Increasing Incidence of Crohn's Disease with Familial Clustering in the Kingdom of Bahrain: A 25-Year Population-based Study.
The incidence of Crohn's disease has been increasing in developed countries; whether this trend has extended to countries in Middle East, especially in the Arab world, remains unclear. Our aim was to study the epidemiology, incidence, time trends and clustering of Crohn's disease within the population of the Kingdom of Bahrain. A retrospective case-cohort study was conducted on patients diagnosed with Crohn's disease at Bahrain Specialist Hospital between 1990 and 2015. The diagnosis was based on clinical, radiological, endoscopic, and histological examinations. Five hundred twenty-two cases were eligible for analysis; 14.5% were below the age of 19 with a male-to-female ratio of 1.1:1. The overall incidence was 4.8/100,000 person-years and significantly increased from 5.5/100,000 person-years during the 1990's to 8.0/100,000 person-years during the last study period [incidence rate ratio (IRR) 0.32, 95% CI = 0.26-0.42]. This trend was persistent for adults, children, men and women. There were 129 patients with at least one family member diagnosed with Crohn's disease consisting of 40 families. Three clusters were identified based on first or second degree relationship of the family member. The mean interval for diagnosis between family members was significantly shorter between siblings than second degree relatives; (2.0 ± 1.2 years) versus (5.0 ± 2.8 years), respectively; (P = 0.04). The incidence rate of Crohn's disease in Bahrain is comparable to the U.S.A and has increased for men and women in all age groups. Crohn's disease clusters were common among families and included up to 3 generations consistent with presence of a common source or common genetic factors.


Leaching and sorption of neonicotinoid insecticides and fungicides from seed coatings.
Seed coatings are a treatment used on a variety of crops to improve production and offer protection against pests and fungal outbreaks. The leaching of the active ingredients associated with the seed coatings and the sorption to soil was evaluated under laboratory conditions using commercially available corn and soybean seeds to study the fate and transport of these pesticides under controlled conditions. The active ingredients (AI) included one neonicotinoid insecticide (thiamethoxam) and five fungicides (azoxystrobin, fludioxonil, metalaxyl, sedaxane thiabendazole). An aqueous leaching experiment was conducted with treated corn and soybean seeds. Leaching potential was a function of solubility and seed type. The leaching of fludioxonil, was dependent on seed type with a shorter time to equilibrium on the corn compared to the soybean seeds. Sorption experiments with the treated seeds and a solution of the AIs were conducted using three different soil types. Sorption behavior was a function of soil organic matter as well as seed type. For most AIs, a negative relationship was observed between the aqueous concentration and the log Koc. Sorption to all soils tested was limited for the hydrophilic pesticides thiamethoxam and metalaxyl. However, partitioning for the more hydrophobic fungicides was dependent on both seed type and soil properties. The mobility of fludioxonil in the sorption experiment varied by seed type indicating that the adjuvants associated with the seed coating could potentially play a role in the environmental fate of fludioxonil. This is the first study to assess, under laboratory conditions, the fate of pesticides associated with seed coatings using commercially available treated seeds. This information can be used to understand how alterations in agricultural practices (e.g., increasing use of seed treatments) can impact the exposure (concentration and duration) and potential effects of these chemicals to aquatic and terrestrial organisms.


Nomogram prediction of overall survival for patients with non-small-cell lung cancer incorporating pretreatment peripheral blood markers.
The objective of this study is to build a novel prognostic nomogram in non-small-cell lung cancer (NSCLC) incorporating pre-treatment peripheral blood markers beyond known pathoclinical predictors. We analysed 7158 patients with NSCLC diagnosed between 1 January 1997 and 31 December 2012 from a single institution with a uniform medical record and routine follow-up information. Besides common clinicopathological factors, we investigated the prognostic value of the neutrophil to lymphocyte ratio, monocytes and haemoglobin level in peripheral blood before treatment. Patients were randomly assigned to training (4772 patients, 66.7%) or validation cohorts (2386 patients, 33.3%). Cox proportional hazards models determined the effects of multiple factors on overall survival (OS). A nomogram was developed to predict median survival and 1-, 3-, 5- and 10-year OS for NSCLC. The performance of the nomogram was assessed by a concordance index and calibration curve. In the training cohort, the multivariate Cox model identified the neutrophil to lymphocyte ratio, monocytes and haemoglobin level before treatment as significant prognostic factors for OS independent of patient age, gender, smoking history of intensity and cessation, performance status, disease stage, tumour cell type and differentiation grade and therapies. All the significant prognostic variables were incorporated into a nomogram. In the validation cohort, the nomogram showed notable accuracy in predicting OS, with a concordance index of 0.81, and was well calibrated for predictions of OS. The proposed nomogram incorporating peripheral blood markers and known prognostic factors could accurately predict individualized survival probability of patients with NSCLC. It could be used in treatment planning and stratification in clinical trials.


Consent and Assent in Pediatric Research: Whose Right Is It Anyway?
Although the right to health care is not written into the U.S. Constitution, moral and ethical tenets govern the delivery of optimal medical care universally and across the life continuum. Pertaining to children, in accordance with the Geneva Declaration of the Rights of the Child of 1924 and the United Nations Human Rights General Assembly adoption of the Rights of the Child in 1959, parents or guardians are responsible for the health and well-being of a child until age 18 years. Much consideration is needed regarding the anatomic, physiologic, emotional, and cognitive development of children when making decisions regarding their health care and, particularly, when enrolling them into research studies. .


Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade.
Ketamine is a N-methyl-D-aspartate receptor (NMDAR) antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDAR activation at rest, which inhibits eukaryotic elongation factor 2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from adult animals. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDARs is sufficient to trigger this effect. These findings suggest that global blockade of NMDARs in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.


Cobalt(II) Oxidation by the Marine Manganese(II)-Oxidizing Bacillus sp. Strain SG-1.
The geochemical cycling of cobalt (Co) has often been considered to be controlled by the scavenging and oxidation of Co(II) on the surface of manganese [Mn(III,IV)] oxides or manganates. Because Mn(II) oxidation in the environment is often catalyzed by bacteria, we have investigated the ability of Mn(II)-oxidizing bacteria to bind and oxidize Co(II) in the absence of Mn(II) to determine whether some Mn(II)-oxidizing bacteria also oxidize Co(II) independently of Mn oxidation. We used the marine Bacillus sp. strain SG-1, which produces mature spores that oxidize Mn(II), apparently due to a protein in their spore coats (R.A. Rosson and K. H. Nealson, J. Bacteriol. 151:1027-1034, 1982; J. P. M. de Vrind et al., Appl. Environ. Microbiol. 52:1096-1100, 1986). A method to measure Co(II) oxidation using radioactive Co as a tracer and treatments with nonradioactive (cold) Co(II) and ascorbate to discriminate bound Co from oxidized Co was developed. SG-1 spores were found to oxidize Co(II) over a wide range of pH, temperature, and Co(II) concentration. Leucoberbelin blue, a reagent that reacts with Mn(III,IV) oxides forming a blue color, was found to also react with Co(III) oxides and was used to verify the presence of oxidized Co in the absence of added Mn(II). Co(II) oxidation occurred optimally around pH 8 and between 55 and 65 degrees C. SG-1 spores oxidized Co(II) at all Co(II) concentrations tested from the trace levels found in seawater to 100 mM. Co(II) oxidation was found to follow Michaelis-Menten kinetics. An Eadie-Hofstee plot of the data suggests that SG-1 spores have two oxidation systems, a high-affinity-low-rate system (K(m), 3.3 x 10 M; V(max), 1.7 x 10 M . spore . h) and a low-affinity-high-rate system (K(m), 5.2 x 10 M; V(max), 8.9 x 10 M . spore . h). SG-1 spores did not oxidize Co(II) in the absence of oxygen, also indicating that oxidation was not due to abiological Co(II) oxidation on the surface of preformed Mn(III,IV) oxides. These results suggest that some microorganisms may directly oxidize Co(II) and such biological activities may exert some control on the behavior of Co in nature. SG-1 spores may also have useful applications in metal removal, recovery, and immobilization processes.


Bridging the Gap: research informing practice and policy for healthy youth behavior.
Bridging the Gap (BTG) is a collaborative research initiative supported by the Robert Wood Johnson Foundation. Ten years ago, BTG was created to assess the impact of policies, programs, and other environmental influences on adolescent alcohol, tobacco, and illicit drug use and related outcomes. This multidisciplinary, multisite initiative examines these factors at multiple levels of social organization, including schools, communities, and states. More recently, the significant increases in obesity among children, adolescents, and adults led BTG to expand its efforts to include research on the role of policies, programs, and other factors on adolescent obesity and the physical inactivity and dietary habits that contribute to this growing problem. Eleven papers resulting from BTG's obesity-related research are contained in this supplement, along with two papers describing the National Cancer Institute-supported efforts to track relevant state policies. Bridging the Gap involves a variety of data-collection efforts built largely around the Monitoring the Future (MTF) surveys of 8th-, 10th-, and 12th-grade students. These include: surveys of administrators in the MTF schools that gather extensive information on the school food environment, physical education in schools, and other relevant information; collection of contextual information from the communities in which the MTF schools are located; tracking of relevant state policies; and gathering of a wide variety of data from archival and commercial databases. These databases are analyzed individually and in various combinations. Bridging the Gap's extensive research has shown the importance of a range of school, community, state, and other influences in affecting adolescent substance use and related outcomes. BTG's early research on adolescent diet, physical activity, and obesity--much of which is contained in this supplement--similarly demonstrates the role of environmental factors in influencing these outcomes and in explaining observed racial/ethnic and socioeconomic-related disparities in them. The growing recognition of the public health and economic consequences of childhood, adolescent, and adult obesity has led to a variety of policies, programs, and other interventions to stimulate healthy eating and physical activity, often despite the lack of evidence on their impact. BTG and others are working to build the evidence base for effective interventions to address this significant problem, but much remains to be learned.


The neuropsychological basis of addictive behaviour.
The argument advanced in this review is that drug addiction can be understood in terms of normal learning and memory systems of the brain which, through the actions of chronically self-administered drugs, are pathologically subverted, thereby leading to the establishment of compulsive drug-seeking habits, strengthened by the motivational impact of drug-associated stimuli and occurring at the expense of other sources of reinforcement. We review data from our studies that have utilized procedures which reveal the various influences of pavlovian stimuli on goal-directed behaviour, namely discriminated approach, pavlovian-to-instrumental transfer and conditioned reinforcement, in order to demonstrate their overlapping and also unique neural bases. These fundamental studies are also reviewed in the context of the neural and psychological mechanisms underlying drug-seeking behaviour that is under the control of drug-associated environmental stimuli. The ways in which such drug-seeking behaviour becomes compulsive and habitual, as well as the propensity for relapse to drug-seeking even after long periods of relapse, are discussed in terms of the aberrant learning set in train by the effects of self-administered drugs on plastic processes in limbic cortical-ventral striatal systems.


A review of nabilone in the treatment of chemotherapy-induced nausea and vomiting.
Chemotherapy-induced nausea and vomiting (CINV) in cancer patients places a significant burden on patients' function and quality of life, their families and caregivers, and healthcare providers. Despite the advances in preventing CINV, a substantial proportion of patients experience persistent nausea and vomiting. Nabilone, a cannabinoid, recently received Food and Drug Administration approval for the treatment of the nausea and vomiting in patients receiving cancer chemotherapy who fail to achieve adequate relief from conventional treatments. The cannabinoids exert antiemetic effects via agonism of cannabinoid receptors (CB1 and CB2). Clinical trials have demonstrated the benefits of nabilone in cancer chemotherapy patients. Use of the agent is optimized with judicious dosing and selection of patients.


Utilization of former military medical corpsmen in the provision of jail health services.
In an effort to improve the quality of health services within a large urban jail, former military medical corpsmen have been employed as an integral component of a jail health service. Medical corpsmen are responsible for the performance of intake medical evaluations, delivery of prescription medications, triage for physician sick call, and provision of elementary health services on the jail tiers. Utilization of medical corpsmen has been associated with improved rates of medication delivery as well as beneficial effects in relation to tuberculosis and venereal disease control, and a more appropriate utilization of physician services. Effective utilization of medical corpsmen requires cooperation from the correctional staff as well as consistent supervision and support by qualified physicians.


One-step multiplex real-time RT-PCR assay for detecting and genotyping wild-type group A rotavirus strains and vaccine strains (Rotarix® and RotaTeq®) in stool samples.
Background. Group A rotavirus (RVA) infection is the major cause of acute gastroenteritis (AGE) in young children worldwide. Introduction of two live-attenuated rotavirus vaccines, RotaTeq® and Rotarix®, has dramatically reduced RVA associated AGE and mortality in developed as well as in many developing countries. High-throughput methods are needed to genotype rotavirus wild-type strains and to identify vaccine strains in stool samples. Quantitative RT-PCR assays (qRT-PCR) offer several advantages including increased sensitivity, higher throughput, and faster turnaround time. Methods. In this study, a one-step multiplex qRT-PCR assay was developed to detect and genotype wild-type strains and vaccine (Rotarix® and RotaTeq®) rotavirus strains along with an internal processing control (Xeno or MS2 RNA). Real-time RT-PCR assays were designed for VP7 (G1, G2, G3, G4, G9, G12) and VP4 (P[4], P[6] and P[8]) genotypes. The multiplex qRT-PCR assay also included previously published NSP3 qRT-PCR for rotavirus detection and Rotarix® NSP2 and RotaTeq® VP6 qRT-PCRs for detection of Rotarix® and RotaTeq® vaccine strains respectively. The multiplex qRT-PCR assay was validated using 853 sequence confirmed stool samples and 24 lab cultured strains of different rotavirus genotypes. By using thermostable rTth polymerase enzyme, dsRNA denaturation, reverse transcription (RT) and amplification (PCR) steps were performed in single tube by uninterrupted thermocycling profile to reduce chances of sample cross contamination and for rapid generation of results. For quantification, standard curves were generated using dsRNA transcripts derived from RVA gene segments. Results. The VP7 qRT-PCRs exhibited 98.8-100% sensitivity, 99.7-100% specificity, 85-95% efficiency and a limit of detection of 4-60 copies per singleplex reaction. The VP7 qRT-PCRs exhibited 81-92% efficiency and limit of detection of 150-600 copies in multiplex reactions. The VP4 qRT-PCRs exhibited 98.8-100% sensitivity, 100% specificity, 86-89% efficiency and a limit of detection of 12-400 copies per singleplex reactions. The VP4 qRT-PCRs exhibited 82-90% efficiency and limit of detection of 120-4000 copies in multiplex reaction. Discussion. The one-step multiplex qRT-PCR assay will facilitate high-throughput rotavirus genotype characterization for monitoring circulating rotavirus wild-type strains causing rotavirus infections, determining the frequency of Rotarix® and RotaTeq® vaccine strains and vaccine-derived reassortants associated with AGE, and help to identify novel rotavirus strains derived by reassortment between vaccine and wild-type strains.


Long non-coding RNA urothelial carcinoma associated 1 (UCA1) mediates radiation response in prostate cancer.
Radioresistance remains a significant obstacle in the treatment of Prostate Cancer (PCa). To simulate the clinical scenario of irradiation resistance (IRR), we created DU145-IRR PCa cell lines by treatment with 2 Gy daily IR for 59 fractions. DU145-IRR cells acquired an aggressive phenotype as evidenced by increased clonogenic survival, tumorigenic potential and invasiveness. We performed transcriptome profiling to discover dysregulated genes in DU145-IRR cells and identified the long non-coding RNA (lncRNA), Urothelial carcinoma-associated 1 (UCA1). We first investigated the role of UCA1 in radiation response and found that UCA1 abundance was significantly higher in DU145-IRR cells compared to control cells. UCA1 siRNA-knockdown reversed the aggressive phenotype and significantly increased sensitivity to IR. UCA1 depletion inhibited growth, induced cell cycle arrest at the G2/M transition and decreased activation of the pro-survival Akt pathway. We then studied the clinical significance of UCA1 expression in two independent cohorts of PCa patients: MSKCC (130 patients) and CPC-GENE (209 patients). UCA1 over-expression was associated with decreased 5-year disease-free survival in MSKCC patients (HR = 2.9; p = 0.007) and a trend toward lower biochemical recurrence-free survival in CPC-GENE patients (HR = 2.7; p = 0.05). We showed for the first time that UCA1 depletion induces radiosensitivity, decreases proliferative capacity and disrupts cell cycle progression, which may occur through altered Akt signaling and induced cell cycle arrest at the G2/M transition. Our results indicate that UCA1 might have prognostic value in PCa and be a potential therapeutic target.


QconCAT standard for calibration of ion mobility-mass spectrometry systems.
Ion mobility-mass spectrometry (IM-MS) is a useful technique for determining information about analyte ion conformation in addition to mass/charge ratio. The physical principles that govern the mobility of an ion through a gas in the presence of a uniform electric field are well understood, enabling rotationally averaged collision cross sections (Ω) to be directly calculated from measured drift times under well-defined experimental conditions. However, such "first principle" calculations are not straightforward for Traveling Wave (T-Wave) mobility separations due to the range of factors that influence ion motion through the mobility cell. If collision cross section information is required from T-Wave mobility separations, then calibration of the instruments using known standards is essential for each set of experimental conditions. To facilitate such calibration, we have designed and generated an artificial protein based on the QconCAT technology, QCAL-IM, which upon proteolysis can be used as a universal ion mobility calibration standard. This single unique standard enables empirical calculation of peptide ion collision cross sections from the drift time on a T-Wave mobility instrument.


The fork head product directly specifies the tissue-specific hormone responsiveness of the Drosophila Sgs-4 gene.
Here we describe the identification of four binding sites of secretion enhancer binding protein 2 (SEBP2) in the regulatory region of the Drosophila salivary gland secretion protein gene 4 (Sgs-4) and show that despite these sites' correspondence with previously described Broad-Complex protein binding sites, SEBP2 is a Broad-Complex-independent factor encoded by the region-specific homeotic gene fork head (fkh). Two of the Fork head/SEBP2 binding sites are located within an ecdysone response unit which controls the tissue- and stage-specific responses of Sgs-4 to the steroid hormone 20-hydroxyecdysone. We demonstrate that these binding sites are relevant to the transcriptional activation of Sgs-4 and show that Fork head also binds to the Sgs-4 ecdysone response unit in vivo. Aside from being involved in the control of decisions during embryonic development, fkh thus participates directly in the control of specialized functions of differentiated cells at later stages of development.


Geographic differences in fractures among women.
Osteoporotic fracture is associated with considerable morbidity and mortality in women throughout the world. However, significant variation in hip fracture rates among women from different nations has been observed and is likely to represent a combination of real and apparent differences due to ascertainment bias. Higher rates are observed in Caucasian women, with lowest rates observed in black women and intermediate rates among Asian women. These differences are likely to represent a combination of genetic and environmental differences; for example, among European women, the highest fracture rates are observed in Scandinavian women where vitamin D insufficiency is common. In all groups, an increase in absolute fracture numbers is anticipated due to demographic changes.


Cytomegalovirus viraemia is associated with poor growth and T-cell activation with an increased burden in HIV-exposed uninfected infants.
Factors associated with poor health in HIV-exposed-uninfected (HEU) infants are poorly defined. We describe the prevalence and correlates of cytomegalovirus (CMV) viraemia in HEU and HIV-unexposed-uninfected (HUU) infants, and quantify associations with anthropometric, haematological, and immunological outcomes. Cross-sectional, including HEU and HUU infants from rural coastal Kenya. Infants aged 2-8 months were studied. The primary outcome was CMV viraemia and viral load, determined by quantitative PCR. Correlates were tested by logistic and linear regression; coefficients were used to describe associations between CMV viraemia and clinical/immunological parameters. In total, 42 of 65 (64.6%) infants had CMV viraemia [median viral load, 3.0 (interquartile ranges: 2.7-3.5) log10 IU/ml]. Compared to community controls, HEU infants had six-fold increased odds of being viraemic (adjusted odds ratio 5.95 [95% confidence interval: 1.82-19.36], P = 0.003). Age, but not HEU/HUU status, was a strong correlate of CMV viral load (coefficient = -0.15, P = 0.009). CMV viral load associated negatively with weight-for-age (WAZ) Z-score (coefficient = -1.06, P = 0.008) and head circumference-for-age Z-score (coefficient = -1.47, P = 0.012) and positively with CD8 T-cell coexpression of CD38/human leucocyte antigen DR (coefficient = 15.05, P = 0.003). The odds of having CMV viraemia was six-fold greater in HEU than HUU infants when adjusted for age. CMV viral load was associated with adverse growth and heightened CD8 T-cell immune activation. Longitudinal assessments of the clinical effects of primary CMV infection and associated immunomodulation in early life in HEU and HUU populations are warranted.


Frequency of Self-reported Unpleasant Events and Harm in a Mindfulness-Based Program in Two General Population Samples.
Evidence-based mindfulness programs have well-established benefits, but the potential for harmful effects is understudied. We explored the frequency and severity of unpleasant experiences and harm in two nonclinical samples participating in an adaptation of mindfulness-based cognitive therapy (MBCT) for the general population. Study 1 included 84 schoolteachers; study 2 included 74 university students. Both studies were uncontrolled. Participants completed self-report questionnaires about psychological symptoms before and after the 8-week mindfulness course. After the course, they responded to a survey designed for this study that included Likert ratings and free-text questions about unpleasant experiences and harm. All data were collected online. In both samples, about two-thirds of participants reported unpleasant experiences associated with mindfulness practice during the course. Most participants (85-92%) rated these experiences as not at all or somewhat upsetting; some indicated that difficult experiences led to important learning or were beneficial in some way. The proportion of participants reporting harm from the mindfulness course ranged from 3 to 7%. The proportion showing reliable deterioration on symptom questionnaires ranged from 2 to 7%. Those reporting harm and those showing reliable deterioration on questionnaires were largely separate subgroups; only one participant fell in both. Findings highlight the need for mindfulness teachers to manage expectations about benefits and difficulties that may occur in mindfulness-based programs and to work skilfully with participants experiencing difficulties. Experiences of harm may not be captured by symptom questionnaires and should be explicitly assessed in other ways. The online version contains supplementary material available at 10.1007/s12671-020-01547-8.


Non-communicable diseases among adolescents: current status, determinants, interventions and policies.
Addressing non-communicable disease (NCDs) is a global priority in the Sustainable Development Goals, especially for adolescents. However, existing literature on NCD burden, risk factors and determinants, and effective interventions and policies for targeting these diseases in adolescents, is limited. This study develops an evidence-based conceptual framework, and highlights pathways between risk factors and interventions to NCD development during adolescence (ages 10-19 years) and continuing into adulthood. Additionally, the epidemiologic profile of key NCD risk factors and outcomes among adolescents and preventative NCD policies/laws/legislations are examined, and a multivariable analysis is conducted to explore the determinants of NCDs among adolescents and adults. We reviewed literature to develop an adolescent-specific conceptual framework for NCDs. Global data repositories were searched from Jan-July 2018 for data on NCD-related risk factors, outcomes, and policy data for 194 countries from 1990 to 2016. Disability-Adjusted Life Years were used to assess disease burden. A hierarchical modeling approach and ordinary least squares regression was used to explore the basic and underlying causes of NCD burden. Mental health disorders are the most common NCDs found in adolescents. Adverse behaviours and lifestyle factors, specifically smoking, alcohol and drug use, poor diet and metabolic syndrome, are key risk factors for NCD development in adolescence. Across countries, laws and policies for preventing NCD-related risk factors exist, however those targeting contraceptive use, drug harm reduction, mental health and nutrition are generally limited. Many effective interventions for NCD prevention exist but must be implemented at scale through multisectoral action utilizing diverse delivery mechanisms. Multivariable analyses showed that structural/macro, community and household factors have significant associations with NCD burden among adolescents and adults. Multi-sectoral efforts are needed to target NCD risk factors among adolescents to mitigate disease burden and adverse outcomes in adulthood. Findings could guide policy and programming to reduce NCD burden in the sustainable development era.


Risk of obstructive sleep apnea in patients with Sjögren syndrome and Behçet's disease: a nationwide, population-based cohort study.
Patients with obstructive sleep apnea (OSA) have a higher risk of Behçet's disease (BD) and Sjögren syndrome (SS). However, the bidirectional relationship between these autoimmune diseases and OSA is unclear. We investigated the relationship between autoimmune diseases (SS and BD) and OSA. SS and BD patients were identified through the Taiwan National Health Insurance Research Database from 2002 to 2012. Patients with SS or BD were matched according to age and sex with a control group in a ratio of 1:4. The study included 12,926 patients with SS and 51,704 non-SS controls. Similarly, 1221 patients with BD were matched with 4884 non-BD controls. We used a Cox regression model, stratified by age, gender, and comorbidities, to assess the risk of OSA. OSA was diagnosed in 0.61% of the SS cohort and 1.23% of the BD cohort. The higher overall risk for OSA was observed significantly in patients with SS than in controls (adjusted hazard ratio [HR] = 2.48, 95% confidence interval [CI] = 1.89-3.24). The higher risk was also observed significantly in BD patients than in controls (HR = 1.99, 95% CI = 1.06-3.72). Furthermore, men with SS or BD exhibited HR of 2.62 (95% CI 1.89 to 3.62) and 6.40 (95% CI 2.96 to 13.84) for developing OSA, respectively. Risk of OSA was significantly elevated in SS or BD patients compared with controls. Further study is warranted to elucidate underlying mechanisms.


Predicting 3-year outcomes of early-identified children with hearing impairment.
PROBLEM/OBJECTIVES: Permanent childhood hearing loss has major negative impacts on children's health and development. To improve outcomes, universal newborn hearing screening (UNHS) has been implemented widely. However, high-quality evidence on its efficacy was lacking. To address this evidence gap, we conducted the Longitudinal Outcomes of Children with Hearing Impairment (LOCHI) study to directly compare outcomes of early- and late-identified children. This paper investigates whether early performance measured shortly after initial amplification predicts language development at 3 years of age. This is a prospective, population-based study. We assessed outcomes at 6- and 12-months after amplification, and then at 3 and 5 years of age. Main outcome measures included directly-assessed language, receptive vocabulary, speech production; and parent-reported functional performance in everyday life. A range of demographic and audiological information was also collected at evaluation intervals. About 450 children participated, and 3-year outcomes scores were available for 356 participants. Multiple regression analysis revealed that early language scores or functional performance ratings were significant predictors of 3-year outcomes. Other significant predictors included the presence or absence of additional disabilities, severity of hearing loss, and age at cochlear implant activation. Early performance, either directly-assessed language ability (PLS-4) or parent-reported functional ratings (PEACH), were significant predictors of 3-year outcomes; along with presence or absence of additional disabilities, severity of hearing loss, and age at CI activation. Earlier implantation is possible with early detection of hearing loss via UNHS. Monitoring performance after initial amplification allows preventive strategies to be implemented early to improve outcomes.


Studies in adipose-derived stromal cells: migration and participation in repair of cranial injury after systemic injection.
Adipose-derived stromal cells are a multipotent cell type with the ability to undergo osteogenic differentiation. The authors sought to examine whether systemically administered adipose-derived stromal cells would migrate to and heal surgically created defects of the mouse cranial skeleton. Mouse adipose-derived stromal cells were harvested from luciferase-positive transgenic mice; human adipose-derived stromal cells were harvested from human lipoaspirate and labeled with luciferase and green fluorescent protein. A 4-mm calvarial defect (critical sized) was made in the mouse parietal bone; skin incisions alone were used as a control (n = 5 per group). Adipose-derived stromal cells were injected intravenously (200,000 cells per animal) and compared with saline injection only. Methods of analyses included micro-computed tomographic scanning, in vivo imaging system detection of luciferase activity, and standard histology. Migration of adipose-derived stromal cells to calvarial defect sites was confirmed by accumulation of luciferase activity and green fluorescent protein stain as early as 4 days and persisting up to 4 weeks. Little activity was observed among control groups. Intravenous administration of either mouse or human adipose-derived stromal cells resulted in histologic evidence of bone formation within the defect site, in comparison with an absence of bone among control defects. By micro-computed tomographic analysis, human but not mouse adipose-derived stromal cells stimulated significant osseous healing. Intravenously administered adipose-derived stromal cells migrate to sites of calvarial injury. Thereafter, intravenous human adipose-derived stromal cells contribute to bony calvarial repair. Intravenous administration of adipose-derived stromal cells may be an effective delivery method for future efforts in skeletal regeneration.


Measurement of contact-angle hysteresis for droplets on nanopillared surface and in the Cassie and Wenzel states: a molecular dynamics simulation study.
We perform large-scale molecular dynamics simulations to measure the contact-angle hysteresis for a nanodroplet of water placed on a nanopillared surface. The water droplet can be in either the Cassie state (droplet being on top of the nanopillared surface) or the Wenzel state (droplet being in contact with the bottom of nanopillar grooves). To measure the contact-angle hysteresis in a quantitative fashion, the molecular dynamics simulation is designed such that the number of water molecules in the droplets can be systematically varied, but the number of base nanopillars that are in direct contact with the droplets is fixed. We find that the contact-angle hysteresis for the droplet in the Cassie state is weaker than that in the Wenzel state. This conclusion is consistent with the experimental observation. We also test a different definition of the contact-angle hysteresis, which can be extended to estimate hysteresis between the Cassie and Wenzel state. The idea is motivated from the appearance of the hysteresis loop typically seen in computer simulation of the first-order phase transition, which stems from the metastability of a system in different thermodynamic states. Since the initial shape of the droplet can be controlled arbitrarily in the computer simulation, the number of base nanopillars that are in contact with the droplet can be controlled as well. We show that the measured contact-angle hysteresis according to the second definition is indeed very sensitive to the initial shape of the droplet. Nevertheless, the contact-angle hystereses measured based on the conventional and new definition seem converging in the large droplet limit.


Unexpected formation of gold nanoflowers by a green synthesis method as agents for a safe and effective photothermal therapy.
Star fruit (Averrhoa carambola) juice rich in vitamin C and polyphenolic antioxidants was used to synthesize branched gold nanoflowers. These biocompatible and stable gold nanoflowers show strong near-infrared absorption. They are successfully demonstrated to be highly efficient for both in vitro and in vivo photothermal therapy by using an 808 nm laser.


Association of estimated sleep duration and naps with mortality and cardiovascular events: a study of 116 632 people from 21 countries.
To investigate the association of estimated total daily sleep duration and daytime nap duration with deaths and major cardiovascular events. We estimated the durations of total daily sleep and daytime naps based on the amount of time in bed and self-reported napping time and examined the associations between them and the composite outcome of deaths and major cardiovascular events in 116 632 participants from seven regions. After a median follow-up of 7.8 years, we recorded 4381 deaths and 4365 major cardiovascular events. It showed both shorter (≤6 h/day) and longer (>8 h/day) estimated total sleep durations were associated with an increased risk of the composite outcome when adjusted for age and sex. After adjustment for demographic characteristics, lifestyle behaviours and health status, a J-shaped association was observed. Compared with sleeping 6-8 h/day, those who slept ≤6 h/day had a non-significant trend for increased risk of the composite outcome [hazard ratio (HR), 1.09; 95% confidence interval, 0.99-1.20]. As estimated sleep duration increased, we also noticed a significant trend for a greater risk of the composite outcome [HR of 1.05 (0.99-1.12), 1.17 (1.09-1.25), and 1.41 (1.30-1.53) for 8-9 h/day, 9-10 h/day, and >10 h/day, Ptrend < 0.0001, respectively]. The results were similar for each of all-cause mortality and major cardiovascular events. Daytime nap duration was associated with an increased risk of the composite events in those with over 6 h of nocturnal sleep duration, but not in shorter nocturnal sleepers (≤6 h). Estimated total sleep duration of 6-8 h per day is associated with the lowest risk of deaths and major cardiovascular events. Daytime napping is associated with increased risks of major cardiovascular events and deaths in those with >6 h of nighttime sleep but not in those sleeping ≤6 h/night.


Dual-color superresolution imaging of genetically expressed probes within individual adhesion complexes.
Accurate determination of the relative positions of proteins within localized regions of the cell is essential for understanding their biological function. Although fluorescent fusion proteins are targeted with molecular precision, the position of these genetically expressed reporters is usually known only to the resolution of conventional optics ( approximately 200 nm). Here, we report the use of two-color photoactivated localization microscopy (PALM) to determine the ultrastructural relationship between different proteins fused to spectrally distinct photoactivatable fluorescent proteins (PA-FPs). The nonperturbative incorporation of these endogenous tags facilitates an imaging resolution in whole, fixed cells of approximately 20-30 nm at acquisition times of 5-30 min. We apply the technique to image different pairs of proteins assembled in adhesion complexes, the central attachment points between the cytoskeleton and the substrate in migrating cells. For several pairs, we find that proteins that seem colocalized when viewed by conventional optics are resolved as distinct interlocking nano-aggregates when imaged via PALM. The simplicity, minimal invasiveness, resolution, and speed of the technique all suggest its potential to directly visualize molecular interactions within cellular structures at the nanometer scale.


Distinct ex vivo susceptibility of B-cell subsets to epstein-barr virus infection according to differentiation status and tissue origin.
Epstein-Barr virus (EBV) uses tonsils as the portal of entry to establish persistent infection. EBV is found in various B-cell subsets in tonsils but exclusively in memory B cells in peripheral blood. The in vitro susceptibilities of B-cell subsets to EBV infection have been studied solely qualitatively. In this work, we examined quantitatively the in vitro susceptibilities of various B-cell subsets from different tissue origins to EBV infection. First, we established a centrifugation-based inoculation protocol (spinoculation) that resulted in a significantly increased proportion of infected cells compared to that obtained by conventional inoculation, enabling a detailed susceptibility analysis. Importantly, B-cell infection occurred via the known EBV receptors and infected cells showed EBV mRNA expression patterns similar to those observed after conventional inoculation, validating our approach. Tonsillar naïve and memory B cells were infected ex vivo at similar frequencies. In contrast, memory B cells from blood, which represent B cells from various lymphoid tissues, were infected at lower frequencies than their naïve counterparts. Immunoglobulin A (IgA)-positive or IgG-positive tonsillar memory B cells were significantly more susceptible to EBV infection than IgM-positive counterparts. Memory B cells were transformed with lower efficiency than naïve B cells. This result was paralleled by lower proliferation rates. In summary, these data suggest that EBV exploits the B-cell differentiation status and tissue origin to establish persistent infection.


The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's Disease (TRC-PAD): Experience from the First 3 Years.
The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD) aims to accelerate enrollment for Alzheimer's disease (AD) clinical trials by remotely identifying and tracking individuals who are at high risk for developing symptoms of AD, and referring these individuals to in-person cognitive and biomarker evaluation with the purpose of engaging them in clinical trials. A risk algorithm using statistical modeling to predict brain amyloidosis will be refined as TRC-PAD advances with a maturing data set. To provide a summary of the steps taken to build this Trial-Ready cohort (TRC) and share results of the first 3 years of enrollment into the program. Participants are remotely enrolled in the Alzheimer Prevention Trials (APT) Webstudy with quarterly assessments, and through an algorithm identified as potentially at high risk, referred to clinical sites for biomarker confirmation, and enrolled into the TRC. Both an online study and in-clinic non-interventional cohort study. APT Webstudy participants are aged 50 or older, with an interest in participation in AD therapeutic trials. TRC participants must have a study partner, stable medical condition, and elevated brain amyloid, as measured by amyloid positron emission tomography or cerebrospinal fluid analysis. Additional risk assessments include apolipoprotein E genotyping. In the APT Webstudy, participants complete the Cognitive Function Index and Cogstate Brief Battery. The TRC includes the Preclinical Alzheimer's Cognitive Composite, comprised of the Free and Cued Selective Reminding Test, the Delayed Paragraph Recall score on the Logical Memory IIa test from the Wechsler Memory Scale, the Digit-Symbol Substitution test from the Wechsler Adult Intelligence Scale-Revised, and the Mini Mental State Examination total score (1). During the first 3 years of this program, the APT Webstudy has 30,650 consented participants, with 23 sites approved for in person screening, 112 participants have been referred for in-clinic screening visits with eighteen enrolled to the TRC. The majority of participants consented to APT Webstudy have a family history of AD (62%), identify as Caucasian (92.5%), have over twelve years of formal education (85%), and are women (73%). Follow up rates for the first quarterly assessment were 38.2% with 29.5% completing the follow up Cogstate Battery. After successfully designing and implementing this program, the study team's priority is to improve diversity of participants both in the APT Webstudy and TRC, to continue enrollment into the TRC to our target of 2,000, and to improve longitudinal retention, while beginning the process of referring TRC participants into clinical trials.


Stimulative activity of Drynaria fortunei (Kunze) J. Sm. extracts and two of its flavonoids on the proliferation of osteoblastic like cells.
The osteoblastic activity of extracts of Drynaria fortunei (Kunze) J. Sm. rhizome was assayed in the UMR106 cell line cultured in vitro. An ethanol extract and its fractions were added to the cell culture at different concentrations. Osteoblastic proliferation stimulating activity was determined using the MTT method. The ethanol extract, and its ethyl acetate and n-butanol fractions exhibited stimulating activity. Two active constituents were isolated from n-butanol fraction by bioassay-directed isolation, and identified as naringin and neoeriocitrin. The latter is reported for the first time from this herbal medicine.


Designing metal hydride complexes for water splitting reactions: a molecular electrostatic potential approach.
The hydridic character of octahedral metal hydride complexes of groups VI, VII and VIII has been systematically studied using molecular electrostatic potential (MESP) topography. The absolute minimum of MESP at the hydride ligand (Vmin) and the MESP value at the hydride nucleus (VH) are found to be very good measures of the hydridic character of the hydride ligand. The increasing/decreasing electron donating feature of the ligand environment is clearly reflected in the increasing/decreasing negative character of Vmin and VH. The formation of an outer sphere metal hydride-water complex showing the HH dihydrogen interaction is supported by the location and the value of Vmin near the hydride ligand. A higher negative MESP suggested lower activation energy for H2 elimination. Thus, MESP features provided a way to fine-tune the ligand environment of a metal-hydride complex to achieve high hydridicity for the hydride ligand. The applicability of an MESP based hydridic descriptor in designing water splitting reactions is tested for group VI metal hydride model complexes of tungsten.


Brassinosteroids Modulate Meristem Fate and Differentiation of Unique Inflorescence Morphology in Setaria viridis.
Inflorescence architecture is a key determinant of yield potential in many crops and is patterned by the organization and developmental fate of axillary meristems. In cereals, flowers and grain are borne from spikelets, which differentiate in the final iteration of axillary meristem branching. In Setaria spp, inflorescence branches terminate in either a spikelet or a sterile bristle, and these structures appear to be paired. In this work, we leverage Setaria viridis to investigate a role for the phytohormones brassinosteroids (BRs) in specifying bristle identity and maintaining spikelet meristem determinacy. We report the molecular identification and characterization of the Bristleless1 (Bsl1) locus in S. viridis, which encodes a rate-limiting enzyme in BR biosynthesis. Loss-of-function bsl1 mutants fail to initiate a bristle identity program, resulting in homeotic conversion of bristles to spikelets. In addition, spikelet meristem determinacy is altered in the mutants, which produce two florets per spikelet instead of one. Both of these phenotypes provide avenues for enhanced grain production in cereal crops. Our results indicate that the spatiotemporal restriction of BR biosynthesis at boundary domains influences meristem fate decisions during inflorescence development. The bsl1 mutants provide insight into the molecular basis underlying morphological variation in inflorescence architecture.


'You shall not pass!': quantifying barrier permeability and proximity avoidance by animals.
Impediments to animal movement are ubiquitous and vary widely in both scale and permeability. It is essential to understand how impediments alter ecological dynamics via their influence on animal behavioural strategies governing space use and, for anthropogenic features such as roads and fences, how to mitigate these effects to effectively manage species and landscapes. Here, we focused primarily on barriers to movement, which we define as features that cannot be circumnavigated but may be crossed. Responses to barriers will be influenced by the movement capabilities of the animal, its proximity to the barriers, and habitat preference. We developed a mechanistic modelling framework for simultaneously quantifying the permeability and proximity effects of barriers on habitat preference and movement. We used simulations based on our model to demonstrate how parameters on movement, habitat preference and barrier permeability can be estimated statistically. We then applied the model to a case study of road effects on wild mountain reindeer summer movements. This framework provided unbiased and precise parameter estimates across a range of strengths of preferences and barrier permeabilities. The quality of permeability estimates, however, was correlated with the number of times the barrier is crossed and the number of locations in proximity to barriers. In the case study we found that reindeer avoided areas near roads and that roads are semi-permeable barriers to movement. There was strong avoidance of roads extending up to c. 1 km for four of five animals, and having to cross roads reduced the probability of movement by 68·6% (range 3·5-99·5%). Human infrastructure has embedded within it the idea of networks: nodes connected by linear features such as roads, rail tracks, pipelines, fences and cables, many of which divide the landscape and limit animal movement. The unintended but potentially profound consequences of infrastructure on animals remain poorly understood. The rigorous framework for simultaneously quantifying movement, habitat preference and barrier permeability developed here begins to address this knowledge gap.


Effect of coronary blood flow on glycolytic flux and intracellular pH in isolated rat hearts.
The rate of coronary blood flow was varied in isolated working rat heart preparations to determine its influence on the rate of glocose utilization, tissue high-energy phosphates, and intracellular pH. A 60% reduction in coronary blood flow resulted in a 30% reduction in oxygen consumption, an accelerated rate of glusoe utilization, lower tissue levels of high-energy phosphate, and higher tissue levels of lactate and H+. Ventricular performance deteriorated as reflected by a decrease in heart rate and peak systolic pressure. Further reductions in coronary blood flow resulted in inhibition of glycolysis, a greater decrease in tissue levels of high-energy phosphates, and higher tissue levels of both lactate and H+. These changes in glycolytic flux, tissue metabolites, and ventricular performance were proportional to the degree of restriction in coronary blood flow. The importance of coronary blood flow and washout of the interstitial space in the maintenance of accelerated glycolytic flux in oxygen-deficient hearts is emphasized. It is concluded that acceleration of ATP production from glycolysis can occur only in the marginally ischemic tissue in the peripheral area of tissue supplied by an occluded artery. The central area of tissue which receives a low rate of coronary blood flow will have a reduced rate of ATP production due to both a lack of oxygen and an inhibition of glycolysis.


Open Label Randomized Controlled Comparison of Three Alternative Regimes of Ciprofloxacin, Azithromycin and Cefixime for Treatment of Uncomplicated Typhoid Fever in Bangladesh.
Multi-drug resistant Typhoid fever (resistant to previously used chloramphenicol, ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole) has been commonly described in the South East Asia region and a recent report suggests that the salmonella typhi have reduced response to fluoroquinolones (nalidixic acid-resistant). The optimum treatment protocol for this type of serovar has not been established. This study compared different antimicrobial regimens for the treatment of uncomplicated typhoid fever which was conducted in the medicine ward of Dhaka Medical College Hospital (DMCH) and outdoor setting in private practice in Dhaka metropolitan city, Mymensingh and Sylhet town from January 2017 to December 2017. Bangladeshi adults with uncomplicated typhoid fever were included in this an open-label randomized controlled trial. Ciprofloxacin (20mg/kg of body weight/day for 14 days), azithromycin (20mg/kg/day for 14 days), and Cefixime (16mg/kg/day for 14 days) were compared. Of the 81 enrolled patients, 62 were eligible for analysis (61 S. enterica serovar Typhi, 1 Salmonella enterica serovar paratyphi A). Of the S enterica serovar Typhi isolates, 88.7% (55/62) were MDR and 93.5% (58/62) were nalidixic acid resistant (NAR). The clinical cure rate was 62% (13/21) with ciprofloxacin, 71% (15/21) with Cefixime, and 85% (17/20) with azithromycin (p=0.053). The mean (95% confidence interval [CI]) fever clearance time for patients treated with azithromycin (5.8 days [5.1 to 6.5 days]) was shorter than that for patients treated with cefixime (7.1 days [6.2 to 8.1 days]) and ciprofloxacin (8.2 days [7.2 to 9.2 days]) (p<0.001). All three antibiotics were well tolerated. A 7-day course of azithromycin can be successfully used in uncomplicated typhoid fever due to isolates of MDR S enterica serovar Typhi.


Stress in childhood, adolescence and early adulthood, and cortisol levels in older age.
The glucocorticoid hypothesis suggests that overexposure to stress may cause permanent upregulation of cortisol. Stress in youth may therefore influence cortisol levels even in older age. Using data from the 6-Day Sample, we investigated the effects of high stress in childhood, adolescence and early adulthood - as well as individual variables contributing to these measures; parental loss, social deprivation, school and home moves, illness, divorce and job instability - upon cortisol levels at age 77 years. Waking, waking +45 min (peak) and evening salivary cortisol samples were collected from 159 participants, and the 150 who were not using steroid medications were included in this study. After correcting for multiple comparisons, the only significant association was between early-adulthood job instability and later-life peak cortisol levels. After excluding participants with dementia or possible mild cognitive impairment, early-adulthood high stress showed significant associations with lower evening and mean cortisol levels, suggesting downregulation by stress, but these results did not survive correction for multiple comparisons. Overall, our results do not provide strong evidence of a relationship between stress in youth and later-life cortisol levels, but do suggest that some more long-term stressors, such as job instability, may indeed produce lasting upregulation of cortisol, persisting into the mid-to-late seventies.


Ascorbate and α-tocopherol differentially modulate reactive oxygen species generation by neutrophils in response to FcγR and TLR agonists.
Periodontitis, a ubiquitous chronic inflammatory disease, is associated with reduced antioxidant defences and neutrophil hyperactivity in terms of reactive oxygen species (ROS) generation. Its phenotype is thus characterized by oxidative stress. We have determined the effect of antioxidant micronutrients ascorbate and α-tocopherol on neutrophil ROS generation. Peripheral neutrophils from periodontally-healthy individuals (n = 20) were challenged with phorbol myristate acetate, IgG-opsonised Staphylococcus aureus, Fusobacterium nucleatum or PBS in the presence and absence of micronutrients (50 µM). Total and extracellular ROS were measured by luminol and isoluminol chemiluminescence respectively. Total and extracellular unstimulated, baseline ROS generation was unaffected by α-tocopherol, but inhibited by ascorbate and a combination of both micronutrients. Fcγ-receptor (Fcγ-R)-stimulated total or extracellular ROS generation was not affected by the presence of individual micronutrients. However, the combination significantly reduced extracellular FcγR-stimulated ROS release. Neither micronutrient inhibited TLR-stimulated total ROS, but the combination caused inhibition. Ascorbate and the micronutrient combination, but not α-tocopherol, inhibited extracellular ROS release by TLR-stimulated cells. Such micronutrient effects in vivo could be beneficial in reducing collateral tissue damage in chronic inflammatory diseases, such as periodontitis, while retaining immune-mediated neutrophil function.


Pomegranate phytoconstituents blunt the inflammatory cascade in a chemically induced rodent model of hepatocellular carcinogenesis.
Liver cancer, predominantly hepatocellular carcinoma (HCC), represents a complex and fatal malignancy driven primarily by oxidative stress and inflammation. Due to dismal prognosis and limited therapeutic intervention, chemoprevention has emerged as a viable approach to reduce the morbidity and mortality of HCC. Pomegranate fruit is a rich source of phytochemicals endowed with potent antioxidant and anti-inflammatory properties. We previously reported that pomegranate phytochemicals inhibit diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats though nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant mechanisms. Since Nrf2 also acts as a key mediator of the nuclear factor-kappaB (NF-κB)-regulated inflammatory pathway, our present study investigated the anti-inflammatory mechanisms of a pomegranate emulsion (PE) during DENA-induced rat hepatocarcinogenesis. Rats were administered with PE (1 or 10 g/kg) 4 weeks before and 18 weeks following DENA initiation. There was a significant increase in hepatic expressions of inducible nitric oxide synthase, 3-nitrotyrosine, heat shock protein 70 and 90, cyclooxygenase-2 and NF-κB in DENA-exposed rat livers. PE dose-dependently suppressed all aforementioned elevated inflammatory markers. A conspicuous finding of this study involves lack of cardiotoxicity of PE as assessed by monitoring cardiac function using noninvasive echocardiography. Our results provide substantial evidence that suppression of the inflammatory cascade through modulation of NF-κB signaling pathway may represent a novel mechanism of liver tumor inhibitory effects of PE against experimental hepatocarcinogenesis. Data presented here coupled with those of our earlier study underline the importance of simultaneously targeting two interconnected molecular circuits, namely, Nrf2-mediated redox signaling and NF-κB-regulated inflammatory pathway, by pomegranate phytoconstituents to achieve chemoprevention of HCC.


Alcohol use among Norwegian workers: associations with health and well-being.
There is a lack of published data on the association between alcohol consumption and health and well-being in working populations. To determine how levels of alcohol consumption are associated with psychological distress, somatic complaints, sleep and job satisfaction in the Norwegian workforce. Survey questionnaire data from a probability sample comprising Norwegian employees. The association between alcohol consumption and health and well-being was assessed using analysis of covariance. There were 1608 respondents (response rate 32%); 20% of the sample were abstainers, 72% were low- to moderate-alcohol users, 6% were moderate to high users and 2% were risky users. Adjusting for age, gender and tobacco use, employees with risky alcohol use reported significantly higher levels of psychological distress and lower job satisfaction when compared to employees who drank less. There were no differences between risky users and other employees with regard to sleep problems and somatic complaints, nor were there any gender differences. Our findings indicate that risky alcohol use in the Norwegian workforce is associated with impaired health and well-being, with no evidence of a gender differential. The findings support the thresholds for risky alcohol use as proposed by internationally recognized guidelines for alcohol consumption.


Stable locking phase limits of optically injected semiconductor lasers.
The stability of an optically injected laser is considered theoretically with an emphasis on the understanding of the locked phase whereas previous works focus primarily on the frequency detuning limits. Exemplary photon and carrier number curves for regions within and outside stable locking are presented. The dependence of the phase limits on injection ratio naturally divides into three regions with qualitatively different descriptions for the phase boundaries in each. Frequency detunings at which the locked phase is zero for different injection ratios are investigated. Using this zero phase point it is shown that the coupling rate between the injected and internal field as well as the linewidth enhancement factor can be determined in a single voltage measurement under weak injection. The modulation response parameters at these detunings are analysed and shown to be strongly interconnected.


Striatal-enriched protein tyrosine phosphatase regulates dopaminergic neuronal development via extracellular signal-regulated kinase signaling.
The striatal-enriched protein tyrosine phosphatase (STEP) is highly expressed within dopaminoceptive neurons, suggesting the possibility that STEP may interact with dopaminergic signaling. We have previously shown that signaling through dopamine D2 receptor (D2R)-mediated extracellular signal-regulated kinase (ERK) activation plays a critical role in mesencephalic dopaminergic neuronal development. Here, we investigate the role of STEP in D2R-mediated ERK signaling, especially in dopaminergic neuronal development. Analyses of developmental expression of STEP and tyrosine hydroxylase (TH) in mouse brain demonstrate that STEP- and TH-positive cells are co-localized in the substantia nigra compacta of brains of postnatal 8-day-old mice, displaying STEP expression in dopaminergic neurons at this stage. Stereological analysis demonstrates a dynamic change in the number of STEP-expressing cells from midbrain to striatum during development in WT mice and significantly decreased number of STEP-expressing cells in mice lacking D2R (D2R(-/-) mice). The knockdown of STEP expression by treatment with oligomeric STEP siRNA significantly decreased the number of mesencephalic TH cells and inhibited D2R-mediated development of dopaminergic neurons on primary mesencephalic culture from WT mice, but not in primary cultures from D2R(-/-) mice. Furthermore, knockdown of STEP expression perturbed D2R-mediated ERK signaling in dopaminergic neuronal cells from WT mice, but not from D2R(-/-) mice. These results suggest that STEP is an important mediator in the dopamine D2R-mediated activation of ERK signaling and in the regulation of dopaminergic neuronal development.


Morganella morganii bacteria produces phenol as the sex pheromone of the New Zealand grass grub from tyrosine in the colleterial gland.
Costelytra zealandica (Coleoptera: Scarabeidae) is a univoltine endemic species that has colonised and become a major pest of introduced clover and ryegrass pastures that form about half of the land area of New Zealand. Female beetles were previously shown to use phenol as their sex pheromone produced by symbiotic bacteria in the accessory or colleterial gland. In this study, production of phenol was confirmed from the female beetles, while bacteria were isolated from the gland and tested for attractiveness towards grass grub males in traps in the field. The phenol-producing bacterial taxon was identified by partial sequencing of the 16SrRNA gene, as Morganella morganii. We then tested the hypothesis that the phenol sex pheromone is biosynthesized from the amino acid tyrosine by the bacteria. This was shown to be correct, by addition of isotopically labelled tyrosine ((13)C) to the bacterial broth, followed by detection of the labelled phenol by SPME-GCMS. Elucidation of this pathway provides specific evidence how the phenol is produced as an insect sex pheromone by a mutualistic bacteria.


The influence of semantically related and unrelated text cues on the intelligibility of sentences in noise.
In two experiments with different subject groups, we explored the relationship between semantic context and intelligibility by examining the influence of visually presented, semantically related, and unrelated three-word text cues on perception of spoken sentences in stationary noise across a range of speech-to-noise ratios (SNRs). In addition, in Experiment (Exp) 2, we explored the relationship between individual differences in cognitive factors and the effect of the cues on speech intelligibility. In Exp 1, cues had been generated by participants themselves in a previous test session (own) or by someone else (alien). These cues were either appropriate for that sentence (match) or for a different sentence (mismatch). A condition with nonword cues, generated by the experimenter, served as a control. Experimental sentences were presented at three SNRs (dB SNR) corresponding to the entirely correct repetition of 29%, 50%, or 71% of sentences (speech reception thresholds; SRTs). In Exp 2, semantically matching or mismatching cues and nonword cues were presented before sentences at SNRs corresponding to SRTs of 16% and 29%. The participants in Exp 2 also performed tests of verbal working memory capacity and the ability to read partially masked text. In Exp 1, matching cues improved perception relative to the nonword and mismatching cues, with largest benefits at the SNR corresponding to 29% performance in the SRT task. Mismatching cues did not impair speech perception relative to the nonword cue condition, and no difference in the effect of own and alien matching cues was observed. In Exp 2, matching cues improved speech perception as measured using both the percentage of correctly reported words and the percentage of entirely correctly reported sentences. Mismatching cues reduced the percentage of repeated words (but not the sentence-based scores) compared with the nonword cue condition. Working memory capacity and ability to read partly masked sentences were positively associated with the number of sentences repeated entirely correctly in the mismatch condition at the 29% SNR. In difficult listening conditions, both relevant and irrelevant semantic context can influence speech perception in noise. High working memory capacity and good linguistic skills are associated with a greater ability to inhibit irrelevant context when uncued sentence intelligibility is around 29% correct.


Timing for antioxidant-priming against rice seed ageing: optimal only in non-resistant stage.
Seed deterioration due to ageing strongly affects both germplasm preservation and agricultural production. Decelerating seed deterioration and boosting seed viability become increasingly urgent. The loss of seed viability is inevitable even under cold storage. For species with short-lived seed or for regions with poor preservation infrastructure where cold storage is not readily available, seed enhancement is more reliable to increase seed viability and longevity. Antioxidant priming as a way of seed enhancement usually improves seed germination. As for post-priming survival, however, significant uncertainty exists. The controversy lies particularly on seeds of high germination percentage (GP > 95%) whose viability is hardly improvable and the benefits of priming depend on prolonging seed longevity. Therefore, this study timed antioxidant priming to prolong the longevity of high-viability seeds under artificially accelerated ageing (AAA). Rice (Nipponbare) seeds (GP > 97%) under room-temperature-storage (RTS) for 6 months. were resistant to AAA first with little viability loss for a certain period, the resistant stage. This resistance gradually vanished without GP change, during a prolonged RTS period which was named the vulnerable stage. According to the results, although antioxidant priming severely curtailed the resistant stage for seeds with a long plateau in the survival curve, it decelerated viability loss for seeds in the vulnerable stage. In complement to seed storage, priming potentially retains high seed GP which would decrease without seed enhancement. To maximize the benefits of priming for high-GP seeds, two time points are advised as the start of a time window for priming: (1) just at the end of the resistant stage without notable viability loss, which is hard to grasp by GP monitoring; (2) slight but identifiable GP decline.


Polyhydroxyalkanoate accumulation in Streptomyces coelicolor affected by SCO7613 gene region.
Polyhydroxyalkanoate (PHA) is stored as an important carbon and energy source in bacterial cells. For biomedical applications, gram-positive bacteria can be better sources of PHAs, since they lack outer membrane lipopolysaccharide. Although gram-positive Streptomyces coelicolor A3(2) has been indicated as a high potential PHA producer, pha C gene that encodes the key enzyme PHA synthase in the metabolic pathway is not determined in its genome. BLAST search results of the GenBank database argued that SCO7613 could specify a putative polyhydroxyalkanoate synthase (PhaC) responsible for PHA biosynthesis. Deduced amino acid sequence of SCO7613 showed the presence of conserved lipase box like sequence, 555GASAG559, in which serine residue was present as the active nucleophile. Present study describes deletion of putative S. coelicolor pha C gene via PCR dependent method. We showed that SCO7613 is not an essential gene in S. coelicolor and its deletion affected PHA accumulation negatively although it is not ceased. Transcomplementation abolished the mutant phenotype, demonstrating that the decrease in PHA resulted from the deletion of SCO7613.


Are multiple platelet-rich plasma injections useful for treatment of chronic patellar tendinopathy in athletes? a prospective study.
Chronic patellar tendinopathy (PT) is one of the most common overuse knee disorders. Platelet-rich plasma (PRP) appears to be a reliable nonoperative therapy for chronic PT. To evaluate clinical and radiological outcomes of 3 consecutive ultrasound (US)-guided PRP injections for the treatment of chronic PT in athletes. Case series; Level of evidence, 4. A total of 28 athletes (17 professional, 11 semiprofessional) with chronic PT refractory to nonoperative management were prospectively included for US-guided pure PRP injections into the site of the tendinopathy. The same treating physician at a single institution performed 3 consecutive injections 1 week apart, with the same PRP preparation used. All patients underwent clinical evaluation, including the Victorian Institute of Sport Assessment-Patella (VISA-P) score, visual analog scales (VAS) for pain, and Lysholm knee scale before surgery and after return to practice sports. Tendon healing was assessed with MRI at 1 and 3 months after the procedure. The VISA-P, VAS, and Lysholm scores all significantly improved at the 2-year follow-up. The average preprocedure VISA-P, VAS, and Lysholm scores improved from 39 to 94 (P < .001), 7 to 0.8 (P < .0001), and 60 to 96 (P < .001), respectively, at the 2-year follow-up. Twenty-one of the 28 athletes returned to their presymptom sporting level at 3 months (range, 2-6 months) after the procedure. Follow-up MRI assessment showed improved structural integrity of the tendon at 3 months after the procedure and complete return to normal structural integrity of the tendon in 16 patients (57%). Seven patients did not recover their presymptom sporting level (among them, 6 were considered treatment failures): 3 patients returned to sport at a lesser level, 1 patient changed his sport activity (for other reasons), and 3 needed surgical intervention. In this study, application of 3 consecutive US-guided PRP injections significantly improved symptoms and function in athletes with chronic PT and allowed fast recovery to their presymptom sporting level. The PRP treatment permitted a return to a normal architecture of the tendon as assessed by MRI.


Predictors of loss to follow-up among children in the first and second years of antiretroviral treatment in Johannesburg, South Africa.
Ninety percent of the world's 2.1 million HIV-infected children live in sub-Saharan Africa, and 2.5% of South African children live with HIV. As HIV care and treatment programmes are scaled-up, a rise in loss to follow-up (LTFU) has been observed. The aim of the study was to determine the rate of LTFU in children receiving antiretroviral treatment (ART) and to identify baseline characteristics associated with LTFU in the first year of treatment. We also explored the effect of patient characteristics at 12 months treatment on LTFU in the second year. The study is an analysis of prospectively collected routine data of HIV-infected children at the Harriet Shezi Children's Clinic (HSCC) in Soweto, Johannesburg. Cox proportional hazards models were fitted to investigate associations between baseline characteristics and 12-month characteristics with LTFU in the first and second year on ART, respectively. The cumulative probability of LTFU at 12 months was 7.3% (95% CI 7.1-8.8). In the first 12 months on ART, independent predictors of LTFU were age <1 year at initiation, recent year of ART start, mother as a primary caregiver, and being underweight (WAZ ≤ -2). Among children still on treatment at 1 year from ART initiation, characteristics that predicted LTFU within the second year were recent year of ART start, mother as a primary caregiver, being underweight (WAZ ≤ -2), and low CD4 cell percentage. There are similarities between the known predictors of death and the predictors of LTFU in the first and second years of ART. Knowing the vital status of children is important to determine LTFU. Although HIV-positive children cared for by their mothers appear to be at greater risk of becoming LTFU, further research is needed to explore the challenges faced by mothers and other caregivers and their impact on long-term HIV care. There is also a need to investigate the effects of differential access to ART between mothers and children and its impact on ART outcomes in children.


Glucose turnover and hormonal changes during insulin-induced hypoglycemia in trained humans.
Eight athletes (T), studied the third morning after the last exercise session, and seven sedentary males (C) (maximal O2 consumption 65 +/- 4 vs. 49 +/- 4 (SE) ml X kg-1 X min-1, for T and C men, respectively) had insulin infused until plasma glucose, at an insulin level of 1,600 pmol X l-1, was 1.9 mmol X l-1. Glucose turnover was determined by primed constant rate infusion of 3-[3H]glucose. Basal C-peptide (0.46 +/- 0.04 vs. 0.73 +/- 0.06 pmol X ml-1) and glucagon (4 +/- 0.4 vs. 10 +/- 2 pmol X l-1) were lower (P less than 0.05) and epinephrine higher (0.30 +/- 0.06 vs. 0.09 +/- 0.03 nmol X l-1) in T than in C subjects. During and after insulin infusion production, disappearance and clearance of glucose changed identically in T and C subjects. However, in spite of identical plasma glucose concentrations, epinephrine (7.88 +/- 0.99 vs. 3.97 +/- 0.40 nmol X l-1), growth hormone (97 +/- 17 vs. 64 +/- 6 mU X l-1), and pancreatic polypeptide (361 +/- 84 vs. 180 +/- 29 pmol X l-1) reached higher levels (P less than 0.05) and glucagon (28 +/- 3 vs. 47 +/- 10 pmol X l-1) lower levels in T than in C subjects. Blood pressures changed earlier in athletes during insulin infusion, and early recovery of heart rate, free fatty acid, and glycerol was faster. Responses of norepinephrine, cortisol, C-peptide, and lactate were similar in the two groups. Training radically changes hormonal responses but not glucose kinetics in insulin hypoglycemia.


Effects of central corneal thickness on the efficacy of topical ocular hypotensive medications.
To determine the effect of central corneal thickness (CCT) on the efficacy of intraocular pressure (IOP)-reducing drugs in patients with ocular hypertension (OHT). This retrospective study analyzed research records of 115 OHT patients and 97 ocular normotensive (ONT) volunteers. CCT was measured by slit-lamp pachymetry and IOP by pneumatonometry. The OHT patients were divided into Thick (>540 microm, n=52) and Thin (<or=540 microm, n=63) Cornea groups. Measurements in the OHT group were made after washout of all IOP-lowering drugs and at 1 week of treatment with latanoprost 0.005%, dorzolamide 2%, brimonidine 0.2%, apraclonidine 0.5%, pilocarpine 2%, or unoprostone 0.15% to 1 eye and vehicle contralaterally. ONT volunteers also were divided into Thick (n=34) and Thin (n=63) Cornea groups. Results were compared between groups using unpaired t tests or nonparametric Wilcoxon tests and within groups using linear regression analyses. Baseline IOPs were not different between CCT groups of OHT patients or of ONT volunteers. After 1 week of drug treatment, IOP was significantly (P=0.02) lower in the OHT Thin Cornea group (16.0+/-3.0 mm Hg, mean+/-SD) than the OHT Thick Cornea group (17.4+/-2.8 mm Hg). There was a positive correlation between IOP and CCT (R=0.06, P=0.007) in OHT drug-treated eyes, but not OHT vehicle-treated or ONT untreated eyes. The final IOP was significantly lower in the Thin than the Thick Cornea group treated with brimonidine (P=0.02) but not with latanoprost (P=0.91). When dosed with IOP lowering drugs, eyes with thinner corneas had lower IOPs than eyes with thicker corneas. This suggests a reduced efficacy of some glaucoma medications in ocular hypertensive patients with thick corneas.


A qualitative study of secondary distribution of HIV self-test kits by female sex workers in Kenya.
Promoting awareness of serostatus and frequent HIV testing is especially important among high risk populations such as female sex workers (FSW) and their sexual partners. HIV self-testing is an approach that is gaining ground in sub-Saharan Africa as a strategy to increase knowledge of HIV status and promote safer sexual decisions. However, little is known about self-test distribution strategies that are optimal for increasing testing access among hard-to-reach and high risk individuals. We conducted a qualitative study with 18 FSW who participated in a larger study that provided them with five oral fluid-based self-tests, training on how to use the tests, and encouragement to offer the self-tests to their sexual partners using their discretion. Women demonstrated agency in the strategies they used to introduce self-tests to their partners and to avoid conflict with partners. They carefully considered with whom to share self-tests, often assessing the possibility for negative reactions from partners as part of their decision making process. When women faced negative reactions from partners, they drew on strategies they had used before to avoid conflict and physical harm from partners, such as not responding to angry partners and forgoing payment to leave angry partners quickly. Some women also used self-tests to make more informed sexual decisions with their partners.


Unconscious processing of unattended features in human visual cortex.
Unconscious processing has been convincingly demonstrated for task-relevant feature dimensions. However, it is possible that the visual system is capable of more complex unconscious operations, extracting visual features even when they are unattended and task irrelevant. In the current study, we addressed this question by measuring unconscious priming using a task in which human participants attended to a target object's shape while ignoring its color. We measured both behavioral priming effects and priming-related fMRI activations from primes that were unconsciously presented using metacontrast masking. The results showed faster RTs and decreases in fMRI activation only when the primes were identical to the targets, indicating that primes were processed both in the attended shape and the unattended color dimensions. Reductions in activation were observed in early visual areas, including primary visual cortex, as well as in feature-responsive areas for shape and color. These results indicate that multiple features can be unconsciously encoded and possibly bound using the same visual networks activated by consciously perceived images.


Adherent and invasive Escherichia coli is associated with granulomatous colitis in boxer dogs.
The mucosa-associated microflora is increasingly considered to play a pivotal role in the pathogenesis of inflammatory bowel disease. This study explored the possibility that an abnormal mucosal flora is involved in the etiopathogenesis of granulomatous colitis of Boxer dogs (GCB). Colonic biopsy samples from affected dogs (n = 13) and controls (n = 38) were examined by fluorescent in situ hybridization (FISH) with a eubacterial 16S rRNA probe. Culture, 16S ribosomal DNA sequencing, and histochemistry were used to guide subsequent FISH. GCB-associated Escherichia coli isolates were evaluated for their ability to invade and persist in cultured epithelial cells and macrophages as well as for serotype, phylogenetic group, genome size, overall genotype, and presence of virulence genes. Intramucosal gram-negative coccobacilli were present in 100% of GCB samples but not controls. Invasive bacteria hybridized with FISH probes to E. coli. Three of four GCB-associated E. coli isolates adhered to, invaded, and replicated within cultured epithelial cells. Invasion triggered a "splash"-type response, was decreased by cytochalasin D, genistein, colchicine, and wortmannin, and paralleled the behavior of the Crohn's disease-associated strain E. coli LF 82. GCB E. coli and LF 82 were diverse in serotype and overall genotype but similar in phylogeny (B2 and D), in virulence gene profiles (fyuA, irp1, irp2, chuA, fepC, ibeA, kpsMII, iss), in having a larger genome size than commensal E. coli, and in the presence of novel multilocus sequence types. We conclude that GCB is associated with selective intramucosal colonization by E. coli. E. coli strains associated with GCB and Crohn's disease have an adherent and invasive phenotype and novel multilocus sequence types and resemble E. coli associated with extraintestinal disease in phylogeny and virulence gene profile.


Understanding the impact of mild traumatic brain injury on veteran service-connected disability: results from Chronic Effects of Neurotrauma Consortium.
Disability evaluation is complex. The association between mild traumatic brain injury (mTBI) history and VA service-connected disability (SCD) ratings can have implications for disability processes in the civilian population. We examined the association of VA SCD ratings with lifetime mTBI exposure in three models: any mTBI, total mTBI number, and blast-related mTBI. Participants were 492 Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn veterans from four US VA Medical Centers enrolled in the Chronic Effects of Neurotrauma Consortium study between January 2015 and August 2016. Analyses entailed standard covariate-adjusted linear regression models, accounting for demographic, military, and health-related confounders and covariates. Unadjusted and adjusted results indicated lifetime mTBI was significantly associated with increased SCD, with the largest effect observed for blast-related mTBI. Every unit increase in mTBI was associated with an increase in 3.6 points of percent SCD. However, hazardous alcohol use was associated with lower SCD. mTBI, especially blast related, is associated with higher VA SCD ratings, with each additional mTBI increasing percent SCD. The association of hazardous alcohol use with SCD should be investigated as it may impact veteran health services access and health outcomes. These findings have implications for civilian disability processes.


Interactive Image Segmentation Framework Based On Control Theory.
Segmentation of anatomical structures in medical imagery is a key step in a variety of clinical applications. Designing a generic, automated method that works for various structures and imaging modalities is a daunting task. Instead of proposing a new specific segmentation algorithm, in this paper, we present a general design principle on how to integrate user interactions from the perspective of control theory. In this formulation, Lyapunov stability analysis is employed to design and analyze an interactive segmentation system. The effectiveness and robustness of the proposed method are demonstrated.


The hidden majority/minority consensus: Minorities show similar preference patterns of immigrant support as the majority population.
The acceptance of new arrivals has become an important topic regarding the social cohesion of the receiving countries. However, previous studies focused only on the native population's drivers of attitudes towards immigrants, disregarding that immigrant-origin inhabitants now form a considerable part of the population. To test whether the drivers for the willingness to support immigrants are the same for natives and immigrants and their descendants, we rely on a vignette study conducted in a representative German online panel (N = 3149) which contains an overrepresentation of immigrant-origin respondents. We presented participants with three vignettes of potential immigrants, varying, amongst other factors, economic prospects, safe and war-ridden countries of origin (to capture deservingness), as well as religious identity. While we find that minority members are generally slightly more welcoming towards immigrants than majority members, at their core are the same factors that drive attitudes to immigrants in both groups: economic cost, cultural similarity, and deservingness. However, we observe differences at the margins: Immigrant-origin respondents take into account economic prospects to a lesser degree than majority members do, and by trend, they are less likely to distinguish between immigrants from war-ridden and safe countries of origin. Furthermore, we can show that the preference for immigrants with the same religious identities not only occurs among majority members but also among minority members.


Chick hair cells do not exhibit voltage-dependent somatic motility.
It is generally believed that mechanical amplification by cochlear hair cells is necessary to enhance the sensitivity and frequency selectivity of hearing. In the mammalian ear, the basis of cochlear amplification is believed to be the voltage-dependent electromotility of outer hair cells (OHCs). The avian basilar papilla contains tall and short hair cells, with the former being comparable to inner hair cells, and the latter comparable to OHCs, based on their innervation patterns. In this study, we sought evidence for somatic electromotility by direct measurements of voltage-dependent length changes in both tall and short hair cells at nanometre resolution. Microchamber and whole-cell voltage-clamp techniques were used. Motility was measured with a photodiode-based measurement system. Non-linear capacitance, an electrical signature of somatic motility, was also measured to complement motility measurement. Significantly, chick hair cells did not exhibit somatic motility nor express non-linear capacitance. The lack of somatic motility suggests that in avian hair cells the active process resides elsewhere, most likely in the hair cell stereocilia.


Confirmation of low genetic diversity and multiple breeding females in a social group of Eurasian badgers from microsatellite and field data.
The Eurasian badger (Meles meles) is a facultatively social carnivore that shows only rudimentary co-operative behaviour and a poorly defined social hierarchy. Behavioural evidence and limited genetic data have suggested that more than one female may breed in a social group. We combine pregnancy detection by ultrasound and microsatellite locus scores from a well-studied badger population from Wytham Woods, Oxfordshire, UK, to demonstrate that multiple females reproduce within a social group. We found that at least three of seven potential mothers reproduced in a group that contained 11 reproductive age females and nine offspring. Twelve primers showed variability across the species range and only five of these were variable in Wytham. The microsatellites showed a reduced repeat number, a significantly higher number of nonperfect repeats, and moderate heterozygosity levels in Wytham. The high frequency of imperfect repeats and demographic phenomena might be responsible for the reduced levels of variability observed in the badger.


Development of mathematical models for the analysis of hepatitis delta virus viral dynamics.
Mathematical models have shown to be extremely helpful in understanding the dynamics of different virus diseases, including hepatitis B. Hepatitis D virus (HDV) is a satellite virus of the hepatitis B virus (HBV). In the liver, production of new HDV virions depends on the presence of HBV. There are two ways in which HDV can occur in an individual: co-infection and super-infection. Co-infection occurs when an individual is simultaneously infected by HBV and HDV, while super-infection occurs in persons with an existing chronic HBV infection. In this work a mathematical model based on differential equations is proposed for the viral dynamics of the hepatitis D virus (HDV) across different scenarios. This model takes into consideration the knowledge of the biology of the virus and its interaction with the host. In this work we will present the results of a simulation study where two scenarios were considered, co-infection and super-infection, together with different antiviral therapies. Although, in general the predicted course of HDV infection is similar to that observed for HBV, we observe a faster increase in the number of HBV infected cells and viral load. In most tested scenarios, the number of HDV infected cells and viral load values remain below corresponding predicted values for HBV. The simulation study shows that, under the most commonly used and generally accepted therapy approaches for HDV infection, such as lamivudine (LMV) or ribavirine, peggylated alpha-interferon (IFN) or a combination of both, LMV monotherapy and combination therapy of LMV and IFN were predicted to more effectively reduce the HBV and HDV viral loads in the case of super-infection scenarios when compared with the co-infection. In contrast, IFN monotherapy was found to reduce the HDV viral load more efficiently in the case of super-infection while the effect on the HBV viral load was more pronounced during co-infection. The results suggest that there is a need for development of high efficacy therapeutic approaches towards the specific inhibition of HDV replication. These approaches may additionally be directed to the reduction of the half-life of infected cells and life-span of newly produced circulating virions.


Potential role of sylvatic and domestic African mosquito species in dengue emergence.
Dengue virus 2 (DENV-2) strains that circulate in sylvatic habitats of Senegal and other parts of west Africa are believed to represent ancestral forms that evolved into endemic/epidemic strains that now circulate widely in urban areas of the tropics. Previous studies suggested that the evolution of the endemic/epidemic strains was mediated by adaptation to the peridomestic mosquito vectors Aedes aegypti and Ae. albopictus. We conducted experimental infections using sylvatic and peridomestic Senegalese mosquitoes, and both sylvatic and urban DENV-2 strains to determine if endemic DENV-2 adaptation was vector species specific, and to assess ancestral vector susceptibility. Aedes furcifer and Ae. luteocephalus, probable sylvatic vectors, were highly susceptible to both sylvatic and urban DENV-2 strains. In contrast, sylvatic Ae. vittatus and both sylvatic and peridomestic populations of Ae. aegypti were relative refractory to all DENV-2 strains tested. These results indicate that adaptation of DENV-2 to urban vectors did not result in a loss of infectivity for some African sylvatic vectors. Implications for dengue emergence in west Africa are discussed.


Hough forests for object detection, tracking, and action recognition.
Abstract—The paper introduces Hough forests, which are random forests adapted to perform a generalized Hough transform in an efficient way. Compared to previous Hough-based systems such as implicit shape models, Hough forests improve the performance of the generalized Hough transform for object detection on a categorical level. At the same time, their flexibility permits extensions of the Hough transform to new domains such as object tracking and action recognition. Hough forests can be regarded as task-adapted codebooks of local appearance that allow fast supervised training and fast matching at test time. They achieve high detection accuracy since the entries of such codebooks are optimized to cast Hough votes with small variance and since their efficiency permits dense sampling of local image patches or video cuboids during detection. The efficacy of Hough forests for a set of computer vision tasks is validated through experiments on a large set of publicly available benchmark data sets and comparisons with the state-of-the-art.


Suppression of tumor growth and metastasis by ethanol extract of Angelica dahurica Radix in murine melanoma B16F10 cells.
The roots of Angelica dahurica have long been used as a traditional medicine in Korea to treat various diseases such as toothache and cold. In this study, we investigated the effect of ethanol extract from the roots of this plant on metastatic melanoma, a highly aggressive skin cancer, in B16F10 melanoma cells and B16F10 cell inoculated-C57BL/6 mice. Our results showed that the ethanol extracts of Angelicae dahuricae Radix (EEAD) suppressed cell growth and induced apoptotic cell death in B16F10 cells. EEAD also activated the mitochondria-mediated intrinsic apoptosis pathway, with decreased mitochondrial membrane potential, and increased production of intracellular reactive oxygen species and ration of Bax/Bcl-2 expression. Furthermore, EEAD reduced the migration, invasion, and colony formation of B16F10 cells through the reduced expression and activity of matrix metalloproteinase (MMP)-2 and -9. In addition, in vivo results demonstrated that oral administration of EEAD inhibited lactate dehydrogenase activity, hepatotoxicity, and nephrotoxicity without weight loss in B16F10 cell inoculated-mice. Importantly, EEAD was able to markedly suppress lung hypertrophy, the incidence of B16F10 cells lung metastasis, and the expression of tumor necrosis factor-alpha in lung tissue. Taken together, our findings suggest that EEAD may be useful for managing metastasis and growth of malignant cancers, including melanoma.


Palliative care for children and adolescents in Switzerland: a needs analysis across three diagnostic groups.
The objective of this qualitative study was to explore the perceptions and needs of families who care for a child with a life-limiting disease. Considering the heterogeneity of life-limiting diseases in childhood, three diagnostic groups were defined: (a) cancer, (b) neurological disorders, and (c) non-cancer/non-neurological conditions. Fifteen parents whose child had been treated in one of four children's hospitals and received palliative care or had died within the previous 2 years were interviewed. The main interview topics were: communication with professionals, need for support in care (at home or hospital), and bereavement support. Irrespective of the center of care, parents of children with diagnoses other than cancer reported a lack of support concerning practical issues of care and psychosocial aspects. Parents of children with cancer expressed difficulties related to coordination of care especially when care was provided at home. Bereaved parents emphasized their wish for bereavement support. Our findings demonstrate shortcomings in pediatric palliative care in Switzerland and outline basic needs of affected families including psychosocial support, coordination of care and bereavement support. Based on these findings we formulate some suggestions on how to initiate pediatric palliative care in a most efficient way and tailored to the needs of families in Switzerland.


A Review of the Impacts of Different Approaches for Diabetes Prevention and a Framework for Making Investment Decisions.
This paper selectively reviews the economic research on individual (i.e., diabetes prevention programs and financial rewards for weight loss) and population-wide based diabetes prevention interventions (such as food taxes, nutritional labeling, and worksite wellness programs) that demonstrate a direct reduction in diabetes incidence or improvements in diabetes risk factors such as weight, glucose or glycated hemoglobin. The paper suggests a framework to guide decision makers on how to use the available evidence to determine the optimal allocation of resources across population-wide and individual-based interventions. This framework should also assist in the discussion of what parameters are needed from research to inform decision-making on what might be the optimal mix of strategies to reduce diabetes prevalence.