depression and hostility of the Symptom Check List-90 (SCL-90) did not change during follow-up, whereas the anxiety scores were somewhat lower at 4 and 8 weeks compared with baseline. No change in plasma PEP activity and no relationships between change in psychiatric parameters and change in plasma PEP activity were found. As more subtle relationships between PEP activity and psychiatric status could have easily been obscured, a role for PEP in the pathophysiology of IFN-alpha-induced mood disturbance can neither be confirmed nor excluded.


Interaction between genetic predisposition to adiposity and dietary protein in relation to subsequent change in body weight and waist circumference.
Genetic predisposition to adiposity may interact with dietary protein in relation to changes of anthropometry. To investigate the interaction between genetic predisposition to higher body mass index (BMI), waist circumference (WC) or waist-hip ratio adjusted for BMI (WHRBMI) and dietary protein in relation to subsequent change in body weight (ΔBW) or change in WC (ΔWC). Three different Danish cohorts were used. In total 7,054 individuals constituted the study population with information on diet, 50 single-nucleotide polymorphisms (SNPs) associated with BMI, WC or WHRBMI, as well as potential confounders. Mean follow-up time was ∼5 years. Four genetic predisposition-scores were based on the SNPs; a complete-score including all selected adiposity- associated SNPs, and three scores including BMI, WC or WHRBMI associated polymorphisms, respectively. The association between protein intake and ΔBW or ΔWC were examined and interactions between SNP-score and protein were investigated. Analyses were based on linear regressions using macronutrient substitution models and meta-analyses. When protein replaced carbohydrate, meta-analyses showed no associations with ΔBW (41.0 gram/y/5 energy% protein, [95% CI: -32.3; 114.3]) or ΔWC (<-0.1 mm/y/5 energy % protein, [-1.1; 1.1]). Similarly, there were no interactions for any SNP-scores and protein for either ΔBW (complete SNP-score: 1.8 gram/y/5 energy% protein/risk allele, [-7.0; 10.6]) or ΔWC (complete SNP-score: <0.1 mm/y/5 energy% protein/risk allele, [-0.1; 0.1]). Similar results were seen when protein replaced fat. This study indicates that the genetic predisposition to general and abdominal adiposity, assessed by gene-scores, does not seem to modulate the influence of dietary protein on ΔBW or ΔWC.


Adjuvant treatment patterns and outcomes in patients with stage IB-IIIA non-small cell lung cancer in France, Germany, and the United Kingdom based on the LuCaBIS burden of illness study.
To inform health-technology assessments of new adjuvant treatments, we describe treatment patterns in patients with complete resection of stage IB-IIIA non-small cell lung cancer (NSCLC) in France, Germany, and the United Kingdom (UK). Data were collected via medical record abstraction. Patients were aged ≥18 years with completely resected stage IB-IIIA NSCLC, diagnosed between 01 January 2009 and 31 December 2011. Median follow-up was 26 months. Adjuvant treatment patterns and clinical outcomes were summarized descriptively. Among the 831 patients studied, 239 (29%) had stage IB disease, 179 (22%) had stage IIA disease, 165 (20%) had stage IIB disease, and 248 (30%) had stage IIIA disease. Adjuvant systemic therapy was received by 402 patients (48.4%), (France, 61.8%; Germany, 51.9%; UK, 33.4%). Use of adjuvant therapy increased with increasing stage of disease. Cisplatin/vinorelbine and carboplatin/vinorelbine were the most frequently prescribed adjuvant regimens. Median disease-free survival was 48.0 months (95% confidence interval [CI] 42.3-not estimable); the 25th percentile was 13.2 months (95% CI, 11.0-15.3). 204 patients (24%) died during the follow-up period. The median overall survival was not reached, the 25th percentile was 31.2 months (95% CI 26.8-36.0 months). 272 patients (33%) had disease recurrence during the follow-up period. For 86 of those patients, the first recurrence was local or regional with no distant metastasis and 14 had further progression to metastatic disease during the follow-up time. For the other 186 patients, the first recurrence involved distant metastases. A total of 200 patients had metastatic disease at any time during study follow-up. Less than half the patients with stage IB-IIIA NSCLC in this observational study received adjuvant systemic therapy. A high rate of first recurrence with distant metastatic disease was observed, emphasising the need for more effective systemic adjuvant therapies in this population.


Skull shape and feeding strategy in Sphenodon and other Rhynchocephalia (Diapsida: Lepidosauria).
The Rhynchocephalia are a group of small diapsid reptiles that were globally distributed during the early Mesozoic. By contrast, the only extant representatives, Sphenodon punctatus and S. guntheri (Tuatara), are restricted to New Zealand off-shore islands. The Rhynchocephalia are widely considered to be morphologically uniform but research over the past 30 years has revealed unexpected phenotypic and taxonomic diversity. Phylogenetically "basal taxa" generally possess relatively simple conical or columnar teeth whereas more derived taxa possessed stouter flanged teeth and sophisticated shearing mechanisms: orthal in some (e.g., Clevosaurus hudsoni) and propalinal in others (e.g., S. punctatus). This variation in feeding apparatus suggests a wide range of feeding niches were exploited by rhynchocephalians. The relationship of skull shape to skull length, phylogenetic grouping, habit, and characters relating to the feeding apparatus are explored here with geometric morphometric analysis on two-dimensional landmarks. Principle components analysis demonstrates that there are significant differences between phylogenetic groups. In particular, Sphenodon differs significantly from all well known fossil taxa including the most phylogenetically basal forms. Therefore, it is not justifiable to use Sphenodon as a solitary outgroup when studying skull shape and feeding strategy in squamates; rhynchocephalian fossil taxa also need to be considered. There are also significant differences between the skull shapes of aquatic taxa and those of terrestrial taxa. Of the observed variation in skull shape, most variation is subsumed by variation in dentary tooth base shape, the type of jaw movement employed (e.g., orthal vs. propalinal) and the number of palatal tooth rows. By comparison, the presence or absence of flanges, dentary tooth number and palatal tooth row orientation subsume much less. Skull length was also found to be a poor descriptor of overall skull shape. Compared to basal rhynchocephalians members of more derived terrestrial radiations possess an enlarged postorbital area, a high parietal, and a jaw joint positioned ventral to the tooth row. Modification of these features is closely associated with increased biting performance and thus access to novel food items. Some of these same trends are apparent during Sphenodon ontogeny where skull growth is allometric and there is evidence for ontogenetic variation in diet.


Multistates and Polyamorphism in Phase-Change K2Sb8Se13.
The phase-change (PC) materials in the majority of optical data storage media in use today exhibit a fast, reversible crystal → amorphous phase transition that allows them to be switched between on (1) and off (0) binary states. Solid-state inorganic materials with this property are relatively common, but those exhibiting an amorphous → amorphous transition called polyamorphism are exceptionally rare. K2Sb8Se13 (KSS) reported here is the first example of a material that has both amorphous → amorphous polyamorphic transition and amorphous → crystal transition at easily accessible temperatures (227 and 263 °C, respectively). The transitions are associated with the atomic coordinative preferences of the atoms, and all three states of K2Sb8Se13 are stable in air at 25 °C and 1 atm. All three states of K2Sb8Se13 exhibit distinct optical bandgaps, Eg = 1.25, 1.0, and 0.74 eV, for the amorphous-II, amorphous-I, and crystalline versions, respectively. The room-temperature electrical conductivity increases by more than 2 orders of magnitude from amorphous-I to -II and by another 2 orders of magnitude from amorphous-II to the crystalline state. This extraordinary behavior suggests that a new class of materials exist which could provide multistate level systems to enable higher-order computing logic circuits, reconfigurable logic devices, and optical switches.


Evaluation of palliative care training and skills retention by medical students.
Training in palliative and end-of-life care has been introduced in medical education; however, the impact of such training and the retention of skills and knowledge have not been studied in detail. This survey study examines long-term follow-up on end-of-life communication skills training, evaluation, and skills retention in medical students. During the surgical clerkship, all third-year medical students received communication skills training in palliative care using simulated patients. The training involved three scenarios involving diverse surgical patients with conditions commonly encountered during the surgical clerkship. The students used web-based best practice guidelines to prepare for the patient encounters. The following communication abilities were evaluated: (1) giving bad news clearly and with empathy, (2) initiating death and dying conversations with patients and/or their family members, (3) discussing do not resuscitate status and exploring preferences for end-of-life care, and (4) initiating conversations regarding religious or spiritual values and practices. All students were surveyed after 1 year (12-24 mo) to ascertain: (1) the retention of skills and/or knowledge gained during this training, (2) application of these skills during subsequent clinical rotations, and (3) overall perception of the value added by the training to their undergraduate medical education. These results were correlated with residency specialty choice. The survey was sent to all graduating fourth-year medical students (n = 105) in our program, of which 69 students responded to the survey (66% response rate). All respondents agreed that palliative care training is essential in medical school training. Seventy percent of the respondents agreed that the simulated encounters allowed development of crucial conversation skills needed for palliative/end-of-life care communications. The most useful part of the training was the deliberate practice of "giving bad news" (85%). Most of the respondents (80%) indicated retention of overall communication skills with regard to approach and useful phrases. Forty-five percent claimed retention of communication skills surrounding death and dying, and 44% claimed retention of end-of-life preferences/advance directives/do not resuscitate. Relatively few respondents (16%) retained skills regarding religious or spiritual values. There was no correlation between training evaluation/skill retention and the area of residency specialty the students pursued on graduation. Early training in palliative and end-of-life care communication is feasible and effective during the surgical clerkship. Students highly valued the simulated patient and/or family discussions and retained most of the skills and knowledge from the experiential simulated encounters. However, students felt the skills developed could be reinforced with opportunities to observe their attending physicians or residents leading such discussions and involving students in such discussions as and when appropriate.


Efficient Production of Chimeric Hepatitis B Virus-Like Particles Bearing an Epitope of Hepatitis E Virus Capsid by Transient Expression in Nicotiana benthamiana.
The core antigen of hepatitis B virus (HBcAg) is capable of self-assembly into virus-like particles (VLPs) when expressed in a number of heterologous systems. Such VLPs are potential carriers of foreign antigenic sequences for vaccine design. In this study, we evaluated the production of chimeric HBcAg VLPs presenting a foreign epitope on their surface, the 551-607 amino acids (aa) immunological epitope of the ORF2 capsid protein of hepatitis E virus. A chimeric construct was made by the insertion of 56 aa into the immunodominant loop of the HBcAg. The sequences encoding the chimera were inserted into the pEAQ-HT vector and infiltrated into Nicotiana benthamiana leaves. The plant-expressed chimeric HBcHEV ORF2 551-607 protein was recognized by an anti-HBcAg mAb and anti-HEV IgG positive swine serum. Electron microscopy showed that plant-produced chimeric protein spontaneously assembled into "knobbly" ~34 nm diameter VLPs. This study shows that HBcAg is a promising carrier platform for the neutralizing epitopes of hepatitis E virus (HEV) and the chimeric HBcAg/HEV VLPs could be a candidate for a bivalent vaccine.


Sprifermin (rhFGF18) modulates extracellular matrix turnover in cartilage explants ex vivo.
Sprifermin (recombinant human fibroblast growth factor 18) is in clinical development as a potential disease-modifying osteoarthritis drug (DMOAD). In vitro studies have shown that cartilage regenerative properties of sprifermin involve chondrocyte proliferation and extracellular matrix (ECM) production. To gain further insight into the process of sprifermin in the cartilage tissue, this study aimed at investigating the ECM turnover of articular cartilage explants in a longitudinal manner. Bovine full-depth articular cartilage explants were stimulated with sprifermin or placebo at weekly intervals, similar to the dosing regimen used in clinical trials. Pre-culturing with oncostatin M and tumour necrosis factor-α, was also used to induce an inflammatory state before treatment. Metabolic activity was measured using AlamarBlue, and chondrocyte proliferation was visualized by immuno-histochemical detection of proliferating cell nuclear antigen. ECM turnover was quantified by biomarker ELISAs; ProC2 reflecting type II collagen formation, CS846 reflecting aggrecan formation, active MMP9, C2M and AGNx2 reflecting matrix metalloproteinase activity, and AGNx1 reflecting aggrecanase activity. Sprifermin was able to reach the chondrocytes through the extracellular matrix, as it increased cell proliferation and metabolic activity of explants. ProC2 and CS846 was dose-dependently increased (P < 0.05) by sprifermin compared to placebo, while C2M and AGNx2 were unaffected, active MMP9 was slightly decreased, and AGNx1 was slightly increased. Over the course of treatment, the temporal order of ECM turnover responses was AGNx1, then ProC2, followed by CS846 and MMP9. Pro-inflammatory activation of the explants diminished the ECM turnover responses otherwise observed under non-inflammatory conditions. The data suggest that sprifermin has chondrogenic effects on articular cartilage ex vivo, exerted through a sequential process of ECM turnover; aggrecan degradation seems to occur first, while type II collagen and aggrecan production increased at a later time point. In addition, it was observed that these chondrogenic effects are dependent on the inflammatory status of the cartilage prior to treatment.


Molecular Inflammation in the Contralateral Eye After Cataract Surgery in the First Eye.
The purpose of this study was to assess the inflammatory status of the aqueous humor in the fellow eye after uneventful cataract surgery in the first eye. At the screening stage, aqueous humor samples from 15 first-eye and 15 second-eye cataract patients were collected just before cataract surgery and assayed using human cytokine antibody array. Screened cytokines were then verified using a suspension array system with aqueous humor samples obtained from 35 first-eye and 36 second-eye cataract patients. The cytokine antibody array revealed that interleukin-1 receptor antagonist (Il-1ra) and macrophage inflammatory protein (MIP)-1a and MIP-1b were expressed at high levels in first-eye patients and were lower in second-eye patients, whereas opposite trends were found for monocyte chemoattractant protein 1 (MCP-1) and for regulated on activation, normal T expressed and secreted (RANTES) (all, P < 0.05, Student's t-test). However, only MCP-1 and IL-1ra were significantly different between the two groups after Bonferroni correction (both P < 0.00125). In the replication stage, the suspension cytokine array revealed that only MCP-1 expression was significantly greater in the aqueous humor of second-eye patients than in that of first-eye patients (P = 0.0067, Student's t-test). This study revealed that expression of MCP-1, a pain-related inflammatory chemokine, was significantly increased in aqueous humor in the contralateral eye after first-eye cataract surgery. This suggests there may be a sympathetic ophthalmic type uveitis in the contralateral eye after first-eye cataract surgery and that may help to explain why second-eye phacoemulsification is often more painful. (ClinicalTrials.gov number, NCT01824927.)


Dynamics of a Volvox embryo turning itself inside out.
Deformations of cell sheets are ubiquitous in early animal development, often arising from a complex and poorly understood interplay of cell shape changes, division, and migration. Here, we explore perhaps the simplest example of cell sheet folding: the "inversion" process of the algal genus Volvox, during which spherical embryos turn themselves inside out through a process hypothesized to arise from cell shape changes alone. We use light sheet microscopy to obtain the first three-dimensional visualizations of inversion in vivo, and develop the first theory of this process, in which cell shape changes appear as local variations of intrinsic curvature, contraction and stretching of an elastic shell. Our results support a scenario in which these active processes function in a defined spatiotemporal manner to enable inversion.


Relationship between trusting behaviors and psychometrics associated with social network and depression among young generation: a pilot study.
Maladaptive social interaction and its related psychopathology have been highlighted in psychiatry especially among younger generations. In Japan, novel expressive forms of psychiatric phenomena such as "modern-type depression" and "hikikomori" (a syndrome of severe social withdrawal lasting for at least six months) have been reported especially among young people. Economic games such as the trust game have been utilized to evaluate real-world interpersonal relationships as a novel candidate for psychiatric evaluations. To investigate the relationship between trusting behaviors and various psychometric scales, we conducted a trust game experiment with eighty-one Japanese university students as a pilot study. Participants made a risky financial decision about whether to trust each of 40 photographed partners. Participants then answered a set of questionnaires with seven scales including the Lubben Social Network Scale (LSNS)-6 and the Patient Health Questionnaire (PHQ)-9. Consistent with previous research, male participants trusted partners more than female participants. Regression analysis revealed that LSNS-family (perceived support from family) for male participants, and item 8 of PHQ-9 (subjective agitation and/or retardation) for female participants were associated with participants' trusting behaviors. Consistent with claims by social scientists, our data suggest that, for males, support from family was negatively associated with cooperative behavior toward non-family members. Females with higher subjective agitation (and/or retardation) gave less money toward males and high attractive females, but not toward low attractive females in interpersonal relationships. We believe that our data indicate the possible impact of economic games in psychiatric research and clinical practice, and validation in clinical samples including modern-type depression and hikikomori should be investigated.


ALDH2/ADH2 polymorphism associated with vasculopathy and neuropathy in type 2 diabetes.
In the history of diabetes, chlorpropamide alcohol flushing test (CPAF) was a big topic in the 1970s to 1980s. Alcohol tolerance after chlorpropamide has prognostic significance, with the intolerant group (CPAF-positive group) being less prone to develop vascular complication than the tolerant group (CPAF-negative group). A mechanism of CPAF has been regarded as the inhibition of aldehyde dehydrogenase 2 (ALDH2) by an N-alkyl-substituted derivative of chlorpropamide, and the expression of these mutations of ALDH2 and alcohol dehydrogenase 2 (ADH2) could determine the alcohol tolerance among the Japanese population. Therefore, we hypothesized that expression of different ALDH2 and ADH2 polymorphisms may induce differences in vascular complications in diabetes and conducted two studies. The first study (study 1) was to determine the association of ALDH2/AHD2 polymorphism with diabetic complications. To know the association of ALDH2/AHD2 polymorphism with diabetic vasculopathy and neuropathy, a total of 158 patients with type 2 diabetes were divided into four groups on the basis of ALDH2 "activity" and ADH2 "superactivity." The frequency of proteinuria and the percentage of proliferative retinopathy among the patients with retinopathy was higher in those with active ALDH2 and superactive ADH2. We speculated that protein kinase C isoforms up-regulated by 4-hydroxynonenal that was detoxified by ALDH2 and ADH2 may account for the long-term development of diabetic nephropathy and severe retinopathy. As for neuropathy, the frequency of symptomatic neuropathy was higher in patients with inactive ALDH2 and usual ADH2. We speculate that increased tissue levels of toxic aldehyde could result from inactive ALDH2 and usual ADH2 expression, which results in the increased level of reactive aldehyde in sensory neuron pathway, thereby causing symptomatic polyneuropathy.


Status and Recommendations of Technological and Data-Driven Innovations in Cancer Care: Focus Group Study.
The status of the data-driven management of cancer care as well as the challenges, opportunities, and recommendations aimed at accelerating the rate of progress in this field are topics of great interest. Two international workshops, one conducted in June 2019 in Cordoba, Spain, and one in October 2019 in Athens, Greece, were organized by four Horizon 2020 (H2020) European Union (EU)-funded projects: BOUNCE, CATCH ITN, DESIREE, and MyPal. The issues covered included patient engagement, knowledge and data-driven decision support systems, patient journey, rehabilitation, personalized diagnosis, trust, assessment of guidelines, and interoperability of information and communication technology (ICT) platforms. A series of recommendations was provided as the complex landscape of data-driven technical innovation in cancer care was portrayed. This study aims to provide information on the current state of the art of technology and data-driven innovations for the management of cancer care through the work of four EU H2020-funded projects. Two international workshops on ICT in the management of cancer care were held, and several topics were identified through discussion among the participants. A focus group was formulated after the second workshop, in which the status of technological and data-driven cancer management as well as the challenges, opportunities, and recommendations in this area were collected and analyzed. Technical and data-driven innovations provide promising tools for the management of cancer care. However, several challenges must be successfully addressed, such as patient engagement, interoperability of ICT-based systems, knowledge management, and trust. This paper analyzes these challenges, which can be opportunities for further research and practical implementation and can provide practical recommendations for future work. Technology and data-driven innovations are becoming an integral part of cancer care management. In this process, specific challenges need to be addressed, such as increasing trust and engaging the whole stakeholder ecosystem, to fully benefit from these innovations.


A framework for exhaustively mapping functional missense variants.
Although we now routinely sequence human genomes, we can confidently identify only a fraction of the sequence variants that have a functional impact. Here, we developed a deep mutational scanning framework that produces exhaustive maps for human missense variants by combining random codon mutagenesis and multiplexed functional variation assays with computational imputation and refinement. We applied this framework to four proteins corresponding to six human genes: UBE2I (encoding SUMO E2 conjugase), SUMO1 (small ubiquitin-like modifier), TPK1 (thiamin pyrophosphokinase), and CALM1/2/3 (three genes encoding the protein calmodulin). The resulting maps recapitulate known protein features and confidently identify pathogenic variation. Assays potentially amenable to deep mutational scanning are already available for 57% of human disease genes, suggesting that DMS could ultimately map functional variation for all human disease genes.


The effect of smoking on quality of life following sinus surgery: 10-year follow-up.
The purpose of this study is to investigate the 10-year postoperative quality of life outcomes in smokers and nonsmokers with chronic rhinosinusitis. This is a single-institution prospective cohort study. 235 patients who have previously been enrolled in a 4-year follow-up study were identified and contacted for a telephone interview. Rates of revision surgery, smoking status and 20-item sinonasal outcomes test (SNOT-20) scores were obtained. Preoperative SNOT-20 scores were compared with those obtained at the 10-year follow-up. Of the patients enrolled in the initial 4-year study, 22.5% were available for a telephone interview, including 43 out of 185 nonsmokers (23.2%) and 9 out of 50 smokers (18%). Demographic data including age, sex and race were analyzed and found to be similar between the two groups. Preoperative SNOT-20 scores were similar between nonsmokers and smokers (28.9 vs. 25.8, p = 0.89). There was no significant difference in long-term SNOT-20 scores (10 years postoperatively) between nonsmokers and smokers (31.5 vs. 28.2, p = 0.629). While cigarette smoke may have long-term adverse effects on the sinonasal mucosa, we found no difference in quality of life outcomes between smokers and nonsmokers 10 years after functional endoscopic sinus surgery.