Probabilistic evaluation of the material properties of the in vivo subject-specific articular surface using a computational model.
This article used probabilistic analysis to evaluate material properties of the in vivo subject-specific tibiofemoral (TF) joint model. Sensitivity analysis, based on a Monte Carlo (MC) method, was performed using a subject-specific finite element (FE) model generated from in vivo computed tomography (CT) and magnetic resonance imaging (MRI) data, subjected to two different loading conditions. Specifically, the effects of inherent uncertainty in ligament stiffness, horn attachment stiffness, and articular surface material properties were assessed using multifactorial global sensitivity analysis. The MRI images were taken before and after axial compression, and when the flexion condition had been maintained at up to 90 degree flexion in the subject-specific knee joint. The loading conditions of the probabilistic subject-specific FE model (axial compression and 90 degree flexion) were similar to the MRI acquisition setup. We were able to detect the influence of material parameters while maintaining the potential effect of parametric interactions. Throughout the in silico property optimization, a subject-specific FE model was used and less sensitive parameters were eliminated in the global sensitivity method. Soft tissue material properties were estimated using an optimization procedure that involved the minimization of the differences between the kinematics predicted by the subject-specific model and those obtained through in vivo subject-specific data. The results of this approach suggest that the articular surface mechanical properties could be found by using in vivo measurements, which clarifies the valuable tool for future subject-specific studies related to TF joint scaffolds, allografts and biologics. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1390-1400, 2017.


Systematic Review of the Effect of Adherence to Statin Treatment on Critical Cardiovascular Events and Mortality in Primary Prevention.
Analyze the relative risks of critical cardiovascular outcomes and mortality associated with adherence to statin treatment in a clinical setting in people with no history of prior cardiovascular disease (CVD). A systematic review of the literature was conducted up to December 2016. The outcomes of interest were cardiovascular fatal or nonfatal events and all-cause mortality. A total of 17 articles were included in a qualitative synthesis. Four were case-control nested in a retrospective cohort design and the other 11 were a cohort design. Seven studies compared the best adherer patients with the worst adherers. In the 3 studies (317 603 participants) that considered ischemic heart disease in this group, the pooled reduction in risk was 18% (95% confidence interval [CI]: 14%-22%, I2 = 0%); for the CVD outcome, 2 studies (131 477 participants) showed a pooled reduction in risk of 47% (95% CI: 36%-56%, I2 = 84.7%) with 1 included study showing a much larger reduction than the others; for the cerebrovascular event (CeVD) outcome, 2 studies (155 726 participants) showed a pooled reduction in risk of 26% (95% CI: 18%-34%, I2 = 0%); and for mortality, the reduction in risk was 49% (95% CI: 39%-57%, I2 = 62.4%). The other 4 studies (147 859 participants) compared the most adherent group with the rest. These showed a pooled risk reduction of CVD of 22% (95% CI: 6%-27%, I2 = 0). Adherence to statins treatment is shown as a key element for primary prevention, although these are observational data and the risk of bias from confounding cannot be ruled out. Standardization of measures of adherence to treatment would improve comparability between studies. Further research is warranted to design effective interventions to improve patients' adherence.


RNA interference is mediated by 21- and 22-nucleotide RNAs.
Double-stranded RNA (dsRNA) induces sequence-specific posttranscriptional gene silencing in many organisms by a process known as RNA interference (RNAi). Using a Drosophila in vitro system, we demonstrate that 21- and 22-nt RNA fragments are the sequence-specific mediators of RNAi. The short interfering RNAs (siRNAs) are generated by an RNase III-like processing reaction from long dsRNA. Chemically synthesized siRNA duplexes with overhanging 3' ends mediate efficient target RNA cleavage in the lysate, and the cleavage site is located near the center of the region spanned by the guiding siRNA. Furthermore, we provide evidence that the direction of dsRNA processing determines whether sense or antisense target RNA can be cleaved by the siRNA-protein complex.


Payers' Views of the Changes Arising through the Possible Adoption of Adaptive Pathways.
Payers are a major stakeholder in any considerations and initiatives concerning adaptive licensing of new medicinal products, also referred to as Medicines Adaptive Pathways to patients (MAPPs). Firstly, the scope and necessity of MAPPs need further scrutiny, especially with regard to the definition of unmet need. Conditional approval pathways already exist for new medicines for seriously debilitating or life-threatening diseases and only a limited number of new medicines are innovative. Secondly, MAPPs will result in new medicines on the market with limited evidence about their effectiveness and safety. Additional data are to be collected after approval. Consequently, adaptive pathways may increase the risk of exposing patients to ineffective or unsafe medicines. We have already seen medicines approved conventionally that subsequently proved ineffective or unsafe amongst a wider, more co-morbid population as well as medicines that could have been considered for approval under MAPPs but subsequently proved ineffective or unsafe in Phase III trials and were never licensed. Thirdly, MAPPs also put high demands on payers. Routine collection of patient level data is difficult with high transaction costs. It is not clear who will fund these. Other challenges for payers include shifts in the risk governance framework, implications for evaluation and HTA, increased complexity of setting prices, difficulty with ensuring equity in the allocation of resources, definition of responsibility and liability and implementation of stratified use. Exit strategies also need to be agreed in advance, including price reductions, rebates, or reimbursement withdrawals when price premiums are not justified. These issues and concerns will be discussed in detail including potential ways forward.


Cochlear implants in children: surgical site infections and prevention and treatment of acute otitis media and meningitis.
The use of cochlear implants is increasingly common, particularly in children younger than 3 years. Bacterial meningitis, often with associated acute otitis media, is more common in children with cochlear implants than in groups of control children. Children with profound deafness who are candidates for cochlear implants should receive all age-appropriate doses of pneumococcal conjugate and Haemophilus influenzae type b conjugate vaccines and appropriate annual immunization against influenza. In addition, starting at 24 months of age, a single dose of 23-valent pneumococcal polysaccharide vaccine should be administered. Before implant surgery, primary care providers and cochlear implant teams should ensure that immunizations are up-to-date, preferably with completion of indicated vaccines at least 2 weeks before implant surgery. Imaging of the temporal bone/inner ear should be performed before cochlear implantation in all children with congenital deafness and all patients with profound hearing impairment and a history of bacterial meningitis to identify those with inner-ear malformations/cerebrospinal fluid fistulas or ossification of the cochlea. During the initial months after cochlear implantation, the risk of complications of acute otitis media may be higher than during subsequent time periods. Therefore, it is recommended that acute otitis media diagnosed during the first 2 months after implantation be initially treated with a parenteral antibiotic (eg, ceftriaxone or cefotaxime). Episodes occurring 2 months or longer after implantation can be treated with a trial of an oral antimicrobial agent (eg, amoxicillin or amoxicillin/clavulanate at a dose of approximately 90 mg/kg per day of amoxicillin component), provided the child does not appear toxic and the implant does not have a spacer/positioner, a wedge that rests in the cochlea next to the electrodes present in certain implant models available between 1999 and 2002. "Watchful waiting" without antimicrobial therapy is inappropriate for children with implants with acute otitis media. If feasible, tympanocentesis should be performed for acute otitis media, and the material should be sent for culture, but performance of this procedure should not result in an undue delay in initiating antimicrobial therapy. For patients with suspected meningitis, cerebrospinal fluid as well as middle-ear fluid, if present, should be sent for culture. Empiric antimicrobial therapy for meningitis occurring within 2 months of implantation should include an agent with broad activity against Gram-negative bacilli (eg, meropenem) plus vancomycin. For meningitis occurring 2 months or longer after implantation, standard empiric antimicrobial therapy for meningitis (eg, ceftriaxone plus vancomycin) is indicated. For patients with meningitis, urgent evaluation by an otolaryngologist is indicated for consideration of imaging and surgical exploration.


Whole-genome sequencing of Burkholderia pseudomallei from an urban melioidosis hot spot reveals a fine-scale population structure and localised spatial clustering in the environment.
Melioidosis is a severe disease caused by the environmental bacterium Burkholderia pseudomallei that affects both humans and animals throughout northern Australia, Southeast Asia and increasingly globally. While there is a considerable degree of genetic diversity amongst isolates, B. pseudomallei has a robust global biogeographic structure and genetic populations are spatially clustered in the environment. We examined the distribution and local spread of B. pseudomallei in Darwin, Northern Territory, Australia, which has the highest recorded urban incidence of melioidosis globally. We sampled soil and land runoff throughout the city centre and performed whole-genome sequencing (WGS) on B. pseudomallei isolates. By combining phylogenetic analyses, Bayesian clustering and spatial hot spot analysis our results demonstrate that some sequence types (STs) are widespread in the urban Darwin environment, while others are highly spatially clustered over a small geographic scale. This clustering matches the spatial distribution of clinical cases for one ST. Results also demonstrate a greater overall isolate diversity recovered from drains compared to park soils, further supporting the role drains may play in dispersal of B. pseudomallei STs in the environment. Collectively, knowledge gained from this study will allow for better understanding of B. pseudomallei phylogeography and melioidosis source attribution, particularly on a local level.


Community perceptions of malaria and vaccines in two districts of Mozambique.
Malaria is a leading cause of mortality and morbidity in Mozambique, with nearly three-quarters of the country's malaria-related deaths occurring in children younger than five years. A malaria vaccine is not yet available, but planning is underway for a possible introduction, as soon as one becomes available. In an effort to inform the planning process, this study explored sociocultural and health communications issues among individuals at the community level who are both responsible for decisions about vaccine use and who are likely to influence decisions about vaccine use. Researchers conducted a qualitative study in two malaria-endemic districts in southern Mozambique. Using criterion-based sampling, they conducted 23 focus group discussions and 26 in-depth interviews. Implementation was guided by the engagement of community stakeholders. Community members recognize that malaria contributes to high death rates and affects the workforce, school attendance, and the economy. Vaccines are seen as a means to reduce the threat of childhood illnesses and to keep children and the rest of the community healthy. Perceived constraints to accessing vaccine services include long queues, staff shortages, and a lack of resources at health care facilities. Local leaders play a significant role in motivating caregivers to have their children vaccinated. Participants generally felt that a vaccine could help to prevent malaria, although some voiced concern that the focus was only on young children and not on older children, pregnant women, and the elderly. Probed on their understanding of vaccine efficacy, participants voiced various views, including the perception that while some vaccines did not fully prevent disease they still had important benefits. Overall, it would be essential for local leaders to be involved in the design of specific messages for a future malaria vaccine communications strategy, and for those messages to be translated into local languages. Acceptance of routine childhood vaccines bodes well for a future malaria vaccine. Vaccinating children is a well-established routine that is viewed favourably in Mozambique. A communications strategy would need to build on existing immunization efforts and use trusted sources-including current government dissemination arrangements-to deliver health information.


Is urbanization a risk factor for substance misuse?
More than half of the world's population is living in urban areas, but the evidence about urban-rural differences in drug use is not clearly defined. The present paper aims to review the international literature addressing the role of urbanization and related parameters in association with substance misuse. In particular, the evidence of urbanization being a risk factor for substance misuse is examined. Although it has been suggested that substance misuse is typically a characteristic of large urban areas, this did not appear to be a consistent observation from the literature review. Furthermore, the urban context may offer a relative proximity of health services and prompter emergency intervention in case of overdose. Although more efforts have to be put into explaining substance misuse in general, identifying which characteristics of the urban context are modifiable, and under what circumstances, is an important theoretical, empirical, and public health question.


From cell death to neuronal regeneration, effects of the p75 neurotrophin receptor depend on interactions with partner subunits.
In the adult mammalian central nervous system (CNS), growth of neuronal fibers is actively inhibited by myelin. The proteins myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgP), and Nogo-66 have been identified as inhibitory components present in CNS myelin. All three proteins exert their inhibitory activity by binding to a neuronal receptor complex containing the Nogo-66 receptor (NgR) and the neurotrophin (NT) receptor p75NTR. In their recent publication, Mi et al. identify the novel protein Lingo-1 as an interactor of p75NTR and NgR. The Lingo-1-NgR-p75NTR complex is shown to confer the inhibitory effects on nerve cell regeneration of Nogo-66, OMgP, and MAG by activating the small guanosine triphosphatase (GTPase) RhoA. Together with the recent finding that p75NTR interacts with the transmembrane protein sortilin to form a different receptor complex with cell death-promoting activity, the results of Mi et al. indicate that p75NTR exerts its diverse cellular functions by associating with function-specific co-receptors.


Postnatal debriefing: have we thrown the baby out with the bath water?
Postnatal debriefing is offered by 78% of maternity services in the UK despite little evidence from randomised controlled trials (RCTs) that it is effective. RCTs in this area have applied debriefing as a prophylactic to all or high risk women, rather than as a treatment for women who request it. This pragmatic trial therefore evaluated existing postnatal debriefing services that provide debriefing as a treatment for women who request it. Forty-six women who met criterion A for posttraumatic stress disorder (PTSD) and requested debriefing 1.3-72.2 months (median 16 weeks) postpartum completed measures of depression, PTSD, support and negative appraisals of the birth before and one month after debriefing. Women were compared with others who gave birth in the same hospitals during the same time period (n=34), who met criterion A for PTSD but had not requested debriefing. Results showed PTSD symptoms reduced over time in both groups but greater decreases were observed in women who attended debriefing. Debriefing also led to reduction in negative appraisals but did not affect symptoms of depression. Therefore, results suggest providing debriefing as a treatment to women who request or are referred to it may help to reduce symptoms of PTSD.


Canalicular adenoma: a clinicopathologic and immunohistochemical analysis of 67 cases with a review of the literature.
There is a lack of a comprehensive immunohistochemical (IHC) analysis of canalicular adenoma (CanAd), especially when combined with a description of the unique histologic features. Given the usual small biopsies, IHC may be useful in distinguishing CanAd from other tumors in the differential diagnosis. Retrospective. The patients included 54 females and 13 males (4.2:1), aged 43-90 years, with a mean age at presentation of 69.9 years. Clinical presentation was generally a mass (n = 61) slowly increasing in size (mean 38.5 months), affecting the upper lip (n = 46), buccal mucosa (n = 17) or palate (n = 4), involving the right (n = 29), left (n = 24) or midline (n = 9), without any major salivary gland tumors. The tumors ranged in size from 0.2 to 3 cm (mean 1.2 cm). Most tumors were multilobular or bosselated (76 %), often surrounded by a capsule. Histologically, the tumors were characterized by cystic spaces, tumor cords with beading, tubule formation, and by the presence of luminal squamous balls (n = 41). The cells were cuboidal to columnar with stippled chromatin. Mitoses were inconspicuous. A myxoid stroma (n = 64), sclerosis (n = 42), luminal hemorrhage (n = 51), and luminal microliths (calcifications) (n = 33) were characteristic. Nine (13.4 %) were multifocal. CanAd showed the following characteristic immunohistochemistry findings: CK-pan and S100 protein (strong, diffuse reaction); peripheral or luminal GFAP reaction; CK5/6 and p16 luminal squamous ball reaction; SOX10 nuclear reaction; cytoplasmic p63 reaction. CanAd are unique minor salivary gland tumors showing a distinct architecture and phenotype. They predilect to older women, with the majority multilobulated and affecting the upper lip, multifocal in 13 %; no major salivary gland tumors were identified. S100 protein, CK-pan, GFAP and SOX10 are positive, with luminal squamous balls highlighted by CK5/6 or p16.


The Impact of Protein Structure and Sequence Similarity on the Accuracy of Machine-Learning Scoring Functions for Binding Affinity Prediction.
It has recently been claimed that the outstanding performance of machine-learning scoring functions (SFs) is exclusively due to the presence of training complexes with highly similar proteins to those in the test set. Here, we revisit this question using 24 similarity-based training sets, a widely used test set, and four SFs. Three of these SFs employ machine learning instead of the classical linear regression approach of the fourth SF (X-Score which has the best test set performance out of 16 classical SFs). We have found that random forest (RF)-based RF-Score-v3 outperforms X-Score even when 68% of the most similar proteins are removed from the training set. In addition, unlike X-Score, RF-Score-v3 is able to keep learning with an increasing training set size, becoming substantially more predictive than X-Score when the full 1105 complexes are used for training. These results show that machine-learning SFs owe a substantial part of their performance to training on complexes with dissimilar proteins to those in the test set, against what has been previously concluded using the same data. Given that a growing amount of structural and interaction data will be available from academic and industrial sources, this performance gap between machine-learning SFs and classical SFs is expected to enlarge in the future.


Prospective Randomized Biomarker Study of Metformin and Lifestyle Intervention for Prevention in Obese Women at Increased Risk for Endometrial Cancer.
Obesity increases risk of endometrial cancer through dysregulation of estrogen and insulin signaling. The primary aim of this study was to evaluate the impact of metformin or lifestyle intervention on endometrial proliferation in postmenopausal obese women. Secondary aims included evaluating obesity-related biomarkers and adverse events experienced. Obese, postmenopausal women with prediabetes were randomized into four groups for a 16-week intervention using a 2 (metformin 1700 mg/day vs. placebo) × 2 (lifestyle intervention vs. no lifestyle intervention) factorial design. Pre- and postintervention endometrial proliferation, anthropometrics, body composition, and serum biomarkers (sex hormones, sex hormone binding globulin, IGF-I, adiponectin, omentin, insulin, glucose, and others) were assessed. Data were analyzed with linear regression models and false-discovery rate correction. Of 576 women approached for the study, 52 attended initial screening, 29 were eligible and randomized, and 26 completed the study. Lifestyle intervention resulted in significant loss of weight (-4.23 kg, P = 0.006) and total fat mass (-3.23 kg, P < 0.001). Participants receiving metformin lost 3.43 kg of weight (P = 0.023), but this was not statistically significant after multiple comparisons adjustment controlling false-discovery rate to 10%. Endometrial proliferation was low at baseline (mean 7.1%) and remained unchanged by 16 weeks, but included substantial variability. Metformin and lifestyle intervention produced minor changes to serum biomarkers. Lifestyle intervention produced the most significant changes in weight and body composition. While it is known that obese postmenopausal women are at increased risk for endometrial cancer, improved biomarkers are needed to stratify risk and test prevention strategies, particularly at the endometrial tissue level. Cancer Prev Res; 11(8); 477-90. ©2018 AACR.


Attained height, sex, and risk of cancer at different anatomic sites in the NIH-AARP diet and health study.
To examine the association of adult height with risk of cancer at different anatomic sites in a cohort of men and women. The association of self-reported height with subsequent cancer risk was assessed in 288,683 men and 192,514 women enrolled in the National Institutes of Health-AARP Diet and Health Study. After a median follow-up of 10.5 years, incident cancer was diagnosed in 51,139 men and 23,407 women. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) for the association of height with cancer risk. After adjustment for covariates, height was positively associated with increased risk of all cancers combined in both men [HR10 cm increase = 1.05 (95 % CI 1.04-1.06)] and women [HR10 cm increase = 1.08 (95 % CI 1.06-1.10)]. Several sites common to men and women showed significant positive associations with height: colon, rectum, kidney, melanoma, and non-Hodgkin's lymphoma. For other shared sites, the association differed by sex. For still other sites, there was no clear association with height. Positive associations were also observed with cancers of the breast, endometrium, and prostate. Different patterns were observed in the height-cancer association by sex. Studies investigating the biological mechanisms underlying the association of height with cancer risk should focus on those sites that show a reproducible association with attained height.


Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction.
This study sought to determine the frequency of left ventricular amyloid in heart failure with preserved ejection fraction (HFpEF). Left ventricular amyloid deposition can cause diastolic dysfunction and HFpEF. Autopsy of left ventricular specimens from patients with antemortem diagnosis of HFpEF without clinically apparent amyloid (n = 109) and from control subjects (n = 131) were screened with sulfated Alcian blue and subsequent Congo red staining with microdissection for mass spectrometry-based proteomics to determine amyloid type. Fibrosis was assessed with quantitative whole-field digital microscopy. The presence of wild-type transthyretin (wtTTR) amyloid was associated with age at death and male sex, but the age- and sex-adjusted prevalence of wtTTR amyloid was higher in HFpEF patients than in control subjects (odds ratio: 3.8, 95% confidence interval: 1.5 to 11.3; p = 0.03). Among HFpEF patients, moderate or severe interstitial wtTTR deposition, consistent with senile systemic amyloidosis as the primary etiology of HFpEF, was present in 5 (5%) patients (80% men), with mild interstitial and/or variable severity of intramural coronary vascular deposition in 13 (12%) patients. While, wtTTR deposition was often mild, adjusting for age and presence of HFpEF, wtTTR amyloid was associated with more fibrosis (p = 0.005) and lower age, sex, and body size-adjusted heart weight (p = 0.04). Given the age- and sex-independent association of HFpEF and wtTTR deposition and an emerging understanding of the pathophysiology of the amyloidoses, the current findings support further investigation of the role of wtTTR in the pathophysiology of HFpEF.


Statins are underused in recent-onset Parkinson's disease with increased vascular risk: findings from the UK Tracking Parkinson's and Oxford Parkinson's Disease Centre (OPDC) discovery cohorts.
Cardiovascular disease (CVD) influences phenotypic variation in Parkinson's disease (PD), and is usually an indication for statin therapy. It is less clear whether cardiovascular risk factors influence PD phenotype, and if statins are prescribed appropriately. To quantify vascular risk and statin use in recent-onset PD, and examine the relationship between vascular risk, PD severity and phenotype. Cardiovascular risk was quantified using the QRISK2 calculator (high ≥20%, medium ≥10 and <20%, low risk <10%). Motor severity and phenotype were assessed using the Movement Disorder Society Unified PD Rating Scale (UPDRS) and cognition by the Montreal cognitive assessment. In 2909 individuals with recent-onset PD, the mean age was 67.5 years (SD 9.3), 63.5% were men and the mean disease duration was 1.3 years (SD 0.9). 33.8% of cases had high vascular risk, 28.7% medium risk, and 22.3% low risk, while 15.2% of cases had established CVD. Increasing vascular risk and CVD were associated with older age (p<0.001), worse motor score (p<0.001), more cognitive impairment (p<0.001) and worse motor phenotype (p=0.021). Statins were prescribed in 37.2% with high vascular risk, 15.1% with medium vascular risk and 6.5% with low vascular risk, which compared with statin usage in 75.3% of those with CVD. Over 60% of recent-onset PD patients have high or medium cardiovascular risk (meriting statin usage), which is associated with a worse motor and cognitive phenotype. Statins are underused in these patients, compared with those with vascular disease, which is a missed opportunity for preventive treatment. GN11NE062, NCT02881099.


Components of small area variation in death rates: a method applied to data from Sweden.
The study aimed to develop and evaluate a method for small area analysis of different non-random components of the variation in death rates. The method was applied to incidence and mortality data for selected malignant neoplasms in 26 administrative health areas in Sweden. Variation in mortality and incidence rates for malignant neoplasms of the trachea, bronchus, and lung; colon; rectum; and cervix uteri in the 26 health areas were analysed after standardisation for age. In addition, the systematic and random components of variance were estimated. The systematic component of variance in mortality was divided into two additive components-one component was dependent on the variation in the corresponding incidence rates and the other remained after adjustment for incidence. SETTING AND PARTICIPANT: All cases diagnosed between 1972 and 1983 and all deaths between 1974 and 1985 for selected malignant neoplasms in Swedish citizens and other residents in Sweden, aged between 0 and 64 years, were analysed. Much of the observed variation in mortality was explained by the estimated random variation. For malignant neoplasms of the trachea, bronchus, and lung the systematic variation in mortality was mainly explained by the variation in incidence. For cancer of the cervix uteri, alone, there was significant systematic variation of moderate magnitude that was not explained by the incidence rates. These methods made it possible to divide the observed variance in mortality into different components. Random effects and variance in incidence rates were found to be of great importance when analysing the variance in death rates between health areas. By studying different systematic components of variation it is possible to identify fields for in depth studies on the quality of prevention and treatment.


The effect of thermal motion on the electron localization in metal-to-ligand charge transfer excitations in [Fe(bpy)3](2+).
Accurate electronic structure calculations of the lowest excited states have been performed on twenty snapshots of a molecular dynamics simulation of [Fe(bpy)3](2+) dissolved in water. The thermal motion distorts the structure of the complex from its average D3 symmetry, causing the localization on one bipyridine ligand of the excited electron in the metal-to-ligand charge transfer (MLCT) state. The excitation energy is about 0.25 eV lower than that for the delocalized description of the MLCT state and is in good agreement with experiments. The composition of the MLCT band is carefully analyzed and the effect of thermal motion on the mechanism of light-induced spin crossover is discussed.


A proportion of mutations fixed in the genomes of in vitro selected isogenic drug-resistant Mycobacterium tuberculosis mutants can be detected as minority variants in the parent culture.
We studied genomic variation in a previously selected collection of isogenic Mycobacterium tuberculosis laboratory strains subjected to one or two rounds of antibiotic selection. Whole genome sequencing analysis identified eleven single, unique mutations (four synonymous, six non-synonymous, one intergenic), in addition to drug resistance-conferring mutations, that were fixed in the genomes of six monoresistant strains. Eight loci, present as minority variants (five non-synonymous, three synonymous) in the genome of the susceptible parent strain, became fixed in the genomes of multiple daughter strains. None of these mutations are known to be involved with drug resistance. Our results confirm previously observed genomic stability for M. tuberculosis, although the parent strain had accumulated allelic variants at multiple locations in an antibiotic-free in vitro environment. It is therefore likely to assume that these so-called hitchhiking mutations were co-selected and fixed in multiple daughter strains during antibiotic selection. The presence of multiple allelic variations, accumulated under non-selective conditions, which become fixed during subsequent selective steps, deserves attention. The wider availability of 'deep' sequencing methods could help to detect multiple bacterial (sub)populations within patients with high resolution and would therefore be useful in assisting in the detailed investigation of transmission chains.


Genetic dissection of naturally occurring basal core promoter mutations of hepatitis B virus reveals a silent phenotype in the overlapping X gene.
During chronic hepatitis B virus (HBV) infection, double substitution mutations in the basal core promoter (BCP) region frequently emerge that include A1762T/G1764A and the neighbouring C1766T/T1768A mutations, here termed BCP1 and BCP2, respectively. Due to a compact viral genome organization, BCP1 and BCP2 mutations result in amino acids changes in the overlapping X gene: K130M/V131I and F132Y, respectively. It has been shown that both BCP mutations lead to a modest increase in viral genome replication. However, the question of whether the alteration that occurs in the overlapping X gene might contribute to the increased viral genome replication has not been properly addressed. This study genetically separated the core promoter from the overlapping X gene using 1.3mer overlength HBV constructs and examined the impact of the X gene mutations on viral genome replication in HepG2 cells. Each BCP mutation resulted in modestly enhanced viral genome replication that occurred via augmented viral transcription. Therefore, it was concluded that these BCP mutations do not affect expression of the overlapping X gene or impair its stimulatory effect on viral genome replication.


Surveillance for adverse drug reactions to combination antimalarial therapy with sulfadoxine-pyrimethamine plus artesunate in Peru.
In 2001, Peru changed its treatment policy for uncomplicated Plasmodium falciparum malaria on the northern Pacific Coast to sulfadoxine-pyrimethamine with atresunate (SP-AS). Because Peru was the first country in the Americas to adopt this combination therapy, we established a surveillance system in the region to assess the frequency of new or worsening symptoms after starting therapy. Over a period of two years, 1,552, or approximately two-thirds of all patients with uncomplicated P. falciparum malaria who had received SP-AS on the northern coast were followed up. Of these, 8.8% reported at least one adverse effect, with the most common being vomiting, nausea, headache, abdominal pain, dizziness, and fever; no severe adverse effects related to SP-AS therapy were identified. Treatment of uncomplicated malaria with SP-AS was associated with a low frequency of mild adverse effects in Peru, and therefore should be considered as a first-line therapy in areas of the Americas where SP efficacy is still high.


Oxyhalides: A new class of high-T C multiferroic materials.
Magnetoelectric multiferroics have attracted enormous attention in the past years because of their high potential for applications in electronic devices, which arises from the intrinsic coupling between magnetic and ferroelectric ordering parameters. The initial finding in TbMnO3 has triggered the search for other multiferroics with higher ordering temperatures and strong magnetoelectric coupling for applications. To date, spin-driven multiferroicity is found mainly in oxides, as well as in a few halogenides. We report multiferroic properties for synthetic melanothallite Cu2OCl2, which is the first discovery of multiferroicity in a transition metal oxyhalide. Measurements of pyrocurrent and the dielectric constant in Cu2OCl2 reveal ferroelectricity below the Néel temperature of ~70 K. Thus, melanothallite belongs to a new class of multiferroic materials with an exceptionally high critical temperature. Powder neutron diffraction measurements reveal an incommensurate magnetic structure below T N, and all magnetic reflections can be indexed with a propagation vector [0.827(7), 0, 0], thus discarding the claimed pyrochlore-like "all-in-all-out" spin structure for Cu2OCl2, and indicating that this transition metal oxyhalide is, indeed, a spin-induced multiferroic material.


Melatonin induces apoptosis in human neuroblastoma cancer cells.
Low concentrations (nanomolar) of melatonin had been previously shown to inhibit cell proliferation in several cancer cell lines as well as in experimental animal models. Additionally, cell growth inhibition and differentiation of prostate cancer cell lines by high concentrations (micromolar to millimolar) of melatonin have been recently reported. In the present paper, we show the induction of apoptosis by high doses of melatonin in the human neuroblastoma cell line SK-N-MC. We found accumulation of cells in the G2/M cell cycle phase and induction of cellular death, measured as lactate dehydrogenase (LDH) released into the culture medium, under millimolar concentration of melatonin. Apoptosis was evaluated using 4,6-diamidino-2-phenylindole staining, DNA gel electrophoresis, electron microscopy, and annexin V binding. Apoptosis progressed through the classical pathway, which involves caspase-3 activation. Cell death was dose and time-dependent; the lowest effective concentration of melatonin was 100 microm. Treatment with 1 mm melatonin for 6 days induced cell death in 75% of the cells. This novel finding shows that a nontoxic natural indoleamine may be potential therapy for some types of human neuroblastomas.


Cross-Reactivity Pattern of Asian and American Human Gnathostomiasis in Western Blot Assays Using Crude Antigens Prepared from Gnathostoma spinigerum and Gnathostoma binucleatum Third-Stage Larvae.
Gnathostomiasis is a zoonotic parasitosis endemic in many Asian and some Latin American countries. Most human infections are caused by Gnathostoma spinigerum in Asia and Gnathostoma binucleatum in the Americas, and recently, imported cases have been increasing among travelers returning from endemic regions. Confirmation of the clinical diagnosis relies largely on serologic tests, with a G. spinigerum-antigen-based immunoblot currently being the diagnostic method of choice. However, we repeatedly experienced that sera from patients with clinically suspected American gnathostomiasis gave negative results in this assay. Therefore, we used homologous methods to prepare G. spinigerum- and G. binucleatum-antigen-based immunoblot assays, and evaluated the cross-reactivity of the two assays. The results show incomplete cross-reactivity between the two assays: the G. spinigerum-antigen-based immunoblot apparently only detects Asian gnathostomiasis caused by G. spinigerum, whereas the G. binucleatum-antigen-based immunoblot is apparently capable of detecting American as well as Asian gnathostomiasis.


Dietary Inflammatory Index Is Associated with Risk of All-Cause and Cardiovascular Disease Mortality but Not with Cancer Mortality in Middle-Aged and Older Japanese Adults.
The Dietary Inflammatory Index (DII) is a comprehensive, literature-derived index for assessing the effect of dietary constituents on inflammatory biomarkers. Several studies have shown an association between DII score and mortality, but there are limited prospective studies in Asian populations. The aim of this study was to investigate the association between DII score and risk of all-cause, total cardiovascular disease (CVD), stroke, coronary heart disease (CHD), total cancer, digestive cancer, and noncancer/non-CVD mortality in the Japanese population. A total of 58,782 Japanese participants aged 40-79 y who were enrolled in the Japan Collaborative Cohort Study during 1988-1990 were included in the analysis. DII scores were calculated based on a food-frequency questionnaire. HRs and 95% CIs for mortality according to DII quintiles were estimated using Cox proportional hazards models. During the median follow-up period of 19.3 y, a total of 11,693 participants died. The multivariable HR for all-cause mortality for the highest compared with the lowest DII quintiles was 1.13 (95% CI: 1.05, 1.21). For CVD mortality, the highest multivariable HRs were 1.30 (95% CI: 1.13, 1.49), 1.29 (95% CI: 1.05, 1.59), and 1.30 (95% CI: 0.96, 1.76) for total CVD, stroke, and CHD, respectively. No significant associations were observed between DII and risk of total cancer, digestive cancer, and noncancer/non-CVD mortality. Our findings suggest that a higher DII was associated with an increased risk of all-cause and CVD mortality among Japanese adults.


The meanings of universal health care in Latin America.
In Latin America, competing definitions of universal health care are found. Variants include traditional universalism, basic universalism, and minimal or residual universalism. These definitions are informed by European traditions, a renewed emphasis on equity among Latin American social policy experts, and World Bank strategy. This essay explores these definitions as well as areas of overlap and points of difference between and among them using examples from several Latin American countries. The most important difference concerns the preventive and curative services not covered by the benefits packages of minimal universal programs, a gap expected to grow increasingly costly for patients.


Examination of virtual phantoms with respect to their possible use in assessing compliance with the electromagnetic field exposure limits specified by Directive 2013/35/EU.
According to Directive 2013/35/EU, any assessment of hazards associated with exposure to electromagnetic fields (EMF) in the workplace needs an evaluation of quantities characterizing biophysical effects caused inside human bodies by exposure. Such quantities (induced electric field or specific energy absorption rate) may be evaluated by computer simulations in virtual models (phantoms), representing interaction between EMF and the worker's body with respect to modelling the EMF source, the structure of the working environment and the human body. The paper describes the effects of the properties of various virtual phantoms used in recently published studies on various aspects of EMF exposure with respect to their possible involvement in assessing occupational electromagnetic hazards as required by Directive 2013/35/ EU. The parameters of phantoms have been discussed with reference to: dimensions, posture, spatial resolution and electric contact with the ground. Such parameters should be considered and specified, and perhaps also standardized, in order to ensure that the numerical simulations yield reliable results in a compliance analysis against exposure limits or in an exposure assessment for EMF-related epidemiological studies. The outcomes of the presented examination of virtual phantoms used in numerical simulations show that they can be effectively used in the assessment of compliance with the exposure limits specified by Directive 2013/35/EU, but various other factors should be also considered, e.g., the relationship between phantom posture and a realistic exposure situation (flexible phantoms use), limited resolution preventing reliable evaluation of physical estimators of exposure, or a non-realistic area of phantom surface in contact with the ground.


The motor unit. Anatomy and physiology.
The physiological and anatomical properties of mammalian motor units are discussed, and the results of human and animal studies are compared. A physiological organization of motor units based on the mechanical properties of their associated muscle units is examined. It is concluded that such an organizing principle has broad universal application in both animal and human studies. An anatomical organization of muscle units by their association with their physiological properties and the histochemical profile of their muscle fibers is also considered. The anatomical organizing principle also has broad-ranging applicability. The organization of muscle units according to muscle architecture and innervation patterns is described and its potential applicability to considerations of muscle structure and function is discussed. It is concluded that a number of gaps in our knowledge of muscle unit organization have been identified, especially among human studies, but the potential to fill these gaps rapidly is great.


Risk factor-based screening compared to universal screening for gestational diabetes mellitus in marginalized Burman and Karen populations on the Thailand-Myanmar border: An observational cohort.
Background: Gestational diabetes mellitus (GDM) contributes significantly to maternal and neonatal morbidity, but data from marginalized populations remains scarce. This study aims to compare risk-factor-based screening to universal testing for GDM among migrants along the Thailand-Myanmar border. Methods: From the prospective cohort (September 2016, February 2019), 374 healthy pregnant women completed a 75g oral glucose tolerance test (OGTT) at 24-32 weeks gestation. Fasting, one hour and two hour cut-offs were based on Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO trial) criteria and cases were treated. The sensitivity and specificity of risk-factor-based screening criteria was calculated using OGTT as the gold standard. Risk factors included at least one positive finding among 10 criteria, e.g., obesity (body mass index (BMI) ≥27.5kg/m 2), 1 st degree relative with diabetes etc. Adverse maternal and neonatal outcomes were compared by GDM status, and risk factors for GDM were explored. Results: GDM prevalence was 13.4% (50/374) (95% CI: 10.3-17.2). Risk-factors alone correctly identified 74.0% (37/50) OGTT positive cases: sensitivity 74.0% (59.7-85.4) and specificity 27.8% (3.0-33.0). Burman women accounted for 29.1% of the cohort population, but 38.0% of GDM cases. Percentiles for birthweight (p=0.004), head circumference (p=0.005), and weight-length ratio (p=0.010) were higher in newborns of GDM mothers compared with non-GDM, yet 21.7% (75/346) of newborns in the cohort were small-for-gestational age. In Burman women, overweight/obese BMI was associated with a significantly increased adjusted odds ratio 5.03 (95% CI: 1.43-17.64) for GDM compared to normal weight, whereas underweight and overweight/obese in Karen women were both associated with similarly elevated adjusted odds, approximately 2.4-fold (non-significant) for GDM. GDM diagnosis by OGTT was highest prior to peak rainfall. Conclusions: Risk-factor-based screening was not sufficiently sensitive or specific to be useful to diagnose GDM in this setting among a cohort of low-risk pregnant women. A two-step universal screening program has thus been implemented.


Treatment-induced oxidative stress and cellular antioxidant capacity determine response to bortezomib in mantle cell lymphoma.
Proteasome inhibition disrupts protein homeostasis and induces apoptosis. Up to 50% of patients with relapsed mantle cell lymphoma (MCL) respond to bortezomib. We used gene expression profiling to investigate the connection between proteasome inhibition, cellular response, and clinical efficacy. We assessed transcriptional changes in primary tumor cells from five patients during treatment with bortezomib in vivo, and in 10 MCL cell lines exposed to bortezomib in vitro, on Affymetrix microarrays. Key findings were confirmed by western blotting. MCL cell lines exposed to bortezomib in vitro showed upregulation of endoplasmic reticulum and oxidative stress response pathways. Gene expression changes were strongest in bortezomib-sensitive cells and these cells were also more sensitive to oxidative stress induced by H2O2. Purified tumor cells obtained at several timepoints during bortezomib treatment in 5 previously untreated patients with leukemic MCL showed strong activation of the antioxidant response controlled by NRF2. Unexpectedly, activation of this homeostatic program was significantly stronger in tumors with the best clinical response. Consistent with its proapoptotic function, we found upregulation of NOXA in circulating tumor cells of responding patients. In resistant cells, gene expression changes in response to bortezomib were limited and upregulation of NOXA was absent. Interestingly, at baseline, bortezomib-resistant cells displayed a relatively higher expression of the NRF2 gene-expression signature than sensitive cells (P < 0.001). Bortezomib triggers an oxidative stress response in vitro and in vivo. High cellular antioxidant capacity contributes to bortezomib resistance.


Crowdsourcing digital health measures to predict Parkinson's disease severity: the Parkinson's Disease Digital Biomarker DREAM Challenge.
Consumer wearables and sensors are a rich source of data about patients' daily disease and symptom burden, particularly in the case of movement disorders like Parkinson's disease (PD). However, interpreting these complex data into so-called digital biomarkers requires complicated analytical approaches, and validating these biomarkers requires sufficient data and unbiased evaluation methods. Here we describe the use of crowdsourcing to specifically evaluate and benchmark features derived from accelerometer and gyroscope data in two different datasets to predict the presence of PD and severity of three PD symptoms: tremor, dyskinesia, and bradykinesia. Forty teams from around the world submitted features, and achieved drastically improved predictive performance for PD status (best AUROC = 0.87), as well as tremor- (best AUPR = 0.75), dyskinesia- (best AUPR = 0.48) and bradykinesia-severity (best AUPR = 0.95).


Iodine supplementation of pregnant women in Europe: a review and recommendations.
Nearly two-thirds of the population of Western and Central Europe live in countries that are iodine deficient. Damage to reproductive function and to the development of the fetus and newborn is the most important consequence of iodine deficiency. The objective of this review was to examine the iodine status of pregnant women in Europe and the potential need for iodine supplementation. A MEDLINE/PubMed search and compilation of all published studies since 1990 of iodine nutrition and iodine supplementation of pregnant women in Europe, as well as an Internet-based search and review on availability and legislation of iodine supplements in the European Union. Although the data suggest most women in Europe are iodine deficient during pregnancy, less than 50% receive supplementation with iodine. Mild-to-moderate iodine deficiency during pregnancy adversely affects thyroid function of the mother and newborn and mental development of the offspring and these adverse effects can be prevented or minimized by supplementation. There are no published data on the effect of iodine supplementation on long-term maternal and child outcomes. The iodine content of prenatal supplements in Europe varies widely; many commonly used products contain no iodine. The European Union is developing legislation to establish permissible levels for iodine in food supplements. In most European countries, pregnant women and women planning a pregnancy should receive an iodine-containing supplement ( approximately 150 microg/day). Kelp and seaweed-based products, because of unacceptable variability in their iodine content, should be avoided. Prenatal supplement manufacturers should be encouraged to include adequate iodine in their products. Professional organizations should influence evolving EU legislation to ensure optimal doses for iodine in prenatal vitamin-mineral supplements. International Council for Control of Iodine Deficiency Disorders.


Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches.
Upon intravenous transplantation, hematopoietic stem cells (HSCs) can home to specialized niches, yet most HSCs fail to engraft unless recipients are subjected to toxic preconditioning. We provide evidence that, aside from immune barriers, donor HSC engraftment is restricted by occupancy of appropriate niches by host HSCs. Administration of ACK2, an antibody that blocks c-kit function, led to the transient removal of >98% of endogenous HSCs in immunodeficient mice. Subsequent transplantation of these mice with donor HSCs led to chimerism levels of up to 90%. Extrapolation of these methods to humans may enable mild but effective conditioning regimens for transplantation.


The Relationship between Visual Acuity, Subjective Vision, and Willingness to Purchase Simultaneous-image Contact Lenses.
This study reports that subjective vision ratings are better indicators of willingness to purchase simultaneous-image contact lenses than visual acuities and are more valuable in evaluating contact lens performance. The purpose of this study was to investigate the relationship between visual acuities, subjective vision ratings, and willingness to purchase simultaneous-image contact lenses in presbyopes. A retrospective analysis of visual acuities, subjective vision ratings, and willingness to purchase from final visits of two masked, crossover clinical trials of nine prototype and four commercially available simultaneous-image contact lenses in 141 presbyopes was performed. Pearson correlation and area under the receiver operating characteristic curve determined correlations between variables. Most subjective vision ratings were weakly correlated (r < 0.3) with visual acuity at all distances and illumination. Moderate correlations (r, 95% confidence intervals) were found between overall vision satisfaction ratings with visual acuity at 40 (-0.34, -0.28 to -0.40) and 50 cm (-0.33, -0.27 to -0.39), near-vision ratings (daytime) with visual acuity at 40 (-0.48, -0.43 to -0.53) and 50 cm (-0.46; -0.41 to -0.51), and intermediate-vision ratings (daytime) with visual acuity at 40 (-0.39, -0.33 to -0.45) and 50 cm (-0.41, -0.35 to -0.46). Highest discrimination for willingness to purchase was with overall vision satisfaction (area under curve, 0.93) and vision stability (daytime; area under curve, 0.77). Ratings from 4 to 9 for vision satisfaction showed a linear increase in willingness to purchase: a 1-unit increase in vision satisfaction increased willingness to purchase by 20%. Ratings lower than 4 had 0% willingness to purchase. Other subjective ratings showed similar relationships, albeit only 10 to 15% increase in willingness to purchase per unit increase for ratings higher than 4. Subjective vision ratings are a better indicator of simultaneous-image contact lens performance than visual acuity. Overall vision satisfaction and vision stability are key predictors of willingness to purchase. Subjective vision ratings should be used to evaluate performance rather than visual acuity alone.


Forgotten public health impacts of cancer - an overview.
Cancer is one of the diseases of greatest concern in developed countries and much effort has been invested in discovering and developing therapeutics for curing cancer. Despite the improvements in antineoplastic therapeutics in the last decades, cancer is still one of the most harmful diseases worldwide. The global burden of cancer also implies financial costs: these can be direct costs, such as those related to treatment, care, and rehabilitation and indirect, which include the loss of economic output due to missed work (morbidity costs) and premature death (mortality costs). There are also hidden costs such as health insurance premiums and nonmedical expenses that are worth noting. This paper intends to present an overview of the generally forgotten impacts that the increasing number of cancer cases can have on the environment, workers who handle antineoplastic drugs, and health services. The knowledge available of each of the impacts will be addressed and discussed regarding the expected development. Overall, lessons learnt reflect on the impact of cancer through aspects not commonly evidenced in the literature or even considered in socio-economic analysis, in part due to the fact that these are difficult to contemplate in direct and indirect cancer costs already defined. Attention may be drawn to the need of continuous investment in prevention to reduce the negative impact on the environment, and in the health of workers who handle antineoplastic drugs for patients' treatment.


Self-sustaining reactions as a tool to study mechanochemical activation.
Ever since Faraday reported on the reduction of AgCl with Zn and Sn the "dry way", the study of Mechanically induced Self-propagating Reactions (MSRs) has been an important area within mechanochemistry. An interesting phenomenon is the mutual suppression of ignition in some mixed metal-chalcogen systems, such as in (1 - x)(Sn + Se) + x(Zn + Se) powders. Here both the Sn + Se and Zn + Se mixtures react in a self-sustaining manner after some activation time, but when they are combined, the reaction is gradual in the middle of the concentration scale. Mechanically induced metal-chalcogen combination reactions were studied by Chakurov et al. in the 1980s, using a low-energy vibratory mill. Similar measurements were carried out in our laboratory using the more energetic SPEX 8000 shaker mill. The results show qualitative similarities, but the details are different. It is suggested that the loss of MSR in mixed systems is the consequence of the very different properties of the binary systems, so that either one of the components (Zn) or a product formed gradually without ignition (e.g. SnSe) can act as an inert component relative to the rest of the system. Several examples are presented and the effect of the milling conditions is discussed. Finding new systems with similar behaviour and detailed studies of the activated state are needed to understand MSR in these systems.


Psychosocial Interventions for Family Carers of People With Dementia: A Systematic Review and Meta-Analysis.
Objective:This study aimed to review and synthesize findings of the effectiveness of psychosocial interventions aimed at improving outcomes for family carers of people with dementia. Method: A systematic review and meta-analysis were conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched the following databases: Cochrane, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo, Excerpta Medica Database (EMBASE), and Applied Social Sciences Index and Abstracts (ASSIA). RevMan 5 software was used to conduct meta-analysis and subgroup analysis using a random-effects model. Results: The search yielded 22 high-quality intervention articles that were suitable for further meta-analysis. Meta-analysis revealed that psychosocial interventions have a small to moderate significant effect on carer burden (standardized mean difference [SMD] = -0.34, confidence interval [CI] = [-0.59, -0.09]), depression (SMD = -0.36, CI = [-0.60, -0.13]), and general health (SMD = 0.34, CI = [0.18, 0.51]). Discussion: Psychosocial interventions had a positive impact on carer outcomes; however, these results should be interpreted with caution, given the significant level of heterogeneity in study designs. Future research could examine contextual and implementation mechanisms underlying psychosocial interventions to develop effective support systems for family carers of people with dementia.


Expression and Molecular Regulation of the Cox2 Gene in Gastroenteropancreatic Neuroendocrine Tumors and Antiproliferation of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).
BACKGROUND Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has had a significant increase over the past 4 decades. The pathophysiological role of the cyclooxygenase-2 (cox-2) gene and factors responsible for the expression in GEP-NETs is of clinical value. Current study determined the expression of cox-2 gene in human GEP-NET tissues and corresponding cell lines, investigated the molecular mechanisms underlying the regulation of cox-2 gene expression and assessed the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on both anchorage-dependent and independent growth of GEP-NET cells. MATERIAL AND METHODS GEP-NET tissues and QGP-1, BON, and LCC-18 GEP-NET cell lines were used. The expression of cox-2 gene was analyzed by immunohistochemistry, western blot, RT-PCR, and enzyme immunoassay. Transient transfection and luciferase assays along with electrophoretic mobility shift assays were conducted to explore the regulation of cox-2 gene expression. The effect of COX-inhibitors on GEP-NET cell growth was determined by proliferation assays and colony growth assessment. RESULTS We found 87.8% of GEP-NET tissues stained positive for COX-2. QGP-1 and LCC-18 cells expressed cox-2 gene. PGE2 (prostaglandin E2) amounts quantified in the supernatants of NET cells matched to cox-2 expression level. The CRE-E-box element (-56 to -48 bp) and binding of USF1, USF2, and CREB transcription factors to this proximal promoter element were essential for cox-2 promoter activity in GEP-NET cells. COX-2-specific inhibitor NS-398 potently and dose-dependently inhibited PGE2 release from QGP-1 cells. Interestingly, both NS-398 and acetylic salicylic acid effectively suppressed proliferation of QGP-1 and BON cells in a dose-dependent manner. CONCLUSIONS The majority of GEP-NETs over express cox-2 gene. The binding of CREB and USF-1/-2 transcription factors to a proximal, overlapping CRE-Ebox element is the underlying mechanism for cox-2 gene expression. NSAIDs potently suppressed the proliferations and may offer a novel approach for chemoprevention and therapy of GEP-NETs.


Teaching cardiac auscultation to trainees in internal medicine and family practice: does it work?
The general proficiency in physical diagnostic skills seems to be declining in relation to the development of new technologies. The few studies that have examined this question have invariably used recordings of cardiac events obtained from patients. However, this type of evaluation may not correlate particularly well with bedside skills. Our objectives were 1) To compare the cardiac auscultatory skills of physicians in training with those of experienced cardiologists by using real patients to test bedside diagnostic skills. 2) To evaluate the impact of a five-month bedside cardiac auscultation training program. 1) In an academic primary care center, 20 physicians (trainees in internal medicine and family practice) and two skilled academic cardiologists listened to 33 cardiac events in 13 patients directly at bedside and identified the cardiac events by completing an open questionnaire. Heart sounds, murmurs and diagnosis were determined beforehand by an independent skilled cardiologist and were validated by echocardiography. Thirteen primary cardiologic diagnoses were possible.2) Ten of the physicians agreed to participate in a course of 45-minute sessions once a week for 5 months. After the course they listened again to the same patients (pre/post-interventional study). 1) The experts were the most skillful, achieving 69% recognition of heart sounds and murmurs and correct diagnoses in 62% of cases. They also heard all of the diastolic murmurs. The residents heard only 40% of the extra heart sounds and made a correct diagnosis in 24% of cases. 2) After the weekly training sessions, their mean percentage for correct diagnosis was 35% [an increase of 66% (p < 0.05)]. The level of bedside diagnostic skills in this relatively small group of physicians in training is indeed low, but can be improved by a course focusing on realistic bedside teaching.


Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease: Advances in Diagnosis and Treatment.
Clinical decision making regarding the appropriate use of aspirin for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) events is complex, and requires an individualized benefit to risk assessment. To review advances in the individualized assessment for ASCVD and bleeding risk, and to provide an update of the randomized clinical trial evidence that examined the use of aspirin for primary prevention (primarily for ASCVD, and secondarily for colorectal cancer). The recently released 2016 US Preventive Services Task Force recommendations are discussed, as well as the role of ASCVD risk, age, sex, and aspirin dose/formulation in clinical decision making. We performed a detailed review of peer-reviewed publications that were identified through searches of MEDLINE and the Cochrane Database through 2016 using the literature search terms "aspirin," "primary prevention," "cardiovascular disease," "mortality," "cancer." Bibliographies from these references as well as meta-analyses of these randomized clinical trials were also reviewed. Evidence from a total of 11 trials involving more than 118 000 patients is available to guide clinical decision making for aspirin use in the primary prevention of ASCVD. Clinicians should balance the benefit to risk ratio and the individual's preferences, calculating the 10-year ASCVD risk and evaluating risk factors for gastrointestinal bleeding, to facilitate a safer and more personalized approach to appropriate selection of candidates for low-dose aspirin (75 to 81 mg/d) for the primary prevention of ASCVD, with secondary considerations for reducing colorectal cancer risk when taken for longer periods (>10 years). Both the net ASCVD benefit and the bleeding risk of aspirin therapy increased as the absolute ASCVD risk increased, but the net benefits generally exceeded the risks at higher baseline ASCVD risk (≥10% ASCVD 10-year risk). The Aspirin-Guide is a clinical decision making support tool (app for mobile devices) with internal risk calculators to help clinicians with this dual assessment by calculating the ASCVD risk and the bleeding risk in the individual patient, and incorporating age- and sex-specific guidance based on randomized trial results. Balancing the benefit of ASCVD reduction with the risk of bleeding from low-dose aspirin is difficult but essential for informed decision making and achieving a net clinical benefit from aspirin for primary prevention. This is facilitated by a free and readily available evidence-based clinical decision support tool.


Demonstration of nonlinearity bias in the measurement of the apparent diffusion coefficient in multicenter trials.
Characterize system-specific bias across common magnetic resonance imaging (MRI) platforms for quantitative diffusion measurements in multicenter trials. Diffusion weighted imaging (DWI) was performed on an ice-water phantom along the superior-inferior (SI) and right-left (RL) orientations spanning ± 150 mm. The same scanning protocol was implemented on 14 MRI systems at seven imaging centers. The bias was estimated as a deviation of measured from known apparent diffusion coefficient (ADC) along individual DWI directions. The relative contributions of gradient nonlinearity, shim errors, imaging gradients, and eddy currents were assessed independently. The observed bias errors were compared with numerical models. The measured systematic ADC errors scaled quadratically with offset from isocenter, and ranged between -55% (SI) and 25% (RL). Nonlinearity bias was dependent on system design and diffusion gradient direction. Consistent with numerical models, minor ADC errors (± 5%) due to shim, imaging and eddy currents were mitigated by double echo DWI and image coregistration of individual gradient directions. The analysis confirms gradient nonlinearity as a major source of spatial DW bias and variability in off-center ADC measurements across MRI platforms, with minor contributions from shim, imaging gradients and eddy currents. The developed protocol enables empiric description of systematic bias in multicenter quantitative DWI studies.


The Influence of Prediagnosis Alcohol Consumption and the Polymorphisms of Ethanol-Metabolizing Genes on the Survival of Head and Neck Cancer Patients.
Although alcohol drinking is an established risk factor of head and neck cancer (HNC), less is known about its role in the prognosis of HNC. The current study investigated the association between pretreatment alcohol consumption and the overall survival (OS) of HNC patients. Cox proportional hazards models were performed to evaluate the association between prediagnosis alcohol drinking and the OS of HNC patients. In addition, the influence of the polymorphisms of two ethanol-metabolizing genes, ADH1B and ALDH2, on this relationship was also evaluated. The results showed a significant positive dose-response relationship between prediagnosis alcohol use and worse OS of HNC patients. This association was more significant for oropharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer than for oral cancer. The association between alcohol use and the poorer OS of HNC patients was mainly through its association with a higher stage of HNC at diagnosis. The worst OS associated with alcohol use was observed among HNC patients with the fast ADH1B and the slow/nonfunctional ALDH2 genotype combination. Our analysis showed a significant positive dose-response relationship between prediagnosis alcohol use and a worse OS of HNC. This association was mainly due to the higher stage of HNC among alcohol drinkers. In addition, the polymorphisms of the ethanol-metabolizing genes, ADH1B and ALDH2, modified the relationship between prediagnosis alcohol use and the OS of HNC patients. Prediagnosis alcohol use may be a prognostic indicator of HNC.


Readiness of US health plans to manage cardiometabolic risk.
American health plans can make a substantial contribution to the control of cardiometabolic risk (CMR), a condition associated with both adverse health outcomes and increased cost of care. Our goal was to determine health plan interest in and ability to provide CMR control services. In January 2008, America's Health Insurance Plans, in collaboration with the HealthPartners Research Foundation, surveyed the chief medical officers of 74 member health insurance plans that offer commercial health maintenance organization, point of service, and preferred provider organization insurance. The response rate was 47%. The 35 responding chief medical officers reported that their plans identify members with CMR through referral from case or care management (89%), health risk assessment data (86%), claims data (82%), and pharmaceutical use data (79%). Nearly all (97%) plans currently offer interventions for tobacco use, obesity/overweight, and nutrition. Ninety-four percent of plans offer interventions to increase physical activity. All plans offer health risk appraisal or assessment with feedback and education, 91% use Web-based tools, and 85% use health coaching to help plan members lower their risk. Perceived barriers to broader implementation of risk control programs included lack of resources (79%), limited available enrollee data (74%), and lack of reporting systems (79%). Few health plan officers viewed lack of purchaser interest to be a barrier to program implementation. Health plans appear to be positioned to provide CMR control services that could improve health outcomes, reduce health care costs, and increase workplace productivity in the United States.


Adapting Ruthenium Sensitizers to Cobalt Electrolyte Systems.
In this work, we report the use of bulky substitutions in a new heteroleptic ruthenium(II) bipyridine complex, Ru(NCS)2LL', coded TT-230 to obtain high open-circuit potential in a dye-sensitized solar cell (where L is a bipyridine ligand appended with two cyclopenta(2,1-b;3,4-bA)dithiophene moieties, and L' = 4,4,'-dicarboxylic acid 2,2'-bipyridine). The electrolytes based on cobalt complexes have shown significant advantages in terms of attainable open-circuit potential compared to the standard iodide/tri-iodide redox mediators. These merits of the cobalt complexes were previously realized with a porphyrin sensitizer, achieving a VOC greater than 1 V in DSC. However, with conventional Ru(II)-polypyridyl complexes such as the C101 dye, similar increase in the VOC could not be attained due to the enhanced recombination. In this work, we have shown that the use of bulky substituents can prevent the back reaction of photogenerated electron and subsequently increase the open-circuit potential of the device. The recombination processes were investigated by transient photovoltage decay measurements.


Synergistic neuroprotective effect of rasagiline and idebenone against retinal ischemia-reperfusion injury via the Lin28-let-7-Dicer pathway.
Retinal ischemia-reperfusion (RIR) injury causes neuronal degeneration and initiates various optic nerve diseases. This study aimed to investigate the synergistic neuroprotective effect of rasagiline and idebenone against RIR injury. A combination of rasagiline and idebenone was administered intraperitoneally immediately after establishment of the RIR model. Treatment with the combination of the two drugs resulted in a significant restoration of retinal thickness and retinal ganglion cells. Apoptosis of cells in ganglion cell layers was also ameliorated, suggesting that the effect of the two drugs was synergistic and the expression of brain-derived neurotrophic factor increased. Furthermore, idebenone and rasagiline induced the expression of Lin28A and Lin28B, respectively, which resulted in a reduced expression of microRNAs in the let-7 family and an increased protein output of Dicer. The data obtained from gene overexpression and knockdown experiments indicated that let-7 and Dicer were necessary for the synergistic neuroprotective effect of the two drugs. Our findings suggested that combination therapy with rasagiline and idebenone produced a synergistic effect that ameliorated RIR injury and restored visual function. In addition, the combined treatment provided neuroprotection via enhancement of the selective regulation of let-7 by Lin28A/B. These findings implied that a treatment with the combination of rasagiline and idebenone is a feasible treatment option for optic nerve diseases.


Assessing the benefits of using mate-pairs to resolve repeats in de novo short-read prokaryotic assemblies.
Next-generation sequencing technologies allow genomes to be sequenced more quickly and less expensively than ever before. However, as sequencing technology has improved, the difficulty of de novo genome assembly has increased, due in large part to the shorter reads generated by the new technologies. The use of mated sequences (referred to as mate-pairs) is a standard means of disambiguating assemblies to obtain a more complete picture of the genome without resorting to manual finishing. Here, we examine the effectiveness of mate-pair information in resolving repeated sequences in the DNA (a paramount issue to overcome). While it has been empirically accepted that mate-pairs improve assemblies, and a variety of assemblers use mate-pairs in the context of repeat resolution, the effectiveness of mate-pairs in this context has not been systematically evaluated in previous literature. We show that, in high-coverage prokaryotic assemblies, libraries of short mate-pairs (about 4-6 times the read-length) more effectively disambiguate repeat regions than the libraries that are commonly constructed in current genome projects. We also demonstrate that the best assemblies can be obtained by 'tuning' mate-pair libraries to accommodate the specific repeat structure of the genome being assembled - information that can be obtained through an initial assembly using unpaired reads. These results are shown across 360 simulations on 'ideal' prokaryotic data as well as assembly of 8 bacterial genomes using SOAPdenovo. The simulation results provide an upper-bound on the potential value of mate-pairs for resolving repeated sequences in real prokaryotic data sets. The assembly results show that our method of tuning mate-pairs exploits fundamental properties of these genomes, leading to better assemblies even when using an off -the-shelf assembler in the presence of base-call errors. Our results demonstrate that dramatic improvements in prokaryotic genome assembly quality can be achieved by tuning mate-pair sizes to the actual repeat structure of a genome, suggesting the possible need to change the way sequencing projects are designed. We propose that a two-tiered approach - first generate an assembly of the genome with unpaired reads in order to evaluate the repeat structure of the genome; then generate the mate-pair libraries that provide most information towards the resolution of repeats in the genome being assembled - is not only possible, but likely also more cost-effective as it will significantly reduce downstream manual finishing costs. In future work we intend to address the question of whether this result can be extended to larger eukaryotic genomes, where repeat structure can be quite different.


Drainage Vein Induced Hydrocephalus Caused by an Unruptured Arteriovenous Malformation in an Adult Presenting with Visual Loss.
Arteriovenous malformations (AVMs) commonly present with seizures and hemorrhage. Hydrocephalus associated with an unruptured AVM in an adult patient is exceedingly rare. A 37-year-old male patient presented with total visual loss in his right eye and severe impairment in his left eye. His evaluation showed an unruptured right frontal AVM and bilaterally dilated lateral ventricles. The major draining vein of the AVM was obstructing the third ventricle. An urgent external ventricular drainage was used as the first line intervention and followed with a ventriculoperitoneal shunt two days later. His definitive treatment for AVM was staged stereotactic gamma-knife radiosurgery. Unruptured AVMs in adult patients may rarely cause hydrocephalus. Visual loss caused by such a hydrocephalus has not been reported before. Both communicating and non-communicating type hydrocephalus can be seen with unruptured AVMs, and have different pathophysiological mechanisms. Our patient was treated with ventriculoperitoneal shunting, and visual examination remained unchanged after the operation. Visual loss caused by hydrocephalus associated with an unruptured AVM in an adult patient has not been reported before. It may indicate an association of different pathophysiological mechanisms. The treatment must depend on the neurological condition of the patient.


Effects of Oral Contraceptive Androgenicity on Visuospatial and Social-Emotional Cognition: A Prospective Observational Trial.
Oral contraceptives (OCs) containing estrogen and progesterone analogues are widely used amongst reproductive-aged women, but their neurocognitive impact is poorly understood. Preliminary studies suggest that OCs improve verbal memory and that OCs with greater androgenic activity may improve visuospatial ability. We sought to explore the cognitive impact of OCs by assessing performance of OC users at different stages of the OC cycle, and comparing this performance between users of different OC formulations according to known androgenic activity. We conducted a prospective, observational trial of OC users, evaluating cognitive performance with CogState software on two occasions: days 7-10 of active hormonal pill phase, and days 3-5 of the inactive pill phase (coinciding with the withdrawal bleed resembling menstruation). Thirty-five OC users (18 taking androgenic formulations, 17 taking anti-androgenic) were assessed. Analysis by androgenic activity showed superior performance by users of androgenic OCs, as compared to anti-androgenic OCs, in visuospatial ability and facial affect discrimination tasks. A growing understanding of cognitive effects of OC progestin androgenicity may have implications in choice of OC formulation for individuals and in future OC development.


Co-expression of the C-terminal domain of Yersinia enterocolitica invasin enhances the efficacy of classical swine-fever-vectored vaccine based on human adenovirus.
The use of adenovirus vector-based vaccines is a promising approach for generating antigen-specific immune responses. Improving vaccine potency is necessary in other approaches to address their inadequate protection for the majority of infectious diseases. This study is the first to reconstruct a recombinant replication-defective human adenovirus co-expressing E2 and invasin C-terminal (InvC) glycoproteins (rAd-E2-InvC). rAd-E2-InvC with 2 x 10(6) TCID50 was intramuscularly administered two times to CSFV-free pigs at 14 day intervals. No adverse clinical reactions were observed in any of the pigs after the vaccination. The CSFV E2-specific antibody titer was significantly higher in the rAd-E2-InvC group than that in the rAdV-E2 group as measured by NPLA and blocking ELISA. Pigs immunized with rAd-E2-InvC were completely protected against lethal challenge. Neither CSFV RNA nor pathological changes were detected in the tissues after CSFV challenge. These results demonstrate that rAd-E2-InvC could be an alternative to the existing CSF vaccine. Moreover, InvC that acts as an adjuvant could enhance the immunogenicity of rAdV-E2 and induce high CSFV E2-specific antibody titer and protection level.


Histological Quantification to Determine Lung Fungal Burden in Experimental Aspergillosis.
The quantification of lung fungal burden is critical for the determination of the relative levels of immune protection and fungal virulence in mouse models of pulmonary fungal infection. Although multiple methods are used to assess fungal burden, quantitative polymerase chain reaction (qPCR) of fungal DNA has emerged as a technique with several advantages over previous culture-based methods. Currently, a comprehensive assessment of lung pathology, leukocyte recruitment, fungal burden, and gene expression in mice with invasive aspergillosis (IA) necessitates the use of a significant number of experimental and control animals. Here the quantification of lung histological staining to determine fungal burden using a reduced number of animals was examined in detail. Lung sections were stained to identify fungal structures with Gomori's modified methanamine silver (GMS) staining. Images were taken from the GMS-stained sections from 4 discrete fields of each formalin-fixed paraffin-embedded lung. The GMS stained areas within each image were quantified using an image analysis program, and from this quantification, the mean percentage of stained area was determined for each sample. Using this strategy, eosinophil-deficient mice exhibited decreased fungal burden and disease with caspofungin therapy, while wild-type mice with IA did not improve with caspofungin. Similarly, fungal burden in mice lacking γδ T cells were also improved by caspofungin, as measured by qPCR and GMS quantification. GMS quantification is therefore introduced as a method for the determination of relative lung fungal burden that may ultimately reduce the quantity of experimental animals required for comprehensive studies of invasive aspergillosis.


Nonlocal electron-phonon coupling in the pentacene crystal: beyond the Γ-point approximation.
There is currently increasing interest in understanding the impact of the nonlocal (Peierls-type) electron-phonon mechanism on charge transport in organic molecular semiconductors. Most estimates of the non-local coupling constants reported in the literature are based on the Γ-point phonon modes. Here, the influence of phonon modes spanning the entire Brillouin zone (phonon dispersion) on the nonlocal electron-phonon couplings is investigated for the pentacene crystal. The phonon modes are obtained by using a supercell approach. The results underline that the overall nonlocal couplings are substantially underestimated by calculations taking sole account of the phonons at the Γ point of the unit cell. The variance of the transfer integrals based on Γ-point normal-mode calculations at room temperature is underestimated in some cases by 40% for herringbone-type dimers and by over 80% for cofacial dimers. Our calculations show that the overall coupling is somewhat larger for holes than for electrons. The results also suggest that the interactions of charge carriers (both electrons and holes) with acoustic and optical phonons are comparable. Therefore, an adequate description of the charge-transport properties in pentacene and similar systems requires that these two electron-phonon coupling mechanisms be treated on the same footing.


Mobile Health Interventions for Physical Activity, Sedentary Behavior, and Sleep in Adults Aged 50 Years and Older: A Systematic Literature Review.
We provide a systematic review of interventions utilizing mobile technology to alter physical activity, sedentary behavior, and sleep among adults aged 50 years and older. A systematic search identified 52 relevant articles (randomized control trial [RCT], quasi-experimental, pre/post single-group design). Of 50 trials assessing physical activity, 17 out of 29 RCTs and 13 out of 21 trials assessed for pre/post changes only supported the effectiveness of mobile interventions to improve physical activity, and 9 studies (five out of 10 RCTs and all four pre/post studies) out of 14 reduced sedentary behavior. Only two of five interventions improved sleep (one out of two RCTs and one out of three pre/post studies). Text messaging was the most frequently used intervention (60% of all studies) but was usually used in combination with other components (79% of hybrid interventions included SMS, plus either web or app components). Although more high-quality RCTs are needed, there is evidence supporting the effectiveness of mHealth approaches in those aged 50 years and older.


Neuropeptide Y genotype, central obesity, and abdominal fat distribution: the POUNDS LOST trial.
Neuropeptide Y is a key peptide affecting adiposity and has been related to obesity risk. However, little is known about the role of NPY variations in diet-induced change in adiposity. The objective was to examine the effects of NPY variant rs16147 on central obesity and abdominal fat distribution in response to dietary interventions. We genotyped a functional NPY variant rs16147 among 723 participants in the Preventing Overweight Using Novel Dietary Strategies trial. Changes in waist circumference (WC), total abdominal adipose tissue, visceral adipose tissue, and subcutaneous adipose tissue (SAT) from baseline to 6 and 24 mo were evaluated with respect to the rs16147 genotypes. Genotype-dietary fat interaction was also examined. The rs16147 C allele was associated with a greater reduction in WC at 6 mo (P < 0.001). In addition, the genotypes showed a statistically significant interaction with dietary fat in relation to WC and SAT (P-interaction = 0.01 and 0.04): the association was stronger in individuals with high-fat intake than in those with low-fat intake. At 24 mo, the association remained statistically significant for WC in the high-fat diet group (P = 0.02), although the gene-dietary fat interaction became nonsignificant (P = 0.30). In addition, we found statistically significant genotype-dietary fat interaction on the change in total abdominal adipose tissue, visceral adipose tissue, and SAT at 24 mo (P = 0.01, 0.05, and 0.04): the rs16147 T allele appeared to associate with more adverse change in the abdominal fat deposition in the high-fat diet group than in the low-fat diet group. Our data indicate that the NPY rs16147 genotypes affect the change in abdominal adiposity in response to dietary interventions, and the effects of the rs16147 single-nucleotide polymorphism on central obesity and abdominal fat distribution were modified by dietary fat.


Barriers and facilitators to cultural competence in rehabilitation services: a scoping review.
There is an important need to evaluate whether rehabilitation services effectively address the needs of minority culture populations with North America's increasingly diverse population. The objective of this paper was therefore to review and assess the state of knowledge of barriers and facilitators to cultural competence in rehabilitation services. Our scoping review focused on cultural competence in rehabilitation services. Rehabilitation services included in this review were: audiology, speech-language pathology, physiotherapy, and occupational therapy. A search strategy was developed to identify relevant articles published from inception of databases until April 2015. Titles and abstracts were screened by two independent reviewers according to specific eligibility criteria with the use of a liberal-accelerated approach. Full-text articles meeting inclusion criteria were then screened. Key study characteristics were abstracted by the first reviewer, and findings were verified by the second reviewer. After duplicates were removed, 4303 citations were screened. Included articles suggest that studies on cultural competence occur most frequently in occupational therapy (n = 17), followed by speech language pathology (n = 11), physiotherapy (n = 6), and finally audiology (n = 1). Primary barriers in rehabilitation services include language barriers, limited resources, and cultural barriers. Primary facilitators include cultural awareness amongst practitioners, cultural awareness in services, and explanations of health care systems. To our knowledge, this review is the first to summarize barriers and facilitators to cultural competence in rehabilitation fields. Insufficient studies were found to draw any conclusions with regards to audiological services. Minimal perspectives based on patient/caregiver experiences in all rehabilitation fields underscore a research gap. Future studies should aim to explore both patient/caregiver and practitioner perspectives as such data can help inform culturally competent practices.


Preventing urinary tract infections after menopause without antibiotics.
Urinary tract infections (UTIs) are the most common bacterial infections in women, and increase in incidence after the menopause. It is important to uncover underlying abnormalities or modifiable risk factors. Several risk factors for recurrent UTIs have been identified, including the frequency of sexual intercourse, spermicide use and abnormal pelvic anatomy. In postmenopausal women UTIs often accompany the symptoms and signs of the genitourinary syndrome of menopause (GSM). Antimicrobial prophylaxis has been demonstrated to be effective in reducing the risk of recurrent UTIs in women, but this may lead to drug resistance of both the causative microorganisms and the indigenous flora. The increasing prevalence of Escherichia coli (the most prevalent uropathogen) that is resistant to antimicrobial agents has stimulated interest in novel non-antibiotic methods for the prevention of UTIs. Evidence shows that topical estrogens normalize vaginal flora and greatly reduce the risk of UTIs. The use of intravaginal estrogens may be reasonable in postmenopausal women not taking oral estrogens. A number of other strategies have been used to prevent recurrent UTIs: probiotics, cranberry juice and d-mannose have been studied. Oral immunostimulants, vaginal vaccines and bladder instillations with hyaluronic acid and chondroitin sulfate are newer strategies proposed to improve urinary symptoms and quality of life. This review provides an overview of UTIs' prophylaxis without antibiotics, focusing on a practical clinical approach to women with UTIs.


EfCCNa survey: European intensive care nurses' attitudes and beliefs towards end-of-life care.
Available literature suggests that critical care nurses have varied experiences in relation to end-of-life (EOL) care. Few studies have examined the involvement of European intensive care nurses' involvement in EOL care decisions and the extent to which their nursing practice is based on shared beliefs, experiences and attitudes. To investigate experiences and attitudes of European intensive care nurses regarding EOL care. Using a survey method, delegates (n = 419) attending an international critical care nursing conference were invited to complete a self-administered questionnaire about their involvement with EOL care practices. The questionnaire composed of 45 items and was available in three European languages. A total of 164 questionnaires were completed, yielding a response rate of 39%. The majority of respondents (91.8%) indicated direct involvement in EOL patient care, while 73.4% reported active involvement in decision-making process. 78.6% of respondents expressed commitment to family involvement in EOL decisions, however only 59.3% of the participants said that this was routinely undertaken (p < 0.0005, Z = -4.778). In decisions to withdraw or withhold therapy, 65% would decrease the flow of inspired oxygen, 98.8% provide continuous pain relief and 91.3% endorse open visiting. The majority (78%) disagreed that dying patients should be transferred to a single room. A division of views was observed in relation to 44% agreeing that patients should be kept deeply sedated and equal numbers contesting the continuation of nutritional support (41.6% versus 42.3%). The involvement of European intensive care nurses in EOL care discussions and decisions is reasonably consistent with many engaged in initiating dialogue with coworkers. In general, views and experiences of EOL care were similar, with the exception of the provision of nutrition and use of sedation. Use of formal guidelines and education may increase nurses' involvement and confidence with EOL decisions.


Relationship between aged and vapor-deposited organic glasses: Secondary relaxations in methyl-m-toluate.
In situ interdigitated electrode broadband dielectric spectroscopy was used to characterize the excess wing relaxations in vapor-deposited and aged glasses of methyl-m-toluate (MMT, Tg = 170 K). MMT displays typical excess wing relaxations in dielectric spectra of its supercooled liquid and glasses. Physical vapor deposition produced glasses with degrees of suppression of the excess wing relaxation that varied systematically with deposition conditions, up to a maximum suppression of more than a factor of 3. The glass deposited at a relatively high temperature, 0.96 Tg (163 K), showed the same amount of suppression as that of a liquid-cooled glass aged to equilibrium at this temperature. The suppression of the excess wing relaxation was strongly correlated with the kinetic stability of the vapor-deposited glasses. Comparisons with aged MMT glasses allowed an estimate of the structural relaxation time of the vapor-deposited glasses. The dependence of the estimated structural relaxation times upon the substrate temperature was found to be stronger than Arrhenius but weaker than Vogel-Fulcher-Tammann dependence predicted from extrapolation of relaxation times in the supercooled liquid. Additionally, this work provides the first example of the separation of primary and secondary relaxations using physical vapor deposition.


Adding purpose to the repetitive exercise of elderly women through imagery.
Many studies have documented the effectiveness of verbally elicited imagery in the enhancement of motor skills in young, nondisabled populations. The present study examined the effects of verbally elicited imagery in the encouragement of two exercises (i.e., reaching up to pick apples and reaching down to pick up coins) in elderly women. The subjects were 27 women between 62 and 96 years of age who were selected from a nursing home, a residential retirement home, and a foster care home. All of the subjects received imagery as well as control conditions, but in a counterbalanced fashion. The Wilcoxon matched-pairs signed rank tests indicated that the imagery condition elicited significantly more repetitions of the reaching-up exercise than did the control condition (z = 2.25, p [one-tailed] = .012). The results in the reaching-down exercise were generally in the same direction but difficult to interpret statistically. The results are discussed in terms of other recent research investigating ways to add purpose to therapeutic exercise through occupation. Clinicians are urged to explore the advantages and disadvantages of imagery-based occupations in treatment.


An Integrated Coral Reef Ecosystem Model to Support Resource Management under a Changing Climate.
Millions of people rely on the ecosystem services provided by coral reefs, but sustaining these benefits requires an understanding of how reefs and their biotic communities are affected by local human-induced disturbances and global climate change. Ecosystem-based management that explicitly considers the indirect and cumulative effects of multiple disturbances has been recommended and adopted in policies in many places around the globe. Ecosystem models give insight into complex reef dynamics and their responses to multiple disturbances and are useful tools to support planning and implementation of ecosystem-based management. We adapted the Atlantis Ecosystem Model to incorporate key dynamics for a coral reef ecosystem around Guam in the tropical western Pacific. We used this model to quantify the effects of predicted climate and ocean changes and current levels of current land-based sources of pollution (LBSP) and fishing. We used the following six ecosystem metrics as indicators of ecosystem state, resilience and harvest potential: 1) ratio of calcifying to non-calcifying benthic groups, 2) trophic level of the community, 3) biomass of apex predators, 4) biomass of herbivorous fishes, 5) total biomass of living groups and 6) the end-to-start ratio of exploited fish groups. Simulation tests of the effects of each of the three drivers separately suggest that by mid-century climate change will have the largest overall effect on this suite of ecosystem metrics due to substantial negative effects on coral cover. The effects of fishing were also important, negatively influencing five out of the six metrics. Moreover, LBSP exacerbates this effect for all metrics but not quite as badly as would be expected under additive assumptions, although the magnitude of the effects of LBSP are sensitive to uncertainty associated with primary productivity. Over longer time spans (i.e., 65 year simulations), climate change impacts have a slight positive interaction with other drivers, generally meaning that declines in ecosystem metrics are not as steep as the sum of individual effects of the drivers. These analyses offer one way to quantify impacts and interactions of particular stressors in an ecosystem context and so provide guidance to managers. For example, the model showed that improving water quality, rather than prohibiting fishing, extended the timescales over which corals can maintain high abundance by at least 5-8 years. This result, in turn, provides more scope for corals to adapt or for resilient species to become established and for local and global management efforts to reduce or reverse stressors.