Mechanical circulatory support pathways that maximize post-heart transplant survival.
Heart transplant (HTx) recipients reach transplantation through increasing numbers of support pathways, including transition from one pathway to another. Outcomes of patients successfully bridged with various support pathways are unknown. We sought to identify mechanical circulatory support pathways that maximize survival after HTx. A supplemented United Network Organ Sharing Dataset tracked status 1 HTx outcomes from 2000 to 2010. Recipients were grouped based on support pathway before HTx, including those transitioning from one pathway to another. Multivariable factors for time-related death were sought using Cox proportional hazard regression models. We identified 13,250 status 1 HTx recipients. Initial support pathways were inotropes (n = 7,607), left ventricular assist device (LVAD [n = 4,034]), intraaortic balloon pump (n = 729), biventricular assist device (n = 521), extracorporeal membrane oxygenation (ECMO [n = 316]), and right ventricular assist device (n = 43). Multivariable analysis demonstrated that LVAD use conferred a survival advantage (hazard ratio [HR] 0.71; p < 0.001), whereas all other support pathways, including inotropes (HR 1.1; p = 0.02), right ventricular assist device (HR 1.9; p = 0.01), and ECMO (HR 2.2; p < 0.001) increased the risk of post-HTx death. Support pathway transition (both escalation and reduction) occurred in 2,175 patients. Patients who transitioned from either ECMO or biventricular assist device support at listing to LVAD-only support at HTx had improved post-HTx survival that was comparable to patients who had LVAD-only therapy throughout their course (p = 0.74). The LVAD supported HTx recipients have better posttransplant survival than patients after all other mechanical support pathways. Survival after HTx is optimized when ECMO or biventricular assist device support can be transitioned to LVAD-only support. Our findings should aid clinical decision making and inform organ allocation policy development intended to maximize societal benefits of HTx.


ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer.
Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p ≤ 0.001 in BT474; p ≤ 0.01 in SKBR3) and in vivo (p ≤ 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p ≤ 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p ≤ 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p ≤ 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients.


Direct-Acting Antiviral Agents for Patients With Hepatitis C Virus Genotype 1 Infection Are Cost-Saving.
Direct-acting antivirals (DAAs) are effective in treatment of hepatitis C virus (HCV) genotype 1 infection, but their cost and value have been debated. We performed a systematic review of published cost-effectiveness analyses of DAAs, synthesized their results with updated drug prices, and calculated the maximum price at which DAA therapy for HCV genotype 1 infection is cost-effective (increased quality-adjusted life-years [QALYs] and increased cost that the society is willing to pay) and cost-saving (increased QALYs and decreased costs). We conducted a systematic review of the PubMed, Medline, EMBASE, Cochrane library, EconLit, Database of Abstracts of Reviews of Effects, National Health Service Economic Evaluation Database, Health Technology Assessment, and Tufts University databases for cost-effectiveness analyses published from 2011 through 2015. Our analysis included cost effectiveness of DAAs versus previous standard-of-care regimens (peginterferon and ribavirin, boceprevir and telaprevir), or no treatment, performed for patients with HCV genotype 1 infection. We excluded studies that were not written in English or those that did not report QALYs. Reported incremental cost-effectiveness ratios (ICERs) and treatment costs for each comparison were extracted; the threshold price was estimated for each analysis in which regimens were found to be cost-effective (ICER ≤$100,000/QALY) or cost-saving (ICER <$0), those that decreased costs and increased QALYs. We identified 24 cost-effectiveness studies that reported 170 ICERs for combinations of 11 drugs, from 11 countries. Of those, 81 ICERs were determined for first-generation DAAs (boceprevir and telaprevir) and 89 ICERs were determined for second-generation DAAs (drugs approved after the first-generation DAAs) as a primary intervention. The median threshold prices at which first-generation and second-generation DAAs became cost-effective were estimated as $120,100 (interquartile range, $90,700-$176,800) and $227,200 (interquartile range, $142,800-$355,800), respectively. At the discounted price of $60,000, a total of 71% of the analyses found second-generation DAAs to be cost-saving and 22% to be cost-effective. In a systematic review, we found treatment of HCV genotype 1 infection with second-generation DAAs to be cost-effective when they cost less than and $227,200; these drugs produced cost savings at current discounts.


Hand-Held Photometer for Instant On-Spot Quantification of Nucleic Acids, Proteins, and Cells.
This paper presents a novel hand-held photometer, termed "Photopette", for on-spot absorbance measurements of biochemical analytes. The Photopette is a multicomponent, highly portable device with an overall weight of 160 g, which fits within 202 mm × 47 mm × 42 mm. Designed in the form factor of a micropipette, Photopette integrates a photodiode detector with light emitting diodes (LEDs) to form a highly customizable photometer which supports a wide variety of applications within the wavelengths between 260 and 1050 nm. A dual-purpose disposable reflective tip was designed to act as a sample holder and a light-reflecting system, which is in stark contrast to the operation of mainstream spectrophotometers and photometers. Small volume analytes may be measured with low sample loss using this proprietary CuveTip. A user-friendly software application running on smart devices was developed to control and read the values from Photopette via a low-energy Bluetooth link. This one-step strategy allows measurements on-spot without sample transfer, minimizing cross-contamination and human error. The results reported in this paper demonstrate Photopette's great potential to quantify DNA, direct protein, and cell density directly within the laminar flow hood. Results are compared with a Nanodrop 2000c spectrophotometer, a mainstream spectrophotometer for small-volume measurements.


Clinical spectrum and diagnosis of cobalamin deficiency.
To better estimate how frequently patients with low serum cobalamin (Cbl) levels in current clinical practice are truly deficient in Cbl and to determine the incidence of atypical or nonclassic presentations of Cbl deficiency, we prospectively studied 300 unselected consecutive patients with serum Cbl concentrations less than 200 pg/mL seen at two medical centers over a 2-year period. Baseline hematologic, neuropsychiatric, and biochemical measurements were obtained, followed by a course of parenteral Cbl therapy and reassessment. A response to Cbl therapy was defined as one or more of the following: (1) an increase in hematocrit of 0.05 or more; (2) a decrease in mean cell volume of 5 fL or more; (3) a clearing of hypersegmented neutrophilis and macroovalocytes from the peripheral blood smear; and (4) an unequivocal and prompt improvement of neuropsychiatric abnormalities. Of the 300 patients with serum Cbl levels less than 200 pg/mL, 86 had one or more responses to Cbl therapy and 59 had no response. In 155, insufficient data was available. In the Cbl-responsive patients, normal values were found for the following tests: hematocrit, 44%; mean cell volume less than or equal to 100 fL, 36%; white blood cell count, 84%; platelet count, 79%; serum lactic dehydrogenase, 43%; and serum bilirubin, 83%. Peripheral blood smears were nondiagnostic in 6% when reviewed by the investigators, but 33% as reported by routine laboratories. Serum Cbl levels in the 100 to 199 pg/mL range were present in 38%. Neuropsychiatric abnormalities were noted in 28%, often in the absence of anemia, macrocytosis, or both. Serum levels of methylmalonic acid and/or total homocysteine were elevated greater than 3 SDs above the mean for normal subjects in 94% of the Cbl-responsive patients. We conclude that Cbl deficiency should be considered and investigated in patients with unexplained hematologic or neuropsychiatric abnormalities of the kind seen in Cbl deficiency, even if anemia, an elevated mean cell volume, a marked depression of the serum Cbl, or other classic hematologic or biochemical abnormalities are lacking. Levels of serum methylmalonic acid and total homocysteine are useful as ancillary diagnostic tests in the diagnostis of Cbl deficiency.


microRNA-mediated noise processing in cells: A fight or a game?
In the past decades, microRNAs (miRNA) have much attracted the attention of researchers at the interface between life and theoretical sciences for their involvement in post-transcriptional regulation and related diseases. Thanks to the always more sophisticated experimental techniques, the role of miRNAs as "noise processing units" has been further elucidated and two main ways of miRNA noise-control have emerged by combinations of theoretical and experimental studies. While on one side miRNAs were thought to buffer gene expression noise, it has recently been suggested that miRNAs could also increase the cell-to-cell variability of their targets. In this Mini Review, we focus on the role of miRNAs in molecular noise processing and on the advantages as well as current limitations of theoretical modelling.


[Evaluation of the association between the use of oral anti-hyperglycemic agents and hypoglycemia in Japan by data mining of the Japanese Adverse Drug Event Report (JADER) database].
Hypoglycemia due to treatment with oral anti-hyperglycemic agents (OHAs) is a major clinical problem in patients with type 2 diabetes mellitus. The aim of the present study was to evaluate the risk of hypoglycemia due to OHA use by using the Japanese Adverse Drug Event Report (JADER) database. To this end, reports of hypoglycemia events included in the JADER database between 2004 and 2012 were analyzed by calculating the reporting odds ratio (OR). The Medical Dictionary for Regulatory Activities Preferred Terms was used to identify hypoglycemia; 254392 reports were found in the JADER database, of which 13269 were excluded because the age and sex of the patient were not reported. Finally, 241123 reports were analyzed. Among OHAs, sulfonylureas showed the highest adjusted OR (adjusted OR, 10.13; 95% confidence interval, 9.08-11.26). The adjusted ORs for meglitinides, biguanide, thiazolidinedione, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were significantly lower than that of sulfonylureas. The adjusted OR of meglitinides (3.17; 95% confidence interval, 2.23-4.36) was significantly higher than that of alpha-glucosidase inhibitors or thiazolidinedione. We observed no difference between the adjusted ORs for biguanide, thiazolidinedione, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors. Data mining of the JADER database was useful for analyzing OHA-associated hypoglycemia events. The results of our study suggested a low risk of hypoglycemia associated with biguanide, thiazolidinedione, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors in clinical practice.


Considering Age Variation When Coining Drugs as High versus Low Hepatic Extraction Ratio.
The hepatic extraction ratio (EH) is commonly considered an "inherent attribute" of drug. It determines the main physiological and biological elements of the system (patient attributes) that are most significant in interindividual variability of clearance. The EH consists of three age-dependent parameters: fraction of unbound drug in blood (fu.B), hepatic intrinsic clearance of unbound drug (CLu.int,H), and hepatic blood flow (QH). When the age-effects on these elements are not proportional, a given drug may shift from so-called high extraction status to low extraction. To demonstrate the impact of age-related changes on fu.B, CLu int,H, and QH, the EH of midazolam and two hypothetical drugs with 10-fold higher and 10-fold lower CLu.int,H than midazolam were investigated in pediatrics based on known ontogeny functions. The EH was simulated using Simcyp software, version 14. This was then complemented by a comprehensive literature survey to identify the commonly applied covariates in pediatric population pharmacokinetic (PopPK) studies. Midazolam EH decreased from 0.6 in adults to 0.02 at birth, making its clearance much more susceptible to changes in CLu.int,H and fu.B than in adults and reducing the impact of QH on clearance. The drug with 10-fold higher CLu.int,H was categorized as high extraction from 4 days old onward whereas the drug with 10-fold lower CLu.int,H remained low extraction from birth to adulthood. Approximately 50% of collected PopPK studies (n = 120) did not consider interaction between age and other covariates. Interaction between covariates and age should be considered as part of studies involving younger pediatric patients. The EH cannot be considered an inherent drug property without considering the effect of age.


Inventory and evaluation of publicly available sources of information on hazards and risks of industrial chemicals.
Regulatory authorities from developing countries have expressed a need for guidance in locating environmental, health and safety (EHS) information on industrial chemicals. In response, possible sources were identified via a search of the Internet using relevant terms and by soliciting suggestions from more than 200 knowledgeable stakeholders. This initially identified greater than 100 databases, 41 of which were chosen for further profiling and analysis based on their size and comprehensiveness. They were divided for analysis into three distinct groups: (1) data portals that provide information seekers with an efficient simultaneous search of multiple, third-party owned and maintained databases; (2) primary EHS information sources; and (3) databases that provide only EHS-type regulatory decisions but not raw data. Descriptive evaluations of each database were performed, including: (1) scope; (2) ease of access and use; (3) breadth and depth of EHS information available; (4) quality of the underlying information; and (5) procedures to keep the information current. We conclude that, although there exists EHS information to support screening level hazard and risk assessment for the majority of the highest production volume chemicals, information gaps for lower production volume chemicals persist, and Confidential Business Information claims for some chemicals can limit the information available to the general public. A lack of information on uses and exposures to chemicals, particularly in developing countries is especially challenging. Nevertheless, there are reasons (e.g. advances in regulations, marketplace pressures, and computational toxicology science) to be optimistic that going forward information gaps can be closed at an accelerated rate.


Prediction and Early Evaluation of Anticancer Therapy Response: From Imaging of Drug Efflux Pumps to Targeted Therapy Response.
Multidrug resistance (MDR) describes the resistance of tumor cells to chemotherapy and has been ascribed to the overexpression of drug efflux pumps. Molecular imaging of drug efflux pumps is helpful to identify the patients who may be resistant to the chemotherapy and thus will avoid the unnecessary treatment and increase the therapeutic effectiveness. Imaging probes targeting drug efflux pumps can non-invasively evaluate the Pgp function and play an important role in identification of MDR, prediction of response, and monitoring MDR modulation. On the other hand, new anticancer agents based on molecular targets such as epidermal growth factor receptor (EGFR) and angiogenic factor receptor may potentially be combined with chemotherapeutic drugs to overcome the MDR. Imaging of molecular targets visualize treatment response of patients at molecular level vividly and help to select right patients for certain targeted anticancer therapy. Among all the imaging modalities, nuclear imaging including positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging has the greatest promise for rapid translation to the clinic and can realize quantitative visualization of biochemical processes in vivo. In this review, we will summarize the nuclear imaging probes utilized for predicting and evaluating the early anticancer therapy response.99mTc labeled agents and PET based radiopharmaceuticals like 18F-Paclitaxel, 11C-Verapamil for drug efflux pumps imaging will be discussed here. Moreover, molecular imaging probes used for targeted therapy response evaluation like 18F-Tamoxifen,89Zr-Trastuzumab will also be introduced in this review.


Effect of diabetes self-management education on glycaemic control among type 2 diabetic patients at a family medicine clinic in Kenya: A randomised controlled trial.
Diabetes self-management education (DSME) is a key component of diabetes care aimed at delaying complications. Unlike usual care, DSME is a more structured educational approach provided by trained, certified diabetes educators (CDE). In Kenya, many diabetic patients are yet to receive this integral component of care. At the family medicine clinic of the Aga Khan University Hospital (AKUH), Nairobi, the case is no different; most patients lack education by CDE. This study sought to assess effects of DSME in comparison to usual diabetes care by family physicians. Family Medicine Clinic, AKUH, Nairobi. Non-blinded randomised clinical trial among sub-optimally controlled (glycated haemoglobin (HbA1c) ≥ 8%) type 2 diabetes patients. The intervention was DSME by CDE plus usual care versus usual care from family physicians. Primary outcome was mean difference in HbA1c after six months of follow-up. Secondary outcomes included blood pressure and body mass index. A total of 220 diabetes patients were screened out of which 140 met the eligibility criteria and were randomised. Around 96 patients (69%) completed the study; 55 (79%) in the DSME group and 41 (59%) in the usual care group. The baseline mean age and HbA1c of all patients were 48.8 (standard deviation [SD]: 9.8) years and 9.9% (SD: 1.76%), respectively. After a 6-month follow-up, no significant difference was noted in the primary outcome (HbA1c) between the two groups, with a mean difference of 0.37 (95% confidence interval: -0.45 to 1.19; p = 0.37). DSME also made no remarkable change in any of the secondary outcome measures. From this study, short-term biomedical benefits of a structured educational approach seemed to be limited. This suggested that offering a short, intensified education programme might have limited additional benefit above and beyond the family physicians' comprehensive approach in managing chronic conditions like diabetes.


Cerebellar modules operate at different frequencies.
Due to the uniform cyto-architecture of the cerebellar cortex, its overall physiological characteristics have traditionally been considered to be homogeneous. In this study, we show in awake mice at rest that spiking activity of Purkinje cells, the sole output cells of the cerebellar cortex, differs between cerebellar modules and correlates with their expression of the glycolytic enzyme aldolase C or zebrin. Simple spike and complex spike frequencies were significantly higher in Purkinje cells located in zebrin-negative than zebrin-positive modules. The difference in simple spike frequency persisted when the synaptic input to, but not intrinsic activity of, Purkinje cells was manipulated. Blocking TRPC3, the effector channel of a cascade of proteins that have zebrin-like distribution patterns, attenuated the simple spike frequency difference. Our results indicate that zebrin-discriminated cerebellar modules operate at different frequencies, which depend on activation of TRPC3, and that this property is relevant for all cerebellar functions.DOI: http://dx.doi.org/10.7554/eLife.02536.001.


Empirical antimicrobial therapy for probable v. directed therapy for possible ventilator-associated pneumonia in critically injured patients.
Ventilator-associated pneumonia (VAP) has recently been classified as possible or probable. Although direct attributable mortality has been difficult to prove, delay in instituting appropriate therapy has been reported to increase morbidity and mortality. Recent literature suggests that in possible VAP, instituting directed therapy while awaiting microbiological culture does not prejudice outcome compared with best-guess empirical therapy. To ascertain outcomes of directed v. empirical therapy in possible and probable VAP, respectively. Endotracheal aspirates were obtained from patients with suspected VAP. Those considered to have possible VAP were given directed therapy following culture results, whereas patients with more convincing evidence of VAP were classed as having probable VAP and commenced on empirical antimicrobials based on microbiological surveillance. Pneumonia was suspected in 106 (36.8%) of 288 patients admitted during January - December 2014. Of these, 13 did not fulfil the criteria for VAP. Of the remaining 93 (32.2%), 31 (33.3%) were considered to have probable and 62 (66.7%) possible VAP. The former were commenced on empirical antimicrobials, with 28 (90.3%) receiving appropriate therapy. Of those with possible VAP, 34 (54.8%) were given directed therapy and in 28 (45.2%) no antimicrobials were prescribed. Of the latter, 24 recovered without antimicrobials and 4 died, 3 from severe traumatic brain injury and 1 due to overwhelming intra-abdominal sepsis. No death was directly attributable to failure to treat VAP. No significant difference in mortality was found between the 34 patients with possible VAP who were commenced on directed therapy and the 31 with probable VAP who were commenced on empirical antimicrobials (p=0.75). Delaying antimicrobial therapy for VAP where clinical doubt exists does not adversely affect outcome. Furthermore, this policy limits the use of antimicrobials in patients with possible VAP following improvement in their clinical condition despite no therapy.


Microtensile Bond Strength and Failure Modes of Flowable Composites on Primary Dentin with Application of Different Adhesive Strategies.
Resin composite is an option for the restoration of primary teeth, and new materials with simplified procedures are increasingly being suggested. This study aims to evaluate the microtensile bond strengths and fracture modes of flowable composites on primary dentin with application of different adhesive strategies. Sixty extracted noncaries primary molars were abraded from buccal surfaces to expose dentin surface. The teeth were randomly divided into three groups as follows: Group 1, Vertise™ Flow (Kerr) (self-adhering flowable composite); Group 2, G-aenial Universal Flo® (GC Europe) (used with one-step self-etch system); Group 3, Tetric® N-Flow (Ivoclar/Vivadent) (used with two-step total etch system). Then, the flowable composites were applied to buccal dentin surfaces with the help of guide mold. Samples were embedded in acrylic blocks and sectioned to form dentin-composite sticks with a surface area of approximately 1 mm2. Finally, a total of 180 sticks were obtained to give each group of 60 sticks. Microtensile bond strengths were measured using a universal testing machine (1 mm/min). Fracture modes were evaluated with scanning electron microscopy. Microtensile bond strengths data were analyzed by Kruskal-Wallis nonparametric test. The microtensile bond strengths of G-aenial (15.5 megapascals [Mpa]) and Tetric (13.0 MPa) were statistically significant higher than Vertise (2.3 MPa). It was recorded that most of fractures in G-aenial was 40% cohesive, Tetric was 53.3% mixed, and Vertise was 83.3% adhesive. The self-adhering flowable composite Vertise™ Flow had the lowest and G-aenial Universal Flo® had the highest microtensile bond values.


Alfentanil for procedural sedation in the emergency department.
We administer alfentanil sedation for minor procedures in the emergency department (ED), and our primary objective is to assess the incidence of airway and respiratory adverse events leading to an intervention. Our secondary goals are to assess for other adverse events, the depth and duration of sedation, the incidence of subclinical respiratory depression, and patient perceptions of the quality of the sedation. In this observational study of adults receiving alfentanil for ED procedures, we recorded the incidence of airway or respiratory adverse events leading to an intervention (increase/addition of supplemental oxygen, bag-valve-mask ventilation, airway repositioning, or stimulation to induce breathing). Secondary goals were assessed with monitoring (including capnography), the Observer's Assessment of Alertness/Sedation (OAA/S) scale, and postprocedure patient visual analog scale ratings of pain, recall, and satisfaction. Airway or respiratory events leading to intervention were observed in 39% of the 148 subjects (supplemental oxygen 18%, bag-valve mask 3%, airway repositioning 2%, stimulation 18%); none were clinically significant. The median OAA/S nadir was 4 (interquartile range 3 to 5). Median patient ratings were positive (pain 26 mm, recall 98, satisfaction 100 mm). Alfentanil appears effective for ED procedural sedation but displays a rate of airway or respiratory events leading to an intervention similar to that of previous reports of deeper sedation with propofol.


Robotic Lymphadenectomy During Pancreatoduodenectomy with First Superior Mesenteric Artery Dissection.
An expert consensus meeting had defined the standard lymphadenectomy during pancreatoduodenectomy for an adenocarcinoma of the head of the pancreas. There is a controversy regarding the possibility to perform this optimal lymphadenectomy by minimally invasive approach. The patient was a 68-year-old man with the diagnosis of an adenocarcinoma of the head of the pancreas. The 3D reconstructions evidenced the existence of a right hepatic artery. The patient was positioned in the French position with the assistant between the legs and the robot at the head. Five trocars were used; the camera was introduced through the umbilicus trocar. The operation began with a peritoneal and liver exploration, and with an inter-aortico-caval picking. Because lymph nodes were noninvaded, pancreatoduodenectomy was decided with the first dissection of the superior mesenteric artery helped with a hanging maneuver. The right hepatic artery was dissected. Each structure of the hepatic pedicle was skeletonized. The camera was switched to the right side. The first jejunal loop was divided with a stapler. The specimen was totally mobilized en bloc, freed from the portal vascular axis with a dissection of the right border of the coeliac trunk. The pancreas was divided. At the end of the dissection, the different arterial and venous structures were skeletonized with a resection of the lymph node group 5-6-8a-12a,b,c-13a,b-14a,b-17a,b. Pathology confirmed R0 resection for a well-differentiated pancreatic adenocarcinoma graded pT3N1 (5/20). Robotic pancreatoduodenectomy could be performed with an optimal standard lymphadenectomy as recommended by the expert consensus.


Quinol derivatives as potential trypanocidal agents.
Quinols have been developed as a class of potential anti-cancer compounds. They are thought to act as double Michael acceptors, forming two covalent bonds to their target protein(s). Quinols have also been shown to have activity against the parasite Trypanosoma brucei, the causative organism of human African trypanosomiasis, but they demonstrated little selectivity over mammalian MRC5 cells in a counter-screen. In this paper, we report screening of further examples of quinols against T. brucei. We were able to derive an SAR, but the compounds demonstrated little selectivity over MRC5 cells. In an approach to increase selectivity, we attached melamine and benzamidine motifs to the quinols, because these moieties are known to be selectively concentrated in the parasite by transporter proteins. In general these transporter motif-containing analogues showed increased selectivity; however they also showed reduced levels of potency against T. brucei.


Social categorization and individuation in the own-age bias.
Young adults recognize other young adult faces more accurately than older adult faces, an effect termed the own-age bias (OAB). The categorization-individuation model (CIM) proposes that recognition memory biases like the OAB occur as unfamiliar faces are initially quickly categorized. In-group faces are seen as socially relevant which motivates the processing of individuating facial features. Outgroup faces are processed more superficially with attention to category-specific information which hinders subsequent recognition. To examine the roles of categorization and individuation in the context of the OAB, participants completed a face recognition task and a speeded age categorization task including young and older adult faces. In the recognition task, half of the participants were given instructions aimed to encourage individuation of other-age faces. An OAB emerged that was not influenced by individuation instructions, but the magnitude of the OAB was correlated with performance in the categorization task. The larger the categorization advantage for older adult over young adult faces, the larger the OAB. These results support the premise that social categorization processes can affect the subsequent recognition of own- and other-age faces, but do not provide evidence for the effectiveness of individuation instructions in reducing the OAB.


The Drug Data to Knowledge Pipeline: Large-Scale Claims Data Classification for Pharmacologic Insight.
In biomedical informatics, assigning drug codes to categories is a common step in the analysis pipeline. Unfortunately, incomplete mappings are the norm rather than the exception with coverage values less than 85% not uncommon. Here, we perform this linking task on a nationwide insurance claims database with over 13 million members who were dispensed, according to National Drug Codes (NDCs), over 50,000 unique product forms of medication. The chosen approach employs Cerner Multum's VantageRx and the U.S. National Library of Medicine's RxMix. As a result, 94.0% of the NDCs were successfully mapped to categories used by common drug terminologies, e.g., Anatomical Therapeutic Chemical (ATC). Implemented as an SQL database and scripts, the approach is generic and can be setup for a new data set in a few hours. Thus, the method is a viable option for large-scale drug classification.


Opposite Polarity Monospore Genome De Novo Sequencing and Comparative Analysis Reveal the Possible Heterothallic Life Cycle of Morchella importuna.
Morchella is a popular edible fungus worldwide due to its rich nutrition and unique flavor. Many research efforts were made on the domestication and cultivation of Morchella all over the world. In recent years, the cultivation of Morchella was successfully commercialized in China. However, the biology is not well understood, which restricts the further development of the morel fungus cultivation industry. In this paper, we performed de novo sequencing and assembly of the genomes of two monospores with a different mating type (M04M24 and M04M26) isolated from the commercially cultivated strain M04. Gene annotation and comparative genome analysis were performed to study differences in CAZyme (Carbohydrate-active enzyme) enzyme content, transcription factors, duplicated sequences, structure of mating type sites, and differences at the gene and functional levels between the two monospore strains of M. importuna. Results showed that the de novo assembled haploid M04M24 and M04M26 genomes were 48.98 and 51.07 Mb, respectively. A complete fine physical map of M. importuna was obtained from genome coverage and gene completeness evaluation. A total of 10,852 and 10,902 common genes and 667 and 868 endemic genes were identified from the two monospore strains, respectively. The Gene Ontology (GO) and KAAS (KEGG Automatic Annotation Serve) enrichment analyses showed that the endemic genes performed different functions. The two monospore strains had 99.22% collinearity with each other, accompanied with certain position and rearrangement events. Analysis of complete mating-type loci revealed that the two monospore M. importuna strains contained an independent mating-type structure and remained conserved in sequence and location. The phylogenetic and divergence time of M. importuna was analyzed at the whole-genome level for the first time. The bifurcation time of morel and tuber was estimated to be 201.14 million years ago (Mya); the two monospore strains with a different mating type represented the evolution of different nuclei, and the single copy homologous genes between them were also different due to a genetic differentiation distance about 0.65 Mya. Compared with truffles, M. importuna had an extension of 28 clusters of orthologous genes (COGs) and a contraction of two COGs. The two different polar nuclei with different degrees of contraction and expansion suggested that they might have undergone different evolutionary processes. The different mating-type structures, together with the functional clustering and enrichment analysis results of the endemic genes of the two different polar nuclei, imply that M. importuna might be a heterothallic fungus and the interaction between the endemic genes may be necessary for its complete life history. Studies on the genome of M. importuna facilitate a better understanding of morel biology and evolution.


National Survey of Volunteer Pharmacy Preceptors: effects of region, practice setting, and population density on responses.
To survey volunteer pharmacy preceptors regarding experiential education and determine whether differences in responses relate to such factors as geographic region, practice setting, and population density. An online survey was sent to 4396 volunteer experiential preceptors. The survey consisted of 41 questions asking the preceptor to comment on the experiential education environment. Experiential education administrators from 9 schools of pharmacy administered the survey to their volunteer preceptors in all regions (Northeast, Midwest, South, and West) of the United States, in various pharmacy practice settings, and areas of differing population densities. A total of 1163 (26.5%) preceptors responded. Regionally, preceptors in the West disagreed more than those in the Midwest and the South that they had enough time to spend with students to provide a quality experience and also required compensation less often than their counterparts in the Northeast and South. Concerning practice settings, hospital preceptors accepted students from more schools, had greater increases in requests, turned away more students, and spent less time with the students compared to preceptors in other settings. Population density differences reflected that preceptors at urban sites took and turned away more students than those at rural sites. Preceptors from rural areas spent more time with students and felt they were spending enough time with their students to provide quality experiences when compared to other preceptors. The results of this national volunteer preceptor survey may assist pharmacy school leaders in understanding how location, practice type, and population density affect experiential education, preceptor time-quality issues, and site compensation so they can take necessary actions to improve quality of student practice experiences.


Irradiated NC adenocarcinoma cells transduced with both B7.1 and interleukin-2 induce CD4+-mediated rejection of established tumors.
Previous studies have shown that expression of the immune co-stimulator B7.1 reduces the tumorigenicity of some, but not all, malignant cell lines. However, B7.1-expressing tumor cells are not very effective in inducing the rejection of established tumors. This may in part be due to induction of anergy in the potentially reactive T cells. Previous studies have shown that IL-2 can reverse the anergic state both in vitro and in vivo. Therefore, we have examined the effect of retrovirus-mediated delivery and expression of murine B7.1 and interleukin-2 on tumor formation and rejection of established MHC class I+/II- NC adenocarcinomas. Neither the expression of B7.1 nor IL-2 alone had a significant effect on NC tumorigenicity. In contrast, combined expression of B7.1 and IL-2 substantially decreased the tumorigenicity of these cells in the immunecompetent syngeneic hosts. T-cell depletion studies show this to be dependent primarily on the activation of CD4+ cells. Furthermore, distant subcutaneous injection of irradiated NC/IL-2/B7.1 can induce, much more effectively than NC/B7.1 or NC/IL-2, the rejection of small NC tumors, and prevent the recurrence of large surgically resected tumors. Together, these results suggest that tumor cells genetically modified to express B7.1 and IL-2 can induce the immune-mediated rejection of established class II- tumors by a mechanism involving CD4+ cells.


Considerations in Human Papillomavirus-Associated Oropharyngeal Cancer Screening: A Review.
The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is anticipated to rise over the next few decades until the effects of prophylactic vaccination are realized, which highlights the potential importance of secondary prevention. The objective of this review is to evaluate the evidence associated with screening for HPV-positive OPC. Evaluation of a potential clinical preventive screening service requires characterization of the disease burden, the at-risk target screening population, screening tests, treatment, and screening benefits and harms. The lifetime risk of OPC is 0.7% for men and 0.2% for women and is expected to increase. The disease burden of HPV-positive OPC is substantial; most patients undergo morbid multimodality treatment and incur high costs in the process. Middle-aged and older adult men with elevated number of lifetime vaginal or oral sex partners are at highest risk. Patients may benefit from early detection of the disease-the 4-year overall survival of patients with stage I HPV-positive OPC is 87%, a considerable portion of whom are eligible for less morbid single-modality therapy. However, available screening tests are insufficiently sensitive and specific considering the current HPV-positive OPC incidence rates in the most at-risk patients. Further, the benefits and harms of screening for HPV-positive OPC are unknown. The current and projected future population-level burden of HPV-positive OPC supports further exploration of secondary preventive interventions. However, screening for HPV-positive OPC is not currently justified. Advances in biomarker discovery and improved characterization of (1) a highly at-risk, target screening population and (2) the benefits and harms of screening will be necessary. Large-scale clinical trials and rigorous evaluation of how to best implement this service into clinical practice will also be needed.


Indium doped ZnO films prepared by RF magnetron sputtering: effect of substrate temperature on the strain-induced band gap.
Indium doped zinc oxide (InZnO) thin films were deposited onto corning glass substrates by RF magnetron sputtering. The dependence of crystal structure, surface morphology, optical properties and electrical conductivity on substrate temperature was investigated using XRD, AFM, UV-vis Spectrophotometer, Fluorescence Spectrophotometer and four-point probe. The films were prepared at different substrate temperatures viz, room temperature (RT), 473 K and 673 K at RF power 200 W. All the films showed preferred orientation along (002) direction. Crystallite size increased from 14 to 19 nm as the substrate temperature was increased to 473 K. With increase in substrate temperature the crystallites did not show any further growth. AFM analysis showed that the rms roughness value decreased from 60 nm to 23 nm when the substrate temperature was increased to 673 K. Optical measurements revealed maximum band gap and minimum refractive index for the film prepared at 473 K. A strong correlation between the band gap variation and the strain developed at different substrate temperatures is established.


Leishmania major pteridine reductase 1 belongs to the short chain dehydrogenase family: stereochemical and kinetic evidence.
Pteridine reductase 1 (PTR1) is a novel broad spectrum enzyme of pterin and folate metabolism in the protozoan parasite Leishmania. Overexpression of PTR1 confers methotrexate resistance to these protozoa, arising from the enzyme's ability to reduce dihydrofolate and its relative insensitivity to methotrexate. The kinetic mechanism and stereochemical course for the catalyzed reaction confirm PTR1's membership within the short chain dehydrogenase/reductase (SDR) family. With folate as a substrate, PTR1 catalyzes two rounds of reduction, yielding 5,6,7, 8-tetrahydrofolate and oxidizing 2 equiv of NADPH. Dihydrofolate accumulates transiently during folate reduction and is both a substrate and an inhibitor of PTR1. PTR1 transfers the pro-S hydride of NADPH to carbon 6 on the si face of dihydrofolate, producing the same stereoisomer of THF as does dihydrofolate reductase. Product inhibition and isotope partitioning studies support an ordered ternary complex mechanism, with NADPH binding first and NADP+ dissociating after the reduced pteridine. Identical kinetic mechanisms and NAD(P)H hydride chirality preferences are seen with other SDRs. An observed tritium effect upon V/K for reduction of dihydrofolate arising from isotopic substitution of the transferred hydride was suppressed at a high concentration of dihydrofolate, consistent with a steady-state ordered kinetic mechanism. Interestingly, half of the binary enzyme-NADPH complex appears to be incapable of rapid turnover. Fluorescence quenching results also indicate the existence of a nonproductive binary enzyme-dihydrofolate complex. The nonproductive complexes observed between PTR1 and its substrates are unique among members of the SDR family and may provide leads for developing antileishmanial therapeutics.


Aging induced decline in T-lymphopoiesis is primarily dependent on status of progenitor niches in the bone marrow and thymus.
Age-related decline in the generation of T cells is associated with two primary lymphoid organs, the bone marrow (BM) and thymus. Both organs contain lympho-hematopoietic progenitor/stem cells (LPCs) and non-hematopoietic stromal/niche cells. Murine model showed this decline is not due to reduced quantities of LPCs, nor autonomous defects in LPCs, but rather defects in their niche cells. However, this viewpoint is challenged by the fact that aged BM progenitors have a myeloid skew. By grafting young wild-type (WT) BM progenitors into aged IL-7R-/- hosts, which possess WT-equivalent niches although LPCs are defect, we demonstrated that these young BM progenitors also exhibited a myeloid skew. We, further, demonstrated that aged BM progenitors, recruited by a grafted fetal thymus in the in vivo microenvironment, were able to compete with their young counterparts, although the in vitro manipulated old BM cells were not able to do so in conventional BM transplantation. Both LPCs and their niche cells inevitably get old with increasing organismal age, but aging in niche cells occurred much earlier than in LPCs by an observation in thymic T-lymphopoiesis. Therefore, the aging induced decline in competence to generate T cells is primarily dependent on status of the progenitor niche cells in the BM and thymus.


How important are conidial appendages?
The genus The genus Dinemasporium is used as a case study to evaluate the importance of conidial appendages for generic level classification of coelomycetous fungi. Based on morphology and sequence data of the large subunit nuclear ribosomal RNA gene (LSU, 28S) and the internal transcribed spacers and 5.8S rRNA gene of the nrDNA operon, the genus Dinemasporium is circumscribed, and an epitype designated for D. strigosum, the type of the genus. A further five species are introduced in Dinemasporium, namely D. pseudostrigosum (isolated from Triticum aestivum, Germany and Stigmaphyllon sagraeanum, Cuba), D. americana (soil, USA), D. polygonum (Polygonum sachalinense, Netherlands), D. pseudoindicum (soil, USA), and D. morbidum (human sputum, Netherlands and hare dung, New Zealand). Brunneodinemasporium, based on B. brasiliense, is introduced to accommodate Dinemasporium-like species with tightly aggregated brown conidiogenous cells, and pale brown conidia. Dendrophoma (= Amphitiarospora) is reinstated as distinct from Dinemasporium, and an epitype designated for D. cytisporoides, characterised by its superficial, stipitate to cupulate conidiomata, and small conidia with two polar, tubular, exogenous appendages. The genus Stauronema is reduced to synonymy under Dinemasporium. Pseudolachnea (1-septate conidia) is supported as distinct from Dinemasporium (aseptate conidia), and P. fraxini introduced as a novel species. Taxa in this generic complex differ by combination of morphological characters of conidiomata, setae, conidia and appendages. Appendage morphology alone is rejected as informative at the generic level.


Mindfulness-based cognitive therapy to prevent relapse in recurrent depression.
For people at risk of depressive relapse, mindfulness-based cognitive therapy (MBCT) has an additive benefit to usual care (H. F. Coelho, P. H. Canter, & E. Ernst, 2007). This study asked if, among patients with recurrent depression who are treated with antidepressant medication (ADM), MBCT is comparable to treatment with maintenance ADM (m-ADM) in (a) depressive relapse prevention, (b) key secondary outcomes, and (c) cost effectiveness. The study design was a parallel 2-group randomized controlled trial comparing those on m-ADM (N = 62) with those receiving MBCT plus support to taper/discontinue antidepressants (N = 61). Relapse/recurrence rates over 15-month follow-ups in MBCT were 47%, compared with 60% in the m-ADM group (hazard ratio = 0.63; 95% confidence interval: 0.39 to 1.04). MBCT was more effective than m-ADM in reducing residual depressive symptoms and psychiatric comorbidity and in improving quality of life in the physical and psychological domains. There was no difference in average annual cost between the 2 groups. Rates of ADM usage in the MBCT group was significantly reduced, and 46 patients (75%) completely discontinued their ADM. For patients treated with ADM, MBCT may provide an alternative approach for relapse prevention.


Three frameworks to predict physical activity behavior in middle school inclusive physical education: a multilevel analysis.
The purpose of this study was to examine three frameworks, (a) process-product, (b) student mediation, and (c) classroom ecology, to understand physical activity (PA) behavior of adolescents with and without disabilities in middle school inclusive physical education (PE). A total of 13 physical educators teaching inclusive PE and their 503 students, including 22 students with different disabilities, participated in this study. A series of multilevel regression analyses indicated that physical educators' teaching behavior and students' implementation intentions play important roles in promoting the students' PA in middle school inclusive PE settings when gender, disability, lesson content, instructional model, and class location are considered simultaneously. The findings suggest that the ecological framework should be considered to effectively promote PA of adolescents with and without disabilities in middle school PE classes.


Crucial Role for Basophils in Acquired Protective Immunity to Tick Infestation.
Ticks are blood-sucking arthropods that can transmit various pathogenic organisms to host animals and humans, causing serious infectious diseases including Lyme disease. Tick feeding induces innate and acquired immune responses in host animals, depending on the combination of different species of animals and ticks. Acquired tick resistance (ATR) can diminish the chance of pathogen transmission from infected ticks to the host. Hence, the elucidation of cellular and molecular mechanism underlying ATR is important for the development of efficient anti-tick vaccines. In this review article, we briefly overview the history of studies on ATR and summarize recent findings, particularly focusing on the role for basophils in the manifestation of ATR. In several animal species, including cattle, guinea pigs, rabbits and mice, basophil accumulation is observed at the tick re-infestation site, even though the frequency of basophils among cellular infiltrates varies in different animal species, ranging from approximately 3% in mice to 70% in guinea pigs. Skin-resident, memory CD4+ T cells contribute to the recruitment of basophils to the tick re-infestation site through production of IL-3 in mice. Depletion of basophils before the tick re-infestation abolishes ATR in guinea pigs infested with Amblyomma americanum and mice infested with Haemaphysalis longicornis, demonstrating the crucial role of basophils in the manifestation of ATR. The activation of basophils via IgE and its receptor FcεRI is essential for ATR in mice. Histamine released from activated basophils functions as an important effector molecule in murine ATR, probably through promotion of epidermal hyperplasia which interferes with tick attachment or blood feeding in the skin. Accumulating evidence suggests the following scenario. The 1st tick infestation triggers the production of IgE against tick saliva antigens in the host, and blood-circulating basophils bind such IgE on the cell surface via FcεRI. In the 2nd infestation, IgE-armed basophils are recruited to tick-feeding sites and stimulated by tick saliva antigens to release histamine that promotes epidermal hyperplasia, contributing to ATR. Further studies are needed to clarify whether this scenario in mice can be applied to ATR in other animal species and humans.


Primary biliary cholangitis.
Primary biliary cholangitis is an autoimmune liver disease that predominantly affects women. It is characterised by a chronic and destructive, small bile duct, granulomatous lymphocytic cholangitis, with typical seroreactivity for antimitochondrial antibodies. Patients have variable risks of progressive ductopenia, cholestasis, and biliary fibrosis. Considerations for the cause of this disease emphasise an interaction of chronic immune damage with biliary epithelial cell responses and encompass complex, poorly understood genetic risks and environmental triggers. Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid. For patients who do not respond sufficiently, or patients with ursodeoxycholic acid intolerance, conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid. Off-label therapy is recognised as an alternative, notably with the pan-PPAR agonist bezafibrate; clinical trial agents are also under development. Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.


Racial disparities in emergency general surgery: Do differences in outcomes persist among universally insured military patients?
Racial disparities in surgical care are well described. As many minority patients are also uninsured, increasing access to care is thought to be a viable solution to mitigate inequities. The objectives of this study were to determine whether racial disparities in 30-/90-/180- day outcomes exist within a universally insured population of military-/civilian-dependent emergency general surgery (EGS) patients and ascertain whether differences in outcomes differentially persist in care received at military versus civilian hospitals and among sponsors who are enlisted service members versus officers. It also considered longer-term outcomes of EGS care. Five years (2006-2010) of TRICARE data, which provides insurance to active/reserve/retired members of the US Armed Services and dependents, were queried for adults (≥18 years) with primary EGS conditions, defined by the AAST. Risk-adjusted survival analyses assessed race-associated differences in mortality, major acute care surgery-related morbidity, and readmission at 30/90/180 days. Models accounted for clustering within hospitals and possible biases associated with missing race using reweighted estimating equations. Subanalyses considered restricted effects among operative interventions, EGS diagnostic categories, and effect modification related to rank and military- versus civilian-hospital care. A total of 101,011 patients were included: 73.5% white, 14.5% black, 4.4% Asian, and 7.7% other. Risk-adjusted survival analyses reported a lack of worse mortality and readmission outcomes among minority patients at 30, 90, and 180 days. Major morbidity was higher among black versus white patients (hazard ratio [95% confidence interval): 30 days, 1.23 [1.13-1.35]; 90 days, 1.18 [1.09-1.28]; and 180 days, 1.15 [1.07-1.24], a finding seemingly driven by appendiceal disorders (hazard ratio, 1.69-1.70). No other diagnostic categories were significant. Variations in military- versus civilian-managed care and in outcomes for families of enlisted service members versus officers altered associations, to some extent, between outcomes and race. While an imperfect proxy of interventions is directly applicable to the broader United States, the contrast between military observations and reported racial disparities among civilian EGS patients merits consideration. Apparent mitigation of disparities among military-/civilian-dependent patients provides an example for which we as a nation and collective of providers all need to strive. The data will help to inform policy within the Department of Defense and development of disparities interventions nationwide, attesting to important differences potentially related to insurance, access to care, and military culture and values. Prognostic and epidemiologic study, level III.


Diffraction of femtosecond pulses; nonparaxial regime.
We present a systematic study of linear propagation of ultrashort laser pulses in media with dispersion, dispersionless media, and vacuum. The applied method of amplitude envelopes makes it possible to estimate the limits of the slowly varying amplitude approximation and to describe an amplitude integrodifferential equation governing propagation of optical pulses in the single-cycle regime in solids. The well-known slowly varying amplitude equation and the amplitude equation for the vacuum case are written in dimensionless form. Three parameters are obtained defining different linear regimes of optical pulse evolution. In contrast to previous studies we demonstrate that in the femtosecond region the nonparaxial terms are not small and can dominate over the transverse Laplacian. The normalized amplitude nonparaxial equations are solved using the method of Fourier transforms. Fundamental solutions with spectral kernels different from those according to Fresnel are found. Exact unidirectional analytical solution of the nonparaxial amplitude equations and the 3D wave equations with initial conditions compatible with Gaussian light bullets are obtained also. One unexpected new result is the relative stability of light bullets (pulses with spherical and spheroidal spatial form) when we compare their transverse enlargement with paraxial diffraction of light beams in air. It is important to emphasize here the case of light disks, i.e., pulses whose longitudinal size is small with respect to the transverse one, which in some partial cases are practically diffractionless over distances of a thousand kilometers. A new formula that calculates the diffraction length of optical pulses is suggested. Finally, propagation of single-cycle pulses in air and vacuum was investigated, and a coronal (semispherical) form of diffraction at short distances was observed.


Successful pregnancy in a patient with polycystic kidney disease and advanced renal failure without prophylactic dialysis.
Pregnancies in women suffering from advanced chronic renal failure are frequently associated with deterioration of maternal renal function, premature births and low birth weights. Prophylactic dialysis is sometimes instituted since this intervention ameliorates the uremic milieu and improves maternal status and fetal uterine environment. This report describes a successful pregnancy and delivery in a hypertensive woman with advanced chronic renal failure due to polycystic kidney disease without accelerating the natural deterioration of renal function and without instituting prophylactic dialysis. The infant was delivered at full term with a normal birth weight. Thirty months after delivery, growth and development of the child were normal and the rate of deterioration of maternal renal function, assessed by 1/creatinine, was unaffected by pregnancy. Conservative management and effective control of blood pressure may be sufficient to achieve successful pregnancy outcome when women with advanced chronic renal failure become pregnant.


Exploring the Multi-Layered Affordances of Composing and Performing Interactive Music with Responsive Technologies.
The question motivating the work presented here, starting from a view of music as embodied and situated activity, is how can we account for the complexity of interactive music performance situations. These are situations in which human performers interact with responsive technologies, such as sensor-driven technology or sound synthesis affected by analysis of the performed sound signal. This requires investigating in detail the underlying mechanisms, but also providing a more holistic approach that does not lose track of the complex whole constituted by the interactions and relationships of composers, performers, audience, technologies, etc. The concept of affordances has frequently been invoked in musical research, which has seen a "bodily turn" in recent years, similar to the development of the embodied cognition approach in the cognitive sciences. We therefore begin by broadly delineating its usage in the cognitive sciences in general, and in music research in particular. We argue that what is still missing in the discourse on musical affordances is an encompassing theoretical framework incorporating the sociocultural dimensions that are fundamental to the situatedness and embodiment of interactive music performance and composition. We further argue that the cultural affordances framework, proposed by Rietveld and Kiverstein (2014) and recently articulated further by Ramstead et al. (2016) in this journal, although not previously applied to music, constitutes a promising starting point. It captures and elucidates this complex web of relationships in terms of shared landscapes and individual fields of affordances. We illustrate this with examples foremost from the first author's artistic work as composer and performer of interactive music. This sheds new light on musical composition as a process of construction-and embodied mental simulation-of situations, guiding the performers' and audience's attention in shifting fields of affordances. More generally, we believe that the theoretical perspectives and concrete examples discussed in this paper help to elucidate how situations-and with them affordances-are dynamically constructed through the interactions of various mechanisms as people engage in embodied and situated activity.


Physical map and gene survey of the Ochrobactrum anthropi genome using bacterial artificial chromosome contigs.
Bacterial artificial chromosome (BAC) clones are effective mapping and sequencing reagents for use with a wide variety of small and large genomes. This report describes research aimed at determining the genome structure of Ochrobactrum anthropi, an opportunistic human pathogen that has potential applications in biodegradation of hazardous organic compounds. A BAC library for O. anthropi was constructed that provides a 70-fold genome coverage based on an estimated genome size of 4.8 Mb. The library contains 3072 clones with an average insert size of 112 kb. High-density colony filters of the library were made, and a physical map of the genome was constructed using a hybridization without replacement strategy. In addition, 1536 BAC clones were fingerprinted with HindIII and analyzed using IMAGE and Fingerprint Contig software (FPC, Sanger Centre, U.K.). The FPC results supported the hybridization data, resulting in the formation of two major contigs representing the two major replicons of the O. anthropi genome. After determining a reduced tiling path, 138 BAC ends from the reduced tile were sequenced for a preliminary gene survey. A search of the public databases with the BLASTX algorithm resulted in 77 strong hits (E-value < 0.001), of which 89% showed similarity to a wide variety of prokaryotic genes. These results provide a contig-based physical map to assist the cloning of important genomic regions and the potential sequencing of the O. anthropi genome.


Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response.
The mechanism by which trauma initiates healing remains unclear. Precise understanding of these events may define interventions for accelerating healing that could be translated to the clinical arena. We previously reported that addition of low-dose recombinant human TNF (rhTNF) at the fracture site augmented fracture repair in a murine tibial fracture model. Here, we show that local rhTNF treatment is only effective when administered within 24 h of injury, when neutrophils are the major inflammatory cell infiltrate. Systemic administration of anti-TNF impaired fracture healing. Addition of rhTNF enhanced neutrophil recruitment and promoted recruitment of monocytes through CCL2 production. Conversely, depletion of neutrophils or inhibition of the chemokine receptor CCR2 resulted in significantly impaired fracture healing. Fragility, or osteoporotic, fractures represent a major medical problem as they are associated with permanent disability and premature death. Using a murine model of fragility fractures, we found that local rhTNF treatment improved fracture healing during the early phase of repair. If translated clinically, this promotion of fracture healing would reduce the morbidity and mortality associated with delayed patient mobilization.


Semisynthetic neoboutomellerone derivatives as ubiquitin-proteasome pathway inhibitors.
The interesting pharmacological properties of neoboutomellerones 1 and 2 were the basis for the assembly of a small library of analogues consisting of natural products isolated from the plant Neoboutonia melleri and of semisynthetic derivatives. As the two enone systems (C23-C24a and C1-C3) and the two hydroxyls groups (C22 and C26) of neoboutomellerones are required for activity, modifications were focused on these functional groups. Biological evaluation by using a cellular assay for proteasome activity provided clues regarding the mechanism of action of these natural products and synthetic derivatives. Certain neoboutomellerone derivatives inhibited the proliferation of human WM-266-4 melanoma tumor cells at submicromolar concentration and warrant evaluation as anticancer agents.


Immune Checkpoint Inhibitors for the Treatment of Unresectable Stage III Non-Small Cell Lung Cancer: Emerging Mechanisms and Perspectives.
There has been no improvement in outcome for patients with unresectable locally advanced (stage III) non-small cell lung cancer (NSCLC) for more than 10 years. The standard treatment for these patients is definitive concurrent chemotherapy and radiation (CCRT). Although the goal of treatment in this setting is to achieve a cure, most patients progress and their prognosis is poor, with a 5-year survival rate of 15-30%. There is thus an urgent need for the development of novel anticancer treatments in this patient population. Recent advances in cancer immunotherapy have led to a marked improvement in clinical outcome for advanced NSCLC. Such immunotherapy mainly consists of the administration of immune checkpoint inhibitors (ICIs) such as antibodies to cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or to either programmed cell death-1 (PD-1) or its ligand PD-L1. Durvalumab (MEDI4736) is a high-affinity human immunoglobulin G1 monoclonal antibody that blocks the binding of PD-L1 on tumor cells or antigen-presenting cells to PD-1 on T cells. The PACIFIC study recently evaluated consolidation immunotherapy with durvalumab versus placebo administered after concurrent chemoradiotherapy (CCRT) in patients with unresectable stage III NSCLC. It revealed a significant improvement in both progression-free and overall survival with durvalumab, and this improvement was associated with a favorable safety profile. This achievement has made durvalumab a standard of care for consolidation after CCRT in patients with unresectable stage III NSCLC, and it has now been approved in this setting by regulatory agencies in the United States, Canada, Japan, Australia, Switzerland, Malaysia, Singapore, India, and the United Arab Emirates. In this review, we briefly summarize the results of the PACIFIC trial, including those of post hoc analysis, and we address possible molecular mechanisms, perspectives, and remaining questions related to combined treatment with CCRT and ICIs in this patient population.


Tumour necrosis is an indicator of aggressive biology in patients with urothelial carcinoma of the upper urinary tract.
Prognostic factors after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) are inconclusive, because most data in the literature have been obtained from small series. To assess the association of tumour necrosis with cancer recurrence and survival in a large international series of patients treated with RNU. Data were collected from 1425 patients treated with RNU at 13 centres and combined into a relational database. Pathologic slides were re-reviewed by genitourinary pathologists according to strict criteria. Extensive tumour necrosis was scored as >10% of the tumour area. Patients underwent either open or laparoscopic RNU. Lymph node dissection was performed in the presence of enlarged nodes. Recurrence was defined as tumour relapse in the operative field, lymph node (LN) metastasis, and/or distant metastases. Bladder recurrences were not considered. Associations of extensive tumour necrosis with recurrence-free survival and cancer-specific survival were evaluated by univariate and multivariate analyses. Extensive tumour necrosis was observed in 364 patients (25.5%) and was associated with advanced tumour stage, high tumour grade, sessile architecture, lymphovascular invasion (LVI), concomitant carcinoma in situ, and LN metastasis (p<0.0001 each). Extensive tumour necrosis was independently associated with disease recurrence and survival (p=0.037 and p=0.046, respectively) after adjusting for the effects of pathologic stage, grade, LVI, and LN status. The addition of extensive tumour necrosis to a base model comprising standard pathologic predictors marginally improved its predictive accuracy for both cancer-specific recurrence (1.5%) and survival (1.4%). Extensive tumour necrosis is an independent predictor of clinical outcomes in patients who undergo RNU for UTUC. Assessment of tumour necrosis may help to identify patients who could benefit from multimodal therapy after RNU in the future. Evaluation of extensive tumour necrosis should be part of standard pathologic reporting.


227 Views of RNA: Is RNA Unique in Its Chemical Isomer Space?
Ribonucleic acid (RNA) is one of the two nucleic acids used by extant biochemistry and plays a central role as the intermediary carrier of genetic information in transcription and translation. If RNA was involved in the origin of life, it should have a facile prebiotic synthesis. A wide variety of such syntheses have been explored. However, to date no one-pot reaction has been shown capable of yielding RNA monomers from likely prebiotically abundant starting materials, though this does not rule out the possibility that simpler, more easily prebiotically accessible nucleic acids may have preceded RNA. Given structural constraints, such as the ability to form complementary base pairs and a linear covalent polymer, a variety of structural isomers of RNA could potentially function as genetic platforms. By using structure-generation software, all the potential structural isomers of the ribosides (BC5H9O4, where B is nucleobase), as well as a set of simpler minimal analogues derived from them, that can potentially serve as monomeric building blocks of nucleic acid-like molecules are enumerated. Molecules are selected based on their likely stability under biochemically relevant conditions (e.g., moderate pH and temperature) and the presence of at least two functional groups allowing the monomers to be incorporated into linear polymers. The resulting structures are then evaluated by using molecular descriptors typically applied in quantitative structure-property relationship (QSPR) studies and predicted physicochemical properties. Several databases have been queried to determine whether any of the computed isomers had been synthesized previously. Very few of the molecules that emerge from this structure set have been previously described. We conclude that ribonucleosides may have competed with a multitude of alternative structures whose potential proto-biochemical roles and abiotic syntheses remain to be explored.


The effect of intercostal artery reimplantation on spinal cord injury in thoracoabdominal aortic aneurysm surgery.
Intercostal artery (ICA) reimplantation (ICAR) is thought to decrease spinal cord injury (SCI) in thoracic aortic aneurysm and thoracoabdominal aortic aneurysm (TAAA) surgery. Patients treated from 1989 to 2005 without ICAR were compared with those treated from 2005 to 2013 with ICAR to determine whether ICAR reduced SCI. We hypothesized that ICAR would reduce SCI, especially in the highest-risk patients. This was a retrospective analysis using a prospectively maintained Investigational Review Board-approved database from a university tertiary referral center. The analysis included all patients (n = 805) undergoing thoracic aortic aneurysm and TAAA surgery from 1989 to 2013. The main outcome measure was any transient or permanent paraplegia or paraparesis (SCI). From 1989 to 2004, ICAR was not performed in patients, and open ICAs were ligated; from 2005 to 2013, open ICAs at T7 to L2 were reimplanted in patients with Crawford type I, II, and III TAAAs. Surgical technique was cross clamp without assisted circulation. Anesthetic management was the same from 1989 to 2013. Demographic, intraoperative, and outcome variables were assessed by univariate and multivariate analysis. Observed/expected ratios for paralysis were calculated. A total of 540 patients had surgery before 2005, and 265 had surgery after 2005, when ICAR was begun. There were 275 type I, II, and III TAAAs before 2005 and 164 after 2005. Aneurysm extent, acuity, SCI, mortality, renal failure, and pulmonary failure were the same in patients treated before and after 2005. Multivariate modeling of all patients showed type II TAAA (P = .0001), dissection (P = .00015), and age as a continuous variable (P = .0085) were significant for SCI. Comparing only type I, II, and III TAAAs, there was no difference in SCI between those with ICAR after 2005 and those without ICAR before 2005 (5.1% vs 8.8%; P = .152). In a subanalysis of the highest-risk patients (type II, dissection, acute), ICAR was not significant (P = .27). Observed/expected ratios ratios were 0.23 before 2005 and 0.16 after 2005 (χ2 = .796; P = .37). Although there was a small decrease in SCI with ICAR, reattaching ICAs did not produce a statistically significant reduction in SCI, even in the highest-risk patients.


Anxiety and Depression among Hypertensive Outpatients in Afghanistan: A Cross-Sectional Study in Andkhoy City.
There is a relationship between mental and physical health. Depression and anxiety are linked with the development of several chronic diseases. The purpose of the present study was to determine the prevalence and factors associated with anxiety and depression among adult hypertensive outpatients in Afghanistan. Methods. Two hundred thirty-four consecutive hypertensive patients from December 2015 to August 2016 were recruited to complete the Hospital Anxiety and Depression Scale (HADS) questionnaire, which has scores for classifying the participants having anxiety and depression symptoms. Results. Of the total 234 patients, 81 (34.6%) were males and 153 (65.4%) were females. The mean age was 54.6 ± 12.7 for the hypertensive patients with anxiety and 63.8 ± 15.0 for the hypertensive patients with depression while this figure was 49.5 ± 10.2 for the adult participants in general population in Kabul city (Saeed, 2013). The prevalence of anxiety and depression (42.3% vs. 58.1%) among hypertensive persons is compared with the same mental disorders among Afghan refugees (39.3% vs. 22.1%) in Dalakee Refugee Camp (in Iran) (Hosseini Divkolaye and Burkle, 2017). Of the total participants, 99 had anxiety (42.3%), 136 had depression (58.1%), and 66 had (28.2%) comorbid anxiety-depression. Multivariate analysis was used. For anxiety age, female gender, smoking, diabetes mellitus, and 2 or more chronic diseases had a significant association. For depression, age and diabetes mellitus had a significant association, and for comorbid anxiety, depression, age, diabetes mellitus, and 2 or more chronic diseases had a significant association. Conclusion. This study shows that anxiety and depression are highly prevalent among hypertensive patients in an outpatient clinic in Afghanistan. There was an association between some sociodemographic and clinical characteristics and anxiety and depression. More studies are needed on a national level to inform the development of strategies for the prevention and control of psychological distress among patients with chronic diseases in Afghanistan.


Changing nucleosome positions in vivo through modification of the DNA rotational information.
The effects of the rotational information of DNA in determining the in vivo localization of nucleosomal core particles (ncps) have been studied in the Saccharomyces cerevisiae 5 S rRNA repeat gene. The distribution of the phased series of flexibility signals present in this DNA has been altered by inserting in its centre a 25 bp tract. The effects of such alteration on the in vivo distribution of the helically phased, alternatively located ncps have been determined relative to a reference 21 bp insertion mutant. The results show that the answers provided in vitro and in vivo by the yeast 5 S rRNA gene sequence to specific modifications of the DNA rotational frame are similar, thus pointing to the relevance of DNA rotational information in vivo.


Functional interplay between p53 and E2F through co-activator p300.
Both E2F and p53 are sequence specific transcription factors that regulate early cell cycle progression. The pathway of control mediated through E2F governs the transition from G1 into S phase whereas p53 in response to genotoxic stress can facilitate cell cycle arrest or apoptosis. The mechanisms which influence the outcome of p53 induction are not clear, although transcription of the p53 target gene, encoding the cdk-inhibitor p21(Waf1/Cip1), correlates with p53-mediated cell cycle arrest. Here using a combination of biochemical and functional assays we identify p300 as a co-activator required for p53-dependent transcriptional activation of Waf1/Cip1. Furthermore, we show that the cdk-inhibitor p21(Waf1/Cip1) autoregulates in a positive fashion transcription through modulating the activity of the p53/p300 complex, whilst negatively regulating the activity of E2F by preventing cdk-dependent phosphorylation of pRb. Consistent with a role for p21(Waf1/Cip1) in the autoregulation of p53-dependent transcription, p300 augments the ability of p53 to cause G1 arrest and, conversely, cells undergoing p53-dependent apoptosis are rescued by p300. Thus, our data suggest that the ability of p300 to interact with p53 influences the physiological consequence of p53 activation. From previous studies it is known that cells expressing aberrant levels of E2F-1 can undergo p53-dependent apoptosis. In addition, we find that E2F-1 can cause apoptosis in p53-/- tumour cells and further p300, which also functions as a co-activator for the E2F/DP heterodimer, enhances the apoptotic activity of E2F-1. In conditions where E2F-1 and p53 co-operate in apoptosis E2F-1 can effectively compete for p300, causing a reduction in p53-dependent transcription. Thus, a functional interaction between p300 and either p53 or E2F-1 has a profound impact on early cell cycle progression, specifically in regulating the contrasting outcomes of cell cycle arrest and apoptosis. These results suggest a critical role for p300 in integrating and co-ordinating the functional interplay between the pathways of growth control mediated by E2F and p53.


Infant interest in their mother's face is associated with maternal psychological health.
Early experience can alter infants' interest in faces in their environment. This study investigated the relationship between maternal psychological health, mother-infant bonding, and infant face interest in a community sample. A visual habituation paradigm was used to independently assess 3.5-month old infants' attention to a photograph of their mother's face and a stranger's face. In this sample of 54 healthy mother-infant pairs, 57% of mothers (N = 31) reported symptoms of at least one of stress response to trauma, anxiety, or depression. Interest in the mother-face, but not stranger-face, was positively associated with the mother's psychological health. In regression analyses, anxiety and depression predicted 9% of the variance in looking to the mother-face. Anxiety was the only significant predictor within the model. No direct associations were found between mother-infant bonding and infants' face interest. Taken together, these findings indicate that infant's visual engagement with their mother's face varies with maternal symptoms of emotional distress, even within a community sample.


Spin-stripe phase in a frustrated zigzag spin-1/2 chain.
Motifs of periodic modulations are encountered in a variety of natural systems, where at least two rival states are present. In strongly correlated electron systems, such behaviour has typically been associated with competition between short- and long-range interactions, for example, between exchange and dipole-dipole interactions in the case of ferromagnetic thin films. Here we show that spin-stripe textures may develop also in antiferromagnets, where long-range dipole-dipole magnetic interactions are absent. A comprehensive analysis of magnetic susceptibility, high-field magnetization, specific heat and neutron diffraction measurements unveils β-TeVO4 as a nearly perfect realization of a frustrated (zigzag) ferromagnetic spin-1/2 chain. Notably, a narrow spin-stripe phase develops at elevated magnetic fields due to weak frustrated short-range interchain exchange interactions, possibly assisted by the symmetry-allowed electric polarization. This concept provides an alternative route for the stripe formation in strongly correlated electron systems and may help understanding of other widespread, yet still elusive, stripe-related phenomena.


Higher Paraspinal Muscle Density Effect on Outcomes After Anterior Cervical Discectomy and Fusion.
Retrospective cohort study. Studies in the lumbar spine suggest a correlation between sarcopenia and worse patient outcomes. The purpose of this study was to determine whether paraspinal Goutalier grade of fat degeneration is associated with patient-reported outcomes in patients undergoing anterior cervical discectomy and fusion (ACDF). We performed a retrospective review of a prospective cohort of patients undergoing 1- to 3-level ACDF at a single institution between the years 2011-2014. We utilized preoperative magnetic resonance images to classify patients into Goutalier grades. Patient-reported outcomes, including Neck Disability Index (NDI), RAND score, and EQ-5D score were collected and analyzed according to patients' Goutalier grade. We identified 69 patients for inclusion. A total of 29 patients were classified as Goutalier 0-1 (group 1), 29 were Goutalier 1.5-2 (group 2), and 11 were Goutalier 2.5-4.0 (group 3). All Goutalier groups experienced significant improvement in all 3 outcome scores. Average postoperative NDI scores were 25.3 in group 1, 13.9 in group 2, and 25.1 in group 3 (P = .02). The percentage of patients in each group reporting worse disability after surgery was 17.2%, 3.3%, and 9.1%, respectively (P = .05). No statistically significant difference was seen between groups in postoperative EQ-5D (P = .07) or RAND scores (P > .05). The present study is the first to assess the association between cervical paraspinal muscle Goutalier grade and patient-reported outcomes following ACDF. Based on our study, patients with worse cervical paraspinal degeneration may benefit from improved symptom relief in comparison to patients with a lesser degree of degeneration undergoing ACDF.


High sensitivity C-reactive protein as a disease activity marker in rheumatoid arthritis.
To elucidate the potential contribution of high sensitivity C-reactive protein (hs-CRP) testing in the assessment of disease activity in rheumatoid arthritis (RA). We recorded clinical and psychological variables, the hs-CRP, and erythrocyte sedimentation rate (ESR) in 146 consecutive patients with RA. We analyzed the associations between the ESR and hs-CRP versus the other recorded variables. The median (interquartile range) ESR (mm/h) and hs-CRP (mg/l) were 15 (7-36) and 5 (2.3-13.9), respectively. Thirty-two (22%) patients had an hs-CRP < 2 mg/l, 61 (42%) an hs-CRP of 2-8 mg/l and 53 (36%) an hs-CRP > 8 mg/l. In patients with an hs-CRP of 2-8 mg/l, the swollen joint counts and the physician disease activity scales were higher, and remission rates were lower than in patients with an hs-CRP of < 2 mg/l. The hs-CRP was consistently more closely associated with disease activity, depression, and helplessness than was the ESR. High sensitivity CRP testing reveals systemic inflammation that is generally not detectable with routine CRP assays and that is associated with disease activity in RA.


Developmental toxicity assay using high content screening of zebrafish embryos.
Typically, time-consuming standard toxicological assays using the zebrafish (Danio rerio) embryo model evaluate mortality and teratogenicity after exposure during the first 2 days post-fertilization. Here we describe an automated image-based high content screening (HCS) assay to identify the teratogenic/embryotoxic potential of compounds in zebrafish embryos in vivo. Automated image acquisition was performed using a high content microscope system. Further automated analysis of embryo length, as a statistically quantifiable endpoint of toxicity, was performed on images post-acquisition. The biological effects of ethanol, nicotine, ketamine, caffeine, dimethyl sulfoxide and temperature on zebrafish embryos were assessed. This automated developmental toxicity assay, based on a growth-retardation endpoint should be suitable for evaluating the effects of potential teratogens and developmental toxicants in a high throughput manner. This approach can significantly expedite the screening of potential teratogens and developmental toxicants, thereby improving the current risk assessment process by decreasing analysis time and required resources.


HIV and syphilis prevalence trends among men who have sex with men in Guangxi, China: yearly cross-sectional surveys, 2008-2012.
Men who have sex with men (MSM) represent the fastest growing key population for incident HIV cases in China. We examined five consecutive years of HIV and syphilis prevalence and risk factors data among MSM in Guangxi Province with the second highest estimated number of people living with HIV/AIDS (PLWHAs) in China in 2011. We collected demographic and behavioral data from national sentinel surveillance and HIV/syphilis blood samples in five annual cross-sectional surveys from 2008 to 2012. We analyzed HIV and syphilis prevalence trends stratified by social/behavioral characteristics. HIV prevalence climbed steadily from 1.7% (95% confidence interval [CI]: 1.0 to 3.0) in 2008 to 3.7% (95% CI: 3.0 to 5.0) in 2012. Syphilis prevalence increased steadily from 5.1% (95% CI: 4.0 to 6.0) in 2008 to 8.4% (95% CI: 7.0 to 10.0) in 2012. HIV prevalence rose notably among MSM who were ≤25 years of age, never married, did not engage in sexual intercourse with women in the past six months, and had not been tested for HIV in the past year. Syphilis prevalence rose notably among MSM who were >25 years of age, ever married or living with a partner, and engaged in sexual intercourse with women in the past six months. HIV prevalence was much higher in MSM with current syphilis than without. Finally, current syphilis was the most significant predictor of HIV infection, and age was the most significant predictor of syphilis infection. HIV and the syphilis prevalence expansion among MSM suggest an urgent public health prevention challenge for Guangxi provincial health officials. Risk factors for each infection differed such that all MSM, each of whom might be at risk of HIV, syphilis or both, should be targets for heavy intervention.


The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis.
Safer and more effective oral drugs are required to treat visceral leishmaniasis, a parasitic disease that kills 50,000 to 60,000 people each year in parts of Asia, Africa, and Latin America. Here, we report that fexinidazole, a drug currently in phase 1 clinical trials for treating African trypanosomiasis, shows promise for treating visceral leishmaniasis. This 2-substituted 5-nitroimidazole drug is rapidly oxidized in vivo in mice, dogs, and humans to sulfoxide and sulfone metabolites. Both metabolites of fexinidazole were active against Leishmania donovani amastigotes grown in macrophages, whereas the parent compound was inactive. Pharmacokinetic studies with fexinidazole (200 mg/kg) showed that fexinidazole sulfone achieves blood concentrations in mice above the EC(99) (effective concentration inhibiting growth by 99%) value for at least 24 hours after a single oral dose. A once-daily regimen for 5 days at this dose resulted in a 98.4% suppression of infection in a mouse model of visceral leishmaniasis, equivalent to that seen with the drugs miltefosine and Pentostam, which are currently used clinically to treat this tropical disease. In African trypanosomes, the mode of action of nitro drugs involves reductive activation via a NADH (reduced form of nicotinamide adenine dinucleotide)-dependent bacterial-like nitroreductase. Overexpression of the leishmanial homolog of this nitroreductase in L. donovani increased sensitivity to fexinidazole by 19-fold, indicating that a similar mechanism is involved in both parasites. These findings illustrate the potential of fexinidazole as an oral drug therapy for treating visceral leishmaniasis.


Hpertrophic subaortic stenosis is not rare in the eighth decade.
During a five year period, idiopathic hypertrophic subaortic stenosis was diagnosed in nine patients 70 to 79 years of age and in 26 patients 20 to 66 years of age who were referred to the cardiology division of the Long Island Jewish-Hillside Medical Center because of symptomatic heart disease. Only one of the older patients, compared with 19 of the younger ones, was referred with the correct diagnosis. Coronary artery disease with papillary muscle dysfunction was incorrectly diagnosed in four of the older patients. Cardiac catheterization confirmed the diagnosis of idiopathic hypertrophic subaortic stenosis in all of the 26 younger patients and in five of the nine older ones; diagnosis was based on typical echocardiographic features in the other four patients. Symptoms, physical findings, and electrocardiographic observations were similar in both groups. Aortic valve calcification was found in one younger patient and three older ones. The ratio of women to men was higher in the older group (7:2) than in the younger group (12:14). Coronary artery disease was more frequent in the older patients (three of five, compared with six of 26). Our experience indicates that idiopathic hypertrophic subaortic stenosis is not rare during the eighth decade. The diagnosis should be considered in any patient with an unexplained appropriate heart murmur, and definitive studies, such as echocardiography, should be done. As with any condition, proper management depends on accurate diagnosis.


Formula diet alters small intestine morphology, microbial abundance and reduces VE-cadherin and IL-10 expression in neonatal porcine model.
Breastfeeding is associated with a variety of positive health outcomes in children and is recommended exclusively for the first 6 months of life; however, 50-70 % of infants in the US are formula-fed. To test the hypothesis that immune system development and function in neonates and infants are significantly influenced by diet, 2-day old piglets were fed soy or milk formula (n = 6/group/gender) until day 21 and compared to a sow-fed group (n = 6/gender). Histomorphometric analyses of ileum, jejunum and Peyer's patches were carried out, to determine the inflammation status, mRNA and protein expression of pro-inflammatory, anti-inflammatory and growth-related chemokines and cytokines. In formula-fed animals, increases in ileum and jejunum villus height and crypt depth were observed in comparison to sow-fed animals (jejunum, p < 0.01 villus height, p < 0.04 crypt depth; ileum p < 0.001 villus height, p < 0.002 crypt depth). In formula-fed the lymphoid follicle size (p < 0.01) and germinal centers (p < 0.01) with in the Peyer's patch were significantly decreased in comparison to sow-fed, indicating less immune education. In ileum, formula diet induced significant up-regulation of AMCFII, IL-8, IL-15, VEGFA, LIF, FASL, CXCL11, CCL4, CCL25 and down-regulation of IL-6, IL-9, IL-10, IL-27, IFNA4, CSF3, LOC100152038, and LOC100736831 at the transcript level. We have confirmed some of the mRNA data by measuring protein, and significant down-regulation of anti-inflammatory molecule IL-10 in comparison to sow-fed piglets was observed. To further determine the membrane protein expression in the ileum, VE-cadherin, occludin, and claudin-3, Western blot analyses were conducted. Sow fed piglets showed significantly more VE-Cadherin, which associated with levels of calcium, and putrescine measured. It is possible that differences in GI tract and immune development are related to shifts in the microbiome; notably, there were 5-fold higher amounts of Lactobacillaceae spp and 3 fold higher Clostridia spp in the sow fed group in comparison to milk formula-fed piglets, whereas in milk formula-fed pigs Enterobacteriaceae spp was 5-fold higher. In conclusion, formula diet alters GI morphology, microbial abundance, intestinal barrier protein VE-cadherin and anti-inflammatory molecule IL-10 expression. Further characterization of formula effects could lead to modification of infant formula to improve immune function, reduce inflammation and prevent conditions such as allergies and infections.


Measuring and modelling the effects of systematic non-adherence to mass drug administration.
It is well understood that the success or failure of a mass drug administration campaign critically depends on the level of coverage achieved. To that end coverage levels are often closely scrutinised during campaigns and the response to underperforming campaigns is to attempt to improve coverage. Modelling work has indicated, however, that the quality of the coverage achieved may also have a significant impact on the outcome. If the coverage achieved is likely to miss similar people every round then this can have a serious detrimental effect on the campaign outcome. We begin by reviewing the current modelling descriptions of this effect and introduce a new modelling framework that can be used to simulate a given level of systematic non-adherence. We formalise the likelihood that people may miss several rounds of treatment using the correlation in the attendance of different rounds. Using two very simplified models of the infection of helminths and non-helminths, respectively, we demonstrate that the modelling description used and the correlation included between treatment rounds can have a profound effect on the time to elimination of disease in a population. It is therefore clear that more detailed coverage data is required to accurately predict the time to disease elimination. We review published coverage data in which individuals are asked how many previous rounds they have attended, and show how this information may be used to assess the level of systematic non-adherence. We note that while the coverages in the data found range from 40.5% to 95.5%, still the correlations found lie in a fairly narrow range (between 0.2806 and 0.5351). This indicates that the level of systematic non-adherence may be similar even in data from different years, countries, diseases and administered drugs.


Group-based healthy lifestyle workplace interventions for shift workers: a systematic review.
Objective Shift work is a risk factor for many chronic diseases and has been associated with unhealthy lifestyle behaviors. Workplaces have great potential for promoting and supporting behavior change. We conducted a systematic review of group-based lifestyle workplace interventions for shift workers to (i) identify adaptations and intervention components that accommodate shift working and (ii) assess their impact on weight, physical activity, sedentary behavior and healthy eating. Methods A systematic search was conducted in Scopus, Web of Knowledge, EBSCO and Ovid databases. Using pre-established criteria, independent pairs of researchers conducted the study selection, quality appraisal and data extraction. Results In total, 22 studies on group-based workplace interventions for shift workers were included. Many demonstrated organizational level adaptations, such as flexible delivery times and paying employees' time for their involvement. Delivery locations near the workplace and management support were other key features. Common intervention components included competitive group activities, individualized goal setting, self-monitoring and feedback, staff involvement in intervention delivery, and incentives. There was moderate evidence for effectiveness on weight and physical activity outcomes, but insufficient evidence for healthy eating outcomes. No interventions focusing on sedentary behavior among shift workers were found. Conclusion Current evidence demonstrates that group-based workplace interventions can be effective for supporting shift workers to lose weight and increase physical activity, while further research is needed to change healthy eating and sedentary behaviors. Our findings offer decision support on organizational-level adaptations and intervention components that are important to make interventions that promote healthy lifestyles more accessible to shift workers.


Diagnosis, treatment and prevention of ankle sprains: update of an evidence-based clinical guideline.
This guideline aimed to advance current understandings regarding the diagnosis, prevention and therapeutic interventions for ankle sprains by updating the existing guideline and incorporate new research. A secondary objective was to provide an update related to the cost-effectiveness of diagnostic procedures, therapeutic interventions and prevention strategies. It was posited that subsequent interaction of clinicians with this guideline could help reduce health impairments and patient burden associated with this prevalent musculoskeletal injury. The previous guideline provided evidence that the severity of ligament damage can be assessed most reliably by delayed physical examination (4-5 days post trauma). After correct diagnosis, it can be stated that even though a short time of immobilisation may be helpful in relieving pain and swelling, the patient with an acute lateral ankle ligament rupture benefits most from use of tape or a brace in combination with an exercise programme.New in this update: Participation in certain sports is associated with a heightened risk of sustaining a lateral ankle sprain. Care should be taken with non-steroidal anti-inflammatory drugs (NSAIDs) usage after an ankle sprain. They may be used to reduce pain and swelling, but usage is not without complications and NSAIDs may suppress the natural healing process. Concerning treatment, supervised exercise-based programmes preferred over passive modalities as it stimulates the recovery of functional joint stability. Surgery should be reserved for cases that do not respond to thorough and comprehensive exercise-based treatment. For the prevention of recurrent lateral ankle sprains, ankle braces should be considered as an efficacious option.