Resting functional connectivity reveals residual functional activity in Alzheimer's disease.
Functional magnetic resonance imaging (fMRI) has great potential for measuring mechanisms of functional changes in Alzheimer's disease (AD) and mild cognitive impairment, but task fMRI studies have produced conflicting results, partly due to failure to account for underlying morphological changes and to variations in patients' ability to perform the tasks. Resting fMRI has potential for assessing brain function independently from a task, but greater understanding of how networks of resting functional connectivity relate to the functioning of the brain is needed. We combined resting fMRI and task fMRI to examine the correspondence between these methods in individuals with cognitive impairment. Eighty elderly (25 control subjects, 25 mild cognitive impairment, 30 AD) underwent a combined multimodal magnetic resonance imaging protocol including task fMRI and resting fMRI. Task fMRI data were acquired during the execution of a memory paradigm designed to account for differences in task performance. Structural and physiological confounds were modeled for both fMRI modalities. Successful recognition was associated with increased task fMRI activation in lateral prefrontal regions in AD relative to control subjects; this overlapped with increased resting fMRI functional connectivity in the same regions. Our results show that task fMRI and resting fMRI are sensitive markers of residual ability over the known changes in brain morphology and cognition occurring in AD and suggest that resting fMRI has a potential to measure the effect of new treatments.


Modeling initiation of Ewing sarcoma in human neural crest cells.
Ewing sarcoma family tumors (ESFT) are aggressive bone and soft tissue tumors that express EWS-ETS fusion genes as driver mutations. Although the histogenesis of ESFT is controversial, mesenchymal (MSC) and/or neural crest (NCSC) stem cells have been implicated as cells of origin. For the current study we evaluated the consequences of EWS-FLI1 expression in human embryonic stem cell-derived NCSC (hNCSC). Ectopic expression of EWS-FLI1 in undifferentiated hNCSC and their neuro-mesenchymal stem cell (hNC-MSC) progeny was readily tolerated and led to altered expression of both well established as well as novel EWS-FLI1 target genes. Importantly, whole genome expression profiling studies revealed that the molecular signature of established ESFT is more similar to hNCSC than any other normal tissue, including MSC, indicating that maintenance or reactivation of the NCSC program is a feature of ESFT pathogenesis. Consistent with this hypothesis, EWS-FLI1 induced hNCSC genes as well as the polycomb proteins BMI-1 and EZH2 in hNC-MSC. In addition, up-regulation of BMI-1 was associated with avoidance of cellular senescence and reversible silencing of p16. Together these studies confirm that, unlike terminally differentiated cells but consistent with bone marrow-derived MSC, NCSC tolerate expression of EWS-FLI1 and ectopic expression of the oncogene initiates transition to an ESFT-like state. In addition, to our knowledge this is the first demonstration that EWS-FLI1-mediated induction of BMI-1 and epigenetic silencing of p16 might be critical early initiating events in ESFT tumorigenesis.


Crystal structure of Porphyromonas gingivalis peptidylarginine deiminase: implications for autoimmunity in rheumatoid arthritis.
Periodontitis (PD) is a known risk factor for rheumatoid arthritis (RA) and there is increasing evidence that the link between the two diseases is due to citrullination by the unique bacterial peptidylarginine deiminase (PAD) enzyme expressed by periodontal pathogen Pophyromonas gingivalis (PPAD). However, the precise mechanism by which PPAD could generate potentially immunogenic peptides has remained controversial due to lack of information about the structural and catalytic mechanisms of the enzyme. By solving the 3D structure of PPAD we aim to characterise activity and elucidate potential mechanisms involved in breach of tolerance to citrullinated proteins in RA. PPAD and a catalytically inactive mutant PPAD(C351A) were crystallised and their 3D structures solved. Key residues identified from 3D structures were examined by mutations. Fibrinogen and α-enolase were incubated with PPAD and P. gingivalis arginine gingipain (RgpB) and citrullinated peptides formed were sequenced and quantified by mass spectrometry. Here, we solve the crystal structure of a truncated, highly active form of PPAD. We confirm catalysis is mediated by the following residues: Asp130, His236, Asp238, Asn297 and Cys351 and show Arg152 and Arg154 may determine the substrate specificity of PPAD for C-terminal arginines. We demonstrate the formation of 37 C-terminally citrullinated peptides from fibrinogen and 11 from α-enolase following incubation with tPPAD and RgpB. PPAD displays an unequivocal specificity for C-terminal arginine residues and readily citrullinates peptides from key RA autoantigens. The formation of these novel citrullinated peptides may be involved in breach of tolerance to citrullinated proteins in RA.


Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
Traumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognised as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. We aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016, and to estimate the proportion of TBI and SCI cases caused by different types of injury. We used results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 to measure the global, regional, and national burden of TBI and SCI by age and sex. We measured the incidence and prevalence of all causes of injury requiring medical care in inpatient and outpatient records, literature studies, and survey data. By use of clinical record data, we estimated the proportion of each cause of injury that required medical care that would result in TBI or SCI being considered as the nature of injury. We used literature studies to establish standardised mortality ratios and applied differential equations to convert incidence to prevalence of long-term disability. Finally, we applied GBD disability weights to calculate YLDs. We used a Bayesian meta-regression tool for epidemiological modelling, used cause-specific mortality rates for non-fatal estimation, and adjusted our results for disability experienced with comorbid conditions. We also analysed results on the basis of the Socio-demographic Index, a compound measure of income per capita, education, and fertility. In 2016, there were 27·08 million (95% uncertainty interval [UI] 24·30-30·30 million) new cases of TBI and 0·93 million (0·78-1·16 million) new cases of SCI, with age-standardised incidence rates of 369 (331-412) per 100 000 population for TBI and 13 (11-16) per 100 000 for SCI. In 2016, the number of prevalent cases of TBI was 55·50 million (53·40-57·62 million) and of SCI was 27·04 million (24·98-30·15 million). From 1990 to 2016, the age-standardised prevalence of TBI increased by 8·4% (95% UI 7·7 to 9·2), whereas that of SCI did not change significantly (-0·2% [-2·1 to 2·7]). Age-standardised incidence rates increased by 3·6% (1·8 to 5·5) for TBI, but did not change significantly for SCI (-3·6% [-7·4 to 4·0]). TBI caused 8·1 million (95% UI 6·0-10·4 million) YLDs and SCI caused 9·5 million (6·7-12·4 million) YLDs in 2016, corresponding to age-standardised rates of 111 (82-141) per 100 000 for TBI and 130 (90-170) per 100 000 for SCI. Falls and road injuries were the leading causes of new cases of TBI and SCI in most regions. TBI and SCI constitute a considerable portion of the global injury burden and are caused primarily by falls and road injuries. The increase in incidence of TBI over time might continue in view of increases in population density, population ageing, and increasing use of motor vehicles, motorcycles, and bicycles. The number of individuals living with SCI is expected to increase in view of population growth, which is concerning because of the specialised care that people with SCI can require. Our study was limited by data sparsity in some regions, and it will be important to invest greater resources in collection of data for TBI and SCI to improve the accuracy of future assessments. Bill & Melinda Gates Foundation.


Single-molecule dissection of the high-affinity cohesin-dockerin complex.
Cellulose-degrading enzyme systems are of significant interest from both a scientific and technological perspective due to the diversity of cellulase families, their unique assembly and substrate binding mechanisms, and their potential applications in several key industrial sectors, notably cellulose hydrolysis for second-generation biofuel production. Particularly fascinating are cellulosomes, the multimodular extracellular complexes produced by numerous anaerobic bacteria. Using single-molecule force spectroscopy, we analyzed the mechanical stability of the intermolecular interfaces between the cohesin and the dockerin modules responsible for self-assembly of the cellulosomal components into the multienzyme complex. The observed cohesin-dockerin rupture forces (>120 pN) are among the highest reported for a receptor-ligand system to date. Using an atomic force microscope protocol that quantified single-molecule binding activity, we observed force-induced dissociation of calcium ions from the duplicated loop-helix F-hand motif located within the dockerin module, which in the presence of EDTA resulted in loss of affinity to the cohesin partner. A cohesin amino acid mutation (D39A) that eliminated hydrogen bonding with the dockerin's critically conserved serine residues reduced the observed rupture forces. Consequently, no calcium loss occurred and dockerin activity was maintained throughout multiple forced dissociation events. These results offer insights at the single-molecule level into the stability and folding of an exquisite class of high-affinity protein-protein interactions that dictate fabrication and architecture of cellulose-degrading molecular machines.


Improved attribution of climate forcing to emissions.
Evaluating multicomponent climate change mitigation strategies requires knowledge of the diverse direct and indirect effects of emissions. Methane, ozone, and aerosols are linked through atmospheric chemistry so that emissions of a single pollutant can affect several species. We calculated atmospheric composition changes, historical radiative forcing, and forcing per unit of emission due to aerosol and tropospheric ozone precursor emissions in a coupled composition-climate model. We found that gas-aerosol interactions substantially alter the relative importance of the various emissions. In particular, methane emissions have a larger impact than that used in current carbon-trading schemes or in the Kyoto Protocol. Thus, assessments of multigas mitigation policies, as well as any separate efforts to mitigate warming from short-lived pollutants, should include gas-aerosol interactions.


The distribution of haemoglobin C and its prevalence in newborns in Africa.
Haemoglobin C (HbC) is one of the commonest structural haemoglobin variants in human populations. Although HbC causes mild clinical complications, its diagnosis and genetic counselling are important to prevent inheritance with other haemoglobinopathies. Little is known about its contemporary distribution and the number of newborns affected. We assembled a global database of population surveys. We then used a Bayesian geostatistical model to create maps of HbC frequency across Africa and paired our predictions with high-resolution demographics to calculate heterozygous (AC) and homozygous (CC) newborn estimates and their associated uncertainty. Data were too sparse outside Africa for this methodology to be applied. The highest frequencies were found in West Africa but HbC was commonly found in other parts of the continent. The expected annual numbers of AC and CC newborns in Africa were 672,117 (interquartile range (IQR): 642,116-705,163) and 28,703 (IQR: 26,027-31,958), respectively. These numbers are about two times previous estimates.


Subpopulations of human embryonic stem cells with distinct tissue-specific fates can be selected from pluripotent cultures.
Directed differentiation of human embryonic stem cells (hESCs) has generated much interest in the field of regenerative medicine. While subpopulations of hESCs within pluripotent cultures have been identified based on expression of specific surface antigens, their significance and fates are not well understood. To determine whether such subpopulations indicate specific tissue fates or represent stochastic antigen distributions within proliferating cultures, we isolated CD133(+) or CD135(+) hESCs from proliferating cultures constitutively expressing enhanced green fluorescent protein (GFP), and co-cultured these with unselected GFP(-) hESCs. After passage in culture, GFP(+) hESCs reanalyzed for the persistence of CD133 or CD135 expression, as well as other surface antigens (Tra-1-60, SSEA-4, FGFR-1), demonstrated that these two subpopulations continued to express CD133 or CD135 over serial passage, and that CD133(+) hESCs were enriched for SSEA-4 expression as well. Upon differentiation in vitro, CD133(+)GFP(+) hESCs gave rise solely to ectoderm, as detected by expression of nestin. Tissues representing endoderm (alpha-fetoprotein(+)) and mesoderm (smooth muscle actin(+)) were not seen among GFP(+) tissues. In contrast, selection against CD133 gave rise almost exclusively to mesoderm and endoderm. In contrast, CD135(+)GFP(+) hESCs gave rise to tissues representing all three embryonic germ layers, and were virtually indistinguishable from CD135(-)-derived tissues. Similar results were obtained by in vivo differentiation in teratomas. These data establish that subpopulations of proliferating hESCs whose tissue fate is predetermined exist, and challenge the notion that all cells within proliferating hESC cultures are truly "pluripotent." This co-culture approach also will enable identification of other distinct hESC subpopulations, and selection for these should prove valuable in generating tissue-specific reagents for cell-based therapy.


Learning to identify CNS drug action and efficacy using multistudy fMRI data.
The therapeutic effects of centrally acting pharmaceuticals can manifest gradually and unreliably in patients, making the drug discovery process slow and expensive. Biological markers providing early evidence for clinical efficacy could help prioritize development of the more promising drug candidates. A potential source of such markers is functional magnetic resonance imaging (fMRI), a noninvasive imaging technique that can complement molecular imaging. fMRI has been used to characterize how drugs cause changes in brain activity. However, variation in study protocols and analysis techniques has made it difficult to identify consistent associations between subtle modulations of brain activity and clinical efficacy. We present and validate a general protocol for functional imaging-based assessment of drug activity in the central nervous system. The protocol uses machine learning methods and data from multiple published studies to identify reliable associations between drug-related activity modulations and drug efficacy, which can then be used to assess new data. A proof-of-concept version of this approach was developed and is shown here for analgesics (pain medication), and validated with eight separate studies of analgesic compounds. Our results show that the systematic integration of multistudy data permits the generalized inferences required for drug discovery. Multistudy integrative strategies of this type could help optimize the drug discovery and validation pipeline.


Trends in neoadjuvant chemotherapy use and oncological outcomes for muscle-invasive bladder cancer in Japan: a multicenter study.
Despite benefits of neoadjuvant chemotherapy (NAC), the adoption of guideline recommendations for NAC use in patients with muscle-invasive bladder cancer (MIBC) has been slow. We aimed to evaluate temporal trends in NAC use and oncological outcomes in a representative cohort of patients with MIBC. We included 532 patients from 4 hospitals who underwent radical cystectomy (RC) for ≥ cT2 MIBC in 1996-2017. We retrospectively evaluated temporal changes in NAC use and progression-free and overall survival. Candidates for NAC were administered with either cisplatin- or carboplatin-based regimens. The impact of NAC on oncological outcomes was examined using multivariate Cox regression analysis with inverse probability of treatment weighting (IPTW) models. Of 532 patients, 336 underwent NAC followed by RC (NAC group) and 196 underwent RC alone (Ctrl group). NAC use significantly increased from 10% (1996-2004) to 83% (2005-2016). The number of patients administered with cisplatin- and carboplatin-based regimens was 43 and 280, respectively. Oncological outcomes in the NAC group were significantly improved compared to those in the Ctrl group. Multivariable analysis with IPTW models revealed that NAC significantly improved oncological outcomes in patients with MIBC. A nomogram for 5-year overall survival predicted 16% improvement in patients undergoing NAC. NAC use for MIBC increased after 2005. Platinum-based NAC for MIBC potentially improves oncological outcomes.


Multidisciplinary treatment and survival of patients with vertebral metastases from thyroid carcinoma.
Distant metastases from differentiated thyroid carcinoma occur in up to 20% of cases and represent the most frequent cause of thyroid cancer-related death. Metastatic disease to the spine has the potential to cause severe morbidity, including pain, neurological deficit, and paraplegia. We present a case series of eight consecutive patients with symptomatic spinal metastases due to thyroid carcinoma treated by our multidisciplinary team consisting of spinal surgeons, oncologists, and radiologists, with management of each case determined by our surgical algorithm. Four patients underwent surgical decompression and stabilization for spinal metastases causing instability, spinal cord compression, neurological deficit, or intractable pain. Three patients underwent vertebroplasty for focal mechanical pain due to osteolytic metastases in the absence of significant spinal cord compression or spinal instability; one of these patients required subsequent surgical decompression for spinal cord compression. One patient was nonoperatively treated. All patients underwent total thyroidectomy for the primary cancer and adjuvant radioiodine-131 treatment. The only patient with poorly differentiated thyroid cancer, which was refractory to radioiodine-131 died at 6 months after vertebroplasty procedures for symptomatic spinal metastases. One patient with medullary thyroid carcinoma died at 18 months after vertebroplasty. All remaining six patients who had well-differentiated papillary or follicular thyroid carcinoma were alive at an average of 50 months (range: 17-96 months) after diagnosis and treatment of symptomatic spinal metastases and were ambulant, independent, and able to perform activities of daily living and had no significant pain or neurologic symptoms. The potential for long-term survival of several years following development of spinal metastases should be considered during the counseling and decision-making process for patients with thyroid cancer.


Injecting realism in surgical training-initial simulation experience with custom 3D models.
The traditionally accepted form of training is direct supervision by an expert; however, modern trends in medicine have made this progressively more difficult to achieve. A 3-dimensional printer makes it possible to convert patients imaging data into accurate models, thus allowing the possibility to reproduce models with pathology. This enables a large number of trainees to be trained simultaneously using realistic models simulating actual neurosurgical procedures. The aim of this study was to assess the usefulness of these models in training surgeons to perform standard procedures that require complex techniques and equipment. Multiple models of the head of a patient with a deep-seated small thalamic lesion were created based on his computed tomography and magnetic resonance imaging data. A workshop was conducted using these models of the head as a teaching tool. The surgical trainees were assessed for successful performance of the procedure as well as the duration of time and number of attempts taken to learn them. All surgical candidates were able to learn the basics of the surgical procedure taught in the workshop. The number of attempts and time taken reflected the seniority and previous experience of each candidate. Surgical trainees need multiple attempts to learn essential procedures. The use of these models for surgical-training simulation allows trainees to practice these procedures repetitively in a safe environment until they can master it. This would theoretically shorten the learning curve while standardizing teaching and assessment techniques of these trainees.


The Cinderella syndrome: why do malaria-infected cells burst at midnight?
An interesting quirk of many malaria infections is that all parasites within a host - millions of them - progress through their cell cycle synchronously. This surprising coordination has long been recognized, yet there is little understanding of what controls it or why it has evolved. Interestingly, the conventional explanation for coordinated development in other parasite species does not seem to apply here. We argue that for malaria parasites, a critical question has yet to be answered: is the coordination due to parasites bursting at the same time or at a particular time? We explicitly delineate these fundamentally different scenarios, possible underlying mechanistic explanations and evolutionary drivers, and discuss the existing corroborating data and key evidence needed to solve this evolutionary mystery.


Electrophysiological studies of color processing in human visual cortex.
Electrophysiological recordings from human visual cortex were carried out with electrodes chronically implanted in 13 patients for localization of an epileptogenic focus. Visual evoked potentials (VEPs) elicited by red or blue checkerboard stimuli were recorded using an adaptation stimulus-test stimulus design in which color was the most salient feature. A "significant color effect," defined as a statistically significant effect of the adaptation stimulus on test stimulus VEPs evoked by the same or a different color, was determined for various cortical regions: medial lingual gyrus, 20%; lateral lingual gyrus, 38%; posterior fusiform gyrus, 50%; anterior fusiform gyrus, 0%; inferior temporal gyrus, 5%; occipital pole, 30%; lateral surface of non-visual cortex, 6%; inferior parietal and temporal cortex, 5%. The time course of the significant color effects suggests that wave length-selective neuronal activity occurs initially at the first stage of cortical processing in the medial lingual gyrus, followed by progressively later activation of the lateral lingual gyrus, the posterior fusiform gyrus, and the inferior temporal gyrus. In two patients, stimulation of the lateral lingual and fusiform gyri elicited color sensations in the contralateral half-field, whereas stimulation of the medial lingual and cuneate gyri evoked retinotopically appropriate quadrantic "shimmering" devoid of color. These results suggest that a region of inferior occipital cortex, primarily the posterior portion of the fusiform gyrus, is involved in color perception and may be homologous with area V4 in monkeys. There is also a region of dorsolateral surface cortex which exhibits a fairly high percentage of significant color effects and when stimulated may evoke sensations of color. This region may be the same as the dorsolateral region thought to be involved in selective attention to color.


Measuring the effects of online health information for patients: item generation for an e-health impact questionnaire.
The internet is a valuable resource for accessing health information and support. We are developing an instrument to assess the effects of websites with experiential and factual health information. This study aimed to inform an item pool for the proposed questionnaire. Items were informed through a review of relevant literature and secondary qualitative analysis of 99 narrative interviews relating to patient and carer experiences of health. Statements relating to identified themes were re-cast as questionnaire items and shown for review to an expert panel. Cognitive debrief interviews (n=21) were used to assess items for face and content validity. Eighty-two generic items were identified following secondary qualitative analysis and expert review. Cognitive interviewing confirmed the questionnaire instructions, 62 items and the response options were acceptable to patients and carers. Using a clear conceptual basis to inform item generation, 62 items have been identified as suitable to undergo further psychometric testing. The final questionnaire will initially be used in a randomized controlled trial examining the effects of online patient's experiences. This will inform recommendations on the best way to present patients' experiences within health information websites.


Multiple miscarriages are associated with the risk of ovarian cancer: results from the European Prospective Investigation into Cancer and Nutrition.
While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR(≥4vs.0): 1.74, 95% CI: 1.20-2.70; number of cases in this category: n = 23). This association was particularly evident for multiple miscarriages (HR(≥4vs.0): 1.99, 95% CI: 1.06-3.73; number of cases in this category: n = 10), with no significant association for multiple induced abortions (HR(≥4vs.0): 1.46, 95% CI: 0.68-3.14; number of cases in this category: n = 7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories.


Amygdala-prefrontal coupling underlies individual differences in emotion regulation.
Despite growing evidence on the neural bases of emotion regulation, little is known about the mechanisms underlying individual differences in cognitive regulation of negative emotion, and few studies have used objective measures to quantify regulatory success. Using a trait-like psychophysiological measure of emotion regulation, corrugator electromyography, we obtained an objective index of the ability to cognitively reappraise negative emotion in 56 healthy men (Session 1), who returned 1.3 years later to perform the same regulation task using fMRI (Session 2). Results indicated that the corrugator measure of regulatory skill predicted amygdala-prefrontal functional connectivity. Individuals with greater ability to down-regulate negative emotion as indexed by corrugator at Session 1 showed not only greater amygdala attenuation but also greater inverse connectivity between the amygdala and several sectors of the prefrontal cortex while down-regulating negative emotion at Session 2. Our results demonstrate that individual differences in emotion regulation are stable over time and underscore the important role of amygdala-prefrontal coupling for successful regulation of negative emotion.


Reappraisal of known malaria resistance loci in a large multicenter study.
Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10(-4) with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.


Dynamic attentional modulation of vision across space and time after right hemisphere stroke and in ageing.
Attention modulates the availability of sensory information to conscious perception. In particular, there is evidence of pathological, spatial constriction of the effective field of vision in patients with right hemisphere damage when a central task exhausts available attentional capacity. In the current study we first examined whether this constriction might be modulated across both space and time in right hemisphere stroke patients without neglect. Then we tested healthy elderly people to determine whether non-pathological ageing also leads to spatiotemporal impairments of vision under conditions of high attention load. Right hemisphere stroke patients completed a task at fixation while attempting to discriminate letters appearing in the periphery. Attentional load of the central task was modulated by increasing task difficulty. Peripheral letters appeared simultaneously with the central task or at different times (stimulus onset asynchronies, SOAs) after it. In a second study healthy elderly volunteers were tested with a modified version of this paradigm. Under conditions of high attention load right hemisphere stroke patients have a reduced effective visual field, over a significantly extended 'attentional blink', worse for items presented to their left. In the second study, older participants were unable to discriminate otherwise salient items across the visual field (left or right) when their attention capacity was loaded on the central task. This deficit extended temporally, with peripheral discrimination ability not returning to normal for up to 450 msec. Dynamically tying up attention resources on a task at fixation can have profound effects in patient populations and in normal ageing. These results demonstrate that items can escape conscious detection across space and time, and can thereby impact significantly on visual perception in these groups.


A literature review and investigation of staphylococcal necrotic dermatitis in sheep.
An outbreak of necrotic dermatitis in sheep was intensively investigated. Initially 19 of 147 Letelle (Merino-type) ewes were identified but closer inspection revealed 57 sheep that had skin lesions, some very slight, and that the majority (46 or 80%) had lesions only above the lips. A small number of them had multiple lesions on the legs or vulvae apart from lip lesions. Seven had only vulvar lesions and 2 only leg lesions. Among the sheep with lip lesions, twice as many had lesions on the right as on the left. Electron micrographs did not reveal any virus particles from the lesions, but all bacterial swabs yielded pure cultures of beta-haemolytic, Gram-positive cocci that were catalase, coagulase and DNase positive. The organism was identified as Staphylococcus aureus. Histopathology was consistent with a dermotoxic insult. A review of available literature indicated that this outbreak was consistent with a diagnosis of ovine necrotic (staphylococcal) dermatitis, supported by data on signalment, lesions, distribution, size, number, epidemiology as well as specific tests. The range of differential diagnoses and possible confusers are discussed.


Anatomically-distinct genetic associations of APOE epsilon4 allele load with regional cortical atrophy in Alzheimer's disease.
APOE epsilon4 is the best-established genetic risk factor for sporadic Alzheimer's disease (AD). However, while homozygotes show greater disease susceptibility and earlier age of onset than heterozygotes, they may not show faster rates of clinical progression. We hypothesize that there are differential APOE epsilon4 allele-load dependent influences on neuropathology across the brain. Our aim was to define the relationship between APOE epsilon4 allele load and regionally-specific brain cortical atrophy in Alzheimer's Disease (AD). For this reason voxel-based morphometry (VBM) was performed using T1-weighted MR images from 83 AD patients, contrasting regional cortical grey matter by APOE epsilon4 load according to either dominant or genotypic models. Patients fulfilled NINCDS-ADRDA criteria and were genotyped for APOE epsilon4 (15 epsilon4/epsilon4, 39 epsilon4/- and 29-/-). We observed that grey matter volume (GMV) decreased additively with increasing allele load in the medial (MTL) and anterior temporal lobes bilaterally. By contrast, a 2 degree-of-freedom genotypic model suggested a dominant effect of the APOE epsilon4 allele in the left temporal lobe. Brain regions showing a significant APOE epsilon4 allele load effect on GMV in AD included only some of those typically described as having greatest amyloid plaque deposition and atrophy. Temporal regions appeared to show a dominant effect of APOE epsilon4 allele load instead of the additive effect previously strongly associated with age of onset. Regional variations with allele load may be related to different mechanisms for effects of APOE epsilon4 load on susceptibility and disease progression.


Genetic admixture, self-reported ethnicity, self-estimated admixture, and skin pigmentation among Hispanics and Native Americans.
The relationship between ethnicity and biology is of interest to anthropologists, biomedical scientists, and historians in understanding how human groups are constructed. Ethnic self-identification in recently admixed groups such as Hispanics, African Americans, and Native Americans (NA) is likely to be complex due to the heterogeneity in individual admixture proportions and social environments within these groups. This study examines the relationships between self-identified ethnicity, self-estimated admixture proportions, skin pigmentation, and genetic marker estimated admixture proportions. These measures were assessed using questionnaires, skin color measurements, and genotyping of a panel of 76 ancestry informative markers, among 170 Hispanics and NAs from New Mexico, a state known for its complex history of interactions between people of NA and European (EU) ancestry. Results reveal that NAs underestimate their degree of EU admixture, and that Hispanics underestimate their degree of NA admixture. Within Hispanics, genetic-marker estimated admixture is better predicted by forehead skin pigmentation than by self-estimated admixture. We also find that Hispanic individuals self-identified as "half-White, half Hispanic" and "Spanish" have lower levels of NA admixture than those self-identified as "Mexican" and "Mexican American." Such results highlight the interplay between culture and biology in how individuals identify and view themselves, and have implications for how ethnicity and disease risk are assessed in a medical setting.


Ethical Issues in Consent for the Reuse of Data in Health Data Platforms.
Data platforms represent a new paradigm for carrying out health research. In the platform model, datasets are pooled for remote access and analysis, so novel insights for developing better stratified and/or personalised medicine approaches can be derived from their integration. If the integration of diverse datasets enables development of more accurate risk indicators, prognostic factors, or better treatments and interventions, this obviates the need for the sharing and reuse of data; and a platform-based approach is an appropriate model for facilitating this. Platform-based approaches thus require new thinking about consent. Here we defend an approach to meeting this challenge within the data platform model, grounded in: the notion of 'reasonable expectations' for the reuse of data; Waldron's account of 'integrity' as a heuristic for managing disagreement about the ethical permissibility of the approach; and the element of the social contract that emphasises the importance of public engagement in embedding new norms of research consistent with changing technological realities. While a social contract approach may sound appealing, however, it is incoherent in the context at hand. We defend a way forward guided by that part of the social contract which requires public approval for the proposal and argue that we have moral reasons to endorse a wider presumption of data reuse. However, we show that the relationship in question is not recognisably contractual and that the social contract approach is therefore misleading in this context. We conclude stating four requirements on which the legitimacy of our proposal rests.


Soya intake and plasma concentrations of daidzein and genistein: validity of dietary assessment among eighty British women (Oxford arm of the European Prospective Investigation into Cancer and Nutrition).
Soya products contain high levels of the isoflavones genistein and daidzein, and their glucosides, and may lower the risk of cardiovascular disease, osteoporosis and cancer. The present cross-sectional study investigated plasma concentrations of daidzein and genistein and their correlations with dietary soya consumption in four groups of twenty premenopausal British women. The women were selected from the Oxford arm of the European Prospective Investigation into Cancer and Nutrition using data from food-frequency questionnaires (FFQ) to guarantee a wide variation in soya consumption, and to investigate the utility of the question related to soya milk consumption compared with the utility of the question related to other soya foods. Dietary intakes of isoflavones were additionally assessed by 7 d food diaries. Plasma concentrations of daidzein and genistein were measured by time-resolved fluoroimmunoassay. Geometric mean plasma concentrations (nmol/l) were for the four groups, which were based on increasing soya intake, 4.9, 8.4, 39.2 and 132 for daidzein and 14.3, 16.5, 119 and 378 for genistein. The Spearman correlation coefficients for plasma isoflavone concentrations with estimated dietary intakes were between 0.66 and 0.80 for the diary-based estimates and between 0.24 and 0.74 for the FFQ-based estimates. The correlations for soya milk intakes were clearly higher than the correlations for intakes of other soya foods. We conclude that both the food diary and the FFQ estimate dietary soya isoflavone intakes sufficiently well to use them in epidemiological studies, and that plasma concentrations of daidzein and genistein in Western women who consumed soya products as a part of their regular diet were close to those in Asian populations.


Does telecare prolong community living in dementia? A study protocol for a pragmatic, randomised controlled trial.
Assistive technology and telecare (ATT) are relatively new ways of delivering care and support to people with social care needs. It is claimed that ATT reduces the need for community care, prevents unnecessary hospital admission, and delays or prevents admission into residential or nursing care. The current economic situation in England has renewed interest in ATT instead of community care packages. However, at present, the evidence base to support claims about the impact and effectiveness of ATT is limited, despite its potential to mitigate the high financial cost of caring for people with dementia and the social and psychological cost to unpaid carers. ATTILA (Assistive Technology and Telecare to maintain Independent Living At Home for People with Dementia) is a pragmatic, multi-centre, randomised controlled trial over 104 weeks that compares outcomes for people with dementia who receive ATT and those who receive equivalent community services but not ATT. The study hypothesis is that fewer people in the ATT group will go into institutional care over the 4-year period for which the study is funded. The study aims to recruit 500 participants, living in community settings, with dementia or significant cognitive impairment, who have recently been referred to social services.Primary outcome measures are time in days from randomisation to institutionalisation and cost effectiveness. Secondary outcomes are caregiver burden, health-related quality of life in carers, number and severity of serious adverse events, and data on acceptability, applicability and reliability of ATT intervention packages. Assessments will be undertaken in weeks 0 (baseline), 12, 24, 52 and 104 or until institutionalisation or withdrawal of the participant from the trial. In a time of financial austerity, CASSRs in England are increasingly turning to ATT in the belief that it will deliver good outcomes for less money. There is an absence of robust evidence for the cost-effectiveness and benefit of using assistive technology and telecare. The ATTILA trial meets a pressing need for robust, generalisable evidence to either justify continuing investment or reappraise the appropriate scale of ATT use. Current Controlled Trials ISRCTN86537017.


Dynamics of immunoglobulin sequence diversity in HIV-1 infected individuals.
Advances in immunoglobulin (Ig) sequencing technology are leading to new perspectives on immune system dynamics. Much research in this nascent field has focused on resolving immune responses to viral infection. However, the dynamics of B-cell diversity in early HIV infection, and in response to anti-retroviral therapy, are still poorly understood. Here, we investigate these dynamics through bulk Ig sequencing of samples collected over 2 years from a group of eight HIV-1 infected patients, five of whom received anti-retroviral therapy during the first half of the study period. We applied previously published methods for visualizing and quantifying B-cell sequence diversity, including the Gini index, and compared their efficacy to alternative measures. While we found significantly greater clonal structure in HIV-infected patients versus healthy controls, within HIV patients, we observed no significant relationships between statistics of B-cell clonal expansion and clinical variables such as viral load and CD4(+) count. Although there are many potential explanations for this, we suggest that important factors include poor sampling resolution and complex B-cell dynamics that are difficult to summarize using simple summary statistics. Importantly, we find a significant association between observed Gini indices and sequencing read depth, and we conclude that more robust analytical methods and a closer integration of experimental and theoretical work is needed to further our understanding of B-cell repertoire diversity during viral infection.


Ischemia-reperfusion injury accelerates human antibody-mediated transplant vasculopathy.
Background. The pathogenesis of transplant vasculopathy (TV) is a multifactorial process. We hypothesized that ischemia-reperfusion injury and antibody-mediated damage contribute to the development of TV.Methods. Human vessels were procured from nine separate donors undergoing cardiac surgery and stored in saline solution on ice until transplantation. BALB/c Rag2-/-IL-2Rgamma-/- mice were transplanted with a human vessel graft on day 0. Purified anti-human leukocyte antigen class I antibody (W6/32), isotype control antibody, or saline was injected into recipient mice weekly until day 42, at which point the degree of intimal expansion (IE) of vessels was assessed by histologic analysis.Results. We found that a prolonged cold ischemia time (6-12 hr) alone did not induce IE. In mice that received antibody where vessels were transplanted within 6 hr of procurement, no IE was observed. By contrast, in vessels exposed to more than 6 hr cold ischemia, both W6/32 antibody (30.4%T6.9%) and isotype control antibody(39.5%T6.0%) promoted significant IE (P<0.05 vs. saline [12.4%T1.7%]). Importantly, the isotype control antibody did not cross-react with human tissue. Interestingly, the number of mouse Fc-receptor-positive cells was significantly increased in human vessels exposed to more than 6 hr cold ischemia but only in the presence of antibody (P<0.05).Conclusions. Antibody, regardless of its specificity, may promote IE in human vessels that are injured through cold ischemia via interaction with Fc-receptor-positive cells. This highlights the importance of controlling the degree of cold ischemia in clinical transplantation in an effort to reduce the risk of TV development.


Visual search for arbitrary objects in real scenes.
How efficient is visual search in real scenes? In searches for targets among arrays of randomly placed distractors, efficiency is often indexed by the slope of the reaction time (RT) × Set Size function. However, it may be impossible to define set size for real scenes. As an approximation, we hand-labeled 100 indoor scenes and used the number of labeled regions as a surrogate for set size. In Experiment 1, observers searched for named objects (a chair, bowl, etc.). With set size defined as the number of labeled regions, search was very efficient (~5 ms/item). When we controlled for a possible guessing strategy in Experiment 2, slopes increased somewhat (~15 ms/item), but they were much shallower than search for a random object among other distinctive objects outside of a scene setting (Exp. 3: ~40 ms/item). In Experiments 4-6, observers searched repeatedly through the same scene for different objects. Increased familiarity with scenes had modest effects on RTs, while repetition of target items had large effects (>500 ms). We propose that visual search in scenes is efficient because scene-specific forms of attentional guidance can eliminate most regions from the "functional set size" of items that could possibly be the target.


Echicetin coated polystyrene beads: a novel tool to investigate GPIb-specific platelet activation and aggregation.
von Willebrand factor/ristocetin (vWF/R) induces GPIb-dependent platelet agglutination and activation of αIIbβ3 integrin, which also binds vWF. These conditions make it difficult to investigate GPIb-specific signaling pathways in washed platelets. Here, we investigated the specific mechanisms of GPIb signaling using echicetin-coated polystyrene beads, which specifically activate GPIb. We compared platelet activation induced by echicetin beads to vWF/R. Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling. Echicetin beads induced αIIbβ3-dependent aggregation of washed platelets, while under the same conditions vWF/R treatment led only to αIIbβ3-independent platelet agglutination. The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation, while the total amount of echicetin used for activation is not critical. Echicetin beads induced strong phosphorylation of several proteins including p38, ERK and PKB. Synergistic signaling via P2Y12 and thromboxane receptor through secreted ADP and TxA2, respectively, were important for echicetin bead triggered platelet activation. Activation of PKG by the NO/sGC/cGMP pathway inhibited echicetin bead-induced platelet aggregation. Echicetin-coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb-triggered pathways.


Speeding up social waves. Propagation mechanisms of shimmering in giant honeybees.
Shimmering is a defence behaviour in giant honeybees (Apis dorsata), whereby bees on the nest surface flip their abdomen upwards in a Mexican wave-like process. However, information spreads faster than can be ascribed to bucket bridging, which is the transfer of information from one individual to an adjacent one. We identified a saltatoric process that speeds up shimmering by the generation of daughter waves, which subsequently merge with the parental wave, producing a new wave front. Motion patterns of individual "focus" bees (n = 10,894) and their shimmering-active neighbours (n = 459,558) were measured with high-resolution video recording and stereoscopic imaging. Three types of shimmering-active surface bees were distinguished by their communication status, termed "agents": "Bucket-bridging" agents comprised 74.98% of all agents, affected 88.17% of their neighbours, and transferred information at a velocity of v = 0.317±0.015 m/s. "Chain-tail" agents comprised 9.20% of the agents, were activated by 6.35% of their neighbours, but did not motivate others to participate in the wave. "Generator agents" comprised 15.82% of agents, showed abdominal flipping before the arrival of the main wave front, and initiated daughter waves. They affected 6.75% of their neighbourhood and speeded up the compound shimmering process compared to bucket bridging alone by 41.5% to v = 0.514±0.019 m/s. The main direction of shimmering was reinforced by 35.82% of agents, whereas the contribution of the complementing agents was fuzzy. We discuss that the saltatoric process could enable the bees to instantly recruit larger cohorts to participate in shimmering and to respond rapidly to changes in flight direction of preying wasps. A third, non-exclusive explanation is that at a distance of up to three metres from the nest the acceleration of shimmering could notably contribute to the startle response in mammals and birds.


Engineering antigen-specific T cells from genetically modified human hematopoietic stem cells in immunodeficient mice.
There is a desperate need for effective therapies to fight chronic viral infections. The immune response is normally fastidious at controlling the majority of viral infections and a therapeutic strategy aimed at reestablishing immune control represents a potentially powerful approach towards treating persistent viral infections. We examined the potential of genetically programming human hematopoietic stem cells to generate mature CD8+ cytotoxic T lymphocytes that express a molecularly cloned, "transgenic" human anti-HIV T cell receptor (TCR). Anti-HIV TCR transduction of human hematopoietic stem cells directed the maturation of a large population of polyfunctional, HIV-specific CD8+ cells capable of recognizing and killing viral antigen-presenting cells. Thus, through this proof-of-concept we propose that genetic engineering of human hematopoietic stem cells will allow the tailoring of effector T cell responses to fight HIV infection or other diseases that are characterized by the loss of immune control.


Directional persistence and the optimality of run-and-tumble chemotaxis.
E. coli does chemotaxis by performing a biased random walk composed of alternating periods of swimming (runs) and reorientations (tumbles). Tumbles are typically modelled as complete directional randomisations but it is known that in wild type E. coli, successive run directions are actually weakly correlated, with a mean directional difference of approximately 63 degrees. We recently presented a model of the evolution of chemotactic swimming strategies in bacteria which is able to quantitatively reproduce the emergence of this correlation. The agreement between model and experiments suggests that directional persistence may serve some function, a hypothesis supported by the results of an earlier model. Here we investigate the effect of persistence on chemotactic efficiency, using a spatial Monte Carlo model of bacterial swimming in a gradient, combined with simulations of natural selection based on chemotactic efficiency. A direct search of the parameter space reveals two attractant gradient regimes, (a) a low-gradient regime, in which efficiency is unaffected by directional persistence and (b) a high-gradient regime, in which persistence can improve chemotactic efficiency. The value of the persistence parameter that maximises this effect corresponds very closely with the value observed experimentally. This result is matched by independent simulations of the evolution of directional memory in a population of model bacteria, which also predict the emergence of persistence in high-gradient conditions. The relationship between optimality and persistence in different environments may reflect a universal property of random-walk foraging algorithms, which must strike a compromise between two competing aims: exploration and exploitation. We also present a new graphical way to generally illustrate the evolution of a particular trait in a population, in terms of variations in an evolvable parameter.


Foxp3+ T reg cells control psoriasiform inflammation by restraining an IFN-I-driven CD8+ T cell response.
Psoriasis is a complex inflammatory skin disease affecting ∼3% of the population worldwide. Although type I interferons (IFN-I) are thought to be involved in its pathogenesis, the details of this relationship remain elusive. Here we show that in a murine model of imiquimod-driven psoriatic skin inflammation, Foxp3+ regulatory T cells (T reg cells) control inflammation severity by restraining IFN-I. Depletion of T reg cells induces IFN-I and IFN-stimulated gene expression, and leads to accumulation of CD8+ T cells in lesional skin. Mononuclear phagocytes (MNPs) were the source of IFN-I, and their depletion reversed the effect of T reg cell depletion. Blockade of IFN-I signaling abolished CD8+ T cell infiltration and excess inflammation in the skin of T reg cell-depleted mice. Depletion of CD8+ T cells attenuated pathology, confirming their role as critical effector cells downstream of IFN-I. Our results describe an unexpected role for T reg cells in restraint of an MNP-IFN-I-driven CD8+ T cell response during psoriasiform skin inflammation. These findings highlight a pathway with potential relevance for the treatment of early-stage disease.


The hitchhiking effect on the site frequency spectrum of DNA polymorphisms.
The level of DNA sequence variation is reduced in regions of the Drosophila melanogaster genome where the rate of crossing over per physical distance is also reduced. This observation has been interpreted as support for the simple model of genetic hitchhiking, in which directional selection on rare variants, e.g., newly arising advantageous mutants, sweeps linked neutral alleles to fixation, thus eliminating polymorphisms near the selected site. However, the frequency spectra of segregating sites of several loci from some populations exhibiting reduced levels of nucleotide diversity and reduced numbers of segregating sites did not appear different from what would be expected under a neutral equilibrium model. Specifically, a skew toward an excess of rare sites was not observed in these samples, as measured by Tajima's D. Because this skew was predicted by a simple hitchhiking model, yet it had never been expressed quantitatively and compared directly to DNA polymorphism data, this paper investigates the hitchhiking effect on the site frequency spectrum, as measured by Tajima's D and several other statistics, using a computer simulation model based on the coalescent process and recurrent hitchhiking events. The results presented here demonstrate that under the simple hitchhiking model (1) the expected value of Tajima's D is large and negative (indicating a skew toward rare variants), (2) that Tajima's test has reasonable power to detect a skew in the frequency spectrum for parameters comparable to those from actual data sets, and (3) that the Tajima's Ds observed in several data sets are very unlikely to have been the result of simple hitchhiking. Consequently, the simple hitchhiking model is not a sufficient explanation for the DNA polymorphism at those loci exhibiting a decreased number of segregating sites yet not exhibiting a skew in the frequency spectrum.


Genetic and splice variations of Bos taurus CD46 shift cell permissivity to BVDV, the bovine pestivirus.
The pestivirus bovine viral diarrhea virus (BVDV) is known to bind to the CD46 molecule, which subsequently promotes entry of the virus. Mapping of the BVD-virion-binding site has shown that two peptides, 66EQIV69 and 82GQVLAL87, located on antiparallel beta sheets in the most distal complement control protein module (CCP1), provide the attachment platform. In the present study, we reveal the existence of ten distinct allelic versions of the CCP1 module, varying significantly in frequency among taurine and indicine races. A complex mRNA splicing pattern was also evidenced for bovine CD46, generating three different serine-threonine-proline segments and five different cytoplasmic domains. The four most frequent allelic variants and the six splice variants were then expressed in BVDV-nonpermissive porcine cells and the quantity of progeny virions generated by each cell preparation was measured 48 h post-infection. As expected, ectopic expression of the 10 bovine CD46 isoforms rendered the PK15 cells permissive to BVDV, as attested by the 100,000-fold greater recovery of virions from these cells than from non-transfected cells. This permissivity increase was significantly lower (-33%, P<0.001) when the canonical CCP1 was replaced with the variant most frequent in zebus, suggesting positive or negative selection of this allele in the latter and in the former, respectively. The predicted secondary structure of this variant suggests that the measured loss of function is due to the disappearance of one of the two beta sheets constituting the BVDV attachment platform. On the other hand we showed that for a given CCP1, the titer recovered at 48 hpi also depended on the nature of the CD46 cytoplasmic domain (P<0.001). This result implies that virus binding generates a cytoplasmic-tail-dependent outside-in signal that determines permissivity to BVDV.


The structure of foot-and-mouth disease virus.
Structural studies of foot-and-mouth disease virus (FMDV) have largely focused on the mature viral particle, providing atomic resolution images of the spherical protein capsid for a number of sero- and sub-types, structures of the highly immunogenic surface loop, Fab and GAG receptor complexes. Additionally, structures are available for a few non-structural proteins. The chapter reviews our current structural knowledge and its impact on our understanding of the virus life cycle proceeding from the mature virus through immune evasion/inactivation, cell-receptor binding and replication and alludes to future structural targets.


1,25-dihydroxyvitamin D3 treatment delays cellular aging in human mesenchymal stem cells while maintaining their multipotent capacity.
1,25-dihydroxyvitamin D3 (1,25D3) was reported to induce premature organismal aging in fibroblast growth factor-23 (Fgf23) and klotho deficient mice, which is of main interest as 1,25D3 supplementation of its precursor cholecalciferol is used in basic osteoporosis treatment. We wanted to know if 1,25D3 is able to modulate aging processes on a cellular level in human mesenchymal stem cells (hMSC). Effects of 100 nM 1,25D3 on hMSC were analyzed by cell proliferation and apoptosis assay, β-galactosidase staining, VDR and surface marker immunocytochemistry, RT-PCR of 1,25D3-responsive, quiescence- and replicative senescence-associated genes. 1,25D3 treatment significantly inhibited hMSC proliferation and apoptosis after 72 h and delayed the development of replicative senescence in long-term cultures according to β-galactosidase staining and P16 expression. Cell morphology changed from a fibroblast like appearance to broad and rounded shapes. Long term treatment did not induce lineage commitment in terms of osteogenic pathways but maintained their clonogenic capacity, their surface marker characteristics (expression of CD73, CD90, CD105) and their multipotency to develop towards the chondrogenic, adipogenic and osteogenic pathways. In conclusion, 1,25D3 delays replicative senescence in primary hMSC while the pro-aging effects seen in mouse models might mainly be due to elevated systemic phosphate levels, which propagate organismal aging.


Projections of hip arthroplasty in OECD countries up to 2050.
The study aims to estimate the future demand of hip arthroplasty for OECD countries and to compare the results with earlier studies. Based on data availability and validity 20 countries out of the OECD sample have been selected for projection analysis. Using historic data (1995-2012) and multiple linear regression technics a projection model was designed by an iterative process considering different explanatory variables such as health care expenditure, age groups, and projection time frames. The utilisation of hip implants in OECD countries continues to grow by a compound annual growth rate (CAGR) of 1.2%, leading to an increase from 1.8 million per year in 2015 to 2.8 (2.6-2.9) in the year 2050. The mean utilisation rate (incidence) of hip implants will increase from 184 (143-312) to 275 (174-457) per 100.000 total population in the same time. Australia, Ireland, Norway, Switzerland and other countries will face a significant increase of utilisation of hip implants between +95% and +120% from 2015 to 2050. Hip arthroplasty continues to rise significantly over the next 35 years. Therefore, some countries will face an exponential use of hip arthroplasty of additional 100% or more and thus challenges for their health care budgets. Revision burden will increase disproportionately. Thus, health technology assessment (HTA) for medical devices, longevity and quality control will become more relevant.


Uncomplicated obesity is associated with abnormal aortic function assessed by cardiovascular magnetic resonance.
Obese subjects with insulin resistance and hypertension have abnormal aortic elastic function, which may predispose them to the development of left ventricular dysfunction. We hypothesised that obesity, uncomplicated by other cardiovascular risk factors, is independently associated with aortic function. We used magnetic resonance imaging to measure aortic compliance, distensibility and stiffness index in 27 obese subjects (BMI 33 kg/m2) without insulin resistance and with normal cholesterol and blood pressure, and 12 controls (BMI 23 kg/m2). Obesity was associated with reduced aortic compliance (0.9 +/- 0.1 vs. 1.5 +/- 0.2 mm2/mmHg in controls, p < 0.02) and distensibility (3.3 +/- 0.01 vs. 5.6 +/- 0.01 mmHg-1 x 10-3, p < 0.02), as well as higher stiffness index (3.4 +/- 0.3 vs. 2.1 +/- 0.1, p < 0.02). Body mass index and fat mass were negatively correlated with aortic function. Leptin was higher in obesity (8.9 +/- 0.6 vs. 4.7 +/- 0.6 ng/ml, p < 0.001) and also correlated with aortic measures. In multiple regression models, fat mass, leptin and body mass index were independent predictors of aortic function. Aortic elastic function is abnormal in obese subjects without other cardiovascular risk factors. These findings highlight the independent importance of obesity in the development of cardiovascular disease.


Guided image filtering.
In this paper, we propose a novel explicit image filter called guided filter. Derived from a local linear model, the guided filter computes the filtering output by considering the content of a guidance image, which can be the input image itself or another different image. The guided filter can be used as an edge-preserving smoothing operator like the popular bilateral filter [1], but it has better behaviors near edges. The guided filter is also a more generic concept beyond smoothing: It can transfer the structures of the guidance image to the filtering output, enabling new filtering applications like dehazing and guided feathering. Moreover, the guided filter naturally has a fast and nonapproximate linear time algorithm, regardless of the kernel size and the intensity range. Currently, it is one of the fastest edge-preserving filters. Experiments show that the guided filter is both effective and efficient in a great variety of computer vision and computer graphics applications, including edge-aware smoothing, detail enhancement, HDR compression, image matting/feathering, dehazing, joint upsampling, etc.


Korean red ginseng improves blood pressure stability in patients with intradialytic hypotension.
Introduction. Intradialytic hypotension (IDH) is a common complication during hemodialysis which may increase mortality risks. Low dose of Korean red ginseng (KRG) has been reported to increase blood pressure. Whether KRG can improve hemodynamic stability during hemodialysis has not been examined. Methods. The 8-week study consisted of two phases: observation phase and active treatment phase. According to prehemodialysis blood pressure (BP), 38 patients with IDH were divided into group A (BP ≥ 140/90 mmHg, n = 18) and group B (BP < 140/90 mmHg, n = 20). Patients were instructed to chew 3.5 gm KRG slices at each hemodialysis session during the 4-week treatment phase. Blood pressure changes, number of sessions disturbed by symptomatic IDH, plasma levels of vasoconstrictors, blood biochemistry, and adverse effects were recorded. Results. KRG significantly reduced the degree of blood pressure drop during hemodialysis (P < 0.05) and the frequency of symptomatic IDH (P < 0.05). More activation of vasoconstrictors (endothelin-1 and angiotensin II) during hemodialysis was found. The postdialytic levels of endothelin-1 and angiotensin II increased significantly (P < 0.01). Conclusion. Chewing KRG renders IDH patients better resistance to acute BP reduction during hemodialysis via activation of vasoconstrictors. Our results suggest that KRG could be an adjuvant treatment for IDH.


Nerve injury evoked loss of latexin expression in spinal cord neurons contributes to the development of neuropathic pain.
Nerve injury leads to sensitization mechanisms in the peripheral and central nervous system which involve transcriptional and post-transcriptional modifications in sensory nerves. To assess protein regulations in the spinal cord after injury of the sciatic nerve in the Spared Nerve Injury model (SNI) we performed a proteomic analysis using 2D-difference gel electrophoresis (DIGE) technology. Among approximately 2300 protein spots separated on each gel we detected 55 significantly regulated proteins after SNI whereof 41 were successfully identified by MALDI-TOF MS. Out of the proteins which were regulated in the DIGE analyses after SNI we focused on the carboxypeptidase A inhibitor latexin because protease dysfunctions contribute to the development of neuropathic pain. Latexin protein expression was reduced after SNI which could be confirmed by Western Blot analysis, quantitative RT-PCR and in-situ hybridisation. The decrease of latexin was associated with an increase of the activity of carboxypeptidase A indicating that the balance between latexin and carboxypeptidase A was impaired in the spinal cord after peripheral nerve injury due to a loss of latexin expression in spinal cord neurons. This may contribute to the development of cold allodynia because normalization of neuronal latexin expression in the spinal cord by AAV-mediated latexin transduction or administration of a small molecule carboxypeptidase A inhibitor significantly reduced acetone-evoked nociceptive behavior after SNI. Our results show the usefulness of proteomics as a screening tool to identify novel mechanisms of nerve injury evoked hypernociception and suggest that carboxypeptidase A inhibition might be useful to reduce cold allodynia.


Childhood pemphigus vulgaris successfully treated with rituximab.
Pemphigus is a potentially fatal autoimmune epidermal bullous disorder. Rituximab is a novel therapy for the treatment of refractory pemphigus. However, there is limited clinical data on safety and efficacy of rituximab in pediatric age group. Herein, we report an 11-year-old boy of childhood pemphigus vulgaris who failed to respond to dexamethasone pulse therapy and was subsequently treated with rituximab and achieved complete remission.


Interplay between lysine methylation and Cdk phosphorylation in growth control by the retinoblastoma protein.
As a critical target for cyclin-dependent kinases (Cdks), the retinoblastoma tumour suppressor protein (pRb) controls early cell cycle progression. We report here a new type of regulation that influences Cdk recognition and phosphorylation of substrate proteins, mediated through the targeted methylation of a critical lysine residue in the Cdk substrate recognition site. In pRb, lysine (K) 810 represents the essential and conserved basic residue (SPXK) required for cyclin/Cdk recognition and phosphorylation. Methylation of K810 by the methyltransferase Set7/9 impedes binding of Cdk and thereby prevents subsequent phosphorylation of the associated serine (S) residue, retaining pRb in the hypophosphorylated growth-suppressing state. Methylation of K810 is under DNA damage control, and methylated K810 impacts on phosphorylation at sites throughout the pRb protein. Set7/9 is required for efficient cell cycle arrest, and significantly, a mutant derivative of pRb that cannot be methylated at K810 exhibits compromised cell cycle arrest. Thus, the regulation of phosphorylation by Cdks reflects the combined interplay with methylation events, and more generally the targeted methylation of a lysine residue within a Cdk-consensus site in pRb represents an important point of control in cell cycle progression.


Circulating and Tissue-Resident CD4+ T Cells With Reactivity to Intestinal Microbiota Are Abundant in Healthy Individuals and Function Is Altered During Inflammation.
Interactions between commensal microbes and the immune system are tightly regulated and maintain intestinal homeostasis, but little is known about these interactions in humans. We investigated responses of human CD4+ T cells to the intestinal microbiota. We measured the abundance of T cells in circulation and intestinal tissues that respond to intestinal microbes and determined their clonal diversity. We also assessed their functional phenotypes and effects on intestinal resident cell populations, and studied alterations in microbe-reactive T cells in patients with chronic intestinal inflammation. We collected samples of peripheral blood mononuclear cells and intestinal tissues from healthy individuals (controls, n = 13-30) and patients with inflammatory bowel diseases (n = 119; 59 with ulcerative colitis and 60 with Crohn's disease). We used 2 independent assays (CD154 detection and carboxy-fluorescein succinimidyl ester dilution assays) and 9 intestinal bacterial species (Escherichia coli, Lactobacillus acidophilus, Bifidobacterium animalis subsp lactis, Faecalibacterium prausnitzii, Bacteroides vulgatus, Roseburia intestinalis, Ruminococcus obeum, Salmonella typhimurium, and Clostridium difficile) to quantify, expand, and characterize microbe-reactive CD4+ T cells. We sequenced T-cell receptor Vβ genes in expanded microbe-reactive T-cell lines to determine their clonal diversity. We examined the effects of microbe-reactive CD4+ T cells on intestinal stromal and epithelial cell lines. Cytokines, chemokines, and gene expression patterns were measured by flow cytometry and quantitative polymerase chain reaction. Circulating and gut-resident CD4+ T cells from controls responded to bacteria at frequencies of 40-4000 per million for each bacterial species tested. Microbiota-reactive CD4+ T cells were mainly of a memory phenotype, present in peripheral blood mononuclear cells and intestinal tissue, and had a diverse T-cell receptor Vβ repertoire. These cells were functionally heterogeneous, produced barrier-protective cytokines, and stimulated intestinal stromal and epithelial cells via interleukin 17A, interferon gamma, and tumor necrosis factor. In patients with inflammatory bowel diseases, microbiota-reactive CD4+ T cells were reduced in the blood compared with intestine; T-cell responses that we detected had an increased frequency of interleukin 17A production compared with responses of T cells from blood or intestinal tissues of controls. In an analysis of peripheral blood mononuclear cells and intestinal tissues from patients with inflammatory bowel diseases vs controls, we found that reactivity to intestinal bacteria is a normal property of the human CD4+ T-cell repertoire, and does not necessarily indicate disrupted interactions between immune cells and the commensal microbiota. T-cell responses to commensals might support intestinal homeostasis, by producing barrier-protective cytokines and providing a large pool of T cells that react to pathogens.


Sound preconditioning therapy inhibits ototoxic hearing loss in mice.
Therapeutic drugs with ototoxic side effects cause significant hearing loss for thousands of patients annually. Two major classes of ototoxic drugs are cisplatin and the aminoglycoside antibiotics, both of which are toxic to mechanosensory hair cells, the receptor cells of the inner ear. A critical need exists for therapies that protect the inner ear without inhibiting the therapeutic efficacy of these drugs. The induction of heat shock proteins (HSPs) inhibits both aminoglycoside- and cisplatin-induced hair cell death and hearing loss. We hypothesized that exposure to sound that is titrated to stress the inner ear without causing permanent damage would induce HSPs in the cochlea and inhibit ototoxic drug–induced hearing loss. We developed a sound exposure protocol that induces HSPs without causing permanent hearing loss. We used this protocol in conjunction with a newly developed mouse model of cisplatin ototoxicity and found that preconditioning mouse inner ears with sound has a robust protective effect against cisplatin-induced hearing loss and hair cell death. Sound therapy also provided protection against aminoglycoside-induced hearing loss. These data indicate that sound preconditioning protects against both classes of ototoxic drugs, and they suggest that sound therapy holds promise for preventing hearing loss in patients receiving these drugs.


Motivations and values associated with combining sex and illicit drugs ('chemsex') among gay men in South London: findings from a qualitative study.
There is considerable public health concern about the combining of sex and illicit drugs (chemsex) among gay men. With a view to inform supportive therapeutic and clinical interventions, we sought to examine the motivations for engaging in chemsex among gay men living in South London. Community advertising recruited 30 gay men for qualitative semi-structured interview. Aged between 21 and 53 years, all lived in South London in the boroughs of Lambeth, Southwark and Lewisham and all had combined crystal methamphetamine, mephedrone and/or γ-hydroxybutyric acid/γ-butyrolactone with sex in the past 12 months. Transcripts were subjected to a thematic analysis. We broadly distinguished two groups of reasons for combining sex and drugs, within which we described eight distinct motivations. The first major group of motivations for combining drugs with sex was that drugs provide the means by which men can have the sex they desire by increasing libido, confidence, disinhibition and stamina. The second major group of motivations for chemsex was that drugs enhance the qualities of the sex that men value. Drugs made other men seem more attractive, increased physical sensations, intensified perceptions of intimacy and facilitated a sense of sexual adventure. Analysis revealed that sexualised drug use provides both motivation and capability to engage in the kinds of sex that some gay men value: sex that explores and celebrates adventurism. Those services providing (talking) interventions to men engaging in chemsex should consider these benefits of sexualised drug use alongside the harms arising.


Prevalence of toxoplasmosis and its association with dementia in older adults in Central Africa: a result from the EPIDEMCA programme.
We aimed at estimating the seroprevalence of Toxoplasma gondii (T. gondii) infection in older adults living in Central Africa and investigating its association with dementia using data from the Epidemiology of Dementia in Central Africa (EPIDEMCA) programme. A cross-sectional multicentre population-based study was carried out among participants aged 73 (±7) years on average, living in rural and urban areas of the Central African Republic and the Republic of Congo between November 2011 and December 2012. Blood samples were collected from each consenting participant. The detection of anti-T. gondii immunoglobulin G antibodies was performed in 2014 in France using a commercially available ELISA kit. Participants were interviewed using a standardised questionnaire including sociodemographic characteristics. DSM-IV criteria were required for a diagnosis of dementia. Multivariate binary logistic regression models were used to assess the association between toxoplasmosis infection and dementia. Among 1662 participants, the seroprevalence of toxoplasmosis was 63.0% (95% confidence interval (CI): 60.7-65.3) overall, 66.6% (95%CI: 63.4-69.8) in Central African Republic and 59.4% (95%CI: 56.1-62.7) in the Republic of Congo. In multivariate analyses, toxoplasmosis status was significantly associated with increasing age (P = 0.006), Republic of Congo (P = 0.002), urban area (P = 0.001) and previous occupation (P = 0.002). No associations between dementia and toxoplasmosis status or anti-T. gondii IgG titres were found. Toxoplasma gondii infection was not associated with dementia among older adults in Central Africa. Our findings are consistent with previous studies and add to the knowledge on the relationship between T. gondii infection and neurological disorders.


Plant movements and climate warming: intraspecific variation in growth responses to nonlocal soils.
Most range shift predictions focus on the dispersal phase of the colonization process. Because moving populations experience increasingly dissimilar nonclimatic environmental conditions as they track climate warming, it is also critical to test how individuals originating from contrasting thermal environments can establish in nonlocal sites. We assess the intraspecific variation in growth responses to nonlocal soils by planting a widespread grass of deciduous forests (Milium effusum) into an experimental common garden using combinations of seeds and soil sampled in 22 sites across its distributional range, and reflecting movement scenarios of up to 1600 km. Furthermore, to determine temperature and forest-structural effects, the plants and soils were experimentally warmed and shaded. We found significantly positive effects of the difference between the temperature of the sites of seed and soil collection on growth and seedling emergence rates. Migrant plants might thus encounter increasingly favourable soil conditions while tracking the isotherms towards currently 'colder' soils. These effects persisted under experimental warming. Rising temperatures and light availability generally enhanced plant performance. Our results suggest that abiotic and biotic soil characteristics can shape climate change-driven plant movements by affecting growth of nonlocal migrants, a mechanism which should be integrated into predictions of future range shifts.


Hedgehog signaling pathway regulates gene expression profile of epididymal principal cells through the primary cilium.
Primary cilia (PC) are organelles that sense and respond to dynamic changes of the extracellular milieu through the regulation of target genes. By using the epididymis as a model system, we determined the contribution of primary cilia in the regulation of epithelial cell functions through the transduction of the Hedgehog (Hh) signaling pathway. Both Sonic (SHH) and Indian Hedgehog (IHH) ligands were detected in epididymal epithelial cells by confocal microscopy and found secreted in the extracellular space. Gene expression profiling preformed on ciliated epithelial cells indicated that 153 and 1052 genes were differentially expressed following treatment with the Hh agonist SAG or the Hh antagonist cyclopamine (Cyclo), respectively. Strikingly, gene ontology analysis indicated that genes associated with immune response were the most affected following Hh modulation. The contribution of epididymal PC to canonical Hh pathway transduction was validated by ciliobrevin D treatment, which induced a significant decrease in PC length and a reduction in the expression Hh signaling targets. Such findings bring us closer to a molecular understanding of the subtle immune balance observed in some epithelia, including the epididymis and the intestine, which are organs featuring both tolerance toward autoimmune spermatozoa (or commensal bacteria) and defense against pathogens.


Emotional activation of limbic circuitry in elderly normal subjects in a PET study.
This study was undertaken to identify brain structures associated with emotion in normal elderly subjects. Eight normal subjects aged 55-78 years were shown film clips intended to provoke the emotions of happiness, fear, or disgust as well as a neutral state. During emotional activation, regional cerebral blood flow was measured with the use of [15O]H2O positron emission tomography imaging, and subjective emotional responses were recorded. Data were analyzed by subtracting the values during the neutral condition from the values in the various emotional activations. The stimuli produced a general activation in visual pathways that included the primary and secondary visual cortex, involving regions associated with object and spatial recognition. In addition, the specific emotions produced different regional limbic activations, which suggests that different pathways may be used for different types of emotional stimuli. Emotional activation in normal elderly subjects was associated with increases in blood flow in limbic and paralimbic brain structures. Brain activation may be specific to the emotion being elicited but probably involves complex sensory, association, and memory circuitry. Further studies are needed to identify activations that are specific for emotion.


Attention regulation and monitoring in meditation.
Meditation can be conceptualized as a family of complex emotional and attentional regulatory training regimes developed for various ends, including the cultivation of well-being and emotional balance. Among these various practices, there are two styles that are commonly studied. One style, focused attention meditation, entails the voluntary focusing of attention on a chosen object. The other style, open monitoring meditation, involves nonreactive monitoring of the content of experience from moment to moment. The potential regulatory functions of these practices on attention and emotion processes could have a long-term impact on the brain and behavior.


Impact of surface tension in pharmaceutical sciences.
Surface chemistry has a large influence in many industries. In the life sciences, surface area is gaining importance in the characterization of materials during their development, formulation and manufacturing. The chemical activity, adsorption, dissolution, and bioavailability of a drug may depend on the surface of the molecule. In order to meet manufacturing challenges and develop new and better performing products with improved qualities, knowledge of surface tension is of utmost importance. An attempt has been made in this paper to review the application of interfacial tension in the key domains of pharmaceutical applications.


Clonal analysis of Salmonella-specific effector T cells reveals serovar-specific and cross-reactive T cell responses.
To tackle the complexity of cross-reactive and pathogen-specific T cell responses against related Salmonella serovars, we used mass cytometry, unbiased single-cell cloning, live fluorescence barcoding, and T cell-receptor sequencing to reconstruct the Salmonella-specific repertoire of circulating effector CD4+ T cells, isolated from volunteers challenged with Salmonella enterica serovar Typhi (S. Typhi) or Salmonella Paratyphi A (S. Paratyphi). We describe the expansion of cross-reactive responses against distantly related Salmonella serovars and of clonotypes recognizing immunodominant antigens uniquely expressed by S. Typhi or S. Paratyphi A. In addition, single-amino acid variations in two immunodominant proteins, CdtB and PhoN, lead to the accumulation of T cells that do not cross-react against the different serovars, thus demonstrating how minor sequence variations in a complex microorganism shape the pathogen-specific T cell repertoire. Our results identify immune-dominant, serovar-specific, and cross-reactive T cell antigens, which should aid in the design of T cell-vaccination strategies against Salmonella.


(31)P cardiac magnetic resonance spectroscopy during leg exercise at 3 Tesla.
Investigation of phosphorus ((31)P) magnetic resonance spectroscopy under stress conditions provides a non-invasive tool to examine alterations in cardiac high-energy phosphate metabolism that may not be evident at rest. Our aim was to establish cardiac (31)P MR spectroscopy during leg exercise at 3T. The increased field strength should provide a higher signal to noise ratio than at lower field strengths. Furthermore, relatively high temporal resolution at a sufficiently fine spatial resolution should be feasible. (31)P MR spectra were obtained with a 3D acquisition weighted chemical shift imaging sequence in 20 healthy volunteers at rest, during dynamic physiological leg exercise and after recovery at 3T. Haemodynamic measurements were made throughout and the rate pressure product calculated. With exercise, the mean heart rate increased by 73%, achieving a mean increase in rate pressure product of 115%. The corrected PCr/ATP ratio for subjects at rest was 2.02 +/- 0.43, exercise 2.14 +/- 0.67 (P = 0.54 vs. rest) and at recovery 2.03 +/- 0.52 (P = 0.91 vs. rest, P = 0.62 vs. exercise). A cardiac (31)P MR spectroscopy physiological exercise-recovery protocol is feasible at 3T. There was no significant change in high-energy cardiac phosphate metabolite concentrations in healthy volunteers at rest, during physiological leg exercise or during recovery. When applied to patients with heart disease, this protocol should provide insights into physiological and pathological cardiac metabolism.


Diversity of Xenorhabdus and Photorhabdus spp. and their symbiotic entomopathogenic nematodes from Thailand.
Xenorhabdus and Photorhabdus spp. are bacterial symbionts of entomopathogenic nematodes (EPNs). In this study, we isolated and characterized Xenorhabdus and Photorhabdus spp. from across Thailand together with their associated nematode symbionts, and characterized their phylogenetic diversity. EPNs were isolated from soil samples using a Galleria-baiting technique. Bacteria from EPNs were cultured and genotyped based on recA sequence. The nematodes were identified based on sequences of 28S rDNA and internal transcribed spacer regions. A total of 795 soil samples were collected from 159 sites in 13 provinces across Thailand. A total of 126 EPNs isolated from samples taken from 10 provinces were positive for Xenorhabdus (n = 69) or Photorhabdus spp. (n = 57). Phylogenetic analysis separated the 69 Xenorhabdus isolates into 4 groups. Groups 1, 2 and 3 consisting of 52, 13 and 1 isolates related to X. stockiae, and group 4 consisting of 3 isolates related to X. miraniensis. The EPN host for isolates related to X. stockiae was S. websteri, and for X. miraniensis was S. khoisanae. The Photorhabdus species were identified as P. luminescens (n = 56) and P. asymbiotica (n = 1). Phylogenenic analysis divided P. luminescens into five groups. Groups 1 and 2 consisted of 45 and 8 isolates defined as subspecies hainanensis and akhurstii, respectively. One isolate was related to hainanensis and akhurstii, two isolates were related to laumondii, and one isolate was the pathogenic species P. asymbiotica subsp. australis. H. indica was the major EPN host for Photorhabdus. This study reveals the genetic diversity of Xenorhabdus and Photorhabdus spp. and describes new associations between EPNs and their bacterial symbionts in Thailand.


Whitening and Impaired Glucose Utilization of Brown Adipose Tissue in a Rat Model of Type 2 Diabetes Mellitus.
Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by 18F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic 18F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. 18F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased 18F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.


Statutory health insurance competition in Europe: a four-country comparison.
This paper explores the goals and implementation of reforms introducing choice of and competition among insurers providing statutory health coverage in Belgium, Germany, the Netherlands and Switzerland. In theory, health insurance competition can enhance efficiency in health care administration and delivery only if people have free choice of insurer (consumer mobility), if insurers do not have incentives to select risks, and if insurers are able to influence health service quality and costs. In practice, reforms in the four countries have not always prioritised efficiency and implementation has varied. Differences in policy goals explain some but not all of the differences in implementation. Despite significant investment in risk adjustment, incentives for risk selection remain and consumer mobility is not evenly distributed across the population. Better risk adjustment might make it easier for older and less healthy people to change insurer. Policy makers could also do more to prevent insurers from linking the sale of statutory and voluntary health insurance, particularly where take-up of voluntary coverage is widespread. Collective negotiation between insurers and providers in Belgium, Germany and Switzerland curbs insurers' ability to influence health care quality and costs. Nevertheless, while insurers in the Netherlands have good access to efficiency-enhancing tools, data and capacity constraints and resistance from stakeholders limit the extent to which tools are used. The experience of these countries offers an important lesson to other countries: it is not straightforward to put in place the conditions under which health insurance competition can enhance efficiency. Policy makers should not, therefore, underestimate the challenges involved.


Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study.
Conflicting evidence exists regarding the association between saturated fatty acids (SFAs) and type 2 diabetes. In this longitudinal case-cohort study, we aimed to investigate the prospective associations between objectively measured individual plasma phospholipid SFAs and incident type 2 diabetes in EPIC-InterAct participants. The EPIC-InterAct case-cohort study includes 12,403 people with incident type 2 diabetes and a representative subcohort of 16,154 individuals who were selected from a cohort of 340.234 European participants with 3·99 million person-years of follow-up (the EPIC study). Incident type 2 diabetes was ascertained until Dec 31, 2007, by a review of several sources of evidence. Gas chromatography was used to measure the distribution of fatty acids in plasma phospholipids (mol%); samples from people with type 2 diabetes and subcohort participants were processed in a random order by centre, and laboratory staff were masked to participant characteristics. We estimated country-specific hazard ratios (HRs) for associations per SD of each SFA with incident type 2 diabetes using Prentice-weighted Cox regression, which is weighted for case-cohort sampling, and pooled our findings using random-effects meta-analysis. SFAs accounted for 46% of total plasma phospholipid fatty acids. In adjusted analyses, different individual SFAs were associated with incident type 2 diabetes in opposing directions. Even-chain SFAs that were measured (14:0 [myristic acid], 16:0 [palmitic acid], and 18:0 [stearic acid]) were positively associated with incident type 2 diabetes (HR [95% CI] per SD difference: myristic acid 1·15 [95% CI 1·09-1·22], palmitic acid 1·26 [1·15-1·37], and stearic acid 1·06 [1·00-1·13]). By contrast, measured odd-chain SFAs (15:0 [pentadecanoic acid] and 17:0 [heptadecanoic acid]) were inversely associated with incident type 2 diabetes (HR [95% CI] per 1 SD difference: 0·79 [0·73-0·85] for pentadecanoic acid and 0·67 [0·63-0·71] for heptadecanoic acid), as were measured longer-chain SFAs (20:0 [arachidic acid], 22:0 [behenic acid], 23:0 [tricosanoic acid], and 24:0 [lignoceric acid]), with HRs ranging from 0·72 to 0·81 (95% CIs ranging between 0·61 and 0·92). Our findings were robust to a range of sensitivity analyses. Different individual plasma phospholipid SFAs were associated with incident type 2 diabetes in opposite directions, which suggests that SFAs are not homogeneous in their effects. Our findings emphasise the importance of the recognition of subtypes of these fatty acids. An improved understanding of differences in sources of individual SFAs from dietary intake versus endogenous metabolism is needed. EU FP6 programme, Medical Research Council Epidemiology Unit, Medical Research Council Human Nutrition Research, and Cambridge Lipidomics Biomarker Research Initiative.


Summary of available surveillance data on hepatitis C virus infection from eight Arctic countries, 2012 to 2014.
We summarised available hepatitis C virus (HCV) surveillance data for 2012-14 from Arctic/sub-Arctic countries/regions. We sent a HCV data collection template by email to public health authorities in all jurisdictions. Population statistics obtained from census sources for each country were used to estimate rates of reported acute and chronic/undifferentiated HCV cases. Seven countries with Arctic regions (Canada, Denmark, Finland, Greenland, Norway, Sweden and the United States, represented by the state of Alaska), including three Canadian territories and one province, as well as 11 Russian subnational Arctic regions, completed the data collection template. Data on acute HCV infection during 2014 was available from three Arctic countries and all Russian Arctic regions (rate range 0/100,000 population in Greenland, as well as Nenets and Chukotka Automous Okrugs (Russian subnational Arctic regions) to 3.7/100,000 in the Russian Republic of Komi). The rate of people with chronic/undifferentiated HCV infection in 2014 ranged from 0/100,000 in Greenland to 171.2/100,000 in Alaska. In most countries/regions, the majority of HCV-infected people were male and aged 19-64 years. Differences in surveillance methods preclude direct comparisons of HCV surveillance data between Arctic countries/regions. Our data can inform future efforts to develop standardised approaches to HCV surveillance in the Arctic countries/regions by identifying similarities/differences between the surveillance data collected.


Computerized intrapartum electronic fetal monitoring: analysis of the decision to deliver for fetal distress.
We applied computerized methods to assess the Electronic Fetal Monitoring (EFM) in labor. We analyzed retrospectively the last hour of EFM for 1,370 babies, delivered by emergency Cesarean sections before the onset of pushing (data collected at the John Radcliffe Hospital, Oxford, UK). There were two cohorts according to the reason for intervention: (a) fetal distress, n(1) = 524 and (b) failure to progress and/or malpresentation, n(2) = 846. The cohorts were compared in terms of classical EFM features (baseline, decelerations, variability and accelerations), computed by a dedicated Oxford system for automated analysis--OxSys. In addition, OxSys was employed to simulate current clinical guidelines for the classification of fetal monitoring, i.e. providing in real time a three-tier grading system of the EFM (normal, indeterminate, or abnormal). The computerized features and the simulated guidelines corresponded well to the clinical management and to the actual labor outcome (measured by umbilical arterial pH).