Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis.
Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs. We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to Feb 11, 2014. Search terms included "biologics", "rheumatoid arthritis" and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool. We did a Bayesian network meta-analysis of published trials using a binomial likelihood model to assess the risk of serious infections in patients with rheumatoid arthritis who were treated with biological drugs, compared with those treated with traditional DMARDs. The odds ratio (OR) of serious infection was the primary measure of treatment effect and calculated 95% credible intervals using Markov Chain Monte Carlo methods. The systematic review identified 106 trials that reported serious infections and included patients with rheumatoid arthritis who received biological drugs. Compared with traditional DMARDs, standard-dose biological drugs (OR 1.31, 95% credible interval [CrI] 1.09-1.58) and high-dose biological drugs (1.90, 1.50-2.39) were associated with an increased risk of serious infections, although low-dose biological drugs (0.93, 0.65-1.33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug-experienced patients. The absolute increase in the number of serious infections per 1000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs. Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis. Rheumatology Division at the University of Alabama at Birmingham.


Low-energy MOS depletion modulators in silicon-on-insulator micro-donut resonators coupled to bus waveguides.
Electrical, optical and electro-optical simulations are presented for a waveguided, resonant, bus-coupled, p-doped Si micro-donut MOS depletion modulator operating at the 1.55 μm wavelength. To minimize the switching voltage and energy, a high-K dielectric film of HfO₂ or ZrO₂ is chosen as the gate dielectric, while a narrow ring-shaped layer of p-doped poly-silicon is selected for the gate electrode, rather than metal, to minimize plasmonic loss loading of the fundamental TE mode. In a 6-μm-diam high-Q resonator, an infrared intensity extinction ratio of 6 dB is predicted for a modulation voltage of 2 V and a switching energy of 4 fJ/bit. A speed-of-response around 1 ps is anticipated. For a modulator scaled to operate at 1.3 μm, the estimated switching energy is 2.5 fJ/bit.


Quantum Metrology Enhanced by Repetitive Quantum Error Correction.
We experimentally demonstrate the protection of a room-temperature hybrid spin register against environmental decoherence by performing repeated quantum error correction whilst maintaining sensitivity to signal fields. We use a long-lived nuclear spin to correct multiple phase errors on a sensitive electron spin in diamond and realize magnetic field sensing beyond the time scales set by natural decoherence. The universal extension of sensing time, robust to noise at any frequency, demonstrates the definitive advantage entangled multiqubit systems provide for quantum sensing and offers an important complement to quantum control techniques.


Occupational health and safety in Australia.
The focus of OHS in Australia is on workplace-based prevention rather than individual health care. Over the past decade, workers' compensation data have shown continuous improvement in work-related deaths, serious injuries and diseases. Injuries from work-related vehicle incidents are the leading cause of fatalities. There is a high incidence of on-road incidents in light vehicles; this problem is under-recognised, and better incidence data are required to support more effective interventions. Rates of many long-latency diseases such as cancers are underestimated, and again more reliable information is needed, particularly on work-related exposures to carcinogens. Disease-related deaths are largely confined to older workers. Musculoskeletal injuries and disorders are the most frequent and costly OHS problem, constituting a large majority of non-fatal injuries and diseases. There is growing recognition that their risk management should be more evidence based, integrating assessment and control of psychosocial and 'manual handling' hazards. A high rate of population ageing is increasing risk of chronic diseases, including musculoskeletal disorders, which is helping to raise awareness of the importance of protecting and promoting workforce health. Strategies to achieve this have been developed but implementation is at an early stage.


Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct.
Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct contain epithelial cells with numerous, large mitochondria and are cystic precursors to pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), respectively. However, IOPNs do not have the genomic alterations found in other pancreatobiliary neoplasms. In fact, no recurrent genomic alterations have been described in IOPNs. PDACs without activating mutations in KRAS contain gene rearrangements, so we investigated whether IOPNs have recurrent fusions in genes. We analyzed 20 resected pancreatic IOPNs and 3 resected biliary IOPNs using a broad RNA-based targeted sequencing panel to detect cancer-related fusion genes. Four invasive PDACs and 2 intrahepatic CCAs from the same patients as the IOPNs, were also available for analysis. Samples of pancreatic cyst fluid (n = 5, collected before surgery) and bile duct brushings (n = 2) were analyzed for translocations. For comparison, we analyzed pancreatobiliary lesions from 126 patients without IOPN (controls). All IOPNs evaluated were found to have recurring fusions of ATP1B1-PRKACB (n = 13), DNAJB1-PRKACA (n = 6), or ATP1B1-PRKACA (n = 4). These fusions also were found in corresponding invasive PDACs and intrahepatic CCAs, as well as in matched pancreatic cyst fluid and bile duct brushings. These gene rearrangements were absent from all 126 control pancreatobiliary lesions. We identified fusions in PRKACA and PRKACB genes in pancreatic and biliary IOPNs, as well as in PDACs and pancreatic cyst fluid and bile duct cells from the same patients. We did not identify these gene fusions in 126 control pancreatobiliary lesions. These fusions might be used to identify patients at risk for IOPNs and their associated invasive carcinomas.


Comparison of Foot Arch in Shod and Unshod Individuals in East Gojjam, Ethiopia: A Cross-Sectional Study.
The human foot has three arches. The medial longitudinal arch is the longest, the highest, and the most important. The development of a normal foot arch is greatly affected by genetic inheritance, differences in the environment, socioeconomic development, body weight, sex, ethnicity, and culture. The purpose of this study was to compare the arch type between shoe-wearing and barefooted individuals. A cross-sectional study was conducted. The data obtained were checked for clarity and consistency before analysis. The analysis was done using descriptive statistics and chi-square. p-values less than 0.05 were considered to be statistically significant. From a total of 446 subjects, 217 (48.7%) were males, 131 (29.6%) were urban residents and 226 (50.6 %) were shoe wearers. From the total sample, 46.2%, 42.8%, and 11% are high, normal, and flat-arched individuals, respectively. Of the shoe wearers, 6.7% have a flat arch while 4.3% of the barefooted subjects are flat-arched. Of the total flat-arched subjects, 8.3% are males and 2.7% are females. Of the urban residents, 17.5% have a flat foot and 8.3% of rural residents were flat arched. Among the shoe wearers, 8.8% use closed-toe shoes, and 4.4% that wear sandals are flat-arched. The result indicates sex, type of shoes, wearing shoes, and being barefooted affected the development of the foot arch.


Blueberries and neuronal aging.
As the population of people in the United States over the age of 65 years continues to increase, so too will the incidence of age-related pathologies, including decreases in cognitive and motor function. In cases of severe deficits in memory or motor function, hospitalization and/or custodial care would be a likely outcome. This means that unless some way is found to reduce these age-related decrements in neuronal function, health care costs will continue to rise exponentially. Evidence is accumulating that consumption of blueberries may be one strategy to forestall or even reverse age-related neuronal deficits, as well as their subsequent behavioral manifestations, in order to increase healthy aging. Research suggests that the polyphenolic compounds found in blueberries exert their beneficial effects either through their ability to lower oxidative stress and inflammation or directly by altering the signaling involved in neuronal communication. These interventions, in turn, may protect against age-related deficits in cognitive and motor function. Appropriately, the US Department of Agriculture has figured prominently in these discoveries, through the efforts of two USDA researchers who worked for the department 100 years apart.


Modelling the contribution of walking between home and school to daily physical activity in primary age children.
The purpose of this study was to identify the independent association of frequency of walking trips between home and school with daily physical activity in a sample of school-aged children. Participants were 109 children (mean age = 12.05 years [± 0.71]) attending nine primary schools in Adelaide, South Australia. Physical activity was derived from accelerometers with total counts as the outcome variable. Transport patterns were self-reported for each of the previous five school days. Walking trips were summed for each day and across the school week. The relationship between the number of active transport journeys and individual school day and school week physical activity was modelled separately in boys and girls using multiple linear regression. Frequency of walking was positively associated with school day and school week accelerometer counts in boys, accounting for 6% and 12% of the explained variance in total counts, respectively. There were no significant associations among girls. Despite sex-specific differences in associations between active transport to school and total physical activity, active transport is likely to have important ancillary benefits for development of independence and physical activity habits, and should continue to be promoted.


Genome-Wide Analysis of Left Ventricular Image-Derived Phenotypes Identifies Fourteen Loci Associated With Cardiac Morphogenesis and Heart Failure Development.
The genetic basis of left ventricular (LV) image-derived phenotypes, which play a vital role in the diagnosis, management, and risk stratification of cardiovascular diseases, is unclear at present. The LV parameters were measured from the cardiovascular magnetic resonance studies of the UK Biobank. Genotyping was done using Affymetrix arrays, augmented by imputation. We performed genome-wide association studies of 6 LV traits-LV end-diastolic volume, LV end-systolic volume, LV stroke volume, LV ejection fraction, LV mass, and LV mass to end-diastolic volume ratio. The replication analysis was performed in the MESA study (Multi-Ethnic Study of Atherosclerosis). We identified the candidate genes at genome-wide significant loci based on the evidence from extensive bioinformatic analyses. Polygenic risk scores were constructed from the summary statistics of LV genome-wide association studies to predict the heart failure events. The study comprised 16 923 European UK Biobank participants (mean age 62.5 years; 45.8% men) without prevalent myocardial infarction or heart failure. We discovered 14 genome-wide significant loci (3 loci each for LV end-diastolic volume, LV end-systolic volume, and LV mass to end-diastolic volume ratio; 4 loci for LV ejection fraction, and 1 locus for LV mass) at a stringent P<1×10-8. Three loci were replicated at Bonferroni significance and 7 loci at nominal significance (P<0.05 with concordant direction of effect) in the MESA study (n=4383). Follow-up bioinformatic analyses identified 28 candidate genes that were enriched in the cardiac developmental pathways and regulation of the LV contractile mechanism. Eight genes (TTN, BAG3, GRK5, HSPB7, MTSS1, ALPK3, NMB, and MMP11) supported by at least 2 independent lines of in silico evidence were implicated in the cardiac morphogenesis and heart failure development. The polygenic risk scores of LV phenotypes were predictive of heart failure in a holdout UK Biobank sample of 3106 cases and 224 134 controls (odds ratio 1.41, 95% CI 1.26 - 1.58, for the top quintile versus the bottom quintile of the LV end-systolic volume risk score). We report 14 genetic loci and indicate several candidate genes that not only enhance our understanding of the genetic architecture of prognostically important LV phenotypes but also shed light on potential novel therapeutic targets for LV remodeling.


Identification of Interleukin-27 (IL-27)/IL-27 Receptor Subunit Alpha as a Critical Immune Axis for In Vivo HIV Control.
Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/β-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC.IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and the blood is a key conduit for transporting such factors. Investigating the communication factors promoting effective immune responses and having potentially antiviral functions against HIV using a novel focused omics approach ("communicome") has the potential to significantly improve our knowledge of effective host immunity and accelerate the HIV cure agenda. Including 140 subjects with variable viral loads and measuring the plasma levels of >600 soluble proteins, our data highlight the importance of Th17 cells and Wnt/β-catenin signaling in HIV control and especially identify the IL-27/IL-27 receptor subunit alpha (IL-27RA) axis as a predictor of plasma viral load and proviral copy number in the peripheral blood. These data may provide important guidance to therapeutic approaches in the HIV cure agenda.


Bacterial Leaf Spot of Onion Caused by Pseudomonas syringae pv. porri, a New Disease in Korea.
In April 2007, a bacterial leaf spot of onion (Allium cepa L.) was observed in fields of Namjeju, Jeju Province in Korea with incidence varying from 95 to 100%. Symptoms on leaves included leaf blight and white and brown spots on the leaf surface. Eight bacterial isolates were recovered on trypticase soy agar (TSA) from leaf spot and blight lesions that were surface sterilized in 70% ethanol for 1 min. The isolates were fluorescent on King's B agar and gram-negative, aerobic rods with one to three polar flagella. All isolates belonged to P. syringae (LOPAT) group Ia (+, -, -, -, +) (1). The gyrB, rpoD (2), and rpoB regions (4) of the isolates and reference strain Pseudomonas syringae pv. porri CFBP 1908PT (=BC2583) were partially sequenced using reported primers (2,4). The rpoB region (1,119 bp) of the isolates (GenBank Accession Nos. JF719311-JF719318 for rpoB) shared 100% identity with P. syringae pv. porri CFBP 1908PT (GenBank Accession No. JF719319). Phylogenetic analysis based on partial sequences of the gyrB (660 bp) and rpoD (590 bp) loci of Pseudomonas spp. available in the GenBank (2,4), the reference strain P. syringae pv. porri CFBP 1908PT, and the field isolates was conducted using Jukes-Cantor model in MEGA Version 4.1 (3). The isolates and reference strain P. syringae. pv. porri CFBP 1908PT clustered in one group (GenBank Accession Nos. JF719293-JF719300 for gyrB; JF719302-JF719309 for rpoD). On the basis of phenotypic and pathological characteristics and the sequences, the eight isolates were identified as P. syringae pv. porri. Pathogenicity was evaluated on 3-week-old onion plants (cv. Marushino 330) by spot and spray inoculation. Bacteria were grown on TSA for 24 h at 28°C. Five microliters of bacterial suspension in sterile distilled water (1 × 106 CFU/ml) were spot inoculated on pinpricked positions of five leaves for each isolate and incubated in humid plastic boxes at 27°C. Spot-inoculated surfaces turned white 2 days after inoculation, followed by brownish discoloration. A bacterial suspension in sterile distilled water (100 ml at 1 × 106 CFU/ml) was sprayed onto three plants for each isolate. Plants were maintained in a greenhouse at 18 to 27°C and 80% relative humidity. Isolates induced identical symptoms on all inoculated plants 2 weeks after spray inoculation as those originally observed on onion in the fields. Bacteria were reisolated 3 weeks after inoculation from diseased lesions surface sterilized in 70% ethanol for 1 min and the identity of the reisolated bacteria confirmed by analyzing the sequences of rpoD gene (2). No symptoms were noted on intact plants inoculated with sterilized distilled water. To our knowledge, this is the first report of bacterial leaf spot of onion caused by P. syringae pv. porri in Korea. The disease is expected to have a significant economic impact on onion culture in the fields of Jeju Province in Korea. References: (1) R. A. Lelliott et al. J. Appl. Bacteriol. 29:470, 1966. (2) H. Sawada et al. J. Mol. Evol. 49:627, 1999. (3) K. Tamura et al. Mol. Biol. Evol. 24:1596, 2007. (4) L. Tayeb et al. Res. Microbiol. 156:763, 2005.


Cutaneous and local radiation injuries.
The threat of a large-scale radiological or nuclear (R/N) incident looms in the present-day climate, as noted most recently in an editorial in Scientific American (March 2021). These large-scale incidents are infrequent but affect large numbers of people. Smaller-scale R/N incidents occur more often, affecting smaller numbers of people. There is more awareness of acute radiation syndrome (ARS) in the medical community; however, ionising radiation-induced injuries to the skin are much less understood. This article will provide an overview of radiation-induced injuries to the skin, deeper tissues, and organs. The history and nomenclature; types and causes of injuries; pathophysiology; evaluation and diagnosis; current medical management; and current research of the evaluation and management are presented. Cutaneous radiation injuries (CRI) or local radiation injuries (LRI) may lead to cutaneous radiation syndrome, a sub-syndrome of ARS. These injuries may occur from exposure to radioactive particles suspended in the environment (air, soil, water) after a nuclear detonation or an improvised nuclear detonation (IND), a nuclear power plant incident, or an encounter with a radioactive dispersal or exposure device. These incidents may also result in a radiation-combined injury; a chemical, thermal, or traumatic injury, with radiation exposure. Skin injuries from medical diagnostic and therapeutic imaging, medical misadministration of nuclear medicine or radiotherapy, occupational exposures (including research) to radioactive sources are more common but are not the focus of this manuscript. Diagnosis and evaluation of injuries are based on the scenario, clinical picture, and dosimetry, and may be assisted through advanced imaging techniques. Research-based multidisciplinary therapies, both in the laboratory and clinical trial environments, hold promise for future medical management. Great progress is being made in recognising the extent of injuries, understanding their pathophysiology, as well as diagnosis and management; however, research gaps still exist.


Infection of primary human microglia and monocyte-derived macrophages with human immunodeficiency virus type 1 isolates: evidence of differential tropism.
To ascertain whether viruses present at the time of primary viremia can infect the central nervous system and to determine if microglial tropism is distinct from tropism for monocyte-derived macrophages (MDM), 27 human immunodeficiency virus type 1 (HIV-1) isolates obtained from acutely infected individuals, as well as laboratory strains, were assayed for their ability to replicate in primary adult microglial cultures and in MDM. Most of the isolates replicated equally well in both microglia and MDM, but several isolates replicated preferentially in one of the two cell types, differing by as much as 40-fold in p24gag production. This indicated that while MDM and microglial tropism overlap, a subset of isolates is particularly tropic for one of the two cell types. One isolate was further adapted to microglia by 15 sequential passages, raising the peak p24 concentration produced by 1,000-fold. In addition, the passaged virus induced marked cytopathologic changes (vacuolization and syncytium formation) in infected microglial cultures. Sequence comparison of the V3 loop of unpassaged and multiply passaged virus revealed amino acid changes shown to be associated with isolates from patients with HIV dementia. Our data support the hypothesis that HIV-1 infection can be established in the central nervous system by viruses present early in HIV infection, that some of these viruses are particularly tropic for microglia, and that adaptation in this cell type can result in the selection of a pool of predominantly microglia-tropic (neurotropic) viruses.


Construction of full-length Japanese reference panel of class I HLA genes with single-molecule, real-time sequencing.
Human leukocyte antigen (HLA) is a gene complex known for its exceptional diversity across populations, importance in organ and blood stem cell transplantation, and associations of specific alleles with various diseases. We constructed a Japanese reference panel of class I HLA genes (ToMMo HLA panel), comprising a distinct set of HLA-A, HLA-B, HLA-C, and HLA-H alleles, by single-molecule, real-time (SMRT) sequencing of 208 individuals included in the 1070 whole-genome Japanese reference panel (1KJPN). For high-quality allele reconstruction, we developed a novel pipeline, Primer-Separation Assembly and Refinement Pipeline (PSARP), in which the SMRT sequencing and additional short-read data were used. The panel consisted of 139 alleles, which were all extended from known IPD-IMGT/HLA sequences, contained 40 with novel variants, and captured more than 96.5% of allelic diversity in 1KJPN. These newly available sequences would be important resources for research and clinical applications including high-resolution HLA typing, genetic association studies, and analyzes of cis-regulatory elements.


Randomized controlled trials: who fails run-in?
Early identification of participants at risk of run-in failure (RIF) may present opportunities to improve trial efficiency and generalizability. We conducted a partial factorial-design, randomized, controlled trial of calcium and vitamin D to prevent colorectal adenoma recurrence at 11 centers in the United States. At baseline, participants completed two self-administered questionnaires (SAQs) and a questionnaire administered by staff. Participants in the full factorial randomization (calcium, vitamin D, both, or neither) received a placebo during a 3-month single-blinded run-in; women electing to take calcium enrolled in a two-group randomization (calcium with vitamin D, or calcium alone) and received calcium during the run-in. Using logistic regression models, we examined baseline factors associated with RIF in three subgroups: men (N = 1606) and women (N = 301) in the full factorial randomization and women in the two-group randomization (N = 666). Overall, 314/2573 (12 %) participants failed run-in; 211 (67 %) took fewer than 80 % of their tablets (poor adherence), and 103 (33 %) withdrew or were uncooperative. In multivariable models, 8- to 13-fold variation was seen by study center in odds of RIF risk in the two largest groups. In men, RIF decreased with age (adjusted odds ratio [OR] per 5 years 0.85 [95 % confidence interval, CI; 0.76-0.96]) and was associated with being single (OR 1.65 [95 % CI; 1.10-2.47]), not graduating from high school (OR 2.77 [95 % CI; 1.58-4.85]), and missing SAQ data (OR 1.97 [1.40-2.76]). Among women, RIF was associated primarily with health-related factors; RIF risk was lower with higher physical health score (OR 0.73 [95 % CI; 0.62-0.86]) and baseline multivitamin use (OR 0.44 [95 % CI; 0.26-0.75]). Women in the 5-year colonoscopy surveillance interval were at greater risk of RIF than those with 3-year follow-up (OR 1.91 [95 % CI; 1.08-3.37]), and the number of prescription medicines taken was also positively correlated with RIF (p = 0.03). Perceived toxicities during run-in were associated with 12- to 29-fold significantly increased odds of RIF. There were few common baseline predictors of run-in failure in the three randomization groups. However, heterogeneity in run-in failure associated with study center, and missing SAQ data reflect potential opportunities for intervention to improve trial efficiency and retention. ClinicalTrials.gov: NCT00153816 . Registered September 2005.


The Jak-STAT pathway stimulated by interleukin 6.
Signal transducer and activator of transcription 3 (STAT3) is widely expressed and activated by a variety of growth-regulating signals as well as diverse cytokines that use gp130 signaling receptors. STAT3 is critical for embryonic development and stem cell biology, as well as inflammation, growth regulation, and multiple immune regulatory and homeostatic functions. The animation shows activation of STAT3 in response to interleukin 6 (IL6), a cytokine involved in triggering inflammation.


Social communication in mice--are there optimal cage conditions?
Social communication is heavily affected in patients with neuropsychiatric disorders. Accordingly, mouse models designed to study the mechanisms leading to these disorders are tested for this phenotypic trait. Test conditions vary between different models, and the effect of these test conditions on the quantity and quality of social interactions and ultrasonic communication is unknown. The present study examines to which extent the habituation time to the test cage as well as the shape/size of the cage influence social communication in freely interacting mice. We tested 8 pairs of male mice in free dyadic social interactions, with two habituation times (20 min and 30 min) and three cage formats (rectangle, round, square). We tested the effect of these conditions on the different types of social contacts, approach-escape sequences, follow behavior, and the time each animal spent in the vision field of the other one, as well as on the emission of ultrasonic vocalizations and their contexts of emission. We provide for the first time an integrated analysis of the social interaction behavior and ultrasonic vocalizations. Surprisingly, we did not highlight any significant effect of habituation time and cage shape/size on the behavioral events examined. There was only a slight increase of social interactions with the longer habituation time in the round cage. Remarkably, we also showed that vocalizations were emitted during specific behavioral sequences especially during close contact or approach behaviors. The present study provides a protocol reliably eliciting social contacts and ultrasonic vocalizations in adult male mice. This protocol is therefore well adapted for standardized investigation of social interactions in mouse models of neuropsychiatric disorders.


Multilevel influences on resilient healthcare in six countries: an international comparative study protocol.
Resilient healthcare (RHC) is an emerging area of theory and applied research to understand how healthcare organisations cope with the dynamic, variable and demanding environments in which they operate, based on insights from complexity and systems theory. Understanding adaptive capacity has been a focus of RHC studies. Previous studies clearly show why adaptations are necessary and document the successful adaptive actions taken by clinicians. To our knowledge, however, no studies have thus far compared RHC across different teams and countries. There are gaps in the research knowledge related to the multilevel nature of resilience across healthcare systems and the team-based nature of adaptive capacity.This cross-country comparative study therefore aims to add knowledge of how resilience is enabled in diverse healthcare systems by examining adaptive capacity in hospital teams in six countries. The study will identify how team, organisational and national healthcare system factors support or hinder the ability of teams to adapt to variability and change. Findings from this study are anticipated to provide insights to inform the design of RHC systems by considering how macro-level and meso-level structures support adaptive capacity at the micro-level, and to develop guidance for organisations and policymakers. The study will employ a multiple comparative case study design of teams nested within hospitals, in turn embedded within six countries: Australia, Japan, the Netherlands, Norway, Switzerland and the UK. The design will be based on the Adaptive Teams Framework placing adaptive teams at the centre of the healthcare system with layers of environmental, organisational and system level factors shaping adaptive capacity. In each of the six countries, a focused mapping of the macro-level features of the healthcare system will be undertaken by using documentary sources and interviews with key informants operating at the macro-level.A sampling framework will be developed to select two hospitals in each country to ensure variability based on size, location and teaching status. Four teams will be selected in each hospital-one each of a structural, hybrid, responsive and coordinating team. A total of eight teams will be studied in each country, creating a total sample of 48 teams. Data collection methods will be observations, interviews and document analysis. Within-case analysis will be conducted according to a standardised template using a combination of deductive and inductive qualitative coding, and cross-case analysis will be conducted drawing on the Qualitative Comparative Analysis framework. The overall Resilience in Healthcare research programme of which this study is a part has been granted ethical approval by the Norwegian Centre for Research Data (Ref. No. 8643334 and Ref. No. 478838). Ethical approval will also be sought in each country involved in the study according to their respective regulatory procedures. Country-specific reports of study outcomes will be produced for dissemination online. A collection of case study summaries will be made freely available, translated into multiple languages. Brief policy communications will be produced to inform policymakers and regulators about the study results and to facilitate translation into practice. Academic dissemination will occur through publication in journals specialising in health services research. Findings will be presented at academic, policy and practitioner conferences, including the annual RHC Network meeting and other healthcare quality and safety conferences. Presentations at practitioner and academic conferences will include workshops to translate the findings into practice and influence quality and safety programmes internationally.


Restoration of Blood Flow to the Proximal Femoral Epiphysis in Unstable Slipped Capital Femoral Epiphysis by Modified Dunn Procedure: A Preliminary Angiographic and Intracranial Pressure Monitoring Study.
The major complication of unstable slipped capital femoral epiphysis (SCFE) is avascular necrosis (AVN) of the femoral head. The purpose of this study was to document by angiography the preoperative and postoperative perfusion to the proximal femoral epiphysis following an unstable SCFE. A specific aim was to determine whether blood flow could be restored. A secondary aim was to determine the efficacy of an intracranial pressure (ICP) monitor to assess blood flow within the femoral head intraoperatively. Nine patients with an unstable SCFE underwent superselective angiogram of the medial circumflex femoral artery preoperatively, followed by operative fixation with an open reduction using a modified Dunn approach. Femoral head blood flow was evaluated with an ICP monitor. Angiography was repeated postoperatively. Patients were followed radiographically to assess for AVN. Follow-up averaged 22 months. Six patients did not have arterial flow to the femoral head on the preoperative angiogram. Flow was restored postoperatively on angiogram in 4 of the 6 patients. Two patients developed AVN. One had no flow to the femoral head preoperatively or postoperatively on angiogram and complete tearing of the periosteum was noted. In 1 patient, there was no ICP waveform after the initial reduction. After removing more callous and repeating reduction, the waveform returned. Of the 2 patients with AVN, 1 had an ICP waveform after reduction. This study documents that some patients with unstable SCFE present with reduced femoral head blood supply due to SCFE. It also demonstrates blood flow restoration in 4 patients by angiogram and 5 by ICP monitor after surgical treatment. No patient immediately lost blood flow due to surgery. ICP monitor is a safe intraoperative tool for real-time assessment of femoral head blood flow during open reduction of unstable SCFE. Presence of flow by ICP is not a guarantee that AVN will not develop, but absence of flow was predictive of AVN. Therapeutic level I-prognostic. See Instructions for Authors for a complete description of levels of evidence.


Treatment practices and outcomes of patients with established peripheral arterial disease hospitalized with acute myocardial infarction in a community setting.
There are little contemporary data available describing the hospital and long-term outcomes of patients with peripheral arterial disease (PAD) who are hospitalized with acute myocardial infarction (AMI). The objectives of our population-based study were to examine the hospital and long-term outcomes, as well as the use of different treatment practices, among patients with established PAD who were hospitalized with AMI. The study sample consisted of 4480 patients hospitalized with AMI at all Worcester, Mass, medical centers in 4 alternate years between 1997 and 2003. Among the metropolitan Worcester residents hospitalized with AMI, 13.5% had a history of PAD. Prior use of proven cardiac therapies in patients with, and without, PAD was less than optimal though more often used in patients with prior PAD. Patients with PAD were significantly less likely to be treated with thrombolytic therapy during hospitalization than patients without PAD. Patients with PAD were not at significantly increased risk of dying during hospitalization (adjusted OR 1.29, 0.95% CI 0.97-1.71), though they were at a significantly increased risk of dying at 1 year after hospital discharge (adjusted OR 2.00, 95% CI 1.58-2.52) in comparison with patients without prior PAD. Approximately 1 in 8 patients presenting with AMI in this community-wide study had a history of clinically recognized PAD. These patients are at increased risk of dying during the first year after hospital discharge. Our data indicate that there is a room for improvement for the enhanced use of effective treatment modalities and implementation of secondary prevention strategies in these high-risk patients.


Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype.
Cerebral angiopathy contributes to cognitive decline and dementia in Alzheimer's disease (AD) through cerebral blood flow (CBF) reductions and dysregulation. We report vascular smooth muscle cells (VSMC) in small pial and intracerebral arteries, which are critical for CBF regulation, express in AD high levels of serum response factor (SRF) and myocardin (MYOCD), two interacting transcription factors that orchestrate a VSMC-differentiated phenotype. Consistent with this finding, AD VSMC overexpressed several SRF-MYOCD-regulated contractile proteins and exhibited a hypercontractile phenotype. MYOCD overexpression in control human cerebral VSMC induced an AD-like hypercontractile phenotype and diminished both endothelial-dependent and -independent relaxation in the mouse aorta ex vivo. In contrast, silencing SRF normalized contractile protein content and reversed a hypercontractile phenotype in AD VSMC. MYOCD in vivo gene transfer to mouse pial arteries increased contractile protein content and diminished CBF responses produced by brain activation in wild-type mice and in two AD models, the Dutch/Iowa/Swedish triple mutant human amyloid beta-peptide (Abeta)-precursor protein (APP)- expressing mice and APPsw(+/-) mice. Silencing Srf had the opposite effect. Expression of SRF did not change in VSMC subjected to Alzheimer's neurotoxin, Abeta. Thus, SRF-MYOCD overexpression in small cerebral arteries appears to initiate independently of Abeta a pathogenic pathway mediating arterial hypercontractility and CBF dysregulation, which are associated with Alzheimer's dementia.


The longevity of arteriovenous graft for hemodialysis patients--externally supported or nonsupported.
Because thrombosis and stenosis are the most frequent causes of arteriovenous graft (AVG) failure, several externally supported grafts were designed to enhance incompressibility and kinking resistance to improve the patency. However, consensus on advantage of these modifications having still not been reached might relate to the previous limited patient numbers and small studies. This study analyzed the longevity of externally supported and nonsupported AVG on the basis of the nationwide database to understand whether the externally supported design could improve the duration of patency of AVG. Adult incident patients (n = 4402) were retrospectively enrolled who had began hemodialysis between January 1, 2002 and December 31, 2005. All incident patients with AVG, before or after beginning regular hemodialysis, between January 1, 2000 and December 31, 2006 were identified. The Cox proportional hazard model was used to compare the longevity of externally supported and nonsupported AVG by controlling other covariates. There were 990 patients with externally supported AVG and 3412 patients with nonsupported AVG. The patency rates of externally supported AVG were 49.4%, 31.6%, and 20.2% at 1, 2 and 3 years, respectively; those of nonsupported AVG were 31.9%, 17.4%, and 10.8%. The survival of nonsupported AVG was significantly inferior to that of externally supported AVG. Externally supported AVG are superior to nonsupported AVG for long-term patency. The incompressibility and kinking resistance of ringed grafts may shed light on a direction for the future development of dialysis graft design.


Acute stress alters transcript expression pattern and reduces processing of proBDNF to mature BDNF in Dicentrarchus labrax.
Stress involves alterations of brain functioning that may precipitate to mood disorders. The neurotrophin Brain Derived Neurotrophic Factor (BDNF) has recently been involved in stress-induced adaptation. BDNF is a key regulator of neuronal plasticity and adaptive processes. Regulation of BDNF is complex and may reflect not only stress-specific mechanisms but also hormonal and emotional responses. For this reason we used, as an animal model of stress, a fish whose brain organization is very similar to that of higher vertebrates, but is generally considered free of emotional reactions. We provide a comprehensive characterization of BDNF gene in the Dicentrarchus labrax and its transcriptional, translational and post-translational regulation following acute stress. While total BDNF mRNA levels are unchanged, BDNF transcripts 1c and 1d resulted down regulated after acute stress. Acute stress induces also a significant increase in proBDNF levels and reduction in mature BDNF suggesting altered regulation of proBDNF proteolytic processing. Notably, we provide here the first evidence that fishes possess a simplified proteolytic regulation of BDNF since the pro28Kda form, generated by the SKI-1 protease in mammals, is absent in fishes because the cleavage site has first emerged in reptilians. Finally, we show that the proBDNF/totBDNF ratio is a highly predictive novel quantitative biomarker to detect stress in fishes with sensitivity = 100%, specificity = 87%, and Negative Predictive Value = 100%. The high predictivity of proBDNF/totBDNF ratio for stress in lower vertebrates indicates that processing of BDNF is a central mechanism in adaptation to stress and predicts that a similar regulation of pro/mature BDNF has likely been conserved throughout evolution of vertebrates from fish to man.


Low-Fat Dietary Pattern among Postmenopausal Women Influences Long-Term Cancer, Cardiovascular Disease, and Diabetes Outcomes.
The preferred macronutrient dietary composition, and the health consequences of dietary fat reduction specifically, have been debated for decades. Here we provide a comprehensive overview of long-term health outcomes in the Women's Health Initiative Dietary Modification (DM) trial. The DM trial aimed to examine whether a low-fat dietary pattern would reduce the risk of invasive breast cancer, colorectal cancer, and, secondarily, coronary heart disease (CHD), with various other health outcomes also considered. The DM trial is a randomized controlled trial conducted at 40 centers in the US, among 48,835 postmenopausal women aged 50-79 y with baseline intake of ≥32% energy from fat. Participants were randomly assigned to a low-fat dietary pattern intervention group or to a usual-diet comparison group, during 1993-1998. Intervention goals were to reduce fat intake from ∼35% to 20% of total energy, in conjunction with increasing vegetables and fruit to 5 servings/d and grains to 6 servings/d. Over an 8.5-y (median) intervention period, intervention and comparison group differences included lower fat by 8-10%, and higher carbohydrate by 8-10%, of total energy, in conjunction with higher consumption of vegetables, fruit, and grains. Time-to-outcome analyses did not show significant differences between intervention and comparison groups for invasive breast cancer, colorectal cancer, or CHD, either over the intervention period or over longer-term cumulative follow-up. Additional analyses showed significant intervention group benefits related to breast cancer, CHD, and diabetes, without adverse effects. Over a 19.6-y (median) follow-up period, HRs (95% CIs) were 0.84 (0.74, 0.96) for breast cancer followed by death, and 0.87 (0.77, 0.98) for diabetes requiring insulin. Reduction in dietary fat with corresponding increase in vegetables, fruit, and grains led to benefits related to breast cancer, CHD, and diabetes, without adverse effects, among healthy postmenopausal US women. This trial was registered at clinicaltrials.gov as NCT00000611.


Point-of-Care Haematology Analyser Quality Assurance Programme: a rural nursing perspective.
BACKGROUND AND CONTEXT Rural health services without an onsite laboratory lack timely access to haematology results. Set in New Zealand's far north, this paper provides a rural nursing perspective on how a health service remote from a laboratory introduced a haematology analyser suitable for point-of-care use and established the associated quality assurance programme. ASSESSMENT OF PROBLEM Five broad areas were identified that could impact on successful implementation of the haematology analyser: quality control, staff training, physical resources, costs, and human resource requirements. RESULTS Quality control testing, staff training and operating the haematology analyser was more time intensive than anticipated. Finding adequate physical space for placement and operation of the analyser was challenging and costs per patient tests were higher than predicted due to low volumes of testing. STRATEGIES FOR IMPROVEMENT Through a collaborative team approach, a modified quality assurance programme was agreed on with the supplier and regional point-of-care testing co-ordinator, resulting in a reduced cost per test. The supplier provided dedicated hours of staff training. Allocated time was assigned to run point-of-care testing quality assurance. LESSONS Having access to laboratory tests can reduce inequalities for rural patients, but natural enthusiasm to introduce new point-of-care technologies and devices needs to be tempered by a thorough consideration of the realities on the ground. Quality assurance programmes need to fit the locality while being overseen and supported by laboratory staff knowledgeable in point-of-care testing requirements. Associated costs need to be sustainable in both human and physical resources.


Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE.
Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.


Tolerance and safety of the potentially probiotic strain Lactobacillus rhamnosus PRSF-L477: a randomised, double-blind placebo-controlled trial in healthy volunteers.
In Europe, the species Lactobacillus rhamnosus is currently on the Qualified Presumption of Safety list used by the European Food Safety Authority (EFSA) for internal safety assessment, but according to the EFSA the species should remain a topic of surveillance. In the present study, the safety and tolerance of the potentially probiotic strain L. rhamnosus PRSF-L477 was investigated in a placebo-controlled double-blind volunteer trial following FAO/WHO guidelines. A total of thirty-four subjects received daily doses of 1 × 10¹¹ colony-forming units (cfu) of L. rhamnosus PRSF-L477 (n 17) or placebo (n 17) for a period of 3 weeks, followed by a wash-out period of another 3 weeks. A questionnaire on gastrointestinal tolerance and a diary was kept daily to record compliance throughout these 6 weeks. Faecal and blood samples were collected for microbiological and haematological analysis. The recorded gastrointestinal symptoms, defecation frequency and stool consistency were not influenced indicating that L. rhamnosus PRSF-L477 was well tolerated. The species L. rhamnosus was detected in the faeces of sixteen out of seventeen subjects of the probiotic group during the intervention period. Using pulsed-field gel electrophoresis, re-isolates of L. rhamnosus PRSF-L477 were confirmed in nine of these subjects. Antibiotic susceptibility profiles of these re-isolates were unchanged compared with PRSF-L477. No clinically relevant changes in blood parameters such as liver and kidney function and no serious adverse events appeared during and after administration. Therefore, we conclude that L. rhamnosus PRSF-L477 can safely be administrated to healthy subjects at a daily dose of 1 × 10¹¹ cfu.


An eScience-Bayes strategy for analyzing omics data.
The omics fields promise to revolutionize our understanding of biology and biomedicine. However, their potential is compromised by the challenge to analyze the huge datasets produced. Analysis of omics data is plagued by the curse of dimensionality, resulting in imprecise estimates of model parameters and performance. Moreover, the integration of omics data with other data sources is difficult to shoehorn into classical statistical models. This has resulted in ad hoc approaches to address specific problems. We present a general approach to omics data analysis that alleviates these problems. By combining eScience and Bayesian methods, we retrieve scientific information and data from multiple sources and coherently incorporate them into large models. These models improve the accuracy of predictions and offer new insights into the underlying mechanisms. This "eScience-Bayes" approach is demonstrated in two proof-of-principle applications, one for breast cancer prognosis prediction from transcriptomic data and one for protein-protein interaction studies based on proteomic data. Bayesian statistics provide the flexibility to tailor statistical models to the complex data structures in omics biology as well as permitting coherent integration of multiple data sources. However, Bayesian methods are in general computationally demanding and require specification of possibly thousands of prior distributions. eScience can help us overcome these difficulties. The eScience-Bayes thus approach permits us to fully leverage on the advantages of Bayesian methods, resulting in models with improved predictive performance that gives more information about the underlying biological system.


Rubella Virus Infection, the Congenital Rubella Syndrome, and the Link to Autism.
Rubella is a systemic virus infection that is usually mild. It can, however, cause severe birth defects known as the congenital rubella syndrome (CRS) when infection occurs early in pregnancy. As many as 8%-13% of children with CRS developed autism during the rubella epidemic of the 1960s compared to the background rate of about 1 new case per 5000 children. Rubella infection and CRS are now rare in the U.S. and in Europe due to widespread vaccination. However, autism rates have risen dramatically in recent decades to about 3% of children today, with many cases appearing after a period of normal development ('regressive autism'). Evidence is reviewed here suggesting that the signs and symptoms of rubella may be due to alterations in the hepatic metabolism of vitamin A (retinoids), precipitated by the acute phase of the infection. The infection causes mild liver dysfunction and the spillage of stored vitamin A compounds into the circulation, resulting in an endogenous form of hypervitaminosis A. Given that vitamin A is a known teratogen, it is suggested that rubella infection occurring in the early weeks of pregnancy causes CRS through maternal liver dysfunction and exposure of the developing fetus to excessive vitamin A. On this view, the multiple manifestations of CRS and associated autism represent endogenous forms of hypervitaminosis A. It is further proposed that regressive autism results primarily from post-natal influences of a liver-damaging nature and exposure to excess vitamin A, inducing CRS-like features as a function of vitamin A toxicity, but without the associated dysmorphogenesis. A number of environmental factors are discussed that may plausibly be candidates for this role, and suggestions are offered for testing the model. The model also suggests a number of measures that may be effective both in reducing the risk of fetal CRS in women who acquire rubella in their first trimester and in reversing or minimizing regressive autism among children in whom the diagnosis is suspected or confirmed.


ace, Which encodes an adhesin in Enterococcus faecalis, is regulated by Ers and is involved in virulence.
Enterococcus faecalis is an opportunistic pathogen that causes numerous infectious diseases in humans and is a major agent of nosocomial infections. In this work, we showed that the recently identified transcriptional regulator Ers (PrfA like), known to be involved in the cellular metabolism and the virulence of E. faecalis, acts as a repressor of ace, which encodes a collagen-binding protein. We characterized the promoter region of ace, and transcriptional analysis by reverse transcription-quantitative PCR and mobility shift protein-DNA binding assays revealed that Ers directly regulates the expression of ace. Transcription of ace appeared to be induced by the presence of bile salts, probably via the deregulation of ers. Moreover, with an ace deletion mutant and the complemented strain and by using an insect (Galleria mellonella) virulence model, as well as in vivo-in vitro murine macrophage models, we demonstrated for the first time that Ace can be considered a virulence factor for E. faecalis. Furthermore, animal experiments revealed that Ace is also involved in urinary tract infection by E. faecalis.


Training and practice activities of hematology and medical oncology diplomates.
Diplomates of the American Board of Internal Medicine in hematology or medical oncology were surveyed about the content and setting of their practices, adequacy of training for professional activities, and preferences for certification. The response rate was 60% (N = 2516). Approximately 20% of cases seen by diplomates in hematology involve nonhematopoietic neoplasms, and 10% of cases managed by oncologists concern hematologic disorders. Diplomates were satisfied with training in areas corresponding to their own field(s) of certification, except for immune and/or acquired immunodeficiency syndrome-related and nonneoplastic leukocyte disorders. Training deficits most frequently recalled were office management skills and psychosocial/communication skills. Nearly half of the respondents preferred to maintain separate certificates. Data indicate that the two fields are distinct. However, the overlap in practice brings into question the adequacy of training for diplomates who manage problems outside of their field of certification and suggests that some degree of cross-fertilization in all training would be beneficial.


The effects of phototherapy on eosinophil and eosinophilic cationic protein in newborns with hyperbilirubinemia.
Newborns with jaundice requiring or not requiring phototherapy (PT) are at greater risk of developing asthma later in life. In this study, we investigated the effect of PT treatment on eosinophil and eosinophilic cationic protein (ECP) levels in newborns with severe hyperbilirubinemia. Thirty newborns diagnosed with severe hyperbilirubinemia and exposed to light-emitting diode (LED) PT were enrolled into the study. Total serum bilirubin (TSB) levels, complete blood count and serum ECP concentrations were measured before and after PT. TSB and hemoglobin (Hb) counts were lower after PT (p = 0.001). There was no difference between leukocyte, lymphocyte, neutrophil and platelet count before and after PT. Eosinophil levels were increased after PT, although not significantly. ECP levels were higher after PT (p = 0.006). It may be speculated that newborns treated with LED PT, increased ECP might play a role in developing allergic diseases later in life.


Behavioural responses of diamondback moth Plutella xylostella (Lepidoptera: Plutellidae) to extracts derived from Melia azedarach and Azadirachta indica.
The impact of three different doses of botanical insecticide derived from the syringa tree, Melia azedarach and the neem tree, Azadirachta indica was tested on the behaviour of the diamondback moth, Plutella xylostella (Linnaeus). Both botanical insecticides had a significant impact on larval behaviour. At higher doses the extracts showed feeding deterrent activity, with larvae preferring the untreated sides of cabbage leaves and consuming less of the treated half of cabbage leaves. The botanical insecticides had less of an effect on the oviposition behaviour of P. xylostella moths. In laboratory and glasshouse trials, significantly fewer eggs were oviposited on the plants that had been treated with syringa extracts. Therefore, the syringa extracts appear to have a repellent effect. In contrast, when exposed to the neem extracts the moths did not discriminate between control plants and treated plants. Behavioural observation indicated that, despite the lower number of eggs oviposited on cabbage treated with syringa extracts, the moths chose cabbage treated with the highest dose of syringa more often than they chose control cabbage plants. Similar observations were found in cabbage plants treated with neem, moths chose the medium dose more often than they chose the control. Oviposition and feeding deterrent properties are important factors in pest control, and results from this study indicate that botanical insecticides have the potential to be incorporated into control programmes for P. xylostella in South Africa.


The landscape of pain management in people with dementia living in care homes: a mixed methods study.
The aim of this study is to explore the current landscape of pain management in people with dementia living in care home settings. Pain is extremely common in this patient group, yet there is very limited guidance for healthcare professionals. Triangulation of stakeholder consultation and quality review of pain management guidance were performed. A review of existing pain management guidance was conducted using published quality criteria adapted for the field. Three focus group discussions were held with care home staff and two focus group discussions and an online survey with family carers. Data were subjected to thematic analysis to identify themes and sub-themes. Outcomes were reviewed by an expert panel, which gave recommendations. Fifteen existing guidelines were identified, of which three were designed for use in dementia and none were tailored for care home settings. Thematic analysis revealed six major themes in current pain management in dementia: importance of person-centredness, current lack of pain awareness in staff, communication as a core element, disparities in staff responsibility and confidence, the need for consistency of care and current lack of staff training. In addition to the needs for practice, the expert panel identified promising pharmacological treatment candidates, which warrant clinical evaluation. The findings of this study clearly articulate a need for an evidence-based pain management programme for care homes, which is informed by stakeholder input and based within a conceptual framework for this setting. There are novel opportunities for clinical trials of alternative analgesics for use in this patient group. Copyright © 2016 John Wiley & Sons, Ltd.


New generation of two-dimensional spintronic systems realized by coupling of Rashba and Dirac fermions.
Intriguing phenomena and novel physics predicted for two-dimensional (2D) systems formed by electrons in Dirac or Rashba states motivate an active search for new materials or combinations of the already revealed ones. Being very promising ingredients in themselves, interplaying Dirac and Rashba systems can provide a base for next generation of spintronics devices, to a considerable extent, by mixing their striking properties or by improving technically significant characteristics of each other. Here, we demonstrate that in BiTeI@PbSb2Te4 composed of a BiTeI trilayer on top of the topological insulator (TI) PbSb2Te4 weakly- and strongly-coupled Dirac-Rashba hybrid systems are realized. The coupling strength depends on both interface hexagonal stacking and trilayer-stacking order. The weakly-coupled system can serve as a prototype to examine, e.g., plasmonic excitations, frictional drag, spin-polarized transport, and charge-spin separation effect in multilayer helical metals. In the strongly-coupled regime, within ~100 meV energy interval of the bulk TI projected bandgap a helical state substituting for the TI surface state appears. This new state is characterized by a larger momentum, similar velocity, and strong localization within BiTeI. We anticipate that our findings pave the way for designing a new type of spintronics devices based on Rashba-Dirac coupled systems.


Radical resection for carcinoma of the ampulla of Vater.
One hundred four consecutive patients who underwent radical resection for ampullary cancer between 1965 and 1989 were retrospectively reviewed. Frequent clinical findings included jaundice (67%), significant (greater than 10%) weight loss (42%), and anemia (27%). Eighty-seven patients (84%) underwent a subtotal pancreatectomy, and 17 patients (16%) underwent a total pancreatectomy. The postoperative mortality was 5.7% (six patients), and reoperation for postoperative complications was required in six patients. The 5- and 10-year survival rates were 34% and 25%, respectively. Eight patients died of tumor recurrence more than 5 years after resection. Patient survival was significantly impaired by microscopic lymphatic invasion, regional nodal metastasis, tumor grade, and the epithelium of origin. In a multivariate analysis, only microscopic lymphatic invasion significantly reduced patient survival. Radical resection for ampullary cancer can be performed with a low morbidity and mortality and should remain the procedure of choice for ampullary carcinoma.


Radiation dosimetry and biodistribution of 11C-ABP688 measured in healthy volunteers.
In this study, we assessed the whole-body biodistribution and radiation dosimetry of the new glutamatergic ligand (11)C-ABP688. This ligand binds specifically to the metabotropic glutamatergic receptor of subtype 5 (mGluR5). The study included five healthy male volunteers aged 20-29 years. After intravenous injection of 240-260 MBq, a series of four to ten whole-body positron emission tomography/computed tomography scans were initiated, yielding 60-80 min of data. Residence times were then calculated in the relevant organs, and the software packages Mirdose and Olinda were used to calculate the absorbed radiation dose and the effective dose equivalent. Of the excreted (11)C activity at 1 hour, approximately 80% were eliminated via the hepato-biliary pathway and 20% through the urinary tract. The absorbed dose (mGy/MBq) was highest in the liver (1.64 E (-2) +/- 5.08 E (-3)), gallbladder (8.13 E (-3) +/- 5.6 E (-3)), and kidneys (7.27 E (-3) +/- 2.79 E (-3)). The effective dose equivalent was 3.68 +/- 0.84 microSv/MBq. Brain uptake in the areas with high mGluR5 density was 2-3 (SUV). The agreement between the values obtained from Mirdose and the Olinda was excellent. (11)C-ABP688 is a very promising ligand for the investigation of mGluR5 receptors in humans. Brain uptake is high and the effective dose equivalent so low that serial examinations in the same subject seem feasible.


Lifestyle interventions for hypertension and dyslipidemia among women of reproductive age.
Hypertension and dyslipidemia often precede cardiovascular disease. Lifestyle modifications help prevent these conditions, and referrals for women may be possible during reproductive health care visits. However, screening recommendations vary, which may affect screening rates. The objectives of this systematic review were to 1) assess the available literature on the effectiveness of lifestyle interventions, 2) review hypertension and dyslipidemia screening recommendations for consistency, and 3) report prevalence data for hypertension and dyslipidemia screening among women of reproductive age. We conducted a systematic literature search (January 1990-November 2010) for 1) randomized controlled trials on the impact of lifestyle interventions on cardiovascular disease risk factors in women of reproductive age, 2) evidence-based guidelines on hypertension and dyslipidemia screening, and 3) population-based prevalence studies on hypertension or dyslipidemia screening or both. Twenty-one of 555 retrieved studies (4%) met our inclusion criteria. Lifestyle interventions improved lipid levels in 10 of 18 studies and blood pressure in 4 of 9 studies. Most guidelines recommended hypertension screening at least every 2 years and dyslipidemia screening every 5 years, but recommendations for who should receive dyslipidemia screening varied. One study indicated that 82% of women of reproductive age received hypertension screening during the preceding year. In another study, only 49% of women aged 20 to 45 years received recommended dyslipidemia screening. Lifestyle interventions may offer modest benefits for reducing blood pressure and lipids in this population. Inconsistency among recommendations for dyslipidemia screening may contribute to low screening rates. Future studies should clarify predictors of and barriers to cholesterol screening in this population.


An interlaboratory study to test instrument performance of hydrogen dual-inlet isotope-ratio mass spectrometers.
An interlaboratory comparison of forty isotope-ratio mass spectrometers of different ages from several vendors has been performed to test 2H/1H performance with hydrogen gases of three different isotopic compositions. The isotope-ratio results (unsufficiently corrected for H3+ contribution to the m/z = 3 collector, uncorrected for valve leakage in the change-over valves, etc.) expressed relative to one of these three gases covered a wide range of values: -630% to -790% for the second gas and -368% to -462% for the third gas. After normalizing the isotopic abundances of these test gases (linearly adjusting the delta values so that the gases with the lowest and highest 2H content were identical for all laboratories), the standard deviation of the 40 measurements of the intermediate gas was a remarkably low 0.85%. It is concluded that the use of scaling factors is mandatory for providing accurate internationally comparable isotope-abundance values. Linear scaling for the isotope-ratio scales of gaseous hydrogen mass spectrometers is completely adequate.


Mechanisms, diagnosis, and treatment of heart failure with preserved ejection fraction and diastolic dysfunction.
Heart failure with preserved ejection fraction (HFpEF) continues to be a major challenge for clinicians. Many crucial aspects of the syndrome remain unclear, including the exact pathophysiology, early diagnosis, and treatment. Patients with HFpEF are often asymptomatic late into the disease process, and treatment with medications commonly used in heart failure with reduced ejection fraction (HFrEF) has not been proven to be beneficial. In addition, the confusion of similar terms with HFpEF, such as diastolic heart failure, and diastolic dysfunction (DD), has led to a misunderstanding of the true scope of HFpEF. Areas covered: In this review, authors highlight the differences in terminology and critically review the current knowledge on the underlying mechanisms, diagnosis, and latest treatment strategies of HFpEF. Expert commentary: While significant advances have been made in the understanding of HFpEF, the definitive diagnosis of HFpEF continues to be difficult. The development of improved and standardized methods for detecting DD has shown promise in identifying early HFpEF. However, even with early detection, there are few treatment options shown to provide mortality benefit warranting further investigation.


PATHOPHYSIOLOGIC EVALUATION OF THE TRANSGENIC CFTR "GUT-CORRECTED" PORCINE MODEL OF CYSTIC FIBROSIS.
This study evaluated the pulmonary pathophysiology of the transgenic CFTR "gut-corrected" cystic fibrosis (CF) pigs. Four sows produced 18 piglets of which 11 were stillborn with only 2 animals surviving beyond 2 weeks. Failure to survive beyond the neonatal period by 5 piglets was judged to result from metabolic dysfunction related to genetic manipulation for CFTR gut expression or due to cloning artifact. Plasma analysis showed very low plasma proteins, highly elevated liver enzymes, and severe acidosis. All surviving offspring received furosemide for systemic edema. Physiologic evaluation was performed with lung tissues from the two surviving pigs. Both acetylcholine and forskolin induced mucous liquid secretion that was significantly lower in CF bronchi than non-CF bronchi. The percent non-volatile solids in mucus secreted from CF bronchi was elevated following acetylcholine or forskolin. Mucociliary transport in excised tracheas was reduced in the CF tracheas relative to nonCF tracheas. The diameter of CF tracheas was less than that of non-CF pigs in spite of their greater body weight. Despite exhibiting severe metabolic dysfunction during the neonatal period, this CF animal model appears to express important characteristics of human CF pulmonary disease.


Hematological Parameters as Prognostic Biomarkers in Patients with Cardiovascular Diseases.
Cardiovascular diseases are the major causes of preventable health loss from disease in the world and lead to functional disturbances including hematological parameters. The inflammatory and hypoxemic nature of cardiovascular diseases causes a stimulus in the bone marrow and, depending on the intensity of this stimulus, there is a release of immature cells or increase of other cells in the bloodstream. Therefore, their presence in the circulation is an important variable used to diagnose, stratify and predict diseases. In the last five decades, with the advent of automated counting of immature cells in the peripheral blood, the hemogram was transformed into a clinical tool of great importance in hospital surveillance for demonstrating this daily variability in the hematopoietic response according to the existing injury in the patient. Studies have shown that the presence of nucleated red blood cells and increases in mean platelet volume, immature granulocytes and neutrophil to lymphocyte ratio in the systemic circulation are independent prognostic biomarkers. This review article has as main objective to demonstrate the association of these hematological parameters to cardiovascular diseases, emphasizing their importance in clinical decision making.


Light Scattering Calculations for Spherical Metallic Nanoparticles (Ag, Au) Coated by TCO (AZO, ITO, PEDOT:PSS) Shell.
Ag and Au nanostructures became increasingly interesting due to their localized surface plasmon resonance properties. These properties can be successfully exploited in order to enhance the light trapping in solar cell devices by appropriate light scattering phenomena. In solar cell applications, the Ag or Au nanoparticles are, usually, supported on or embedded in a thin transparent conductive oxide layer, mainly AZO and ITO for inorganic solar cells and PEDOT:PSS for organic solar cells. However, the light scattering properties strongly depend on the shape and size of the metal nanostructures and on the optical properties of the surrounding environment. Therefore, the systems need to be well designed to maximize scattering and minimize the light absorption within the metal nanoparticles. In this regard, this work reports, in particular, results concerning calculations, by using the Mie theory, of the angle-dependent light scattering intensity (I(θ)) for spherical Ag and Au nanoparticles coated by a shell of AZO or ITO or PEDOT:PSS. I(θ) and scattering efficiency Qscatt for the spherical core-shell nanoparticles are calculated by changing the radius R of the spherical core (Ag or Au) and the thickness d of the shell (AZO, ITO, or PEDOT:PSS). For each combination of core-shell system, the evolution of I(θ) and Qscatt with the core and shell sizes is drawn and comparisons between the various types of systems is drawn at parity of core and shell sizes. For simplicity, the analysis is limited to spherical core-shell nanoparticles so as to use the Mie theory and to perform analytically exact calculations. However, the results of the present work, even if simplified, can help in establishing the general effect of the core and shell sizes on the light scattering properties of the core-shell nanoparticles, essential to prepare the nanoparticles with desired structure appropriate to the application.


Peer review of the pesticide risk assessment of the active substance blood meal.
The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State Austria and co-rapporteur Member State Lithuania for the pesticide active substance blood meal and the considerations as regards the inclusion of the substance in Annex IV of Regulation (EC) No 396/2005 are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of blood meal as a game repellent on deciduous and coniferous trees in forestry, orchard trees and ornamental plants and as a vole repellent on deciduous and coniferous trees in forestry (field uses). The reliable end points, appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed. No concerns are identified.


Semi-synthetic nanobody-ligand conjugates exhibit tunable signaling properties and enhanced transcriptional outputs at neurokinin receptor-1.
Antibodies have proven highly valuable for therapeutic development; however, they are typically poor candidates for applications that require activation of G protein-coupled receptors (GPCRs), the largest collection of targets for clinically approved drugs. Nanobodies (Nbs), the smallest antibody fragments retaining full antigen-binding capacity, have emerged as promising tools for pharmacologic applications, including GPCR modulation. Past work has shown that conjugation of Nbs with ligands can provide GPCR agonists that exhibit improved activity and selectivity compared to their parent ligands. The neurokinin-1 receptor (NK1R), a GPCR targeted for the treatment of pain, is activated by peptide agonists such as Substance P (SP) and neurokinin A (NKA), which induce signaling through multiple pathways (Gs, Gq and β-arrestin). In this study, we investigated whether conjugating NK1R ligands with Nbs that bind to a separate location on the receptor would provide chimeric compounds with distinctive signaling properties. We employed sortase A-mediated ligation to generate several conjugates consisting of Nbs linked to NK1R ligands. Many of these conjugates exhibited divergent and unexpected signaling properties and transcriptional outputs. For example, some Nb-NKA conjugates showed enhanced receptor binding capacity, high potency partial agonism, prolonged cAMP production, and an increase in transcriptional output associated with Gs signaling; whereas other conjugates were virtually inactive. Nanobody conjugation caused only minor alterations in ligand-induced upstream Gq signaling with unexpected enhancements in transcriptional (downstream) responses. Our findings underscore the potential of nanobody conjugation for providing compounds with advantageous properties such as biased agonism, prolonged duration of action, and enhanced transcriptional responses. These compounds hold promise not only for facilitating fundamental research on GPCR signal transduction mechanisms but also for the development of more potent and enduring therapeutics.


Differences in vascular nitric oxide and endothelium-derived hyperpolarizing factor bioavailability in blacks and whites.
Abnormalities in nitric oxide (NO) bioavailability have been reported in blacks. Whether there are differences in endothelium-derived hyperpolarizing factor (EDHF) in addition to NO between blacks and whites and how these affect physiological vasodilation remain unknown. We hypothesized that the bioavailability of vascular NO and EDHF, at rest and with pharmacological and physiological vasodilation, varies between whites and blacks. In 74 white and 86 black subjects without known cardiovascular disease risk factors, forearm blood flow was measured using plethysmography at rest and during inhibition of NO with N(G)-monomethyl-L-arginine and of K(+) Ca channels (EDHF) with tetraethylammonium. The reduction in resting forearm blood flow was greater with N(G)-monomethyl-L-arginine (P=0.019) and similar with tetraethylammonium in whites compared with blacks. Vasodilation with bradykinin, acetylcholine, and sodium nitroprusside was lower in blacks compared with whites (all P<0.0001). Inhibition with N(G)-monomethyl-L-arginine was greater in whites compared with blacks with bradykinin, acetylcholine, and exercise. Inhibition with tetraethylammonium was lower in blacks with bradykinin, but greater during exercise and with acetylcholine. The contribution to both resting and stimulus-mediated vasodilator tone of NO is greater in whites compared with blacks. EDHF partly compensates for the reduced NO release in exercise and acetylcholine-mediated vasodilation in blacks. Preserved EDHF but reduced NO bioavailability and sensitivity characterizes the vasculature in healthy blacks. http://clinicaltrials.gov/. Unique identifier: NCT00166166.


Differential regulation of muscarinic receptor mRNA levels in neuroblastoma cells by chronic agonist exposure: a comparative polymerase chain reaction study.
The human neuroblastoma line SH-SY5Y expresses three muscarinic receptor genes (m1, m2, and m3). In this study, we have investigated the effect of agonist exposure on the steady state levels of each muscarinic receptor transcript, using a comparative polymerase chain reaction (PCR) assay that allows changes in levels of very rare transcripts to be monitored. Northern blot analysis of cellular RNA revealed the presence of m3 mRNA, whereas PCR amplification of SH-SY5Y cDNA additionally revealed the presence of m1 and m2 transcripts. Cell surface muscarinic receptor number, as assessed by N-[3H]methylscopolamine binding to whole cells, rapidly decreased to 42% of control levels within 1 hr of exposure to 100 microM carbachol; this was followed by a slower decline to 6% of control levels after 48 hr. Total receptor number, measured by binding of [3H]quinuclidinyl benzilate, showed a much slower decline to 21% of control levels after 48 hr of treatment. Comparative PCR analysis showed that each muscarinic transcript was differentially regulated. The level of transcript encoding the major receptor population, the m3 mRNA, was rapidly elevated within 1 hr of agonist challenge and subsequently decreased to about 30% of prestimulation levels within 9 hr; this decrease was sustained for the time course of the experiment. m2 mRNA levels showed a transient increase followed by a decrease to 30% of prestimulation levels after 6 hr but, in contrast to the m3 transcripts, this depression was followed by a transient rise to 270% of prestimulation levels after 24 hr before declining to normal levels by 72 hr after stimulation. Exposure of cells to agonist clearly instigates a complex pattern of changes in levels of receptor and receptor mRNA; comparison of the relative time courses of these changes indicates that the decline in m3 transcripts precedes the loss of muscarinic receptor binding sites.


The relative role of the Child-Pugh classification and the Mayo natural history model in the assessment of survival in patients with primary sclerosing cholangitis.
The Child-Pugh classification is a simple, convenient prognostic measure in patients with liver cirrhosis. We investigated the relative role of the Child-Pugh classification and the Mayo model in the assessment of survival in patients with primary sclerosing cholangitis (PSC). Of the 173 patients described in the original Mayo PSC natural history model, 147 patients had sufficient information in the medical record to allow computation of the Child-Pugh score. We used our most recent modification of the Mayo model to compute the risk score, based on patient's age, serum levels of bilirubin, albumin, and aspartate aminotransferase and history of variceal bleeding. Using the risk score (R), patients were divided into the low- (R < 0), intermediate- (0 </= R < 2), and high-risk (R >/= 2) groups. Kaplan-Meier estimates and proportional hazards analysis were used to evaluate the two prognostic models. Although there was a statistically significant correlation between the Child-Pugh and Mayo risk scores, two-thirds of the patients had a Child-Pugh score of 5 or 6 and a relatively wide range of risk scores (-1.1-4.3). The probability of survival for 7 years in patients in the low-, intermediate-, and high-risk groups was 92%, 74%, and 40% for Child-Pugh class A (n = 96) and 100%, 62%, and 28% for Child-Pugh class B patients (n = 44), respectively. There were only a small number (n = 7) of Child-Pugh class C patients. In our age-adjusted multivariate analysis, each unit increase in the Mayo risk score was associated with a 2.5-fold increase in the risk of death (95% confidence interval: 1.8-3.4, P <.01), whereas Child-Pugh classification had no significant impact on survival (Child-Pugh B vs. A: risk ratio = 1.1 [95% confidence interval: 0.6-2.0]; Child-Pugh C versus A: risk ratio = 0.6 [95% confidence interval: 0. 2-1.8]). In contrast to the Child-Pugh classification, which was developed for advanced liver cirrhosis, the Mayo model provides valid survival information, particularly in patients early in the course of PSC.


First Expert Elicitation of Knowledge on Possible Drivers of Observed Increasing Human Cases of Tick-Borne Encephalitis in Europe.
Tick-borne encephalitis (TBE) is a viral disease endemic in Eurasia. The virus is mainly transmitted to humans via ticks and occasionally via the consumption of unpasteurized milk products. The European Centre for Disease Prevention and Control reported an increase in TBE incidence over the past years in Europe as well as the emergence of the disease in new areas. To better understand this phenomenon, we investigated the drivers of TBE emergence and increase in incidence in humans through an expert knowledge elicitation. We listed 59 possible drivers grouped in eight domains and elicited forty European experts to: (i) allocate a score per driver, (ii) weight this score within each domain, and (iii) weight the different domains and attribute an uncertainty level per domain. An overall weighted score per driver was calculated, and drivers with comparable scores were grouped into three terminal nodes using a regression tree analysis. The drivers with the highest scores were: (i) changes in human behavior/activities; (ii) changes in eating habits or consumer demand; (iii) changes in the landscape; (iv) influence of humidity on the survival and transmission of the pathogen; (v) difficulty to control reservoir(s) and/or vector(s); (vi) influence of temperature on virus survival and transmission; (vii) number of wildlife compartments/groups acting as reservoirs or amplifying hosts; (viii) increase of autochthonous wild mammals; and (ix) number of tick species vectors and their distribution. Our results support researchers in prioritizing studies targeting the most relevant drivers of emergence and increasing TBE incidence.


High prevalence of thyroid nodules in patients with achrocordons (skin tags). Possible role of insulin-resistance.
Due to the observation of a great number of patients having achrocordons, when they underwent fine needle biopsies for thyroid nodules, we decided to perform a prospective study to investigate the relationship between this finding and the presence of insulin resistance (IR), since achrocordons are commonly seen in hyperinsulinemic subjects. A total of 120 consecutive women, aged 18-35 yrs were studied. All subjects were also evaluated by thyroid ultrasound (US) for measuring thyroid volume and the presence of non-palpable nodules. Basal and post-prandial serum insulin was measured in all of them, as well as the Homeostasis Model Assessment (HOMA). Subjects were divided in two groups: Group A, with achrocordons (n = 44) and Group B, without achrocordons (n = 76). Group A showed 24 patients (54.5%) with thyroid nodules, whereas Group B only 13 subjects (17.1%); p = 0.0087. When we considered, as having high normal thyroid volume, the glands weighting more than 16 grams by US, without nodules, it was found that 8/44 cases from Group A (18.6%) and 3/76 from Group B (3.9%) fitted in such category, p = 0.0076. In patients with nodules and/or bigger thyroids, IR was observed in 36/44 (81.8%) of Group A and 14/76 (18.4%) of Group B, p = 0.0069, while the overall prevalence of IR was 0.47 in Group A and 0.05 in Group B, p = 0.00094. It is concluded that patients with achrocordons have a higher prevalence of US-detected thyroid nodules and larger thyroid glands. Then, it may be beneficial to search for thyroid abnormalities in those subjects with skin tags.


Metformin may function as anti-cancer agent via targeting cancer stem cells: the potential biological significance of tumor-associated miRNAs in breast and pancreatic cancers.
Metformin is one of the most used diabetic drugs for the management of type II diabetes mellitus (DM) in the world. Increased numbers of epidemiological and clinical studies have provided convincing evidence supporting the role of metformin in the development and progression of a variety of human tumors including breast and pancreatic cancer. Substantial pre-clinical evidence from in vitro and in vivo experimental studies strongly suggests that metformin has an anti-cancer activity mediated through the regulation of several cell signaling pathways including activation of AMP kinase (AMPK), and other direct and indirect mechanisms; however, the detailed mechanism(s) has not yet been fully understood. The concept of cancer stem cells (CSCs) has gained significant attention in recent years due its identification and defining its clinical implications in many different tumors including breast cancer and pancreatic cancer. In this review, we will discuss the protective role of metformin in the development of breast and pancreatic cancers. We will further discuss the role of metformin as an anti-cancer agent, which is in part mediated through targeting CSCs. Finally, we will discuss the potential role of metformin in the modulation of tumor-associated or CSC-associated microRNAs (miRNAs) as part of the novel mechanism of action of metformin in the development and progression of breast and pancreatic cancers.


The relationship of aerobic capacity, anaerobic peak power and experience to performance in CrossFit exercise.
CrossFit is becoming increasingly popular as a method to increase fitness and as a competitive sport in both the Unites States and Europe. However, little research on this mode of exercise has been performed to date. The purpose of the present investigation involving experienced CrossFit athletes and naïve healthy young men was to investigate the relationship of aerobic capacity and anaerobic power to performance in two representative CrossFit workouts: the first workout was 12 minutes in duration, and the second was based on the total time to complete the prescribed exercise. The participants were 32 healthy adult males, who were either naïve to CrossFit exercise or had competed in CrossFit competitions. Linear regression was undertaken to predict performance on the first workout (time) with age, group (naïve or CrossFit athlete), VO2max and anaerobic power, which were all significant predictors (p < 0.05) in the model. The second workout (repetitions), when examined similarly using regression, only resulted in CrossFit experience as a significant predictor (p < 0.05). The results of the study suggest that a history of participation in CrossFit competition is a key component of performance in CrossFit workouts which are representative of those performed in CrossFit, and that, in at least one these workouts, aerobic capacity and anaerobic power are associated with success.


[Mesothelioma incidence and time trend in the worlds].
Due to its adaptability to different uses, asbestos was increasingly employed in many working and domestic areas up to the 1970s-1980s, when its aetiological role in the onset of pleural mesothelioma (Mm) was recognized. Since then Mm cases have been continuously increasing and no decline is expected until 2020, despite the fact that most industrialized countries banned asbestos use a few decades ago. The aim of this study was to analyse Mm incidence in the World during the last ten years, also considering asbestos consumption in diferent areas. Incidence age-standardized rates (ASR) from Cancer Registries included in Cancer Incidence in Five Continents, Vol. VII and VIII, and, when appropriate, standardized rate ratio (SRR) with confidence interval were estimated. The highest incidence rates among males were observed in Liguria and Australia. After Liguria, Maastricht and Scotland in Europe, North East Regions and Piedmont in Italy showed high rates. Among females, the highest incidence rates were observed in Liguria, among black women in New Orleans and in the province of Varese. SRRs revealed increased rates, not always significant, in almost all areas among males and in about 50% of the areas among females, although the variation was significant only in Varese. These results confirmed a relationship between Mm risk and asbestos use, revealing high incidence rates in Australia (mining), Italy (shipyards, building, goods handling, heavy industries and sea trade) and Great Britain (shipyards). Mm cases increased in areas with elevated incidence rates, suggesting that larger amounts of asbestos were probably used for a longer period. Finally, no Mm cases were registered in some areas, which probably signifies a lack (or a delay) of risk referred to the investigated period.


Evaluating learning and change in orthopaedics: What is the evidence-base?
Learning and change are key elements of clinical governance and are responsible for the progression of our specialty. Although orthopaedics has been slow to embrace quality improvement, recent years have seen global developments in surgical education, quality improvement, and patient outcome research. This review covers recent advances in the evaluation of learning and change and identifies the most important research questions that remain unanswered. Research into proxies of learning is improving but more work is required to identify the best proxy for a given procedure. Learning curves are becoming commonplace but are poorly integrated into postgraduate training curricula and there is little agreement over the most appropriate method to analyse learning curve data. With various organisations promoting centralisation of care, learning curve analysis is more important than ever before. The use of simulation in orthopaedics is developing but is yet to be formally mapped to resident training worldwide. Patient outcome research is rapidly changing, with an increased focus on quality of life measures. These are key to patients and their care. Cost-utility analysis is increasingly seen in orthopaedic manuscripts and this needs to continue to improve evidence-based care. Large-scale international, multi-centre randomised trials are gaining popularity and updated guidance on sample size estimation needs to become widespread. A global lack of surgeon equipoise will need to be addressed. Quality improvement projects frequently employ interrupted time-series analysis to evaluate change. This technique's limitations must be acknowledged, and more work is required to improve the evaluation of change in a dynamic healthcare environment where multiple interventions frequently occur. Advances in the evaluation of learning and change are needed to drive improved international surgical education and increase the reliability, validity, and importance of the conclusions drawn from orthopaedic research.


Angiopreventive efficacy of pure flavonolignans from milk thistle extract against prostate cancer: targeting VEGF-VEGFR signaling.
The role of neo-angiogenesis in prostate cancer (PCA) growth and metastasis is well established, but the development of effective and non-toxic pharmacological inhibitors of angiogenesis remains an unaccomplished goal. In this regard, targeting aberrant angiogenesis through non-toxic phytochemicals could be an attractive angiopreventive strategy against PCA. The rationale of the present study was to compare the anti-angiogenic potential of four pure diastereoisomeric flavonolignans, namely silybin A, silybin B, isosilybin A and isosilybin B, which we established previously as biologically active constituents in Milk Thistle extract. Results showed that oral feeding of these flavonolignans (50 and 100 mg/kg body weight) effectively inhibit the growth of advanced human PCA DU145 xenografts. Immunohistochemical analyses revealed that these flavonolignans inhibit tumor angiogenesis biomarkers (CD31 and nestin) and signaling molecules regulating angiogenesis (VEGF, VEGFR1, VEGFR2, phospho-Akt and HIF-1α) without adversely affecting the vessel-count in normal tissues (liver, lung, and kidney) of tumor bearing mice. These flavonolignans also inhibited the microvessel sprouting from mouse dorsal aortas ex vivo, and the VEGF-induced cell proliferation, capillary-like tube formation and invasiveness of human umbilical vein endothelial cells (HUVEC) in vitro. Further studies in HUVEC showed that these diastereoisomers target cell cycle, apoptosis and VEGF-induced signaling cascade. Three dimensional growth assay as well as co-culture invasion and in vitro angiogenesis studies (with HUVEC and DU145 cells) suggested the differential effectiveness of the diastereoisomers toward PCA and endothelial cells. Overall, these studies elucidated the comparative anti-angiogenic efficacy of pure flavonolignans from Milk Thistle and suggest their usefulness in PCA angioprevention.


Cholesterol screening in general practice.
Serum cholesterol levels were measured in 250 men and 250 women aged 25-60 years attending a general practice. Seventy three per cent of the sample had levels above 5.2 mM and of these 98 patients agreed to follow a low cholesterol/low saturated fat diet for six months. The overall reduction in serum cholesterol level among these patients was 13%, suggesting that lipid screening in general practice could be worthwhile.