Screening for lung cancer: Does MRI have a role?
While the inauguration of national low dose computed tomographic (LDCT) lung cancer screening programs has started in the USA, other countries remain undecided, awaiting the results of ongoing trials. The continuous technical development achieved by stronger gradients, parallel imaging and shorter echo time has made lung magnetic resonance imaging (MRI) an interesting alternative to CT. For the detection of solid lesions with lung MRI, experimental and clinical studies have shown a threshold size of 3-4mm for nodules, with detection rates of 60-90% for lesions of 5-8mm and close to 100% for lesions of 8mm or larger. From experimental work, the sensitivity for infiltrative, non-solid lesions would be expected to be similarly high as that for solid lesions, but the published data for the MRI detection of lepidic growth type adenocarcinoma is sparse. Moreover, biological features such as a longer T2 time of lung cancer tissue, tissue compliance and a more rapid uptake of contrast material compared to granulomatous diseases, in principle should allow for the multi-parametric characterization of lung pathology. Experience with the clinical use of lung MRI is growing. There are now standardized protocols which are easy to implement on current scanner hardware configurations. The image quality has become more robust and currently ongoing studies will help to further contribute experience with multi-center, multi-vendor and multi-platform implementation of this technology. All of the required prerequisites have now been achieved to allow for a dedicated prospective large scale MRI based lung cancer screening trial to investigate the outcomes from using MRI rather than CT for lung cancer screening. This is driven by the hypothesis that MRI would reach a similarly high sensitivity for the detection of early lung cancer with fewer false positive exams (better specificity) than LDCT. The purpose of this review article is to discuss the potential role of lung MRI for the early detection of lung cancer from a technical point of view and to discuss a few of the possible scenarios for lung cancer screening implementation using this imaging modality. There is little doubt that MRI could play a significant role in lung cancer screening, but how and when will depend on the threshold needed for positive screens (e.g. lesion volume and required diagnostic accuracy), cost-effectiveness and improved patient outcomes from a reduction in the need to follow up benign nodules. Potential applications range from lung MRI as the first choice screening modality to the role of an ad hoc on site test for the detailed evaluation of a subgroup of positive screening results.


Araport: the Arabidopsis information portal.
The Arabidopsis Information Portal (https://www.araport.org) is a new online resource for plant biology research. It houses the Arabidopsis thaliana genome sequence and associated annotation. It was conceived as a framework that allows the research community to develop and release 'modules' that integrate, analyze and visualize Arabidopsis data that may reside at remote sites. The current implementation provides an indexed database of core genomic information. These data are made available through feature-rich web applications that provide search, data mining, and genome browser functionality, and also by bulk download and web services. Araport uses software from the InterMine and JBrowse projects to expose curated data from TAIR, GO, BAR, EBI, UniProt, PubMed and EPIC CoGe. The site also hosts 'science apps,' developed as prototypes for community modules that use dynamic web pages to present data obtained on-demand from third-party servers via RESTful web services. Designed for sustainability, the Arabidopsis Information Portal strategy exploits existing scientific computing infrastructure, adopts a practical mixture of data integration technologies and encourages collaborative enhancement of the resource by its user community.


Senior dental students' experience with Cariogram in a pediatric dentistry clinic.
The study objective was to assess predoctoral dental students' experience with a caries risk assessment computer program in the pediatric dentistry clinic at Marquette University School of Dentistry. In 2005, spring semester sophomore dental students (class of 2008) were introduced to the caries risk assessment computer program "Cariogram." The students received a fifty-minute lecture on caries risk assessment and a demonstration on how to use Cariogram in the clinic. After two years of clinical exposure to Cariogram, sixty-six out of eighty senior dental students completed an anonymous eleven-item questionnaire on their experience with the tool. Each item on the questionnaire was scored on a five-point Likert scale with the exception of two questions. Full- and part-time faculty members in the pediatric dentistry clinic were involved in teaching and supervising students in the use of Cariogram for caries risk assessment after their training and calibration. Forty-five percent of the students who participated in the study agreed that Cariogram was easy to understand, and 18 percent disagreed. Thirty-six percent felt that it was easy to apply, and 25 percent reported that it was useful in determining caries preventive procedures. The students reported that 60 percent of full-time and 33 percent of part-time faculty were knowledgeable about Cariogram use. A majority of the students felt that Cariogram was not easy to understand, and eighty-two percent of them reported that they would not be using Cariogram in their private offices. Future studies should explore reasons why students do not feel inclined to use Cariogram as a caries risk assessment tool in their private practices even after being exposed to the tool in dental school.


Self-Scanned HIFU Ablation of Moving Tissue Using Real-Time Hybrid US-MR Imaging.
High intensity focused ultrasound (HIFU) treatment in the abdominal cavity is challenging due to the respiratory motion. In the self-scanning HIFU ablation method, the focal spot is kept static and the heating pattern is obtained through natural tissue motion. This paper describes a novel approach for modulating the HIFU power during self-scanning in order to compensate for the effect of tissue motion on thermal buildup. The therapy, using hybrid ultrasound (US)/magnetic resonance (MR) imaging, consists of detecting and tracking speckle on US images in order to predict the next tissue position, and modulating the HIFU power according to the tissue speed in order to obtain a rectilinear pattern of uniform temperature elevation. Experiments were conducted on ex vivo tissue subjected to a breathing-like motion generated by an MR-compatible robot and sonicated by a phased array HIFU transducer. US and MR data were free from interferences. For both periodic and non-periodic motion, MR temperature maps showed a substantial improvement in the uniformity of the temperature elevation by using acoustic power modulation. The presented method does not require a learning stage and enables a duty cycle close to 100%, higher average acoustic intensity and avoidance of side lobe effects versus performing HIFU beam steering to compensate tissue motion. To our knowledge, the proposed method provides the first experimental validation of the self-scanning HIFU ablation paradigm via a real-time hybrid MRI/US imaging, opening the path toward self-scanning in vivo therapies.


Zipf's Law for Word Frequencies: Word Forms versus Lemmas in Long Texts.
Zipf's law is a fundamental paradigm in the statistics of written and spoken natural language as well as in other communication systems. We raise the question of the elementary units for which Zipf's law should hold in the most natural way, studying its validity for plain word forms and for the corresponding lemma forms. We analyze several long literary texts comprising four languages, with different levels of morphological complexity. In all cases Zipf's law is fulfilled, in the sense that a power-law distribution of word or lemma frequencies is valid for several orders of magnitude. We investigate the extent to which the word-lemma transformation preserves two parameters of Zipf's law: the exponent and the low-frequency cut-off. We are not able to demonstrate a strict invariance of the tail, as for a few texts both exponents deviate significantly, but we conclude that the exponents are very similar, despite the remarkable transformation that going from words to lemmas represents, considerably affecting all ranges of frequencies. In contrast, the low-frequency cut-offs are less stable, tending to increase substantially after the transformation.


Glycemic index, glycemic load, and pancreatic cancer risk (Canada).
There is some evidence that plasma insulin and postload plasma glucose may be associated with risk of pancreatic cancer. Glycemic index and glycemic load are measures, which allow the carbohydrate content of individual foods to be classified according to their postprandial glycemic effects and hence their effects on circulating insulin levels. Therefore, we examined pancreatic cancer risk in association with glycemic index (GI), glycemic load (GL), and intake of dietary carbohydrate and sugar in a prospective cohort of 49,613 Canadian women enrolled in the National Breast Screening Study (NBSS) who completed a self-administered food frequency questionnaire between 1980 and 1985. Linkages to national cancer and mortality databases yielded data on cancer incidence and deaths, with follow-up ending between 1998 and 2000. During a mean 16.5 years of follow-up, we observed 112 incident pancreatic cancer cases. There was no association between overall glycemic index, glycemic load, total carbohydrate and total sugar intake and pancreatic cancer risk. In multivariate adjusted models, the hazard ratio (HR) for the highest versus lowest quartile levels of overall GI and GL were 1.43 (95% confidence interval [CI]=0.56-3.65, P(trend)=0.58) and 0.80 (95% CI=0.45-1.41, P(trend)=0.41), respectively. Our data suggest that overall glycemic index and glycemic load, as well as total sugar and total carbohydrate intake, are not associated with pancreatic cancer risk. However, given the limited literature regarding the role of diet in the etiology of pancreatic cancer, particularly with respect to glycemic index/load, further investigation is warranted.


Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) blocks differentiation and maintains the expression of pluripotency markers in human embryonic stem cells.
hESCs (human embryonic stem cells) have enormous potential for use in pharmaceutical development and therapeutics; however, to realize this potential, there is a requirement for simple and reproducible cell culture methods that provide adequate numbers of cells of suitable quality. We have discovered a novel way of blocking the spontaneous differentiation of hESCs in the absence of exogenous cytokines by supplementing feeder-free conditions with EHNA [erythro-9-(2-hydroxy-3-nonyl)adenine], an established inhibitor of ADA (adenosine deaminase) and cyclic nucleotide PDE2 (phosphodiesterase 2). hESCs maintained in feeder-free conditions with EHNA for more than ten passages showed no reduction in hESC-associated markers including NANOG, POU5F1 (POU domain class 5 transcription factor 1, also known as Oct-4) and SSEA4 (stage-specific embryonic antigen 4) compared with cells maintained in feeder-free conditions containing bFGF (basic fibroblast growth factor). Spontaneous differentiation was reversibly suppressed by the addition of EHNA, but, upon removing EHNA, hESC populations underwent efficient spontaneous, multi-lineage and directed differentiation. EHNA also acts as a strong blocker of directed neuronal differentiation. Chemically distinct inhibitors of ADA and PDE2 lacked the capacity of EHNA to suppress hESC differentiation, suggesting that the effect is not driven by inhibition of either ADA or PDE2. Preliminary structure-activity relationship analysis found the differentiation-blocking properties of EHNA to reside in a pharmacophore comprising a close adenine mimetic with an extended hydrophobic substituent in the 8- or 9-position. We conclude that EHNA and simple 9-alkyladenines can block directed neuronal and spontaneous differentiation in the absence of exogenous cytokine addition, and may provide a useful replacement for bFGF in large-scale or cGMP-compliant processes.


Transmission of a psychometric indicator for liability to schizophrenia in normal families.
The genetic analysis of schizophrenia would be facilitated by identification of a heritable correlate of liability. Deviance on an index of Minnesota Multiphasic Personality Inventory (MMPI) signs is associated with the disease phenotype; the familial aggregation and mode of transmission of this continuous psychometric indicator have yet to be established. In this paper, we examine the indicator through commingling analysis and segregation analysis with both the mixed and unified models on 65 nuclear families containing 211 normal individuals. Evidence for a high degree of familiality is found. Analysis of untransformed data under a conditional likelihood provides evidence for Mendelian transmission of a major gene with commingling of two distributions. The frequency of the "high index score" allele is 0.15, with the gene accounting for 31% of the total population variance; such a locus would be relevant to the study of psychopathology as 28% of the population would carry at least one deviant allele. When power-transformed scores are used to eliminate skewness, there is evidence for one distribution and it is not possible to distinguish single gene from multifactorial (polygenic or cultural) inheritance. While our findings regarding mode of transmission must be interpreted cautiously and confirmation of a single locus requires further study, demonstration of familiality warrants continued investigation of the index as an indicator of liability for schizophrenia.


Thymoquinone Inhibition of Acquisition and Expression of Alcohol-Induced Behavioral Sensitization.
Repeated low doses of alcohol have been shown to progressively enhance locomotor activity in mice, and this phenomenon is designated as behavioral sensitization. Thymoquinone, a major active component of Nigella sativa oil has been investigated in a number of studies for its neuroprotective effects against a variety of ailments. This study was conducted to explore the therapeutic potential of thymoquinone on the acquisition and expression of alcohol-induced behavioral sensitization. Mice treated with alcohol (2.2 g/kg/day) or saline for 13 days and subsequently challenged with an acute alcohol dose (2.2 g/kg) 5 days later were orally administered acute doses of thymoquinone (10, 20 and 30 mg/kg). Thymoquinone subacute treatment with all doses throughout alcohol exposure significantly inhibited both the development and expression phases of alcohol behavioral sensitization in a dose-dependent manner. However, acute treatment with thymoquinone (30 mg/kg) only reversed the expression phase of sensitization. These findings are explained in terms of the known GABA promoting action of thymoquinone in relation to the motive circuit within the limbic component of the basal ganglia. It is concluded that thymoquinone may be a potential therapeutic option for the treatment and prevention of alcohol induced behavioral sensitization.


The impact of recent CHIP eligibility expansions on children's insurance coverage, 2008-12.
Following the reauthorization of the Children's Health Insurance Program (CHIP) in 2009, fifteen states raised their CHIP income eligibility thresholds to further reduce uninsurance among children. We examined the impact of these expansions on uninsurance, public insurance, and private insurance among children who became newly eligible for CHIP after the expansions. Using a difference-in-differences approach, we estimated that the expansions reduced uninsurance by 1.1 percentage points among the newly eligible, cutting their uninsurance rate by nearly 15 percent. Public coverage increased by 2.9 percentage points, with variations in take-up among the states. A better understanding of these state-level differences in take-up could inform efforts to enroll children who remain uninsured but are eligible for CHIP. CHIP is up for reauthorization in 2015, and further funding will be needed to maintain the program, which provides insurance to children who might not have access to affordable private coverage.


Auditory sensitivity in opiate addicts with and without a history of noise exposure.
Several case reports suggest that some individuals are susceptible to hearing loss from opioids. A combination of noise and opium exposure is possible in either occupational setting such as military service or recreational settings. According to the Drug Enforcement Agency of the U.S. Department of Justice, prescriptions for opiate-based drugs have skyrocketed in the past decade. Since both opium and noise independently can cause hearing loss, it is important to know the prevalence of hearing loss among individuals who are exposed to opium or both opium and noise. The purpose of this research was to evaluate auditory sensitivity in individuals with a history of opium abuse and/or occupational or nonoccupational noise exposure. Twenty-three men who reported opiate abuse served as participants in the study. Four of the individuals reported no history of noise exposure, 12 reported hobby-related noise exposure, 7 reported occupational noise exposure including 2 who also reported hobby-related noise exposure. Fifty percent (2/4) of the individuals without any noise exposure had a hearing loss confirming previous reports that some of the population is vulnerable to the ototoxic effects of opioids. The percentage of population with hearing loss increased with hobby-related (58%) and occupational noise exposure (100%). Mixed MANOVA revealed a significant ear, frequency, and noise exposure interaction. Health professionals need to be aware of the possible ototoxic effects of opioids, since early detection of hearing loss from opium abuse may lead to cessation of abuse and further progression of hearing loss. The possibility that opium abuse may interact with noise exposure in determining auditory thresholds needs to be considered in noise exposed individuals who are addicted to opiates. Possible mechanisms of cochlear damage from opium abuse, possible reasons for individual susceptibility, and recommendations for future studies are presented in the article.


Older fallers with poor working memory overestimate their postural limits.
To compare the accuracy of perceived postural limits between older fallers with good working memory and those with poor working memory. Cross-sectional study. Research laboratory. Thirty-three community-dwelling older adults with a history of falls. Not applicable. We measured the accuracy of perceived postural limits by using the perceived reach test in 33 fallers. The difference between the verbal digits forward test score and the verbal digits backward test score was used to provide an index of the central executive component of working memory. Participants were then allocated into 2 groups: (1) good working memory or (2) poor working memory. Comparisons of group characteristics and scores were undertaken by using Student independent-sample t tests for differences in means between those with good working memory and those with poor memory. One hierarchical linear regression model was constructed to determine the independent association of the central executive component of working memory with the accuracy of older fallers' perceived reach capacity. There was a significant difference in the mean percentage error in perceived reach between older fallers with good working memory and those with poor working memory (P=.01). The verbal digit span difference score was independently associated with the percentage error in perceived reach. The verbal digit span difference score resulted in an R(2) change of 18.2% and significantly improved the regression model (F(1,26) change, 7.45; P=.01). Our novel results suggest that impaired executive functioning may increase falls risk by impairing older adults' judgment in motor planning for daily activities. However, future studies with larger sample sizes are needed to confirm our current results.


Jumping between protein conformers using normal modes.
The relationship between the normal modes of a protein and its functional conformational change has been studied for decades. However, using this relationship in a predictive context remains a challenge. In this work, we demonstrate that, starting from a given protein conformer, it is possible to generate in a single step model conformers that are less than 1 Å (Cα -RMSD) from the conformer which is the known endpoint of the conformational change, particularly when the conformational change is collective in nature. Such accurate model conformers can be generated by following either the so-called robust or the 50 lowest-frequency modes obtained with various Elastic Network Models (ENMs). Interestingly, the quality of many of these models compares well with actual crystal structures, as assessed by the ROSETTA scoring function and PROCHECK. The most accurate and best quality conformers obtained in the present study were generated by using the 50 lowest-frequency modes of an all-atom ENM. However, with less than ten robust modes, which are identified without any prior knowledge of the nature of the conformational change, nearly 90% of the motion described by the 50 lowest-frequency modes of a protein can be captured. Such results strongly suggest that exploring the robust modes of ENMs may prove efficient for sampling the functionally relevant conformational repertoire of many proteins. © 2017 Wiley Periodicals, Inc.


Pediatric inflatable bouncer-related injuries in the United States, 1990-2010.
To investigate inflatable bouncer-related injuries to children in the United States. Records were analyzed from the National Electronic Injury Surveillance System for patients ≤17 years old treated in US emergency departments (EDs) for inflatable bouncer-related injuries from 1990 to 2010. An estimated 64 657 (95% confidence interval [CI]: 32 420-96 893) children ≤17 years of age with inflatable bouncer-related injuries were treated in US EDs from 1990 to 2010. From 1995 to 2010, there was a statistically significant 15-fold increase in the number and rate of these injuries, with an average annual rate of 5.28 injuries per 100 000 US children (95% CI: 2.62-7.95). The increase was more rapid during recent years, with the annual injury number and rate more than doubling between 2008 and 2010. In 2010, a total of 31 children per day were treated in US EDs for an inflatable bouncer-related injury, which equals a child every 46 minutes nationally. A majority of patients were male (54.6%), and the mean patient age was 7.50 years (95% CI: 7.17-7.83). Most injuries were fractures (27.5%) and strains or sprains (27.3%), and most injuries occurred to the lower (32.9%) or upper (29.7%) extremities. Most injuries occurred at a place of sports or recreation (43.7%) or at home (37.5%), and 3.4% of injured children were hospitalized or kept for <24 hours for observation. The number and rate of pediatric inflatable bouncer-related injuries have increased rapidly in recent years. This increase, along with similarities to trampoline-related injuries, underscores the need for guidelines for safer bouncer usage and improvements in bouncer design to prevent these injuries among children.


Making new vaccines affordable: a comparison of financing processes used to develop and deploy new meningococcal and pneumococcal conjugate vaccines.
Mechanisms to increase access to health products are varied and controversial. Two innovative mechanisms have been used to accelerate the development of low-price supply lines for conjugate vaccines. The Meningitis Vaccine Project is a so-called push mechanism that facilitated technology transfer to an Indian company to establish capacity to manufacture a vaccine. The Advanced Market Commitment for pneumococcal vaccines is a so-called pull mechanism that guarantees companies a supplement paid in addition to the purchase price for vaccines for a specific period. We compare these approaches, identifying key dimensions of each and considering their potential for replication. We also discuss issues that the Global Alliance for Vaccines and Immunisation (GAVI) face now that these new vaccines are available. Progress towards GAVI's strategic aims is needed and funding is crucial. Approaches that decrease the financial pressure on GAVI and greatly increase political and financial engagement by low-income countries should also be considered.


Approach to diagnosis of Parkinson disease.
To review the clinical features of Parkinson disease (PD) and other causes of motor parkinsonism with an emphasis on diagnosis in elderly patients. SOURCES OF INFORMATION MEDLINE: and Google Scholar were searched for original research articles describing clinical diagnosis of parkinsonism. Consensus statements and articles summarizing diagnostic criteria for parkinsonian syndromes were also reviewed. Most evidence was levels II or III. Diagnosis of PD is made clinically and can be challenging. In older patients, PD can present with general functional decline and nonspecific symptoms. Clinical criteria for diagnosing PD and the TRAP mnemonic can be helpful. A 2-week trial of levodopa-carbidopa treatment can be considered. Specific signs and a minimal response to levodopa treatment suggest other causes of parkinsonism. Clinical features of other causes of parkinsonism are reviewed in the article. Parkinsonism and PD are common in older patients. Family physicians should consider parkinsonism in the differential diagnosis of patients who have falls and exhibit general functional decline.


Determinants of insecticide-treated net ownership and utilization among pregnant women in Nigeria.
Malaria during pregnancy is a major public health problem in Nigeria leading to increase in the risk of maternal mortality, low birth weight and infant mortality. This paper is aimed at highlighting key predictors of the ownership of insecticide treated nets (ITNs) and its use among pregnant women in Nigeria. A total of 2348 pregnant women were selected by a multi-stage probability sampling technique. Structured interview schedule was used to elicit information on socio-demographic characteristics, ITN ownership, use, knowledge, behaviour and practices. Logistic regression was used to detect predictors of two indicators: ITN ownership, and ITN use in pregnancy among those who owned ITNs. ITN ownership was low; only 28.8% owned ITNs. Key predictors of ITN ownership included women who knew that ITNs prevent malaria (OR = 3.85; p < 0001); and registration at antenatal clinics (OR = 1.34; p = 0.003). The use of ITNs was equally low with only 7.5% of all pregnant women, and 25.7% of all pregnant women who owned ITNs sleeping under a net. The predictors of ITN use in pregnancy among women who owned ITNs (N = 677) identified by logistic regression were: urban residence (OR = 1.87; p = 0.001); knowledge that ITNs prevent malaria (OR = 2.93; p < 0001) and not holding misconceptions about malaria prevention (OR = 1.56; p = 0.036). Educational level was not significantly related to any of the two outcome variables. Although registration at ANC is significantly associated with ownership of a bednet (perhaps through free ITN distribution) this does not translate to significant use of ITNs. ITN use lagged well behind ITN ownership. This seems to suggest that the current mass distribution of ITNs at antenatal facilities and community levels may not necessarily lead to use unless it is accompanied by behaviour change interventions that address the community level perceptions, misconceptions and positively position ITN as an effective prevention device to prevent malaria.


Quality-of-life scores in neurogenic thoracic outlet syndrome patients undergoing first rib resection and scalenectomy.
First rib resection and scalenectomy (FRRS) has been shown to improve short-term quality of life (QOL) in the treatment of neurogenic thoracic outlet syndrome (NTOS). Long-term benefits are not well studied but are believed to decrease over time. Our objective was to evaluate long-term NTOS outcomes using validated QOL instruments. We identified 162 NTOS patients aged ≥18 years treated by FRRS from 2003 to 2010 after they had not responded to conservative management. The patients were mailed three surveys to assess QOL (Short-Form 12 [SF-12], Brief Pain Inventory [BPI], and Cervical Brachial Symptom Questionnaire [CBSQ]), with five total outcomes measures including the SF-12 Physical Component Score (PCS), SF-12 Mental Component Score (MCS), BPI severity, BPI interference, and CBSQ score. Demographic and clinical data were extracted from patient records. Each FRRS was categorized based on postoperative clinical assessment as successful, failed, or leading to recurrent symptoms. Survey yield was 53.7% (n = 87) with mean follow-up of 44.7 months (range, 12.4-91.9 months). There was no significant difference in QOL scores associated with long-term compared with short-term follow-up. Significantly poorer scores on all instruments were associated with comorbid chronic pain syndromes, opioid use, and unfavorable clinical assessment (P < .05). Significantly poorer scores on select instruments were associated with smoking (BPI both; P < .02), age ≥40 years (SF-12 PCS, BPI interference, CBSQ; P < .03), neck and/or shoulder disease (SF-12 both, BPI both; P < .01), postoperative injections (BPI both, CBSQ; P < .05), and complications (SF-12 PCS, CBSQ; P < .05). A positive preoperative scalene block was not significantly associated with long-term QOL scores. The QOL after FRRS shows no significant difference with longer follow-up. Clinical assessment reflects patient-reported outcomes and can gauge postoperative improvement. Patient factors, particularly comorbidities and opioid use, are more predictive of long-term QOL than is preoperative scalene block and should also be considered when selecting patients for surgical intervention.


Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in people with non-valvular atrial fibrillation.
Chronic anticoagulation with vitamin K antagonists (VKAs) prevents ischaemic stroke and systemic embolism in people with non-valvular atrial fibrillation (AF) but dose adjustment, coagulation monitoring and bleeding limits its use. Direct thrombin inhibitors (DTIs) are under investigation as potential alternatives. To assess (1) the comparative efficacy of long-term anticoagulation using DTIs versus VKAs on vascular deaths and ischaemic events in people with non-valvular AF, and (2) the comparative safety of chronic anticoagulation using DTIs versus VKAs on (a) fatal and non-fatal major bleeding events including haemorrhagic strokes, (b) adverse events other than bleeding and ischaemic events that lead to treatment discontinuation and (c) all-cause mortality in people with non-valvular AF. We searched the Cochrane Stroke Group Trials Register (July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, May 2013), MEDLINE (1950 to July 2013), EMBASE (1980 to October 2013), LILACS (1982 to October 2013) and trials registers (September 2013). We also searched the websites of clinical trials and pharmaceutical companies and handsearched the reference lists of articles and conference proceedings. Randomised controlled trials (RCTs) comparing DTIs versus VKAs for prevention of stroke and systemic embolism in people with non-valvular AF. All three review authors independently performed data extraction and assessment of risk of bias. Primary analyses compared all DTIs combined versus warfarin. We performed post hoc analyses excluding ximelagatran because this drug was withdrawn from the market owing to safety concerns. We included eight studies involving a total of 27,557 participants with non-valvular AF and one or more risk factors for stroke; 26,601 of them were assigned to standard doses groups and included in the primary analysis. The DTIs: dabigatran 110 mg twice daily and 150 mg twice daily (three studies, 12,355 participants), AZD0837 300 mg once per day (two studies, 233 participants) and ximelagatran 36 mg twice per day (three studies, 3726 participants) were compared with the VKA warfarin (10,287 participants). Overall risk of bias and statistical heterogeneity of the studies included were low.The odds of vascular death and ischaemic events were not significantly different between all DTIs and warfarin (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.85 to 1.05). Sensitivity analysis by dose of dabigatran on reduction in ischaemic events and vascular mortality indicated that dabigatran 150 mg twice daily was superior to warfarin although the effect estimate was of borderline statistical significance (OR 0.86, 95% CI 0.75 to 0.99). Sensitivity analyses by other factors did not alter the results. Fatal and non-fatal major bleeding events, including haemorrhagic strokes, were less frequent with the DTIs (OR 0.87, 95% CI 0.78 to 0.97). Adverse events that led to discontinuation of treatment were significantly more frequent with the DTIs (OR 2.18, 95% CI 1.82 to 2.61). All-cause mortality was similar between DTIs and warfarin (OR 0.91, 95% CI 0.83 to 1.01). DTIs were as efficacious as VKAs for the composite outcome of vascular death and ischaemic events and only the dose of dabigatran 150 mg twice daily was found to be superior to warfarin. DTIs were associated with fewer major haemorrhagic events, including haemorrhagic strokes. Adverse events that led to discontinuation of treatment occurred more frequently with the DTIs. We detected no difference in death from all causes.


Local adeno-associated virus-mediated interleukin 10 gene transfer has disease-modifying effects in a murine model of Sjögren's syndrome.
Female nonobese diabetic (NOD) mice develop spontaneous autoimmune sialadenitis and loss of salivary flow, and are a widely used model of Sjögren's syndrome. We examined the feasibility of local salivary gland immunomodulatory gene delivery to alter these sequelae in NOD mice. We constructed recombinant adeno-associated virus (rAAV) vectors encoding either human interleukin 10 (rAAVhIL-10) or beta-galactosidase (rAAVLacZ, control vector). Mice received rAAVhIL-10 or rAAVLacZ by retrograde submandibular ductal instillation either at age 8 weeks (early, before onset of sialadenitis), or at 16 weeks (late, after onset of sialadenitis). As a systemic treatment control, separate mice received intramuscular delivery of rAAVhIL-10 at each time point. Both submandibular and intramuscular delivery of vector led to low circulating levels of hIL-10. After submandibular administration of rAAVhIL-10, salivary flow rates at 20 weeks for both the early and late treatment groups were significantly higher than for both rAAVLacZ-administered and untreated mice. Systemic delivery of rAAVhIL-10 led to improved salivary flow in the late treatment group. Inflammatory infiltrates in submandibular glands, however, were significantly reduced only in mice receiving rAAVhIL-10 locally in the salivary gland compared with mice receiving this vector intramuscularly, or rAAVLacZ or no treatment. In addition, after submandibular rAAVhIL-10 delivery, NOD mice exhibited significantly lower blood glucose, and higher serum insulin, levels than all other groups, indicating some systemic benefit of this treatment. These studies show that expression of hIL-10 by rAAV vectors can have disease-modifying effects in the salivary glands of NOD mice, and suggest that local immunomodulatory gene transfer may be useful for managing the salivary gland pathology in Sjögren's syndrome.


Gambling in Britain: the application of restraint erosion theory.
To provide an overview of gambling and problem gambling in Britain, including historical background, current regulations and the recognition, prevalence and treatment of problem gambling. A new theory, Gambling Restraint Erosion Theory (GRET), is used as a framework for understanding the history of gambling regulation in Britain in the 20th century and evidence about the prevalence of gambling and problem gambling, as well as public attitudes towards gambling, in Britain in the first decade of the 21st century. Restraints on gambling were progressively dismantled as regulation moved from partial prohibition, to tolerance, and then to liberalization by the turn of the millennium. British adult gambling prevalence surveys carried out in 1999/2000, 2006/07 and 2009/10 suggest that the British public is still relatively restrained in its engagement in gambling, and is still suspicious of gambling. There is evidence from the last of those surveys that engagement in some forms of gambling, and the prevalence of problem gambling, have risen, and that attitudes have become less negative towards gambling. Restraints which kept British gambling circumscribed, and the prevalence of problem gambling low, may be in the process of being eroded. Meanwhile, an effective public health response to problem gambling is constrained by lack of Department of Health interest and a failure to develop a research and treatment base independent of the gambling industry.


Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer.
We have recently reported a novel function for carbonyl reductase (CR), namely, its ability to modulate the metastatic potential of malignant mouse cells. Because there are currently no data addressing a similar function for CR in human cancers, the aim of this study was to assess a correlation between survival and metastasis, and CR level in epithelial ovarian cancer. Using anti-CR antibody, immunohistochemical staining was performed on 73 epithelial ovarian cancers, 13 borderline malignant tumours, and 25 benign ovarian tumours for a total of 111 specimens. The combined rate for strongly and weakly positive reactions for CR was 32.0% for benign tumours, 38.5% for borderline malignant tumours, and 61.6% for ovarian cancers. The CR-positive rate was 35.7% (weakly positive alone) for ovarian cancers with retroperitoneal lymph node (RLN) metastasis and 67.8% for those without RLN metastasis (P< 0.05). The 5-year survival rate was 62.7% for the patients with CR-negative cancer and 86.1% for those with CR-positive cancer (P< 0.05). The present results indicate that decreased CR expression in epithelial ovarian cancer is associated with RLN metastasis and poor survival.


Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children.
To gain insight into the long-term impact of vagus nerve stimulation (with VNS Therapy) in children with drug-resistant epilepsy, we conducted the largest retrospective multicenter study to date over an extended follow-up period of up to 24 months. The primary objective was to assess change in seizure frequency of the predominant seizure type (defined as the most disabling seizure) following VNS device implantation. Treating physicians collected data from patient records from baseline to 6, 12, and 24 months of follow-up. The analysis population included 347 children (aged 6 months to 17.9 years at the time of implant). At 6, 12, and 24 months after implantation, 32.5%, 37.6%, and 43.8%, respectively, of patients had ≥ 50% reduction in baseline seizure frequency of the predominant seizure type. The responder rate was higher in a subgroup of patients who had no change in antiepileptic drugs (AEDs) during the study. Favorable results were also evident for all secondary outcome measures including changes in seizure duration, ictal severity, postictal severity, quality of life, clinical global impression of improvement, and safety. Post hoc analyses demonstrated a statistically significant correlation between VNS total charge delivered per day and an increase in response rate. VNS Therapy is indicated as adjunctive therapy in children with focal, structural epilepsies, who for any reason are not good candidates for surgical treatment following the trial of two or more AEDs. Children with predominantly generalized seizures from genetic, structural epilepsies, like Dravet syndrome or Lennox-Gastaut syndrome, could also benefit from VNS Therapy. The results demonstrate that adjunctive VNS Therapy in children with drug-resistant epilepsy reduces seizure frequency and is well tolerated over a 2-year follow-up period. No new safety issues were identified. A post hoc analysis revealed a dose-response correlation for VNS in patients with epilepsy.


The Association between Sulfonylurea Use and All-Cause and Cardiovascular Mortality: A Meta-Analysis with Trial Sequential Analysis of Randomized Clinical Trials.
Sulfonylureas are an effective and inexpensive treatment for type 2 diabetes. There is conflicting data about the safety of these drugs regarding mortality and cardiovascular outcomes. The objective of the present study was to evaluate the safety of the sulfonylureas most frequently used and to use trial sequential analysis (TSA) to analyze whether the available sample was powered enough to support the results. Electronic databases were reviewed from 1946 (Embase) or 1966 (MEDLINE) up to 31 December 2014. Randomized clinical trials (RCTs) of at least 52 wk in duration evaluating second- or third-generation sulfonylureas in the treatment of adults with type 2 diabetes and reporting outcomes of interest were included. Primary outcomes were all-cause and cardiovascular mortality. Additionally, myocardial infarction and stroke events were evaluated. Data were summarized with Peto odds ratios (ORs), and the reliability of the results was evaluated with TSA. Forty-seven RCTs with 37,650 patients and 890 deaths in total were included. Sulfonylureas were not associated with all-cause (OR 1.12 [95% CI 0.96 to 1.30]) or cardiovascular mortality (OR 1.12 [95% CI 0.87 to 1.42]). Sulfonylureas were also not associated with increased risk of myocardial infarction (OR 0.92 [95% CI 0.76 to 1.12]) or stroke (OR 1.16 [95% CI 0.81 to 1.66]). TSA could discard an absolute difference of 0.5% between the treatments, which was considered the minimal clinically significant difference. The major limitation of this review was the inclusion of studies not designed to evaluate safety outcomes. Sulfonylureas are not associated with increased risk for all-cause mortality, cardiovascular mortality, myocardial infarction, or stroke. Current evidence supports the safety of sulfonylureas; an absolute risk of 0.5% could be firmly discarded. PROSPERO CRD42014004330.


Granulocyte and monocyte adsorption apheresis for refractory skin diseases due to activated neutrophils, psoriasis, and associated arthropathy.
Granulocyte and monocyte adsorption apheresis (GMA), an extracorporeal apheresis instrument whose column contains cellulose acetate (CA) beads, is designed to remove activated granulocytes and monocytes. We previously demonstrated that GMA was useful for treating neutrophilic dermatoses and associated arthropathy as it adsorbs Mac-1 (CD11b/CD18)-expressing neutrophils to the CA beads by the binding of complement component (iC3b) and CD11b expressed on activated neutrophils. The objective of this study is to further assess the clinical effectiveness of GMA in the treatment of neutrophilic dermatoses and associated arthropathy. The effect of GMA for skin lesions and joint lesions was assessed in 44 and 23 patients, respectively. Mac-1 expression on peripheral neutrophils was measured by flow cytometry. Skin lesions and arthropathy improved in 39 of 44 patients (88.6%) and 22 of 23 (95.6%), respectively. Mac-1 (CD11b/CD18) expression on the peripheral neutrophils, 27.1 ± 6.66 MFI (mean fluorescence intensity) before treatment, was reduced to 17.9 ± 3.02 MFI by GMA (P < 0.05). Clinical effectiveness of GMA for the treatment of intractable neutrophilic dermatoses and associated arthropathy was further confirmed.


Genomic selection for the improvement of antibody response to Newcastle disease and avian influenza virus in chickens.
Newcastle disease (ND) and avian influenza (AI) are the most feared diseases in the poultry industry worldwide. They can cause flock mortality up to 100%, resulting in a catastrophic economic loss. This is the first study to investigate the feasibility of genomic selection for antibody response to Newcastle disease virus (Ab-NDV) and antibody response to Avian Influenza virus (Ab-AIV) in chickens. The data were collected from a crossbred population. Breeding values for Ab-NDV and Ab-AIV were estimated using a pedigree-based best linear unbiased prediction model (BLUP) and a genomic best linear unbiased prediction model (GBLUP). Single-trait and multiple-trait analyses were implemented. According to the analysis using the pedigree-based model, the heritability for Ab-NDV estimated from the single-trait and multiple-trait models was 0.478 and 0.487, respectively. The heritability for Ab-AIV estimated from the two models was 0.301 and 0.291, respectively. The estimated genetic correlation between the two traits was 0.438. A four-fold cross-validation was used to assess the accuracy of the estimated breeding values (EBV) in the two validation scenarios. In the family sample scenario each half-sib family is randomly allocated to one of four subsets and in the random sample scenario the individuals are randomly divided into four subsets. In the family sample scenario, compared with the pedigree-based model, the accuracy of the genomic prediction increased from 0.086 to 0.237 for Ab-NDV and from 0.080 to 0.347 for Ab-AIV. In the random sample scenario, the accuracy was improved from 0.389 to 0.427 for Ab-NDV and from 0.281 to 0.367 for Ab-AIV. The multiple-trait GBLUP model led to a slightly higher accuracy of genomic prediction for both traits. These results indicate that genomic selection for antibody response to ND and AI in chickens is promising.


An 8-week high-fat diet induces obesity and insulin resistance with small changes in the muscle transcriptome of C57BL/6J mice.
Skeletal muscle is responsible for most of the insulin-stimulated glucose uptake and metabolism. Therefore, it plays an important role in the development of insulin resistance, one of the characteristics of the metabolic syndrome (MS). As the prevalence of the MS is increasing, there is an urgent need for more effective intervention strategies. C57BL/6J mice were fed an 8-week low-fat diet (10 kcal%; LFD) or high-fat diet (45 kcal%; HFD). Microarray analysis was performed by using two comparisons: (1) 8-week HFD transcriptome versus 8-week LFD transcriptome and (2) transcriptome of mice sacrificed at the start of the intervention versus 8-week LFD transcriptome and 8-week HFD transcriptome, respectively. Although an 8-week HFD induced obesity and impaired insulin sensitivity, HFD-responsive changes in the muscle transcriptome were relatively small (<1.3-fold). In fact, 8-weeks of aging induced more pronounced changes than an HFD. One comparison revealed the transcriptional downregulation of the mito- gen-activated protein kinase cascade, whereas both comparisons showed the upregulation of fatty acid oxidation, demonstrating that the two comparison strategies are confirmative as well as complementary. We suggest using complementary analysis strategies in the genome-wide search for gene expression changes induced by mild interventions, such as an HFD.


Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies.
The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies because of its high rate of deregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K. Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. For each cell line, 10 mice were treated in each of the experimental arms tested. Moreover, in vitro experiments in 21 cell lines (MTT, immunoblot analysis, plasmid transfection, reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response. All statistical tests were two-sided. MSC2363318A decreased tumor growth and metastases in multiple murine orthotopic models of ovarian (SKOV3ip1, HeyA8, and Igrov1) and uterine (Hec1a) cancer by reducing proliferation and angiogenesis and increasing cell death. Statistically significant prolonged overall survival was achieved with combination MSC2363318A and paclitaxel in the SKUT2 (endometrioid) uterine cancer mouse model ( P < .001). Mice treated with combination MSC2363318A and paclitaxel had the longest overall survival (mean = 104.2 days, 95% confidence interval [CI] = 97.0 to 111.4) compared with those treated with vehicle (mean = 61.9 days, 95% CI = 46.3 to 77.5), MSC2363318A alone (mean = 89.7 days, 95% CI = 83.0 to 96.4), and paclitaxel alone (mean = 73.6 days, 95% CI = 53.4 to 93.8). Regression and stabilization of established tumors in the Ishikawa (endometrioid) uterine cancer model was observed in mice treated with combination MSC2363318A and paclitaxel. Synergy between MSC2363318A and paclitaxel was observed in vitro in cell lines that had an IC50 of 5 µM or greater. RPPA results identified YAP1 as a candidate marker to predict cell lines that were most sensitive to MSC2363318A (R = 0.54, P = .02). After establishment of a murine ovarian cancer model of adaptive anti-angiogenic resistance (SKOV3ip1-luciferase), we demonstrate that resensitization to bevacizumab occurs with the addition of MSC2363318A, resulting in improved overall survival ( P = .01) using the Kaplan-Meier method. Mice treated with bevacizumab induction followed by MSC2363318A had the longest overall survival (mean = 66.0 days, 95% CI = 53.9 to 78.1) compared with mice treated with control (mean = 42.0 days, 95% CI = 31.4 to 52.6) and bevacizumab-sensitive mice (mean = 47.2 days; 95% CI = 37.5 to 56.9). MSC2363318A has therapeutic efficacy in multiple preclinical models of ovarian and uterine cancer. These findings support clinical development of a dual AKT/P70S6K inhibitor.


Alpha-adrenergic receptor stimulation during simulated ischemia and reperfusion in canine cardiac Purkinje fibers.
We studied the effects of alpha-adrenergic receptor stimulation and calcium on automaticity of isolated canine Purkinje fibers during simulated ischemia and reperfusion. Ischemia included acidosis (pH 6.7), hypoxia (PO2 = 10-25 mm Hg), hyperkalemia (10 mM K+), and either normal or elevated [Ca2+]o (2.7 or 10.8 mM). Control automatic rate and maximum diastolic potential were 18 +/- 2 beats/min and -94 +/- 1 mV, respectively. Simulated ischemia led to depolarization (to -60 +/- 1 mV), cessation of normal automaticity, and in 21% of fibers, bursts of an abnormal automatic rhythm. Phenylephrine, 5 X 10(-8) M, increased the incidence of the automatic rhythm during ischemia to 44%; this effect was blocked by prazosin but not by propranolol. During reperfusion after simulated ischemia at 2.7 mM [Ca2+]o, automatic rhythm and maximum diastolic potential returned toward control values; after simulated ischemia at 10.8 mM [Ca2+]o, automatic rates were greater than those seen after normal Ca2+ ischemia and were associated with sustained membrane depolarization. Phenylephrine (5 X 10(-8) M) at 2.7 mM [Ca2+]o rapidly restored membrane potential during reperfusion, an effect that was blocked by prazosin. At 10.8 mM [Ca2+]o, phenylephrine also restored membrane potential during reperfusion and blunted the increase in reperfusion rate induced by high [Ca2+]o alone. These effects were blocked by propranolol but not by prazosin. Our results show that the effects of phenylephrine on automatic rhythms during simulated ischemia are blocked by alpha-adrenergic receptor antagonists and that rhythms occurring during reperfusion have alpha- and beta-adrenergic receptor components.


A qualitative study conducted in the USA exploring Latino fathers' beliefs, attitudes and practices related to their young children's eating, physical activity and sedentary behaviours.
Increasing evidence documents fathers' influential role in their children's eating, physical activity (PA) and sedentary behaviours (SB). We aimed to expand limited existing research examining fathers' influence in these areas by exploring Latino fathers' beliefs, attitudes and practices related to eating, PA and SB of their young children. Seven focus group discussions were conducted in Spanish with Latino fathers (n 28) of children aged 2-8 years. Audio recordings were transcribed and translated verbatim without identifiers. Data were analysed using thematic analysis to identify key concepts and themes using NVivo 11 software. Fathers expressed positive beliefs and attitudes about the importance of healthy eating for their young children, themselves and their families. Nevertheless, the majority reported familial practices including eating out, getting take-out, etc. that have been linked to increased obesity risk among Latino children. Fathers were more involved and engaged in children's PA than eating and feeding. However, several fathers reported engaging predominantly in sedentary activities with their children, appeared permissive of children's sedentary habits and struggled to set limits on children's screen-time. We provide new information on Latino fathers' beliefs and child feeding and PA practices that may provide important targets for interventions aimed at promoting healthful eating and PA behaviours of Latino children. Future research should further quantify the influence of Latino fathers' parenting styles and practices on development of children's eating, PA and SB. This information is needed to identify risk factors amenable to interventions and to design culturally appropriate parenting and family-based interventions targeting Latino children's home environment and designed to meet this ethnic group's specific needs.


High internal ionic liquid phase emulsion stabilized by metal-organic frameworks.
The emulsification of metal-organic frameworks (MOFs) for the two immiscible phases of water and ionic liquid (IL) was investigated for the first time. It was found that Ni-BDC (BDC = 1,4-dicarboxybenzene) can emulsify water and ILs and favor the formation of high internal phase emulsions (HIPEs) under certain experimental conditions. The microstructures of the HIPEs were characterized by confocal laser scanning microscopy using a fluorescent dye Rhodamine B, which proves that the HIPEs are the IL-in-water type. Further results reveal that the HIPE forms during the IL-in-water to water-in-IL emulsion inversion. The possibilities of the HIPE formation by other MOFs (Cu-BDC and Zn-BDC) were explored and the mechanism for HIPE formation was discussed. The MOF-stabilized HIPE was applied to the in situ synthesis of a MOF/polymer composite by HIPE polymerization. The macroporous MOF/polyacrylamide network and MOF/polystyrene microspheres were obtained from the HIPEs, respectively.


Dispersal and other population parameters of Aedes aegypti in an African village and their possible significance in epidemiology of vector-borne diseases.
Dispersal of Aedes aegypti aegypti adults within Shauri Moyo, an African village in the Rabai area north of Mombasa, Kenya, was studied using the mark-release-recapture method. A total of 920 mosquitoes were captured and uniquely marked, of which 828 (90%) were released and 332 (40%) recaptured. A great majority of mosquitoes were recaptured once, but some individuals were recaptured up to 10 times. Most females visited 1 or 2 houses (40.8%, 44.9%, respectively), but there were females that visited as many as 5 houses. Mosquito movement among houses of the village is summarized in tables. Dispersal ability of Aedes aegypti females was d = 0.592 and males d = 0.433. The maximum distance females and males moved per 24 hr was 154 m and 113 m, respectively. The mean distance rate was 57.0 m/day for females and 44.2 m/day for males. The size of the mosquito population at Shauri Moyo village was estimated to be 331.1 +/- 146.5 using the Lincoln index method, 533.3 by the Fisher and Ford method, 270.3 +/- 179.5 by Bailey's triple catch method and 380.1 +/- 92.9 by the Jolly-Seber method. The mean female and male survival was 10.7 and 5.8 days, respectively. The maximum survival of females was 42 days and males 18 days. The daily survival of females and males estimated by the Fisher and Ford method was 0.825 and 0.693, respectively. The daily survival estimated using the Jolly-Seber method was 0.852 for females and 0.532 for males. Longevity is discussed in relation to extrinsic incubation periods of yellow fever and dengue viruses. The recapture rates, survivorship, and size of the village population indicate that the Ae. aegypti population in Shauri Moyo village is fairly stable. Presence or absence of blood in the stomach, and developmental stages of the ovaries were measured, showing that the majority of females fed twice and some fed as many as 3 times during one gonotrophic cycle.


Abdominal obesity and other risk factors largely explain the high CRP in indigenous Australians relative to the general population, but not gender differences: a cross-sectional study.
Previous studies reported high C-reactive protein (CRP) levels in Indigenous Australians, which may contribute to their high risk of cardiovascular disease. We compared CRP levels in Indigenous Australians and the general population, accounting for obesity and other risk factors. Cross-sectional study of CRP and risk factors (weight, height, waist and hip circumferences, blood pressure, lipids, blood glucose, and smoking status) in population-based samples from the Diabetes and Related conditions in Urban Indigenous people in the Darwin region (DRUID) study, and the Australian Diabetes, Obesity and Lifestyle study (AusDiab) follow-up. CRP concentrations were higher in women than men and in DRUID than AusDiab. After multivariate adjustment, including waist circumference, the odds of high CRP (>3.0 mg/L) in DRUID relative to AusDiab were no longer statistically significant, but elevated CRP was still more likely in women than men. After adjusting for BMI (instead of waist circumference) the odds for elevated CRP in DRUID participants were still higher relative to AusDiab participants among women, but not men. Lower HDL cholesterol, impaired glucose tolerance (IGT), and higher diastolic blood pressure were associated with having a high CRP in both men and women, while current smoking was associated with high CRP in men but not women. High concentrations of CRP in Indigenous participants were largely explained by other risk factors, in particular abdominal obesity. Irrespective of its independence as a risk factor, or its aetiological association with coronary heart disease (CHD), the high CRP levels in urban Indigenous women are likely to reflect increased vascular and metabolic risk. The significance of elevated CRP in Indigenous Australians should be investigated in future longitudinal studies.


Global image properties do not guide visual search.
While basic visual features such as color, motion, and orientation can guide attention, it is likely that additional features guide search for objects in real-world scenes. Recent work has shown that human observers efficiently extract global scene properties such as mean depth or navigability from a brief glance at a single scene (M. R. Greene & A. Oliva, 2009a, 2009b). Can human observers also efficiently search for an image possessing a particular global scene property among other images lacking that property? Observers searched for scene image targets defined by global properties of naturalness, transience, navigability, and mean depth. All produced inefficient search. Search efficiency for a property was not correlated with its classification threshold time from M. R. Greene and A. Oliva (2009b). Differences in search efficiency between properties can be partially explained by low-level visual features that are correlated with the global property. Overall, while global scene properties can be rapidly classified from a single image, it does not appear to be possible to use those properties to guide attention to one of several images.


A survey of dedicated PASC clinics: Characteristics, barriers and spirit of collaboration.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can produce prolonged multi-organ system dysfunction and a worsened quality of life, a condition known as Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). In response, clinics have emerged dedicated to the treatment of individuals with PASC. To better understand the current characteristics of these clinics, the barriers they face, and the interest in collaboration between clinics. A cross-sectional survey study. Clinicians working within dedicated PASC centers (N = 94) identified primarily through the Survivor Corps database of Post-COVID Care Centers. Additional clinics were found through news articles, an American Academy of Physical Medicine and Rehabilitation Database, and word of mouth. The branching logic electronic survey consisting of up to 39 questions was sent electronically to potential participants. Complete survey responses were obtained from 45 clinics. There was a wide variety of different clinical models and specialties involved. The majority of clinics were homed in physical medicine and rehabilitation (40%), pulmonology (22%), and internal medicine (16%). Most clinics (73%) reported experiencing obstacles in the treatment of their patients, the most common of which included needing more established protocols (45%) and more clinical resources (24%). Most clinics (76%) also reported an interest in participating in a collaborative clinical network. Despite wide variability in current clinical models of PASC clinics, there are common practices such as using telemedicine, having initial visits longer than 30 minutes, involving certain specialties in the treatment team, and having the ability for follow-up. Clinicians involved with PASC clinics have a strong interest in collaboration to improve patient care and overcome clinical obstacles, the most common of which is the lack of clear treatment protocols. More research is needed to identify which clinical models lead to better patient outcomes.


Genome-wide association study of prostate cancer mortality.
A pressing clinical issue in prostate cancer is to distinguish which men will have an indolent or aggressive course of disease. Clinical variables such as Gleason grade and stage are useful predictors of lethal cancer; however, the low predictive values of the common Gleason scores, changes in grading over time, and earlier diagnosis of patients due to screening limits their clinical utility. Identifying genetic variants associated with lethal prostate cancer could inform clinical decision making. We conducted a genome-wide association study, comparing lethal prostate cancer cases to cases surviving at least 10 years beyond their initial diagnosis. Genotyping was done with the Affymetrix 5.0 chip [∼500,000 single nucleotide polymorphisms (SNP) and 1,483 copy number variants (CNV)] on DNA from participants in the Physicians' Health Study and Health Professionals Follow-up Study (196 lethal cases, 368 long-term survivors). After excluding SNPs and individuals based on quality control criteria, logistic regression assuming an additive model was done using the PLINK software. No SNP reached genome-wide significance (P ≤ 1 × 10(-7)); however, three independent SNPs had P < 1 × 10(-5). One top-ranked SNP replicated (P = 0.05) in an independent follow-up study. Although no CNV had genome-wide significance, 14 CNVs showed nominal association with prostate cancer mortality (P < 0.05). No variants were significantly associated at a genome-wide level with prostate cancer mortality. Common genetic determinants of lethal prostate cancer are likely to have odds ratios <2.0. Genetic markers identified could provide biological insight to improve therapy for men with potentially fatal cancer. Larger studies are necessary to detect the genetic causes of prostate cancer mortality.


Methods, procedures, and contextual characteristics of health technology assessment and health policy decision making: comparison of health technology assessment agencies in Germany, United Kingdom, France, and Sweden.
The objectives of this study were (i) to develop a systematic framework for describing and comparing different features of health technology assessment (HTA) agencies, (ii) to identify and describe similarities and differences between the agencies, and (iii) to draw conclusions both for producers and users of HTA in research, policy, and practice. We performed a systematic literature search, added information from HTA agencies, and developed a conceptual framework comprising eight main domains: organization, scope, processes, methods, dissemination, decision, implementation, and impact. We grouped relevant items of these domains in an evidence table and chose five HTA agencies to test our framework: DAHTA@DIMDI, HAS, IQWiG, NICE, and SBU. Item and domain similarity was assessed using the percentage of identical characteristics in pairwise comparisons across agencies. RESULTS were interpreted across agencies by demonstrating similarities and differences. Based on 306 included documents, we identified 90 characteristics of eight main domains appropriate for our framework. After applying the framework to the five agencies, we were able to show 40 percent similarities in "dissemination," 38 percent in "scope," 35 percent in "organization," 29 percent in "methods," 26 percent in "processes," 23 percent in "impact," 19 percent in "decision," and 17 percent in "implementation." We found considerably more differences than similarities of HTA features across agencies and countries. Our framework and comparison provides insights and clarification into the need for harmonization. Our findings could serve as descriptive database facilitating communication between producers and users.


Occupational exposure to lead compounds and risk of cancer among men: a population-based case-control study.
The International Agency for Research on Cancer recently classified inorganic lead as a probable carcinogen, while organic lead remained unclassifiable. Uncertainty persists because of limited epidemiologic evidence. The authors addressed the relation between occupational exposure to lead and the risk of 11 types of cancer among men in a case-control study conducted in Montreal, Quebec, Canada, in the 1980s. Incident cases (n = 3,730) and general population controls (n = 533) were interviewed to elicit information on job history and potential confounders. Expert chemists translated each job into a list of substances to which the subject had potentially been exposed. Exposure to lead was classified into three categories: organic lead (3% of subjects ever exposed), inorganic lead (17%), and lead in gasoline emissions (39%). Odds ratios and 95% confidence intervals were estimated by logistic regression using two control groups: general population controls and cancer controls. Stomach cancer was associated with organic lead when the authors used population controls (odds ratio (OR) = 3.0, 95% confidence interval (CI): 1.2, 7.3) and cancer controls (OR = 2.0, 95% CI: 1.1, 3.8) and with substantial exposure to lead in gasoline emissions when they used cancer controls (OR = 2.9, 95% CI: 1.4, 5.9). There was no association with inorganic lead and little evidence for associations with other cancer types.


A healthy heart is not a metronome: an integrative review of the heart's anatomy and heart rate variability.
Heart rate variability (HRV), the change in the time intervals between adjacent heartbeats, is an emergent property of interdependent regulatory systems that operate on different time scales to adapt to challenges and achieve optimal performance. This article briefly reviews neural regulation of the heart, and its basic anatomy, the cardiac cycle, and the sinoatrial and atrioventricular pacemakers. The cardiovascular regulation center in the medulla integrates sensory information and input from higher brain centers, and afferent cardiovascular system inputs to adjust heart rate and blood pressure via sympathetic and parasympathetic efferent pathways. This article reviews sympathetic and parasympathetic influences on the heart, and examines the interpretation of HRV and the association between reduced HRV, risk of disease and mortality, and the loss of regulatory capacity. This article also discusses the intrinsic cardiac nervous system and the heart-brain connection, through which afferent information can influence activity in the subcortical and frontocortical areas, and motor cortex. It also considers new perspectives on the putative underlying physiological mechanisms and properties of the ultra-low-frequency (ULF), very-low-frequency (VLF), low-frequency (LF), and high-frequency (HF) bands. Additionally, it reviews the most common time and frequency domain measurements as well as standardized data collection protocols. In its final section, this article integrates Porges' polyvagal theory, Thayer and colleagues' neurovisceral integration model, Lehrer et al.'s resonance frequency model, and the Institute of HeartMath's coherence model. The authors conclude that a coherent heart is not a metronome because its rhythms are characterized by both complexity and stability over longer time scales. Future research should expand understanding of how the heart and its intrinsic nervous system influence the brain.


Development of a practical sandwich assay to detect human pluripotent stem cells using cell culture media.
Human pluripotent stem cells are considered to be ideal cell sources for regenerative medicine, but their clinical and industrial application is hindered by their tumorigenic potential. Previously we have identified a pluripotent stem cell-specific lectin rBC2LCN recognizing podocalyxin as a cell surface ligand. More recently, podocalyxin was found to be a soluble ligand of rBC2LCN that is secreted specifically from human pluripotent stem cells into cell culture media. Taking advantage of this phenomenon, we have previously developed a sandwich assay targeting the soluble podocalyxin using rBC2LCN as a capturing probe and another lectin rABA as an overlay probe to detect human pluripotent stem cells residing in cell therapy products derived from human pluripotent stem cells. A drawback to this, however, was that cell culture media containing fetal bovine serum was found to cause a substantial background signal to the sandwich assay. To reduce the background and increase the sensitivity, we screened different overlay probes to detect the soluble podocalyxin. Among them, an anti-keratan sulfate monoclonal antibody called R-10G showed the highest sensitivity and provided a low background signal to fetal bovine serum. The established sandwich assay using rBC2LCN and R-10G was proved to be powerful, which allowed the high-sensitive detection of human induced pluripotent stem cells residing among clinical-grade cardiomyocytes and neural stem cells, both derived from human induced pluripotent stem cells. The developed method has a possibility to be a standard technology to detect human induced pluripotent stem cells resided in various types of cell therapy products.


Evaluation of the use of a stabilization device to improve the quality of care in patients with peripherally inserted central catheters.
This project evaluated the implementation of use of the StatLock stabilization device (Bard Access Systems, Inc, Salt Lake City, Utah) for peripherally inserted central catheters (PICCs) in pediatric cardiology patients. The aim was to implement the use of the StatLock device and evaluate its effects on the following 4 outcomes: incidence of dislodgement, infection, catheter dwell time, and the number of catheter replacements. The primary goal was to determine whether the StatLock device offered advantages over tape and sutures. A quality improvement design was used to evaluate whether the use of the StatLock stabilization device for PICC securement on 30 pediatric cardiology patients decreased the number of PICC complications compared with 30 historical comparison patients. The comparison group had a significantly higher number of catheter dislodgements (n = 16; 59.3%) than the StatLock group (n = 8; 30.8%; P = .035). The comparison group did not have a significantly higher number of catheter replacements (n = 16; 59.3%) than the StatLock group (n = 10; 34.5%; P = .10). No significant differences were found in the rate of infection or in the catheter dwell time between the 2 groups (StatLock group, mean ± SD = 33.13 ± 22.71 days; comparison group, mean ± SD = 28.10 ± 24.83 days; P > .20). Use of the StatLock device resulted in better outcomes when compared with the use of sutures, and it provided a more effective way to stabilize and secure PICCs.


Characterization of a plastic scintillating detector for the Small Animal Radiation Research Platform (SARRP).
The purpose of this study was to characterize a small plastic scintillator developed for high resolution, real-time dosimetry of therapy and imaging x-ray beams delivered by an image-guided small animal irradiator. A 1 mm diameter, 1 mm long polystyrene BCF-60 scintillating fiber dosimeter was characterized with 220 kVp therapy and 40, 50, 60, 70, and 80 kVp imaging beams on the Small Animal Research Platform (SARRP). Scintillator output, sensitivity (charge per unit dose), linearity, and 0.2-mm resolution beam profile measurements were performed. A validated in-house Monte Carlo (MC) model of the SARRP was used to compute detailed energy spectra at locations of dosimetry, and validated scintillator measurement with MC simulations. Mass energy-absorption coefficients from the National Institute of Standards and Technology (NIST) tables convolved with MC-derived spectra were used in conjunction with Birks ionization quenching factors to correct scintillator output. An air kerma calibration method was employed to correct scintillator output for in-air beam profile measurements with open, 5 × 5, and 3 × 3 mm2 square field sizes, and compared to MC simulations. Scintillator dose response showed excellent linearity (R2 ≥ 0.999) for all sensitivity measurements, including output as a function of tube current. Detector sensitivity was 2.41 μC Gy-1 for the 220 kVp therapy beam, and it ranged from 1.21 to 1.32 μC Gy-1 for the 40-80 imaging beams. Percentage difference in sensitivity between the therapy and imaging beams before sensitivity correction and after using the Birks quenching factors were 52.3% and 10.2%, respectively. Percentage differences between the therapy and imaging beam sensitivities after using the air kerma calibration method for in-air measurements was excellent and below 0.3%. In-air beam profile measurements agreed to MC simulations within a mean difference of 2.4% for the 5 × 5 and 3 × 3 mm2 field sizes, however, the scintillator showed signs of volume averaging at the penumbra edges. A small plastic scintillator was characterized for therapy and imaging energies of a small animal irradiator, with output corrected for using an in-house MC model of the irradiator. The characterization of the scintillator detector system for small fields presents steps toward implementing real-time measurements for quality assurance and small animal treatment and imaging dose verification.


The interactive bending wrinkling behaviour of inflated beams.
A model is proposed based on a Fourier series method to analyse the interactive bending wrinkling behaviour of inflated beams. The whole wrinkling evolution is tracked and divided into three stages by identifying the bifurcations of the equilibrium path. The critical wrinkling and failure moments of the inflated beam can then be predicted. The global-local interactive buckling pattern is elucidated by the proposed theoretical model and also verified by non-contact experimental tests. The effects of geometric parameters, internal pressure and boundary conditions on the buckling of inflated beams are investigated finally. The results reveal that the interactive buckling characteristics of an inflated beam under bending are more sensitive to the dimensions of the structure and boundary conditions. We find that for beams which are simply supported at both ends or clamped and simply supported, boundary conditions may prevent the wrinkling formation. The results provide significant support for our understanding of the bending wrinkling behaviour of inflated beams.


First record of Mollisquama sp. (Chondrichthyes: Squaliformes: Dalatiidae) from the Gulf of Mexico, with a morphological comparison to the holotype description of Mollisquama parini Dolganov.
The description of the pocket shark genus Mollisquama (M. parini Dolganov, 1984) is based on a single known specimen collected from the Nazca Ridge of the southeast Pacific Ocean. A second Mollisquama specimen has been captured in the central Gulf of Mexico establishing a considerable range extension and a parturition locality because the specimen has a healed vitelline scar. Both the holotype of M. parini and the Gulf of Mexico specimen possess the remarkable pocket gland with its large slit-like external opening located just above the pectoral fin. Features found on the Gulf of Mexico specimen that were not noted in the description of M. parini include a series of ventral abdominal photophore agglomerations and a modified dermal denticle surrounded by a radiating arrangement of denticles just posterior to the mouth. Based on a morphometric and meristic comparison of the Gulf of Mexico specimen with information in the description of M. parini, the Gulf of Mexico specimen is identified as Mollisquama sp. due to differences in tooth morphology and vertebral counts. Phylogenetic analysis of NADH2 gene sequences places Mollisquama sister to Dalatias plus Isistius within the family Dalatiidae.


Resourcefulness, Desperation, Shame, Gratitude and Powerlessness: Common Themes Emerging from A Study of Food Bank Use in Northeast Scotland.
There is growing policy maker and public concern about current trends in food bank use in Scotland. Yet little is known about the experiences of those seeking help from food banks in this country. This research aimed to address this issue by studying the use and operation of a food bank situated in a rich northeast city during January and June 2014. The study aimed to establish who was seeking help from the food bank, their reasons for doing so, and what those who did thought of, and dealt with the food they received from it. Consequently, an audit of the food bank's client database, four months of participant observation based in the food bank, and seven face-to-face interviews with current and former food bank clients were conducted. The audit revealed that clients came from a range of socio-economic backgrounds, with men more likely to access it compared to women. Debt and social security benefit delays were cited as the main reasons for doing so. Qualitative data confirmed that sudden and unanticipated loss of income was a key driver of use. Resourcefulness in making donated food last as long as possible, keeping fuel costs low, and concern to minimise food waste were commonly described by participants. Desperation, gratitude, shame and powerlessness were also prevalent themes. Furthermore, clients were reluctant to ask for food they normally ate, as they were acutely aware that the food bank had little control over what it was able offer. Insights from this study suggest that recent UK policy proposals to address food poverty may have limited impact, without concomitant effort to address material disadvantage. Research is urgently required to determine the precise nature and extent of household level food insecurity in Scotland, and to consider monitoring for adverse physical and mental health outcomes for those affected by it.


Acting parentally: an argument against sex selection.
The Human Fertilisation and Embryology Authority's (HFEA) recent restrictive recommendations on sex selection have highlighted the need for consideration of the plausibility of ethical arguments against sex selection. In this paper, the author suggests a parental virtues approach to some questions of reproductive ethics (including sex selection) as a superior alternative to an exclusively harm focused approach such as the procreative liberty framework. The author formulates a virtue ethics argument against sex selection based on the idea that acceptance is a character trait of the good parent. It is concluded that, because the argument presented posits a wrong in the sex selecting agent's action that is not a harm, the argument could not function as a justification of the HFEA's restrictive position in light of their explicit commitment to procreative liberty; it does, however, suggest that ethical approaches focused exclusively on harm fail to capture all the relevant moral considerations and thus that we should look beyond such approaches.


Human immunodeficiency virus (HIV) infection in CD4+ T lymphocytes genetically deficient in LFA-1: LFA-1 is required for HIV-mediated cell fusion but not for viral transmission.
In the present study, we demonstrated that expression of the LFA-1 molecule is necessary for cell fusion and syncytia formation in human immunodeficiency virus (HIV)-infected CD4+ T lymphocytes. In contrast, the lack of expression of LFA-1 does not influence significantly cell-to-cell transmission of HIV. In fact, LFA-1- T lymphocytes obtained from a leukocyte adhesion deficiency patient were unable to fuse and form syncytia when infected with HIV-1 or HIV-2, despite the fact that efficiency of HIV infection (i.e., virus entry, HIV spreading, and levels of virus replication) was comparable with that observed in LFA-1+ T lymphocytes. In addition, we provide evidence that LFA-1 by mediating cell fusion contributes to the depletion of HIV-infected CD4+ T lymphocytes in vitro.


The virtual doctor: An interactive clinical-decision-support system based on deep learning for non-invasive prediction of diabetes.
Artificial intelligence (AI) will pave the way to a new era in medicine. However, currently available AI systems do not interact with a patient, e.g., for anamnesis, and thus are only used by the physicians for predictions in diagnosis or prognosis. However, these systems are widely used, e.g., in diabetes or cancer prediction. In the current study, we developed an AI that is able to interact with a patient (virtual doctor) by using a speech recognition and speech synthesis system and thus can autonomously interact with the patient, which is particularly important for, e.g., rural areas, where the availability of primary medical care is strongly limited by low population densities. As a proof-of-concept, the system is able to predict type 2 diabetes mellitus (T2DM) based on non-invasive sensors and deep neural networks. Moreover, the system provides an easy-to-interpret probability estimation for T2DM for a given patient. Besides the development of the AI, we further analyzed the acceptance of young people for AI in healthcare to estimate the impact of such a system in the future.


Cycling and walking to work in New Zealand, 1991-2006: regional and individual differences, and pointers to effective interventions.
Active commuting increases levels of physical activity and is more likely to be adopted and sustained than exercise programmes. Despite the potential health, environmental, social and economic benefits, cycling and walking are increasingly marginal modes of transport in many countries. This paper investigated regional and individual differences in cycling and walking to work in New Zealand over the 15-year period (1991-2006). New Zealand Census data (collected every five years) were accessed to analyse self-reported information on the "main means of travel to work" from individuals aged 15 years and over who are usually resident and employed in New Zealand. This analysis investigated differences in patterns of active commuting to work stratified by region, age, gender and personal income. In 2006, over four-fifths of New Zealanders used a private vehicle, one in fourteen walked and one in forty cycled to work. Increased car use from 1991 to 2006 occurred at the expense of active means of travel as trends in public transport use remained unchanged during that period. Of the 16 regions defined at meshblock and area unit level, Auckland had the lowest prevalence of cycling and walking. In contrast to other regions, walking to work increased in Wellington and Nelson, two regions which have made substantial investments in local infrastructure to promote active transport. Nationally, cycling prevalence declined with age whereas a U-shaped trend was observed for walking. The numbers of younger people cycling to work and older people walking to work declined substantially from 1991 to 2006. Higher proportions of men compared with women cycled to work. The opposite was true for walking with an increasing trend observed in women aged under 30 years. Walking to work was less prevalent among people with higher income. We observed a steady decline in cycling and walking to work from 1991 to 2006, with two regional exceptions. This together with the important differences in travel patterns by age, gender and personal income highlights opportunities to target and modify transport policies in order to promote active commuting.


Prompt Electromagnetic Transients from Binary Black Hole Mergers.
Binary black hole (BBH) mergers provide a prime source for current and future interferometric GW observatories. Massive BBH mergers may often take place in plasma-rich environments, leading to the exciting possibility of a concurrent electromagnetic (EM) signal observable by traditional astronomical facilities. However, many critical questions about the generation of such counterparts remain unanswered. We explore mechanisms that may drive EM counterparts with magnetohydro-dynamic simulations treating a range of scenarios involving equal-mass black-hole binaries immersed in an initially homogeneous fluid with uniform, orbitally aligned magnetic fields. We find that the time development of Poynting luminosity, which may drive jet-like emissions, is relatively insensitive to aspects of the initial configuration. In particular, over a significant range of initial values, the central magnetic field strength is effectively regulated by the gas flow to yield a Poynting luminosity of 1045 - 1046 ρ -13 M 8 2 ergs-1, with BBH mass scaled to M 8 ≡ M/(108 M ⨀) and ambient density ρ -13 ≡ ρ/(10-13 g cm-3). We also calculate the direct plasma synchrotron emissions processed through geodesic ray-tracing. Despite lensing effects and dynamics, we find the observed synchrotron flux varies little leading up to merger.


Angiogenesis, inflammation, platelets count, and metastatic status as a predictor for thrombosis risk in nasopharyngeal carcinoma patients.
to assess the use of of angiogenesis, inflammation, platelets count, and metastatic status as predictors for thrombosis risk represented by soluble P-selectin level in nasopharyngeal carcinoma (NPC) patients. a cross sectional study was conducted on NPC patients at the Hematology and Oncology Clinic of Cipto Mangunkusumo Hospital, Jakarta, during Mei to October 2012. Data regarding angiogenesis (CD105 and VEGFR-2), inflammation (IL-6), platelets count, and metastatic status were assessed at enrollment, as well as soluble P-selectin levels in all eligible patients. Bivariate analysis continued with multiple linear regression analysis were done to identify independent predictors for soluble P-selectin levels. sixty NPC patients were enrolled in the study. There was correlation between platelet counts (r=0.389; p=0.002), IL-6 (r=0.595; p<0.001) and number of metastatic sites (r=0.542; p<0.001) with soluble P-selectin level, and a linear regression analysis showed that these three variables can predict soluble P-selectin levels with adjusted R-square 65%. There was no correlation between VEGFR-2 and CD105 levels with soluble P-selectin levels. platelet counts, IL-6 level, and number of sites of metastasis can be used as predictors of soluble P-selectin level as parameter of thrombosis risk in NPC patients.


Enhanced IgE allergic response to Aspergillus fumigatus in CFTR-/- mice.
To gain insight into aberrant cytokine regulation in cystic fibrosis (CF), we compared the phenotypic manifestations of allergen challenge in gut-corrected CFTR-deficient mice with background-matched C57Bl6 (B6) mice. Aspergillus fumigatus (Af) antigen was used to mimic allergic bronchopulmonary aspergillosis, a peculiar hyper-IgE syndrome with a high prevalence in CF patients. CFTR-/-, C57BL/6 and FVB/NJ mice were sensitized with Af antigen by serial intraperitoneal injections. Control mice were mock sensitized with PBS. Challenges were performed by inhalation of Af antigen aerosol. After Af antigen challenge, histologic analysis showed goblet cell hyperplasia and lymphocytic infiltration in both strains. However, total serum IgE levels were markedly elevated in CF mice. Sensitized CF mice showed a five-fold greater IgE response to sensitization as compared with B6- and FVB-sensitized controls. Additional littermate controls to fully normalize for B6-FVB admixture in the strain background confirmed the role of CFTR mutation in the hyper-IgE syndrome. Cytokine mRNA levels of IL-5 and GM-CSF in the bronchoalveolar lavage (BAL) fluid, and BAL cell differentials indicated that CFTR mutation caused a shift from an IL-5-predominant to an IL-4-predominant cytokine profile. This system models a very specific type of airway inflammation in CF and could provide insights into pathogenesis and treatment of the disease.


The yeast phosphotyrosyl phosphatase activator is part of the Tap42-phosphatase complexes.
Phosphotyrosyl phosphatase activator PTPA is a type 2A phosphatase regulatory protein that possesses an ability to stimulate the phosphotyrosyl phosphatase activity of PP2A in vitro. In yeast Saccharomyces cerevisiae, PTPA is encoded by two related genes, RRD1 and RRD2, whose products are 38 and 37% identical, respectively, to the mammalian PTPA. Inactivation of either gene renders yeast cells rapamycin resistant. In this study, we investigate the mechanism underling rapamycin resistance associated with inactivation of PTPA in yeast. We show that the yeast PTPA is an integral part of the Tap42-phosphatase complexes that act downstream of the Tor proteins, the target of rapamycin. We demonstrate a specific interaction of Rrd1 with the Tap42-Sit4 complex and that of Rrd2 with the Tap42-PP2Ac complex. A small portion of PTPA also is found to be associated with the AC dimeric core of PP2A, but the amount is significantly less than that associated with the Tap42-containing complexes. In addition, our results show that the association of PTPA with Tap42-phosphatase complexes is rapamycin sensitive, and importantly, that rapamycin treatment results in release of the PTPA-phosphatase dimer as a functional phosphatase unit.


Cardiologists' and patients' views about the informed consent process and their understanding of the anticipated treatment benefits of coronary angioplasty: A survey study.
Percutaneous coronary intervention is a common revascularisation technique. Serious complications are uncommon, but death is one of them. Seeking informed consent in advance of percutaneous coronary intervention is mandatory. Research shows that percutaneous coronary intervention patients have inaccurate perceptions of risks, benefits and alternative treatments. To assess cardiologists' and patients' views about the informed consent process and anticipated treatment benefits. Two cross-sectional, anonymous surveys were distributed in England: an electronic version to a sample of cardiologists and a paper-based version to patients recruited from 10 centres. A sample of 118 cardiologists and 326 patients completed the surveys. Cardiologists and patients shared similar views on the purpose of informed consent; however, over 40% of patients and over a third of cardiologists agreed with statements that patients do not understand, or remember, the information given to them. Patients placed less value than cardiologists on the consent process and over 60% agreed that patients depended on their doctor to make the decision for them. Patients' and cardiologists' views on the benefits of percutaneous coronary intervention were significantly different; notably, 60% of patients mistakenly believed that percutaneous coronary intervention was curative. The percutaneous coronary intervention informed consent process requires improvement to ensure that patients are more involved and accurately understand treatment benefits to make an informed decision. Redesign of the patient pathway is recommended to allow protected time for health professionals to engage in discussions using evidence-based approaches such as 'teach back' and decision support which improve patient comprehension.


An overview of assessment and management in COPD.
Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease, which has a huge impact on both families and individual patients lives. Even though COPD is largely a preventable disease, it is increasing worldwide. Therefore, healthcare professionals working within primary care are likely to come into daily contact with patients with this condition. However, statistics tell us that there are many more patients that are undiagnosed. The aim of this article is to provide an overview of this condition and to identify the various drug therapies that are available to ensure patients are receiving optimal treatment to control their symptoms of COPD.


Effect of age on the processing and import of matrix-destined mitochondrial proteins in skeletal muscle.
Deregulation of muscle mitochondrial biogenesis may explain the altered mitochondrial properties associated with aging. Maintenance of the mitochondrial network requires the continuous incorporation of nascent proteins into their subcompartments via the protein import pathway. We examined whether this pathway was impaired in muscle of aged animals, focusing on the subsarcolemmal and intermyofibrillar mitochondrial populations. Our results indicate that the import of proteins into the mitochondrial matrix was unaltered with age. Interestingly, import assays supplemented with the cytosolic fraction illustrated an attenuation of protein import, and this effect was similar between age groups. We observed a 2.5-fold increase in protein degradation in the presence of the cytosolic fraction obtained from aged animals. Thus, the reduction of mitochondrial content and/or function observed with aging may not rely on altered activity of the import pathway but rather on the availability of preproteins that are susceptible to elevated rates of degradation by cytosolic factors.


Is partial wrist denervation beneficial in chronic wrist pain? A systematic review.
The prevalence of chronic wrist pain and subsequent functional decline is increasing. Diagnosis is challenging, with non-surgical treatment frequently failing. Recently, partial wrist denervation (PWD) has gained popularity as a procedure to alleviate chronic pain. A systematic review was performed in April 2019. Inclusion criteria involved clinical studies with a minimum of ten wrists, focusing on PROMs, objective measures of function and complications. Papers investigating complete or mixed denervation procedures were excluded. Nine studies were included (292 wrists), all of which were observational in study design and limited in patient numbers, evaluation techniques and follow-up length. PWD appears to be associated with a reduction in pain, and functional improvement. Further surgery was required in 54 (24%) wrists at an average follow-up of 18 months. PWD was not found to complicate further surgery. PWD is associated with improvement in short-term pain relief and functional status, yet carries a high re-operation rate without contraindicating further salvage surgery. Further research is required to evaluate the benefits, duration of relief and long-term complications of PWD.


The interactive effect of advanced cancer patient and caregiver prognostic understanding on patients' completion of Do Not Resuscitate orders.
Advanced cancer patients' prognostic understanding is associated with completion of Do Not Resuscitate (DNR) orders, which often represent engagement in advance care planning (ACP). Given caregivers' critical roles in patient decision-making about ACP and end-of-life care, caregivers' prognostic understanding may have a large additive effect. The present study examined the association between the main and interactive effects of advanced cancer patient and caregiver prognostic understanding on DNR order completion. Data were analyzed from a combined dataset of 2 sequential multi-institutional, longitudinal cohort studies of patients with advanced cancer and their informal caregivers (n = 279 dyads) from 2002 to 2008 (Coping with Cancer 1) and 2010 to 2015 (Coping with Cancer 2). Patients' and caregivers' prognostic understanding regarding life-expectancy (≤ 12 months [prognostic understanding], >12 months [lack of prognostic understanding]) was assessed. DNR order completion was assessed through self-report and confirmed through cross-checking with medical records. Multivariable modeling of the main and interactive effects revealed the interactive effect, but not the individual effects, of patients' and caregivers' prognostic understanding was significantly associated with higher odds of patients' DNR order completion, adjusting for potential confounds (AOR = 5.89, P = 0.04). For dyads in which both the patient and caregiver had prognostic understanding regarding life expectancy of ≤12 months, 70.7% of patients had completed DNR orders compared with 31.6% to 38.9% in which 1 or both lacked prognostic understanding. Findings highlight the need for ensuring accurate patient and caregiver prognostic understanding in increasing DNR order completion, which may provide a framework for improving engagement in ACP more broadly.