Factors associated with development and distribution of granular/fuzzy astrocytes in neurodegenerative diseases.
Granular/fuzzy astrocytes (GFAs), a subtype of "aging-related tau astrogliopathy," are noted in cases bearing various neurodegenerative diseases. However, the pathogenic significance of GFAs remains unclear. We immunohistochemically examined the frontal cortex, caudate nucleus, putamen and amygdala in 105 cases composed of argyrophilic grain disease cases (AGD, N = 26), and progressive supranuclear palsy (PSP, N = 10), Alzheimer's disease (AD, N = 20) and primary age-related tauopathy cases (PART, N = 18) lacking AGD, as well as 31 cases bearing other various neurodegenerative diseases to clarify (i) the distribution patterns of GFAs in AGD, and PSP, AD and PART lacking AGD, (ii) the impacts of major pathological factors and age on GFA formation and (iii) immunohistochemical features useful to understand the formation process of GFAs. In AGD cases, GFAs consistently occurred in the amygdala (100%), followed by the putamen (69.2%) and caudate nucleus and frontal cortex (57.7%, respectively). In PSP cases without AGD, GFAs were almost consistently noted in all regions examined (90-100%). In AD cases without AGD, GFAs were less frequent, developing preferably in the putamen (35.0%) and caudate nucleus (30.0%). PART cases without AGD had GFAs most frequently in the amygdala (35.3%), being more similar to AGD than to AD cases. Ordered logistic regression analyses using all cases demonstrated that the strongest independent factor of GFA formation in the frontal cortex and striatum was the diagnosis of PSP, while that in the amygdala was AGD. The age was not significantly associated with GFA formation in any region. In GFAs in AGD cases, phosphorylation and conformational change of tau, Gallyas-positive glial threads indistinguishable from those in tufted astrocytes, and the activation of autophagy occurred sequentially. Given these findings, AGD, PSP, AD and PART cases may show distinct distributions of GFAs, which may provide clues to predict the underlying processes of primary tauopathies.


Low vitamin D status is associated with nonalcoholic Fatty liver disease independent of visceral obesity in Korean adults.
To investigate the association between serum 25-hydroxyvitamin D [25(OH)D] levels and nonalcoholic fatty liver disease (NAFLD) independent of visceral obesity in Koreans and to examine whether the associations differ according to the presence of diabetes or insulin resistance. A total of 1081 adults were enrolled from a population-based cohort in Ansan city. Serum 25(OH)D concentrations were measured in all subjects. Insulin resistance was measured by homeostasis model assessment of insulin resistance (HOMA-IR). Using computed tomography, NAFLD was diagnosed if the liver attenuation index (LAI, the difference between the mean hepatic and splenic attenuation) was <5 Hounsfield Units. In subjects with diabetes (n = 282), 25(OH)D levels were negatively associated with waist circumference, fasting insulin, HOMA-IR, triglyceride levels, and visceral abdominal fat, and were positively associated with LAI after adjusting for age, sex, season, exercise, and vitamin supplementation. In subjects without diabetes, only triglyceride level was negatively associated with 25(OH)D. The adjusted odds ratio (OR) for NAFLD increased sequentially across decreasing quartiles of 25(OH)D in subjects with diabetes even after adjusting for visceral fat [Q1 vs. Q4; OR for NAFLD 2.5 (95% CI:1.0-6.2)]. In contrast, no significant difference in OR was observed in subjects without diabetes. When we classified non-diabetic subjects by HOMA-IR, an increase in the OR for NAFLD across decreasing quartiles of 25(OH)D was observed in the high HOMA-IR (≥2.5) group [n = 207, Q1 vs. Q4; OR 3.8(1.4-10.3)], but not in the low HOMA-IR (<2.5) group [n = 592, OR 0.8 (0.3-1.9)]. Low vitamin D status is closely associated with NAFLD, independent of visceral obesity in subjects with diabetes or insulin resistance.


Glycemic control, complications, and death in older diabetic patients: the diabetes and aging study.
To identify the range of glycemic levels associated with the lowest rates of complications and mortality in older diabetic patients. We conducted a retrospective cohort study (2004-2008) of 71,092 patients with type 2 diabetes, aged ≥60 years, enrolled in Kaiser Permanente Northern California. We specified Cox proportional hazards models to evaluate the relationships between baseline glycated hemoglobin (A1C) and subsequent outcomes (nonfatal complications [acute metabolic, microvascular, and cardiovascular events] and mortality). The cohort (aged 71.0 ± 7.4 years [means ± SD]) had a mean A1C of 7.0 ± 1.2%. The risk of any nonfatal complication rose monotonically for levels of A1C >6.0% (e.g., adjusted hazard ratio 1.09 [95% CI 1.02-1.16] for A1C 6.0-6.9% and 1.86 [1.63-2.13] for A1C ≥11.0%). Mortality had a U-shaped relationship with A1C. Compared with the risk with A1C <6.0%, mortality risk was lower for A1C levels between 6.0 and 9.0% (e.g., 0.83 [0.76-0.90] for A1C 7.0-7.9%) and higher at A1C ≥11.0% (1.31 [1.09-1.57]). Risk of any end point (complication or death) became significantly higher at A1C ≥8.0%. Patterns generally were consistent across age-groups (60-69, 70-79, and ≥80 years). Observed relationships between A1C and combined end points support setting a target of A1C <8.0% for older patients, with the caution that A1Cs <6.0% were associated with increased mortality risk. Additional research is needed to evaluate the low A1C-mortality relationship, as well as protocols for individualizing diabetes care.


Prevalence of childhood celiac disease and changes in infant feeding.
Between 1984 and 1996, Sweden experienced an "epidemic" of clinical celiac disease in children <2 years of age, attributed partly to changes in infant feeding. Whether infant feeding affects disease occurrence and/or the clinical presentation remains unknown. We investigated and compared the total prevalence of celiac disease in 2 birth cohorts of 12-year-olds and related the findings to each cohort's ascertained infant feeding. A 2-phase cross-sectional screening study was performed in which 13 279 children from 2 birth cohorts participated: children born during the epidemic (1993) and children born after the epidemic (1997). Previously diagnosed cases were reported and confirmed. Blood samples were analyzed for serological markers and children with positive values were referred for small intestinal biopsy. Infant feeding practices in the cohorts were ascertained via questionnaires. Prevalence comparisons were expressed as prevalence ratios. The total prevalence of celiac disease was 29 in 1000 and 22 in 1000 for the 1993 and 1997 cohorts, respectively. Children born in 1997 had a significantly lower risk of having celiac disease compared with those born in 1993 (prevalence ratio: 0.75; 95% confidence interval: 0.60-0.93; P = .01). The cohorts differed in infant feeding (specifically, in the proportion of infants introduced to dietary gluten in small amounts during ongoing breastfeeding). A significantly reduced prevalence of celiac disease in 12-year-olds indicates an option for disease prevention. Our findings suggest that the present infant feeding recommendation to gradually introduce gluten-containing foods from 4 months of age, preferably during ongoing breastfeeding, is favorable.


Multimodal stimulus coding by a gustatory sensory neuron in Drosophila larvae.
Accurate perception of taste information is crucial for animal survival. In adult Drosophila, gustatory receptor neurons (GRNs) perceive chemical stimuli of one specific gustatory modality associated with a stereotyped behavioural response, such as aversion or attraction. We show that GRNs of Drosophila larvae employ a surprisingly different mode of gustatory information coding. Using a novel method for calcium imaging in the larval gustatory system, we identify a multimodal GRN that responds to chemicals of different taste modalities with opposing valence, such as sweet sucrose and bitter denatonium, reliant on different sensory receptors. This multimodal neuron is essential for bitter compound avoidance, and its artificial activation is sufficient to mediate aversion. However, the neuron is also essential for the integration of taste blends. Our findings support a model for taste coding in larvae, in which distinct receptor proteins mediate different responses within the same, multimodal GRN.


A longitudinal analysis of human papillomavirus 16 infection, nutritional status, and cervical dysplasia progression.
To evaluate the effect of potential risk factors, especially human papillomavirus type 16 (HPV-16) infection and nutritional status on the course of cervical dysplasia, we analyzed data from an intervention trial conducted from 1985 to 1990, in Birmingham, Alabama. With the use of data of four repeated evaluations of dysplasia at an interval of 2 months, specific relationships between HPV-16 infection, plasma retinol and zinc levels, and dysplasia progression were evaluated through longitudinal data analysis of generalized estimating equations. Repeated assessments of nutritional status from blood samples, HPV-16 infection, and dysplasia diagnosis were available from 206 women. Dysplasia diagnosis was confirmed by both Papanicolaou smear and colposcopy examinations and was classified as normal, low, or high grade squamous intraepithelial lesions according to the Bethesda system and assigned a score of 0, 1, or 2, respectively. Generalized estimating equation analyses were performed with assumptions of variance of Poisson and link of logarithm. Separate analyses were also conducted for HPV-16-positive and HPV-16-negative women. By multivariate modeling with adjustment for age, race, smoking, oral contraceptive use, and plasma levels of nutrients, HPV-16 infection was found to be related to the progression of cervical dysplasia, with a relative risk of 1.19 and a 95% confidence interval of 1.03-1.38. High plasma levels of retinol were related to the regression of cervical dysplasia, especially in HPV-16-positive women. A protective effect was also observed for high levels of zinc.(ABSTRACT TRUNCATED AT 250 WORDS)


Diarrheal Illness and Healthcare Seeking Behavior among a Population at High Risk for Diarrhea in Dhaka, Bangladesh.
Diarrhea remains one of the major causes of death in Bangladesh. We studied diarrheal disease risk and healthcare seeking behavior among populations at high risk for diarrhea in Dhaka, Bangladesh. Data were obtained from a cross-sectional survey conducted during April and September 2010. The prevalence of diarrhea was calculated by age-group and sex. A generalized estimating equation with logit link function was used to predict diarrheal disease risk and seeking care from a professional healthcare provider. Of 316,766 individuals, 10% were young children (<5 years). The prevalence of diarrhea was 16 per 1000 persons among all ages; young children accounted for 44 per 1000 persons. Prevalence of diarrhea was significantly higher (p=.003) among younger males (<15 years) compared to that among younger females. In contrast, prevalence of diarrhea was significantly higher (p<.0001) among older females (≥15 years) compared to that among older males. An increased risk for diarrhea was observed in young children, males, and those staying in rented houses, lower family members in the house, using non-sanitary toilets, living in the area for short times, living in a community with less educated persons, living in a community with less use of safe water source for drinking, or living close to the hospital. About 80% of those with diarrhea sought care initially from a non-professional healthcare provider. Choice of the professional healthcare provider was driven by age of the patient, educational status of the household head, and hygienic practices by the household. The study reaffirms that young children are at greater risk for diarrhea. Like other developing countries most people in this impoverished setting of Dhaka are less likely to seek care from a professional healthcare provider than from a non-professional healthcare provider, which could be attributed to a higher number of diarrheal deaths among young children in Bangladesh. Dissemination of information on health education, increasing the supply of skilled healthcare providers, and low-cost and quality healthcare services may encourage more people to seek care from professional healthcare providers, thus may help reduce child mortality in the country. Further studies are warranted to validate the results.


Short communication: Folates and vitamin B12 in colostrum and milk from dairy cows fed different energy levels during the dry period.
This study was undertaken to evaluate folate and vitamin B12 concentrations of colostrum and milk in early lactation of dairy cows fed different levels of energy during the dry period. A total of 84 multiparous Holstein cows were assigned to one of the following dietary treatments fed as a total mixed ration 57 d before the expected calving date: (1) high-energy one-group dry cow diet [1.35 Mcal of net energy for maintenance/kg of dry matter (DM); 56% corn silage, 12% wheat straw, and 32% concentrate mix on a daily DM basis]; (2) controlled-energy one-group dry cow diet (1.14 Mcal of net energy for maintenance/kg of DM; 29% corn silage, 36% wheat straw, and 35% concentrate mix on a daily DM basis); or (3) an intermediate step-up diet (controlled-energy diet from dry off until 29 d before the expected calving date and then switching to a diet representing a 50:50 blend of the controlled- and high-energy diets from 28 d before expected calving date until parturition; 1.24 Mcal of net energy for maintenance/kg of DM). After calving, all cows were fed the same diet served as a total mixed ration (44% corn silage, 14% grass silage, and 42% concentrate mix on a daily DM basis) until 42 d in milk (DIM). Colostrum samples were taken at the first milking after parturition and milk samples were taken during the morning milking at 11 and 39±2 DIM. Colostrum from the first milking and milk yields were weighed on the day of sampling. Colostrum yield from the first milking postpartum and milk yields at 11 and 39 DIM were unaffected by treatments. Colostrum yield averaged 6.8±0.7mg at the first milking postpartum, whereas milk yields at 11 and 39 DIM were, on average, 40.3±1.5 and 48.9±1.3mg/d, respectively. Folate concentrations in colostrum and milk were not different among treatments. Folate concentration of colostrum (440.3±18.8ng/mL) was higher than folate concentration in milk at 11 (93.7±3.0ng/mL) and at 39 DIM (78.4±2.6ng/mL). Vitamin B12 concentration in colostrum was higher for controlled-energy cows (31.7±1.4ng/mL) than intermediate cows (23.5±1.4ng/mL), whereas no treatment effect was noted for vitamin B12 concentration in milk. At 11 and 39 DIM, milk concentrations of vitamin B12 averaged 3.8 and 3.2±1.4ng/mL, respectively. In summary, results suggest that dietary change during the dry period could modify vitamin B12 concentration in colostrum, but had no effect on milk concentration of folates and vitamin B12 during early lactation.


Watchful waiting for acute otitis media: are parents and physicians ready?
To assess the current use of initial observation ("watchful waiting") of acute otitis media among community physicians and the acceptability of this option to parents of young children. Sixteen nonoverlapping Massachusetts communities enrolled in a community intervention study on appropriate antibiotic use. Pediatricians, family physicians, and a random sample of parents of children <6 years old were surveyed. Parents predicted what their satisfaction would be with initial observation of an ear infection without antibiotics if suggested by their physician and concerns they would have regarding this watchful-waiting approach. Physicians reported the frequency with which they use this approach in children > or =2 years and those <2 years old. Separate multivariable models identified factors independently associated with parental satisfaction and with frequency of self-reported use by physicians. All models accounted for clustering of responses within communities. Two thousand fifty-four (40%) parents and 160 (58%) physicians responded. Of the parents, 34% would be somewhat or extremely satisfied if initial observation was recommended, another 26% would be neutral, and the remaining 40% would be somewhat or extremely dissatisfied. The multivariable model showed lower parental education (odds ratio [OR]: 0.50; 95% confidence interval [CI]: 0.35, 0.71, for high school education or less compared with college graduation) and Medicaid enrollment (OR: 0.77; CI: 0.57, 1.0) was associated with lower predicted satisfaction. Higher antibiotic-related knowledge (OR: 1.2; CI: 1.1, 1.3, per question correct), belief that antibiotic resistance is a serious problem (OR: 2.3; CI: 1.8, 2.8), and reporting feeling included in medical decisions (OR: 1.4; CI: 1.1, 1.7) all were independently associated with higher predicted satisfaction. Thirty-eight percent of physicians treating children > or =2 years old never or almost never reported using initial observation, 39% reported use occasionally, 17% sometimes, and 6% most of the time. In a multivariable model, only more years in practice (OR: 0.96; CI: 0.93, 0.99) was associated with a decreased likelihood of occasional or more-frequent use of watchful waiting (compared with those who never use initial observation). However, a secondary model that combined occasional users with nonusers (compared with those reporting use sometimes or more often) identified several correlates of use of observation: years in practice (OR: 0.95; CI: 0.91, 0.99), family medicine specialization (OR: 4.5; CI: 1.9, 11), belief that antibiotic resistance is a significant problem (OR: 4.3; CI: 1.3, 14.5), and practice in a community receiving a judicious antibiotic-use intervention (OR: 3.5; CI: 1.3, 9.1). A majority of physicians reported at least occasionally using initial observation, but few use it frequently. Many parents have concerns regarding this option, but acceptability is increased among those with more education and those who feel included in medical decisions. Substantial change in both parental and provider views would be needed to make initial observation a widely used alternative for acute otitis media.


Visualisation and quantitative analysis of the rodent malaria liver stage by real time imaging.
The quantitative analysis of Plasmodium development in the liver in laboratory animals in cultured cells is hampered by low parasite infection rates and the complicated methods required to monitor intracellular development. As a consequence, this important phase of the parasite's life cycle has been poorly studied compared to blood stages, for example in screening anti-malarial drugs. Here we report the use of a transgenic P. berghei parasite, PbGFP-Luc(con), expressing the bioluminescent reporter protein luciferase to visualize and quantify parasite development in liver cells both in culture and in live mice using real-time luminescence imaging. The reporter-parasite based quantification in cultured hepatocytes by real-time imaging or using a microplate reader correlates very well with established quantitative RT-PCR methods. For the first time the liver stage of Plasmodium is visualized in whole bodies of live mice and we were able to discriminate as few as 1-5 infected hepatocytes per liver in mice using 2D-imaging and to identify individual infected hepatocytes by 3D-imaging. The analysis of liver infections by whole body imaging shows a good correlation with quantitative RT-PCR analysis of extracted livers. The luminescence-based analysis of the effects of various drugs on in vitro hepatocyte infection shows that this method can effectively be used for in vitro screening of compounds targeting Plasmodium liver stages. Furthermore, by analysing the effect of primaquine and tafenoquine in vivo we demonstrate the applicability of real time imaging to assess parasite drug sensitivity in the liver. The simplicity and speed of quantitative analysis of liver-stage development by real-time imaging compared to the PCR methodologies, as well as the possibility to analyse liver development in live mice without surgery, opens up new possibilities for research on Plasmodium liver infections and for validating the effect of drugs and vaccines on the liver stage of Plasmodium.


Defense mechanisms of conifers : differences in constitutive and wound-induced monoterpene biosynthesis among species.
Levels of monoterpene cyclase activity were determined in extracts from wounded and unwounded saplings of 10 conifer species to assess whether oleoresin biosynthesis is induced by stem wounding. Species of Abies and Picea, with low to moderate levels of constitutive monoterpene cyclase activity, exhibited a five- to 15-fold increase in cyclase activity 7 days after wounding relative to unwounded controls. In contrast, species of genera such as Pinus, with high levels of constitutive cyclase activity, did not significantly respond to wounding by alteration in the level of cyclase activity. The highest fold increase in monoterpene cyclase activity was consistently observed in Abies grandis, and the time-course of induction of activity following stem wounding in this species demonstrated a threefold increase at 2 days relative to unwounded controls, rising to a maximum increase in the response at 9 days (greater than 10-fold) followed by an apparent decline. The wound response was localized, and both bark (phloem) and wood (xylem) tissues displayed increased cyclase activity at the wound site. The magnitude of the increase in cyclase activity was dependent on the severity of the wound.


Reporting Bias Leading to Discordant Venous Thromboembolism Rates in the United States Versus Non-US Countries Following Radical Cystectomy: A Systematic Review and Meta-analysis.
Postcystectomy bladder cancer (BCa) patients are at high risk for developing venous thromboembolism (VTE). The literature varies widely in the reporting of VTE in this population. To determine the VTE rate in subjects undergoing radical cystectomy (RC) and highlight specific factors affecting this rate. This meta-analysis was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database, registration number: CRD42015016776. We queried MEDLINE, the Cochrane Library, Embase, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science. Search terms captured BCa, RC, and VTE. Per the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, abstracts were reviewed for inclusion/exclusion criteria by two reviewers, and disagreements were resolved by a third reviewer. A search of the gray literature and references of pertinent articles was also performed. The date of our last search was December 15, 2014. For unreported data, authors were contacted. Data were abstracted in duplicate and pooled using a random effects (RE) model. Subgroup analyses and meta-regression were performed to determine risk factors for VTE. We identified 2927 publications, of which 223 met inclusion criteria for this review. A total of 1 115 634 surgeries were performed on patient population (80% men) with a total of 51 908 VTEs. The VTE rate estimated by the RE model was 3.7%. Due to significant heterogeneity, subgroup and meta-regression analyses were undertaken. These revealed a higher rate of VTE in US studies at 4.49% compared with "westernized" non-US studies at 3.43% and "nonwesternized" non-US based studies at 2.50%. Other important modifiers included minimally invasive surgery at 5.54% versus open surgery at 3.55%, and age. The case-fatality rate of pulmonary emboli was 44%. VTE is common in patients undergoing RC. Reporting of VTE is heterogeneous and the rate varies according to study-level factors, including surgery type and country of origin. Limitations of this study include the preponderance of observational studies in the final analysis and lack of complete reporting of all variables of interest within each study. In this review, we determined the venous thromboembolism (VTE) rate in postsurgical bladder cancer patients. VTE events did vary significantly among certain subgroups.


Leadership curriculum in undergraduate medical education: a study of student and faculty perspectives.
Leaders in medicine have called for transformative changes in healthcare to address systems challenges and improve the health of the public. The purpose of this study was to elicit the perspectives of students, faculty physicians and administrators regarding the knowledge and competencies necessary in an undergraduate leadership curriculum. A mixed-methods study was conducted using focus group discussions and semi-structured interviews with faculty physicians and administrative leaders, as well as a written survey of medical student leaders. Twenty-two faculties participated in focus groups and interviews; 21 medical students responded to the written survey. Participants identified emotional intelligence, confidence, humility and creativity as necessary qualities of leaders; and teamwork, communication, management and quality improvement as necessary knowledge and skills. Students perceived themselves as somewhat or fully competent in communication (90%), conflict resolution (70%) and time management (65%), but reported minimal or no knowledge or competence in coding and billing (100%), writing proposals (90%), managed care (85%) and investment principles (85%). Both faculty and students believed that experiential training was the most effective for teaching leadership skills. Study participants identified the necessary qualities, knowledge and skills to serve as goals for an undergraduate leadership curriculum. Future studies should address optimal methods of teaching and assessing leadership skills among medical students.


The criterion-related validity of personality measures for predicting GPA: a meta-analytic validity competition.
Interest in the role of personality traits in predicting academic performance outcomes has steadily increased over the last several decades, enough to produce a number of meta-analyses that summarize this research (e.g., Poropat, 2009; Richardson, Abraham, & Bond, 2012). These previous meta-analyses combine a variety of alternative personality measures under the assumption that they all reflect the same personality traits and thus predict outcomes similarly. The current meta-analysis tests this assumption by comparing different personality measures when predicting postsecondary grade point average (GPA). The operational validities (r+) of 5 frequently used measures of the Big Five personality traits were compared: the NEO Personality Inventory--Revised (NEO-PI-R; Costa & McCrae, 1992), the NEO Five-Factor Inventory (NEO-FFI; Costa & McCrae, 1992), the Big Five Inventory (BFI; e.g., Benet-Martínez & John, 1998), Goldberg's (1992) unipolar Big Five Factor Markers (Markers), and the Big Five International Personality Item Pool (IPIP; Goldberg, 1999). A systematic review of the psychological literature from 1992 to 2012 was conducted, identifying 51 studies containing 274 correlations. Conscientiousness demonstrated the strongest criterion-related validity for predicting GPA (r+ = .23), consistent with previous meta-analyses; in addition, this overall validity was found to be robust across measures (r(BFI)(+) = .24, r(IPIP)(+) = .21, r(Markers)(+) = .15, r(NEO-FFI)(+) = .24, r(NEO-PI-R)(+) = .26). Although the criterion-related validities for Extraversion, Agreeableness, Neuroticism, and Openness to Experience (Intellect) differed by measure, they were generally low (r+s < .10). Practical implications of the findings and directions for future research are discussed.


Biology and pathogenesis of Acanthamoeba.
Acanthamoeba is a free-living protist pathogen, capable of causing a blinding keratitis and fatal granulomatous encephalitis. The factors that contribute to Acanthamoeba infections include parasite biology, genetic diversity, environmental spread and host susceptibility, and are highlighted together with potential therapeutic and preventative measures. The use of Acanthamoeba in the study of cellular differentiation mechanisms, motility and phagocytosis, bacterial pathogenesis and evolutionary processes makes it an attractive model organism. There is a significant emphasis on Acanthamoeba as a Trojan horse of other microbes including viral, bacterial, protists and yeast pathogens.


WiseEye: Next Generation Expandable and Programmable Camera Trap Platform for Wildlife Research.
The widespread availability of relatively cheap, reliable and easy to use digital camera traps has led to their extensive use for wildlife research, monitoring and public outreach. Users of these units are, however, often frustrated by the limited options for controlling camera functions, the generation of large numbers of images, and the lack of flexibility to suit different research environments and questions. We describe the development of a user-customisable open source camera trap platform named 'WiseEye', designed to provide flexible camera trap technology for wildlife researchers. The novel platform is based on a Raspberry Pi single-board computer and compatible peripherals that allow the user to control its functions and performance. We introduce the concept of confirmatory sensing, in which the Passive Infrared triggering is confirmed through other modalities (i.e. radar, pixel change) to reduce the occurrence of false positives images. This concept, together with user-definable metadata, aided identification of spurious images and greatly reduced post-collection processing time. When tested against a commercial camera trap, WiseEye was found to reduce the incidence of false positive images and false negatives across a range of test conditions. WiseEye represents a step-change in camera trap functionality, greatly increasing the value of this technology for wildlife research and conservation management.


Bactericidal Effect of Pterostilbene Alone and in Combination with Gentamicin against Human Pathogenic Bacteria.
The antibacterial activity of pterostilbene in combination with gentamicin against six strains of Gram-positive and Gram-negative bacteria were investigated. The minimum inhibitory concentration and minimum bactericidal concentration of pterostilbene were determined using microdilution technique whereas the synergistic antibacterial activities of pterostilbene in combination with gentamicin were assessed using checkerboard assay and time-kill kinetic study. Results of the present study showed that the combination effects of pterostilbene with gentamicin were synergistic (FIC index < 0.5) against three susceptible bacteria strains: Staphylococcus aureus ATCC 25923, Escherichia coli O157 and Pseudomonas aeruginosa 15442. However, the time-kill study showed that the interaction was indifference which did not significantly differ from the gentamicin treatment. Furthermore, time-kill study showed that the growth of the tested bacteria was completely attenuated with 2 to 8 h treatment with 0.5 × MIC of pterostilbene and gentamicin. The identified combinations could be of effective therapeutic value against bacterial infections. These findings have potential implications in delaying the development of bacterial resistance as the antibacterial effect was achieved with the lower concentrations of antibacterial agents.


Spreading dynamics on spatially constrained complex brain networks.
The study of dynamical systems defined on complex networks provides a natural framework with which to investigate myriad features of neural dynamics and has been widely undertaken. Typically, however, networks employed in theoretical studies bear little relation to the spatial embedding or connectivity of the neural networks that they attempt to replicate. Here, we employ detailed neuroimaging data to define a network whose spatial embedding represents accurately the folded structure of the cortical surface of a rat brain and investigate the propagation of activity over this network under simple spreading and connectivity rules. By comparison with standard network models with the same coarse statistics, we show that the cortical geometry influences profoundly the speed of propagation of activation through the network. Our conclusions are of high relevance to the theoretical modelling of epileptic seizure events and indicate that such studies which omit physiological network structure risk simplifying the dynamics in a potentially significant way.


Cross-Disciplinary Consultancy to Bridge Public Health Technical Needs and Analytic Developers: Asyndromic Surveillance Use Case.
We document a funded effort to bridge the gap between constrained scientific challenges of public health surveillance and methodologies from academia and industry. Component tasks are the collection of epidemiologists' use case problems, multidisciplinary consultancies to refine them, and dissemination of problem requirements and shareable datasets. We describe an initial use case and consultancy as a concrete example and challenge to developers. Supported by the Defense Threat Reduction Agency Biosurveillance Ecosystem project, the International Society for Disease Surveillance formed an advisory group to select tractable use case problems and convene inter-disciplinary consultancies to translate analytic needs into well-defined problems and to promote development of applicable solution methods. The initial consultancy's focus was a problem originated by the North Carolina Department of Health and its NC DETECT surveillance system: Derive a method for detection of patient record clusters worthy of follow-up based on free-text chief complaints and without syndromic classification. Direct communication between public health problem owners and analytic developers was informative to both groups and constructive for the solution development process. The consultancy achieved refinement of the asyndromic detection challenge and of solution requirements. Participants summarized and evaluated solution approaches and discussed dissemination and collaboration strategies. A solution meeting the specification of the use case described above could improve human monitoring efficiency with expedited warning of events requiring follow-up, including otherwise overlooked events with no syndromic indicators. This approach can remove obstacles to collaboration with efficient, minimal data-sharing and without costly overhead.


Ferroptosis-protective membrane domains in quiescence.
Quiescence is a common cellular state, required for stem cell maintenance and microorganismal survival under stress conditions or starvation. However, the mechanisms promoting quiescence maintenance remain poorly known. Plasma membrane components segregate into distinct microdomains, yet the role of this compartmentalization in quiescence remains unexplored. Here, we show that flavodoxin-like proteins (FLPs), ubiquinone reductases of the yeast eisosome membrane compartment, protect quiescent cells from lipid peroxidation and ferroptosis. Eisosomes and FLPs expand specifically in respiratory-active quiescent cells, and mutants lacking either show accelerated aging and defective quiescence maintenance and accumulate peroxidized phospholipids with monounsaturated or polyunsaturated fatty acids (PUFAs). FLPs are essential for the extramitochondrial regeneration of the lipophilic antioxidant ubiquinol. FLPs, alongside the Gpx1/2/3 glutathione peroxidases, prevent iron-driven, PUFA-dependent ferroptotic cell death. Our work describes ferroptosis-protective mechanisms in yeast and introduces plasma membrane compartmentalization as an important factor in the long-term survival of quiescent cells.


The RNA workbench 2.0: next generation RNA data analysis.
RNA has become one of the major research topics in molecular biology. As a central player in key processes regulating gene expression, RNA is in the focus of many efforts to decipher the pathways that govern the transition of genetic information to a fully functional cell. As more and more researchers join this endeavour, there is a rapidly growing demand for comprehensive collections of tools that cover the diverse layers of RNA-related research. However, increasing amounts of data, from diverse types of experiments, addressing different aspects of biological questions need to be consolidated and integrated into a single framework. Only then is it possible to connect findings from e.g. RNA-Seq experiments and methods for e.g. target predictions. To address these needs, we present the RNA Workbench 2.0 , an updated online resource for RNA related analysis. With the RNA Workbench we created a comprehensive set of analysis tools and workflows that enables researchers to analyze their data without the need for sophisticated command-line skills. This update takes the established framework to the next level, providing not only a containerized infrastructure for analysis, but also a ready-to-use platform for hands-on training, analysis, data exploration, and visualization. The new framework is available at https://rna.usegalaxy.eu , and login is free and open to all users. The containerized version can be found at https://github.com/bgruening/galaxy-rna-workbench.


Effects of Cultivar and Maternal Environment on Seed Quality in Vicia sativa.
Production of high quality seeds is of fundamental importance for successful crop production. However, knowledge of the effects of increased temperature resulting from global warming on seed quality of alpine species is limited. We investigated the effect of maternal environment on seed quality of three cultivars of the leguminous forage species Vicia sativa, giving particular attention to temperature. Plants of each cultivar were grown at 1700 and 3000 m a.s.l., and mass, germination, electrical conductivity (EC) of leakage and longevity were determined for mature seeds. Seeds of all three cultivars produced at the low elevation had a significantly lower mass and longevity but higher EC of leachate than those produced at the high elevation, suggesting that increased temperatures decreased seed quality. However, seed viability did not differ between elevations. The effects of maternal environment on seed germination strongly depended on cultivar and germination temperature. At 10 and 15°C, seeds of "Lanjian 3" produced at high elevation germinated to higher percentages and rates than those produced at low elevation, but the opposite trend was observed at 20°C. However, for seeds of "Lanjian 1" and "Lanjian 2," no significant effect of elevation was observed in germination percentage. Our results indicate that the best environment for the production of high quality seeds (e.g., high seed mass, low EC, high seed longevity) of V. sativa is one in which temperatures are relatively low during seed development.


A dynamic ventilation model for gravity sewer networks.
To implement any effective odour and corrosion control technology in the sewer network, it is imperative that the airflow through gravity sewer airspaces be quantified. This paper presents a full dynamic airflow model for gravity sewer systems. The model, which is developed using the finite element method, is a compressible air transport model. The model has been applied to the North Head Sewerage Ocean Outfall System (NSOOS) and calibrated using the air pressure and airflow data collected during October 2008. Although the calibration is focused on forced ventilation, the model can be applied to natural ventilation as well.


Targeted inactivation of the X-linked adrenoleukodystrophy gene in mice.
In its severe form, X-linked adrenoleukodystrophy (ALD) is a lethal neurologic disease of children, characterized by progressive cerebral demyelination and adrenal insufficiency. Associated with a biochemical defect of peroxisomal beta-oxidation, very long-chain fatty acids (VLCFA) build up in tissues that have a high turnover of lipids, such as central nervous system (CNS) white matter, adrenal cortex, and testis. Whether the abnormal accumulation of VLCFA is the underlying cause of demyelination or merely an associated biochemical marker is unknown. ALD is caused by mutations in the gene for a peroxisomal membrane protein (ALDP) that shares structural features with ATP-binding-cassette (ABC) transporters. To analyze the cellular function of ALDP and to obtain an animal model of this debilitating disease, we have generated transgenic mice with a targeted inactivation of the ald gene. Motor functions in ALDP-deficient mice developed at schedule, and unexpectedly, adult animals appeared unaffected by neurologic symptoms up to at least 6 months of age. Biochemical analyses demonstrated impaired beta-oxidation in mutant fibroblasts and abnormal accumulation of VLCFAs in the CNS and kidney. In 6-month-old mutants, adrenal cortex cells displayed a ballooned morphology and needle-like lipid inclusions, also found in testis and ovaries. However, lipid inclusions and demyelinating lesions in the CNS were not a feature. Thus, complete absence of ALDP expression results in a VLCFA storage disease but does not impair CNS function of young adult mice by pathologic and clinical criteria. This suggests that additional genetic or environmental conditions must be fulfilled to model the early-onset and lethality of cerebral ALD in transgenic mice.


Hypothermia on admission and its association with neonatal mortality and morbidity in neonatal intensive care unit.
Neonatal hypothermia is a drop in the newborn's core temperature less than 36.5°C. It is crucial in neonatal morbidity and mortality, particularly in preterm infants. This research aimed to assess the incidence and risk factors of neonatal hypothermia and its effect on neonatal mortality and short-term morbidity during Neonatal Intensive Care Unit (NICU) admission. This observational study was conducted on all neonates admitted to the NICU at Benha University Hospital. The core temperature was measured on admission for all admitted neonates and were followed up to assess the impact of hypothermia on short-term outcomes and mortality. A total of 323 neonates were admitted to the NICU throughout the research period. Thirty-five cases were excluded due to congenital anomalies or missing or late admission temperature recordings. The study included 288 neonates whose mean gestational age was 34.6±3.4 weeks, and their mean birth weight was 2.35±0.9 kg. Two-thirds (66%) of the neonates had core temperatures indicating hypothermia (axillary temperature of less than 36.5°C), one-third (33%) were normothermic, and only three (1%) were hyperthermic. Neonates with hypothermia had statistically lower gestational age, higher frequency of multiple births, prolonged need for respiratory support, higher rates of pulmonary hemorrhage, sepsis, intraventricular hemorrhage (IVH), and necrotizing enterocolitis, longer hospital stay, and mortality. There is a high incidence of neonatal hypothermia at NICU admission. Lower gestational age, increased multiples, lower APGAR score, lower birth weight, and lack of antenatal steroids were significantly associated with hypothermia at NICU admission. Hypothermia was found to be a significant factor contributing to increased mortality and morbidity rates in affected neonates.


Long-term results of laparoscopic common bile duct exploration by choledochotomy for choledocholithiasis: 15-year experience from a single center.
The aim of this study is to assess the long-term results of laparoscopic common bile duct exploration (LCBDE) and validate its effectiveness as a primary treatment modality for CBD stone. A retrospective review of the medical records of 157 patients who underwent LCBDE from 1997 to 2011 was conducted. All LCBDE were performed by choledochotomy. Clinical demographics, operative outcome, recurrence rate of CBD stones, and long-term bile duct complications were analyzed. The mean follow-up period was 51.9 months. LCBDE was completed in 152 patients (96.8%) and 5 patients (3.2%) had open conversion. The male/female ratio was 78/79 and mean age was 67.3 years. Stone clearance was successful in 149 of 152 patients (98.0%). Nonlethal complications were noted in 11 patients (7.2%), including bile leakage in 6 patients (3.9%). Recurrent CBD stones developed in 9 of 152 patients (5.9%). Preoperative endoscopic sphincterotomy (P = 0.492) and choledochotomy repair type (T-tube drainage vs. primary closure, P = 0.740) were not significantly related to stone recurrence. There were no signs of any type of biliary injury or stricture observed in any of the patients during the follow-up period. LCBDE can be performed without increased risk of long-term complications such as bile duct stricture and recurrent CBD stones. LCBDE is a safe and effective treatment option for choledocholithiasis in terms of long-term outcome as well as short-term outcome.


Isolation of Jeotgalibacillus malaysiensis sp. nov. from a sandy beach, and emended description of the genus Jeotgalibacillus.
A Gram-stain-positive, endospore-forming, rod-shaped bacterial strain, designated D5(T), was isolated from seawater collected from a sandy beach in a southern state of Malaysia and subjected to a polyphasic taxonomic study. Sequence analysis of the 16S rRNA gene demonstrated that this isolate belongs to the genus Jeotgalibacillus, with 99.87% similarity to Jeotgalibacillus alimentarius JCM 10872(T). DNA-DNA hybridization of strain D5(T) with J. alimentarius JCM 10872(T) demonstrated 26.3% relatedness. The peptidoglycan type was A1α linked directly to L-lysine as the diamino acid. The predominant quinones identified in strain D5(T) were menaquinones MK-7 and MK-8.The major fatty acids were iso-C15:0 and anteiso-C15:0. The G+C content of its DNA was 43.0 mol%. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and sulfoquinovosyl diacylglycerol, as well as two unknown phospholipids and three unknown lipids. The phenotypic, chemotaxonomic and genotypic data indicated that strain D5(T) represents a novel species of the genus Jeotgalibacillus, for which the name Jeotgalibacillus malaysiensis sp. nov. is proposed (type strain D5(T) = DSM 28777(T) = KCTC33550(T)). An emended description of the genus Jeotgalibacillus is also provided.


Next generation vaccines: single-dose encapsulated vaccines for improved global immunisation coverage and efficacy.
Vaccination is considered the most successful health intervention; yet incomplete immunisation coverage continues to risk outbreaks of vaccine preventable diseases worldwide. Vaccination coverage improvement through a single-dose prime-boost technology would revolutionise modern vaccinology, impacting on disease prevalence, significantly benefiting health care and lowering economic burden of disease. Over the past 30 years, there have been efforts to develop a single-dose delayed release vaccine technology that could replace the repeated prime-boost immunisations required for many current vaccines. Biocompatible polymers have been employed to encapsulate model vaccines for delayed delivery in vivo, using either continuous or pulsed release. Biomaterial considerations, safety aspects, particle characteristics and immunological aspects of this approach are discussed in detail. Despite many studies showing the feasibility of vaccine encapsulation for single-dose prime-boost administration, none have been translated into convincing utility in animal models or human trials. Further development of the encapsulation technology, through optimising the particle composition, formulation, antigen loading efficacy and stability, could lead to the application of this important approach in vaccine deployment. If successful, this would provide a solution to better global vaccination coverage through a reduction in the number of immunisations needed to achieve protection against infectious diseases. This review provides an overview of single-dose vaccination in the context of today's vaccine needs and is derived from a body of literature that has not been reviewed for over a decade.


Multiple roles of integrin-linked kinase in epidermal development, maturation and pigmentation revealed by molecular profiling.
Integrin-linked kinase (ILK) is an important scaffold protein that mediates a variety of cellular responses to integrin stimulation by extracellular matrix proteins. Mice with epidermis-restricted inactivation of the Ilk gene exhibit pleiotropic phenotypic defects, including impaired hair follicle morphogenesis, reduced epidermal adhesion to the basement membrane, compromised epidermal integrity, as well as wasting and failure to thrive leading to perinatal death. To better understand the underlying molecular mechanisms that cause such a broad range of alterations, we investigated the impact of Ilk gene inactivation on the epidermis transcriptome. Microarray analysis showed over 700 differentially regulated mRNAs encoding proteins involved in multiple aspects of epidermal function, including keratinocyte differentiation and barrier formation, inflammation, regeneration after injury, and fundamental epidermal developmental pathways. These studies also revealed potential effects on genes not previously implicated in ILK functions, including those important for melanocyte and melanoblast development and function, regulation of cytoskeletal dynamics, and homeobox genes. This study shows that ILK is a critical regulator of multiple aspects of epidermal function and homeostasis, and reveals the previously unreported involvement of ILK not only in epidermal differentiation and barrier formation, but also in melanocyte genesis and function.


Microplastic pollution, a threat to marine ecosystem and human health: a short review.
Human populations are using oceans as their household dustbins, and microplastic is one of the components which are not only polluting shorelines but also freshwater bodies globally. Microplastics are generally referred to particles with a size lower than 5 mm. These microplastics are tiny plastic granules and used as scrubbers in cosmetics, hand cleansers, air-blasting. These contaminants are omnipresent within almost all marine environments at present. The durability of plastics makes it highly resistant to degradation and through indiscriminate disposal they enter in the aquatic environment. Today, it is an issue of increasing scientific concern because these microparticles due to their small size are easily accessible to a wide range of aquatic organisms and ultimately transferred along food web. The chronic biological effects in marine organisms results due to accumulation of microplastics in their cells and tissues. The potential hazardous effects on humans by alternate ingestion of microparticles can cause alteration in chromosomes which lead to infertility, obesity, and cancer. Because of the recent threat of microplastics to marine biota as well as on human health, it is important to control excessive use of plastic additives and to introduce certain legislations and policies to regulate the sources of plastic litter. By setup various plastic recycling process or promoting plastic awareness programmes through different social and information media, we will be able to clean our sea dustbin in future.


Ambident Reactivity of Acetyl- and Formyl-Stabilized Phosphonium Ylides.
The kinetics and mechanism of the reactions of formyl-stabilized ylide Ph3P═CHCHO (1) and acetyl-stabilized ylide Ph3P═CHCOMe (2) with benzhydrylium ions (Ar2CH(+), 3) were investigated by UV-vis and NMR spectroscopy. As ambident nucleophiles, ylides 1 and 2 can react at oxygen as well as at the α-carbon. For some reactions, it was possible to determine the second-order rate constant for O-attack as well as for C-attack and to derive the nucleophile-specific parameters N and sN according to the correlation lg k (20 °C) = sN(E + N) for both nucleophilic sites. Generally, O-attack of benzhydrylium ions is faster than C-attack. However, the initially formed benzhydryloxyvinylphosphonium ions can only be observed by NMR spectroscopy when benzhydryl cations with high Lewis acidity are employed. In other cases, rearrangement to the thermodynamically more stable products arising from C-attack occurs. The results derived from our investigations are employed to rationalize the behavior of ambident nucleophiles 1 and 2 in reactions with carbon-centered electrophiles in general. It is shown that the principle of hard and soft acids and bases (HSAB) and the related Klopman-Salem concept of charge and orbital control lead to incorrect predictions of regioselectivity. We also show that the rate of the Wittig reaction of ylide 2 with aldehyde 14 is significantly faster than the rate of either C- or O-attack calculated using lg k (20 °C) = sN(E + N), thus indicating that the oxaphosphetane is formed by a concerted [2 + 2] cycloaddition.


Precursors of endometrial clear cell carcinoma.
The recognition of morphologically identifiable lesions which may confer an increased risk for subsequent development of an invasive malignancy offers an opportunity to investigate and better understand the molecular-genetic etiopathogenesis of the well-developed tumor, and potentially, to administer a therapeutic intervention before its development. In contrast to uterine endometrioid and serous carcinomas, very little is known about the potential precursor lesions of endometrial clear cell carcinoma (ECCC). In our routine practice, we have noted the presence of a spectrum of atypical glandular changes in the endometria adjacent to ECCC or endometrial carcinomas with a clear cell component, which on the basis of current criteria, would not qualify for any specific designation. We hypothesize that these lesions represent the earliest morphologically recognizable precursor lesions of ECCC and systematically characterize their clinicopathologic features herein. Thirty archived cases of pure ECCC (n=14) or mixed endometrial carcinomas with a >10% clear cell component (n=16) were retrieved and the "normal" endometria adjacent to the malignancies were evaluated in detail. Thirty-eight benign uteri and 30 uteri with classic endometrial endometrioid carcinoma (EEC) served as controls. All cases were reviewed in a blinded fashion. Putative precursor lesions (PPL) were searched for and identified microscopically. The lesions were typically isolated glands or surface epithelium (within an otherwise normal endometrial region) that displayed cytoplasmic clarity and/or eosinophilia with varying degrees of nuclear atypia. Twenty-seven (90%) of the 30 cases had at least 1 PPL. In contrast, PPL were identified neither in the benign uteri nor in endometrioid carcinoma control groups (P<0.001). A total of 67 foci of PPL were identified in the 27 cases with an average of 2.5 foci per case. The immunohistochemical expression of p53, mib-1, estrogen receptor (ERs), and progesterone receptor in the benign endometria, ECCC, and the PPL were evaluated on all 27 cases. The mean p53 scores for the benign endometria, PPL, and ECCC were 0, 4.5, and 6.2, respectively. Parallel values for mib-1 were 15%, 45%, and 63%. ER/progesterone receptor indices for benign endometria, PPL, and carcinoma were 90/80, 21.52/4.61, and 11/4, respectively. The PPL described herein have a morphologic and immunophenotypic profile which seems to be distinct from both the benign endometria in which they reside and the adjacent areas of ECCC. The high frequency of association of these lesions with ECCC, their frequent occurrence as isolated lesions within otherwise "benign-appearing" endometria, and their continuous spectrum of nuclear atypia from minimum (grade 1, cytologic atypia falls short of ECCC cells) to maximum (grade 3, cytologically identical to ECCC cells), argues in favor of our hypothesis that these may represent precursor lesions of ECCC. Further studies are required to conclusively define the nature of these lesions. However, such studies can only be performed if diagnostic surgical pathologists recognize, highlight, and segregate these lesions for further analysis.


How continuity of care is experienced within the context of integrated palliative care: A qualitative study with patients and family caregivers in five European countries.
Patients with advanced diseases often experience deficient continuity of care. Although integrated palliative care promotes continuity of care, it is not clear how it can be optimized to improve continuity of care experiences. To examine how relational, informational and management continuity of care are experienced by patients with advanced diseases and their family caregivers receiving care from several integrated palliative care initiatives in five European countries. We adopted a longitudinal qualitative study design including two interviews (interval 3 months) with patients and family caregivers focusing on how health care professionals responded to their needs. Interviews were audio-recorded and transcribed verbatim. Analysis involved a two-step qualitative content approach. A total of 22 integrated palliative care initiatives (established local palliative care collaborations) were selected in Belgium, Germany, Hungary, the Netherlands and the United Kingdom. We recruited 152 patients (63% cancer, 24% chronic obstructive pulmonary disease, 13% heart failure; life expectancy <1 year; mean age 68 years, 56% female) and 92 family caregivers (mean age 61 years, 66% female). Trusted relationships with a small number of key health care professionals to receive tailored care and easily access help were essential. Relational continuity was often deficient, especially with general practitioners. Although informational and management continuity was often lacking in care provision, collaborative integrated palliative care initiatives were related to consistent and coherent care. Patients and family caregivers most likely experience continuity of care by having a small number of trusted health care professionals who are available, provide multidisciplinary care and regularly transfer information to all health care professionals involved. Optimizing continuity of care requires further integration of integrated palliative care initiatives with other health care professionals involved in the patients' care networks.


Mobile tele-echography: user interface design.
Ultrasound imaging allows the evaluation of the degree of emergency of a patient. However, in some instances, a well-trained sonographer is unavailable to perform such echography. To cope with this issue, the Mobile Tele-Echography Using an Ultralight Robot (OTELO) project aims to develop a fully integrated end-to-end mobile tele-echography system using an ultralight remote-controlled robot for population groups that are not served locally by medical experts. This paper focuses on the user interface of the OTELO system, consisting of the following parts: an ultrasound video transmission system providing real-time images of the scanned area, an audio/video conference to communicate with the paramedical assistant and with the patient, and a virtual-reality environment, providing visual and haptic feedback to the expert, while capturing the expert's hand movements. These movements are reproduced by the robot at the patient site while holding the ultrasound probe against the patient skin. In addition, the user interface includes an image processing facility for enhancing the received images and the possibility to include them into a database.


Cost-effectiveness of second-generation direct-acting antiviral agents in chronic HCV infection: a systematic literature review.
Our objectives were to review the economic modelling methods and cost-effectiveness of second-generation direct-acting antiviral agents for the treatment of chronic HCV infection. A systematic literature search was performed in February 2017 using Scopus and OVID to review relevant publications between 2011 to present. Two independent reviewers screened potential papers. The database search resulted in a total of 1,536 articles; after deduplication, title/abstract and full text screening, 67 studies were included for qualitative analysis. The vast majority of studies were conducted in high-income countries (n=59) and used Markov-based modelling techniques (n=60). Most of the analyses utilized long-term time horizons; 58 studies calculated lifetime costs and outcomes. The examined treatments were heterogenic among the studies; seven analyses did not directly evaluate treatments (just with screening or genotype testing). The examined treatments (n=60) were either dominant (23%), or cost-effective at base case (57%) or in given subgroups (18%). Only one (2%) study reported that the assessed treatment was not cost-effective with the given setting and price. Despite their high initial therapeutic costs, second-generation direct-acting antiviral agents were found to be cost-effective to treat chronic HCV infection. Studies were predominantly conducted in higher income countries, although we have limited information on cost-effectiveness in low- and middle-income countries, where assessment of cost-effectiveness is even more essential due to more limited health-care resources and potentially higher public health burden due to unsafe medical interventions.


Predicting transition from acute to chronic low back pain with quantitative sensory tests-A prospective cohort study in the primary care setting.
It would be desirable to identify patients with acute low back pain (ALBP) who are at high risk for transition to chronic pain early in the course of their disease. This would enable early preventive or therapeutic interventions. Patients with chronic low back pain (CLBP) display signs of central hypersensitivity. This may contribute to the transition to CLBP. We tested the hypothesis that central hypersensitivity as assessed by quantitative sensory tests predicts transition to CLBP. We performed a prospective cohort study in 130 patients with ALBP recruited in a primary care setting to determine the ability of 14 tests using electrical, pressure and temperature stimulation to predict transition to CLBP after 6 months. We assessed the association of tests with transition to CLBP in multivariable analyses adjusted for socio-demographic, psychological and clinical characteristics, quantified the performance of tests using receiver operating characteristic (ROC) curves, and calculated likelihood ratios for different cut-off values for most promising tests. None of the evaluated tests showed a statistically significant or clinically relevant ability to predict the transition to CLBP, with 95% CI of crude and adjusted associations of all tests including one as measure of no association. Corresponding estimates of areas under the ROC curves were below 0.5, and none of the 95% CI crossed the pre-specified boundary of clinical relevance set at 0.70. We found no evidence to support a clinically relevant ability of current quantitative sensory tests to predict the transition from acute to CLBP.


Errors of interpretation and modeling: a reply to Grinband et al.
Grinband et al., 2011 compare evidence that they have collected from a neuroimaging study of the Stroop task with a simulation model of performance and conflict in that task, and interpret the results as providing evidence against the theory that activity in dorsal medial frontal cortex (dMFC) reflects monitoring for conflict. Here, we discuss several errors in their methods and conclusions and show, contrary to their claims, that their findings are entirely consistent with previously published predictions of the conflict monitoring theory. Specifically, we point out that their argument rests on the assumption that conflict must be greater on all incongruent trials than on all congruent trials-an assumption that is theoretically and demonstrably incorrect. We also point out that their simulations are flawed and diverge substantially from previously published implementations of the conflict monitoring theory. When simulated appropriately, the conflict monitoring theory predicts precisely the patterns of results that Grinband et al. take to present serious challenges to the theory. Finally, we note that their proposal that dMFC activity reflects time on task is theoretically weak, pointing to a direct relationship between behavior (RT) and neural activity but failing to identify any intervening psychological construct to relate the two. The conflict monitoring theory provides such a construct, and a mechanistic implementation that continues to receive strong support from the neuroimaging literature, including the results reported by Grinband et al.


Donald A.B. Lindberg, Pioneer in Biomedical and Health Informatics: His Involvement in Creating Professional Organizations.
Among the many contributions of Donald A.B. Lindberg was his work on behalf of a variety or professional organizations in the field of biomedical and health informatics. These began during his early days at the University of Missouri and continued throughout his 30 years at the National Library of Medicine. This chapter summarizes that work, which occurred both through his personal efforts and through the impact of the NLM under his leadership. Examples include his role in the development of organizations themselves (e.g., the International Medical Informatics Association, the American College of Medical Informatics, and the American Medical Informatics Association) and also his contributions to the professional scientific meetings that have advanced the field (e.g., the Symposium on Computer Applications in Medical Care, MEDINFO, and the AMIA Annual Symposium).


Cytosine Methylation Within Marine Sediment Microbial Communities: Potential Epigenetic Adaptation to the Environment.
Marine sediments harbor a vast amount of Earth's microbial biomass, yet little is understood regarding how cells subsist in this low-energy, presumably slow-growth environment. Cells in marine sediments may require additional methods for genetic regulation, such as epigenetic modification via DNA methylation. We investigated this potential phenomenon within a shallow estuary sediment core spanning 100 years of age. Here, we provide evidence of dynamic community m5-cytosine methylation within estuarine sediment metagenomes. The methylation states of individual CpG sites were reconstructed and quantified across three depths within the sediment core. A total of 6,254 CpG sites were aligned for direct comparison of methylation states between samples, and 4,235 of these sites mapped to taxa and genes. Our results demonstrate the presence of differential methylation within environmental CpG sites across an age gradient of sediment. We show that epigenetic modification can be detected via Illumina sequencing within complex environmental communities. The change in methylation state of environmentally relevant genes across depths may indicate a dynamic role of DNA methylation in regulation of biogeochemical processes.


Coupling of whispering-gallery modes in size-mismatched microdisk photonic molecules.
Mechanisms of whispering-gallery (WG)-mode coupling in microdisk photonic molecules (PMs) with slight and significant size mismatches are numerically investigated. The results reveal two different scenarios of modes interaction depending on the degree of this mismatch and offer new insight into how PM parameters can be tuned to control and modify WG-mode wavelengths and Q factors. From a practical point of view, these findings offer a way to fabricate PM microlaser structures that exhibit low thresholds and directional emission and at the same time are more tolerant to fabrication errors than previously explored coupled-cavity structures composed of identical microresonators.


Contrasting Regulation of Catecholamine Neurotransmission in the Behaving Brain: Pharmacological Insights from an Electrochemical Perspective.
Catecholamine neurotransmission plays a key role in regulating a variety of behavioral and physiologic processes, and its dysregulation is implicated in both neurodegenerative and neuropsychiatric disorders. Over the last four decades, in vivo electrochemistry has enabled the discovery of contrasting catecholamine regulation in the brain. These rapid and spatially resolved measurements have been conducted in brain slices, and in anesthetized and freely behaving animals. In this review, we describe the methods enabling in vivo measurements of dopamine and norepinephrine, and subsequent findings regarding their release and regulation in intact animals. We thereafter discuss key studies in awake animals, demonstrating that these catecholamines are not only differentially regulated, but are released in opposition of each other during appetitive and aversive stimuli.


Analysis of non-enzymatically glycated peptides: neutral-loss-triggered MS(3) versus multi-stage activation tandem mass spectrometry.
Non-enzymatic glycation of tissue proteins has important implications in the development of complications of diabetes mellitus. While electron transfer dissociation (ETD) has been shown to outperform collision-induced dissociation (CID) in sequencing glycated peptides by tandem mass spectrometry, ETD instrumentation is not yet widely available and often suffers from significantly lower sensitivity than CID. In this study, we evaluated different advanced CID techniques (i.e., neutral-loss-triggered MS(3) and multi-stage activation) during liquid chromatography/multi-stage mass spectrometric (LC/MS(n)) analyses of Amadori-modified peptides enriched from human serum glycated in vitro. During neutral-loss-triggered MS(3) experiments, MS(3) scans triggered by neutral losses of 3 H(2)O or 3 H(2)O + HCHO produced similar results in terms of glycated peptide identifications. However, neutral losses of 3 H(2)O resulted in significantly more glycated peptide identifications during multi-stage activation experiments. Overall, the multi-stage activation approach produced more glycated peptide identifications, while the neutral-loss-triggered MS(3) approach resulted in much higher specificity. Both techniques are viable alternatives to ETD for identifying glycated peptides.


Does adherence to the therapeutic regimen associate with health related quality of life: Findings from an observational study of type 2 diabetes mellitus patients in Pakistan.
Patient adherence with a therapeutic regimen predicts successful treatment and reduces the severity of negative complications. The purpose of this work was to find the relationship between general Health Related Quality of Life (HRQoL) and compliance to the treatment among type 2 diabetes mellitus patients (T2DM) in Sargodha, Pakistan. The research was planned as a cross-sectional survey. T2DM patients attending a tertiary care institute in Sargodha, Pakistan were targeted for the study. The Urdu version of the Morisky Medication Adherence Scale (MMAS-Urdu) and EuroQol Quality of Life Scale were employed to evaluate adherence to treatment regimen and HRQoL correspondingly. Descriptive statistics were used for the elaboration of socio-demographic characteristics. The Spearman rank order test was employed to determine the relationship between medicine adherence and HRQoL. P<0.05 was considered statistically significant. A total of 392 patients were selected for the survey. Most participants were males (n=222, 56.6%) with 5.58±4.09 years of history of T2DM. Majority of respondents (n=137, 34.9%) were categorized in age group of 51 to 60 years with mean age of 50.77±9.671 years. The present study highlighted that individuals with type 2 diabetes mellitus had decreased HRQoL (0.4715±0.3360) and poor medication adherence (4.44±1.8). Significant, yet weak positive correlations were observed between medication adherence and HRQoL (r=0.217 and 0.136 for EQ-5D and EQVAS respectively). Although the association between adherence to therapeutic regimen and HRQoL in the present study cohort was significant, it was rated as weak, hence failed in producing an overall impression on quality of life. The study highlights the need of identifying other individual factors affecting HRQoL among T2DM patients in Pakistan.


Complete mitochondrial genomes of the New World jacanas: Jacana spinosa and Jacana jacana.
The New World jacanas, Jacana spinosa (Mexico to Panama and also the West Indies) and Jacana jacana (Panama and South America), are polyandrous freshwater waders that are common throughout the Neotropics. These two species hybridize narrowly at their contact zone in Panama, and as part of a study of the hybrid zone dynamics, we present complete, annotated mitochondrial genomes for both species. The two species have very similar mitochondrial genomes, showing identical gene orders, and differing in size in only two RNA features and the control region, and among protein-coding genes, the two genomes had average uncorrected pairwise divergence of 1.8%, ranging from 0.7% for ND4L and 3.6% for ATP8. However, control region divergence is high (∼ 16%). These mitochondrial genome sequences may be useful tools for understanding jacana hybridization dynamics, especially regarding potential mitonuclear incompatibilities.


Neuronal Dysfunction Is Linked to the Famine-Associated Risk of Proliferative Retinopathy in Patients With Type 2 Diabetes.
Persons with type 2 diabetes born in the regions of famine exposures have disproportionally elevated risk of vision-threatening proliferative diabetic retinopathy (PDR) in adulthood. However, the underlying mechanisms are not known. In the present study, we aimed to investigate the plausible molecular factors underlying progression to PDR. To study the association of genetic variants with PDR under the intrauterine famine exposure, we analyzed single nucleotide polymorphisms (SNPs) that were previously reported to be associated with type 2 diabetes, glucose, and pharmacogenetics. Analyses were performed in the population from northern Ukraine with a history of exposure to the Great Ukrainian Holodomor famine [the Diagnostic Optimization and Treatment of Diabetes and its Complications in the Chernihiv Region (DOLCE study), n = 3,583]. A validation of the top genetic findings was performed in the Hong Kong diabetes registry (HKDR, n = 730) with a history of famine as a consequence of the Japanese invasion during WWII. In DOLCE, the genetic risk for PDR was elevated for the variants in ADRA2A, PCSK9, and CYP2C19*2 loci, but reduced at PROX1 locus. The association of ADRA2A loci with the risk of advanced diabetic retinopathy in famine-exposed group was further replicated in HKDR. The exposure of embryonic retinal cells to starvation for glucose, mimicking the perinatal exposure to famine, resulted in sustained increased expression of Adra2a and Pcsk9, but decreased Prox1. The exposure to starvation exhibited a lasting inhibitory effects on neurite outgrowth, as determined by neurite length. In conclusion, a consistent genetic findings on the famine-linked risk of ADRA2A with PDR indicate that the nerves may likely to be responsible for communicating the effects of perinatal exposure to famine on the elevated risk of advanced stages of diabetic retinopathy in adults. These results suggest the possibility of utilizing neuroprotective drugs for the prevention and treatment of PDR.


Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes.
Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), along with a small amount of porphyrin-phospholipid (PoP). Near-infrared (NIR) light caused release of entrapped Dox via PoP-mediated DOTAP photo-oxidation. The formulation was optimized to enable extremely rapid NIR light-triggered Dox release (i.e., in 15 seconds), while retaining reasonable serum stability. In vitro, cationic PoP liposomes readily bound to both MIA PaCa-2 human pancreatic cancer cells and human vascular endothelial cells. When administered intravenously, cationic PoP liposomes were cleared from circulation within minutes, with most accumulation in the liver and spleen. Fluorescence imaging revealed that some cationic PoP liposomes also localized at the tumor blood vessels. Compared with analogous neutral liposomes, strong tumor photoablation was induced with a single treatment of cationic PoP liposomes and laser irradiation (5 mg/kg Dox and 100 J/cm2 NIR light). Unexpectedly, empty cationic PoP liposomes (lacking Dox) induced equally potent antitumor phototherapeutic effects as the drug loaded ones. A more balanced chemo- and phototherapeutic response was subsequently achieved when antitumor studies were repeated using higher drug dosing (7 mg/kg Dox) and a low fluence phototreatment (20 J/cm2 NIR light). These results demonstrate the feasibility of vessel-targeted chemophototherapy using cationic PoP liposomes and also illustrate synergistic considerations. Mol Cancer Ther; 16(11); 2452-61. ©2017 AACR.


Incorporating Sex As a Biological Variable in Neuropsychiatric Research: Where Are We Now and Where Should We Be?
Understanding the multiplicity of ways in which sex can alter the brain is essential to crafting policies and treatments that are beneficial for all human beings. This is particularly true for the field of neuropsychopharmacology, as many neuropsychiatric disorders exhibit gender bias in the frequency, severity, or response to treatment. The goal of this circumspective is to provide two views on the current state of the art of the relations between sex and the brain, relations that are studied almost exclusively by comparing females and males on specific end points, from gene expression to behavior. We start by suggesting a framework for defining what is being measured and what it means. We suggest that 'sex differences' can be classified on four dimensions: (1) persistent vs transient across the lifespan; (2) context independent vs dependent; (3) dimorphic vs continuous; and (4) a direct vs an indirect consequence of sex. To accurately classify a sex difference along these dimensions, one may need to compare females and males under varied conditions. We next discuss current data on the mechanisms of sexual differentiation of the brain and on sex differences in the brain to conclude that the brain of each male and female is a mosaic of relative masculinization, feminization, and sameness, which theoretically could produce an infinite variety of individuals. We also raise the possibility that sex differences in the brain are canalized, which may act to both enhance and restrain variation between males and females. We end by discussing ways to consider sex when studying neuropsychiatric disorders.


Next-generation polyploid phylogenetics: rapid resolution of hybrid polyploid complexes using PacBio single-molecule sequencing.
Difficulties in generating nuclear data for polyploids have impeded phylogenetic study of these groups. We describe a high-throughput protocol and an associated bioinformatics pipeline (Pipeline for Untangling Reticulate Complexes (Purc)) that is able to generate these data quickly and conveniently, and demonstrate its efficacy on accessions from the fern family Cystopteridaceae. We conclude with a demonstration of the downstream utility of these data by inferring a multi-labeled species tree for a subset of our accessions. We amplified four c. 1-kb-long nuclear loci and sequenced them in a parallel-tagged amplicon sequencing approach using the PacBio platform. Purc infers the final sequences from the raw reads via an iterative approach that corrects PCR and sequencing errors and removes PCR-mediated recombinant sequences (chimeras). We generated data for all gene copies (homeologs, paralogs, and segregating alleles) present in each of three sets of 50 mostly polyploid accessions, for four loci, in three PacBio runs (one run per set). From the raw sequencing reads, Purc was able to accurately infer the underlying sequences. This approach makes it easy and economical to study the phylogenetics of polyploids, and, in conjunction with recent analytical advances, facilitates investigation of broad patterns of polyploid evolution.


Modulating the therapeutic response of tumours to dietary serine and glycine starvation.
The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis, many others rely on exogenous serine for optimal growth. Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.


Incidence and transmission patterns of acute hepatitis C in the United States, 1982-2006.
Monitoring disease incidence and transmission patterns is important to characterize groups at risk for hepatitis C virus (HCV) infection. Clinical cases generally represent about 20% to 30% of all newly acquired infections. We used sentinel surveillance to determine incidence and transmission patterns for acute hepatitis C in the United States using data from 25 years of population-based surveillance in the general community. Acute cases of hepatitis C were identified from 1982 through 2006 by a stimulated passive surveillance system in 4 to 6 US counties. Cases were defined by a discrete onset of symptoms, alanine aminotransferase (ALT) levels greater than 2.5 times the upper limit of normal (×ULN), negative findings for serologic markers for acute hepatitis A and B, and positive findings for antibody to HCV or HCV RNA. Incidence and frequency of reported risk factors were the main outcome measures. Of 2075 patients identified, the median age was 31 years, 91.5% had ALT values greater than 7×ULN, 77.3% were jaundiced, 22.5% were hospitalized, and 1.2% died. Incidence averaged 7.4 per 100,000 individuals (95% confidence interval [CI], 6.4-8.5 per 100,000) during 1982 to 1989 then declined averaging 0.7 per 100,000 (95% CI, 0.5-1.0 per 100,000) during 1994 to 2006. Among 1748 patients interviewed (84.2%), injection drug use (IDU) was the most commonly reported risk factor. The average number of IDU-related cases declined paralleling the decline in incidence, but the proportion of IDU-related cases rose from 31.8% (402 of 1266) during 1982 to 1989 to 45.6% (103 of 226) during 1994 to 2006. Among IDU-related cases reported during 1994 to 2006, 56 of 61 individuals (91.8%) had been in a drug treatment program and/or incarcerated. The incidence of acute HCV declined substantially over the 25 years of population-based surveillance. Despite declines, IDU is the most common risk factor for new HCV infection.


Effect of acupuncture treatment on the immune function impairment found in anxious women.
It is presently accepted that emotional disturbances lead to immune system impairment, and that therefore their treatment could restore the immune response. Thus, the aim of the present work was to study the effect of an acupuncture treatment, designed specifically to relieve the emotional symptoms stemming from anxiety, on several functions (adherence, chemotaxis, phagocytosis, basal and stimulated superoxide anion levels, lymphocyte proliferation in response to phytohemagglutinin A (PHA) and natural killer (NK) activity) of leukocytes (neutrophils and lymphocytes) from anxious women. The acupuncture protocol consisted of manual needle stimulation of 19 acupoints, with each session lasting 30 min. It was performed on 34 female 30-60 year old patients, suffering from anxiety, as determined by the Beck Anxiety Inventory (BAI). Before and 72 hours after receiving the first acupuncture session, peripheral blood samples were drawn. In 12 patients, samples were also collected immediately after the first single acupuncture session and one month after the end of the whole acupuncture treatment, which consisted of 10 sessions during a year, until the complete remission of anxiety. Twenty healthy non-anxious women in the same age range were used as controls. The results showed that the most favorable effects of acupuncture on the immune functions appear 72 hours after the single session and persist one month after the end of the complete treatment. Impaired immune functions in anxious women (chemotaxis, phagocytosis, lymphoproliferation and NK activity) were significantly improved by acupuncture, and augmented immune parameters (superoxide anion levels and lymphoproliferation of the patient subgroup whose values had been too high) were significantly diminished. Acupuncture brought the above mentioned parameters to values closer to those of healthy controls, exerting a modulatory effect on the immune system.


Endocrine function after hetero- and ortho-topic segmental pancreatic transplantation in primates.
This study assessed the early postoperative pancreatic endocrine function after intraperitoneal segmental hetero- and ortho-topic pancreatic allotransplantation in hemipancreatectomized, nonimmunesuppressed chacma baboons. Hemipancreatectomized animals remained normoglycaemic but rendered significantly reduced K values and insulin release during IVGTT, findings consistent with major pancreatic resection. Segmental hetero- or ortho-topic pancreatic transplantation did not improve reduced K values and hypoinsulinaemia following hemipancreatectomy although orthotopically sited grafts rendered the best glucose tolerance test curves. Glucagon output during IVGTT remained the same in both transplant models. It is concluded that the postoperative hormonal response was similar in both orthotopic and heterotopic transplant recipients, which indicates that drainage of graft venous effluent into the portal circulation has no advantage over systemic insulin drainage as reflected in this "diabetic" model.


The Impact and Statistical Analysis of a Multifaceted Anticoagulation Strategy in Children Supported on ECMO: Performance and Pitfalls.
We sought to determine whether the introduction of a new anticoagulation protocol improved the frequency with which target anticoagulation parameters were met in children supported with extracorporeal membrane oxygenation (ECMO). Additionally, we sought to correlate the results of various tests of anticoagulation with the heparin infusion dose (HID) for patients on ECMO and to evaluate the utility of these anticoagulation monitoring tests for the titration of the HID. A retrospective chart review of 18 patients who received ECMO at an academic tertiary care children's hospital. Nine patients who were managed using a new anticoagulation protocol were matched by age and diagnosis with 9 patients managed with the old protocol. We collected data relating to patient demographics, type of extracorporeal support, disease process, and incidence of bleeding or thrombosis. Anticoagulation parameters collected include the activated clotting time (ACT), activated partial thromboplastin time (aPTT), prothrombin time/international normalized ratio, anti-factor Xa level, and antithrombin 3 level along with the HID at each time point. Patient groups were compared using a Generalized Linear Mixed Model, a mixed model analysis of variance, and correlational studies. The percentage of in-range ACT values was not different between the 2 protocols, whereas the percentage of in-range aPTT values was higher in the new anticoagulation protocol (ACT: 37.7% vs 39.5%; aPTT: 25.1% vs 39.8%). After accounting for repeated and variable measures within patients, the probability of obtaining an in-range ACT and aPTT did not differ significantly between the 2 protocols (ACT: P = .3488; aPTT: P = .16). The mean HID did not differ between the 2 groups (35.0 unit/kg/h vs 37.6 unit/kg/h, P = .56). Correlation coefficients demonstrated a significant inverse correlation between the ACT and the HID in both the groups (old: r = -.22, P < .0001; new: r = -.26, P < .0001). We observed a significant positive correlation between the aPTT and the HID in the historical group (r = .25, P < .0001), but no correlation between the aPTT and the HID in the current group (r = -.02, P = .71). The anti-factor Xa level showed a significantly positive correlation with the HID in the current group (r = .62, P < .0001). A multipronged monitoring regimen slightly increased the amount of time that anticoagulation parameters were within range. Correlations between the HID and the aPTT differed based on anticoagulation protocol, with a positive correlation in the older protocol and no correlation in the new protocol. This may highlight a problem in study design and analysis that requires further examination. Further trials are needed to assess the most useful markers with which anticoagulation protocols for ECMO can be created, adjusted, and evaluated.


Metabolic and cardiovascular genes in polycystic ovary syndrome: a candidate-wide association study (CWAS).
The role of metabolic disturbance in polycystic ovary syndrome (PCOS) has been well established, with insulin resistance and the resulting compensatory hyperinsulinemia thought to promote hyperandrogenemia. Genome-wide association studies (GWAS) have established a large number of loci for metabolic conditions such as type 2 diabetes and obesity. A subset of these loci has been investigated for a role in PCOS; these studies generally have not revealed a confirmed role for these loci in PCOS risk. However, a large scale investigation of genes related to these pathways has not previously been performed. We conducted a two stage case control association study of 121,715 single nucleotide polymorphisms (SNPs) selected to represent susceptibility loci associated with traits such as type 2 diabetes, obesity measures, lipid levels and cardiovascular function using the Cardio-Metabochip in 847 PCOS cases and 845 controls. Several hypothesis-generating associations with PCOS were observed (top SNP rs2129107, P=3.8×10(-6)). We did not find any loci definitively associated with PCOS after strict correction for multiple testing, suggesting that cardio-metabolic loci are not major risk factors underlying the susceptibility to PCOS.


The impact of forensic investigations following assisted suicide on post-traumatic stress disorder.
In Switzerland, all deaths through assisted suicide are reported as unnatural deaths and investigated by a forensic team (police, medical examiner, and state attorney). However, there is limited knowledge concerning the impact these forensic investigations have on the development of post-traumatic stress disorder, complicated grief, or depression in those who have lost a loved one. A cross-sectional survey of 85 family members or close friends who were present at an assisted suicide was conducted in December 2007. The Impact of Event Scale, Inventory of Complicated Grief, and Brief Symptom Inventory were used to assess mental health. The newly developed Forensic Investigation Experience Scale measured the emotional experience of the legal investigation at the death scene. The data suggest that the diagnosis of post-traumatic stress disorder is significantly related to having experienced the forensic investigation as emotionally difficult. Thus, the way the forensic investigation is conducted immediately after an unnatural death is evidently associated with the development of post-traumatic stress. It is recommended that a protocol be developed establishing a standardised response to cases of assisted suicide and that specific training be provided for the legal professionals involved.


Full genome sequence analysis of a newly emerged QX-like infectious bronchitis virus from Sudan reveals distinct spots of recombination.
Infectious bronchitis virus (IBV) infection continues to cause economically important diseases in poultry while different geno- and serotypes continue to circulate globally. Two infectious bronchitis viruses (IBV) were isolated from chickens with respiratory disease in Sudan. Sequence analysis of the hypervariable regions of the S1 gene revealed a close relation to the QX-like genotype which has not been detected in Sudan before. Whole genome analysis of IBV/Ck/Sudan/AR251-15/2014 isolate by next generation sequencing revealed a genome size of 27,646 nucleotides harbouring 13 open reading frames: 5'-1a-1b-S-3a-3b-E-M-4b-4c-5a-5b-N-6b-3'. Highest nucleotide sequence identity of 93% for the whole genome was found with the Chinese IBV strain Ck/CH/LHLJ/140906, the Italian IBV isolate ITA/90254/2005 and the 4/91 vaccine strain. Phylogenetic analysis of the S1 gene revealed that the IBV/Ck/Sudan/AR251-15/2014 isolate clustered together with viruses of the GI-19 lineage. Recombination analysis gave evidence for distinct patterns of origin of RNA in the Sudanese isolate in multiple genes. Several sites of recombination were scattered throughout the genome suggesting that the Sudan-QX-like strain emerged as a unique recombinant from multiple recombination events of parental viruses from 4/91, H120 and ITA/90254/2005 genotypes. The Sudanese QX-like isolate is plausibly genetically different from IBV strains previously reported in Africa and elsewhere.


Differential magnesium implant corrosion coat formation and contribution to bone bonding.
Magnesium alloys are presently under investigation as promising biodegradable implant materials with osteoconductive properties. To study the molecular mechanisms involved, the potential contribution of soluble magnesium corrosion products to the stimulation of osteoblastic cell differentiation was examined. However, no evidence for the stimulation of osteoblast differentiation could be obtained when cultured mesenchymal precursor cells were differentiated in the presence of metallic magnesium or in cell culture medium containing elevated magnesium ion levels. Similarly, in soft tissue no bone induction by metallic magnesium or by the corrosion product magnesium hydroxide could be observed in a mouse model. Motivated by the comparatively rapid accumulation solid corrosion products physicochemical processes were examined as an alternative mechanism to explain the stimulation of bone growth by magnesium-based implants. During exposure to physiological solutions a structured corrosion coat formed on magnesium whereby the elements calcium and phosphate were enriched in the outermost layer which could play a role in the established biocompatible behavior of magnesium implants. When magnesium pins were inserted into avital bones, corrosion lead to increases in the pull out force, suggesting that the expanding corrosion layer was interlocking with the surrounding bone. Since mechanical stress is a well-established inducer of bone growth, volume increases caused by the rapid accumulation of corrosion products and the resulting force development could be a key mechanism and provide an explanation for the observed stimulatory effects of magnesium-based implants in hard tissue. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 697-709, 2017.


Alcohol health literacy in young adults with type 1 diabetes and its impact on diabetes management.
To investigate the knowledge of alcohol and carbohydrate content of commonly consumed alcoholic drinks among young adults with Type 1 diabetes and to explore alcohol consumption while identifying diabetes self-management strategies used to minimize alcohol-associated risk. We conducted an open-access, multiple-choice web survey to investigate knowledge of alcohol and carbohydrate content of typical alcoholic drinks using images. Respondents to the survey also recorded their current alcohol consumption and diabetes self-management strategies when drinking. A total of 547 people aged 18-30 years responded to the survey (341 women; 192 men; mean (sd) age 24.5 (3.7) years), of whom 365 (66.7%) drank alcohol. In all, 84 (32.9%) women and 31 (22.6%) men scored higher than the cut-off score for increased-risk drinking. Knowledge accuracy of alcohol units was poor: only 7.3% (n = 40) correctly identified the alcohol content of six or more out of 10 drinks. Knowledge of carbohydrate content was also poor: no respondent correctly identified the carbohydrate content of six or more out of 10 drinks. Various and inconsistent strategies to minimize alcohol-associated risk were reported. Alcohol consumption was common among the survey respondents, but knowledge of alcohol and carbohydrate content was poor. Greater alcohol-related health literacy is required to minimize alcohol-associated risk. Further research should help develop effective strategies to improve health literacy and support safe drinking for young adults with Type 1 diabetes.


Two Clinically Unusual Cases of Folliculotropic Mycosis Fungoides: One with and the Other without Syringotropism.
Mycosis fungoides is the most common form of cutaneous T-cell lymphoma, and it rarely exhibits predilection for hair follicle and eccrine gland infiltration. Here, we present 2 similar cases that display folliculotropism with varying amounts of follicular mucinosis, with and without syringotropism. The features observed in both cases were cystic, comedo-like, acneiform lesions; generalized involvement with loss of body hair; pruritus; and hidradenitis suppurativa-like lesions. Hypohidrosis as well as nail and palmoplantar involvement with lichen planopilaris-like clinical features were unique characteristics of the first case. Despite the well-known aggressive behavior of follicular mycosis fungoides, the presented cases had a subtle, slowly progressive, but persistent, clinical course. Folliculotropic and syringotropic mycosis fungoides are variants of cutaneous T-cell lymphoma. Clinical presentations might be challenging, and multiple, deep biopsy specimens containing adnexal structures are required for this critical diagnosis. Aggressive treatment may not be necessary in cases having an indolent course, especially in those with syringotropism.