A Single Dose of 225Ac-RPS-074 Induces a Complete Tumor Response in an LNCaP Xenograft Model.
Promising biochemical responses to 225Ac-prostate-specific membrane antigen (PSMA) 617, even in patients who are refractory to β-particle radiation, illustrate the potential of targeted α-therapy for the treatment of metastatic castration-resistant prostate cancer. However, side effects such as xerostomia are severe and irreversible. To fully harness the potential of targeted α-therapy, it is necessary to increase the therapeutic index of the targeted radioligands. One emerging strategy is to increase clearance half-life through enhanced binding to serum albumin. We have evaluated the albumin-binding PSMA-targeting ligand RPS-074 in a LNCaP xenograft model to determine its potential value to the treatment of prostate cancer. Methods:225Ac-RPS-074 was evaluated in male BALB/c mice bearing LNCaP xenograft tumors. A biodistribution study was performed over 21 d to determine the dosimetry in tumors and normal tissue. The dose response was measured in groups of 7 mice using 37, 74, and 148 kBq of 225Ac-RPS-074 and compared with positive and negative control groups. Mice were sacrificed when tumor volume exceeded 1,500 mm3Results:225Ac-RPS-074 was labeled in greater than 98% radiochemical yield and showed high (>10% injected dose/g) and sustained accumulation in LNCaP tumors from 24 h to beyond 14 d. Signal in blood and highly vascularized tissues was evident over the first 24 h after injection and cleared by 7 d. The tumor-to-kidney ratio was 4.3 ± 0.7 at 24 h and 62.2 ± 9.5 at 14 d. A single injection of 148 kBq induced a complete response in 6 of 7 tumors, with no apparent toxic effects. Treatment with 74 kBq induced a partial response in 7 of 7 tumors, but from 42 d, 6 of 7 experienced significant regrowth. The 37-kBq group experienced a survival benefit relative to the negative control but not compared with the positive control group. Conclusion: A single dose of 148 kBq of 225Ac-RPS-074 induced a complete response in 86% of tumors, with tumor-to-normal-tissue ratios that predict an improved therapeutic index. The use of the macropa chelator enabled quantitative radiolabeling and may facilitate the clinical translation of this promising targeted α-therapeutic.


A novel system for stable, high-level expression from the T7 promoter.
The most widespread, efficient prokaryotic protein-producing system is one where the T7 phage polymerase recognizes the T7 phage promoter (T7 p/p system). Unfortunately, in this system, target protein expression gradually declines and is often undetectable following 3 to 5 subcultures. Although a number of studies have attempted to stabilize the expression levels of the T7 p/p system, none has resolved the problem adequately and thus precludes the use of this system for the production of recombinant proteins on a large scale. We created an expression cassette enabling stable, high-level expression in the T7p/p system. The cassette was tested with two different vector backbones and two target proteins. In all experiments, the expression system using the new cassette exhibited high and stable protein expression levels when compared to the traditional system. Herein, we describe a universal expression cassette that enables high-level, stable target protein expression in T7 RNA polymerase-based expression systems. We also present the successful use of this cassette as a novel expression platform and demonstrate its ability to overcome the main deficiency of the T7 p/p system. Thus, we provide a method for using the T7 p/p system on an industrial scale.


Are alcoholism treatments effective? The Project MATCH data.
Project MATCH was the largest and most expensive alcoholism treatment trial ever conducted. The results were disappointing. There were essentially no patient-treatment matches, and three very different treatments produced nearly identical outcomes. These results were interpreted post hoc as evidence that all three treatments were quite effective. We re-analyzed the data in order to estimate effectiveness in relation to quantity of treatment. This was a secondary analysis of data from a multisite clinical trial of alcohol dependent volunteers (N = 1726) who received outpatient psychosocial therapy. Analyses were confined to the primary outcome variables, percent days abstinent (PDA) and drinks per drinking day (DDD). Overall tests between treatment outcome and treatment quantity were conducted. Next, three specific groups were highlighted. One group consisted of those who dropped out immediately; the second were those who dropped out after receiving only one therapy session, and the third were those who attended 12 therapy sessions. Overall, a median of only 3% of the drinking outcome at follow-up could be attributed to treatment. However this effect appeared to be present at week one before most of the treatment had been delivered. The zero treatment dropout group showed great improvement, achieving a mean of 72 percent days abstinent at follow-up. Effect size estimates showed that two-thirds to three-fourths of the improvement in the full treatment group was duplicated in the zero treatment group. Outcomes for the one session treatment group were worse than for the zero treatment group, suggesting a patient self selection effect. Nearly all the improvement in all groups had occurred by week one. The full treatment group had improved in PDA by 62% at week one, and the additional 11 therapy sessions added only another 4% improvement. The results suggest that current psychosocial treatments for alcoholism are not particularly effective. Untreated alcoholics in clinical trials show significant improvement. Most of the improvement which is interpreted as treatment effect is not due to treatment. Part of the remainder appears to be due to selection effects.


The many forks in FOXO's road.
The FOXO family of transcription factors constitute an evolutionarily conserved subgroup within the larger family known as winged helix or Forkhead transcriptional regulators. Building upon work in the nematode, researchers have uncovered a role for these proteins in a diverse set of cellular responses that include glucose metabolism, stress response, cell cycle regulation, and apoptosis. At the organismal level, FOXO transcription factors are believed to function in various pathological processes ranging from cancer and diabetes to organismal aging. A number of studies have also shed light on the signaling pathways that regulate FOXO activity in response to external stimuli and have identified multiple FOXO target genes that mediate this varied set of biological responses.


Policy statement--Child abuse, confidentiality, and the health insurance portability and accountability act.
The federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 has significantly affected clinical practice, particularly with regard to how patient information is shared. HIPAA addresses the security and privacy of patient health data, ensuring that information is released appropriately with patient or guardian consent and knowledge. However, when child abuse or neglect is suspected in a clinical setting, the physician may determine that release of information without consent is necessary to ensure the health and safety of the child. This policy statement provides an overview of HIPAA regulations with regard to the role of the pediatrician in releasing or reviewing patient health information when the patient is a child who is a suspected victim of abuse or neglect. This statement is based on the most current regulations provided by the US Department of Health and Human Services and is subject to future changes and clarifications as updates are provided.


Restless legs syndrome and functional limitations among American elders in the Health and Retirement Study.
Restless legs syndrome (RLS) is a common condition associated with decreased quality of life in older adults. This study estimates the prevalence, risk factors, and functional correlates of among U.S. elders. Subjects (n = 1,008) were sub-sampled from the 2002 cross-sectional interview survey of the Health and Retirement Study (HRS), a nationally representative study of U.S. elders. Symptoms and sleep disturbances consistent with RLS were identified. Activities of daily living (ADL), instrumental activities of daily living (IADL), and limitations for mobility, large muscle groups, gross and fine motor function were measured using standardized questions. Incident functional limitations were detected over six years of observation. The prevalence of RLS among U.S. elders born before 1947 was 10.6%. Factors associated with increased prevalence RLS at baseline included: overweight body mass index (multivariate adjusted prevalence ratio = 1.77; 95% confidence interval (CI) 1.05-2.99); mild-to-moderate pain (2.67, 1.47-4.84) or pain inferring with activity (3.44, 2.00-5.93); three or more chronic medications (2.54, 1.26-5.12), highest quartile of out-of-pocket medical expenses (2.12, 1.17-3.86), frequent falls (2.63, 1.49-4.66), health limiting ability to work (2.91, 1.75-4.85), or problems with early waking or frequent wakening (1.69, 1.09-2.62 and 1.55, 1.00-2.41, respectively). Current alcohol consumption (0.59, 0.37-0.92) and frequent healthcare provider visits (0.49, 0.27-0.90) were associated with decreased RLS prevalence. RLS did not predict incident disability for aggregate measures but was associated with increased risk for specific limitations, including: difficulty climbing several stair flights (multivariate-adjusted hazard ratio = 2.38, 95% CI 1.39-4.06), prolonged sitting (2.17, 1.25-3.75), rising from a chair (2.54, 1.62-3.99), stooping (2.66, 1.71-4.15), moving heavy objects (1.79, 1.08-2.99), carrying ten pounds (1.61, 1.05-2.97), raising arms (1.76, 1.05-2.97), or picking up a dime (1.97, 1.12-3.46). RLS sufferers are more likely to have functional disability, even after adjusting for health status and pain syndrome correlates.


Concurrent Training in Prepubescent Children: The Effects of 8 Weeks of Strength and Aerobic Training on Explosive Strength and V[Combining Dot Above]O2max.
Alves, AR, Marta, CC, Neiva, HP, Izquierdo, M, and Marques, MC. Concurrent training in prepubescent children: the effects of 8 weeks of strength and aerobic training on explosive strength and V[Combining Dot Above]O2max. J Strength Cond Res 30(7): 2019-2032, 2016-The purpose of this study was to compare the effects of 8-week training periods of strength training alone (GS), combined strength and aerobic training in the same session (GCOM1), or in 2 different sessions (GCOM2) on explosive strength and maximal oxygen uptake (V[Combining Dot Above]O2max) in prepubescent children. Of note, 168 healthy children, aged 10-11 years (10.9 ± 0.5), were randomly selected and assigned to 3 training groups to train twice a week for 8 weeks: GS (n = 41), GCOM1 (n = 45), GCOM2 (n = 38) groups, and a control group (GC) (n = 44; no training program). The GC maintained the baseline level, and trained-induced differences were found in the experimental groups. Differences were observed in the 1 and 3-kg medicine ball throws (GS: +5.8 and +8.1%, respectively; GCOM1: +5.7 and +8.7%, respectively; GCOM2: +6.2 and +8%, respectively, p < 0.001) and in the countermovement jump height and in the standing long jump length (GS: +5.1 and +5.2%, respectively; GCOM1: +4.2 and +7%, respectively; GCOM2: +10.2 and +6.4%, respectively, p < 0.001). In addition, the training period induced gains in the 20-m time (GS: +2.1%; GCOM1: +2.1%; GCOM2: +2.3%, p < 0.001). It was shown that the experimental groups (GCOM1, GCOM2, and GS) increased V[Combining Dot Above]O2max, muscular strength, and explosive strength from pretraining to posttraining. The higher gains were observed for concurrent training when it was performed in different sessions. These results suggest that concurrent training in 2 different sessions seems to be an effective and useful method for training-induced explosive strength and V[Combining Dot Above]O2max in prepubescent children. This could be considered as an alternative way to optimize explosive strength training and cardiorespiratory fitness in school-based programs.


Antiproliferative and antioxidant properties of anthocyanin rich extracts from blueberry and blackcurrant juice.
The present study was aimed at evaluating the antiproliferative potential of anthocyanin-rich fractions (ARFs) obtained from two commercially available juices (blueberry and blackcurrant juices) on three tumor cell lines; B16F10 (murine melanoma), A2780 (ovarian cancer) and HeLa (cervical cancer). Individual anthocyanin determination, identification and quantification were done using HPLC-MS. Antioxidant activity of the juices was determined through different mechanism methods such as DPPH and ORAC. For biological testing, the juices were purified through C18 cartridges in order to obtain fractions rich in anthocyanins. The major anthocyanins identified were glycosylated cyanidin derivatives. The antiproliferative activity of the fractions was tested using the MTT assay. The antiproliferative potential of ARF was found to be associated with those bioactive molecules, anthocyanins due to their antioxidant potential. The results obtained indicated that both blueberry and blackcurrants are rich sources of antioxidants including anthocyanins and therefore these fruits are highly recommended for daily consumption to prevent numerous degenerative diseases.


Muscle Mechanography: A Novel Method to Measure Muscle Function in Older Adults.
Muscle function decline is a commonly observed process that occurs with aging. Low muscle function, an essential component of sarcopenia, is associated with negative outcomes, including falls, fractures, and dependency. Although many tools have been developed and are used to assess muscle function in older adults, most have important limitations. Muscle mechanography is a novel method that can quantitatively assess muscle function by performing movements such as heel raises, chair rises, or jumps on a ground reaction force plate. It can also assess balance by measuring sway of the center of pressure. Muscle mechanography promises to have advantages over currently used tools, appears to have better reproducibility, and can assess a broader range of physical function-from master athletes to frail individuals. Older adults can safely perform muscle mechanography measurements. Further research is needed to determine whether muscle mechanography can predict outcomes such as falls, fractures, and mortality. [Res Gerontol Nurs. 2017; 10(1):17-24.].


Impact of interface roughness on the performance of broadband blackbody absorber based on dielectric-metal film multilayers.
We report on factors affecting the performance of a broadband, mid-IR absorber based on multiple, alternating dielectric / metal layers. In particular, we investigate the effect of interface roughness. Atomic layer deposition produces both a dramatic suppression of the interface roughness and a significant increase in the optical absorption as compared to devices fabricated using a conventional thermal evaporation source. Absorption characteristics greater than 80% across a 300 K black body spectrum are achieved. We demonstrate a further increase in this absorption via the inclusion of a patterned, porous anti-reflection layer.


Effect of lovastatin on cholesterol content of cardiac and red blood cell membranes in normal and cardiomyopathic hamsters.
Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A, is used therapeutically to lower plasma cholesterol levels. However, the effect of this therapy on cell membrane cholesterol in vivo is not known. The goal of this study was to investigate whether lovastatin treatment of hamsters decreases cholesterol in cardiac cell membranes and in red blood cell (RBC) membranes. Because abnormal cellular Ca++ regulation has been associated with altered membrane cholesterol in hearts of cardiomyopathic (CM) hamsters, we also measured the cholesterol content of cardiac and RBC membranes from lovastatin-treated and untreated Bio 14.6 CM hamsters to determine whether any differences existed with respect to normals. Sarcolemma-enriched cardiac membranes and RBC membranes were obtained from 42 to 45-day normal and CM hamsters after 13 days of lovastatin treatment (0.1% of food/day) and from untreated normal and CM hamsters. Plasma cholesterol, membrane cholesterol/phospholipid (C/PL) ratio and cholesterol per milligram of membrane protein (C/prot) were determined. In hearts from untreated CM hamsters, C/prot was significantly lower (P < .05) than in untreated normals. Lovastatin decreased plasma cholesterol by 76% and 81% in normal and CM hamsters, respectively (P < .001), but after lovastatin treatment, there was no significant change in C/PL or C/prot in cardiac membranes from either strain; there was also no significant decrease in C/prot or in C/PL of RBC membranes from normals or C/PL of CM hamster RBC membranes. However, lovastatin feeding resulted in a significant (P < .01) 24% decrease in C/prot of CM RBC membranes.(ABSTRACT TRUNCATED AT 250 WORDS)


Exploring multidimensional operationalizations of precarious employment in Swedish register data - a typological approach and a summative score approach.
Objectives This study aimed to explore multidimensional operationalizations of precarious employment (PE) in Swedish register data using two approaches: (i) a typological approach and (ii) a dimensional, summative scale approach. It also examined the distribution of sociodemographic and occupational characteristics of precarious employees in Sweden. Method Register data was retrieved on individuals and their employers in the Swedish workforce. Five items corresponding to three dimensions of PE were operationalized: contractual relationship insecurity, contractual temporariness, multiple jobs/sectors, income level, and lack of unionization. First, latent class analysis was applied and a typology of six employment types emerged. Second, a summative scale was constructed by scoring all PE-items. Results Three types of PE were found using the typological approach, which were characterized by direct employment, solo self-employment and multiple job holding, respectively. The summative scale score ranged between -10 and +2 (average: -1.8). Particularly poor scores were seen for solo self-employed, multiple job holders/multiple sectors, and low income. Female gender, young age, low education and foreign origin were prone to precariousness. PE was more frequent among certain economic sectors and occupations. Conclusions Using an existing register of labor market data, two operationalizations of PE were constructed and rendered promising for exposure assessment. Hence, the operationalizations could be of interest for countries with similar data structure. Both approaches highlighted precarious combinations of employment conditions and pointed towards the existence of a wide continuum of precariousness on the labor market. Etiological studies and research assessing trends over time are needed to validate these findings.


Lung function and asthma control in school-age children managed in UK primary care: a cohort study.
Spirometry and fraction of exhaled nitric oxide (FeNO) are commonly used in specialist centres to monitor children with asthma. The National Institute for Health and Care Excellence recommends spirometry for asthma monitoring from 5 years in all healthcare settings. There is little spirometry and FeNO data in children managed for asthma in UK primary care to support their use. To study the prevalence of abnormal spirometry and FeNO in children with asthma managed in primary care and to explore their relationship with asthma control and unplanned healthcare attendances (UHA). Prospective observational cohort study in children aged 5-16 years with suspected or doctor-diagnosed asthma attending an asthma review in UK general practice. Spirometry, FeNO, asthma control test (ACT) scores and number of UHAs were studied. Of 612 children from 10 general practices, 23.5% had abnormal spirometry, 36.0% had raised FeNO ≥35 parts per billion and 41.8% reported poor control. Fifty-four per cent of children reporting good asthma control had abnormal spirometry and/or raised FeNO. At follow-up, the mean number of UHAs fell from 0.31/child in the 6 months preceding review to 0.20/child over the 6 months following review (p=0.0004). Median ACT scores improved from 20 to 22 (p=0.032), and children's ACT from 21 to 23 (p<0.0001). Abnormal lung function and FeNO are common in children attending for asthma review in primary care and relate poorly to symptom scores. A symptoms-based approach to asthma monitoring without objective testing is likely to miss children at high risk of future severe asthma attacks.


Marijuana in pediatric and adult congenital heart disease heart transplant listing: A survey of provider practices and attitudes.
Despite increasing legalization and use of marijuana, there is no consensus among pediatric heart transplant institutions or providers regarding users' eligibility for cardiac transplant. We sent a survey to pediatric and ACHD transplant providers (physicians, surgeons, transplant coordinators, and pharmacists) assessing their current institution's policies and their personal opinions about marijuana use in patients being considered for heart transplantation. Of the respondents, 84% practice in the United States and Canada. Most providers (80%) care for both pediatric and ACHD patients. Respondents included cardiologists (77%) and surgeons (11%), with the remaining being coordinators and pharmacists. Most providers (73%) reported their institution had no policy regarding marijuana use in heart transplant candidates. Only 20% of respondents' institutions consider mode of consumption, with 87% and 53% approving of oral and transdermal routes, respectively, and only 7% approving of vaporized or smoked routes. While 73% of providers would consider illegal marijuana use an absolute/relative contraindication to heart transplant listing, the number decreases to 57% for legal recreational users and 21% for legal medical users. Most providers personally believe marijuana to be physically and mentally/emotionally harmful to pediatric patients (67% and 72%, respectively). Many institutions lack a policy regarding marijuana use in pediatric and ACHD heart transplant candidates, and there is considerable disagreement among providers on the best practice. With increasing legalization and use of marijuana, each institution will have to address this issue thoughtfully to continue to provide high-quality, consistent, and equitable care for pediatric and ACHD heart transplant candidates.


Analysis of Homeostatic Mechanisms in Biochemical Networks.
Cell metabolism is an extremely complicated dynamical system that maintains important cellular functions despite large changes in inputs. This "homeostasis" does not mean that the dynamical system is rigid and fixed. Typically, large changes in external variables cause large changes in some internal variables so that, through various regulatory mechanisms, certain other internal variables (concentrations or velocities) remain approximately constant over a finite range of inputs. Outside that range, the mechanisms cease to function and concentrations change rapidly with changes in inputs. In this paper we analyze four different common biochemical homeostatic mechanisms: feedforward excitation, feedback inhibition, kinetic homeostasis, and parallel inhibition. We show that all four mechanisms can occur in a single biological network, using folate and methionine metabolism as an example. Golubitsky and Stewart have proposed a method to find homeostatic nodes in networks. We show that their method works for two of these mechanisms but not the other two. We discuss the many interesting mathematical and biological questions that emerge from this analysis, and we explain why understanding homeostatic control is crucial for precision medicine.


Enhanced Living by Assessing Voice Pathology Using a Co-Occurrence Matrix.
A large number of the population around the world suffers from various disabilities. Disabilities affect not only children but also adults of different professions. Smart technology can assist the disabled population and lead to a comfortable life in an enhanced living environment (ELE). In this paper, we propose an effective voice pathology assessment system that works in a smart home framework. The proposed system takes input from various sensors, and processes the acquired voice signals and electroglottography (EGG) signals. Co-occurrence matrices in different directions and neighborhoods from the spectrograms of these signals were obtained. Several features such as energy, entropy, contrast, and homogeneity from these matrices were calculated and fed into a Gaussian mixture model-based classifier. Experiments were performed with a publicly available database, namely, the Saarbrucken voice database. The results demonstrate the feasibility of the proposed system in light of its high accuracy and speed. The proposed system can be extended to assess other disabilities in an ELE.


Detection of extended-spectrum beta-lactamases in clinical isolates of Klebsiella pneumoniae and Escherichia coli.
Forty clinical isolates of Escherichia coli and 141 isolates of Klebsiella pneumoniae that either transferred ceftazidime resistance or showed sulbactam enhancement of oxyimino-beta-lactam susceptibility were tested by disk diffusion methodology for susceptibility to aztreonam, cefotaxime, ceftazidime, and cefoxitin. With standard 30 micrograms antibiotic disks, the fraction of these extended-spectrum beta-lactamase (ESBL)-producing isolates testing resistant by National Committee for Clinical Laboratory Standards criteria was lowest (24%) with cefotaxime disks. Forty percent of the E. coli and 29% of the K. pneumoniae isolates appeared susceptible with at least one oxyimino-beta-lactam disk. Ceftazidime and aztreonam disks were equivalent in differentiating ESBL production, and both were superior to cefotaxime disks. Over half the E. Coli and 29% of the K. pneumoniae isolates tested cefoxitin resistant. In 30 isolates, cefoxitin resistance was transmissible and due to a plasmid-mediated AmpC-type beta-lactamase. With a 5-micrograms ceftazidime disk, a breakpoint could be chosen with high sensitivity and specificity for ESBL-producing organisms. Present disk diffusion criteria underestimate the prevalence of ESBL-producing strains.


Endogenous erythropoietin and the association with inflammation and mortality in diabetic chronic kidney disease.
Anemia and inflammation are prevalent in diabetic patients with chronic kidney disease (CKD). The role of endogenous erythropoietin (EPO) in the pathophysiology of anemia in chronic diseases and its relationship to clinical outcomes remain uncertain. In this cohort study, we aimed to identify factors associated with endogenous EPO levels and investigate their relation to all-cause mortality. Between 2004 and 2005, 215 patients with type 2 diabetes were enrolled. Exclusion criteria included stage renal disease ESRD and any form of anemia therapy. The association of EPO levels with clinical and laboratory variables was investigated by linear regression modeling. Predictors of all-cause mortality were evaluated by Cox proportional hazards analyses. Patients (median age, 67 years; 52% men; median duration of diabetes, 10 years; median estimated GFR, 49 ml/min per 1.73 m²) were followed for up to 7.0 years. Forty-one patients died. Elevated EPO levels were independently associated with elevated C-reactive protein, low ferritin, and hypertension, in a multivariate model that also included age, cardiovascular disease, kidney function, albumin, cholesterol, and hemoglobin. Higher EPO levels were independently predictive for mortality, as were age, low levels of albumin, and cardiovascular disease. In diabetic patients with CKD, elevated endogenous EPO levels were predictive for mortality and were related mainly to markers of inflammation, independent of kidney function, and despite low hemoglobin levels. Understanding the phenomenon of EPO resistance and iron dysregulation caused by inflammation is crucial for effective and safe treatment of anemia in patients with CKD.


Advances in evidence-based cancer adoptive cell therapy.
Adoptive cell therapy (ACT) has been developed in cancer treatment by transferring/infusing immune cells into cancer patients, which are able to recognize, target, and destroy tumor cells. Recently, sipuleucel-T and genetically-modified T cells expressing chimeric antigen receptors (CAR) show a great potential to control metastatic castration-resistant prostate cancer and hematologic malignancies in clinic. This review summarized some of the major evidence-based ACT and the challenges to improve cell quality and reduce the side effects in the field. This review also provided future research directions to make sure ACT widely available in clinic.


Digitally switchable multi-focal lens using freeform optics.
Optical technologies offering electrically tunable optical power have found a broad range of applications, from head-mounted displays for virtual and augmented reality applications to microscopy. In this paper, we present a novel design and prototype of a digitally switchable multi-focal lens (MFL) that offers the capability of rapidly switching the optical power of the system among multiple foci. It consists of a freeform singlet and a customized programmable optical shutter array (POSA). Time-multiplexed multiple foci can be obtained by electrically controlling the POSA to switch the light path through different segments of the freeform singlet rapidly. While this method can be applied to a broad range of imaging and display systems, we experimentally demonstrate a proof-of-concept prototype for a multi-foci imaging system.


Isolation of a new clathrin heavy chain gene with muscle-specific expression from the region commonly deleted in velo-cardio-facial syndrome.
Velo-cardio-facial syndrome (VCFS) and DiGeorge syndrome (DGS) are developmental disorders characterized by a spectrum of phenotypes including velopharyngeal insufficiency, conotruncal heart defects and facial dysmorphology among others. Eighty to eighty-five percent of VCFS/DGS patients are hemizygous for a portion of chromosome 22. It is likely that the genes encoded by this region play a role in the etiology of the phenotypes associated with the disorders. Using a cDNA selection protocol, we isolated a novel clathrin heavy chain cDNA (CLTD) from the VCFS/DGS minimally deleted interval. The cDNA encodes a protein of 1638 amino acids. CLTD shares significant homology, but is not identical to the ubiquitously expressed clathrin heavy chain gene. The CLTD gene also shows a unique pattern of expression, having its maximal level of expression in skeletal muscle. Velopharyngeal insufficiency and muscle weakness are common features of VCFS patients. Based on the location and expression pattern of CLTD, we suggest hemizygosity at this locus may play a role in the etiology of one of the VCFS-associated phenotypes.


Cost-effectiveness of salmeterol xinafoate/fluticasone propionate combination inhaler in chronic asthma.
To determine where in the treatment steps recommended by the British Thoracic Society and Scottish Intercollegiate Guidelines Network (BTS/SIGN) Asthma Guideline it is cost-effective to use salmeterol xinafoate/fluticasone propionate combination inhaler (SFC) (Seretide) compared with other inhaled corticosteroid (ICS) containing regimens (with and without a long acting beta-2 agonist (LABA)) for chronic asthma in adults and children. Meta-analyses of percentage symptom-free days (%SFD) were used within a cost-effectiveness model. Time spent in two asthma control health states, 'symptom-free' and 'with-symptoms' was used as the measure of differential treatment effectiveness. SFC was compared with varying doses of fluticasone propionate (FP) and beclometasone dipropionate (BDP) with or without a separate salmeterol inhaler, and with the budesonide/formoterol combination inhaler (BUD/FORM) (Symbicort). Drug costs, non-drug costs and quality adjusted life years (QALY) were incorporated into the analyses. Results are presented as cost per QALY ratios and uncertainty explored using probabilistic sensitivity analysis. Compared with an increased dose of FP in adults, SFC either 'dominates' (i.e. cheaper and more effective) FP or the cost per QALY is 6852 pounds sterling. The cost per QALYs estimated in sensitivity analyses using BDP costs range from 5679 pounds sterling to 15,997 pounds sterling. For children the cost per QALY for SFC 50 Evohaler compared with an increased dose of FP is pound 15,739 pounds sterling. SFC is similarly clinically effective in improving %SFDs compared with FP plus salmeterol delivered in separate inhalers (mean differences for each dose comparison of -3.9 (low) (with a 95% confidence interval (CI): -12.96; 5.16); 4.10 (medium) (95% CI: -3.01; 11.21); -0.4 (high) (95% CI: -8.88; 8.08)) and BUD/FORM (mean difference of 0.40 (95% CI -3.69; 4.49)) in adults, and a cheaper SFC option is available at all doses (annual cost savings range from 18 pounds sterling-427 pounds sterling per patient). SFC was similarly effective compared with FP plus salmeterol in separate inhalers in children under 12 and also resulted in annual cost savings of between 47 pounds sterling and 77 pounds sterling. A number of other comparisons were also made and the results are available as electronic supplementary data. This is the first analysis to estimate the cost-effectiveness of SFC in chronic asthma compared with multiple comparators and based on a systematic identification of relevant trials and data on %SFDs. The findings suggest that for adults and children uncontrolled on BDP 400 microg/day or equivalent it is a cost-effective option to switch to SFC (at an equivalent ICS dose) compared with increasing the dose of ICS. For adults and children aged 12 years and over who have passed this point and are uncontrolled on BDP 800 microg/day or equivalent, switching to SFC remains a cost-effective approach. Where an adult or child requires an ICS and a LABA to be co-prescribed, SFC is a cost-effective option compared with FP or BDP plus salmeterol delivered in separate inhalers. In adults who require combination therapy, SFC is a cost-effective option compared with BUD/FORM.


Can guanine-based purines be considered modulators of intestinal motility in rodents?
Adenine-based purines play a pivotal role in the control of gastrointestinal motility in rodents. Recently, guanine-based purines have been also shown to exert extracellular effects in the central nervous system raising the possibility of the existence of distinct receptors for guanine-based purines. Thus, it seems likely to speculate that also guanine-based purines may play a role in the modulation of the intestinal contractility. Spontaneous and neurally-evoked mechanical activity was recorded in vitro as changes in isometric tension in circular muscle strips from mouse distal colon. Guanosine up to 3mM or guanine up to 1mM failed to affect the spontaneous mechanical activity, but reduced the amplitude of the electrical field stimulation (EFS)-induced cholinergic contractions, without affecting the early nitrergic relaxation. Both compounds failed to affect the direct contractile responses evoked by carbachol. No desensitization of the response was observed. Guanine-based purine effects were not altered by theophylline, P1 purinoceptor antagonist, by PPADS or suramin, P2 purinoceptor antagonists, by ODQ, guanilyl cyclase inhibitor, or by DDA, adenylyl cyclase inhibitor. Nucleoside uptake inhibitors, dipyridamole or 6-[(4-Nitrobenzyl)thio]-9-β-D-ribofuranosylpurine (NBTI), antagonized the inhibitory effects induced by guanosine without interfering with guanine. On the contrary, adenine, a competitive inhibitor of nucleobase uptake, antagonized guanine-induced effects. In conclusion, our data indicate that guanosine and guanine are able to modulate negatively the excitatory cholinergic neurotransmission in the circular muscle layer of mouse colon. Guanine-based purines appear to interfere with prejunctional acethylcoline release. Their effects are dependent by their cellular uptake, and independent by adenine-based purine receptors.


Development and validation of the French-Canadian Chronic Pain Self-efficacy Scale.
Perceived self-efficacy is a non-negligible outcome when measuring the impact of self-management interventions for chronic pain patients. However, no validated, chronic pain-specific self-efficacy scales exist for studies conducted with French-speaking populations. To establish the validity of the use of the French-Canadian Chronic Pain Self-efficacy Scale (FC-CPSES) among chronic pain patients. The Chronic Disease Self-Efficacy Scale is a validated 33-item self-administered questionnaire that measures perceived self-efficacy to perform self-management behaviours, manage chronic disease in general and achieve outcomes (a six-item version is also available). This scale was adapted to the context of chronic pain patients following cross-cultural adaptation guidelines. The FC-CPSES was administered to 109 fibromyalgia and 34 chronic low back pain patients (n=143) who participated in an evidence-based self-management intervention (the PASSAGE program) offered in 10 health care centres across the province of Quebec. Cronbach's alpha coefficients (α) were calculated to determine the internal consistency of the 33- and six-item versions of the FC-CPSES. With regard to convergent construct validity, the association between the FC-CPSES baseline scores and related clinical outcomes was examined. With regard to the scale's sensitivity to change, pre- and postintervention FC-CPSES scores were compared. Internal consistency was high for both versions of the FC-CPSES (α=0.86 to α=0.96). Higher self-efficacy was significantly associated with higher mental health-related quality of life and lower pain intensity and catastrophizing (P<0.05), supporting convergent validity of the scale. There was a statistically significant increase in FC-CPSES scores between pre- and postintervention measures for both versions of the FC-CPSES (P<0.003), which supports their sensitivity to clinical change during an intervention. These data suggest that both versions of the FC-CPSES are reliable and valid for the measurement of pain management self-efficacy among chronic pain patients.


ATF3 upregulation in glia during Wallerian degeneration: differential expression in peripheral nerves and CNS white matter.
Many changes in gene expression occur in distal stumps of injured nerves but the transcriptional control of these events is poorly understood. We have examined the expression of the transcription factors ATF3 and c-Jun by non-neuronal cells during Wallerian degeneration following injury to sciatic nerves, dorsal roots and optic nerves of rats and mice, using immunohistochemistry and in situ hybridization. Following sciatic nerve injury--transection or transection and reanastomosis--ATF3 was strongly upregulated by endoneurial, but not perineurial cells, of the distal stumps of the nerves by 1 day post operation (dpo) and remained strongly expressed in the endoneurium at 30 dpo when axonal regeneration was prevented. Most ATF3+ cells were immunoreactive for the Schwann cell marker, S100. When the nerve was transected and reanastomosed, allowing regeneration of axons, most ATF3 expression had been downregulated by 30 dpo. ATF3 expression was weaker in the proximal stumps of the injured nerves than in the distal stumps and present in fewer cells at all times after injury. ATF3 was upregulated by endoneurial cells in the distal stumps of injured neonatal rat sciatic nerves, but more weakly than in adult animals. ATF3 expression in transected sciatic nerves of mice was similar to that in rats. Following dorsal root injury in adult rats, ATF3 was upregulated in the part of the root between the lesion and the spinal cord (containing Schwann cells), beginning at 1 dpo, but not in the dorsal root entry zone or in the degenerating dorsal column of the spinal cord. Following optic nerve crush in adult rats, ATF3 was found in some cells at the injury site and small numbers of cells within the optic nerve displayed weak immunoreactivity. The pattern of expression of c-Jun in all types of nerve injury was similar to that of ATF3. These findings raise the possibility that ATF3/c-Jun heterodimers may play a role in regulating changes in gene expression necessary for preparing the distal segments of injured peripheral nerves for axonal regeneration. The absence of the ATF3 and c-Jun from CNS glia during Wallerian degeneration may limit their ability to support regeneration.


Molecular insights into RBR E3 ligase ubiquitin transfer mechanisms.
RING-in-between-RING (RBR) ubiquitin (Ub) ligases are a distinct class of E3s, defined by a RING1 domain that binds E2 Ub-conjugating enzyme and a RING2 domain that contains an active site cysteine similar to HECT-type E3s. Proposed to function as RING/HECT hybrids, details regarding the Ub transfer mechanism used by RBRs have yet to be defined. When paired with RING-type E3s, E2s perform the final step of Ub ligation to a substrate. In contrast, when paired with RBR E3s, E2s must transfer Ub onto the E3 to generate a E3~Ub intermediate. We show that RBRs utilize two strategies to ensure transfer of Ub from the E2 onto the E3 active site. First, RING1 domains of HHARI and RNF144 promote open E2~Ubs. Second, we identify a Ub-binding site on HHARI RING2 important for its recruitment to RING1-bound E2~Ub. Mutations that ablate Ub binding to HHARI RING2 also decrease RBR ligase activity, consistent with RING2 recruitment being a critical step for the RBR Ub transfer mechanism. Finally, we demonstrate that the mechanism defined here is utilized by a variety of RBRs.


Efficacy of liposomal amphotericin B for prophylaxis of acute or reactivation models of invasive pulmonary aspergillosis.
The efficacy of antifungal prophylaxis for prevention of invasive aspergillosis (IA) may depend on whether IA results from recent inhalation of spores or reactivation of latent colonisation. Compare the efficacy of liposomal amphotericin B (LAmB) for prophylaxis in acute and reactivation models of IA. In the acute model, mice immunosuppressed from day 0 were challenged at day 3 with an aerosol of Aspergillus fumigatus. LAmB (15 mg kg(-1) ) was administered at day 0 or at challenge. In the reactivation model, naïve mice exposed to A. fumigatus remained untreated until clearance of spores from the lungs, then immunosuppressed to induce reactivation. A single LAmB dose was administered at start of immunosuppression. In the acute model, a single administration of LAmB at start of immunosuppression was not effective, but an additional administration resulted in a significant decrease in lung fungal burden (P < 0.05 vs. controls). A significant prophylactic efficacy was observed when LAmB was administered once at challenge (P < 0.01). In the reactivation model, a single LAmB administration at start of immunosuppression significantly reduced both reactivation rate and fungal burden vs. controls (P < 0.01). Our results show that the conditions under which IA develop and timing of administration of LAmB were determinant variables for prophylactic efficacy.


Effects of Propamocarb Hydrochloride on Mycelial Growth, Sporulation, and Infection by Phytophthora nicotianae Isolates from Virginia Nurseries.
Propamocarb hydrochloride is a systemic fungicide commonly used for control of Phytophthora diseases of nursery crops. Here we report on the effect of this compound on different growth stages of Phytophthora nicotianae, a major pathogen of numerous herbaceous and some woody ornamental plants. A total of 71 isolates were assayed for sensitivity to propamocarb at two concentrations of 1.8 mg/ml (label rate) and 10 mg/ml using clarified V8 agar as a base medium. All isolates grew at 10 mg/ml with the most sensitive isolate having 34.8% relative growth compared with growth on nonamended medium. Nine isolates were selected and further tested for mycelial growth at 0, 1, 10, 25, 50, and 100 mg/ml, and for sporangium production, zoospore motility, and germination at 0, 5, 50, 500, 5,000, and 50,000 μg/ml. EC50 values ranged from 2.2 to 90.1 mg/ml for mycelial growth, 133.8 to 481.3 μg/ml for sporangium production, 88.1 to 249.8 μg/ml for zoospore motility, and 1.9 to 184.6 μg/ml for zoospore germination, respectively. In addition, 17 selected isolates were evaluated for propamocarb sensitivity on Pelargonium × hortorum cv. White Orbit. Two days after seedlings were treated with propamocarb at 3.6 mg/ml, they were inoculated by either inverting one 5-mm-diameter plug of a 3-day-old culture or applying a 10-μl drop containing 20 zoospores onto each cotyledon. Propamocarb hydrochloride provided good protection of geranium seedlings from zoospore infections but not from mycelial infections. These results suggest that this fungicide must be used preventively for Phytophthora disease management and that mycelial growth may not be the most reliable measurement to determine the development of fungicide resistance to this compound in Phytophthora species at production facilities and in the landscape.


Severe intimate partner violence and alcohol use among female trauma patients.
The lifetime prevalence of intimate partner violence (IPV) among women in the United States is reported to be between 18 and 50%. One-third of female homicide victims are killed by an intimate partner and alcohol is often involved. Despite these figures, 77% of women have never been screened for IPV. Substance abuse in male partners is known to place women at risk. We examined the role of female alcohol use on rates of severe IPV. Our hypotheses were: (1) the prevalence of IPV among women seen in trauma centers is greater than that found in national surveys; (2) alcohol problems among abused women and their partners are greater than those among non-abused women; (3) females and their partners alcohol problems are each independently associated with IPV; and (4) female trauma center patients support domestic violence screening. An in-person survey was administered to 95 consecutive adult female trauma patients admitted to a Level I Trauma Center. The survey included questions about past-year and lifetime severe IPV, female and male partner alcohol use, and willingness to participate in IPV screening and referral. The multivariate associations of female and partner alcohol use with past-year severe IPV were assessed with logistic regression. Nearly one-half (46.3%) of women reported a lifetime history of severe IPV, with 26% experiencing severe IPV in the past year. Past-year IPV was identified in 59.1% of women screening positive for drinking problems, but in only 12.7% of those screening negative for drinking problems (p = 0.001). Similarly, past-year IPV prevalence was 55.2% when the partner was a problem drinker versus 8.3% when he was not (p = 0.001). Multivariate analysis showed that female problem drinking (odds ratio [OR] = 5.8) and partner problem drinking (OR=8.9) were independent predictors of past-year severe IPV. The majority of women (90.5%) felt that it was appropriate for health care professionals to screen for IPV; 90% of women with a history of IPV thought screening was important and 71% wished a previous healthcare provider had asked them about it. Female trauma patients demonstrate a higher prevalence of severe IPV than the general population. IPV rates appear to be related to both female and partner alcohol misuse. Female trauma patients endorsed IPV screening and thus should be screened for alcohol use and IPV in a way that minimizes future violence risk. Further research is needed to elucidate whether intervention for alcohol misuse has an impact on rates of IPV in this population.


Predictors of mortality and the provision of dialysis in patients with acute tubular necrosis. The Auriculin Anaritide Acute Renal Failure Study Group.
To explore the natural history of critically ill patients with acute renal failure due to acute tubular necrosis, we evaluated 256 patients enrolled in the placebo arm of a randomized clinical trial. Death and the composite outcome, death or the provision of dialysis, were determined with follow-up to 60 d. The relative risks (RR) and 95% confidence intervals (95% CI) associated with routinely available demographic, clinical, and laboratory variables were estimated using proportional hazards regression. Ninety-three (36%) deaths were documented; an additional 52 (20%) patients who survived received dialysis. Predictors of mortality included male gender (RR, 2.01; 95% CI, 1.21 to 3.36), oliguria (RR, 2.25; 95% CI, 1.43 to 3.55), mechanical ventilation (RR, 1.86; 95% CI, 1.18 to 2.93), acute myocardial infarction (RR, 3.14; 95% CI, 1.85 to 5.31), acute stroke or seizure (RR, 3.08; 95% CI, 1.56 to 6.06), chronic immunosuppression (RR, 2.37; 95% CI, 1.16 to 4.88), hyperbilirubinemia (RR, 1.06; 95% CI, 1.03 to 1.08 per 1 mg/dl increase in total bilirubin) and metabolic acidosis (RR, 0.95; 95% CI, 0.90 to 0.99 per 1 mEq/L increase in serum bicarbonate concentration). Predictors of death or the provision of dialysis were oliguria (RR, 5.95; 95% CI, 3.96 to 8.95), mechanical ventilation (RR, 1.53; 95% CI, 1.07 to 2.21), acute myocardial infarction (RR, 1.95; 95% CI, 1.24 to 3.07), arrhythmia (RR, 1.51; 95% CI, 1.04 to 2.19), and hypoalbuminemia (RR, 0.56; 95% CI, 0.42 to 0.74 per 1 g/dl increase in serum albumin concentration). Neither mortality nor the provision of dialysis was related to patient age. These observations can be used to estimate risk early in the course of acute tubular necrosis. Furthermore, these and related models may be used to adjust for case-mix variation in quality improvement efforts, and to objectively stratify patients in future intervention trials aimed at favorably altering the course of hospital-acquired acute renal failure.


Early ART initiation among HIV-positive pregnant women in central Mozambique: a stepped wedge randomized controlled trial of an optimized Option B+ approach.
Despite effective prevention strategies and increasing investments in global health, maternal to child transmission (MTCT) of HIV remains a significant problem globally, especially in sub-Saharan Africa. In 2012, there were 94,000 HIV-positive pregnant women in Mozambique. Approximately 15% of these women transmitted HIV to their newborn infants, resulting in nearly 14,000 new pediatric HIV infections that year. To address this issue, in 2013, the Mozambican Ministry of Health implemented the World Health Organization-recommended "Option B+" strategy in which all newly diagnosed HIV-positive pregnant women are counseled to initiate combination anti-retroviral therapy (ART) immediately upon diagnosis regardless of CD4 count and to continue treatment for life. Given the limited experience with Option B+ in sub-Saharan Africa, few rigorous pragmatic trials have studied this new treatment strategy. This study utilizes an initial formative research process involving patient and health care provider interviews and focus groups, workforce assessments, value stream mapping, and commodity utilization assessments to understand the strengths and weaknesses in the current Option B+ care cascade. The formative research is intended to guide identification and prioritization of key workflow modifications and the development of an enhanced adherence and retention package. These two components are bundled into a defined intervention implemented and evaluated across six health facilities utilizing a stepped wedge randomized controlled trial study design. The overall objective of this trial is to develop and test a pilot intervention in central Mozambique to implement the new Option B+ guidelines with high fidelity and increase the proportion of HIV-positive pregnant women in target antenatal clinics (ANC) who start ART prior to delivery and are retained in care. This pragmatic study utilizes research strategies that have the potential to meaningfully improve the Option B+ care cascade in central Mozambique and to decrease the MTCT of HIV. This trial is designed to identify critical low-cost improvement strategies that can be bundled into a defined intervention. If this intervention has a measurable impact, it can be rapidly scaled up to other ANC in Mozambique and sub-Saharan Africa. ClinicalTrials.gov: NCT02371265.


Reactive trajectories of the Ru2+/3+ self-exchange reaction and the connection to Marcus' theory.
Outer sphere electron transfer between two ions in aqueous solution is a rare event on the time scale of first principles molecular dynamics simulations. We have used transition path sampling to generate an ensemble of reactive trajectories of the self-exchange reaction between a pair of Ru2+ and Ru3+ ions in water. To distinguish between the reactant and product states, we use as an order parameter the position of the maximally localised Wannier center associated with the transferring electron. This allows us to align the trajectories with respect to the moment of barrier crossing and compute statistical averages over the path ensemble. We compare our order parameter with two typical reaction coordinates used in applications of Marcus theory of electron transfer: the vertical gap energy and the solvent electrostatic potential at the ions.


The electrostatic origin of Abraham's solute polarity parameter.
A computational method was developed which relates the empirical linear solvation energy relationship (LSER) solute polarity parameter, S (formerly denoted ), to two more fundamental quantities: a polarizability term and a computed solvent-accessible-surface electrostatic term. Electrostatics computations were conducted explicitly or with dielectric field polarizable continuum models (PCM, SCIPCM, IPCM), employing a density functional theory (B3LYP/6-311G(2df,2p)) or efficient Hartree-Fock (HF/MIDI!) method for 90 polar and nonpolar organic solutes. Electrostatic parameters calculated at electron isodensity solute surfaces were found to produce significantly better correlations with empirical S values than the same electrostatic parameters deduced from a fixed Bondi atomic radii based surface. The best-fit expression was found employing SCIPCM/IPCM at the 0.0004 e(-)/bohr(3) solvent-accessible-surface: S(fit)() = 0.46E - 0.091SigmaV(s)()(2), with squared correlation coefficient = 0.96 and standard deviation = 0.10, where E is a measured solute excess polarizability scale and SigmaV(s)()(2) is a quantum-calculated solute electrostatic descriptor in kcal A/mol. The resulting model is more accurate than previously developed estimation approaches and relies on only two fitted coefficients; it has the potential advantage of applicability to any solute composed of C, H, N, O, S, F, Cl, and Br. Finally, this investigation offers quantitative insight into the relative contributions of solute polarity and solute polarizability to the empirical LSER polarity parameter, S.


Genome-wide association studies: potential next steps on a genetic journey.
Genome-wide association studies have successfully identified numerous loci at which common variants influence disease risk or quantitative traits. Despite these successes, the variants identified by these studies have generally explained only a small fraction of the heritable component of disease risk, and have not pinpointed with certainty the causal variant(s) at the associated loci. Furthermore, the mechanisms of action by which associated loci influence disease or quantitative phenotypes are often unclear, because we do not know through which gene(s) the associated variants exert their effects or because these gene(s) are of unknown function or have no clear connection to known disease biology. Thus, the initial set of genome-wide association studies serve as a starting point for future genetic and functional studies. We outline possible next steps that may help accelerate progress from genetic studies to the biological knowledge that can guide the development of predictive, preventive, or therapeutic measures.


Advanced imaging in COPD: insights into pulmonary pathophysiology.
Chronic obstructive pulmonary disease (COPD) involves a complex interaction of structural and functional abnormalities. The two have long been studied in isolation. However, advanced imaging techniques allow us to simultaneously assess pathological processes and their physiological consequences. This review gives a comprehensive account of the various advanced imaging modalities used to study COPD, including computed tomography (CT), magnetic resonance imaging (MRI), and the nuclear medicine techniques positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Some more recent developments in imaging technology, including micro-CT, synchrotron imaging, optical coherence tomography (OCT) and electrical impedance tomography (EIT), are also described. The authors identify the pathophysiological insights gained from these techniques, and speculate on the future role of advanced imaging in both clinical and research settings.


Triggers in advanced neurological conditions: prediction and management of the terminal phase.
The challenge to provide a palliative care service for individuals with advanced neurological conditions is compounded by variability in disease trajectories and symptom profiles. The National End of Life Care Programme (2010) recommended seven 'triggers' for a palliative approach to care for patients with advanced neurological conditions. To establish the frequency of triggers in the palliative phase, and if they could be reduced to fewer components. Management of the terminal phase also was evaluated. Retrospective study of 62 consecutive patients under the care of a specialist palliative neurology service, who had died. Principle component analysis (PCA) was performed to establish the interrelationship between triggers. Frequency of triggers increased as each patient approached death. PCA found that four symptom components explained 76.8% of the variance. These represented: rapid physical decline; significant complex symptoms, including pain; infection in combination with cognitive impairment; and risk of aspiration. Median follow-up under the palliative care service was 336 days. In 56.5% of patients, the cause of death was pneumonia. The terminal phase was recognised in 72.6%. The duration of the terminal phase was 8.8 days on average, and the Liverpool Care of the dying Pathway was commenced in 33.9%. All carers were offered bereavement support. Referral criteria based on the triggers can facilitate appropriate and timely patient access to palliative care. The components deduced through PCA have face validity; however larger studies prospectively validating the triggers are required. Closer scrutiny of the terminal phase is necessary to optimise management.


Effect of coverage gap on healthcare utilization among Medicare beneficiaries with chronic obstructive pulmonary disorder.
To evaluate the association between the Medicare coverage gap with hospitalization, emergency room (ER) visits, and time to hospitalization in chronic obstructive pulmonary disease (COPD) patients. Retrospective cohort study using data from a Medicare Advantage (MA) plan. Patients with ≥1 claim for COPD at baseline, ≥65 years, continuous 24-months enrollment and without any cancer/end stage renal disease diagnosis were eligible. Patients not reaching the coverage gap (no coverage gap) were matched and compared to those reaching the coverage gap and those reaching catastrophic coverage in separate analyses. Chi-square tests and Cox proportional hazards model were used to compare outcomes across matched cohorts. In total, 3142 COPD patients were identified (79% no coverage gap, 10% coverage gap, and 11% catastrophic coverage). Compared to the no coverage gap group, a larger number of beneficiaries in the coverage gap group had ≥1 hospitalization (26% vs 32%, p < .05), ≥ 1 ER visits (43% vs 49%, p < .05), and ≥1 hospitalization/ER (total visit) (47% vs 54%, p < .05), respectively. Compared to the no coverage gap group, a greater number of beneficiaries in catastrophic coverage had ≥1 ER visit (45% vs 53%, p < .05) or ≥1 total visits (48% vs 56%, p < .05), respectively. Time to hospitalization was shorter among those entering the coverage gap as compared to the no coverage gap [Hazards Ratio (HR) = 1.5; p = .040]. COPD patients entering the coverage gap and catastrophic coverage were associated with increased utilization of healthcare services. Entering the coverage gap was also associated with shorter time to hospitalization as compared to the no coverage gap.


Pseudo-Casimir stresses and elasticity of a confined elastomer film.
Investigations of the elastic behavior of bulk elastomers have traditionally proceeded on the basis of classical rubber elasticity, which regards chains as thermally fluctuating but disregards the thermal fluctuations of the cross-links. Herein, we consider an incompressible and flat elastomer film of an axisymmetric shape confined between two large hard co-planar substrates, with the axis of the film perpendicular to the substrates. We address the impact that thermal fluctuations of the cross-links have on the free energy of elastic deformation of the system, subject to the requirement that the fluctuating elastomer cannot detach from the substrates. We examine the behavior of the deformation free energy for one case where a rigid pinning boundary condition is applied to a class of elastic fluctuations at the confining surfaces, and another case where the same elastic fluctuations are subjected to soft "gluing" potentials. We find that there can be significant departures (both quantitative and qualitative) from the prediction of classical rubber elasticity theory when elastic fluctuations are included. Finally, we compare the character of the attractive part of the elastic fluctuation-induced, or pseudo-Casimir, stress with the standard thermal Casimir stress in confined but non-elastomeric systems, finding the same power law decay behavior when a rigid pinning boundary condition is applied; for the case of the gluing potential, we find that the leading order correction to the attractive part of the fluctuation stress decays inversely with the inter-substrate separation.


Identifying Breeding Priorities for Blueberry Flavor Using Biochemical, Sensory, and Genotype by Environment Analyses.
Breeding for a subjective goal such as flavor is challenging, as many blueberry cultivars are grown worldwide, and identifying breeding targets relating to blueberry flavor biochemistry that have a high degree of genetic control and low environmental variability are priorities. A variety of biochemical compounds and physical characters induce the sensory responses of taste, olfaction, and somatosensation, all of which interact to create what is perceived flavor. The goal of this study was to identify the flavor compounds with a larger genetic versus environmental component regulating their expression over an array of cultivars, locations, and years. Over the course of three years, consumer panelists rated overall liking, texture, sweetness, sourness, and flavor intensity of 19 southern highbush blueberry (Vaccinium corymbosum hybrids) genotypes in 30 sensory panels. Significant positive correlations to overall liking of blueberry fruit (P<0.001) were found with sweetness (R2 = 0.70), texture (R2 = 0.68), and flavor (R2 = 0.63). Sourness had a significantly negative relationship with overall liking (R2 = 0.55). The relationship between flavor and texture liking was also linear (R2 = 0.73, P<0.0001) demonstrating interaction between olfaction and somatosensation. Partial least squares analysis was used to identify sugars, acids, and volatile compounds contributing to liking and sensory intensities, and revealed strong effects of fructose, pH, and several volatile compounds upon all sensory parameters measured. To assess the feasibility of breeding for flavor components, a three year study was conducted to compare genetic and environmental influences on flavor biochemistry. Panelists could discern genotypic variation in blueberry sensory components, and many of the compounds affecting consumer favor of blueberries, such as fructose, pH, β-caryophyllene oxide and 2-heptanone, were sufficiently genetically controlled that allocating resources for their breeding is worthwhile.


Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle.
TBC1 domain family, member 4 (TBC1D4; also known as AS160) is a cellular signalling intermediate to glucose transport regulated by insulin-dependent and -independent mechanisms. Skeletal muscle insulin sensitivity is increased after acute exercise by an unknown mechanism that does not involve modulation at proximal insulin signalling intermediates. We hypothesised that signalling through TBC1D4 is involved in this effect of exercise as it is a common signalling element for insulin and exercise. Insulin-regulated glucose metabolism was evaluated in 12 healthy moderately trained young men 4 h after one-legged exercise at basal and during a euglycaemic-hyperinsulinaemic clamp. Vastus lateralis biopsies were taken before and immediately after the clamp. Insulin stimulation increased glucose uptake in both legs, with greater effects (approximately 80%, p < 0.01) in the previously exercised leg. TBC1D4 phosphorylation, assessed using the phospho-AKT (protein kinase B)substrate antibody and phospho- and site-specific antibodies targeting six phosphorylation sites on TBC1D4, increased at similar degrees to insulin stimulation in the previously exercised and rested legs (p < 0.01). However, TBC1D4 phosphorylation on Ser-318, Ser-341, Ser-588 and Ser-751 was higher in the previously exercised leg, both in the absence and in the presence of insulin (p < 0.01; Ser-588, p = 0.09; observed power = 0.39). 14-3-3 binding capacity for TBC1D4 increased equally (p < 0.01) in both legs during insulin stimulation. We provide evidence for site-specific phosphorylation of TBC1D4 in human skeletal muscle in response to physiological hyperinsulinaemia. The data support the idea that TBC1D4 is a nexus for insulin- and exercise-responsive signals that may mediate increased insulin action after exercise.


Concomitant targeting of tumor cells and induction of T-cell response synergizes to effectively inhibit trastuzumab-resistant breast cancer.
Trastuzumab is an iconic rationally designed targeted therapy for HER2-positive breast cancers. However, the low response rate and development of resistance call for novel approaches for the treatment of patients. Here, we report that concurrent targeting of tumor cells and activation of T cells in the tumor microenvironment results in a synergistic inhibitory effect on tumor growth and overcomes resistance in two distinct PTEN loss-mediated trastuzumab-resistant mammary tumor mouse models. In vivo combination treatment with HER2/Neu antibody and Akt inhibitor triciribine effectively inhibited tumor growth in both models via inhibiting PI3K/AKT and mitogen-activated protein kinase signaling accompanied by increased T-cell infiltration in the tumor microenvironment. We showed that both CD8(+) and CD4(+) T cells were essential to the optimal antitumor effect of this combination treatment in an IFN-γ-dependent manner. Importantly, the antitumor activities of HER2/Neu antibody and triciribine combination treatment were further improved when coinhibitory receptor cytotoxic T-lymphocyte-associated antigen 4 was blocked to enhance the T-cell response. Our data indicate that multitargeted combinatorial therapies targeting tumor cells and concomitantly enhancing T-cell response in the tumor microenvironment could cooperate to exert maximal therapeutic activity, suggesting a promising clinical strategy for treating trastuzumab-resistant breast cancers and other advanced malignancies.


Gamma-hydroxybutyric acid decreases intravenous cocaine self-administration in rats.
Gamma-hydroxybutyric acid (GHB) is an endogenous compound present in mammalian brain suggested as a putative neurotransmitter, which has been shown to affect several aspects of dependence from various classes of drugs of abuse. In the present study, two sets of experiments were performed to investigate the effects of acute pretreatment with GHB on intravenous cocaine self-administration in rats. In the first experiment GHB was administered intragastrically at the doses of 175, 350, and 700 mg/kg to Long-Evans rats trained to self-administer cocaine using nose-poke as operandum. In the second experiment, GHB was administered intraperitoneally at the doses of 100, 200, and 400 mg/kg to Wistar rats trained to self-administer cocaine intravenously using lever-pressing as operandum. In both experiments acute pretreatment with GHB significantly and dose dependently reduced cocaine self-administration. The effectiveness of GHB was similar in both experiments, indicating that the effect of GHB on cocaine self-administration is independent of animal strain. route of administration, and type of operant response required. These results indicate that GHB reduces cocaine-seeking behavior in rats, modulating the acute reinforcing effect of cocaine. The clinical effectiveness of GHB in dependence from various classes of abused drugs warrants further studies to evaluate the possibility that GHB might represent a useful therapeutic agent for cocaine addiction in humans.


Using discriminant analysis to determine sources of salinity in shallow groundwater prior to hydraulic fracturing.
High-volume hydraulic fracturing (HVHF) gas-drilling operations in the Marcellus Play have raised environmental concerns, including the risk of groundwater contamination. Fingerprinting water impacted by gas-drilling operations is not trivial given other potential sources of contamination. We present a multivariate statistical modeling framework for developing a quantitative, geochemical fingerprinting tool to distinguish sources of high salinity in shallow groundwater. The model was developed using new geochemical data for 204 wells in New York State (NYS), which has a HVHF moratorium and published data for additional wells in NYS and several salinity sources (Appalachian Basin brines, road salt, septic effluent, and animal waste). The model incorporates a stochastic simulation to predict the geochemistry of high salinity (>20 mg/L Cl) groundwater impacted by different salinity sources and then employs linear discriminant analysis to classify samples from different populations. Model results indicate Appalachian Basin brines are the primary source of salinity in 35% of sampled NYS groundwater wells with >20 mg/L Cl. The model provides an effective means for differentiating groundwater impacted by basin brines versus other contaminants. Using this framework, similar discriminatory tools can be derived for other regions from background water quality data.


Serum and host liver activities of glycosidases and sialyltransferases in animals bearing transplantable tumors.
Rats bearing Reuber H-35 or Novikoff hepatomas and mice bearing L1210 or L5178Y murine leukemias exhibited elevated serum levels of fetuin : N-acetylneuraminic acid transferase (EC 18.104.22.168) activity. The serum transferase activity could be correlated with the growth rate of the tumor; in animals bearing the more rapidly growing Novikoff hepatoma, activity was higher than in animals bearing the Reuber H-35 hepatoma. Higher transferase levels were also found in L1210 leukemic mice than in mice with the slightly slower growing L5178Y leukemia. Serum from rats bearing Reuber H-35 hepatoma and mice bearing L1210 murine leukemia had elevated levels of alpha- and beta-glucosidase (EC 18.104.22.168 and EC 18.104.22.168), alpha- and beta-galactosidase (EC 126.96.36.199 and (188.8.131.52), beta mannosidase (EC 188.8.131.52), alpha- and beta-fucosidase (EC 3.2.1.- and EC 220.127.116.11), beta-N-acetylglucosaminidase (EC 188.8.131.52) and acid phosphatase (EC 126.96.36.199); alpha-mannosidase (EC 18.104.22.168), beta-N-acetylgalactosaminidase (EC 3.2.2.-) and beta-xylosidase (EC 188.8.131.52) were not elevated. In animals bearing Reuber H-35 hepatoma, host liver levels of glycosidases, beta-glucuronidase (EC 18.104.22.168) and acid phosphatase were elevated over both the control and the hepatoma values. The data are interpreted to mean that the tumors or various host tissues release large quantities of enzymes into the serum and that enzyme levels in host organs may also be affected by the tumor.


Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex.
Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system, and numerous studies have shown that MS has a strong genetic component. Independent studies to identify MS-associated genes have often indicated multiple signals in physically close genomic regions, although by their proximity it is not always clear if these data indicate redundant or truly independent genetic signals. Recently, three MS study samples were genotyped in parallel using an Illumina Custom BeadChip. These revealed multiple significantly associated single-nucleotide polymorphisms within a 600 kb stretch on chromosome 16p13. Here we present a detailed analysis of variants in this region that clarifies the independent nature of these signals. The linkage disequilibrium patterns in the region and logistic regression analysis of the associations suggest that this region likely harbors three independent MS disease loci. Further, we examined cis-expression QTLs, histone modifications and CCCTC-binding factor (CTCF) binding data in the region. We also tested for correlated expression of the genes from the region using whole-genome expression array data from lymphoblastoid cell lines. Three of the genes show expression correlations across loci. Furthermore, in the GM12878 lymphoblastoid cell line, these three genes are in a continuous region devoid of H3K27 methylation, suggesting an open chromatin configuration. This region likely only contributes minimal risk to MS; however, investigation of this region will undoubtedly provide insight into the functional mechanisms of these genes. These data highlight the importance of taking a closer look at the expression and function of chromosome 16p13 in the pathogenesis of MS.


Effects of neuromuscular electrical stimulation, laser therapy and LED therapy on the masticatory system and the impact on sleep variables in cerebral palsy patients: a randomized, five arms clinical trial.
Few studies demonstrate effectiveness of therapies for oral rehabilitation of patients with cerebral palsy (CP), given the difficulties in chewing, swallowing and speech, besides the intellectual, sensory and social limitations. Due to upper airway obstruction, they are also vulnerable to sleep disorders. This study aims to assess the sleep variables, through polysomnography, and masticatory dynamics, using electromiography, before and after neuromuscular electrical stimulation, associated or not with low power laser (Gallium Arsenide- Aluminun, =780 nm) and LED (= 660 nm) irradiation in CP patients. 50 patients with CP, both gender, aged between 19 and 60 years will be enrolled in this study. The inclusion criteria are: voluntary participation, patient with hemiparesis, quadriparesis or diparetic CP, with ability to understand and respond to verbal commands. The exclusion criteria are: patients undergoing/underwent orthodontic, functional maxillary orthopedic or botulinum toxin treatment. Polysomnographic and surface electromyographic exams on masseter, temporalis and suprahyoid will be carry out in all sample. Questionnaire assessing oral characteristics will be applied. The sample will be divided into 5 treatment groups: Group 1: neuromuscular electrical stimulation; Group 2: laser therapy; Group 3: LED therapy; Group 4: neuromuscular electrical stimulation and laser therapy and Group 5: neuromuscular electrical stimulation and LED therapy. All patients will be treated during 8 consecutive weeks. After treatment, polysomnographic and electromiographic exams will be collected again. This paper describes a five arm clinical trial assessing the examination of sleep quality and masticatory function in patients with CP under non-invasive therapies. The protocol for this study is registered with the Brazilian Registry of Clinical Trials - ReBEC RBR-994XFS.


Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent.
A 70 percent reduction in the rate of blood flow through the common carotid artery in rabbits caused a 21 percent decrease in the diameter of this artery within 2 weeks. The smooth muscle relaxant papaverine did not attenuate the response; therefore, such reductions in diameter probably reflect a structural modification of the arterial wall rather than sustained contraction of smooth muscle. This arterial response to reduced blood flow was abolished when the endothelium was removed from the vessels. It appears that the endothelium is essential for the compensatory arterial response to long-term changes in luminal blood flow rates.


HbA1c measurements from dried blood spots: validation and patient satisfaction.
This study evaluates HbA1c measurements from dried blood spots collected on filter paper and compares HbA1c from filter paper (capillary blood) with HbA1c measured in venous blood. Patient satisfaction was evaluated using a questionnaire. The performance with the filter paper method was assessed by comparing HbA1c results from EDTA-blood samples obtained via dried blood spots with HbA1c results obtained with freshly hemolyzed blood (routine HbA1c). Adult patients visiting the outpatient clinic for HbA1c analyses were recruited for the evaluation of dried blood spot sampling at home. Laboratory personnel collected a capillary blood sample on filter paper as well as a venous EDTA-blood sample. The participants collected another capillary blood sample at home and sent the dried filter paper back to the laboratory. Samples were analyzed with an immunoturbidimetric assay. Between-filter coefficient of variation was 1.8%. Filter paper HbA1c increased slightly during storage, particularly during the first 5 days. Filter paper HbA1c highly correlated with routine HbA1c (r=0.987). The evaluation of samples collected at home showed comparable HbA1c values by filter paper and routine sampling methods (n=93). Eighty-three percent of participants said they would like the filter method to be brought into practice. Home HbA1c sampling on filter paper is an acceptable sampling alternative for analysis of HbA1c.


How long do nosocomial pathogens persist on inanimate surfaces? A systematic review.
Inanimate surfaces have often been described as the source for outbreaks of nosocomial infections. The aim of this review is to summarize data on the persistence of different nosocomial pathogens on inanimate surfaces. The literature was systematically reviewed in MedLine without language restrictions. In addition, cited articles in a report were assessed and standard textbooks on the topic were reviewed. All reports with experimental evidence on the duration of persistence of a nosocomial pathogen on any type of surface were included. Most gram-positive bacteria, such as Enterococcus spp. (including VRE), Staphylococcus aureus (including MRSA), or Streptococcus pyogenes, survive for months on dry surfaces. Many gram-negative species, such as Acinetobacter spp., Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, Serratia marcescens, or Shigella spp., can also survive for months. A few others, such as Bordetella pertussis, Haemophilus influenzae, Proteus vulgaris, or Vibrio cholerae, however, persist only for days. Mycobacteria, including Mycobacterium tuberculosis, and spore-forming bacteria, including Clostridium difficile, can also survive for months on surfaces. Candida albicans as the most important nosocomial fungal pathogen can survive up to 4 months on surfaces. Persistence of other yeasts, such as Torulopsis glabrata, was described to be similar (5 months) or shorter (Candida parapsilosis, 14 days). Most viruses from the respiratory tract, such as corona, coxsackie, influenza, SARS or rhino virus, can persist on surfaces for a few days. Viruses from the gastrointestinal tract, such as astrovirus, HAV, polio- or rota virus, persist for approximately 2 months. Blood-borne viruses, such as HBV or HIV, can persist for more than one week. Herpes viruses, such as CMV or HSV type 1 and 2, have been shown to persist from only a few hours up to 7 days. The most common nosocomial pathogens may well survive or persist on surfaces for months and can thereby be a continuous source of transmission if no regular preventive surface disinfection is performed.


Agmatine inhibits matrix metalloproteinase-9 via endothelial nitric oxide synthase in cerebral endothelial cells.
Matrix metalloproteinases (MMPs) are up-regulated by ischemic injury and degrade the basement membrane of brain vessels to promote cell death and tissue injury. We previously showed that agmatine has a neuroprotective effect on neurons against ischemic injury. In the present study, we investigated the effect of agmatine on the expression of MMPs and nitric oxide (NO) production in cerebral endothelial cells (CECs) after oxygen-glucose deprivation (OGD)-reperfusion injury and its potential association with endothelial nitric oxide synthase (eNOS). Primary cultured endothelial cells from murine brain and bEnd.3 cells were subjected to OGD-reperfusion injury. Protein and mRNA levels of both MMP-2 and MMP-9 were determined by immunocytochemical analysis, Western blot and RT-PCR. Protein levels of eNOS were evaluated by Western blot in the CECs. The production of NO was measured using the Griess reagent. Agmatine attenuated the expression of MMP-2 and MMP-9 induced by ischemic injury at the protein and mRNA level, while agmatine increased the expression of eNOS directly. NO production was decreased in CECs after similar insult and was increased by agmatine treatment. In the presence of a nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), the expression levels of MMP-2 were decreased, but the expression of MMP-9 was not decreased by agmatine administration. However, NO production was suppressed by a non-specific NOS inhibitor in the agmatine treatment group. Our study supports that the down-regulation of MMP-9 by agmatine runs parallel to the up-regulation of eNOS and the maintenance of functional NO release.


Plasma thiols levels in Alzheimer's disease mice under diet-induced hyperhomocysteinemia: effect of S-adenosylmethionine and superoxide-dismutase supplementation.
Widely confirmed reports were published on association between hyperhomocysteinemia, B vitamin deficiency, oxidative stress, and amyloid-β in Alzheimer's disease (AD). Homocysteine, cysteine, cysteinylglycine and glutathione are metabolically interrelated thiols that may be potential indicators of health status and disease risk; they all participate in the metabolic pathway of homocysteine. Previous data obtained in one of our laboratories showed that B vitamin deficiency induced exacerbation of AD-like features in TgCRND8 AD mice; these effects were counteracted by S-adenosylmethionine (SAM) supplementation, through the modulation of DNA methylation and antioxidant pathways. Since the cellular response to oxidative stress typically involves alteration in thiols content, a rapid and sensitive HPLC method with fluorescence detection was here used to evaluate the effect of SAM and superoxide-dismutase (SOD) supplementation on thiols level in plasma, in TgCRND8 mice. The quantitative data obtained from HPLC analysis of mice plasma samples showed significant decrease of thiols level when the B vitamin deficient diet was supplemented with SAM + SOD and SOD alone, the latter showing the greatest effect. All these considerations point out the measurement of plasma thiols concentration as a powerful tool of relevance for all clinical purposes involving the evaluation of oxidative stress. The coupling of HPLC with fluorimetric detection, here used, provided a strong method sensitivity allowing thiols determination at very low levels.


A Journey to the West: The Ancient Dispersal of Rice Out of East Asia.
Rice is one of the most culturally valued and widely grown crops in the world today, and extensive research over the past decade has clarified much of the narrative of its domestication and early spread across East and South Asia. However, the timing and routes of its dispersal into West Asia and Europe, through which rice eventually became an important ingredient in global cuisines, has remained less clear. In this article, we discuss the piecemeal, but growing, archaeobotanical data for rice in West Asia. We also integrate written sources, linguistic data, and ethnohistoric analogies, in order to better understand the adoption of rice outside its regions of origin. The human-mediated westward spread of rice proceeded gradually, while its social standing and culinary uses repeatedly changing over time and place. Rice was present in West Asia and Europe by the tail end of the first millennium BC, but did not become a significant crop in West Asia until the past few centuries. Complementary historical, linguistic, and archaeobotanical data illustrate two separate and roughly contemporaneous routes of westward dispersal, one along the South Asian coast and the other through Silk Road trade. By better understanding the adoption of this water-demanding crop in the arid regions of West Asia, we explore an important chapter in human adaptation and agricultural decision making.


The coiled coils of cohesin are conserved in animals, but not in yeast.
The SMC proteins are involved in DNA repair, chromosome condensation, and sister chromatid cohesion throughout Eukaryota. Long, anti-parallel coiled coils are a prominent feature of SMC proteins, and are thought to serve as spacer rods to provide an elongated structure and to separate domains. We reported recently that the coiled coils of mammalian condensin (SMC2/4) showed moderate sequence divergence (approximately 10-15%) consistent with their functioning as spacer rods. The coiled coils of mammalian cohesins (SMC1/3), however, were very highly constrained, with amino acid sequence divergence typically <0.5%. These coiled coils are among the most highly conserved mammalian proteins, suggesting that they make extensive contacts over their entire surface. Here, we broaden our initial analysis of condensin and cohesin to include additional vertebrate and invertebrate organisms and multiple species of yeast. We found that the coiled coils of SMC1/3 are highly constrained in Drosophila and other insects, and more generally across all animal species. However, in yeast they are no more constrained than the coils of SMC2/4 and Ndc80/Nuf2p, suggesting that they are serving primarily as spacer rods. SMC1/3 functions for sister chromatid cohesion in all species. Since its coiled coils apparently serve only as spacer rods in yeast, it is likely that this is sufficient for sister chromatid cohesion in all species. This suggests an additional function in animals that constrains the sequence of the coiled coils. Several recent studies have demonstrated that cohesin has a role in gene expression in post-mitotic neurons of Drosophila, and other animal cells. Some variants of human Cornelia de Lange Syndrome involve mutations in human SMC1/3. We suggest that the role of cohesin in gene expression may involve intimate contact of the coiled coils of SMC1/3, and impose the constraint on sequence divergence.


Soil test phosphorus and cumulative phosphorus budgets in fertilized grassland.
We analyzed the linearity of relationships between soil test P (STP) and cumulative phosphorus (P) budget using data from six long-term fertilized grassland sites in four countries: France (Ercé and Gramond), Switzerland (Les Verrières), Canada (Lévis), and Finland (Maaninka and Siikajoki). STP was determined according to existing national guidelines. A linear-plateau model was used to determine the presence of deflection points in the relationships. Deflection points with (x, y) coordinates were observed everywhere but Maaninka. Above the deflection point, a significant linear relationship was obtained (0.33 < r (2) < 0.72) at four sites, while below the deflection point, the relationship was not significant, with a negligible rate of STP decrease. The relationship was not linear over the range of STP encountered at most sites, suggesting a need for caution when using the P budget approach to predict STP changes in grasslands, particularly in situations of very low P fertilization. Our study provides insights and description of a tool to improve global P strategies aimed at maintaining STP at levels adequate for grassland production while reducing the risk of P pollution of water.


Electrochemical artifacts originating from nanoparticle contamination by Ag/AgCl quasi-reference electrodes.
Electrochemical techniques rely on the stability of a defined reference potential. Due to the need for miniaturization, electrochemical lab-on-a-chip platforms often employ Ag/AgCl quasi-reference electrodes for this purpose. Here, we report on electrochemical artifacts resulting from nanoparticle-electrode collisions originating from standard chlorinated silver wires.


Staff attitudes towards aggression in health care: a review of the literature.
The aim of this literature review was to explore the attitudes of health care workers towards inpatient aggression and to analyse the extent to which attitudes, as defined from a theoretical point of view, were addressed in the selected studies. Databases from 1980 up to the present were searched, and a content analysis was done on the items of the selected studies. The concepts 'cognition' and 'attitude' from the framework of 'The Theory of Reasoned Action' served as categories. The self-report questionnaire was the most common instrument used and three instruments specifically designed to measure attitudes were found. These instruments lacked profound validity testing. From a total of 74 items, two thirds focussed on cognitions and only a quarter really addressed attitudes towards aggression. Research was particularly concerned with the cognitions that nurses had about aggression, and attitudes were studied only to a limited extent. Researchers used different instruments, which makes it difficult to compare results across settings.


Bologna guidelines for diagnosis and management of adhesive small bowel obstruction (ASBO): 2017 update of the evidence-based guidelines from the world society of emergency surgery ASBO working group.
Adhesive small bowel obstruction (ASBO) is a common surgical emergency, causing high morbidity and even some mortality. The adhesions causing such bowel obstructions are typically the footprints of previous abdominal surgical procedures. The present paper presents a revised version of the Bologna guidelines to evidence-based diagnosis and treatment of ASBO. The working group has added paragraphs on prevention of ASBO and special patient groups. The guideline was written under the auspices of the World Society of Emergency Surgery by the ASBO working group. A systematic literature search was performed prior to the update of the guidelines to identify relevant new papers on epidemiology, diagnosis, and treatment of ASBO. Literature was critically appraised according to an evidence-based guideline development method. Final recommendations were approved by the workgroup, taking into account the level of evidence of the conclusion. Adhesion formation might be reduced by minimally invasive surgical techniques and the use of adhesion barriers. Non-operative treatment is effective in most patients with ASBO. Contraindications for non-operative treatment include peritonitis, strangulation, and ischemia. When the adhesive etiology of obstruction is unsure, or when contraindications for non-operative management might be present, CT is the diagnostic technique of choice. The principles of non-operative treatment are nil per os, naso-gastric, or long-tube decompression, and intravenous supplementation with fluids and electrolytes. When operative treatment is required, a laparoscopic approach may be beneficial for selected cases of simple ASBO.Younger patients have a higher lifetime risk for recurrent ASBO and might therefore benefit from application of adhesion barriers as both primary and secondary prevention. This guideline presents recommendations that can be used by surgeons who treat patients with ASBO. Scientific evidence for some aspects of ASBO management is scarce, in particular aspects relating to special patient groups. Results of a randomized trial of laparoscopic versus open surgery for ASBO are awaited.


Efforts to alter the trajectory of neonatal mortality in Malawi: evaluating relative effects of access to maternal care services and birth history risk factors.
The neonatal mortality rate (NMR) in Malawi has remained stagnant at around 27 per 1000 live births over the last 15 years, despite an increase in the uptake of targeted health care interventions. We used the nationally representative 2015/16 Demographic Health Survey data set to evaluate the effect of two types of maternal exposures, namely, lack of access to maternal or intra-partum care services and birth history factors, on the risk of neonatal mortality. A causal inference approach was used to estimate a population attributable risk parameter for each exposure, adjusting for co-exposures and household, maternal and child-specific covariates. The maternal exposures evaluated were unmet family planning needs, less than 4+ antenatal care visits, lack of institutional delivery or skilled birth attendance, having prior neonatal mortality, short (8-24 months) birth interval preceding the index birth, first pregnancy, and two or more pregnancy outcomes within the preceding five years of the survey interview. We included 9553 women and their most recent live birth within 3 years of the survey. The sample's overall neonatal mortality rate was 18.5 per 1000 live births. The adjusted population attributable risk for first pregnancies was 3.9/1000 (P < 0.001), while non-institutional deliveries and the shortest preceding birth interval (8-24 months) each had an attributable risk of 1.3/1000 (Ps = 0.01). Having 2 or more pregnancy outcomes within the last 5 years had an attributable risk of 3/1000 (P = 0.006). Attending less than 4 ANC visits had, a relatively large attributable risk (2.1/1,000), and it was not statistically significant at alpha level 0.05. Our analysis addresses the gap in the literature on evaluating the effect of these exposures on neonatal mortality in Malawi. It also helps inform programs and current efforts such as the Every Newborn Action 2020 Plan. Increasing access to maternal care interventions has an important role to play in changing the trajectory of neonatal mortality, and women who are at an increased risk may not be receiving adequate care. Recent studies indicate an urgent need to assess gaps in service readiness and quality of care at the antenatal and obstetric care facilities.


Efficacy of soft tissue augmentation around dental implants and in partially edentulous areas: a systematic review.
To review the dental literature in terms of efficacy of soft tissue augmentation procedures around dental implants and in partially edentulous sites. A Medline search was performed for human studies augmenting keratinized mucosa (KM) and soft tissue volume around implants and in partially edentulous areas. Due to heterogeneity in between the studies, no meta-analyses could be performed. Nine (KM) and eleven (volume) studies met the inclusion criteria. An apically positioned flap/vestibuloplasty (APF/V) plus a graft material [free gingival graft (FGG)/subepithelial connective tissue graft (SCTG)/collagen matrix (CM)] resulted in an increase of keratinized tissue (1.4-3.3 mm). Statistically significantly better outcomes were obtained for APF/V plus FGG/SCTG compared with controls (APF/V alone; no treatment) (p < 0.05). For surgery time and patient morbidity, statistically significantly more favourable outcomes were reported for CM compared to SCTGs (p < 0.05) in two randomized controlled clinical trials (RCTs), even though rendering less keratinized tissue. SCTGs were the best-documented method for gain of soft tissue volume at implant sites and partially edentulous sites. Aesthetically at immediate implant sites, better papilla fill and higher marginal mucosal levels were obtained using SCTGs compared to non-grafted sites. An APF/V plus FGG/SCTG was the best-documented and most successful method to increase the width of KM. APF/V plus CM demonstrated less gain in KM, but also less patient morbidity and surgery time compared to APF/V plus SCTG based on two RCTs. Autogenous grafts (SCTG) rendered an increase in soft tissue thickness and better aesthetics compared to non-grafted sites.


Frequency distribution of antimalarial drug-resistant alleles among isolates of Plasmodium falciparum in Bangui, Central African Republic.
We determined the baseline frequency distribution of mutant alleles of genes associated with resistance to chloroquine and sulfadoxine-pyrimethamine in Plasmodium falciparum isolates in Bangui, Central African Republic. Mutant alleles of the P. falciparum chloroquine resistance transporter (pfcrt) gene were found in all samples and the frequency of the deduced CIET pfcrt haplotype was high (45%). The most common allele of the P. falciparum multidrug resistance 1 (pfmdr1) gene among the field isolates of P. falciparum was 86Y (21.9%). The 1246Y allele was also common (18.0%). Of the 167 P. falciparum isolates in which the dihydrofolate reductase gene was studied, only 11 carried the wild-type allele (6.6%) whereas many (50.3%) were quadruple mutants (50R, 51I, 59R, 108N). The frequency of the 436A mutant allele of the dihydropteroate synthase gene was high (74.3%), but the frequencies of the 437G (18.6%) and 540E (5.2%) mutant alleles were low. Molecular analyses of antimalarial drug-resistant alleles of P. falciparum isolates in Bangui strongly suggest the widespread distribution of chloroquine and pyrimethamine resistance and to a lesser extent sulfadoxine resistance.