Statistical synthesis of contextual knowledge to increase the effectiveness of theory-based behaviour change interventions.
Tailored implementation strategies targeting health professionals' adoption of evidence-based recommendations are currently being developed. Research has focused on how to select an appropriate theoretical base, how to use that theoretical base to explore the local context, and how to translate theoretical constructs associated with the key factors found to influence innovation adoption into feasible and tailored implementation strategies. The reasons why an intervention is thought not to have worked are often cited as being: inappropriate choice of theoretical base; unsystematic development of the implementation strategies; and a poor evidence base to guide the process. One area of implementation research that is commonly overlooked is how to synthesize the data collected in a local context in order to identify what factors to target with the implementation strategies. This is suggested to be a critical process in the development of a theory-based intervention. The potential of multilevel modelling techniques to synthesize data collected at different hierarchical levels, for example, individual attitudes and team level variables, is discussed. Future research is needed to explore further the potential of multilevel modelling for synthesizing contextual data in implementation studies, as well as techniques for synthesizing qualitative and quantitative data.


Waveguide surface plasmon resonance sensor for electrochemically controlled surface reactions.
Electrochemical oxidation of the surface of a thin gold film overlaid on an optical waveguide and placed in a cell containing sulfuric acid is monitored by integrated optical surface plasmon resonance (IOSPR) combined with cyclic voltammetry. Waveguide transmittance correlates well with the charge transferred to and from the electrode to oxidize and reduce the surface, with a 60% reduction in transmittance being observed for complete formation of the surface oxide. IOSPR sensors combined with electrochemical measurement and control show potential for sensitive and robust integrated multisensors for electroactive species.


Evidence for the Perception of Time Distortion During Episodes of Alice in Wonderland Syndrome.
Alice in Wonderland syndrome (AIWS) is a rare perceptual disorder associated with sensation of one or several visual and/or auditory perceptual distortions including size of body parts, size of external objects, or passage of time (either speeding up or slowing down). Cause for AIWS is yet to be widely agreed, and the implications are widely varied. One of the research difficulties is the brevity of each episode, typically not exceeding few tens of minutes. This article presents a male adult in late 20s who has apparently experienced AIWS episodes since childhood, and infection has been ruled out. Reaction speed tests were conducted during and after AIWS episodes, across a span of 13 months. Statistically significant evidence is present for delayed response time during AIWS episodes when the patient claims to experience a sensation of time distortion: where events seem to move faster and people appear to speak quicker.


The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial.
Heart failure with preserved ejection fraction is associated with substantial morbidity and mortality, but effective treatments are lacking. We assessed the efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), in patients with this disorder. PARAMOUNT was a phase 2, randomised, parallel-group, double-blind multicentre trial in patients with New York Heart Association (NYHA) class II-III heart failure, left ventricular ejection fraction 45% or higher, and NT-proBNP greater than 400 pg/mL. Participants were randomly assigned (1:1) by central interactive voice response system to LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and treated for 36 weeks. Investigators and participants were masked to treatment assignment. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks; analysis included all patients randomly assigned to treatment groups who had a baseline and at least one postbaseline assessment. This trial is registered at Clinicaltrials.gov, number NCT00887588. 149 patients were randomly assigned to LCZ696 and 152 to valsartan; 134 in the LCZ696 group and 132 in the valsartan group were included in analysis of the primary endpoint. NT-proBNP was significantly reduced at 12 weeks in the LCZ696 group compared with the valsartan group (LCZ696: baseline, 783 pg/mL [95% CI 670-914], 12 weeks, 605 pg/mL [512-714]; valsartan: baseline, 862 pg/mL [733-1012], 12 weeks, 835 [710-981]; ratio LCZ696/valsartan, 0·77, 95% CI 0·64-0·92, p=0·005). LCZ696 was well tolerated with adverse effects similar to those of valsartan; 22 patients (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event. In patients with heart failure with preserved ejection fraction, LCZ696 reduced NT-proBNP to a greater extent than did valsartan at 12 weeks and was well tolerated. Whether these effects would translate into improved outcomes needs to be tested prospectively. Novartis.


The Significance of Pain in Chronic Venous Disease and its Medical Treatment.
Chronic venous disease (CVeD) is a highly prevalent condition in the general population, and it has a significant impact on quality of life. While it is usually manifested by obvious signs, such as varicose veins and venous ulcers, other symptoms of the disease are less specific. Among the other symptoms, which include heaviness, swelling, muscle cramps and restless legs, pain is the symptom that most frequently compels CVeD patients to seek medical aid. However, there is a substantial discrepancy between pain severity and clinically detectable signs of CVeD, questioned by several opposing studies. Further evaluation is needed to clarify this subject, and to analyse whether pain development predicts objective CVeD progression. General management of CVeD starts with advising lifestyle changes, such as lowering body mass index and treating comorbidities. However, the mainstay of treatment is compression therapy, with the additional use of pharmacological substances. Venoactive drugs proved to be the drugs of choice for symptom alleviation and slowing the progression of CVeD, with micronized purified flavonoid fraction being the most effective one. Interventional therapy is reserved for advanced stages of the disease.


Reporting, updating, and correcting systematic reviews of the effects of health care.
The recent growth in the numbers of published systematic reviews reflects growing recognition of their importance for improving knowledge about the effects of health care. In Britain the NHS R&D Programme has established two centres to prepare systematic reviews of existing information, and the Cochrane Collaboration--an international network of individuals and institutions--evolved to produce systematic, periodically updated reviews of randomised controlled trials. The large amount of existing evidence that needs to be considered creates a problem for the reporting of systematic reviews: the need to ensure that methods and results of systematic reviews are adequately described has to be reconciled with the limited space available in printed journals. A possible solution is the use of electronic publications: reviews could be published simultaneously in a short, printed form and in a more detailed electronic form. Electronic publications also have the advantage of the ease with which reviews may be updated as new evidence becomes available or mistakes are identified.


The disclosure of incidental genomic findings: an "ethically important moment" in pediatric research and practice.
Although there are numerous position papers on the issues and challenges surrounding disclosure of incidental genomic findings involving children, there is very little research. To fill this gap, the purpose of this study was to explore the perspectives of multiple professional (N = 103) and public (N = 63) stakeholders using both interviews and focus groups. Using qualitative analysis, we identified one overarching theme, "It's hard for us; it's hard for them," and three subthemes/questions: "What to disclose?," "Who gets the information?," and "What happens later?" Perspectives differed between professional (Institutional Review Board chairs, clinicians, and researchers) and public stakeholders. While professionals focused on the complexities of what to disclose, the lay public stated that parents should have all information laid out for them. Professionals pondered multiple parent and child situations, while the public identified parents as informational gatekeepers who know their children best. Professionals described the potential requirement for follow-up over time as a logistical "nightmare," while the public believed that parents have the responsibility for managing their children's health information over time. However, the parent role as gatekeeper was seen as time limited and in need of professional support and backup. Our findings present a case for needed dialogue around what we propose as an "ethically important moment," with the goal of protecting and respecting the viewpoints of all stakeholders when policies regarding children are developed.


Impact of social franchising on contraceptive use when complemented by vouchers: a quasi-experimental study in rural Pakistan.
Pakistan has had a low contraceptive prevalence rate for the last two decades; with preference for natural birth spacing methods and condoms. Family planning services offered by the public sector have never fulfilled the demand for contraception, particularly in rural areas. In the private sector, cost is a major constraint. In 2008, Marie Stopes Society - a local NGO started a social franchise programme along with a free voucher scheme to promote uptake of IUCDs amongst the poor. This paper evaluates the effectiveness of this approach, which is designed to increase modern long term contraceptive awareness and use in rural areas of Pakistan. We used a quasi-experimental study design with controls, selecting one intervention district and one control district from the Sindh and Punjab provinces. In each district, we chose a total of four service providers. A baseline survey was carried out among 4,992 married women of reproductive age (MWRA) in February 2009. Eighteen months after the start of intervention, an independent endline survey was conducted among 4,003 women. We used multilevel logistic regression for analysis using Stata 11. Social franchising used alongside free vouchers for long term contraceptive choices significantly increased the awareness of modern contraception. Awareness increased by 5% in the intervention district. Similarly, the ever use of modern contraceptive increased by 28.5%, and the overall contraceptive prevalence rate increased by 19.6%. A significant change (11.1%) was recorded in the uptake of IUCDs, which were being promoted with vouchers. Family planning franchise model promotes awareness and uptake of contraceptives. Moreover, supplemented with vouchers, it may enhance the use of IUCDs, which have a significant cost attached. Our research also supports a multi-pronged approach- generating demand through counselling, overcoming financial constraints by offering vouchers, training, accreditation and branding of the service providers, and ensuring uninterrupted contraceptive supplies.


Fibrocystic breast disease in oral-contraceptive users. A histopathological evaluation of epithelial atypia.
Epidemiological studies show a lower frequency of fibrocystic breast disease among long-term users of oral contraceptives than among women who have never used them. Fibrocystic disease may be a precursor of breast cancer; yet the incidence of breast cancer does not appear to differ between pill-takers and nontakers. To resolve this conflict, we examined the problem from a histologic standpoint in 205 premenopausal women, and found that this decreased frequency applied only to fibrocystic disease in which epithelial atypia was minimal or absent. In women with marked atypia there was no significant difference in frequency among long-term users as compared to women who have never used oral contraceptives. These findings suggest that a spectrum of cystic disease exists and that the long-term use of oral contraceptives protects against the forms of fibrocystic disease that are not firmly associated with an increased risk of breast cancer, but not against the premalignant forms.


Childhood IQ and adult mental disorders: a test of the cognitive reserve hypothesis.
Cognitive reserve has been proposed as important in the etiology of neuropsychiatric disorders. However, tests of the association between premorbid IQ and adult mental disorders other than schizophrenia have been limited and inconclusive. The authors tested the hypothesis that low childhood IQ is associated with increased risk and severity of adult mental disorders. Participants were members of a representative 1972-1973 birth cohort of 1,037 males and females in Dunedin, New Zealand, who were followed up to age 32 with 96% retention. WISC-R IQ was assessed at ages 7, 9, and 11. Research diagnoses of DSM mental disorders were made at ages 18, 21, 26, and 32. Lower childhood IQ was associated with increased risk of developing schizophrenia spectrum disorder, adult depression, and adult anxiety. Lower childhood IQ was also associated with greater comorbidity and with persistence of depression; the association with persistence of generalized anxiety disorder was nearly significant. Higher childhood IQ predicted increased risk of adult mania. Lower cognitive reserve, as reflected by childhood IQ, is an antecedent of several common psychiatric disorders and also predicts persistence and comorbidity. Thus, many patients who seek mental health treatment may have lower cognitive ability; this should be considered in prevention and treatment planning.


Work ability assessment in a worker population: comparison and determinants of Work Ability Index and Work Ability score.
Public authorities in European countries are paying increasing attention to the promotion of work ability throughout working life and the best method to monitor work ability in populations of workers is becoming a significant question. The present study aims to compare the assessment of work ability based on the use of the Work Ability Index (WAI), a 7-item questionnaire, with another one based on the use of WAI's first item, which consists in the worker's self-assessment of his/her current work ability level as opposed to his/her lifetime best, this single question being termed "Work Ability score" (WAS). Using a database created by an occupational health service, the study intends to answer the following questions: could the assessment of work ability be based on a single-item measure and which are the variables significantly associated with self-reported work ability among those systematically recorded by the occupational physician during health examinations? A logistic regression model was used in order to estimate the probability of observing "poor" or "moderate" WAI levels depending on age, gender, body mass index, smoking status, position held, firm size and diseases reported by the worker in a population of workers aged 40 to 65 and examined between January 2006 and June 2010 (n=12389). The convergent validity between WAS and WAI was statistically significant (rs=0.63). In the multivariable model, age (p<0.001), reported diseases (OR=1.13, 95%CI [1.11-1.15]) and holding a position mostly characterized by physical activity (OR=1.67, 95%CI [1.49-1.87]) increased the probability of reporting moderate or poor work ability. A work position characterized by the predominance of mental activity (OR=0.71, 95%CI [0.61-0.84]) had a favourable impact on work ability. These relations were observed regardless of the work ability measurement tool used. The convergent validity and the similarity in results between WAI and WAS observed in a large population of employed workers should thus foster the use of WAS for systematic screening of work ability. Ageing, overweight, decline in health status, holding a mostly physical job and working in a large-sized firm increase the risk of presenting moderate or poor work ability.


Radiographic classification of osteoarthritis in commonly affected joints of the foot.
To develop a radiographic atlas for the classification of osteoarthritis (OA) in commonly affected joints of the foot based on observations of osteophytes and joint space narrowing, and to assess its intra- and inter-examiner reliability. Weightbearing dorso-plantar and lateral foot radiographs from people aged over 65 years were examined, and an atlas was developed incorporating characteristic OA features of five foot joints: the first metatarsophalangeal joint, the first cuneo-metatarsal joint (1(st) CMJ), the second cuneo-metatarsal (2(nd) CMJ), the navicular-first cuneiform joint and the talonavicular joint. To assess the reliability of the atlas, two examiners independently rated 50 radiographs on two separate occasions. Observations using the atlas demonstrated moderate to excellent reliability within examiners (percentage agreement from 86 to 99% and weighted kappa from 0.45 to 0.95), and, with the exception of joint space narrowing of the 2(nd) CMJ from the lateral projection, fair to excellent reliability between examiners (percentage agreement from 86 to 97% and weighted kappa from 0.32 to 0.87). Intra-class correlation coefficients for the overall foot OA score (representing the sum of observations for all joints from both feet) ranged between 0.83 and 0.89 for intra-examiner comparisons, and between 0.72 and 0.74 for inter-examiner comparisons. Radiographic features of OA in commonly affected foot joints can be documented with high levels of agreement within examiners and moderate levels of agreement between examiners. Provided single examiners or consensus gradings are used, the atlas appears to be a useful tool to assist in the standardization of foot OA assessment for epidemiological and clinical studies.


Dynamic optimal learning rates of a certain class of fuzzy neural networks and its applications with genetic algorithm.
The stability analysis of the learning rate for a two-layer neural network (NN) is discussed first by minimizing the total squared error between the actual and desired outputs for a set of training vectors. The stable and optimal learning rate, in the sense of maximum error reduction, for each iteration in the training (back propagation) process can therefore be found for this two-layer NN. It has also been proven in this paper that the dynamic stable learning rate for this two-layer NN must be greater than zero. Thus it Is guaranteed that the maximum error reduction can be achieved by choosing the optimal learning rate for the next training iteration. A dynamic fuzzy neural network (FNN) that consists of the fuzzy linguistic process as the premise part and the two-layer NN as the consequence part is then illustrated as an immediate application of our approach. Each part of this dynamic FNN has its own learning rate for training purpose. A genetic algorithm is designed to allow a more efficient tuning process of the two learning rates of the FNN. The objective of the genetic algorithm is to reduce the searching time by searching for only one learning rate, which is the learning rate of the premise part, in the FNN. The dynamic optimal learning rates of the two-layer NN can be found directly using our innovative approach. Several examples are fully illustrated and excellent results are obtained for the model car backing up problem and the identification of nonlinear first order and second order systems.


Prognostic Significance of Serum Interleukins and Soluble ST2 in Traditional Chinese Medicine (TCM) Syndrome-Differentiated Rheumatoid Arthritis.
BACKGROUND The aim of this study was to explore the possible correlations of serum interleukins and soluble ST2 (sST2) protein with clinical features and inflammatory cytokines in rheumatoid arthritis (RA) patients, as well as to assess ability of TCM (Traditional Chinese Medicine) syndromes to differentiate RA patients and evaluate prognosis. MATERIAL AND METHODS Thirty RA patients and 25 healthy individuals were enrolled. Syndrome activity was evaluated, and lab tests were performed. Serum levels of IL-10, IL-17, IL-33, and sST2 were assessed by ELISA. RESULTS Serum levels of sST2, IL-33, and pro-inflammation cytokine IL-17 were all up-regulated, while the immunosuppressive cytokine IL-10 was decreased in RA patients. Serum IL-33 level was positively associated with ESR, CRP, and RF, as well as with HAQ score, VAS score, and DAS28 scores (P<0.05). Serum sST2 level was correlated with the morning stiffness time and ESR, as well as scores of HAQ and DAS28 (P<0.05). In addition, IL-33 level was positively corelated with IL-17 (r=0.83, P<0.01) and the relative ratio of IL-10/IL-17 (r=0.904, P<0.01), and was negatively related with IL-10 (r=-0.632, P<0.01). TCM syndrome differentiation was conducted for RA patients, including the hot syndromes and cold syndromes groups. Hot syndromes RA patients had significantly more severe inflammation compared with cold syndromes patients. CONCLUSIONS IL-33 is a possible index for monitoring disease activity and inflammation condition in RA. IL-33 contributes to RA pathogenesis through unbalancing IL-10 and IL-17. In terms of TCM, hot syndromes RA presented more serious inflammation and more active disease activity, indicating a poorer prognosis.


The use of the Behavioral Pain Scale to assess pain in conscious sedated patients.
Assessing pain in mechanically ventilated critically ill patients is a great challenge. There is a need for an adequate pain measurement tool for use in conscious sedated patients because of their questionable communicative abilities. In this study, we evaluated the use of the Behavioral Pain Scale (BPS) in conscious sedated patients in comparison with its use in deeply sedated patients, for whom the BPS was developed. Additionally, in conscious sedated patients, the combination of the BPS and the patient-rated Verbal Rating Scale (VRS-4) was evaluated. We performed a prospective evaluation study in 80 nonparalyzed critically ill adult intensive care unit patients. Over 2 mo, nurses performed 175 observation series: 126 in deeply sedated patients and 49 in conscious sedated patients. Each observation series consisted of BPS ratings (range 3-12) at 4 points: at rest, during a nonpainful procedure, at retest rest, and during a routine painful procedure. Patients in the conscious sedated state also self-reported their pain using the 4-point VRS-4. BPS scores during painful procedures were significantly higher than those at rest, both in deeply sedated patients (5.1 [4.8-5.5] vs 3.4 [3.3-3.5], respectively) and conscious sedated patients (5.4 [4.9-5.9] vs 3.8 [3.5-4.1], respectively) (mean [95% confidence interval]). For both groups, scores obtained during the nonpainful procedure and at rest did not significantly differ. There was a strong correlation between nurses' BPS ratings and conscious sedated patients' VRS-4 ratings during the painful procedure (r(s) = 0.67, P < 0.001). At rest and during nonpainful procedures, 98% of the observations were rated as acceptable pain (VRS 1 or 2) by both nurses and patients. During painful procedures, nurses rated the pain higher than patients did in 16% of the observations and lower in 12% of the observations. The BPS is a valid tool for measuring pain in conscious sedated patients during painful procedures. Thus, for noncommunicative and mechanically ventilated patients, it may be regarded as a bridge between the observational scale used by nurses and the VRS-4 used by patients who are able to self-report pain.


Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma.
Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues.


Mechanical forces and feedbacks in cell motility.
Cell movement is driven by a self-organized assembly of numerous actin polymers and accessory proteins surrounded by a flexible membrane. While the identity of the molecular components involved is largely known, we are still far from understanding how this enormous ensemble of molecules self-organizes into a dynamic motile cell. A great deal of work in the field has focused on the role of biochemical signaling in establishing and maintaining cellular organization. More recently, mechanical forces and feedbacks have emerged as equally important contributors to the large-scale organization of motile cells. Here we review recent progress in the field, focusing on processes related to the actin cytoskeleton and its interplay with the cell membrane.


Reverse innovation: an opportunity for strengthening health systems.
Canada, when compared to other OECD countries, ranks poorly with respect to innovation and innovation adoption while struggling with increasing health system costs. As a result of its failure to innovate, the Canadian health system will struggle to meet the needs and demands of both current and future populations. The purpose of this initiative was to explore if a competition-based reverse innovation challenge could mobilize and stimulate current and future leaders to identify and lead potential reverse innovation projects that address health system challenges in Canada. An open call for applications took place over a 4-month period. Applicants were enticed to submit to the competition with a $50,000 prize for the top submission to finance their project. Leaders from a wide cross-section of sectors collectively developed evaluation criteria and graded the submissions. The criteria evaluated: proof of concept, potential value, financial impact, feasibility, and scalability as well as the use of prize money and innovation team. The competition received 12 submissions from across Canada that identified potential reverse innovations from 18 unique geographical locations that were considered developing and/or emerging markets. The various submissions addressed health system challenges relating to education, mobile health, aboriginal health, immigrant health, seniors health and women's health and wellness. Of the original 12 submissions, 5 finalists were chosen and publically profiled, and 1 was chosen to receive the top prize. The results of this initiative demonstrate that a competition that is targeted to reverse innovation does have the potential to mobilize and stimulate leaders to identify reverse innovations that have the potential for system level impact. The competition also provided important insights into the capacity of Canadian students, health care providers, entrepreneurs, and innovators to propose and implement reverse innovation in the context of the Canadian health system.


Translation and psychometric evaluation of the Swedish version of the Interdisciplinary Education Perception Scale.
Interprofessional education (IPE) is widely accepted worldwide, as a key part of training for health professionals and critical to an effective, patient-centred healthcare system. Several tools have been developed to evaluate IPE programmes and interventions globally. Many of the widely-used tools have been successfully adapted to suit specific cohorts and different languages; the Interdisciplinary Education Perception Scale (IEPS), however, has not yet been translated and validated for use in Sweden. The aim of this study was to translate the IEPS into Swedish and validate the psychometric properties of this new version. The 12-item IEPS underwent translation into Swedish and back-translation into English by suitable independent translators to ensure items retained their meaning. The new Swedish version was completed by 164 medical and nursing, occupational therapy and physiotherapy students on clinical placements in Stockholm. Principal Axis Factoring (PAF) and Oblique Oblimin Rotation confirmed a three-factor structure, that explained 77.4% of variance. The new 10-item Swedish version IEPS displayed good internal consistency with an overall Cronbach's alpha of a = .88 and subscale values of .89, .88 and .66. The exclusion of two-items limits the transferability of this scale; however, the factor makeup was very similar to the original 12-item English version. It is suspected that minor differences were due to unavoidable deviations in meaning following translation (i.e. certain English words have no equivalent in Swedish). Nevertheless, the results imply that the Swedish version of the IEPS is a valid and reliable tool for assessing students' perceptions and attitudes towards IPE within the Swedish health education system.


Keratoconjunctivitis sicca and corneal ulcers.
We reviewed the records of 56 patients (109 eyes) who satisfied our criteria for keratoconjunctivitis sicca (KCS) to determine factors associated with the development of sterile corneal ulcers. The patient's age, sex, and associated local ocular surface and/or systemic disease were studied. We found a statistically significant association between the development of corneal ulceration and the presence of an underlying condition or disease state, especially chronic rheumatoid arthritis. Patient sex and age were not significantly associated with the development of corneal ulceration. We present three case histories that illustrate the complications that arise in managing KCS plus an associated disease and methods of management.


Cloning of rat thymic stromal lymphopoietin receptor (TSLPR) and characterization of genomic structure of murine Tslpr gene.
Thymic stromal derived lymphopoietin receptor (TSLPR) is a novel receptor subunit that is related in sequence to the interleukin (IL)-2 receptor common gamma chain. TSLPR forms a heterodimeric complex with the IL-7 receptor alpha chain to form the receptor for thymic stromal derived lymphopoietin, a cytokine involved in B- and T-cell function. We have cloned the TSLP receptor from rat and find that the WSXWX motif commonly found in extracellular domains of cytokine receptors is conserved as a W(T/S)XV(T/A) motif among TSLP receptors from mouse, rat and human. As in the mouse, TSLP receptor is widely expressed in rats suggesting that TSLPR may have roles in signaling outside the hematopoietic system. A zooblot analysis revealed that TSLPR is expressed in all vertebrate species examined. The absence of TSLPR in Saccharomyces cerevisiae, Drosophila melanogaster and Caenorhabditis elegans genomes is similar to the expression of several other cytokine receptors that have been characterized thus far. We have also characterized the genomic structure of the murine Tslpr gene which shows that in addition to primary sequence homology, it shares a common genomic organization of coding exons with the murine IL-2 receptor common gamma chain (Il2rg). Use of an alternative splice acceptor site leads to two alternatively spliced transcript variants of murine TSLPR, both of which are functional receptors. Finally, using linkage analysis, we mapped the murine Tslpr gene to mouse chromosome 5 between the Ecm2 and Pxn genes.


Hypothyroidism and Nephrotic Syndrome: Why, When and How to Treat.
Hypothyroidism, characterised by low/normal free thyroxine (FT4) and free triiodothyronine (FT3) with elevated thyroid-stimulating hormone (TSH), is a well-known complication of nephrotic syndrome (NS). This is a common feature of primary and secondary glomerular diseases and comprises loss of protein in the urine and increased urinary excretion of thyroid hormones and thyroxine- binding globulin. With a normal thyroid reserve, this scenario is associated with the development of subclinical hypothyroidism, with a slight increase in TSH and normal free fractions. However, with a low thyroid reserve the transition toward overt hypothyroidism is almost inevitable, affecting morbidity and mortality. As T4 replacement is a cheap and well-established treatment to achieve a stable hormone status in different types of thyroid deficiency, it is essential to recognise and appropriately treat this condition. In this article we summarise the evidence on this nephro-endocrine disorder in humans and focus on diagnostic and therapeutic strategies.


The impact of mobility on HIV control: a modelling study.
Mobility is associated with HIV due to more risky sexual behaviour of mobile groups such as travellers and migrants. Limited participation of such groups may reduce the effectiveness of HIV interventions disproportionally. The established STDSIM model, which simulates transmission and control of HIV and STD, was extended to simulate mobility patterns based on data from Tanzania. We explored the impact of non-participation of mobile groups (travellers and recent migrants) on the effectiveness of two interventions: condom promotion and health education aiming at partner reduction. If mobile groups do not participate, the effectiveness of both interventions could be reduced by 40%. The impact of targeting travellers with a combined HIV campaign is close to that of a general population intervention. In conclusion, it is important to account for possible non-participation of migrants and travellers. If non-participation is substantial, impact of interventions can be greatly improved by actively approaching these people.


Free formula milk for infants of HIV-infected women: blessing or curse?
There is vigorous controversy around whether HIV-infected women in developing countries should choose formula or breastfeeding for their infants. Formula eliminates HIV transmission but incurs risk of increased mortality, whereas breastfeeding has multiple benefits but entails risk of HIV transmission. International guidelines are available but need to be strengthened. This commentary summarizes data on the scale and rate of mother-to-child transmission (MTCT) of HIV through breastfeeding, and the hazards and benefits of breast- and formula-feeding. The case against providing free or subsidized formula to HIV-infected mothers is based on the following: it exacerbates disadvantages of formula feeding; compromises free choice; targets beneficiaries erroneously; creates a false perception of endorsement by health workers; compromises breastfeeding; results in disclosure of HIV status; ignores hidden costs of preparation of formula; increases mixed breastfeeding, which is an unsatisfactory method for all women; requires organization and management of programmes that are complicated and costly; and finally increases the 'spill-over' effect into the normal breastfeeding population. Recommendations to minimize these drawbacks include use of affordable antiretrovirals to reduce MTCT; investments in high-quality, widely available HIV counselling; support for choice of feeding; and exclusive breastfeeding for those who choose to breastfeed.


Tailoring Common Hydrogels into 3D Cell Culture Templates.
Physiologically relevant cell-based models require engineered microenvironments which recapitulate the topographical, biochemical, and mechanical properties encountered in vivo. In this context, hydrogels are the materials of choice. Here a light-based toolbox is able to craft such microniches out of common place materials. Extensive use of benzophenone photoinitiators and their interaction with oxygen achieves this. First, the oxygen inhibition of radicals is harnessed to photoprint hydrogel topographies. Then the chemical properties of benzophenone are exploited to crosslink and functionalize native hydrogels lacking photosensitive moieties. At last, photoscission is introduced: an oxygen-driven, benzophenone-enabled reaction that photoliquefies Matrigel and other common gels. Using these tools, soft hydrogel templates are tailored for cells to grow or self-organize into standardized structures. The described workflow emerges as an effective microniche manufacturing toolset for 3D cell culture.


Leoligin, the major lignan from Edelweiss, inhibits 3-hydroxy-3-methyl-glutaryl-CoA reductase and reduces cholesterol levels in ApoE-/- mice.
The health benefit through the control of lipid levels in hyperlipidaemic individuals is evident from a large number of studies. The pharmacological options to achieve this goal shall be as specific and personalized as the reasons for and co-factors of hyperlipidaemia. It was the goal of this study to reveal the impact of leoligin on cholesterol levels and to define its mechanism of action. Oral application of leoligin in ApoE-/- mice led to significantly reduced total serum cholesterol levels and a reduction in postprandial blood glucose peak levels. In the absence of biochemical signs of toxicity, leoligin treatment resulted in reduced weight gain in mice. The effects of leoligin on serum cholesterol levels may be due to a direct inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) by a unique, non-statin-like binding mode. Postprandial serum glucose peaks may be reduced by a mild peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonistic activity of leoligin. No effect on atherosclerotic plaque size was observed. As a non-toxic, cholesterol-, peak glucose-, and weight gain-lowering compound, leoligin continues to fulfil characteristics of a potential agent for the treatment of cardiovascular disease (CVD). The counterregulatory overexpression of hepatic HMGCR in leoligin treated animals possibly explains the missing permanent anti-atherosclerotic effect.


Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2.
RBFOX1 and RBFOX2 are alternative splicing factors that are predominantly expressed in the brain and skeletal muscle. They specifically bind the RNA element UGCAUG, and regulate alternative splicing positively or negatively in a position-dependent manner. The molecular basis for the position dependence of these and other splicing factors on alternative splicing of their targets is not known. We explored the mechanisms of RBFOX splicing activation and repression using an MS2-tethering assay. We found that the Ala/Tyr/Gly-rich C-terminal domain is sufficient for exon activation when tethered to the downstream intron, whereas both the C-terminal domain and the central RRM are required for exon repression when tethered to the upstream intron. Using immunoprecipitation and mass spectrometry, we identified hnRNP H1, RALY, and TFG as proteins that specifically interact with the C-terminal domain of RBFOX1 and RBFOX2. RNA interference experiments showed that hnRNP H1 and TFG modulate the splicing activity of RBFOX1/2, whereas RALY had no effect. However, TFG is localized in the cytoplasm, and likely modulates alternative splicing indirectly.


Evaluation of enzyme-linked immunosorbent assay in serological diagnosis of human neurocysticercosis using paired samples of serum and cerebrospinal fluid.
The applicability of micro-ELISA was evaluatd in human neuro-cysticercosis using paired samples of serum and CSF. A total of 355 cases who were mostly neurologic patients was subjected. Cystic fluid of C. cellulosae was used as antigen in protein concentration of 2.5 micro-g/ml. Serum was diluted to 1:100 and CSF was undiluted in the assay for the specific IgG antibody level. The differential criterion of the positive reaction was the abs. of 0.18 in both samples. The results were summarized as follows: The overall sensitivity of the micro-ELISA in 71 confirmed neurocysticercosis was 90.1%; the sensitivity by serum was 77.5% and that by CSF was 83.1%. CSF was a more sensitive and valuable material. Most of the false negative cases of neuro-cysticercosis showed far lower level of abs. rather than marginal. The overall specificity of the micro-ELISA in 52 confirmed other neurologic diseases was 88.5%; the specificities by serum and by CSF were 94.2% respectively. Cases of other neurologic diseases did not show false positive reactions in both samples. When serum was assayed, taeniasis(2/18), sparganosis(2/20), paragonimiasis(1/56), clonorchiasis(1/15) and fascioliasis(1/1) cases showed cross reactions. When CSF was assayed, 2 of 10 neuro-sparganosis showed cross reactions while none of 9 neuro-paragonimiasis showed it. Out of 71 confirmed neuro-cysticercosis cases, 6 and 11 showed cross reactions by serum and CSF to crude extract antigen of sparganum; but no case did show it to crude extract antigen of Paragonimus westermani. Ventricular CSF showed low or negative levels of IgG antibody than lumbar CSF unless the lesion was at the lateral ventricle itself. Out of 4 racemose cysticercosis cases, 3 showed positive reaction in serum while all of 3 examined CSF were positive. The above results indicated that the serological test for detecting the specific IgG antibody by micro-ELISA using paired samples of serum and CSF was very helpful for clinical differentiation of neuro-cysticercosis from neurologic diseases of other causes.


Effect of osteopathic manipulative treatment on length of stay in a population of preterm infants: a randomized controlled trial.
The use of osteopathic manipulative treatment (OMT) in preterm infants has been documented and results from previous studies suggest the association between OMT and length of stay (LOS) reduction, as well as significant improvements in several clinical outcomes. The aim of the present study is to investigate the effect of OMT on LOS in premature infants. A randomized controlled trial was conducted on preterm newborns admitted to a single NICU between 2008-2009. N=110 subjects free of medical complications and with gestational age >28 and < 38 weeks were enrolled and randomized in two groups: study group (N=55) and control group (N=55). All subjects received routine pediatric care and OMT was performed to the study group for the entire period of hospitalization. Endpoints of the study included differences in LOS and daily weight gain. Results showed a significant association between OMT and LOS reduction (mean difference between treated and control group: -5.906; 95% C.I. -7.944, -3.869; p<0.001). OMT was not associated to any change in daily weight gain. The present study suggests that OMT may have an important role in the management of preterm infants hospitalization. ClinicalTrials.gov, NCT01544257.


The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus.
Dengue and chikungunya are increasing global public health concerns due to their rapid geographical spread and increasing disease burden. Knowledge of the contemporary distribution of their shared vectors, Aedes aegypti and Aedes albopictus remains incomplete and is complicated by an ongoing range expansion fuelled by increased global trade and travel. Mapping the global distribution of these vectors and the geographical determinants of their ranges is essential for public health planning. Here we compile the largest contemporary database for both species and pair it with relevant environmental variables predicting their global distribution. We show Aedes distributions to be the widest ever recorded; now extensive in all continents, including North America and Europe. These maps will help define the spatial limits of current autochthonous transmission of dengue and chikungunya viruses. It is only with this kind of rigorous entomological baseline that we can hope to project future health impacts of these viruses.


The Shrail: A Comparison of a Novel Attachable Rail System With the Current Deployment Operating Table.
The current forward surgical team (FST) operating table is heavy and burdensome and hinders essential movement flexibility. A novel attachable rail system, the Shrail, has been developed to overcome these obstacles. The Shrail turns a North Atlantic Treaty Organization litter into a functional operating table. A local FST compared the assembly of the FST operating table with assembling the Shrail. Device weight, storage space, and assembly space were directly measured and compared. The mean assembly time required for the Shrail was significantly less compared with the operating table (23.36 versus 151.6 seconds; p ≤ .01). The Shrail weighs less (6.80kg versus 73.03kg) and requires less storage space (0.019m3 versus 0.323m3) compared with the current FST operating table. The Shrail provides an FST with a faster, lighter surgical table assembly. For these reasons, it is better suited for the demands of an FST and the implementation of prolonged field care.


In situ hybridization with non-radioactive digoxigenin-11-UTP-labeled cRNA probes: localization of developmentally regulated mouse tenascin mRNAs.
An improved method for in situ hybridization was developed in order to identify the tissue-specific expression of messenger RNA (mRNA) for the novel extracellular matrix glycoprotein, tenascin, during mouse development. Non-radioactive RNA probes were generated by incorporating digoxigenin-11-UTP instead of conventional isotopic labels. Hybridization of anti-sense probes to complementary mRNAs was detected by a chromogenic staining reaction catalyzed by an anti-digoxigenin antibody-alkaline phosphatase conjugate. Markedly improved enhancement of staining was achieved by expanding the complexity of probes and strictly controlling the degree of proteolytic digestion of paraformaldehyde-fixed tissue sections. Six different complementary RNA (cRNA) probes representing most of the tenascin mRNA sequence were prepared. Very weak signals were obtained after single applications of each probe, but strong specific signals were present when all six probes were mixed together. In either case, no signal was found without prior proteolytic digestion of tissue sections with proteinase K. Treatment with increasing concentrations of proteinase K initially resulted in increased sensitivity of signal detection, but extensive digestion resulted in histological sections of poor quality for light microscopy. Optimal conditions varied according to the tissue type examined. In lung, in situ hybridization detected tenascin mRNA in the relatively large cells lining alveolar walls adjacent to type I pneumocytes. In cerebellum, glial cells of the Purkinje cell layer contained tenascin mRNA, but Purkinje cells did not. In both cases, hybridization signals were confined to the cytoplasm of cells, and no extracellular staining was observed. This method provides a promising new tool for analysis of spatio-temporal regulation of tenascin gene expression during embryogenesis and oncogenesis.


First Report of Polymyxa graminis f. sp. temperata, a Vector of Soilborne Cereal Viruses in the Czech Republic.
Polymyxa graminis L. is an eukaryotic, obligate, biotrophic parasite of plant roots (1), which belongs to a poorly studied, discrete, taxonomic unit informally called the 'plasmodiophorids'. P. graminis has the ability to acquire and transmit a range of soilborne viruses that belong to at least three separate genera and can cause economically significant diseases in cereal crops. For example, the winter barley disease caused by Barley yellow mosaic virus (BaYMV) and/or Barley mild mosaic virus (BaMMV) is widespread in Europe, Japan, and China; yield losses of >50% may occur when susceptible barley cultivars are grown on severely infested soils (2). Monitoring for P. graminis was started in the Czech Republic in May 2008. Fifty-six soil samples were collected from different localities of cereal production (wheat and barley) in the Královéhradecký Region (eastern Czech Republic). Soil from each sample was placed in five replicate pots (12 × 12 cm) in a greenhouse at 22 to 25°C. Seeds of barley cv. Florian were sown into the soil (10 seeds per pot). Negative control soil (noninfested soils from the Czech Republic) and positive control soil (known P. graminis-infested soil from Germany) were also planted to barley in five replicate pots. After 90 days, plants were collected and the roots were washed thoroughly in sterilized water and examined with a light microscope without staining. The fungus was identified as P. graminis on the basis of morphology of resting spores (cystosori) and sporangia and the size of individual cystosori (4 to 5 μm in diameter) according to Thouvenel et al. (3). Cystosori of P. graminis were observed in the roots of plants grown in 20 of the 56 soil samples, especially the samples from Ceské Mezirici. The presence of P. graminis in the roots of plants grown in the soil samples and the positive control sample versus the absence of the vector in roots of plants in the negative control soil was verified by PCR assay with DNA extracts and the Psp1 and Psp2rev primers according to Legrève et al. (Page 40 in: Proceedings of the Fifth Symposium of the International Working Group on Plant Viruses with Fungal Vectors, 2003). The PCR assay included denaturation at 94°C for 2 min, then 35 cycles including denaturation of 30 s at 94°C, annealing at 60°C for 1 min, and elongation at 72°C for 35 s. A final elongation was completed at 72°C for 7 min. To characterize the P. graminis isolates, the amplified PCR product (a DNA fragment of 472 bp) was sequenced and blasted for each of the samples that tested positive. These sequences were aligned with a known sequence (GenBank Accession No. AM259276) for P. graminis. The sequences from P. graminis on barley were 100% homologous to the published sequence of P. graminis f. sp. temperata. To our knowledge, this is the first report of P. graminis f. sp. temperata in the Czech Republic. References: (1) G. A. Ledingham. Can. J. Res. 17:50, 1939. (2) R. T. Plumb et al. Plant Pathol. 35:314, 1986. (3) J. C. Thouvenel et al. Plant Dis. 64:957, 1980.


Piracetam and chlormethiazole in acute alcohol withdrawal: a controlled clinical trial.
Sixty in-patient alcoholics, presenting with an alcohol withdrawal syndrome after at least one week's drinking bout, were randomly allocated to fixed dose regimens of either piracetam or chlormethiazole in a one-week double-blind trial. The patients were studied in respect to physical and biochemical parameters as well as symptom reduction and side-effects. The battery of rating scales demonstrated a good symptom reduction in both drug groups. On the whole a small tendency to more symptom items being reduced on piracetam in comparison with chlormethiazole was found. But the tree items, sleep disturbances, decreased libido at the initial phase, and the staff's assessment showed statistically significant differences in favour of chlormethiazole. This study demonstrated that piracetam was just as efficient as chlormethiazole in patients not requiring sedation.


Investigating the impact of selection bias in dose-response analyses of preventive interventions.
This paper focuses on the impact of selection bias in the context of extended, community-based prevention trials that attempt to "unpack" intervention effects and analyze mechanisms of change. Relying on dose-response analyses as the most general form of such efforts, this study provides two examples of how selection bias can affect the estimation of treatment effects. In Example 1, we describe an actual intervention in which selection bias was believed to influence the dose-response relation of an adaptive component in a preventive intervention for young children with severe behavior problems. In Example 2, we conduct a series of Monte Carlo simulations to illustrate just how severely selection bias can affect estimates in a dose-response analysis when the factors that affect dose are not recorded. We also assess the extent to which selection bias is ameliorated by the use of pretreatment covariates. We examine the implications of these examples and review trial design, data collection, and data analysis factors that can reduce selection bias in efforts to understand how preventive interventions have the effects they do.


1-O-Acetylgeopyxin A, a derivative of a fungal metabolite, blocks tetrodotoxin-sensitive voltage-gated sodium, calcium channels and neuronal excitability which correlates with inhibition of neuropathic pain.
Chronic pain can be the result of an underlying disease or condition, medical treatment, inflammation, or injury. The number of persons experiencing this type of pain is substantial, affecting upwards of 50 million adults in the United States. Pharmacotherapy of most of the severe chronic pain patients includes drugs such as gabapentinoids, re-uptake blockers and opioids. Unfortunately, gabapentinoids are not effective in up to two-thirds of this population and although opioids can be initially effective, their long-term use is associated with multiple side effects. Therefore, there is a great need to develop novel non-opioid alternative therapies to relieve chronic pain. For this purpose, we screened a small library of natural products and their derivatives in the search for pharmacological inhibitors of voltage-gated calcium and sodium channels, which are outstanding molecular targets due to their important roles in nociceptive pathways. We discovered that the acetylated derivative of the ent-kaurane diterpenoid, geopyxin A, 1-O-acetylgeopyxin A, blocks voltage-gated calcium and tetrodotoxin-sensitive voltage-gated sodium channels but not tetrodotoxin-resistant sodium channels in dorsal root ganglion (DRG) neurons. Consistent with inhibition of voltage-gated sodium and calcium channels, 1-O-acetylgeopyxin A reduced reduce action potential firing frequency and increased firing threshold (rheobase) in DRG neurons. Finally, we identified the potential of 1-O-acetylgeopyxin A to reverse mechanical allodynia in a preclinical rat model of HIV-induced sensory neuropathy. Dual targeting of both sodium and calcium channels may permit block of nociceptor excitability and of release of pro-nociceptive transmitters. Future studies will harness the core structure of geopyxins for the generation of antinociceptive drugs.


Cuprous hydroxide in a solid form: does it exist?
Experimental studies have been performed to obtain the unknown cuprous hydroxide compound, which has recently been predicted theoretically (P. A. Korzhavyi et. al., Proc. Natl. Acad. Sci. U. S. A., 2012, 109, 686-689) to be metastable in a solid form. The reduction of Cu(2+) with ferrous ethylenediamine tetraacetate (EDTA) results in the formation of a yellow powder precipitate whose composition corresponds to CuOH × H2O as probed by Fourier Transform Infrared Spectroscopy (FTIR) and cryogenic X-ray Photoelectron Spectroscopy (XPS). A similar compound has been found on the surface of Cu-CuH powder stored in water, as detected by XPS. The reduction of Cu(2+) to Cu(+) with free radicals in aqueous solutions results in a Cu2O precipitate as the final product, while the formation of the yellow cuprous hydroxide colloids may be an intermediate step. Our studies reveal that cuprous hydroxide does exist in a solid form and most likely has a hydrated form, CuOH × H2O.


The hidden hyperbolic geometry of international trade: World Trade Atlas 1870-2013.
Here, we present the World Trade Atlas 1870-2013, a collection of annual world trade maps in which distance combines economic size and the different dimensions that affect international trade beyond mere geography. Trade distances, based on a gravity model predicting the existence of significant trade channels, are such that the closer countries are in trade space, the greater their chance of becoming connected. The atlas provides us with information regarding the long-term evolution of the international trade system and demonstrates that, in terms of trade, the world is not flat but hyperbolic, as a reflection of its complex architecture. The departure from flatness has been increasing since World War I, meaning that differences in trade distances are growing and trade networks are becoming more hierarchical. Smaller-scale economies are moving away from other countries except for the largest economies; meanwhile those large economies are increasing their chances of becoming connected worldwide. At the same time, Preferential Trade Agreements do not fit in perfectly with natural communities within the trade space and have not necessarily reduced internal trade barriers. We discuss an interpretation in terms of globalization, hierarchization, and localization; three simultaneous forces that shape the international trade system.


Accountable care organizations: back to the future?
Accountable Care Organizations (ACOs) are networks of providers that assume risk for the quality and total cost of the care they deliver. Public policymakers and private insurers hope that ACOs will achieve the elusive "triple aim" of improving quality of care, improving population health, and reducing costs. The model is still evolving, but the premise is that ACOs will accomplish these aims by coordinating care, managing chronic disease, and aligning financial incentives for hospitals and physicians. If this sounds familiar, it may be because the integrated care networks of the 1990s tried some of the same things, and mostly failed in their attempts. This Issue Brief summarizes the similarities and differences between the new ACOs and the integrated delivery networks of the 1990s, and presents the authors' analysis of the likely success of these new organizations in affecting the costs and quality of health care.


Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies.
Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10(-8)), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05-1·12, p=1·48 × 10(-8); minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity-a marker of cerebral small vessel disease-in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2-32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b(-/-) cerebral vessels show decreased smooth muscle cell and pericyte coverage. We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.


Gene expression analyses in breast cancer epidemiology: the Norwegian Women and Cancer postgenome cohort study.
The introduction of high-throughput technologies, also called -omics technologies, into epidemiology has raised the need for high-quality observational studies to reduce several sources of error and bias. The Norwegian Women and Cancer (NOWAC) postgenome cohort study consists of approximately 50,000 women born between 1943 and 1957 who gave blood samples between 2003 and 2006 and filled out a two-page questionnaire. Blood was collected in such a way that RNA is preserved and can be used for gene expression analyses. The women are part of the NOWAC study consisting of 172,471 women 30 to 70 years of age at recruitment from 1991 to 2006 who answered one to three questionnaires on diet, medication use, and lifestyle. In collaboration with the Norwegian Breast Cancer Group, every NOWAC participant born between 1943 and 1957 who is admitted to a collaborating hospital for a diagnostic biopsy or for surgery of breast cancer will be asked to donate a tumor biopsy and two blood samples. In parallel, at least three controls are approached for each breast cancer case in order to obtain blood samples from at least two controls per case. The controls are drawn at random from NOWAC matched by time of follow-up and age. In addition, 400 normal breast tissues as well as blood samples will be collected among healthy women participating at the Norwegian Mammography Screening program at the Breast Imaging Center at the University Hospital of North-Norway, Tromsø. The NOWAC postgenome cohort offers a unique opportunity (a) to study blood-derived gene expression profiles as a diagnostic test for breast cancer in a nested case-control design with adjustment for confounding factors related to different exposures, (b) to improve the reliability and accuracy of this approach by adjusting for an individual's genotype (for example, variants in genes coding for hormone and drug-metabolizing and detoxifying enzymes), (c) to study gene expression profiles from peripheral blood as surrogate tissue to biomonitor defined exposure (for example, hormone) and its association with disease risk (that is, breast cancer), and (d) to study gene variants (single nucleotide polymorphisms and copy number variations) and environmental exposure (endogenous and exogenous hormones) and their influence on the incidence of different molecular subtypes of breast cancer. The NOWAC postgenome cohort combining a valid epidemiological approach with richness of biological samples should make an important contribution to the study of the etiology and system biology of breast cancer.


Moved by Observing the Love of Others: Kama Muta Evoked Through Media Fosters Humanization of Out-Groups.
People often view out-groups as less human than their in-group. Some media video content is heart-warming and leaves one feeling touched or moved. Recent research indicates that this reflects a positive social emotion, kama muta, which is evoked by a sudden increase in interpersonal closeness, specifically by the relational model of communal sharing. Because forming strong, close, and communal bonds exemplifies valued human qualities, and because other humans are our primary target partners of communal sharing, we predicted that feeling kama muta in response to observing communal sharing among out-group strangers would make people view out-groups as more human. In Study 1, we replicated a model obtained through a large exploratory preliminary study which indicated that videos depicting out-group members enacting communal sharing evoked kama muta and increased protagonist humanization. This, in turn, led to decreased blatant dehumanization of the entire out-group via perceived out-group warmth and motivation to develop a communal sharing relationship with the protagonist. The preregistered Study 2 further tested our model, demonstrating (1) that the relationship between protagonist humanization and kama muta is bidirectional such that baseline humanization of the protagonist also increases feelings of kama muta in response to acts of communal sharing; (2) that watching videos of communal sharing, as compared to funny videos, increased protagonist humanization; and (3) that kama muta videos, compared to funny videos, had an indirect effect on the reduction of out-group blatant dehumanization, which was mediated by protagonist humanization and out-group warmth.


Oxidative cyclization, 1,4-benzothiazine formation and dimerization of 2-bromo-3-(glutathion-S-yl)hydroquinone.
Several lines of evidence suggest that the renal-specific toxicity of quinol-linked GSH conjugates is probably a result of their metabolism by gamma-glutamyl transpeptidase and selective accumulation by proximal tubular cells. Transport of the resultant quinol-cysteine and/or cystein-S-ylglycine conjugate followed by oxidation to the quinone may be important steps in the mechanism of toxicity of these compounds. Factors modulating the intracellular and/or intralumenal concentration of the cystein-S-yl and cystein-S-ylglycine conjugate will, therefore, be important determinants of toxicity. We have now studied the gamma-glutamyl transpeptidase-mediated metabolism of 2-bromo-3-(glutathion-S-yl)hydroquinone. The product of this reaction, 2-bromo-3-(cystein-S-ylglycyl)hydroquinone, undergoes an intramolecular cyclization to yield a 1,4-benzothiazine derivative that retains the glycine residue. A similar cyclization reaction occurs with 2-bromo-3-(cystein-S-yl)hydroquinone, which is unstable in aqueous solutions and undergoes a pH-dependent rearrangement that requires initial oxidation to the quinone. UV spectroscopy revealed that, at neutral pH, further reaction results in the formation of a chromophore, consistent with 1,4-benzothiazine formation. This product arises via cyclization of the cysteine residue via an intramolecular 1,4 Michael addition. Further reaction results in the precipitation of a pigment that exhibits properties of a pH indicator. The pigment undergoes a marked pH-dependent bathochromic shift (approximately 100 nm); it is red in alkali (lambda max, 480 nm) and violet in acid (lambda max, 578 nm). These properties are similar to those of the trichochrome polymers that are formed during melanin biosynthesis from S-(3,4-dihydroxyphenylalanine)-L-cysteine. Because the intramolecular cyclization reactions remove the reactive quinone moiety from the molecules, they may be regarded as detoxication reactions. 1,4-Benzothiazine formation represents a novel pathway that diverges from the usual route of mercapturic acid synthesis and may represent previously unrecognized and important products of quinone metabolism in vivo.


Low Raman-noise correlated photon-pair generation in a dispersion-engineered chalcogenide As2S3 planar waveguide.
We demonstrate low Raman-noise correlated photon-pair generation in a dispersion-engineered 10 mm As2S3 chalcogenide waveguide at room temperature. We show a coincidence-to-accidental ratio (CAR) of 16.8, a 250 times increase compared with previously published results in a chalcogenide waveguide, with a corresponding brightness of 3×10(5) pairs·s(-1)·nm(-1) generated at the chip. Dispersion engineering of our waveguide enables photon passbands to be placed in the low spontaneous Raman scattering (SpRS) window at 7.4 THz detuning from the pump. This Letter shows the potential for As2S3 chalcogenide to be used for nonlinear quantum photonic devices.


Remote Effects of Electromagnetic Millimeter Waves on Experimentally Induced Cold Pain: A Double-Blinded Crossover Investigation in Healthy Volunteers.
The hypoalgesic effect of electromagnetic millimeter waves (MW) is well studied in animal model; however, the results of human research are controversial. The aim of this study was to evaluate the effects of various frequency ranges of MW on hypoalgesia using the cold pressor test (CPT). Experimental pain was induced using standardized CPT protocols in 20 healthy male volunteers. The skin of the lower part of sternum was exposed to MW with a frequency of 42.25 GHz (active generator); MW within 50-75 GHz frequency range (noise generator); or an inactive MW device (placebo generator) in a random crossover double-blinded manner. Pain threshold, measured using the CPT, was the primary outcome. Other CPT parameters, heart rate, blood pressure, incidence of subjective sensations (paresthesia) during exposure, as well as quality of volunteers' blinding were also recorded. The end points of the condition with exposure to 42.25 GHz, were compared with baseline; exposure to noise 50-75 GHz; and placebo generators. Pain threshold increased during exposure to the 42.25 GHz generator when compared with baseline: median difference (MD), 1.97 seconds (95% confidence interval [CI], 0.35-3.73) and noise generator: MD, 1.27 seconds (95% CI, 0.05-2.33) but not compared with the placebo generator. Time to onset of cold and increasing pain sensations as well as diastolic blood pressure increased under the exposure to the 42.25 GHz generator when compared with baseline and noise generator. Other outcome measures were comparable among the study conditions. We were able to partially confirm the previously suggested hypoalgesic effects of low-intensity electromagnetic MW. However, the effect was indistinguishable from the placebo condition in our investigation.


Mild Anemia and Risk for All-Cause, Cardiovascular and Cancer Deaths in Apparently Healthy Elderly Koreans.
Being common, mild anemia is sometimes considered a mere consequence of aging; however, aging alone is unlikely to lead to anemia. Therefore, this study aimed to investigate the association between mild anemia and total mortality and cause-specific mortality in apparently healthy elderly subjects. A retrospective cohort study was conducted on 10,114 apparently healthy elderly individuals who underwent cancer screening and routine medical check-ups at one Health Promotion Center between May 1995 and December 2007. We defined mild anemia as a hemoglobin concentration between 10.0 g/dL and 11.9 g/dL in women and between 10.0 g/dL and 12.9 g/dL in men. We assessed the relationship between the overall, cardiovascular (CV), and cancer mortality and mild anemia using Cox proportional hazard models. Mild anemia was present in 143 men (3.1%) and 246 women (6.1%). During an average follow-up of 7.6 years, 495 deaths occurred, including 121 CV and 225 cancer deaths. After adjustments, mild anemia was associated with a 128% increase in the risk of all-cause mortality hazard ratio (HR, 2.28; 95% confidence interval [CI], 1.54- 3.37) in men and cancer-related mortality (HR, 2.25; 95% CI, 1.22-4.13), particularly lung cancer (HR, 2.70; 95% CI, 1.03-7.08) in men, but not in women. In the subgroup analyses based on smoking status, obesity, and age, the associations were more prominent in never or former smoker groups and the older group. The present study shows that overall and cancer-related mortality was associated with mild anemia in elderly men. Future prospective studies are needed to consolidate our findings.


Identification of poly(ADP-ribose) polymerase-1 as a cell cycle regulator through modulating Sp1 mediated transcription in human hepatoma cells.
The transcription factor Sp1 is implicated in the activation of G0/G1 phase genes. Modulation of Sp1 transcription activities may affect G1-S checkpoint, resulting in changes in cell proliferation. In this study, our results demonstrated that activated poly(ADP-ribose) polymerase 1 (PARP-1) promoted cell proliferation by inhibiting Sp1 signaling pathway. Cell proliferation and cell cycle assays demonstrated that PARP inhibitors or PARP-1 siRNA treatment significantly inhibited proliferation of hepatoma cells and induced G0/G1 cell cycle arrest in hepatoma cells, while overexpression of PARP-1 or PARP-1 activator treatment promoted cell cycle progression. Simultaneously, inhibition of PARP-1 enhanced the expression of Sp1-mediated checkpoint proteins, such as p21 and p27. In this study, we also showed that Sp1 was poly(ADP-ribosyl)ated by PARP-1 in hepatoma cells. Poly(ADP-ribosyl)ation suppressed Sp1 mediated transcription through preventing Sp1 binding to the Sp1 response element present in the promoters of target genes. Taken together, these data indicated that PARP-1 inhibition attenuated the poly(ADP-ribosyl)ation of Sp1 and significantly increased the expression of Sp1 target genes, resulting in G0/G1 cell cycle arrest and the decreased proliferative ability of the hepatoma cells.


Hydrophobic and hydrophilic interactions in aqueous mixtures of alcohols at a hydrophobic surface.
Aqueous solutions of alcohols are interesting because of their anomalous behavior that is believed to be due to the molecular structuring of water and alcohol around each other in solution. The interfacial structuring and properties are significant for application in alcohol purification processes and biomolecular structure. Here we study aqueous mixtures of short alcohols (methanol, ethanol, 1-propanol, and 2-propanol) at a hydrophobic surface using interfacial statistical associating fluid theory which is a perturbation density functional theory. The addition of a small amount of alcohol decreases the interfacial tension of water drastically. This trend in interfacial tension can be explained by the structure of water and alcohol next to the surface. The hydrophobic group of an added alcohol preferentially goes to the surface preserving the structure of water in the bulk. For a given bulk alcohol concentration, water mixed with the different alcohols has different interfacial tensions with propanol having a lower interfacial tension than methanol and ethanol. 2-propanol is not as effective in decreasing the interfacial tension as 1-propanol because it partitions poorly to the surface due to its larger excluded volume. But for a given surface alcohol mole fraction, all the alcohol mixtures give similar values for interfacial tension. For separation of alcohol from water, methods that take advantage of the high surface mole fraction of alcohol have advantages compared to separation using the vapor in equilibrium with a water-alcohol liquid.


Synergism between α-mangostin and TRAIL induces apoptosis in squamous cell carcinoma of the oral cavity through the mitochondrial pathway.
Mangosteen (Garcinia mangostana) is a tree found in South-East Asia and the pericarp of its fruit has been used in folk medicine for the treatment of many human illnesses. Mangosteen fruit rinds contain a high concentration of xanthone, which is a type of polyphenol. One type of xanthone, α-mangostin, has been reported to exert chemopreventive effects against chemically-induced colon cancer through the decrease of c-Myc expression, suppressing tumor growth in a mouse model of mammary cancer. A recent study demonstrated the inhibitive effect of α-mangostin on the growth of prostate cancer. However, it remains unclear whether α-mangostin induces cell death in oral cancer. The present study examined the impact of α-mangostin on human oral squamous cell carcinoma (HOSCC). Firstly we analyzed the expression of c-Myc in five HOSCC cell lines. The highest expression level of c-Myc mRNA was observed in SAS cells and the lowest in HSC-4 cells. Therefore, SAS cells were treated with α-mangostin, which was found to exert a weak cytocidal effect. Since α-mangostin has been reported to exert synergistic effects on cancers when combined with anticancer drugs, we attempted to evaluate such synergistic effects of α-mangostin when used with a cytokine, tumor necrosis factor (TNF)-related apoptosis‑inducing ligand (TRAIL). We found that the combination of α-mangostin with TRAIL induced apoptosis of SAS cells through the mitochondrial pathway via activation of caspase-9 and -3/7, following release of cytochrome c. This apoptosis was induced by S/G2/M-phase arrest. Immunopositivity for c-Myc was observed in the cytoplasm of tumor cells in 16 (40%) of the 40 cases of HOSCC. These data revealed that the combination of α-mangostin and TRAIL may have a considerable potential for the treatment of oral cancer.


Inhibition of glycosphingolipid biosynthesis does not impair growth or morphogenesis of the postimplantation mouse embryo.
Whole embryo culture (WEC) of organogenesis-stage mouse embryos was adapted for glycosphingolipid (GSL) metabolic studies to evaluate the hypothesis that de novo GSL biosynthesis is a prerequisite for growth and morphogenesis of the early postimplantation embryo. WEC supports the growth and development of postimplantation mouse embryos to stages that are indistinguishable from those achieved in vivo. N-Butyldeoxygalactonojirimycin (NB-DGJ) is an N-alkylated imino sugar that specifically inhibits biosynthesis of all glucosylceramide-based GSLs. NB-DGJ inhibited glucosylceramide and lactosylceramide biosynthesis nearly completely and inhibited ganglioside biosynthesis approximately 90% in both the embryo and visceral yolk sac. NB-DGJ also significantly reduced total ganglioside content in both the embryo and visceral yolk sac as estimated by the cholera toxin immunooverlay technique. A shift in expression from the structurally simple to the structurally complex gangliosides was also observed in NB-DGJ-treated embryos and yolk sacs. Despite causing major changes in GSL biosynthesis and composition, NB-DGJ had no effect on embryo viability, growth, or morphology. The findings suggest that de novo GSL biosynthesis may not be a prerequisite for the growth and morphogenesis of the organogenesis-stage mouse embryo.


Intraneuronal substance P contributes to the severity of experimental arthritis.
There is evidence that substance P is a peptide neurotransmitter of some unmyelinated primary afferent nociceptors and that its release from the peripheral terminals of primary afferent fibers mediates neurogenic inflammation. The investigators examined whether substance P also contributes to the severity of adjuvant-induced arthritis, an inflammatory disease in rats. They found that, in the rat, joints that developed more severe arthritis (ankles) were more densely innervated by substance P-containing primary afferent neurons than were joints that developed less severe arthritis (knees). Infusion of substance P into the knee increased the severity of arthritis; injection of a substance P receptor antagonist did not. These results suggest a significant physiological difference between joints that develop mild and severe arthritis and indicate that release of intraneuronal substance P in joints contributes to the severity of the arthritis.


Association between the intake of α-linolenic acid and the risk of CHD.
The intake of the mainly plant-derived n-3 PUFA α-linolenic acid (ALA) has been reported to be associated with a lower risk of CHD. However, the results have been inconsistent. Therefore, the objective of the present study was to examine the association between the intake of ALA and the risk of CHD. Potential effect modification by the intake of long-chain n-3 PUFA (n-3 LCPUFA) was also investigated. Data from eight American and European prospective cohort studies including 148 675 women and 80 368 men were used. The outcome measure was incident CHD (CHD event and death). During 4-10 years of follow-up, 4493 CHD events and 1751 CHD deaths occurred. Among men, an inverse association (not significant) between the intake of ALA and the risk of CHD events and deaths was observed. For each additional gram of ALA consumed, a 15 % lower risk of CHD events (hazard ratios (HR) 0·85, 95 % CI 0·72, 1·01) and a 23 % lower risk of CHD deaths (HR 0·77, 95 % CI 0·58, 1·01) were observed. No consistent association was observed among women. No effect modification by the intake of n-3 LCPUFA was observed.


Performance of swabs, lavage, and diluents to quantify biomarkers of female genital tract soluble mucosal mediators.
Measurement of immune mediators and antimicrobial activity in female genital tract secretions may provide biomarkers predictive of risk for HIV-1 acquisition and surrogate markers of microbicide safety. However, optimal methods for sample collection do not exist. This study compared collection methods. Secretions were collected from 48 women (24 with bacterial vaginosis [BV]) using vaginal and endocervical Dacron and flocked swabs. Cervicovaginal lavage (CVL) was collected with 10 mL of Normosol-R (n = 20), saline (n = 14), or water (n = 14). The concentration of gluconate in Normosol-R CVL was determined to estimate the dilution factor. Cytokine and antimicrobial mediators were measured by Luminex or ELISA and corrected for protein content. Endogenous anti-HIV-1 and anti-E. coli activity were measured by TZM-bl assay or E. coli growth. Higher concentrations of protein were recovered by CVL, despite a 10-fold dilution of secretions, as compared to swab eluents. After protein correction, endocervical swabs recovered the highest mediator levels regardless of BV status. Endocervical and vaginal flocked swabs recovered significantly higher levels of anti-HIV-1 and anti-E. coli activity than Dacron swabs (P<0.001). BV had a significant effect on CVL mediator recovery. Normosol-R tended to recover higher levels of most mediators among women with BV, whereas saline or water tended to recover higher levels among women without BV. Saline recovered the highest levels of anti-HIV-1 activity regardless of BV status. Endocervical swabs and CVL collected with saline provide the best recovery of most mediators and would be the optimal sampling method(s) for clinical trials.


Use of the HLA-B leader to optimize cord blood transplantation
Cord-blood transplantation (CBT) can cure life-threatening blood disorders. The HLA-B leader affects the success of unrelated donor transplantation but its role in CBT is unknown. We tested the hypothesis that the HLA-B leader influences CBT outcomes in unrelated single-unit cord-blood transplants performed by Eurocord/European Blood and Marrow Transplant (EBMT) centers between 1990 and 2018 with data reported to Eurocord. Among 4822 transplants, 2178 had one HLA-B mismatch of which 1013 were HLA-A and HLA-DRB1-matched. The leader (M or T) was determined for each HLA-B allele in patients and units to define the genotype. Among single HLA-B-mismatched transplants, the patient/unit mismatched alleles were defined as leader-matched if they encoded the same leader, or leader-mismatched if they encoded different leaders; the leader encoded by the matched (shared) allele was determined. The risks of GVHD, relapse, non-relapse mortality and overall mortality were estimated for various leaderdefined groups using multivariable regression models. Among the 1013 HLA-A, -DRB1- matched transplants with one HLA-B mismatch, increasing numbers of cord-blood unit M-leader alleles was associated with increased risk of relapse (hazard ratio [HR] for each increase in one M-leader allele 1.30, 95% confidence interval [CI] 1.05 to 1.60, P 0.02). Furthermore, leader mismatching together with an M-leader of the shared HLA-B allele lowered non-relapse mortality (HR 0.44, 95% CI 0.23 to 0.81; P 0.009) relative to leader-matching and a shared T-leader allele. The HLA-B leader may inform relapse and non-relapse mortality risk after CBT. Future patients might benefit from the appropriate selection of units that consider the leader.


Diabetes, insulin use and Helicobacter pylori eradication: a retrospective cohort study.
Diabetic patients may have a higher risk of gastric cancer. However, whether they have a higher incidence of Helicobacter pylori (HP) eradication is not known. Furthermore, whether insulin use in patients with type 2 diabetes may be associated with a higher incidence of HP eradication has not been investigated. This is a retrospective cohort study. The reimbursement databases from 1996 to 2005 of 1 million insurants of the National Health Insurance in Taiwan were retrieved. After excluding those aged <25 years, cases of gastric cancer, cases receiving HP eradication before 2005, patients with type 1 diabetes mellitus and those with unknown living region, the reimbursement data of a total of 601,441 insurants were analyzed. Diabetes status and insulin use in patients with type 2 diabetes before 2005 were the main exposures of interest and the first event of HP eradication in 2005 was the main outcome evaluated. HP eradication was defined as a combination use of proton pump inhibitor or H2 receptor blockers, plus clarithromycin or metronidazole, plus amoxicillin or tetracycline, with or without bismuth, in the same prescription for 7-14 days. The association between type 2 diabetes/insulin use and HP eradication was evaluated by logistic regression, considering the confounding effect of diabetes duration, comorbidities, medications and panendoscopic examination. In 2005, there were 10,051 incident cases receiving HP eradication. HP eradication was significantly increased with age, male sex, diabetes status, insulin use, use of calcium channel blocker, panendoscopic examination, hypertension, dyslipidemia, chronic obstructive pulmonary disease, stroke, nephropathy, ischemic heart disease and peripheral arterial disease. Significant differences were also seen for occupation and living region. Medications including statin, fibrate, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and oral anti-diabetic agents were not associated with HP eradication. The adjusted odds ratios for diabetes, insulin use and use of calcium channel blocker was 1.133 (1.074, 1.195), 1.414 (1.228, 1.629) and 1.147 (1.074, 1.225), respectively. Type 2 diabetes and insulin use in the diabetic patients are significantly associated with a higher incidence of HP eradication. Additionally, use of calcium channel blocker also shows a significant association with HP eradication.


Proposal of Viridibacillus gen. nov. and reclassification of Bacillus arvi, Bacillus arenosi and Bacillus neidei as Viridibacillus arvi gen. nov., comb. nov., Viridibacillus arenosi comb. nov. and Viridibacillus neidei comb. nov.
A polyphasic study was undertaken to clarify the taxonomic position of endospore-forming strains 433-D9, 433-E17 and 121-X1. BOX-PCR-generated fingerprints indicated that they may be members of a single species. 16S rRNA gene sequence similarity demonstrated that a representative of this group, 433-D9, is affiliated closely with Bacillus arvi DSM 16317(T) (100 %), Bacillus arenosi DSM 16319(T) (99.8 %) and Bacillus neidei NRRL BD-87(T) (97.1 %). Sequence similarities revealed Bacillus pycnus NRRL NRS-1691(T) and several Kurthia species as the next nearest relatives. DNA-DNA hybridization results showed that strain 433-D9 is a member of B. arvi. Detection of l-Lys-d-Asp-based peptidoglycan in strain 433-D9, B. arvi DSM 16317(T) and B. arenosi DSM 16319(T) was in agreement with their close relationship, but differentiated these strains from B. neidei NRRL BD-87(T) and B. pycnus NRRL NRS-1691(T), for which l-Lys-d-Glu was reported. A similar quinone system was detected in strains 433-D9, 433-E17, 121-X1, B. arvi DSM 16317(T), B. arenosi DSM 16319(T) and B. neidei NRRL BD-87(T). This system, unusual for bacilli, consisted of the major compound menaquinone MK-8 (69-80 %) and moderate amounts of MK-7 (19-30 %). This observation was in contrast to the predominance of MK-7 of the closest relative B. pycnus NRRL NRS-1691(T), as also reported for representatives of the closely related non-endospore-forming genus Kurthia. Strains 433-D9, B. arvi DSM 16317(T) and B. arenosi DSM 16319(T) exhibited homogeneous and discriminative polar lipid profiles and fatty acid profiles consisting of major acids i-C(15 : 0) and ai-C(15 : 0) and moderate amounts of i-C(17 : 1)omega10c and i-C(17 : 1) I/ai-C(17 : 1) B that discriminated them from closely related strains such as B. neidei NRRL BD-87(T). On the basis of clear-cut discriminative chemotaxonomic markers, we propose strains 433-D9, 433-E17 and 121-X1, B. arvi DSM 16317(T), B. arenosi DSM 16319(T) and B. neidei NRRL BD-87(T) to be reclassified within a separate genus. For this new taxon, we propose the name Viridibacillus gen. nov., and we propose the reclassification of Bacillus arvi, Bacillus arenosi and Bacillus neidei as Viridibacillus arvi gen. nov., comb. nov. (the type species of Viridibacillus, with the type strain DSM 16317(T) =LMG 22165(T)), Viridibacillus arenosi comb. nov. (type strain DSM 16319(T) =LMG 22166(T)) and Viridibacillus neidei comb. nov. (type strain NRRL BD-87(T) =DSM 15031(T) =JCM 11077(T)).


Model-based projections of Zika virus infections in childbearing women in the Americas.
Zika virus is a mosquito-borne pathogen that is rapidly spreading across the Americas. Due to associations between Zika virus infection and a range of fetal maladies(1,2), the epidemic trajectory of this viral infection poses a significant concern for the nearly 15 million children born in the Americas each year. Ascertaining the portion of this population that is truly at risk is an important priority. One recent estimate(3) suggested that 5.42 million childbearing women live in areas of the Americas that are suitable for Zika occurrence. To improve on that estimate, which did not take into account the protective effects of herd immunity, we developed a new approach that combines classic results from epidemiological theory with seroprevalence data and highly spatially resolved data about drivers of transmission to make location-specific projections of epidemic attack rates. Our results suggest that 1.65 (1.45-2.06) million childbearing women and 93.4 (81.6-117.1) million people in total could become infected before the first wave of the epidemic concludes. Based on current estimates of rates of adverse fetal outcomes among infected women(2,4,5), these results suggest that tens of thousands of pregnancies could be negatively impacted by the first wave of the epidemic. These projections constitute a revised upper limit of populations at risk in the current Zika epidemic, and our approach offers a new way to make rapid assessments of the threat posed by emerging infectious diseases more generally.


Deep Learning for Fast and Spatially Constrained Tissue Quantification From Highly Accelerated Data in Magnetic Resonance Fingerprinting.
Magnetic resonance fingerprinting (MRF) is a quantitative imaging technique that can simultaneously measure multiple important tissue properties of human body. Although MRF has demonstrated improved scan efficiency as compared to conventional techniques, further acceleration is still desired for translation into routine clinical practice. The purpose of this paper is to accelerate MRF acquisition by developing a new tissue quantification method for MRF that allows accurate quantification with fewer sampling data. Most of the existing approaches use the MRF signal evolution at each individual pixel to estimate tissue properties, without considering the spatial association among neighboring pixels. In this paper, we propose a spatially constrained quantification method that uses the signals at multiple neighboring pixels to better estimate tissue properties at the central pixel. Specifically, we design a unique two-step deep learning model that learns the mapping from the observed signals to the desired properties for tissue quantification, i.e.: 1) with a feature extraction module for reducing the dimension of signals by extracting a low-dimensional feature vector from the high-dimensional signal evolution and 2) a spatially constrained quantification module for exploiting the spatial information from the extracted feature maps to generate the final tissue property map. A corresponding two-step training strategy is developed for network training. The proposed method is tested on highly undersampled MRF data acquired from human brains. Experimental results demonstrate that our method can achieve accurate quantification for T1 and T2 relaxation times by using only 1/4 time points of the original sequence (i.e., four times of acceleration for MRF acquisition).


Crimean-congo hemorrhagic fever in South Africa.
Crimean-Congo hemorrhagic fever virus was isolated for the first time in South Africa in February 1981, from the blood of a 13-year-old boy who died in Johannesburg after attending a camp in a nature reserve in the western Transvaal. Virus was isolated from 21/120 pools of questing ticks from the nature reserve, the infected species being Hyalomma marginatum rufipes and H. truncatum. Virus was also isolated from 4/38 pools of partially engorged ticks and other ectoparasites collected off hosts, the infected species being H.m. rufipes, H. truncatum and Rhipicephalus evertsi. Antibodies were found in the sera of 5/74 humans, 8/26 wild vertebrates, 74/270 sheep, and 109/170 cattle from the reserve and surrounding farms. Antibodies were also found in 28/200 hares from various locations in the country. It was concluded that the virus is widely prevalent in South Africa, but the full medical and veterinary significance of its presence has yet to be determined.


Population norms for frequency doubling perimetry with uncorrected refractive error.
To compare the effect of uncorrected refractive error on threshold estimation using frequency doubling perimetry (FDP) full-threshold N-30 with emmetropia among normal subjects. One thousand two hundred ninety-nine subjects were enrolled from the Chennai Glaucoma Study, a population-based glaucoma prevalence study. Subjects underwent a comprehensive eye examination including the FDP full-threshold N-30 test. Normal subjects (with spherical equivalent refractive errors within +/-7 D) with no other ocular pathology were stratified into six groups based on the degree of myopia and hyperopia and compared with age-matched emmetropic controls. A subset of 22 subjects with higher refractive errors was assessed for within-subject effect on FDP parameters. The following FDP parameters were compared: mean deviation, pattern standard deviation, central threshold (CT), mean sensitivity (MS), paracentral points (PA), and peripheral threshold. The one-way analysis of variance between all refractive error groups and emmetropes showed no statistically significant difference for the mean deviation (p = 0.1002) and pattern standard deviation (p = 0.4789). FDP parameters did not show a statistically significant difference for between and within-group comparisons. The variability of FDP sensitivity (derived from the 95% confidence interval range) as a proportion of the threshold range of the instrument was 31, 41, 46, and 41% for CT, MS, PA, and peripheral sensitivity, respectively, without spectacle correction and 29, 34, 36, and 35% for CT, MS, PA, and peripheral sensitivity, respectively, with correction. The mean CT, PA, and peripheral sensitivity show a decreasing trend from central to periphery in all the refractive error groups and a similar trend was noted in the emmetropic controls. Between-subject (uncorrected ammetropes and age-matched emmetropes) and within-subject comparisons showed no statistically significant differences in any of the FDP parameters or in the contrast sensitivity estimates between the central and peripheral test locations. This finding is likely due to the high within-subject variability of FDP.


Therapeutic photobiomodulation: nitric oxide and a novel function of mitochondrial cytochrome c oxidase.
Currently, light therapies are widely used in both human and veterinarian medicine. The application of light to clinical therapeutics includes: photodynamic therapy, used to kill cancer cells; UVA therapies, used to treat a variety of skin diseases; and photobiomodulation, used to promote cell growth and recovery from injury. Photobiomodu-lation uses light emitting diodes (LEDs) or low energy lasers, which emit light in the visible red to near infrared range. Light in this range penetrates tissue reasonably well, lacks the carcinogenic/mutagenic properties of UV light, and acts on an endogenous photoreceptor which likely acts to initiate light-altered signaling pathways. Although early studies identified mitochondrial cytochrome c oxidase as an endogenous photoreceptor for photobiomodulation, the cellular and molecular mechanisms underlying photobiomodulation have not been clear. Three recent findings provide important new insight. First, nitric oxide has been implicated. Second, cytochrome c oxidase, an enzyme known to reduce oxygen to water at the end of the mitochondrial respiratory chain, has been shown to have a new enzymatic activity--the reduction of nitrite to nitric oxide. This nitrite reductase activity is elevated under hypoxic conditions but also occurs under normoxia. And third, low intensity light enhances nitric oxide synthesis by cytochrome c oxidase without altering its ability to reduce oxygen. From these findings, we propose that cytochrome c oxidase functions in photobiomodulation by producing nitric oxide, a signaling molecule which can then function in both intra- and extracellular signaling pathways. We also propose that the effectiveness of photobiomodulation is under the control of tissue oxygen and nitrite levels.