Gene therapy for haemophilia.
Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of treatment are expensive, challenging and involve regular administration of clotting factors. Gene therapy for haemophilia is a curative treatment modality currently under investigation. This is an update of a published Cochrane Review. To evaluate the safety and efficacy of gene therapy for treating people with haemophilia A or B. We searched the Cochrane Cystic Fibrosis & Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Date of last search: 17 April 2020. Eligible trials include randomised or quasi-randomised clinical trials, including controlled clinical trials comparing gene therapy (with or without standard treatment) with standard treatment (factor replacement) or other 'curative' treatment such as stem cell transplantation for individuals with haemophilia A or B of all ages who do not have inhibitors to factor VIII or IX. No trials of gene therapy for haemophilia matching the inclusion criteria were identified. No trials of gene therapy for haemophilia matching the inclusion criteria were identified. No randomised or quasi-randomised clinical trials of gene therapy for haemophilia were identified. Thus, we are unable to determine the safety and efficacy of gene therapy for haemophilia. Gene therapy for haemophilia is still in clinical investigation and there is a need for well-designed clinical trials to assess the long-term feasibility, success and risks of gene therapy for people with haemophilia.


Intramural hematoma of the esophagus mimicking hemorrhaging esophageal cancer.
Intramural hematoma of the esophagus (IHE) is an uncommon esophageal injury. Diagnosis requires high index of suspicion as it can mimic various other cardiovascular, pulmonary, mediastinal or esophageal diseases. Although multiple imaging modalities have been reported to be useful, CT with intravenous contrast should be the imaging modality of choice if not contraindicated. Treatment of IHE is mainly supportive; complete resolution in several weeks is the expected outcome. It is crucial that this condition is recognized and considered in the differential diagnosis of any patients who present with chest pain or dysphagia.


Imaging Local Heating and Thermal Diffusion of Nanomaterials with Plasmonic Thermal Microscopy.
Measuring local heat generation and dissipation in nanomaterials is critical for understanding the basic properties and developing applications of nanomaterials, including photothermal therapy and joule heating of nanoelectronics. Several technologies have been developed to probe local temperature distributions in nanomaterials, but a sensitive thermal imaging technology with high temporal and spatial resolution is still lacking. Here, we describe plasmonic thermal microscopy (PTM) to image local heat generation and diffusion from nanostructures in biologically relevant aqueous solutions. We demonstrate that PTM can detect local temperature change as small as 6 mK with temporal resolution of 10 μs and spatial resolution of submicrons (diffraction limit). With PTM, we have successfully imaged photothermal generation from single nanoparticles and graphene pieces, studied spatiotemporal distribution of temperature surrounding a heated nanoparticle, and observed heating at defect sites in graphene. We further show that the PTM images are in quantitative agreement with theoretical simulations based on heat transport theories.


First Report of a Leaf Spot Caused by Bipolaris oryzae on Switchgrass in New York.
Switchgrass (Panicum virgatum L.) is a perennial grass with biofuel potential. From 2007 to 2010, foliar lesions were observed on first year and mature stands of switchgrass in various locations in New York. Foliar lesions were purple, elliptical (up to 1 cm) with either distinct or diffuse margins, and occasionally with yellow halos and/or white necrotic centers. After 2 to 5 days of moist chamber incubation, surface-sterilized, symptomatic leaf tissue produced conidia that when streaked onto potato dextrose agar containing 0.3 g of streptomycin per liter gave rise to cultures with gray-to-black mycelium that developed brown conidia. The fungus was identified as Bipolaris oryzae (Breda de Haan) Shoemaker on the basis of conidial morphology (1,2). Conidiophores were brown, straight, cylindrical, and multiseptate. Conidia were brown, curved, ellipsoidal tapering to rounded ends, with 3 to 14 septa. Conidia averaged 105 μm (54 to 160 μm) long and 16 μm (12 to 20 μm) wide. Sequences of the glyceraldehyde-3-phosphate dehydrogenase (GDP) gene of three isolates from Tompkins County (Cornell Accession and corresponding GenBank Nos.: Bo005NY07 [cv. Cave-in-Rock], JF521648; Bo006NY07 [cv. Kanlow], JF521649; and Bo038NY07 [cv. Shawnee], JF521650) exhibited 100% nucleotide identity to B. oryzae isolates (GenBank Nos. AY277282-AY277285) collected from switchgrass in North Dakota (1). Sequences of the rDNA internal transcribed spacer (ITS) regions of the isolates (Cornell Accession and corresponding GenBank Nos.: Bo005NY07, JF693908; Bo006NY07, JF693909; and Bo038NY07, JF693910) exhibited 100% nucleotide identity to B. oryzae isolates (GenBank Nos. GU222690-GU222693) collected from switchgrass in Mississippi (3). Pathogenicity of two of the sequenced isolates (Bo006NY07 and Bo038NY07) along with one other isolate (Bo116NY09 from 'Cave-in-Rock' in Cayuga County) was evaluated in the greenhouse. Six- to eight-week-old switchgrass plants were inoculated with conidial suspensions (40,000 conidia/ml) of B. oryzae. Inoculum or sterilized water was applied until runoff. There were three plants per treatment of each of 'Blackwell', 'Carthage', 'Cave-in-Rock', 'Kanlow', 'Shawnee', 'Shelter', and 'Sunburst'. After inoculum had dried, plants were placed in a mist chamber for 24 h and then returned to the greenhouse. Symptoms developed 2 to 4 days after inoculation for all cultivars. No symptoms developed on the control plants. Foliar lesions closely resembled those observed in the field. B. oryzae was consistently reisolated from symptomatic tissue collected from greenhouse experiments. B. oryzae was first reported as a pathogen of switchgrass in North Dakota (1) and more recently in Mississippi (3). To our knowledge, this is the first report of B. oryzae causing a leaf spot on switchgrass in New York. Observation of severe leaf spot in several field plots suggests that switchgrass populations should be screened for their reaction to regional isolates of B. oryzae prior to expanded production of switchgrass as a biofuel crop. References: (1) J. M. Krupinsky et al. Can. J. Plant Pathol. 26:371 2004. (2) R. A. Shoemaker. Can. J. Bot. 37:883, 1959. (3) M. Tomaso-Peterson and C. J. Balbalian. Plant Dis. 94:643 2010.


The Irrationality of GOF Avian Influenza Virus Research.
The last two and a half years have witnessed a curious debate in virology characterized by a remarkable lack of discussion. It goes by the misleading epithet "gain of function" (GOF) influenza virus research, or simply GOF. As will be seen, there is nothing good to be gained. The controversial experiments confer aerosol transmission on avian influenza virus strains that can infect humans, but which are not naturally transmitted between humans. Some of the newer strains are clearly highly pathogenic for man. It will be shown here that the benefits of the work are erroneous and overstated while the risk of an accident is finite, if small. The consequence of any accident would be anywhere from a handful of infections to a catastrophic pandemic. There has been a single open international meeting in this period, which is surprising given that openness and discussion are essential to good science. Despite US and EU government funding, no risk-benefit analysis has been published, which again is surprising. This research can be duplicated readily in many labs and requires little high tech. It falls under the definition of DURC without the slightest shadow of a doubt and constitutes the most important challenge facing contemporary biology.


Elevated level of miR-17 along with decreased levels of TIMP-1 and IL-6 in plasma associated with the risk of in-stent restenosis.
In-stent restenosis is highly related to the deposition of inflammatory extracellular matrix and the migration of endothelial and vascular smooth muscle cells. The miR-17/TIMP-1/interleukin pathway regulates vascular matrix remodeling and plays an important role in the inflammatory reaction. This study identified miR-17 and its related biomarkers in serum that potentially indicated susceptibility to in-stent restenosis (ISR) after coronary artery stenting. Subjects were 42 patients with single de novo coronary artery lesions who underwent regular coronary angiography one year after percutaneous coronary intervention. The clinical baseline information was recorded. Serum levels of biomarkers (including miR-17, TIMP-1, IL-6, IL-8, IL-2R, TNF-alpha, IL-10, and IL-1beta) were measured with real-time PCR or ELISA. Intergroup comparisons were used to compare patients with or without ISR. Compared to levels in the non-restenosis group, the serum miR-17 level was significantly higher (3.13 ± 0.22 vs. 1.06 ± 0.04, p < 0.01) and the serum TIMP-1 and IL-6 levels were significantly lower in the ISR group (TIMP-1: 0.33 ± 0.04 vs. 1.00 ± 0.05, p < 0.01; IL-6: 1.64 ± 0.18 vs. 3.52 ± 0.11, p < 0.01). Moreover, the levels of TIMP-1 and IL-6 decreased as the level of miR-17 increased. Spearman's correlation analysis indicated that the miR-17 level was inversely correlated with TIMP-1 and IL-6 levels. Findings suggest that an elevated level of miR-17 and decreased levels of TIMP-1 and IL-6 may be associated with the risk of ISR, which is in accordance with vascular matrix remodeling and an inflammatory reaction during the pathologic process of ISR. This study highlighted the potential for miR-17, TIMP-1, and IL-6 to serve as biomarkers for ISR.


Cyclothiazide differentially modulates desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor splice variants.
Agonist responses for flip splice variants of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR-A, -C, and -D are more strongly potentiated by cyclothiazide than are those for the flop forms. Cyclothiazide shows both greater efficacy and higher apparent affinity for potentiation of GluR-Aflip versus GluR-Aflop. Consistent with higher affinity for the flip splice variant, recovery from potentiation by cyclothiazide proceeds 30 times more slowly for GluR-Aflip than for GluR-Aflop. In the presence of 300 microM cyclothiazide a 6-fold leftward shift in the kainate dose-response curve for GluR-Aflip but not GluR-Aflop additionally contributes to a difference in potentiation for these splice variants. Although control responses to glutamate show strong desensitization for both splice variants of GluR-A, in the presence of 100 microM cyclothiazide desensitization is strongly attenuated for GluR-Aflip, whereas for GluR-Aflop desensitization remains pronounced but with a rate of onset slowed 50-fold, compared with control. In heteromeric AMPA receptors formed from GluR-A and GluR-B, the flip splice variants are dominant for controlling both recovery from potentiation of responses to kainate and block of desensitization of responses to glutamate. Our results suggest that the flip/flop module could directly contribute to the binding site for cyclothiazide, raising the possibility that this site is located in an extracellular receptor domain.


The efficacy of Ginkgo special extract EGb 761 in patients with tinnitus.
The objective of the present study in 60 patients with chronic tinnitus aurium was to confirm the efficacy of oral treatment with 2 x 80 mg Ginkgo special extract EGb 761 per day subsequent to 10-day EGb 761 infusion treatment. Patients with chronic tinnitus aurium underwent 10 days of in-patient infusion treatment with 200 mg/day EGb 761, after which they were randomized to double-blind, oral out-patient treatment with either 2 x 80 mg/day EGb 761 or placebo, given over a scheduled treatment period of 12 weeks. The primary outcome measure was the change in tinnitus volume in the more severely affected ear during randomized treatment. Fifty-two of 60 patients (89.7%) completed the infusion treatment; complete sets of data were available for 40 (66.7%), 30 (50.0%) and 22 (36.7%) patients after 4, 8 and 12 weeks of randomized treatment, respectively. For the primary outcome measure, significant superiority of EGb 761 over placebo was demonstrated in the intention-to-treat analysis data set after 4, 8 and 12 weeks of out-patient treatment (p < 0.05, 1-tailed), although the absolute treatment group difference was moderate. The results were supported by the secondary outcome measures for efficacy (e.g. decreased hearing loss, improved self-assessment of subjective impairment). During out-patient treatment, there were no attributable adverse events under EGb 761. A combination of infusion therapy followed by oral administration of Ginkgo special extract EGb 761 appears to be effective and safe in alleviating the symptoms associated with tinnitus aurium.


Genetic and environmental factors in Alzheimer's disease.
In recent years, considerable progress has been made in unraveling the etiology of Alzheimer's disease (AD). Dominant mutations have been identified, in the beta-amyloid precursor protein gene (APP), and in two homologous genes presenilin 1 (PSEN-1) and presenilin 2 (PSEN-2). The contribution of these mutations to the occurrence of AD in the general population is estimated to be lower than 1p. 100. A genetic risk factor of more importance on the population level is the Apolipoprotein E (APOE) gene that may explain up to 17p. 100 of the prevalence of AD in the general population. It is clear that other yet unknown genes must be involved in the etiology of AD. Two loci on chromosome 12 have been suggested, but no consistent effect could be found. Important progress with regard to non-genetic risk factors concerns the role of vascular and endocrine factors in the pathogenesis. Of major interest for the prevention of AD will be the interaction of genetic and non-genetic risk factors. Large scale, long term follow-up studies, ongoing at present, may clarify this issue.


Rural end-of-life care from the experiences and perspectives of patients and family caregivers: A systematic literature review.
End-of-life care must be relevant to the dying person and their family caregiver regardless of where they live. Rural areas are distinct and need special consideration. Gaining end-of-life care experiences and perspectives of rural patients and their family caregivers is needed to ensure optimal rural care. To describe end-of-life care experiences and perspectives of rural patients and their family caregivers, to identify facilitators and barriers to receiving end-of-life care in rural/remote settings and to describe the influence of rural place and culture on end-of-life care experiences. A systematic literature review utilising the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Four databases (PubMed, CINAHL, Scopus and Web of Science) were searched in January 2016, using a date filter of January 2006 through January 2016; handsearching of included article references and six relevant journals; one author contacted; pre-defined search terms and inclusion criteria; and quality assessment by at least two authors. A total of 27 articles (22 rural/remote studies) from developed and developing countries were included, reporting rural end-of-life care experiences and perspectives of patients and family caregivers. Greatest needs were informational (developed countries) and medications (developing countries). Influence of rural location included distances, inaccessibility to end-of-life care services, strong community support and importance of home and 'country'. Articulation of the rural voice is increasing; however, there still remain limited published rural studies reporting on patient and family caregivers' experiences and perspectives on rural end-of-life care. Further research is encouraged, especially through national and international collaborative work.


Partnerships in purchasing: development of consortium-based purchasing among GP fundholders.
In the last few years there have been considerable changes in the National Health Service (NHS) in the UK. Arguably the most significant of these has been the introduction of competition. Central to this development has been the introduction of general practice (GP) fundholding, whereby practices purchase health care for their patients directly from competing suppliers. Those practices which have become fundholders have faced considerable challenges in developing their purchasing function, given the complexities of contracting within the context of the NHS internal market. Although one of the original aims of GP fundholding was to facilitate locally responsive purchasing, such have been the complexities of contracting that many fundholding practices have attempted to reduce the managerial demands of purchasing through membership of purchasing consortia. Based on an in-depth study of GP fundholders across Scotland, this paper explores the development of consortium-based purchasing. Specifically, this paper seeks to address three issues central to the evolution of such consortium-based purchasing. Firstly, the patterns of organizational structure and the operational dynamics of such consortia. Secondly, the impact of such consortia on the process of fundholder purchasing. Thirdly, the managerial implications of purchasing through such consortia for the participating practices. In addressing these issues, it will examine whether such patterns of purchaser development have impacted on the evolution of locally responsive purchasing.


Work time control, sleep & accident risk: A prospective cohort study.
We examined whether the beneficial impact of work time control (WTC) on sleep leads to lower accident risk, using data from a nationally representative survey conducted in Sweden. Logistic regressions examined WTC in 2010 and 2012 as predictors of accidents occurring in the subsequent 2 years (N = 4840 and 4337, respectively). Sleep disturbance and frequency of short sleeps in 2012 were examined as potential mediators of the associations between WTC in 2010 and subsequent accidents as reported in 2014 (N = 3636). All analyses adjusted for age, sex, education, occupational category, weekly work hours, shift work status, job control and perceived accident risk at work. In both waves, overall WTC was inversely associated with accidents (p = 0.048 and p = 0.038, respectively). Analyses of the sub-dimensions of WTC indicated that Control over Daily Hours (influence over start and finish times, and over length of shift) did not predict accidents in either wave, while Control over Time-off (CoT; influence over taking breaks, running private errands during work and taking paid leave) predicted fewer accidents in both waves (p = 0.013 and p = 0.010). Sleep disturbance in 2012 mediated associations between WTC/CoT in 2010 and accidents in 2014, although effects' sizes were small (effectWTC = -0.006, 95% confidence interval [CI] = -0.018 to -0.001; effectCoT = -0.009, 95%CI = -0.022 to -0.001; unstandardized coefficients), with the indirect effects of sleep disturbance accounting for less than 5% of the total direct and indirect effects. Frequency of short sleeps was not a significant mediator. WTC reduces the risk of subsequently being involved in an accident, although sleep may not be a strong component of the mechanism underlying this association.


Analysis of Intra- and Intersubject Variability in Oral Drug Absorption in Human Bioequivalence Studies of 113 Generic Products.
In this study, the data of 113 human bioequivalence (BE) studies of immediate release (IR) formulations of 74 active pharmaceutical ingredients (APIs) conducted at Sawai Pharmaceutical Co., Ltd., was analyzed to understand the factors affecting intra- and intersubject variabilities in oral drug absorption. The ANOVA CV (%) calculated from area under the time-concentration curve (AUC) in each BE study was used as an index of intrasubject variability (Vintra), and the relative standard deviation (%) in AUC was used as that of intersubject variability (Vinter). Although no significant correlation was observed between Vintra and Vinter of all drugs, Vintra of class 3 drugs was found to increase in association with a decrease in drug permeability (P(eff)). Since the absorption of class 3 drugs was rate-limited by the permeability, it was suggested that, for such drugs, the low P(eff) might be a risk factor to cause a large intrasubject variability. To consider the impact of poor water solubility on the variability in BE study, a parameter of P(eff)/Do (Do; dose number) was defined to discriminate the solubility-limited and dissolution-rate-limited absorption of class 2 drugs. It was found that the class 2 drugs with a solubility-limited absorption (P(eff)/Do < 0.149 × 10(-4) cm/s) showed high intrasubject variability. Furthermore, as a reason for high intra- or intersubject variability in AUC for class 1 drugs, effects of drug metabolizing enzymes were investigated. It was demonstrated that intrasubject variability was high for drugs metabolized by CYP3A4 while intersubject variability was high for drugs metabolized by CYP2D6. For CYP3A4 substrate drugs, the Km value showed the significant relation with Vintra, indicating that the affinity to the enzyme can be a parameter to predict the risk of high intrasubject variability. In conclusion, by analyzing the in house data of human BE study, low permeability, solubility-limited absorption, and high affinity to CYP3A4 are identified as risk factors for high intrasubject variability in oral drug absorption. This information is of importance to design the human BE study for oral drug products containing APIs with a risk of large intrasubject variability in oral absorption.


Accuracy of 64-slice CT angiography for the detection of functionally relevant coronary stenoses as assessed with myocardial perfusion SPECT.
CT angiography (CTA) offers a valuable alternative for the diagnosis of CAD but its value in the detection of functionally relevant coronary stenoses remains uncertain. We prospectively compared the accuracy of 64-slice CTA with that of myocardial perfusion imaging (MPI) using (99m)Tc-tetrofosmin-SPECT as the gold standard for the detection of functionally relevant coronary artery disease (CAD). MPI and 64-slice CT were performed in 100 consecutive patients. CTA lesions were analysed quantitatively and area stenoses > or =50% and > or =75% were compared with the MPI findings. In 23 patients, MPI perfusion defects were found (12 reversible, 13 fixed). A total of 399 coronary arteries and 1,386 segments was analysed. Eighty-four segments (6.1%) in 23 coronary arteries (5.8%) of nine patients (9.0%) were excluded owing to insufficient image quality. In the remaining 1,302 segments, quantitative CTA revealed stenoses > or =50% in 57 of 376 coronary arteries (15.2%) and stenoses > or =75% in 32 (8.5%) coronary arteries. Using a cut-off at > or =75% area stenosis, CTA yielded the following sensitivity, specificity, negative (NPV) and positive predictive value (PPV), and accuracy for the detection of any (fixed and reversible) MPI defect: by patient, 75%, 90%, 93%, 68% and 87%, respectively; by artery, 76%, 95%, 99%, 50% and 94%, respectively. Sixty-four-slice CTA is a reliable tool to rule out functionally relevant CAD in a non-selected population with an intermediate pretest likelihood of disease. However, an abnormal CTA is a poor predictor of ischaemia.


A comparison of fixed-bearing and mobile-bearing total knee arthroplasty at a minimum follow-up of 4.5 years.
Durable long-term independent results with the Low Contact Stress rotating-platform (mobile-bearing) and the Insall Burstein-II (fixed-bearing) total knee prostheses have been reported, but no studies describing either the mid-term or long-term results and comparing the two prostheses are available, to our knowledge. Thirty-two patients who had bilateral arthritis of the knee with similar deformity and preoperative range of motion on both sides and who agreed to have one knee replaced with a mobile-bearing total knee design and the other with a fixed-bearing design were prospectively evaluated. Comparative analysis of both designs was done at a mean follow-up period of six years, minimizing patient, surgeon, and observer-related bias. Clinical and radiographic outcome, survival, and complication rates were compared. Patients with osteoarthritis had better function scores and range of motion compared with patients with rheumatoid arthritis. However, with the numbers available, no benefit of mobile-bearing over fixed-bearing designs could be demonstrated with respect to Knee Society scores, range of flexion, subject preference, or patellofemoral complication rates. Radiographs showed no difference in prosthetic alignment. Two knees with a mobile-bearing prosthesis required a reoperation: one had an early revision because of bearing dislocation and another required conversion to an arthrodesis to treat a deep infection. We found no advantage of the mobile-bearing arthroplasty over the fixed-bearing arthroplasty with regard to the clinical results at mid-term follow-up. The risk of bearing subluxation and dislocation in knees with the mobile-bearing prosthesis is a cause for concern and may necessitate early revision. Therapeutic Level II.


Introducing service improvement to the initial training of clinical staff.
It is well recognised in healthcare settings that clinical staff have a major influence over change in how services are provided. If a culture of systematic service improvement is to be established, it is essential that clinical staff have an understanding of what is required and their role in its application. This paper describes the development of short educational interventions (a module of 6-8 contact hours or a longer module of 18-30 h) for inclusion in the initial training of future clinical staff (nursing, medicine, physiotherapy, occupational therapy, dietetics, social work, operating department practice, public health and clinical psychology) and presents the results of an evaluation of their introduction. Each module included teaching on process/systems thinking, initiating and sustaining change, personal and organisational development, and public and patient involvement. Over 90% of students considered the modules relevant to their career. Nearly 90% of students felt that they could put their learning into practice, although the actual rate of implementation of changes during the pilot period was much lower. The barriers to implementation most commonly cited were blocks presented by existing staff, lack of time and lack of status of students within the workforce. This pilot demonstrates that short educational interventions focused on service improvement are valued by students and that those completing them feel ready to contribute. Nevertheless, the rate of translation into practice is low. While this may reflect the status of students in the health service, further research is needed to understand how this might be enhanced.


Salvage of extremities with ischemic necrosis in diabetic patients by infrapopliteal arterial bypass.
Initial and long-term limb salvage can be achieved by infrapopliteal bypass in diabetic patients with ischemic necrosis of the distal extremity. Mortality is low in all groups, and mortality of subsequent amputation apparently is not affected by the previous bypass. An adequate arteriogram and consideration of distal bypass are frequently indicated in the diabetic patients in whom ischemic necrosis is present. Limb salvage may be feasible even in those diabetic patients in whom popliteal artery is not patent on preoperative arteriogram by bypasses to anterior tibial, posterior tibial, or peroneal artery.


Costs and Benefits of Orthographic Inconsistency in Reading: Evidence from a Cross-Linguistic Comparison.
We compared reading acquisition in English and Italian children up to late primary school analyzing RTs and errors as a function of various psycholinguistic variables and changes due to experience. Our results show that reading becomes progressively more reliant on larger processing units with age, but that this is modulated by consistency of the language. In English, an inconsistent orthography, reliance on larger units occurs earlier on and it is demonstrated by faster RTs, a stronger effect of lexical variables and lack of length effect (by fifth grade). However, not all English children are able to master this mode of processing yielding larger inter-individual variability. In Italian, a consistent orthography, reliance on larger units occurs later and it is less pronounced. This is demonstrated by larger length effects which remain significant even in older children and by larger effects of a global factor (related to speed of orthographic decoding) explaining changes of performance across ages. Our results show the importance of considering not only overall performance, but inter-individual variability and variability between conditions when interpreting cross-linguistic differences.


Caring for a person in advanced illness and suffering from breathlessness at home: threats and resources.
Little is known about the factors that mediate the caregiving experience of informal carers at home, which could inform about ways of supporting them in their caregiving role. Our objective was to investigate the caring experience of carers for patients with an advanced progressive illness (chronic obstructive pulmonary disease [COPD], heart failure, cancer, or motor neuron diseases [MND]), who suffer from breathlessness. A purposive sample of 15 carers was selected. They were recruited via the patients they cared for (who suffered from COPD, cancer, MND, or heart failure) from the hospital and the community. Data were collected through semistructured, in-depth interviews. All were tape-recorded and transcribed verbatim. The analysis used a Grounded Theory approach and NVivo software facilitated the management and analysis of the data. Several key issues affected caring in a positive or a negative way. The threats to caring were uncertainty, carers' own health problems, an imploded world, negative reactions from outside, person loss, and acute exacerbations. Resources that carers drew on were acceptance, self-care, availability of support, feeling that caring is a shared responsibility with the patient, and "getting on with" caring in case of emergencies. Breathlessness was particularly challenging, and carers did not have any strategies to relieve the symptom. They were ill prepared for acute exacerbations. Carers need to be included in opportunities for support provision in advanced illness. Negotiated involvement of a health professional could buffer the heavy responsibilities related to home care. They could provide problem-solving skills and build on the resources that carers draw on in response to what they experience as most threatening to their caring role.


Deflection and diffraction of x rays bound to curved surfaces.
We present two new x-ray optical effects observed on a whispering-gallery waveguide. The first is a gradual in-surface deflection of guided waves caused by the non-Euclidean intrinsic curvature of the waveguide surface. The second is the excitation of in-surface dynamical diffraction modes that reflects the strong influence of the surface photonic band structure of a crystalline waveguide. Both phenomena portend a rich array of basic and applied x-ray optical potentialities.


Topological analysis of group fragmentation in multiagent systems.
In social animals, the presence of conflicts of interest or multiple leaders can promote the emergence of two or more subgroups. Such subgroups are easily recognizable by human observers, yet a quantitative and objective measure of group fragmentation is currently lacking. In this paper, we explore the feasibility of detecting group fragmentation by embedding the raw data from the individuals' motions on a low-dimensional manifold and analyzing the topological features of this manifold. To perform the embedding, we employ the isomap algorithm, which is a data-driven machine learning tool extensively used in computer vision. We implement this procedure on a data set generated by a modified à la Vicsek model, where agents are partitioned into two or more subsets and an independent leader is assigned to each subset. The dimensionality of the embedding manifold is shown to be a measure of the number of emerging subgroups in the selected observation window and a cluster analysis is proposed to aid the interpretation of these findings. To explore the feasibility of using this approach to characterize group fragmentation in real time and thus reduce the computational cost in data processing and storage, we propose an interpolation method based on an inverse mapping from the embedding space to the original space. The effectiveness of the interpolation technique is illustrated on a test-bed example with potential impact on the regulation of collective behavior of animal groups using robotic stimuli.


RAINFOREST: a random forest approach to predict treatment benefit in data from (failed) clinical drug trials.
When phase III clinical drug trials fail their endpoint, enormous resources are wasted. Moreover, even if a clinical trial demonstrates a significant benefit, the observed effects are often small and may not outweigh the side effects of the drug. Therefore, there is a great clinical need for methods to identify genetic markers that can identify subgroups of patients which are likely to benefit from treatment as this may (i) rescue failed clinical trials and/or (ii) identify subgroups of patients which benefit more than the population as a whole. When single genetic biomarkers cannot be found, machine learning approaches that find multivariate signatures are required. For single nucleotide polymorphism (SNP) profiles, this is extremely challenging owing to the high dimensionality of the data. Here, we introduce RAINFOREST (tReAtment benefIt prediction using raNdom FOREST), which can predict treatment benefit from patient SNP profiles obtained in a clinical trial setting. We demonstrate the performance of RAINFOREST on the CAIRO2 dataset, a phase III clinical trial which tested the addition of cetuximab treatment for metastatic colorectal cancer and concluded there was no benefit. However, we find that RAINFOREST is able to identify a subgroup comprising 27.7% of the patients that do benefit, with a hazard ratio of 0.69 (P = 0.04) in favor of cetuximab. The method is not specific to colorectal cancer and could aid in reanalysis of clinical trial data and provide a more personalized approach to cancer treatment, also when there is no clear link between a single variant and treatment benefit. The R code used to produce the results in this paper can be found at github.com/jubels/RAINFOREST. A more configurable, user-friendly Python implementation of RAINFOREST is also provided. Due to restrictions based on privacy regulations and informed consent of participants, phenotype and genotype data of the CAIRO2 trial cannot be made freely available in a public repository. Data from this study can be obtained upon request. Requests should be directed toward Prof. Dr. H.J. Guchelaar (email@example.com). Supplementary data are available at Bioinformatics online.


Origin of the transition voltage in gold-vacuum-gold atomic junctions.
The origin and the distance dependence of the transition voltage of gold-vacuum-gold junctions are investigated by employing first-principles quantum transport simulations. Our calculations show that atomic protrusions always exist on the electrode surface of gold-vacuum-gold junctions fabricated using the mechanically controllable break junction (MCBJ) method. The transition voltage of these gold-vacuum-gold junctions with atomically sharp electrodes is determined by the local density of states (LDOS) of the apex gold atom on the electrode surface rather than by the vacuum barrier shape. More specifically, the absolute value of the transition voltage roughly equals the rising edge of the LDOS peak contributed by the 6p atomic orbitals of the gold atoms protruding from the electrode surface, whose local Fermi level is shifted downwards when a bias voltage is applied. Since the LDOS of the apex gold atom depends strongly on the exact shape of the electrode, the transition voltage is sensitive to the variation of the atomic configuration of the junction. For asymmetric junctions, the transition voltage may also change significantly depending on the bias polarity. Considering that the occurrence of the transition voltage requires the electrode distance to be larger than a critical value, the interaction between the two electrodes is actually rather weak. Consequently, the LDOS of the apex gold atom is mainly determined by its local atomic configuration and the transition voltage only depends weakly on the electrode distance as observed in the MCBJ experiments.


Atypical cardiac myxoma in the course of Carney complex in the child. Case Report.
Cardiac tumors in infants and children are rare. Myxomas are the second (after rhabdomyomas) most common primary cardiac tumors in pediatric patients. Cardiac, cutaneous and mucous myxomas are likewise the second most frequent manifestation of the Carney complex, an autosomal dominant multi neoplasia syndrome, which consists of myxomas in different locations, spotty skin pigmentation and endocrine overactivity. We present a case of 13-years-old boy send to our department from a district hospital because of the large tumor in the right atrium discovered in the echo study. On admission he presented discrete signs of Cushing's syndrome and scarse pigmented nevi on the face and trunc. The detailed echo examination showed the large right atrial tumor with features of myxoma, protruding across the tricuspid valve into the right ventricle during diastolic period. Atypical location of cardiac myxoma as well as the signs of Cushing's syndrome suggested Carney's complex. Detailed endocrine studies confirmed the hypothesis. Thus two-step bilateral adrenalectomy was planned. The histopathologic study confirmed primary pigmented nodular adrenocortical disease.


Demethylation of ITGAV accelerates osteogenic differentiation in a blast-induced heterotopic ossification in vitro cell culture model.
Trauma-induced heterotopic ossification is an intriguing phenomenon involving the inappropriate ossification of soft tissues within the body such as the muscle and ligaments. This inappropriate formation of bone is highly prevalent in those affected by blast injuries. Here, we developed a simplified cell culture model to evaluate the molecular events involved in heterotopic ossification onset that arise from the shock wave component of the disease. We exposed three subtypes of human mesenchymal cells in vitro to a single, high-energy shock wave and observed increased transcription in the osteogenic master regulators, Runx2 and Dlx5, and significantly accelerated cell mineralisation. Reduced representation bisulfite sequencing revealed that the shock wave altered methylation of gene promoters, leading to opposing changes in gene expression. Using a drug to target ITGAV, whose expression was perturbed by the shock wave, we found that we could abrogate the deposition of mineral in our model. These findings show how new therapeutics for the treatment of heterotopic ossification can be identified using cell culture models.


The prevalence of stunting, overweight and obesity, and metabolic disease risk in rural South African children.
Low- to middle-income countries are undergoing a health transition with non-communicable diseases contributing substantially to disease burden, despite persistence of undernutrition and infectious diseases. This study aimed to investigate the prevalence and patterns of stunting and overweight/obesity, and hence risk for metabolic disease, in a group of children and adolescents in rural South Africa. A cross-sectional growth survey was conducted involving 3511 children and adolescents 1-20 years, selected through stratified random sampling from a previously enumerated population living in Agincourt sub-district, Mpumalanga Province, South Africa. Anthropometric measurements including height, weight and waist circumference were taken using standard procedures. Tanner pubertal assessment was conducted among adolescents 9-20 years. Growth z-scores were generated using 2006 WHO standards for children up to five years and 1977 NCHS/WHO reference for older children. Overweight and obesity for those <18 years were determined using International Obesity Task Force BMI cut-offs, while adult cut-offs of BMI > or = 25 and > or = 30 kg/m2 for overweight and obesity respectively were used for those > or = 18 years. Waist circumference cut-offs of > or = 94 cm for males and > or = 80 cm for females and waist-to-height ratio of 0.5 for both sexes were used to determine metabolic disease risk in adolescents. About one in five children aged 1-4 years was stunted; one in three of those aged one year. Concurrently, the prevalence of combined overweight and obesity, almost non-existent in boys, was substantial among adolescent girls, increasing with age and reaching approximately 20-25% in late adolescence. Central obesity was prevalent among adolescent girls, increasing with sexual maturation and reaching a peak of 35% at Tanner Stage 5, indicating increased risk for metabolic disease. The study highlights that in transitional societies, early stunting and adolescent obesity may co-exist in the same socio-geographic population. It is likely that this profile relates to changes in nutrition and diet, but variation in factors such as infectious disease burden and physical activity patterns, as well as social influences, need to be investigated. As obesity and adult short stature are risk factors for metabolic syndrome and Type 2 diabetes, this combination of early stunting and adolescent obesity may be an explosive combination.


Rank-based genome-wide analysis reveals the association of ryanodine receptor-2 gene variants with childhood asthma among human populations.
The standard approach to determine unique or shared genetic factors across populations is to identify risk alleles in one population and investigate replication in others. However, since populations differ in DNA sequence information, allele frequencies, effect sizes, and linkage disequilibrium patterns, SNP association using a uniform stringent threshold on p values may not be reproducible across populations. Here, we developed rank-based methods to investigate shared or population-specific loci and pathways for childhood asthma across individuals of diverse ancestry. We performed genome-wide association studies on 859,790 SNPs genotyped in 527 affected offspring trios of European, African, and Hispanic ancestry using publically available asthma database in the Genotypes and Phenotypes database. Rank-based analyses showed that there are shared genetic factors for asthma across populations, more at the gene and pathway levels than at the SNP level. Although the top 1,000 SNPs were not shared, 11 genes (RYR2, PDE4D, CSMD1, CDH13, ROBO2, RBFOX1, PTPRD, NPAS3, PDE1C, SEMA5A, and CTNNA2) mapped by these SNPs were shared across populations. Ryanodine receptor 2 (RYR2, a statin response-related gene) showed the strongest association in European (p value=2.55×10(-7)) and was replicated in African (2.57×10(-4)) and Hispanic (1.18 × 10(-3)) Americans. Imputation analyses based on the 1000 Genomes Project uncovered additional RYR2 variants associated with asthma. Network and functional ontology analyses revealed that RYR2 is an integral part of dermatological or allergic disorder biological networks, specifically in the functional classes involving inflammatory, eosinophilic, and respiratory diseases. Our rank-based genome-wide analysis revealed for the first time an association of RYR2 variants with asthma and replicated previously discovered PDE4D asthma gene across human populations. The replication of top-ranked asthma genes across populations suggests that such loci are less likely to be false positives and could indicate true associations. Variants that are associated with asthma across populations could be used to identify individuals who are at high risk for asthma regardless of genetic ancestry.


Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12.
Stem cell homing and breast cancer metastasis are orchestrated by the chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4. Here, we report the nuclear magnetic resonance structure of a constitutively dimeric SDF-1 in complex with a CXCR4 fragment that contains three sulfotyrosine residues important for a high-affinity ligand-receptor interaction. CXCR4 bridged the SDF-1 dimer interface so that sulfotyrosines sTyr7 and sTyr12 of CXCR4 occupied positively charged clefts on opposing chemokine subunits. Dimeric SDF-1 induced intracellular Ca2+ mobilization but had no chemotactic activity; instead, it prevented native SDF-1-induced chemotaxis, suggesting that it acted as a potent partial agonist. Our work elucidates the structural basis for sulfotyrosine recognition in the chemokine-receptor interaction and suggests a strategy for CXCR4-targeted drug development.


geneSurv: An interactive web-based tool for survival analysis in genomics research.
Survival analysis methods are often used in cancer studies. It has been shown that the combination of clinical data with genomics increases the predictive performance of survival analysis methods. But, this leads to a high-dimensional data problem. Fortunately, new methods have been developed in the last decade to overcome this problem. However, there is a strong need for easily accessible, user-friendly and interactive tool to perform survival analysis in the presence of genomics data. We developed an open-source and freely available web-based tool for survival analysis methods that can deal with high-dimensional data. This tool includes classical methods, such as Kaplan-Meier, Cox proportional hazards regression, and advanced methods, such as penalized Cox regression and Random Survival Forests. It also offers an optimal cutoff determination method based on maximizing several test statistics. The tool has a simple and interactive interface, and it can handle high dimensional data through feature selection and ensemble methods. To dichotomize gene expressions, geneSurv can identify optimal cutoff points. Users can upload their microarray, RNA-Seq, chip-Seq, proteomics, metabolomics or clinical data as a nxp dimensional data matrix, where n refers to samples and p refers to genes. This tool is available free at www.biosoft.hacettepe.edu.tr/geneSurv. All source code is available at https://github.com/selcukorkmaz/geneSurv under the GPL-3 license.


Two well-differentiated pancreatic neuroendocrine tumor mouse models.
Multiple endocrine neoplasia type 1 (MEN1) is a genetic syndrome in which patients develop neuroendocrine tumors (NETs), including pancreatic neuroendocrine tumors (PanNETs). The prolonged latency of tumor development in MEN1 patients suggests a likelihood that other mutations cooperate with Men1 to induce PanNETs. We propose that Pten loss combined with Men1 loss accelerates tumorigenesis. To test this, we developed two genetically engineered mouse models (GEMMs)-MPR (Men1flox/flox Ptenflox/flox RIP-Cre) and MPM (Men1flox/flox Ptenflox/flox MIP-Cre) using the Cre-LoxP system with insulin-specific biallelic inactivation of Men1 and Pten. Cre in the MPR mouse model was driven by the transgenic rat insulin 2 promoter while in the MPM mouse model was driven by the knock-in mouse insulin 1 promoter. Both mouse models developed well-differentiated (WD) G1/G2 PanNETs at a much shorter latency than Men1 or Pten single deletion alone and exhibited histopathology of human MEN1-like tumor. The MPR model, additionally, developed pituitary neuroendocrine tumors (PitNETs) in the same mouse at a much shorter latency than Men1 or Pten single deletion alone as well. Our data also demonstrate that Pten plays a role in NE tumorigenesis in pancreas and pituitary. Treatment with the mTOR inhibitor rapamycin delayed the growth of PanNETs in both MPR and MPM mice, as well as the growth of PitNETs, resulting in prolonged survival in MPR mice. Our MPR and MPM mouse models are the first to underscore the cooperative roles of Men1 and Pten in cancer, particularly neuroendocrine cancer. The early onset of WD PanNETs mimicking the human counterpart in MPR and MPM mice at 7 weeks provides an effective platform for evaluating therapeutic opportunities for NETs through targeting the MENIN-mediated and PI3K/AKT/mTOR signaling pathways.


Treating Subvalence Correlation Effects in Domain Based Pair Natural Orbital Coupled Cluster Calculations: An Out-of-the-Box Approach.
The validity of the main approximations used in canonical and domain based pair natural orbital coupled cluster methods (CCSD(T) and DLPNO-CCSD(T), respectively) in standard chemical applications is discussed. In particular, we investigate the dependence of the results on the number of electrons included in the correlation treatment in frozen-core (FC) calculations and on the main threshold governing the accuracy of DLPNO all-electron (AE) calculations. Initially, scalar relativistic orbital energies for the ground state of the atoms from Li to Rn in the periodic table are calculated. An energy criterion is used for determining the orbitals that can be excluded from the correlation treatment in FC coupled cluster calculations without significant loss of accuracy. The heterolytic dissociation energy (HDE) of a series of metal compounds (LiF, NaF, AlF3, CaF2, CuF, GaF3, YF3, AgF, InF3, HfF4, and AuF) is calculated at the canonical CCSD(T) level, and the dependence of the results on the number of correlated electrons is investigated. Although for many of the studied reactions subvalence correlation effects contribute significantly to the HDE, the use of an energy criterion permits a conservative definition of the size of the core, allowing FC calculations to be performed in a black-box fashion while retaining chemical accuracy. A comparison of the CCSD and the DLPNO-CCSD methods in describing the core-core, core-valence, and valence-valence components of the correlation energy is given. It is found that more conservative thresholds must be used for electron pairs containing at least one core electron in order to achieve high accuracy in AE DLPNO-CCSD calculations relative to FC calculations. With the new settings, the DLPNO-CCSD method reproduces canonical CCSD results in both AE and FC calculations with the same accuracy.


Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.
Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.


Long term exposure to air pollution and mortality in an elderly cohort in Hong Kong.
Several studies have reported associations between long term exposure to air pollutants and cause-specific mortality. However, since the concentrations of air pollutants in Asia are much higher compared to those reported in North American and European cohort studies, cohort studies on long term effects of air pollutants in Asia are needed for disease burden assessment and to inform policy. To assess the effects of long-term exposure to particulate matter with aerodynamic diameter < 2.5 μm (PM2.5), black carbon (BC) and nitrogen dioxide (NO2) on cause-specific mortality in an elderly cohort in Hong Kong. In a cohort of 66,820 participants who were older than or equal to 65 years old in Hong Kong from 1998 to 2011, air pollutant concentrations were estimated by land use regression and assigned to the residential addresses of all participants at baseline and for each year during a 11 year follow up period. Hazard ratios (HRs) of cause-specific mortality (including all natural cause, cardiovascular and respiratory mortality) associated with air pollutants were estimated with Cox models, including a number of personal and area-level socioeconomic, demographic, and lifestyle factors. The median concentration of PM2.5 during the baseline period was 42.2 μg/m3 with an IQR of 5.5 μg/m3, 12.1 (9.6) μg/m3 for BC and 104 (25.6) μg/m3 for NO2. For PM2.5, adjusted HR per IQR increase and per 10 μg/m3 for natural cause mortality was 1.03 (95%CI: 1.01, 1.06) and 1.06 (95%CI: 1.02, 1.11) respectively. The corresponding HR were 1.06 (95%CI: 1.02, 1.10) and 1.01 (95%CI: 0.96, 1.06) for cardiovascular disease and respiratory disease mortality, respectively. For BC, the HR of an interquartile range increase for all natural cause mortality was 1.03 (95%CI: 1.00, 1.05). The corresponding HR was 1.07 (95%CI: 1.03, 1.11) and 0.99 (95%CI: 0.94, 1.04) for cardiovascular disease and respiratory disease mortality. For NO2, almost all HRs were approximately 1.0, except for IHD (ischemic heart disease) mortality. Long-term exposure to ambient PM2.5 and BC was associated with an elevated risk of cardiovascular mortality. Despite far higher air pollution exposure concentrations, HRs per unit increase in PM2.5 were similar to those from recent comparable studies in North America.


MMP and TIMP expression in quiescent, dividing, and differentiating human lens cells.
Matrix metalloproteinases (MMPs) and the tissue inhibitors of the MMPs (TIMPs) have been implicated in lens differentiation, growth, remodeling, and cataract. Hence, a gene expression analysis was undertaken in epithelial and fiber cells dissected from clear human donor lenses. The human lens was dissected into three regions: anterior epithelial, equatorial, and fiber cells. Primary lens cell cultures were also analyzed. cDNA was generated by reverse transcription of the mRNA portion of the total RNA isolated from each sample. Gene expression data were generated using quantitative real-time reverse transcription PCR. Data were analyzed in terms of cycle threshold number (C(T)) and were normalized to endogenous 18S expression. Western blot analyses were carried out to confirm the presence of two critical MMPs. Anterior and equatorial samples were uncontaminated by fiber cells because they showed high expression of alpha-crystallin genes but low expression of beta- and gamma-crystallins. The fibers had high expression of these genes and of MIP. MMP genes were expressed at uniformly low levels in the native tissues except for MMP-14 and -15 (MT1- and MT2-MMP, respectively). In fact, MT1-MMP declined in expression from the anterior epithelium to fibers, whereas MT2-MMP increased. The presence of MT1 and MT2-MMP proforms and faster migrating bands, indicating processed or activated forms, was confirmed at the protein level. TIMP genes were uniformly highly expressed in native tissues, with TIMP-3 having the highest expression in the epithelial tissues and TIMP-2 in the fibers. MMP expression was generally elevated in both sets of cultured cells, including MMP-2 and -9. TIMP genes were also relatively highly expressed in the cultured cells. MMP expression is generally well regulated in native tissues, with relatively low expression of MMPs and high expression of TIMPs. Membrane-type MMPs (MT1 and 2-MMPs) were the most highly expressed; this is important in a tissue with relatively high membrane content but low extracellular space. The striking reciprocal patterns of expression of MT1-MMP and MT2-MMP indicate that these enzymes are of particular significance in lens function.


Reduced background autofluorescence for cell imaging using nanodiamonds and lanthanide chelates.
Bio-imaging is a key technique in tracking and monitoring important biological processes and fundamental biomolecular interactions, however the interference of background autofluorescence with targeted fluorophores is problematic for many bio-imaging applications. This study reports on two novel methods for reducing interference with cellular autofluorescence for bio-imaging. The first method uses fluorescent nanodiamonds (FNDs), containing nitrogen vacancy centers. FNDs emit at near-infrared wavelengths typically higher than most cellular autofluorescence; and when appropriately functionalized, can be used for background-free imaging of targeted biomolecules. The second method uses europium-chelating tags with long fluorescence lifetimes. These europium-chelating tags enhance background-free imaging due to the short fluorescent lifetimes of cellular autofluorescence. In this study, we used both methods to target E-selectin, a transmembrane glycoprotein that is activated by inflammation, to demonstrate background-free fluorescent staining in fixed endothelial cells. Our findings indicate that both FND and Europium based staining can improve fluorescent bio-imaging capabilities by reducing competition with cellular autofluorescence. 30 nm nanodiamonds coated with the E-selectin antibody was found to enable the most sensitive detective of E-selectin in inflamed cells, with a 40-fold increase in intensity detected.


Influence of the discomfort reported by children on the performance of approximal caries detection methods.
This in vivo study aimed to evaluate the performance of methods of approximal caries detection in primary molars and to assess the influence of the discomfort caused by these methods on their performance. Two examiners evaluated 76 children (4-12 years old) using visual inspection (ICDAS), radiography and a laser fluorescence device (DIAGNOdent pen, LFpen). The reference standard was visual inspection after temporary separation with orthodontic rubbers. Surfaces were classified as sound, noncavitated (NC) or cavitated (Cav), and performance was assessed at both NC and Cav thresholds. Wong-Baker faces scale was employed to assess the discomfort. Multilevel analysis was performed to verify the influence of discomfort on performance, considering the number of false-positives and false-negatives as outcome. At NC threshold, visual inspection achieved better performance (sensitivities and accuracies around 0.67) than other methods (sensitivities around 0.25 and accuracies around 0.35). At Cav threshold, visual inspection presented lower sensitivity (0.23 and 0.19), and LFpen (0.52 and 0.42) and radiography (0.52) presented similar sensitivities. Concerning the influence of the discomfort, at NC threshold, when discomfort was present, the number of false-negative results was lower with LFpen and the number of false-positive results was higher with visual inspection. At Cav threshold, the number of false-positive results was higher with LFpen. In conclusion, radiography and LFpen achieved similar performance in detecting approximal caries lesions in primary teeth and the discomfort caused by visual inspection and LFpen can influence the performance of these methods, since a higher number of false-positive or false-negative results occurred in children who reported discomfort.


International migration of doctors, and its impact on availability of psychiatrists in low and middle income countries.
Migration of health professionals from low and middle income countries to rich countries is a large scale and long-standing phenomenon, which is detrimental to the health systems in the donor countries. We sought to explore the extent of psychiatric migration. In our study, we use the respective professional databases in each country to establish the numbers of psychiatrists currently registered in the UK, US, New Zealand, and Australia who originate from other countries. We also estimate the impact of this migration on the psychiatrist population ratios in the donor countries. We document large numbers of psychiatrists currently registered in the UK, US, New Zealand and Australia originating from India (4687 psychiatrists), Pakistan (1158), Bangladesh (149), Nigeria (384), Egypt (484), Sri Lanka (142), Philippines (1593). For some countries of origin, the numbers of psychiatrists currently registered within high-income countries' professional databases are very small (e.g., 5 psychiatrists of Tanzanian origin registered in the 4 high-income countries we studied), but this number is very significant compared to the 15 psychiatrists currently registered in Tanzania). Without such emigration, many countries would have more than double the number of psychiatrists per 100,000 population (e.g. Bangladesh, Myanmar, Afghanistan, Egypt, Syria, Lebanon); and some countries would have had five to eight times more psychiatrists per 100,000 (e.g. Philippines, Pakistan, Sri Lanka, Liberia, Nigeria and Zambia). Large numbers of psychiatrists originating from key low and middle income countries are currently registered in the UK, US, New Zealand and Australia, with concomitant impact on the psychiatrist/population ratio n the originating countries. We suggest that creative international policy approaches are needed to ensure the individual migration rights of health professionals do not compromise societal population rights to health, and that there are public and fair agreements between countries within an internationally agreed framework.


Engineering excitonic dynamics and environmental stability of post-transition metal chalcogenides by pyridine functionalization technique.
Owing to their strong photon emission, low excitonic binding energies, and nearly-ideal band offset values for water splitting reactions, direct gap quasi-2D gallium chalcogenides are potential candidates for applications in energy harvesting, optoelectronics, and photonics. Unlike other 2D materials systems, chemical functionalization of gallium chalcogenides is still at its seminal stages. Here, we propose vapor phase pyridine intercalation technique to manipulate optical properties of gallium chalcogenides. After functionalization, the excitonic dynamics of quasi-2D GaSe change significantly as evidenced by an increase in integrated PL intensity and emergence of a new emission feature that is below the band edge. Based on our DFT calculations, we attribute these to formation of bound exciton complexes at the trap sites introduced by chemical reaction between pyridine and GaSe. On the contrary, pyridine functionalization does not impact the optical properties of GaTe, instead treats GaTe surface to prevent oxidization of tellurium atoms. Overall, results suggest novel ways to control properties of gallium chalcogenides on demand and unleash their full potential for a range of applications in photonics and optoelectronics.


Haoma-Soma in the world of ancient Greece.
Evidence of the worship of (nonalcoholic) Haoma-Soma in Iran and India (identified by Wasson as Amanita muscaria) can be found in Greece and its neighboring lands. While Iranian and India peoples preserved their original worship in their final settlements, Indo-European tribes, including the Thracians, the Phrygians, and the Greeks, after settling in Europe and Asia Minor, abandoned their ancestral worship of Soma (Sabazios) and substituted the Semitic (alcoholic) Dionysos. However, they retained traces of the original Soma worship in Dionysiac rituals. This modified Dionysiac worship spread throughout the Western world. Six formal criteria are used to establish the identify of Soma with Dionysos (Sabazios): (1) both cults had the same aim (to cause ecstatic behavior); (2) both cults required the attainment of the same spiritual state (purity); (3) both cults had an idiosyncratic myth in common; (4) both cults showed the identical word root in the name of the worshipped god; (5) both cults had identical zoological and botanical associations with their god; and (6) the alcoholic god (Dionysos) was depicted as having the same physical effects on human beings as that of the ancient nonalcoholic god (Soma).


Mobile phone hygiene: potential risks posed by use in the clinics of an Indian dental school.
The objectives of this cross-sectional study were to determine the level and type of bacterial contamination of the mobile phones of dental personnel involved in direct patient care and to determine the usefulness of cleaning with 70 percent isopropyl alcohol for decontamination. Dental faculty and trainees in an Indian dental school were asked to participate in a study in which a questionnaire concerning patterns of mobile phone use and disinfection was administered. Swabs from mobile phones of the participants were taken using moist sterile swabs and plated on blood agar plates. The bacteria isolated were identified by biochemical tests. Eighteen percent of the participants (n=9) reported using their phones while attending patients. Nearly 64 percent (n=32) used their mobiles for checking time, and 64 percent (n=42) reported never cleaning their phones. In total, fifty mobile phones were cultured for microorganisms: 98 percent (n=49) were culture-positive, and 34 percent (n=17) grew potentially pathogenic bacteria. There was significant reduction in the mean number of colony-forming units after decontamination with alcohol (p<0.001). The bacterial load was reduced by around 87 percent. The results of this study show that mobile phones may act as an important source of nosocomial pathogens in the dental setting. Therefore, it is important for dental school administrators to encourage higher compliance with hand-washing practices and routine surface disinfection through framing of strict protocols to reduce the chances of occurrence of nosocomial infections.


Mms2-Ubc13 covalently bound to ubiquitin reveals the structural basis of linkage-specific polyubiquitin chain formation.
Lys63-linked polyubiquitin chains participate in nonproteolytic signaling pathways, including regulation of DNA damage tolerance and NF-kappaB activation. E2 enzymes bound to ubiquitin E2 variants (UEV) are vital in these pathways, synthesizing Lys63-linked polyubiquitin chains, but how these complexes achieve specificity for a particular lysine linkage has been unclear. We have determined the crystal structure of an Mms2-Ubc13-ubiquitin (UEV-E2-Ub) covalent intermediate with donor ubiquitin linked to the active site residue of Ubc13. In the structure, the unexpected binding of a donor ubiquitin of one Mms2-Ubc13-Ub complex to the acceptor-binding site of Mms2-Ubc13 in an adjacent complex allows us to visualize at atomic resolution the molecular determinants of acceptor-ubiquitin binding. The structure reveals the key role of Mms2 in allowing selective insertion of Lys63 into the Ubc13 active site and suggests a molecular model for polyubiquitin chain elongation.


Arsenic(V) reduction in relation to Iron(III) transformation and molecular characterization of the structural and functional microbial community in sediments of a basin-fill aquifer in Northern Utah.
Basin-fill aquifers of the Southwestern United States are associated with elevated concentrations of arsenic (As) in groundwater. Many private domestic wells in the Cache Valley Basin, UT, have As concentrations in excess of the U.S. EPA drinking water limit. Thirteen sediment cores were collected from the center of the valley at the depth of the shallow groundwater and were sectioned into layers based on redoxmorphic features. Three of the layers, two from redox transition zones and one from a depletion zone, were used to establish microcosms. Microcosms were treated with groundwater (GW) or groundwater plus glucose (GW+G) to investigate the extent of As reduction in relation to iron (Fe) transformation and characterize the microbial community structure and function by sequencing 16S rRNA and arsenate dissimilatory reductase (arrA) genes. Under the carbon-limited conditions of the GW treatment, As reduction was independent of Fe reduction, despite the abundance of sequences related to Geobacter and Shewanella, genera that include a variety of dissimilatory iron-reducing bacteria. The addition of glucose, an electron donor and carbon source, caused substantial shifts toward domination of the bacterial community by Clostridium-related organisms, and As reduction was correlated with Fe reduction for the sediments from the redox transition zone. The arrA gene sequencing from microcosms at day 54 of incubation showed the presence of 14 unique phylotypes, none of which were related to any previously described arrA gene sequence, suggesting a unique community of dissimilatory arsenate-respiring bacteria in the Cache Valley Basin.


Characterisation of persons with lower limb amputation who attended a tertiary rehabilitation centre in Bangladesh.
Objective: We aimed to describe the causes, types, and consequences of lower limb amputation and the demographics of subjects with such amputation who attended a tertiary rehabilitation center in Bangladesh, Centre for the Rehabilitation of the Paralysed.Methods: Cross-sectional data were collected from subjects with lower limb amputation who attended a specialized rehabilitation center between January 2014 and August 2016. Telephone interviews were conducted using a structured questionnaire. Descriptive analysis, paired t-test, and Fisher's exact test were conducted as well as a regression analysis was performed.Results: A total of 332 respondents, aged 5 to 76 years (mean 37.5± SD 13.8), with lower limb amputation participated in the study. Of the respondents, the majority were male (87.7%) and lived in rural areas (64.8%). Road traffic accidents were the leading cause (58.7%) of amputation followed by peripheral vascular diseases (7.5%) and hit by sharp objects (7.2%). Age (odds ratio: 0.9) and driving as occupation (odds ratio: 7.3) were found to be statistically significant covariates for amputation from road traffic accidents. The mean duration between having an amputation and receiving the first prosthetic fitting was 6.4 years (±8.9). Among the study participants, 30.7% lost their jobs after amputation and their mean monthly income reduced significantly (p < 0.01) from US$119.9 (±421.5) to US$45.8 (±63.1).Conclusion: Majority of the lower limb amputations resulted from traumatic road traffic accidents. Younger males and drivers were found to be more prone to amputation from road traffic accidents. Lower limb amputation creates great health and economic disparity in the amputee's lives.Implications for rehabilitationMajority of the lower limb amputation cases in Bangladesh were attributable to road traffic accidents-a largely preventable cause.The mean time between amputation and prosthetic fitting was more than 6 years which implies lack of awareness and inaccessibility of prosthetic management.Policymakers, regulators, law enforcement, and traffic safety advocates should take urgent actions to prevent road traffic accidents and raise awareness about and improve availability of prosthetic rehabilitation in Bangladesh.


Hydrophobicity and polymer compatibility of POSS-modified Wyoming Na-montmorillonite for developing polymer-clay nanocomposites.
The aim of the present work was to investigate the hydrophobicity and polymer compatibility of aminopropylisooctyl polyhedral oligomeric silsequioxane (POSS) - modified Na-montmorillonite (Na-MMT) towards developing polymer-clay nanocomposites. The effect of different concentrations of POSS on properties of Na-MMT was studied. The intercalation ability of the POSS molecules into the Na-MMT interlayer was analyzed by X-ray diffraction. It was found that the d001 value was increased with increasing the POSS concentration, indicating the successful intercalation of the POSS molecules into the Na-MMT interlayer. The d001 value was 4.12nm at 0.4 cation exchange capacity (CEC) loading of POSS, increased at a slight rate upon further increase of CEC loading, and finally reached 4.25nm at 1.0 CEC loading of POSS. The results of the thermogravimetric (TGA) analysis confirmed the high thermal stability of the POSS-MMT. The thermal stability was defined as a 5% mass loss (T5) at 0.2 CEC loading of POSS was observed at 352°C and slightly decreased with further increase in the POSS concentration. The porous properties, such as specific surface area (SSA), pore volume, and pore size were estimated by the adsorption of N2 molecules on the Na-MMT surface. The SSA and pore volume were reduced with increasing the concentration of the POSS molecules due to the adsorption of the POSS molecules on the Na-MMT, while the pore size was increased upon the formation of macroporous structure. The interfacial interaction energy between water and POSS-MMT (ΔGClay/Water/ClayIF) was used to evaluate the surface hydrophobicity, and a similar approach was also applied to assess the polymer compatibility of the developed composite. The obtained results confirm that the polymer compatibility of POSS-MMT prepared in this study is better than that of commonly used HDTMA-MMT.


Perioperative aspirin and clonidine and risk of acute kidney injury: a randomized clinical trial.
Acute kidney injury, a common complication of surgery, is associated with poor outcomes and high health care costs. Some studies suggest aspirin or clonidine administered during the perioperative period reduces the risk of acute kidney injury; however, these effects are uncertain and each intervention has the potential for harm. To determine whether aspirin compared with placebo, and clonidine compared with placebo, alters the risk of perioperative acute kidney injury. A 2 × 2 factorial randomized, blinded, clinical trial of 6905 patients undergoing noncardiac surgery from 88 centers in 22 countries with consecutive patients enrolled between January 2011 and December 2013. Patients were assigned to take aspirin (200 mg) or placebo 2 to 4 hours before surgery and then aspirin (100 mg) or placebo daily up to 30 days after surgery, and were assigned to take oral clonidine (0.2 mg) or placebo 2 to 4 hours before surgery, and then a transdermal clonidine patch (which provided clonidine at 0.2 mg/d) or placebo patch that remained until 72 hours after surgery. Acute kidney injury was primarily defined as an increase in serum creatinine concentration from the preoperative concentration by either an increase of 0.3 mg/dL or greater (≥26.5 μmol/L) within 48 hours of surgery or an increase of 50% or greater within 7 days of surgery. Aspirin (n = 3443) vs placebo (n = 3462) did not alter the risk of acute kidney injury (13.4% vs 12.3%, respectively; adjusted relative risk, 1.10; 95% CI, 0.96-1.25). Clonidine (n = 3453) vs placebo (n = 3452) did not alter the risk of acute kidney injury (13.0% vs 12.7%, respectively; adjusted relative risk, 1.03; 95% CI, 0.90-1.18). Aspirin increased the risk of major bleeding. In a post hoc analysis, major bleeding was associated with a greater risk of subsequent acute kidney injury (23.3% when bleeding was present vs 12.3% when bleeding was absent; adjusted hazard ratio, 2.20; 95% CI, 1.72-2.83). Similarly, clonidine increased the risk of clinically important hypotension. In a post hoc analysis, clinically important hypotension was associated with a greater risk of subsequent acute kidney injury (14.3% when hypotension was present vs 11.8% when hypotension was absent; adjusted hazard ratio, 1.34; 95% CI, 1.14-1.58). Among patients undergoing major noncardiac surgery, neither aspirin nor clonidine administered perioperatively reduced the risk of acute kidney injury. clinicaltrials.gov Identifier: NCT01082874.


Image reduction using means on discrete product lattices.
We investigate the problem of averaging values on lattices and, in particular, on discrete product lattices. This problem arises in image processing when several color values given in RGB, HSL, or another coding scheme need to be combined. We show how the arithmetic mean and the median can be constructed by minimizing appropriate penalties, and we discuss which of them coincide with the Cartesian product of the standard mean and the median. We apply these functions in image processing. We present three algorithms for color image reduction based on minimizing penalty functions on discrete product lattices.


The interaction of the molecular chaperone alpha-crystallin with unfolding alpha-lactalbumin: a structural and kinetic spectroscopic study.
The unfolding of the apo and holo forms of bovine alpha-lactalbumin (alpha-LA) upon reduction by dithiothreitol (DTT) in the presence of the small heat-shock protein alpha-crystallin, a molecular chaperone, has been monitored by visible and UV absorption spectroscopy, mass spectrometry and (1)H NMR spectroscopy. From these data, a description and a time-course of the events that result from the unfolding of both forms of the protein, and the state of the protein that interacts with alpha-crystallin, have been obtained. alpha-LA contains four disulphide bonds and binds a calcium ion. In apo alpha-LA, the disulphide bonds are reduced completely over a period of approximately 1500 seconds. Fully reduced alpha-LA adopts a partly folded, molten globule conformation that aggregates and, ultimately, precipitates. In the presence of an equivalent mass of alpha-crystallin, this precipitation can be prevented via complexation with the chaperone. alpha-Crystallin does not interfere with the kinetics of the reduction of disulphide bonds in apo alpha-LA but does stabilise the molten globule state. In holo alpha-LA, the disulphide bonds are less accessible to DTT, because of the stabilisation of the protein by the bound calcium ion, and reduction occurs much more slowly. A two-disulphide intermediate aggregates and precipitates rapidly. Its precipitation can be prevented only in the presence of a 12-fold mass excess of alpha-crystallin. It is concluded that kinetic factors are important in determining the efficiency of the chaperone action of alpha-crystallin. It interacts efficiently with slowly aggregating, highly disordered intermediate (molten globule) states of alpha-LA. Real-time NMR spectroscopy shows that the kinetics of the refolding of apo alpha-LA following dilution from denaturant are not affected by the presence of alpha-crystallin. Thus, alpha-crystallin is not a chaperone that is involved in protein folding per se. Rather, its role is to stabilise compromised, partly folded, molten globule states of proteins that are destined for precipitation.


The German adaptation of the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR).
Individuals with precapillary pulmonary hypertension (PH) experience severely impaired quality of life. A disease-specific outcome measure for PH, the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) was developed and validated in the UK and subsequently adapted for use in additional countries. The aim of this study was to translate and assess the reliability and validity of the CAMPHOR for German-speaking populations. Three main adaptation stages involved; translation (employing bilingual and lay panels), cognitive debriefing interviews with patients and validation (assessment of the adaptation's psychometric properties). The psychometric evaluation included 107 patients with precapillary PH (60 females; age mean (standard deviation) 60 (15) years) from 3 centres in Austria, Germany and Switzerland. No major problems were found with the translation process with most items easily rendered into acceptable German. Participants in the cognitive debriefing interviews found the questionnaires relevant, comprehensive and easy to complete. Psychometric analyses showed that the adaptation was successful. The three CAMPHOR scales (symptoms, activity limitations and quality of life) had excellent test-retest reliability correlations (Symptoms = 0.91; Activity limitations = 0.91; QoL = 0.90) and internal consistency (Symptoms = 0.94; Activity limitations = 0.93; QoL = 0.94). Predicted correlations with the Nottingham Health Profile provided evidence of the construct validity of the CAMPHOR scales. The CAMPHOR adaptation also showed known group validity in its ability to distinguish between participants based on perceived general health, perceived disease severity, oxygen use and NYHA classification. The CAMPHOR has been shown to be valid and reliable in the German population and is recommend for use in clinical practice.


Development of a mnemonic screening tool for identifying subjects with Hunter syndrome.
The Hunter Outcome Survey (HOS), an international, long-term observational registry of patients with Hunter syndrome, was used to develop a simple mnemonic screening tool (HUNTER) to aid in the diagnosis of Hunter syndrome. Data regarding the prediagnosis prevalence of ten specific signs and symptoms present in individual patients enrolled in the HOS were used to develop the HUNTER mnemonic screening tool. A total score of 6 or greater using a weighting scheme in which certain manifestations were assigned a weight of 2 (facial dysmorphism, nasal obstruction or rhinorrhea, enlarged tongue, enlarged liver, enlarged spleen, joint stiffness) and others assigned a weight of 1 (hernia, hearing impairment, enlarged tonsils, airway obstruction or sleep apnea) correctly identified 95 % of patients who had no family history of Hunter syndrome or who were not diagnosed prenatally. No association between age at diagnosis and HUNTER score was found. The HUNTER mnemonic appears to be a useful screening tool. Further validation in the clinical setting will be necessary to confirm its utility.


Application of unmanned aerial systems for high throughput phenotyping of large wheat breeding nurseries.
Low cost unmanned aerial systems (UAS) have great potential for rapid proximal measurements of plants in agriculture. In the context of plant breeding and genetics, current approaches for phenotyping a large number of breeding lines under field conditions require substantial investments in time, cost, and labor. For field-based high-throughput phenotyping (HTP), UAS platforms can provide high-resolution measurements for small plot research, while enabling the rapid assessment of tens-of-thousands of field plots. The objective of this study was to complete a baseline assessment of the utility of UAS in assessment field trials as commonly implemented in wheat breeding programs. We developed a semi-automated image-processing pipeline to extract plot level data from UAS imagery. The image dataset was processed using a photogrammetric pipeline based on image orientation and radiometric calibration to produce orthomosaic images. We also examined the relationships between vegetation indices (VIs) extracted from high spatial resolution multispectral imagery collected with two different UAS systems (eBee Ag carrying MultiSpec 4C camera, and IRIS+ quadcopter carrying modified NIR Canon S100) and ground truth spectral data from hand-held spectroradiometer. We found good correlation between the VIs obtained from UAS platforms and ground-truth measurements and observed high broad-sense heritability for VIs. We determined radiometric calibration methods developed for satellite imagery significantly improved the precision of VIs from the UAS. We observed VIs extracted from calibrated images of Canon S100 had a significantly higher correlation to the spectroradiometer (r = 0.76) than VIs from the MultiSpec 4C camera (r = 0.64). Their correlation to spectroradiometer readings was as high as or higher than repeated measurements with the spectroradiometer per se. The approaches described here for UAS imaging and extraction of proximal sensing data enable collection of HTP measurements on the scale and with the precision needed for powerful selection tools in plant breeding. Low-cost UAS platforms have great potential for use as a selection tool in plant breeding programs. In the scope of tools development, the pipeline developed in this study can be effectively employed for other UAS and also other crops planted in breeding nurseries.


Genetic Analysis Using a Multi-Parent Wheat Population Identifies Novel Sources of Septoria Tritici Blotch Resistance.
Zymoseptoria tritici is the causative fungal pathogen of septoria tritici blotch (STB) disease of wheat (Triticum aestivum L.) that continuously threatens wheat crops in Ireland and throughout Europe. Under favorable conditions, STB can cause up to 50% yield losses if left untreated. STB is commonly controlled with fungicides; however, a combination of Z. tritici populations developing fungicide resistance and increased restrictions on fungicide use in the EU has led to farmers relying on fewer active substances. Consequently, this serves to drive the emergence of Z. tritici resistance against the remaining chemistries. In response, the use of resistant wheat varieties provides a more sustainable disease management strategy. However, the number of varieties offering an adequate level of resistance against STB is limited. Therefore, new sources of resistance or improved stacking of existing resistance loci are needed to develop varieties with superior agronomic performance. Here, we identified quantitative trait loci (QTL) for STB resistance in the eight-founder "NIAB Elite MAGIC" winter wheat population. The population was screened for STB response in the field under natural infection for three seasons from 2016 to 2018. Twenty-five QTL associated with STB resistance were identified in total. QTL either co-located with previously reported QTL or represent new loci underpinning STB resistance. The genomic regions identified and the linked genetic markers serve as useful resources for STB resistance breeding, supporting rapid selection of favorable alleles for the breeding of new wheat cultivars with improved STB resistance.


Venus looks different from day to night across wavelengths: morphology from Akatsuki multispectral images.
Since insertion into orbit on December 7, 2015, the Akatsuki orbiter has returned global images of Venus from its four imaging cameras at eleven discrete wavelengths from ultraviolet (283 and 365 nm) and near infrared (0.9-2.3 µm), to the thermal infrared (8-12 µm) from a near-equatorial orbit. The Venus Express and Pioneer Venus Orbiter missions have also monitored the planet for long periods but from polar or near-polar orbits. The wavelength coverage and views of the planet also differ for all three missions. In reflected light, the images reveal features seen near the cloud tops (~ 70 km altitude), whereas in the near-infrared images of the nightside, features seen are at mid- to lower cloud levels (~ 48-60 km altitude). The dayside cloud cover imaged at the ultraviolet wavelengths shows morphologies similar to what was observed from Mariner 10, Pioneer Venus, Galileo, Venus Express and MESSENGER. The daytime images at 0.9 and 2.02 µm also reveal some interesting features which bear similarity to the ultraviolet images. The nighttime images at 1.74, 2.26 and 2.32 µm and at 8-12 µm reveal features not seen before and show new details of the nightside including narrow wavy ribbons, curved string-like features, long-scale waves, long dark streaks, isolated bright spots, sharp boundaries and even mesoscale vortices. Some features previously seen such as circum-equatorial belts (CEBs) and occasional areal brightenings at ultraviolet (seen in Venus Express observations) of the cloud cover at ultraviolet wavelengths have not been observed thus far. Evidence for the hemispheric vortex organization of the global circulation can be seen at all wavelengths on the day- and nightsides. Akatsuki images reveal new and puzzling morphology of the complex nightside cloud cover. The cloud morphologies provide some clues to the processes occurring in the atmosphere and are thus, a key diagnostic tool when quantitative dynamical analysis is not feasible due to insufficient information.


Yoga might be an alternative training for the quality of life and balance in postmenopausal osteoporosis.
Osteoporotic vertebra and hip fractures are major causes of dysfunction, disability, mortality and impaired life quality in the ageing population. In the postmenopausal period, exercises prevent rapid bone loss and increase muscle strength, mobility and flexibility thereby decreasing the risk of falls and fractures. Yoga exercises, which have been an inseparable part of Eastern culture for hundreds of years, are now being used in the field of osteoporosis rehabilitation. Yoga has a positive effect on balance, posture, flexibility, and life quality resulting from its effects on balance, stretching, relaxation and strengthening. The aim of this study was to evaluate the effect of yoga exercises in postmenopausal osteoporotic women on balance and life quality and to compare the results with a classic osteoporosis exercise program. Twenty-six postmenopausal osteoporotic women over 55 years of age were included in the study. A neuromuscular test battery and the QUALEFFO as a life quality index were used for the assessment of balance and life quality, respectively. The results showed that yoga education has a positive effect on pain, physical functions, social functions, general In conclusion, yoga appears to be an alternative physical activity for the rehabilitation of osteoporotic subjects.


Studying the time trend of Methicillin-resistant Staphylococcus aureus (MRSA) in Norway by use of non-stationary γ-Poisson distributions.
Study the time development of methicillin-resistant Staphylococcus aureus (MRSA) and forecast future behaviour. The major question: Is the number of MRSA isolates in Norway increasing and will it continue to increase? Time trend analysis using non-stationary γ-Poisson distributions. Two data sets were analysed. The first data set (data set I) consists of all MRSA isolates collected in Oslo County from 1997 to 2010; the study area includes the Norwegian capital of Oslo and nearby surrounding areas, covering approximately 11% of the Norwegian population. The second data set (data set II) consists of all MRSA isolates collected in Health Region East from 2002 to 2011. Health Region East consists of Oslo County and four neighbouring counties, and is the most populated area of Norway. Both data sets I and II consist of all persons in the area and time period described in the Settings, from whom MRSA have been isolated. MRSA infections have been mandatory notifiable in Norway since 1995, and MRSA colonisation since 2004. In the time period studied, all bacterial samples in Norway have been sent to a medical microbiological laboratory at the regional hospital for testing. In collaboration with the regional hospitals in five counties, we have collected all MRSA findings in the South-Eastern part of Norway over long time periods. On an average, a linear or exponential increase in MRSA numbers was observed in the data sets. A Poisson process with increasing intensity did not capture the dispersion of the time series, but a γ-Poisson process showed good agreement and captured the overdispersion. The numerical model showed numerical internal consistency. In the present study, we find that the number of MRSA isolates is increasing in the most populated area of Norway during the time period studied. We also forecast a continuous increase until the year 2017.


Digitally enabled aged care and neurological rehabilitation to enhance outcomes with Activity and MObility UsiNg Technology (AMOUNT) in Australia: A randomised controlled trial.
Digitally enabled rehabilitation may lead to better outcomes but has not been tested in large pragmatic trials. We aimed to evaluate a tailored prescription of affordable digital devices in addition to usual care for people with mobility limitations admitted to aged care and neurological rehabilitation. We conducted a pragmatic, outcome-assessor-blinded, parallel-group randomised trial in 3 Australian hospitals in Sydney and Adelaide recruiting adults 18 to 101 years old with mobility limitations undertaking aged care and neurological inpatient rehabilitation. Both the intervention and control groups received usual multidisciplinary inpatient and post-hospital rehabilitation care as determined by the treating rehabilitation clinicians. In addition to usual care, the intervention group used devices to target mobility and physical activity problems, individually prescribed by a physiotherapist according to an intervention protocol, including virtual reality video games, activity monitors, and handheld computer devices for 6 months in hospital and at home. Co-primary outcomes were mobility (performance-based Short Physical Performance Battery [SPPB]; continuous version; range 0 to 3; higher score indicates better mobility) and upright time as a proxy measure of physical activity (proportion of the day upright measured with activPAL) at 6 months. The dataset was analysed using intention-to-treat principles. The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000936628). Between 22 September 2014 and 10 November 2016, 300 patients (mean age 74 years, SD 14; 50% female; 54% neurological condition causing activity limitation) were randomly assigned to intervention (n = 149) or control (n = 151) using a secure online database (REDCap) to achieve allocation concealment. Six-month assessments were completed by 258 participants (129 intervention, 129 control). Intervention participants received on average 12 (SD 11) supervised inpatient sessions using 4 (SD 1) different devices and 15 (SD 5) physiotherapy contacts supporting device use after hospital discharge. Changes in mobility scores were higher in the intervention group compared to the control group from baseline (SPPB [continuous, 0-3] mean [SD]: intervention group, 1.5 [0.7]; control group, 1.5 [0.8]) to 6 months (SPPB [continuous, 0-3] mean [SD]: intervention group, 2.3 [0.6]; control group, 2.1 [0.8]; mean between-group difference 0.2 points, 95% CI 0.1 to 0.3; p = 0.006). However, there was no evidence of a difference between groups for upright time at 6 months (mean [SD] proportion of the day spent upright at 6 months: intervention group, 18.2 [9.8]; control group, 18.4 [10.2]; mean between-group difference -0.2, 95% CI -2.7 to 2.3; p = 0.87). Scores were higher in the intervention group compared to the control group across most secondary mobility outcomes, but there was no evidence of a difference between groups for most other secondary outcomes including self-reported balance confidence and quality of life. No adverse events were reported in the intervention group. Thirteen participants died while in the trial (intervention group: 9; control group: 4) due to unrelated causes, and there was no evidence of a difference between groups in fall rates (unadjusted incidence rate ratio 1.19, 95% CI 0.78 to 1.83; p = 0.43). Study limitations include 15%-19% loss to follow-up at 6 months on the co-primary outcomes, as anticipated; the number of secondary outcome measures in our trial, which may increase the risk of a type I error; and potential low statistical power to demonstrate significant between-group differences on important secondary patient-reported outcomes. In this study, we observed improved mobility in people with a wide range of health conditions making use of digitally enabled rehabilitation, whereas time spent upright was not impacted. The trial was prospectively registered with the Australian New Zealand Clinical Trials Register; ACTRN12614000936628.


Optimisation of follow-up after metabolic surgery.
Bariatric surgery has many benefits beyond weight loss, including improved control of glycaemia, blood pressure, and dyslipidaemia; hence, such surgery has been rebranded as metabolic surgery. The operations are, unfortunately, also associated with major surgical and medical complications. The medical complications include gastro-oesophageal reflux disease, malnutrition, and metabolic complications deriving from vitamin and mineral malabsorption. The benefits of surgery can be optimised by implementing specific protocols before and after surgery. In this Review, we discuss the assessment of the risk of major cardiac complications and severe obstructive sleep apnoea before surgery, and the provision of adequate lifelong postsurgery nutritional, vitamin, and mineral supplementation to reduce complications. Additionally, we examine the best antidiabetic medications to reduce the risk of hypoglycaemia after gastric bypass and sleeve gastrectomy, and the strategies to improve weight loss or reduce weight regain. Although optimising clinical pathways is possible to maximise metabolic benefits and reduce the risks of complications and micronutrient deficiencies, evolution of these strategies can further improve the risk-to-benefit ratio of metabolic surgery.