Lower healthcare costs associated with the use of a single-pill ARV regimen in the UK, 2004-2008.
Investigate the cost and effects of a single-pill versus two- or three pill first-line antiretroviral combinations in reducing viral load, increasing CD4 counts, and first-line failure rate associated with respective regimens at 6 and 12 months. Patients on first-line TDF+3TC+EFV, TDF+FTC+EFV, Truvada®+EFV or Atripla® between 1996-2008 were identified and viral load and CD4 counts measured at baseline, six and twelve months respectively. Factors that independently predicted treatment failure at six and twelve months were derived using multivariate Cox's proportional hazard regression analyses. Use and cost of hospital services were calculated at six and twelve months respectively. All regimens reduced viral load to below the limit of detection and CD4 counts increased to similar levels at six and twelve months for all treatment regimens. No statistically significant differences were observed for rate of treatment failure at six and twelve months. People on Atripla® generated lower healthcare costs for non-AIDS patients at £5,340 (£5,254 to £5,426) per patient-semester and £9,821 (£9,719 to £9,924) per patient-year that was £1,344 (95%CI £1,222 to £1,465) less per patient-semester and £1,954 (95%CI £1,801 to £2,107) less per patient-year compared with Truvada®+EFV; healthcare costs for AIDS patients were similar across all regimens. The single pill regimen is as effective as the two- and three-pill regimens of the same drugs, but if started as first-line induction therapy there would be a 20% savings on healthcare costs at six and 17% of costs at twelve months compared with Truvada®+EFV, that generated the next lowest costs.


Awareness and Attitude of the General Public Toward HIV/AIDS in Coastal Karnataka.
To assess the awareness and attitude of the general public toward people living with HIV/AIDS (PLWHA) in Mangalore, a city in Coastal Karnataka. Community-based cross-sectional study. The study population included 630 individuals aged 18 years and above. The information was collected using a semi structured pre-tested questionnaire. The questionnaire consisted of 24 questions regarding awareness of the modes of transmission of HIV/AIDS (nine questions) and questions to assess the attitude toward People Living With HIV/AIDS (PLWHA) (15 questions). Statistical package SPSS version 11.5 was used, Chi-square test was conducted and P < 0.05 was considered as statistically significant. About one-third of the study population thought that one could get infected by merely touching an HIV positive individual. Approximately 45% stated that they would dismiss their maid on finding out her HIV positive status. About 54% were willing to undergo the HIV test. The respondents with less than secondary school education had a discriminatory attitude toward HIV positive people, with regard to them deserving to suffer, dismissing a HIV positive maid, hesitating to sit next to a HIV positive person in the bus, divorcing the infected spouse, and willingness to get tested for HIV, which was found to be statistically significant. Stigma among the general public was mostly due to fear of contracting the illness. Stigma does exist to significant degrees among the educated people, which was suggested by about 45% of the participants being willing to undergo the HIV test. There is a need for greater attempts toward making information regarding HIV/AIDS available to every individual of the society.


Frozen reaction fronts in steady flows: A burning-invariant-manifold perspective.
The dynamics of fronts, such as chemical reaction fronts, propagating in two-dimensional fluid flows can be remarkably rich and varied. For time-invariant flows, the front dynamics may simplify, settling in to a steady state in which the reacted domain is static, and the front appears "frozen." Our central result is that these frozen fronts in the two-dimensional fluid are composed of segments of burning invariant manifolds, invariant manifolds of front-element dynamics in xyθ space, where θ is the front orientation. Burning invariant manifolds (BIMs) have been identified previously as important local barriers to front propagation in fluid flows. The relevance of BIMs for frozen fronts rests in their ability, under appropriate conditions, to form global barriers, separating reacted domains from nonreacted domains for all time. The second main result of this paper is an understanding of bifurcations that lead from a nonfrozen state to a frozen state, as well as bifurcations that change the topological structure of the frozen front. Although the primary results of this study apply to general fluid flows, our analysis focuses on a chain of vortices in a channel flow with an imposed wind. For this system, we present both experimental and numerical studies that support the theoretical analysis developed here.


Women Saw Large Decrease In Out-Of-Pocket Spending For Contraceptives After ACA Mandate Removed Cost Sharing.
The Affordable Care Act mandates that private health insurance plans cover prescription contraceptives with no consumer cost sharing. The positive financial impact of this new provision on consumers who purchase contraceptives could be substantial, but it has not yet been estimated. Using a large administrative claims data set from a national insurer, we estimated out-of-pocket spending before and after the mandate. We found that mean and median per prescription out-of-pocket expenses have decreased for almost all reversible contraceptive methods on the market. The average percentages of out-of-pocket spending for oral contraceptive pill prescriptions and intrauterine device insertions by women using those methods both dropped by 20 percentage points after implementation of the ACA mandate. We estimated average out-of-pocket savings per contraceptive user to be $248 for the intrauterine device and $255 annually for the oral contraceptive pill. Our results suggest that the mandate has led to large reductions in total out-of-pocket spending on contraceptives and that these price changes are likely to be salient for women with private health insurance.


Aging With Cerebral Palsy: A Photovoice Study Into Citizenship.
Background: Adults with cerebral palsy (CP) may experience an increasing impact of their disability on daily life and this may interfere with their citizenship. Citizenship is a layered construct. Next to formal and theoretical significations, and civil rights acts such as the UN Convention on the Rights for Persons with Disabilities (CRPD), the meaning of citizenship is formed by the person themselves. The present study aimed to gain insight into what citizenship means for adults with CP 40 years or older and what is needed to support and pursue their citizenship to improve person-centered rehabilitation which can facilitate this process. Methods: Adults with CP (>40 years) without intellectual disability were recruited from medical records of a large rehabilitation center to participate in a qualitative study using the photovoice method. Participants were asked to take photos of objects or life situations that constituted citizenship for them; these photos were then the prompts for the semi-structured interviews that were held face-to-face at their homes. Background and clinical characteristics were gathered using a short face-to-face questionnaire. Data were analyzed through inductive thematic analysis. Results: Nineteen adults participated [mean age (SD) 57.8 (9.4) years (range 44-79), six men]. From the analysis four themes emerged: (a) Meanings of citizenship; (b) Citizenship: Facilitator and barriers; (c) Paradoxes of support and participation; and (d) Future. Furthermore, next to the ability to participate in society without restrictions, sense of belonging was reported to be an important aspect of "meanings of citizenship." The physiotherapist was perceived as an important health professional to maintain physical activity and deal with the impact of aging with CP on daily activities. Complex healthcare and support services regulations and aging affected citizenship negatively. Conclusion: Middle-aged and older adults with CP view citizenship as the ability to participate and belong in society. To optimize their citizenship the challenges and individual needs must be seen and supported by person-centered rehabilitation and support services. Simplification of complex healthcare and services regulations can further improve citizenship.


Guidelines for clinical trial protocols for interventions involving artificial intelligence: the SPIRIT-AI Extension.
The SPIRIT 2013 (The Standard Protocol Items: Recommendations for Interventional Trials) statement aims to improve the completeness of clinical trial protocol reporting, by providing evidence-based recommendations for the minimum set of items to be addressed. This guidance has been instrumental in promoting transparent evaluation of new interventions. More recently, there is a growing recognition that interventions involving artificial intelligence need to undergo rigorous, prospective evaluation to demonstrate their impact on health outcomes.The SPIRIT-AI extension is a new reporting guideline for clinical trials protocols evaluating interventions with an AI component. It was developed in parallel with its companion statement for trial reports: CONSORT-AI. Both guidelines were developed using a staged consensus process, involving a literature review and expert consultation to generate 26 candidate items, which were consulted on by an international multi-stakeholder group in a 2-stage Delphi survey (103 stakeholders), agreed on in a consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants).The SPIRIT-AI extension includes 15 new items, which were considered sufficiently important for clinical trial protocols of AI interventions. These new items should be routinely reported in addition to the core SPIRIT 2013 items. SPIRIT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention will be integrated, considerations around the handling of input and output data, the human-AI interaction and analysis of error cases.SPIRIT-AI will help promote transparency and completeness for clinical trial protocols for AI interventions. Its use will assist editors and peer-reviewers, as well as the general readership, to understand, interpret and critically appraise the design and risk of bias for a planned clinical trial.


Going formal or informal, who cares? The influence of public long-term care insurance.
International differences in long-term care (LTC) use are well documented, but not well understood. Using comparable data from two countries with universal public LTC insurance, the Netherlands and Germany, we examine how institutional differences relate to differences in the choice for informal and formal LTC. Although the overall LTC utilization rate is similar in both countries, use of formal care is more prevalent in the Netherlands and informal care use in Germany. Decomposition of the between-country differences in formal and informal LTC use reveals that these differences are not chiefly the result of differences in population characteristics but mainly derive from differences in the effects of these characteristics that are associated with between-country institutional differences. These findings demonstrate that system features such as eligibility rules and coverage generosity and, indirectly, social preferences can influence the choice between formal and informal care. Less comprehensive coverage also has equity implications: for the poor, access to formal LTC is more difficult in Germany than in the Netherlands.


The cyclic vomiting syndrome: a report of 71 cases and literature review.
This study reviews 71 patients who presented between 1968 and 1988 with recurrent, self-limited episodes of nausea and vomiting separated by symptom-free intervals and were diagnosed with cyclic vomiting syndrome (CVS). The length and symptomatology of episodes tended to be stereotyped and characteristic for each patient over time. The disorder may persist from months to decades. There is a coincident relationship between CVS, migraine, and irritable bowel syndrome. The differential diagnosis includes many diseases which may mimic CVS. Management involves a responsive, collaborative doctor-patient relationship, sensitivity to stresses caused by the illness and to feelings and attitudes that may predispose to attacks, use of antiemetic agents to abort or shorten attacks, treatment of complications, and use of prophylactic agents in patients whose episodes are of sufficient frequency and severity to warrant their trial.


Rearranged ergostane-type natural products: chemistry, biology, and medicinal aspects.
Classical steroids are long-known privileged leads in drug discovery. Their rearranged counterparts, though, have so far received less attention, although recent isolation and biological testing programmes have revealed a plethora of molecular entities that are both structurally intriguing, as well as biologically relevant. This review will highlight those natural products, and focus on ergostane-derived seco- and abeo-steroids. Their isolation, structure elucidation, and biological properties are reported. A special emphasis of this review lies in their respective (and typically proposed) biosyntheses, to help guide future bio-inspired synthetic attempts.


The functions of the proprioceptors of the eye muscles.
This article sets out to present a fairly comprehensive review of our knowledge about the functions of the receptors that have been found in the extraocular muscles--the six muscles that move each eye of vertebrates in its orbit--of all the animals in which they have been sought, including Man. Since their discovery at the beginning of the 20th century these receptors have, at various times, been credited with important roles in the control of eye movement and the construction of extrapersonal space and have also been denied any function whatsoever. Experiments intended to study the actions of eye muscle receptors and, even more so, opinions (and indeed polemic) derived from these observations have been influenced by the changing fashions and beliefs about the more general question of how limb position and movement is detected by the brain and which signals contribute to those aspects of this that are perceived (kinaesthesis). But the conclusions drawn from studies on the eye have also influenced beliefs about the mechanisms of kinaesthesis and, arguably, this influence has been even larger than that in the converse direction. Experimental evidence accumulated over rather more than a century is set out and discussed. It supports the view that, at the beginning of the 21st century, there are excellent grounds for believing that the receptors in the extraocular muscles are indeed proprioceptors, that is to say that the signals that they send into the brain are used to provide information about the position and movement of the eye in the orbit. It seems that this information is important in the control of eye movements of at least some types, and in the determination by the brain of the direction of gaze and the relationship of the organism to its environment. In addition, signals from these receptors in the eye muscles are seen to be necessary for the development of normal mechanisms of visual analysis in the mammalian visual cortex and for both the development and maintenance of normal visuomotor behaviour. Man is among those vertebrates to whose brains eye muscle proprioceptive signals provide information apparently used in normal sensorimotor functions; these include various aspects of perception, and of the control of eye movement. It is possible that abnormalities of the eye muscle proprioceptors and their signals may play a part in the genesis of some types of human squint (strabismus); conversely studies of patients with squint in the course of their surgical or pharmacological treatment have yielded much interesting evidence about the central actions of the proprioceptive signals from the extraocular muscles. The results of experiments on the eye have played a large part in the historical controversy, now in at least its third century, about the origin of signals that inform the brain about movement of parts of the body. Some of these results, and more of the interpretations of them, now need to be critically re-examined. The re-examination in the light of recent experiments that is presented here does not support many of the conclusions confidently drawn in the past and leads to both new insights and fresh questions about the roles of information from motor signals flowing out of the brain and that from signals from the peripheral receptors flowing into it. There remain many lacunae in our knowledge and filling some of these will, it is contended, be essential to advance our understanding further. It is argued that such understanding of eye muscle proprioception is a necessary part of the understanding of the physiology and pathophysiology of eye movement control and that it is also essential to an account of how organisms, including Man, build and maintain knowledge of their relationship to the external visual world. The eye would seem to provide a uniquely favourable system in which to study the way in which information derived within the brain about motor actions may interact with signals flowing in from peripheral receptors. The review is constructed in relatively independent sections that deal with particular topics. It ends with a fairly brief piece in which the author sets out some personal views about what has been achieved recently and what most immediately needs to be done. It also suggests some lines of study that appear to the author to be important for the future.


Emerging Species and Genome Editing Tools: Future Prospects in Cyanobacterial Synthetic Biology.
Recent advances in synthetic biology and an emerging algal biotechnology market have spurred a prolific increase in the availability of molecular tools for cyanobacterial research. Nevertheless, work to date has focused primarily on only a small subset of model species, which arguably limits fundamental discovery and applied research towards wider commercialisation. Here, we review the requirements for uptake of new strains, including several recently characterised fast-growing species and promising non-model species. Furthermore, we discuss the potential applications of new techniques available for transformation, genetic engineering and regulation, including an up-to-date appraisal of current Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein (CRISPR/Cas) and CRISPR interference (CRISPRi) research in cyanobacteria. We also provide an overview of several exciting molecular tools that could be ported to cyanobacteria for more advanced metabolic engineering approaches (e.g., genetic circuit design). Lastly, we introduce a forthcoming mutant library for the model species Synechocystis sp. PCC 6803 that promises to provide a further powerful resource for the cyanobacterial research community.


WISECARE+: Results of a European study of a nursing intervention for the management of chemotherapy-related symptoms.
While the use of chemotherapy has significantly improved survival rates, the symptoms associated with chemotherapy remain a major burden for patients. Preventing or appropriately managing side effects significantly improves patients' functional status and quality of life, ultimately leading to greater patient acceptance of chemotherapy. However, symptom assessment and management are fraught with difficulties such as poor patient recall, retrospective assessment conducted by clinicians and lack of appropriate, clinically relevant and patient friendly symptom assessment and management tools. Furthermore the differences between clinician and patient perceptions of stresses and distress during chemotherapy are well recognised. This study aimed to evaluate the impact of a nursing intervention incorporating structured symptom assessment and management, facilitated by information technology, on chemotherapy-related symptoms, nausea, vomiting, fatigue and mucositis. This pan-European study, involved 8 clinical sites from Belgium, Denmark, England, Ireland and Scotland. Adults (n=249) receiving first line chemotherapy for breast, lung, ovarian or colorectal cancer, osteosarcoma, acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) or lymphoma were recruited to the study. Patients completed daily symptom assessment questionnaires for 14 days following consecutive cycles of chemotherapy. Symptom outcomes were compared before and after the introduction of the intervention with positive impact on patients' experiences of nausea, vomiting and oral problems. Fatigue was not significantly improved.


Dependence of the hydration status of bacterial light-harvesting complex 2 on polyol cosolvents.
Low molecular weight (MW) polyols are organic osmolytes influencing protein structure and activity. We have intended to investigate the effects of low MW polyols on the optical and the excited-state properties of the light-harvesting complex 2 (LH2) isolated from the photosynthetic bacterium Thermochromatium (Tch.) tepidum, a thermophile growing at ∼50 °C. Steady state spectroscopy demonstrated that, on increasing glycerol or sorbitol fractions up to 60% (polyol/water, v/v), the visible absorption of carotenoids (Crts) remained unchanged, while the near infrared Qy absorption of bacteriochlorophyll a (BChl) at 800 nm (B800) and 850 nm (B850) varied slightly. Further increasing the fraction of glycerol (but not sorbitol) to 80% (v/v) induced distinct changes of the near infrared absorption and fluorescence spectra. Transient absorption spectroscopy revealed that, following the fast processes of BChl-to-Crt triplet energy transfer, rather weak Qy signals of B800 and B850 remained and evolved in phase with the kinetics of triplet excited state Crt (3Crt*), which are attributed to the Qy band shift as a result of 3Crt*-BChl interaction. The steady state and the transient spectral responses of the Qy bands are found to correlate intimately with the water activity varying against polyol MW and mixing ratio, which are rationalized by the change of the hydration status of the C- and N-termini of LH2. Our results suggest that, with reference to the mesophilic purple bacterium Rhodobacter sphaeroides 2.4.1, Tch. tepidum adopts substantially more robust LH2 hydration against the osmotic effects from the low MW polyols.


Sources of heavy metal input into Winam Gulf, Kenya.
Water and surface sediment from rivers Kisat, Nyamasaria, Nyando, Sondu-Miriu, Kuja, Awach, Yala, and Nzoia, which flow into Winam Gulf, were analyzed for heavy metals in order to assess the influence of the catchment activities on heavy metal input into the lake. Sampling was done both upstream and at river mouths where the rivers entered in to the lake. The mean sediment concentration of exchangeable cations (in microg/g) for Ag, Cd, Co, Cu, Mn, Ni, Pb, Sn, and Zn ranged from 0.01 to 263 (for Mn at Kuja). Ag, Cr, and Cd were poorly leachable with 0.1 MHCl but the other cations were found to be fairly exchangeable. Most exchangeable cations in sediment ranged between 2% and 20% of the total heavy metal content obtained by digestion with strong acid. The mean total dissolved metal (0.45 microm filter cut-off) and mean total sediment concentrations ranged from nd-16 (Ag), nd-8 (Cd), nd-23.3 (Co), nd-50 (Cr), 5-157.5 (Cu), 50-3276 (Mn), nd-54.1 (Ni), 7-93.6 (Pb), 25-219.5 (Zn) in microg/L and from nd-8.34 (Ag), 0.48-1.75 (Co), nd-1.78 (Cd), 2.92-5.36 (Cr), 3.90-150.2 (Cu), 133.5-7237 (Mn), 4.33-42.29 (Ni), 3.09-66.06 (Pb), 23.39-7.83 (Sn) and 23.39-350.8 (Zn) in microg/g dry weight, respectively. The rivers analyzed were found to be non-polluted in terms of sediment loads except river Kisat which was found to be polluted because of elevated levels of Pb, Mn, Cu, and Zn. Nyamasaria and Nyando were also found to have higher concentrations of Pb, Cu, and Zn than those reported previously in the lake sediment. The dissolved metal concentrations were acceptable by WHO maximum limits in drinking water except Mn which was above WHO limit in Kisat, Nyando, and Nyamasaria waters. Enrichment of Cd and Pb was found in all the river sediment samples with factors ranging from 2.12 at Kisat river mouth to 4.41 at Awach (for Cd) and from 1.49 (at Kisat river mouth) to 2.38 (at Nyando river mouth).


The Dynamic Genome and Transcriptome of the Human Fungal Pathogen Blastomyces and Close Relative Emmonsia.
Three closely related thermally dimorphic pathogens are causal agents of major fungal diseases affecting humans in the Americas: blastomycosis, histoplasmosis and paracoccidioidomycosis. Here we report the genome sequence and analysis of four strains of the etiological agent of blastomycosis, Blastomyces, and two species of the related genus Emmonsia, typically pathogens of small mammals. Compared to related species, Blastomyces genomes are highly expanded, with long, often sharply demarcated tracts of low GC-content sequence. These GC-poor isochore-like regions are enriched for gypsy elements, are variable in total size between isolates, and are least expanded in the avirulent B. dermatitidis strain ER-3 as compared with the virulent B. gilchristii strain SLH14081. The lack of similar regions in related species suggests these isochore-like regions originated recently in the ancestor of the Blastomyces lineage. While gene content is highly conserved between Blastomyces and related fungi, we identified changes in copy number of genes potentially involved in host interaction, including proteases and characterized antigens. In addition, we studied gene expression changes of B. dermatitidis during the interaction of the infectious yeast form with macrophages and in a mouse model. Both experiments highlight a strong antioxidant defense response in Blastomyces, and upregulation of dioxygenases in vivo suggests that dioxide produced by antioxidants may be further utilized for amino acid metabolism. We identify a number of functional categories upregulated exclusively in vivo, such as secreted proteins, zinc acquisition proteins, and cysteine and tryptophan metabolism, which may include critical virulence factors missed before in in vitro studies. Across the dimorphic fungi, loss of certain zinc acquisition genes and differences in amino acid metabolism suggest unique adaptations of Blastomyces to its host environment. These results reveal the dynamics of genome evolution and of factors contributing to virulence in Blastomyces.


[Estimating and reporting aggression in relation to personal characteristics of emergency service workers].
Research on aggression in mental health care has focused mainly on patient characteristics, whereas very little research has been done on the characteristics of the care providers in their reporting of aggression. To study the characteristics of the care providers of an emergency service in relation to the reporting of aggression. All emergency service workers( n = 21) in the Uden-Veghel region were asked to complete a neo-pi-r form. Before 576 outreach contacts had been made with patients in psychiatric crises, the Checklist of Risks in the Crisis-team (crc) was also completed and in cases where the patient exhibited aggressive behaviour, a soas-r form was filled in, following contact with the patient. Significant differences were found between the psychiatric emergency service workers with regard to the mean estimates of the likelihood that they would experience aggression during the consultation and with regard to the proportion of patient contacts for which emergency workers reported aggression. There were indications that the level of conscientiousness of the emergency service workers was positively associated with a higher chance that they would report aggressive behaviour following the consultation. Furthermore, altruism was found to be negatively associated with the likelihood, as predicted by the service workers, that they would be confronted with aggression during contact with the patient. Possibly, workers who scored high on conscientiousness and who work thoroughly and in a orderly and systematic manner and who keep to the rules are less flexible in their response to the patient during the interaction. As a result, the patient became irritated more quickly. On the other hand, it could be that conscientious workers completed the form-filling more carefully when aggression had to be reported and as a result they made higher preliminary estimates of the likelihood of aggression and a reported a larger number of incidents of actual aggression.


Lepidoptera genomes: current knowledge, gaps and future directions.
Butterflies and moths (Lepidoptera) are one of the most ecologically diverse and speciose insect orders. With recent advances in genomics, new Lepidoptera genomes are regularly being sequenced, and many of them are playing principal roles in genomics studies, particularly in the fields of phylo-genomics and functional genomics. Thus far, assembled genomes are only available for <10 of the 43 Lepidoptera superfamilies. Nearly all are model species, found in the speciose clade Ditrysia. Community support for Lepidoptera genomics is growing with successful management and dissemination of data and analytical tools in centralized databases. With genomic studies quickly becoming integrated with ecological and evolutionary research, the Lepidoptera community will unquestionably benefit from new high-quality reference genomes that are more evenly distributed throughout the order.


Reduced dietary salt for prevention of cardiovascular disease.
Restricting sodium intake in elevated blood pressure over short periods of time reduces blood pressure. Long term effects (on mortality, morbidity or blood pressure) of advice to reduce salt in patients with elevated or normal blood pressure are unclear. To assess in adults the long term effects (mortality, cardiovascular events, blood pressure, quality of life, weight, urinary sodium excretion, other nutrients and use of anti-hypertensive medications) of advice to restrict dietary sodium using all relevant randomised controlled trials. The Cochrane Library, MEDLINE, EMBASE, bibliographies of included studies and related systematic reviews were searched for unconfounded randomised trials in healthy adults aiming to reduce sodium intake over at least 6 months. Attempts were made to trace unpublished or missed studies and authors of all included trials were contacted. There were no language restrictions. Inclusion decisions were independently duplicated and based on the following criteria: 1) randomisation was adequate; 2) there was a usual or control diet group; 3) the intervention aimed to reduce sodium intake; 4) the intervention was not multifactorial; 5) the participants were not children, acutely ill, pregnant or institutionalised; 6) follow-up was at least 26 weeks; 7) data on any of the outcomes of interest were available. Decisions on validity and data extraction were made independently by two reviewers, disagreements were resolved by discussion or if necessary by a third reviewer. Random effects meta-analysis, sub-grouping, sensitivity analysis and meta-regression were performed. Three trials in normotensives (n=2326), five in untreated hypertensives (n=387) and three in treated hypertensives (n=801) were included, with follow up from six months to seven years. The large, high quality (and therefore most informative) studies used intensive behavioural interventions. Deaths and cardiovascular events were inconsistently defined and reported; only 17 deaths equally distributed between intervention and control groups occurred. Systolic and diastolic blood pressures were reduced at 13 to 60 months in those given low sodium advice as compared with controls (systolic by 1.1 mm Hg, 95% CI 1.8 to 0.4, diastolic by 0.6 mm hg, 95% CI 1.5 to -0.3), as was urinary 24 hour sodium excretion (by 35.5 mmol/ 24 hours, 95% CI 47.2 to 23.9). Degree of reduction in sodium intake and change in blood pressure were not related. People on anti-hypertensive medications were able to stop their medication more often on a reduced sodium diet as compared with controls, while maintaining similar blood pressure control. Intensive interventions, unsuited to primary care or population prevention programmes, provide only minimal reductions in blood pressure during long-term trials. Further evaluations to assess effects on morbidity and mortality outcomes are needed for populations as a whole and for patients with elevated blood pressure. Evidence from a large and small trial showed that a low sodium diet helps in maintenance of lower blood pressure following withdrawal of antihypertensives. If this is confirmed, with no increase in cardiovascular events, then targeting of comprehensive dietary and behavioural programmes in patients with elevated blood pressure requiring drug treatment would be justified.


Exploring Approximate Bayesian Computation for inferring recent demographic history with genomic markers in nonmodel species.
Approximate Bayesian computation (ABC) is widely used to infer demographic history of populations and species using DNA markers. Genomic markers can now be developed for nonmodel species using reduced representation library (RRL) sequencing methods that select a fraction of the genome using targeted sequence capture or restriction enzymes (genotyping-by-sequencing, GBS). We explored the influence of marker number and length, knowledge of gametic phase, and tradeoffs between sample size and sequencing depth on the quality of demographic inferences performed with ABC. We focused on two-population models of recent spatial expansion with varying numbers of unknown parameters. Performing ABC on simulated data sets with known parameter values, we found that the timing of a recent spatial expansion event could be precisely estimated in a three-parameter model. Taking into account uncertainty in parameters such as initial population size and migration rate collectively decreased the precision of inferences dramatically. Phasing haplotypes did not improve results, regardless of sequence length. Numerous short sequences were as valuable as fewer, longer sequences, and performed best when a large sample size was sequenced at low individual depth, even when sequencing errors were added. ABC results were similar to results obtained with an alternative method based on the site frequency spectrum (SFS) when performed with unphased GBS-type markers. We conclude that unphased GBS-type data sets can be sufficient to precisely infer simple demographic models, and discuss possible improvements for the use of ABC with genomic data.


Sexual pleasure and condom use.
The purpose of the present study was to determine whether sexually-experienced individuals' pleasure ratings for protected and unprotected vaginal intercourse would be related to actual condom use. College participants (80 women and 35 men, M age = 22.29 years) who reported engaging in vaginal intercourse in the past 3 months completed a questionnaire that assessed their perceptions of the pleasurability of unprotected and condom-protected vaginal intercourse and their own sexual behaviors. Both women and men rated unprotected vaginal intercourse as more pleasurable than protected vaginal intercourse. However, men's pleasure ratings for unprotected vaginal intercourse were higher than women's. Furthermore, men and women's pleasure ratings for condom-protected intercourse were correlated with their actual condom use behaviors. Men's "pleasure decrement" scores indicated a significantly greater reduction in pleasure ratings between unprotected and protected intercourse than women's scores. Men who perceived a larger decrease in pleasure between unprotected and protected intercourse were less likely to have used condoms in the past 3 months than those who perceived a smaller decrease in pleasure. The results provide evidence that many people believe that condoms reduce sexual pleasure and that men, in particular, who believe that condoms decrease pleasure are less likely to use them. Condom promotion campaigns should work to emphasize the pleasure-enhancing aspects of condom use.


Depression: distress or disease? Some epidemiological considerations.
Surveys using clinical-type interviews have documented a high rate of depression among working-class women, and this is discussed in the light of a recent survey in an inner-city area. While women with caseness of depression contacting a psychiatrist did not differ in number of core depressive symptoms from those who did, they did in certain characteristics that would make them worrying for a general practitioner to deal with. It is concluded that there is a considerable overlap in the severity of depressive conditions between those seen by psychiatrists and those defined as cases in population surveys; any differences that do exist may relate more to the way symptoms are expressed than to the severity of the depressive disorder as such.


Food Waste in Primary Production: Milk Loss With Mitigation Potentials.
Sources and quantities of milk loss in primary production are presented in this paper through an analysis of results from a 2018 survey. Responses from 43 dairy farms in Scotland showed that milk losses occurred due to withdrawal periods for veterinary treatment, parlor infrastructure, and lapses in management routine. A partial life cycle assessment detailed flows of milk from cow to farm gate and captured farm inputs such as imported feeds and fertilizers. Incidence of animal health events such as mastitis, that routinely lead to milk withdrawal were quantified alongside strategies carried out by farmers to reduce milk loss. Treatment for mastitis accounted for 76% of all milk withdrawal days and the remaining 24% stemmed from therapies for health events such as uterine disorders and lameness. Withdrawal periods for mastitis treatments averaged 4.5 days, with a mean incidence of 20% of cows in a herd. Across all farms, an average of 98.2% of total milk produced was sold, 0.66% was purposely retained, 0.55% was rejected due to antibiotic residues, 0.5% was lost from parlor to bulk tank infrastructure and a further 0.09% was rejected by the processor. Carbon footprints found greenhouse gas (GHG) emissions averaged 0.849 kg CO2e/kg across farms for the milking herd. A scenario of 20% fewer withdrawal days reduced GHG's on average by 0.6%. Additional mitigation was attained by reductions in milk loss from parlor infrastructure and the bulk tank, and this showed a 1% reduction in GHG emissions could be achieved through higher volumes of milk sales. Categorizing responses by management system type highlighted differences in proportional losses between all year round housed and conventional grazing regimes. The most predominant health disorder leading to milk withdrawal was mastitis, however losses due to other health events and parlor infrastructure were not insignificant on Scottish dairy farms.


The organization of spinal motor neurons in a monotreme is consistent with a six-region schema of the mammalian spinal cord.
The motor neurons in the spinal cord of an echidna (Tachyglossus aculeatus) have been mapped in Nissl-stained sections from spinal cord segments defined by spinal nerve anatomy. A medial motor column of motor neurons is found at all spinal cord levels, and a hypaxial column is found at most levels. The organization of the motor neuron clusters in the lateral motor column of the brachial (C5 to T3) and crural (L2 to S3) limb enlargements is very similar to the pattern previously revealed by retrograde tracing in placental mammals, and the motor neuron clusters have been tentatively identified according to the muscle groups they are likely to supply. The region separating the two limb enlargements (T4 to L1) contains preganglionic motor neurons that appear to represent the spinal sympathetic outflow. Immediately caudal to the crural limb enlargement is a short column of preganglionic motor neurons (S3 to S4), which it is believed represents the pelvic parasympathetic outflow. The rostral and caudal ends of the spinal cord contain neither a lateral motor column nor a preganglionic column. Branchial motor neurons (which are believed to supply the sternomastoid and trapezius muscles) are present at the lateral margin of the ventral horn in rostral cervical segments (C2-C4). These same segments contain the phrenic nucleus, which belongs to the hypaxial column. The presence or absence of the main spinal motor neuron columns in the different regions echidna spinal cord (and also in that of other amniote vertebrates) provides a basis for dividing the spinal cord into six main regions - prebrachial, brachial, postbrachial, crural, postcrural and caudal. The considerable biological and functional significance of this subdivision pattern is supported by recent studies on spinal cord hox gene expression in chicks and mice. On the other hand, the familiar 'segments' of the spinal cord are defined only by the anatomy of adjacent vertebrae, and are not demarcated by intrinsic gene expression. The recognition of segments defined by vertebrae (somites) is obviously of great value in defining topography, but the emphasis on such segments obscures the underlying evolutionary reality of a spinal cord comprised of six genetically defined regions. The six-region system can be usefully applied to the spinal cord of any amniote (and probably most anurans), independent of the number of vertebral segments in each part of the spinal column.


CT findings of sigmoid volvulus.
The purpose of this study was to evaluate the features of sigmoid volvulus on CT scanograms and cross-sectional images. We retrospectively reviewed 21 cases of sigmoid volvulus in 15 men and six women. Three radiologists evaluated scanograms and cross-sectional images for several classic and two novel imaging signs of volvulus: crossing sigmoid transitions (called the X-marks-the-spot sign) and folding of the sigmoid wall by partial twisting (called the split-wall sign). A general impression was assigned to scanograms and cross-sectional images. CT findings suggesting bowel compromise were compared with pathologic and endoscopic findings. The most sensitive scanogram findings were absence of rectal gas (19 of 21 cases, 90%) and an inverted-U-shaped distended sigmoid (18 of 21 cases, 86%) followed by the coffee bean sign and disproportionate sigmoid enlargement (both 16 of 21 cases, 76%). The most sensitive cross-sectional findings were one sigmoid colon transition point (20 of 21 cases, 95%) and disproportionate enlargement of the sigmoid (18 of 21 cases, 86%). The X-marks-the-spot and split-wall signs were present in nine of 21 (43%) and 11 of 21 (52%) patients, but one of the two signs was present in 18 of 21 patients (86%). Classic radiographic and definitive cross-sectional findings were seen in 11 of 21 (52%) and 16 of 21 (76%) patients. CT findings were definitive in five of seven patients (71%) with indeterminate scanogram findings. Imaging signs suggesting bowel compromise correlated poorly with clinical ischemia, but CT features were present in all three patients with frank necrosis. Sigmoid volvulus has a spectrum of imaging findings. A classic appearance is absent on approximately one half of scanograms and one fourth of CT scans. Use of new signs that model the pathophysiologic characteristics of volvulus (X-marks-the-spot sign for more complete twisting and split-wall sign for less severe twisting) may improve diagnostic confidence.


Population connectivity of pelagic megafauna in the Cuba-Mexico-United States triangle.
The timing and extent of international crossings by billfishes, tunas, and sharks in the Cuba-Mexico-United States (U.S.) triangle was investigated using electronic tagging data from eight species that resulted in >22,000 tracking days. Transnational movements of these highly mobile marine predators were pronounced with varying levels of bi- or tri-national population connectivity displayed by each species. Billfishes and tunas moved throughout the Gulf of Mexico and all species investigated (blue marlin, white marlin, Atlantic bluefin tuna, yellowfin tuna) frequently crossed international boundaries and entered the territorial waters of Cuba and/or Mexico. Certain sharks (tiger shark, scalloped hammerhead) displayed prolonged periods of residency in U.S. waters with more limited displacements, while whale sharks and to a lesser degree shortfin mako moved through multiple jurisdictions. The spatial extent of associated movements was generally associated with their differential use of coastal and open ocean pelagic ecosystems. Species with the majority of daily positions in oceanic waters off the continental shelf showed the greatest tendency for transnational movements and typically traveled farther from initial tagging locations. Several species converged on a common seasonal movement pattern between territorial waters of the U.S. (summer) and Mexico (winter).


Picosecond measurements of absorptive and refractive optical nonlinearities in GaP at 532 nm.
Picosecond time-resolved pump-probe and Z-scan measurements are used to investigate the nonlinear refraction and absorption associated with intense picosecond excitation above the indirect band edge of GaP. The pump-probe results reveal both an instantaneous absorption feature, which is consistent with two-photon absorption, and a long-lived feature that is associated with the generation of free carriers by linear indirect absorption. Z scans conducted with pulses of 25- and 95-ps duration indicate that, for these pulse widths, the nonlinear refraction in GaP is dominated by the linear generation of free carriers and that the role of the electronic Kerr effect is negligible. The measured free-carrier refraction is compared with the value predicted from a simple model based on band filling. This model predicts that the primary contribution to the index change at the applied optical frequency arises from holes blocking direct transitions near the zone center and that similar blocking of indirect transitions has a negligible effect on the index.


Analysis of Evidence-Based Autism Symptoms Enhancement by Acupuncture.
Autism is considered as a complex developmental disability that appears during the first two years of life. It is considered as a neurological disorder that affects brain function leading to impaired development in social interaction and communication skills. Some clinical trials demonstrated that certain acupuncture points play relatively significant role in improving both signs and symptoms of this disease. Owing to limited information available about acupuncture point's combination and protocols, the present study aimed to explore the most frequently used acupuncture points and their channels for children with autism. Thirteen articles about autism enhancement were selected from 2007 to 2015. Acupoints and their channels used in these articles were analyzed according to usage frequencies. The present study identified the following main channels that contribute to autism symptoms enhancement along with the corresponding points' frequencies: Governing Vessel channel (12), Gall bladder channel (9), Kidney channel (8), Pericardium channel (7), Extra points channel (7), Liver channel (7), Heart channel (6), Conception vessel channel (6), and Bladder channel (6). On the other hand, the frequency of each corresponding acupuncture points are EX-HN1 (5), GV-17 (4), PC-6 (4), LR-3 (3), KI-3 (3), HT-7 (3), Lu-9 (3), GV-20 (2), GV-24 (2), GV-24.5 (2), GB-13(2), GB-19 (2), KI-4 (2), LR-4 (2), ST-36 (2), SP-3 (2), SP-6 (2). In conclusion, the consensus is that both channels and points may have an important role in autism symptoms enhancement. Based on the present study, the specific channels and points selection and stimulation types need further investigation through clinical trials.


Adenylyl cyclase type 3, a marker of primary cilia, is reduced in primary cell culture and in lumbar spinal cord in situ in G93A SOD1 mice.
The primary cilium is a solitary organelle important in cellular signaling, that projects from the cell surface of most growth-arrested or post-mitotic cells including neurons in the central nervous system. We hypothesized that primary cilial dysfunction might play a role in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), and as a first step, report on the prevalence of primary cilial markers on cultured motor neurons from the lumbar spinal cord of embryonic wildtype (WT) and transgenic G93A SOD1 mice, and on motor neurons in situ in the lumbar spinal cord. At 7 days in culture there is no difference in the proportion of G93A SOD1 and WT motor neurons staining for the cilial marker ACIII. However, at 21 days there is a large relative drop in the proportion of ciliated G93A SOD1 motor neurons. In situ, at 40 days there was a slight relative drop in the proportion of ciliated motor neurons in G93A SOD1 mice. At 98 days of age there was no change in motor neuron ciliation in WT mice, but there was motor neuron loss and a large reduction in the proportion of surviving motor neurons bearing a primary cilium in G93A SOD1 mice. In primary culture and in situ in G93A SOD1 mice there is a large reduction in the proportion of motor neurons bearing a primary cilium.


Does condom availability make a difference? An evaluation of Philadelphia's health resource centers.
In 1992, nine Philadelphia high schools opened drop-in centers where students could receive reproductive health information, condoms and general health referrals. Analyses of survey data collected in 1991 and 1993 suggest that the presence of the condom availability program did not increase the level of sexual activity among students in these schools and may have contributed to safer sex practices. The proportion of students who had used a condom at last intercourse increased from 52% to 58%; although the change was not statistically significant, it exceeded the increase in a group of comparison schools. Changes in the proportions of students who had ever had intercourse, who had had sex in the previous four weeks, who had used a condom at last intercourse and who had recently had unprotected sex were greatest in schools with higher levels of program usage; however, only the decline in recent unprotected intercourse among students in high-use schools (from 14% to 6%) approached statistical significance.


Activation of a nonselective cationic conductance by metabotropic glutamatergic and muscarinic agonists in CA3 pyramidal neurons of the rat hippocampus.
We have characterized a cationic membrane conductance activated by metabotropic glutamatergic and muscarinic cholinergic agonists in CA3 neurons in hippocampal slice cultures using the patch-clamp technique. When the potassium concentration in the superfusing fluid was raised above 5 mM, a biphasic current was observed in cells held at -60 mV in response to stimulation of postsynaptic metabotropic glutamate receptors (mGluRs) with 1S,3R-ACPD (50 microM) or muscarinic receptors with methacholine (MCh, 5 microM). The initial inward component was due to an increase in a cationic membrane conductance as determined by its reversal potential and its sensitivity to changes in extracellular K+ or Na+. The conductance underlying this current displayed no apparent voltage sensitivity over the range -120 to -50 mV. The response was reduced by extracellular application of Ba2+, Cd2+, Mg2+, or TEA, whereas extracellular Cs+ or loading cells with BAPTA or Cs+ did not affect the current. The effects of 1S,3R-ACPD were reversibly inhibited by bath-applied MCPG, an antagonist at mGluRs. Experiments with atropine and pirenzepine indicated that non-M1 muscarinic receptors mediated the MCh-induced current. A decrease in a resting leak potassium conductance (IK,leak) was responsible for the late component of the 1S,3R-ACPD- and MCh-induced response, seen as an outward current in the bathing solution with high K+ concentration. Loading cells with GDP beta S, GTP gamma S, or GTP did not alter the cationic current, while, in the same cells, the reduction in IKleak was abolished or irreversibly activated. Single-channel recordings of cationic channel activity in the cell-attached configuration provided evidence for the requirement of second messengers in coupling these receptors to the cationic channels. The data indicate that in addition to the previously described reduction of IK,leak, IM, and IAHP, both 1S,3R-ACPD and MCh activate a nonselective cationic conductance that is clearly revealed upon elevating external K+ concentration. This current is mediated by activation of metabotropic receptors, although no evidence could be obtained to show an involvement of G-proteins.


Clinical problems in relation to breast cancer screening with mammography. A preliminary report.
In the mammography screening in Ostergötland county, a shift to more favourable stages of breast tumours has been observed after five years of screening: stage I 71% and stage II 29% in the study group compared with stage I 40% and stage II 60% in the control group. 1 429 women were referred for clinical examination. 418 (29%) turned out to have breast carcinomas. 339 patients (23%) needed more than one clinical examination for definite diagnosis. 49% of the tumours were smaller than 11 mm, and only 32% of the small invasive cancers were suspected of malignancy at the clinical examination.


Genetic association of ARHGAP21 gene variant with mandibular prognathism.
Mandibular prognathism (MP) is a recognizable phenotype associated with dentoskeletal class III malocclusion. MP is a complex genetic trait, although familial recurrence also suggests the contribution of single inherited variations. To date, the genetic causes of MP have been investigated using linkage analysis or association studies in pooled families. Here for the first time, next-generation sequencing was used to study a single family with a large number of MP-affected members and to identify MP-related candidate genes. A 6-generation kindred with MP segregating as an autosomal dominant character was recruited. To identify family members affected by MP, a standard cephalometric procedure was used. In 5 MP subjects separated by the largest number of meioses, whole-exome sequencing was performed. Five promising missense gene variants (BMP3, ANXA2, FLNB, HOXA2, and ARHGAP21) associated with MP were selected and genotyped in most other family members. In this family, MP seemed to consist of 2 distinct genetic branches. Interestingly, the Gly1121Ser variant in the ARHGAP21 gene was found to be shared by all MP individuals in the larger branch of the family with nearly complete penetrance. This variant is rare in the Caucasian population (frequency 0.00034) and is predicted as damaging by all bioinformatic algorithms. ARHGAP21 protein strengthens cell-cell adhesions and may be regulated by bone morphogenetic factors, thus influencing mandibular growth. Further studies in both animal models and human patients are required to clarify the significance of this association.


Cell and protein compatible 3D bioprinting of mechanically strong constructs for bone repair.
Rapid prototyping of bone tissue engineering constructs often utilizes elevated temperatures, organic solvents and/or UV light for materials processing. These harsh conditions may prevent the incorporation of cells and therapeutic proteins in the fabrication processes. Here we developed a method for using bioprinting to produce constructs from a thermoresponsive microparticulate material based on poly(lactic-co-glycolic acid) at ambient conditions. These constructs could be engineered with yield stresses of up to 1.22 MPa and Young's moduli of up to 57.3 MPa which are within the range of properties of human cancellous bone. Further study showed that protein-releasing microspheres could be incorporated into the bioprinted constructs. The release of the model protein lysozyme from bioprinted constructs was sustainted for a period of 15 days and a high degree of protein activity could be measured up to day 9. This work suggests that bioprinting is a viable route to the production of mechanically strong constructs for bone repair under mild conditions which allow the inclusion of viable cells and active proteins.


Reported early family environment covaries with menarcheal age as a function of polymorphic variation in estrogen receptor-α.
Age at menarche, a sentinel index of pubertal maturation, was examined in relation to early family relationships (conflict, cohesion) and polymorphic variation in the gene encoding estrogen receptor-α (ESR1) in a midlife sample of 455 European American women. Consistent with prior literature, women who reported being raised in families characterized by close interpersonal relationships and little conflict tended to reach menarche at a later age than participants reared in families lacking cohesion and prone to discord. Moreover, this association was moderated by ESR1 variation, such that quality of the family environment covaried positively with menarcheal age among participants homozygous for minor alleles of the two ESR1 polymorphisms studied here (rs9304799, rs2234693), but not among women of other ESR1 genotypes. In addition, (a) family relationship variables were unrelated to ESR1 variation, and (b) genotype-dependent effects of childhood environment on age at menarche could not be accounted for by personality traits elsewhere shown to explain heritable variation in reported family conflict and cohesion. These findings are consistent with theories of differential susceptibility to environmental influence, as well as the more specific hypothesis (by Belsky) that girls differ genetically in their sensitivity to rearing effects on pubertal maturation.


Enhancer of polycomb1 acts on serum response factor to regulate skeletal muscle differentiation.
Skeletal muscle differentiation is well regulated by a series of transcription factors. We reported previously that enhancer of polycomb1 (Epc1), a chromatin protein, can modulate skeletal muscle differentiation, although the mechanisms of this action have yet to be defined. Here we report that Epc1 recruits both serum response factor (SRF) and p300 to induce skeletal muscle differentiation. Epc1 interacted physically with SRF. Transfection of Epc1 to myoblast cells potentiated the SRF-induced expression of skeletal muscle-specific genes as well as multinucleation. Proximal CArG box in the skeletal alpha-actin promoter was responsible for the synergistic activation of the promoter-luciferase. Epc1 knockdown caused a decrease in the acetylation of histones associated with serum response element (SRE) of the skeletal alpha-actin promoter. The Epc1.SRF complex bound to the SRE, and the knockdown of Epc1 resulted in a decrease in SRF binding to the skeletal alpha-actin promoter. Epc1 recruited histone acetyltransferase activity, which was potentiated by cotransfection with p300 but abolished by si-p300. Epc1 directly bound to p300 in myoblast cells. Epc1+/- mice showed distortion of skeletal alpha-actin, and the isolated myoblasts from the mice had impaired muscle differentiation. These results suggest that Epc1 is required for skeletal muscle differentiation by recruiting both SRF and p300 to the SRE of muscle-specific gene promoters.


Seeing the world topsy-turvy: The primary role of kinematics in biological motion inversion effects.
Physical inversion of whole or partial human body representations typically has catastrophic consequences on the observer's ability to perform visual processing tasks. Explanations usually focus on the effects of inversion on the visual system's ability to exploit configural or structural relationships, but more recently have also implicated motion or kinematic cue processing. Here, we systematically tested the role of both on perceptions of sex from upright and inverted point-light walkers. Our data suggest that inversion results in systematic degradations of the processing of kinematic cues. Specifically and intriguingly, they reveal sex-based kinematic differences: Kinematics characteristic of females generally are resistant to inversion effects, while those of males drive systematic sex misperceptions. Implications of the findings are discussed.


Occupation-centered assessment of children.
The past 5 years have seen increasing calls to reexamine our assessment and intervention practices to ensure that they reflect the profession's basic focus on occupation. Although a number of noteworthy efforts in this direction have been presented for adult practice areas, implementation of occupation-centered assessment in pediatric has been hampered by the lack of a consistent framework to guide this process. This article will present an adaptation of the functional assessment model proposed by Trombly (1993) designed to better reflect the unique needs and situations of children. It is a multilevel model that examines the pattern of a child's occupations in a particular environment as well as the performance of important tasks and activities that are part of these occupations. It is proposed that this model can serve as an organizing framework for an occupation-centered assessment process by helping to identify the critical questions that need to be addressed at each level of analysis and the kinds of measures that might be used to obtain relevant information. The newly completed School Function Assessment will be used to illustrate application of the framework to examine occupational performance of children in elementary school.


Face shape differs in phylogenetically related populations.
3D analysis of facial morphology has delineated facial phenotypes in many medical conditions and detected fine grained differences between typical and atypical patients to inform genotype-phenotype studies. Next-generation sequencing techniques have enabled extremely detailed genotype-phenotype correlative analysis. Such comparisons typically employ control groups matched for age, sex and ethnicity and the distinction between ethnic categories in genotype-phenotype studies has been widely debated. The phylogenetic tree based on genetic polymorphism studies divides the world population into nine subpopulations. Here we show statistically significant face shape differences between two European Caucasian populations of close phylogenetic and geographic proximity from the UK and The Netherlands. The average face shape differences between the Dutch and UK cohorts were visualised in dynamic morphs and signature heat maps, and quantified for their statistical significance using both conventional anthropometry and state of the art dense surface modelling techniques. Our results demonstrate significant differences between Dutch and UK face shape. Other studies have shown that genetic variants influence normal facial variation. Thus, face shape difference between populations could reflect underlying genetic difference. This should be taken into account in genotype-phenotype studies and we recommend that in those studies reference groups be established in the same population as the individuals who form the subject of the study.


Reciprocal allosteric modulation of carbon monoxide and warfarin binding to ferrous human serum heme-albumin.
Human serum albumin (HSA), the most abundant protein in human plasma, could be considered as a prototypic monomeric allosteric protein, since the ligand-dependent conformational adaptability of HSA spreads beyond the immediate proximity of the binding site(s). As a matter of fact, HSA is a major transport protein in the bloodstream and the regulation of the functional allosteric interrelationships between the different binding sites represents a fundamental information for the knowledge of its transport function. Here, kinetics and thermodynamics of the allosteric modulation: (i) of carbon monoxide (CO) binding to ferrous human serum heme-albumin (HSA-heme-Fe(II)) by warfarin (WF), and (ii) of WF binding to HSA-heme-Fe(II) by CO are reported. All data were obtained at pH 7.0 and 25°C. Kinetics of CO and WF binding to the FA1 and FA7 sites of HSA-heme-Fe(II), respectively, follows a multi-exponential behavior (with the same relative percentage for the two ligands). This can be accounted for by the existence of multiple conformations and/or heme-protein axial coordination forms of HSA-heme-Fe(II). The HSA-heme-Fe(II) populations have been characterized by resonance Raman spectroscopy, indicating the coexistence of different species characterized by four-, five- and six-coordination of the heme-Fe atom. As a whole, these results suggest that: (i) upon CO binding a conformational change of HSA-heme-Fe(II) takes place (likely reflecting the displacement of an endogenous ligand by CO), and (ii) CO and/or WF binding brings about a ligand-dependent variation of the HSA-heme-Fe(II) population distribution of the various coordinating species. The detailed thermodynamic and kinetic analysis here reported allows a quantitative description of the mutual allosteric effect of CO and WF binding to HSA-heme-Fe(II).


IRREGULAR TRICHOME BRANCH1 in Arabidopsis encodes a plant homolog of the actin-related protein2/3 complex activator Scar/WAVE that regulates actin and microtubule organization.
The dynamic actin cytoskeleton is important for a myriad of cellular functions, including intracellular transport, cell division, and cell shape. An important regulator of actin polymerization is the actin-related protein2/3 (Arp2/3) complex, which nucleates the polymerization of new actin filaments. In animals, Scar/WAVE family members activate Arp2/3 complex-dependent actin nucleation through interactions with Abi1, Nap1, PIR121, and HSCP300. Mutations in the Arabidopsis thaliana genes encoding homologs of Arp2/3 complex subunits PIR121 and NAP1 all show distorted trichomes as well as additional epidermal cell expansion defects, suggesting that a Scar/WAVE homolog functions in association with PIR121 and NAP1 to activate the Arp2/3 complex in Arabidopsis. In a screen for trichome branching defects, we isolated a mutant that showed irregularities in trichome branch positioning and expansion. We named this gene IRREGULAR TRICHOME BRANCH1 (ITB1). Positional cloning of the ITB1 gene showed that it encodes SCAR2, an Arabidopsis protein related to Scar/WAVE. Here, we show that itb1 mutants display cell expansion defects similar to those reported for the distorted class of trichome mutants, including disruption of actin and microtubule organization. In addition, we show that the scar homology domain (SHD) of ITB1/SCAR2 is necessary and sufficient for in vitro binding to Arabidopsis BRK1, the plant homolog of HSPC300. Overexpression of the SHD in transgenic plants causes a dominant negative phenotype. Our results extend the evidence that the Scar/WAVE pathway of Arp2/3 complex regulation exists in plants and plays an important role in regulating cell expansion.


A preclinical evaluation of the PI3K alpha/delta dominant inhibitor BAY 80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2-targeted therapies trastuzumab and lapatinib.
The PI3K pathway is a key mechanism of trastuzumab resistance, but early attempts to indirectly target this pathway with mTOR inhibitors have had limited success. We present the results of a preclinical study of the selective alpha/delta isoform dominant PI3K inhibitor BAY 80-6946 tested alone and in combination with HER2-targeted therapies in HER2-positive cell lines, including models with acquired resistance to trastuzumab and/or lapatinib. A panel of HER2-positive breast cancer cells were profiled for their mutational status using Sequenom MassARRAY, PTEN status by Western blot, and anti-proliferative response to BAY 80-6946 alone and in combination with the HER2-targeted therapies trastuzumab, lapatinib and afatinib. Reverse phase protein array was used to determine the effect of BAY 80-6946 on expression and phosphorylation of 68 proteins including members of the PI3K and MAPK pathways. The Boyden chamber method was used to determine if BAY 80-6946 affected cellular invasion and migration. BAY 80-6946 has anti-proliferative and anti-invasive effects when used alone in our panel of cell lines (IC50s 3.9-29.4 nM). BAY 80-6946 inhibited PI3K signalling and was effective in cells regardless of their PI3K, P53 or PTEN status. The combination of HER2-targeted therapies and BAY 80-6946 inhibited growth more effectively than either therapy used alone (with clear synergism in many cases), and can restore sensitivity to trastuzumab and lapatinib in cells with acquired resistance to either trastuzumab and/or lapatinib. The addition of BAY 80-6946 to HER2-targeted therapy could represent an improved treatment strategy for patients with refractory metastatic HER2-positive breast cancer, and should be considered for clinical trial evaluation.


Interagency collaboration models for people with mental ill health in contact with the police: a systematic scoping review.
To identify existing evidence on interagency collaboration between law enforcement, emergency services, statutory services and third sector agencies regarding people with mental ill health. Systematic scoping review. Scoping reviews map particular research areas to identify research gaps. ASSIA, CENTRAL, the Cochrane Library databases, Criminal Justice Abstracts, ERIC, Embase, MEDLINE, PsycINFO, PROSPERO and Social Care Online and Social Sciences Citation Index were searched up to 2017, as were grey literature and hand searches. Eligible articles were empirical evaluations or descriptions of models of interagency collaboration between the police and other agencies. Screening and data extraction were undertaken independently by two researchers. Arksey's framework was used to collate and map included studies. One hundred and twenty-five studies were included. The majority of articles were of descriptions of models (28%), mixed methods evaluations of models (18%) and single service evaluations (14%). The most frequently reported outcomes (52%) were 'organisational or service level outcomes' (eg, arrest rates). Most articles (53%) focused on adults with mental ill health, whereas others focused on adult offenders with mental ill health (17.4%). Thirteen models of interagency collaboration were described, each involving between 2 and 13 agencies. Frequently reported models were 'prearrest diversion' of people with mental ill health (34%), 'coresponse' involving joint response by police officers paired with mental health professionals (28.6%) and 'jail diversion' following arrest (23.8%). We identified 13 different interagency collaboration models catering for a range of mental health-related interactions. All but one of these models involved the police and mental health services or professionals. Several models have sufficient literature to warrant full systematic reviews of their effectiveness, whereas others need robust evaluation, by randomised controlled trial where appropriate. Future evaluations should focus on health-related outcomes and the impact on key stakeholders.


Multi-level, multi-scale resource selection functions and resistance surfaces for conservation planning: Pumas as a case study.
The importance of examining multiple hierarchical levels when modeling resource use for wildlife has been acknowledged for decades. Multi-level resource selection functions have recently been promoted as a method to synthesize resource use across nested organizational levels into a single predictive surface. Analyzing multiple scales of selection within each hierarchical level further strengthens multi-level resource selection functions. We extend this multi-level, multi-scale framework to modeling resistance for wildlife by combining multi-scale resistance surfaces from two data types, genetic and movement. Resistance estimation has typically been conducted with one of these data types, or compared between the two. However, we contend it is not an either/or issue and that resistance may be better-modeled using a combination of resistance surfaces that represent processes at different hierarchical levels. Resistance surfaces estimated from genetic data characterize temporally broad-scale dispersal and successful breeding over generations, whereas resistance surfaces estimated from movement data represent fine-scale travel and contextualized movement decisions. We used telemetry and genetic data from a long-term study on pumas (Puma concolor) in a highly developed landscape in southern California to develop a multi-level, multi-scale resource selection function and a multi-level, multi-scale resistance surface. We used these multi-level, multi-scale surfaces to identify resource use patches and resistant kernel corridors. Across levels, we found puma avoided urban, agricultural areas, and roads and preferred riparian areas and more rugged terrain. For other landscape features, selection differed among levels, as did the scales of selection for each feature. With these results, we developed a conservation plan for one of the most isolated puma populations in the U.S. Our approach captured a wide spectrum of ecological relationships for a population, resulted in effective conservation planning, and can be readily applied to other wildlife species.


Model for second-harmonic generation in glass optical fibers based on asymmetric photoelectron emission from defect sites.
We present a self-consistent calculation of anomalous second-harmonic generation in glass optical fibers. Quantum interference between multiphoton absorption processes leads to asymmetric photoelectric emission from defects, creating a spatially periodic space-charge electric field. The second harmonic is found to grow exponentially along the fiber, then saturate to a maximum value proportional to the square of the fundamental intensity. The predicted conversion efficiency is in reasonable agreement with experiments.


Graphene based enzymatic bioelectrodes and biofuel cells.
The excellent electrical conductivity and ease of functionalization make graphene a promising material for use in enzymatic bioelectrodes and biofuel cells. Enzyme based biofuel cells have attracted substantial interest due to their potential to harvest energy from organic materials. This review provides an overview of the functional properties and applications of graphene in the construction of biofuel cells as alternative power sources. The review covers the current state-of-the-art research in graphene based nanomaterials (physicochemical properties and surface functionalities), the role of these parameters in enhancing electron transfer, the stability and activity of immobilized enzymes, and how enhanced power density can be achieved. Specific examples of enzyme immobilization methods, enzyme loading, stability and function on graphene, functionalized graphene and graphene based nanocomposite materials are discussed along with their advantages and limitations. Finally, a critical evaluation of the performance of graphene based enzymatic biofuel cells, the current status, challenges and future research needs are provided.


Mechanism of Vibrio cholerae autoinducer-1 biosynthesis.
Vibrio cholerae, the causative agent of the disease cholera, uses a cell to cell communication process called quorum sensing to control biofilm formation and virulence factor production. The major V. cholerae quorum-sensing signal CAI-1 has been identified as (S)-3-hydroxytridecan-4-one, and the CqsA protein is required for CAI-1 production. However, the biosynthetic route to CAI-1 remains unclear. Here we report that (S)-adenosylmethionine (SAM) is one of the two biosynthetic substrates for CqsA. CqsA couples SAM and decanoyl-coenzyme A to produce a previously unknown but potent quorum-sensing molecule, 3-aminotridec-2-en-4-one (Ea-CAI-1). The CqsA mechanism is unique; it combines two enzymatic transformations, a β,γ-elimination of SAM and an acyltransferase reaction into a single PLP-dependent catalytic process. Ea-CAI-1 is subsequently converted to CAI-1, presumably through the intermediate tridecane-3,4-dione (DK-CAI-1). We propose that the Ea-CAI-1 to DK-CAI-1 conversion occurs spontaneously, and we identify the enzyme responsible for the subsequent step: conversion of DK-CAI-1 into CAI-1. SAM is the substrate for the synthesis of at least three different classes of quorum-sensing signal molecules, indicating that bacteria have evolved a strategy to leverage an abundant substrate for multiple signaling purposes.


Second-harmonic generation in poled polymers: pre-poling history paradigm.
Experimental studies of second harmonic generation (SHG) from electric-field poled PMMA - DR1 system show occurrence of a maximum in diagonal and off diagonal tensor components χ(2)(-2ω;ω,ω) at 15 mol % concentration and a rapid decrease above, with a stabilization. The origin of the observed concentration dependence is studied using the Monte Carlo (MC) modeling. We find that presence of maximum is conditioned by the pre-poling history of the sample, when entanglement of linear dipolar structures takes place. Length of the pre-poling interval is an important kinetic parameter which differentiates between various nonexponential kinetics of build-up of polar phase responsible for strong/weak SHG susceptibility.


A barbed end interference mechanism reveals how capping protein promotes nucleation in branched actin networks.
Heterodimeric capping protein (CP/CapZ) is an essential factor for the assembly of branched actin networks, which push against cellular membranes to drive a large variety of cellular processes. Aside from terminating filament growth, CP potentiates the nucleation of actin filaments by the Arp2/3 complex in branched actin networks through an unclear mechanism. Here, we combine structural biology with in vitro reconstitution to demonstrate that CP not only terminates filament elongation, but indirectly stimulates the activity of Arp2/3 activating nucleation promoting factors (NPFs) by preventing their association to filament barbed ends. Key to this function is one of CP's C-terminal "tentacle" extensions, which sterically masks the main interaction site of the terminal actin protomer. Deletion of the β tentacle only modestly impairs capping. However, in the context of a growing branched actin network, its removal potently inhibits nucleation promoting factors by tethering them to capped filament ends. End tethering of NPFs prevents their loading with actin monomers required for activation of the Arp2/3 complex and thus strongly inhibits branched network assembly both in cells and reconstituted motility assays. Our results mechanistically explain how CP couples two opposed processes-capping and nucleation-in branched actin network assembly.


Intra-individual variability and continuity of action and perception measures in infants.
The development of action and perception, and their relation in infancy is a central research area in socio-cognitive sciences. In this Perspective Article, we focus on the developmental variability and continuity of action and perception. At group level, these skills have been shown to consistently improve with age. We would like to raise awareness for the issue that, at individual level, development might be subject to more variable changes. We present data from a longitudinal study on the perception and production of contralateral reaching skills of infants aged 7, 8, 9, and 12 months. Our findings suggest that individual development does not increase linearly for action or for perception, but instead changes dynamically. These non-continuous changes substantially affect the relation between action and perception at each measuring point and the respective direction of causality. This suggests that research on the development of action and perception and their interrelations needs to take into account individual variability and continuity more progressively.


In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats.
Environmental estrogens are exogenous estrogen-mimicking compounds that can interfere with endogenous endocrine systems. Several of these endocrine disruptors have been shown to alter normal development and influence tumorigenesis in experimental models. N-butyl benzyl phthalate (BBP), a widely used plasticizer, is a well-known endocrine disruptor. The aim of this study was to elucidate the effect of prenatal exposure to BBP on the morphology, proliferative index, and genomic signature of the rat mammary gland at different ages. In utero exposure was performed by gavage of pregnant Sprague Dawley CD rats with 120mg or 500mg BBP/kg/day from day 10 post-conception to delivery. Female litters were euthanized at 21, 35, 50 and 100 days. The morphology and proliferative index of the mammary gland were studied from whole mount preparations and BrdU incorporation, respectively. Gene expression profile was assessed by microarrays. Several genes found differentially expressed and related to different functional categories were further validated by real time RT-PCR. Prenatal exposure of BBP induced delayed vaginal opening and changes in the post-natal mammary gland long after the end of the treatment, mainly by 35 days of age. Exposure to the high dose resulted in modifications in architecture and proliferative index of the mammary gland, mostly affecting the undifferentiated terminal end buds. Moreover, the expression profiles of this gland in the exposed rats were modified in a dose-dependent fashion. Analysis of functional categories showed that modified genes were related to immune function, cell signaling, proliferation and differentiation, or metabolism. Our data suggest that in utero exposure to BBP induced a delayed pubertal onset and modified morphology of the mammary gland. These alterations were accompanied by modifications in gene expression previously associated with an increased susceptibility to carcinogenesis.


Rabies postexposure consultations in New Zealand from 1998 to 2012.
Rabies is an invariably fatal zoonotic viral disease. New Zealanders going abroad are largely unaware of the risk of contracting the disease. Prevention is the key to controlling the spread of this disease. Data from 363 individuals presenting to New Zealand travel health clinics between 1998 and 2012 for post-travel consultations on potential rabies exposure were collated retrospectively. The data focused on traveler demographics, the country and nature of exposure, the purpose of travel, and pre-travel rabies awareness. The female-to-male ratio of subject travelers presenting was almost equal (1.1 : 1 ratio, respectively); the subjects were typically between 16 and 30 years (44.6%), tourists (64.5%), traveling less than 1 month (55.3%), and likely to have been exposed to animal contact in either Thailand (31.1%), China (13.2%), or Indonesia (12.3%). The animals to which they were exposed were usually dogs (59.5%) or monkeys (28.7%). Most potential exposures were penetrating (69.9%). Injury caused by the animal was more common in the lower limbs (50%) than in the upper limbs (43.4%); 89.4% of exposures were of World Health Organization (WHO) category III. Travelers were more likely to have received pre-travel rabies advice if they had been seen by a travel medicine specialist (96.1%) compared to a general practitioner (GP) (53.3%). Sixteen percent of travelers received rabies preexposure prophylaxis. Of the subjects who were managed following exposure, 79.7% did not receive immunoglobulin when indicated, and 21.5% did not receive any vaccine. Of the travelers that did receive a vaccine, 62.5% did so on the day of exposure. Of the travelers assessed, 16.7% had traveled without insurance. New Zealanders require better guidance in understanding the need for travel-related rabies vaccination, as they are not managed abroad according to WHO guidelines. Few travelers had had pre-travel immunization, and only 20.3% of them had received WHO-advised postexposure management. Thus, 79.7% of the cohort theoretically remained at risk for contracting rabies because of inappropriate management following possible exposure to the disease.


Feeling without seeing? Engagement of ventral, but not dorsal, amygdala during unaware exposure to emotional faces.
The ability to selectively perceive items in the environment may be modulated by the emotional content of those items. The neural mechanism that underlies the privileged processing of emotionally salient content is poorly understood. Here, using fMRI, we investigated this issue via a binocular rivalry procedure when face stimuli depicting fearful or neutral expressions competed for awareness with a house. Results revealed an interesting dissociation in the amygdala during rivalry condition: Whereas its dorsal component exhibited dominant activation to aware fearful faces, a ventral component was more active during the suppression of fearful faces. Moreover, during rivalry, the dorsal and ventral components of the amygdala were coupled with segregated cortical activations in the brainstem and medial PFC, respectively. In summary, this study points to a differential involvement of two clusters within the amygdala and their connected networks in naturally occurring perceptual biases of emotional content in faces.


Rap1 activation in collagen phagocytosis is dependent on nonmuscle myosin II-A.
Rap1 enhances integrin-mediated adhesion but the link between Rap1 activation and integrin function in collagen phagocytosis is not defined. Mass spectrometry of Rap1 immunoprecipitates showed that the association of Rap1 with nonmuscle myosin heavy-chain II-A (NMHC II-A) was enhanced by cell attachment to collagen beads. Rap1 colocalized with NM II-A at collagen bead-binding sites. There was a transient increase in myosin light-chain phosphorylation after collagen-bead binding that was dependent on myosin light-chain kinase but not Rho kinase. Inhibition of myosin light-chain phosphorylation, but not myosin II-A motor activity inhibited collagen-bead binding and Rap activation. In vitro binding assays demonstrated binding of Rap1A to filamentous myosin rods, and in situ staining of permeabilized cells showed that NM II-A filaments colocalized with F-actin at collagen bead sites. Knockdown of NM II-A did not affect talin, actin, or beta1-integrin targeting to collagen beads but targeting of Rap1 and vinculin to collagen was inhibited. Conversely, knockdown of Rap1 did not affect localization of NM II-A to beads. We conclude that MLC phosphorylation in response to initial collagen-bead binding promotes NM II-A filament assembly; binding of Rap1 to myosin filaments enables Rap1-dependent integrin activation and enhanced collagen phagocytosis.


Respiratory health effects of large animal farming environments.
With increases in large animal-feeding operations to meet consumer demand, adverse upper and lower respiratory health effects in exposed agriculture workers are a concern. The aim of this study was to review large animal confinement feeding operational exposures associated with respiratory disease with a focus on recent advances in the knowledge of causative factors and cellular and immunological mechanisms. A PubMed search was conducted with the keywords airway, farm, swine, dairy, horse, cattle inflammation, organic dust, endotoxin, and peptidoglycan, among items were published between 1980 and now. Articles were selected based on their relevance to environmental exposure and reference to airway diseases. Airway diseases included rhinitis, sinusitis, mucus membrane inflammation syndrome, asthma, chronic bronchitis, chronic obstructive pulmonary disease, hypersensitivity pneumonitis, and organic dust toxic syndrome. There is lower prevalence of immunoglobulin (Ig) E-mediated asthma and atopy in farmers and their children, but organic dust worsens existing asthma. Multiple etiologic factors are linked to disease, including allergens, organic dusts, endotoxins, peptidoglycans, and gases. Large animal confinement feeding operations contain a wide diversity of microbes with increasing focus on gram-positive bacteria and archaebacteria as opposed to gram-negative bacteria in mediating disease. Toll-like receptors (TLR) and nucleotide oligomerization domain (NOD)-like innate immune pathways respond to these exposures. Finally, a chronic inflammatory adaptation, tolerance-like response in chronically exposed workers occurs. Large animal confinement farming exposures produce a wide spectrum of upper and lower respiratory tract diseases due to the complex diversity of organic dust, particulates, microbial cell wall components, and gases and resultant activation of various innate immune receptor signaling pathways.


Development and optimization of an LC-MS/MS-based method for simultaneous quantification of vitamin D2 , vitamin D3 , 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3.
Simultaneous and accurate measurement of vitamin D and 25-hydroxyvitamin D in biological samples is a barrier limiting our ability to define "optimal" vitamin D status. Thus, our goal was to optimize conditions and evaluate an LC-MS method for simultaneous detection and quantification of vitamin D(2) , vitamin D(3) , 25-hydroxyvitamin D(2) and 25-hydroxyvitamin D(3) in serum. Extraction and separation of vitamin D forms were achieved using acetone liquid-liquid extraction and by a reversed phase C8 column, respectively. Detection was performed on a triple quadrupole tandem mass spectrometer (QQQ-MS/MS) equipped with atmospheric pressure photo ionization source. The LOQs for all analytes tested were 1 ng/mL for hydroxylated molecules and 2 ng/mL for the parent vitamin Ds. RSD at lower LOQ (2 ng/mL) and in medium (80 ng/mL) and high (200 ng/mL) quality control samples did not exceed 20 and 15% CV, respectively. Accuracy of the method for determination of hydroxylated molecules was also validated using National Institutes of Standards and Technology standard samples and found to be in the range of 90.9-111.2%. In summary, a sensitive and reproducible method is reported for simultaneous quantification of vitamin D(2) , vitamin D(3) , 25-hydroxyvitamin D(2) and 25-hydroxyvitamin D(3) molecules in biological samples.


Interstitial cystitis.
Interstitial cystitis (IC) is a serious debilitating disease often overlooked by medical and health professionals. This paper describes the elusive aetiology and the painful symptoms of IC and how it affects the patient's life. The author outlines the treatments available and offers guidelines for supporting patients with the disease.


An assessment of patient preference and adherence to treatment with Wellbutrin SR: a web-based survey.
Research has shown that lack of treatment adherence is a serious problem, especially among patients with psychiatric disorders. The current study was conducted to assess adherence and patient preference among individuals taking Wellbutrin SR (bupropion) for depression, as well as their interest in a once-daily formulation of bupropion. A 20-item web-based survey was administered to 527 individuals (276 men and 251 women) recruited through an online panel. All participants were at least 18 years of age, diagnosed with major depressive disorder, and had been taking Wellbutrin SR for at least 6 weeks. Survey items addressed treatment regimen, adherence, satisfaction with Wellbutrin SR, and interest in a once-daily formulation of bupropion. The majority of respondents reported taking Wellbutrin SR twice a day (67%). Only 15% of once-daily users were nonadherent compared to 37% of twice-daily users and 65% of thrice-daily users. The most common reason reported for missing a dose of Wellbutrin SR was simply forgetting to take it (49% of twice-daily users and 65% of thrice-daily users). Results indicated that 77% of twice-daily users and 94% of thrice-daily users were interested in a once-daily formula. A reduction in dosing frequency is favored by Wellbutrin SR users and likely to improve their adherence to treatment. Because greater adherence has been shown to facilitate symptom relief, improvements in quality of life, and reductions in healthcare expenses, the results of this study support the value of the recently released once-daily formulation, Wellbutrin XL.


Fractional-Order PID Control Strategy on Hydraulic-Loading System of Typical Electromechanical Platform.
In this paper, a control method for a hydraulic loading system of an electromechanical platform based on a fractional-order PID (Proportion-Integration-Differentiation) controller is proposed, which is used to drive the loading system of a mechatronic journal test rig. The mathematical model of the control system is established according to the principle of the electro-hydraulic system. Considering the indetermination of model parameters, the method of parameter identification was used to verify the rationality of the theoretical model. In order to improve the control precision of the hydraulic loading system, the traditional PID controller and fractional-order PID controller are designed by selecting appropriate tuning parameters. Their control performances are analyzed in frequency domain and time domain, respectively. The results show that the fractional-order PID controller has better control effect. By observing the actual control effect of the fractional-order PID controller on the journal test rig, the effectiveness of this control algorithm is verified.


Locked posterior dislocation of the shoulder.
Of forty patients with forty-one locked posterior dislocations of the shoulder, the diagnosis had been missed by the initial physician in the majority. A motor-vehicle accident, a seizure, an alcohol-related injury, or electroshock therapy had caused the dislocation in these patients, and the average interval from injury to diagnosis was one year. Twenty-five of the forty-one dislocations had been diagnosed in less than six months. An axillary radiograph confirmed the diagnosis in all shoulders and demonstrated the approximate size of the impression defect. There were no associated displaced fractures of the humerus, but in twenty of the shoulders there was an undisplaced fracture of the proximal part of the humerus. The average length of follow-up was 5.5 years. For seven shoulders the deformity was accepted. Treatment in the others consisted of closed reduction, which was attempted in twelve shoulders and was successful in six of the twelve; transfer of the subscapularis tendon, which was attempted in nine shoulders and was successful in four; transfer of the lesser tuberosity, which was successful in all four shoulders that were so treated; hemiarthroplasty, which was performed in nine shoulders and was successful in six (the other three required revision); and total arthroplasty in ten shoulders, one of which dislocated postoperatively and was not treated. Once the diagnosis is established, the majority of patients with this lesion can be successfully managed.


Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain.
Despite the frequency of diabetes mellitus and its relationship to diabetic peripheral neuropathy (DPN) and neuropathic pain (NeP), our understanding of underlying mechanisms leading to chronic pain in diabetes remains poor. Recent evidence has demonstated a prominent role of microglial cells in neuropathic pain states. One potential therapeutic option gaining clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB) are expressed on neurons and microglia. We studied the accumulation and activation of spinal and thalamic microglia in streptozotocin (STZ)-diabetic CD1 mice and the impact of cannabinoid receptor agonism/antagonism during the development of a chronic NeP state. We provided either intranasal or intraperitoneal cannabinoid agonists/antagonists at multiple doses both at the initiation of diabetes as well as after establishment of diabetes and its related NeP state. Tactile allodynia and thermal hypersensitivity were observed over 8 months in diabetic mice without intervention. Microglial density increases were seen in the dorsal spinal cord and in thalamic nuclei and were accompanied by elevation of phosphorylated p38 MAPK, a marker of microglial activation. When initiated coincidentally with diabetes, moderate-high doses of intranasal cannabidiol (cannaboid receptor 2 agonist) and intraperitoneal cannabidiol attenuated the development of an NeP state, even after their discontinuation and without modification of the diabetic state. Cannabidiol was also associated with restriction in elevation of microglial density in the dorsal spinal cord and elevation in phosphorylated p38 MAPK. When initiated in an established DPN NeP state, both CB1 and CB2 agonists demonstrated an antinociceptive effect until their discontinuation. There were no pronociceptive effects demonstated for either CB1 or CB2 antagonists. The prevention of microglial accumulation and activation in the dorsal spinal cord was associated with limited development of a neuropathic pain state. Cannabinoids demonstrated antinociceptive effects in this mouse model of DPN. These results suggest that such interventions may also benefit humans with DPN, and their early introduction may also modify the development of the NeP state.