Bone Marrow Concentrate (BMC) Therapy in Musculoskeletal Disorders: Evidence-Based Policy Position Statement of American Society of Interventional Pain Physicians (ASIPP).
The use of bone marrow concentrate (BMC) for treatment of musculoskeletal disorders has become increasingly popular over the last several years, as technology has improved along with the need for better solutions for these pathologies. The use of cellular tissue raises a number of issues regarding the US Food and Drug Administration's (FDA) regulation in classifying these treatments as a drug versus just autologous tissue transplantation. In the case of BMC in musculoskeletal and spine care, this determination will likely hinge on whether BMC is homologous to the musculoskeletal system and spine. The aim of this review is to describe the current regulatory guidelines set in place by the FDA, specifically the terminology around "minimal manipulation" and "homologous use" within Regulation 21 CFR Part 1271, and specifically how this applies to the use of BMC in interventional musculoskeletal medicine. The methodology utilized here is similar to the methodology utilized in preparation of multiple guidelines employing the experience of a panel of experts from various medical specialties and subspecialties from differing regions of the world. The collaborators who developed these position statements have submitted their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these position statements. The literature pertaining to BMC, its effectiveness, adverse consequences, FDA regulations, criteria for meeting the standards of minimal manipulation, and homologous use were comprehensively reviewed using a best evidence synthesis of the available and relevant literature. RESULTS/Summary of Evidence: In conjunction with evidence-based medicine principles, the following position statements were developed: Statement 1: Based on a review of the literature in discussing the preparation of BMC using accepted methodologies, there is strong evidence of minimal manipulation in its preparation, and moderate evidence for homologous utility for various musculoskeletal and spinal conditions qualifies for the same surgical exemption. Statement 2: Assessment of clinical effectiveness based on extensive literature shows emerging evidence for multiple musculoskeletal and spinal conditions. • The evidence is highest for knee osteoarthritis with level II evidence based on relevant systematic reviews, randomized controlled trials and nonrandomized studies. There is level III evidence for knee cartilage conditions. • Based on the relevant systematic reviews, randomized trials, and nonrandomized studies, the evidence for disc injections is level III. • Based on the available literature without appropriate systematic reviews or randomized controlled trials, the evidence for all other conditions is level IV or limited for BMC injections. Statement 3: Based on an extensive review of the literature, there is strong evidence for the safety of BMC when performed by trained physicians with the appropriate precautions under image guidance utilizing a sterile technique. Statement 4: Musculoskeletal disorders and spinal disorders with related disability for economic and human toll, despite advancements with a wide array of treatment modalities. Statement 5: The 21st Century Cures Act was enacted in December 2016 with provisions to accelerate the development and translation of promising new therapies into clinical evaluation and use. Statement 6: Development of cell-based therapies is rapidly proliferating in a number of disease areas, including musculoskeletal disorders and spine. With mixed results, these therapies are greatly outpacing the evidence. The reckless publicity with unsubstantiated claims of beneficial outcomes having putative potential, and has led the FDA Federal Trade Commission (FTC) to issue multiple warnings. Thus the US FDA is considering the appropriateness of using various therapies, including BMC, for homologous use. Statement 7: Since the 1980's and the description of mesenchymal stem cells by Caplan et al, (now called medicinal signaling cells), the use of BMC in musculoskeletal and spinal disorders has been increasing in the management of pain and promoting tissue healing. Statement 8: The Public Health Service Act (PHSA) of the FDA requires minimal manipulation under same surgical procedure exemption. Homologous use of BMC in musculoskeletal and spinal disorders is provided by preclinical and clinical evidence. Statement 9: If the FDA does not accept BMC as homologous, then it will require an Investigational New Drug (IND) classification with FDA (351) cellular drug approval for use. Statement 10: This literature review and these position statements establish compliance with the FDA's intent and corroborates its present description of BMC as homologous with same surgical exemption, and exempt from IND, for use of BMC for treatment of musculoskeletal tissues, such as cartilage, bones, ligaments, muscles, tendons, and spinal discs. Based on the review of all available and pertinent literature, multiple position statements have been developed showing that BMC in musculoskeletal disorders meets the criteria of minimal manipulation and homologous use. Cell-based therapies, bone marrow concentrate, mesenchymal stem cells, medicinal signaling cells, Food and Drug Administration, human cells, tissues, and cellular tissue-based products, Public Health Service Act (PHSA), minimal manipulation, homologous use, same surgical procedure exemption.


Rich novel zero-dimensional (0D), 1D, and 2D topological elements predicted in the P63/m type ternary boride HfIr3B4.
Topological semimetals, including topological nodal point semimetals (TNPSs), topological nodal line state semimetals (TNLSs), and topological nodal surface semimetals (TNSSs), featuring zero-dimensional (0D), one-dimensional (1D), and two-dimensional (2D) topological elements (TEs), respectively, have attracted widespread attention in recent years. In this work, based on first-principles calculations, we propose for the first time that three different (0D, 1D, and 2D) TEs are simultaneously present in a synthetic compound, HfIr3B4, with a P63/m type structure. In detail, HfIr3B4 hosts a Dirac point (DP) state at the K point, a TNL state in the kz = 0 plane, and a 2D TNS state in the kz = π plane, respectively. All sorts of topological elements, 0D, 1D, and 2D TEs, coexisting in the P63/m type HfIr3B4, provide an ideal platform to study the rich fermionic states and their related physical properties in this type of compound. In addition, because the 0D, 1D, and 2D TEs of HfIr3B4 are equally distributed in different energy ranges relative to the Fermi level, an approach is proposed to utilize individual TEs to build on-demand devices.


Seasonal and ontogenetic changes of mycosporine-like amino acids in planktonic organisms from an alpine lake.
We studied the quantitative and qualitative mycosporine-like amino acid (MAA) composition in phytoplankton and the copepod Cyclops abyssorum tatricus from an alpine lake over a 15-month period. Up to eight MAAs were identified in the samples, with shinorine being predominant. The MAAs occurred year round and showed a strong seasonal pattern. Compared with ice-cover periods, concentrations during the summer were on average 3.6 and 3.0 times higher in phytoplankton and C. abyssorum tatricus, respectively. During the summer, the contents of MAAs in phytoplankton decreased with depth, suggesting their photoprotective role. Chlorophyll a-specific concentrations of MAAs in phytoplankton correlated significantly with the incident solar radiation and ultraviolet (UV) water transparency (r(2) ≤ 0.36), however, the strongest relationship was found with water temperature (r(2) = 0.67). In zooplankton, highest contents of MAAs were found in eggs, nauplii, and young copepodids, presumably providing a high level of photoprotection for progeny. Proportions of the dominant MAAs in the copepod showed seasonal and ontogenetic variations, which were consistent with relative changes in the predominant MAA, but not other abundant MAAs, in phytoplankton. Considering a time lag of approximately 1 month between the synthesis and subsequent accumulation of these compounds, MAA concentrations in late copepodid to adult life stages were significantly correlated to those in phytoplankton. Annual patterns in MAAs with high concentrations during periods of elevated environmental stress are consistent with the idea that these compounds play an important role in protecting aquatic organisms against UV damage.


Early sport specialization: roots, effectiveness, risks.
Year-round training in a single sport beginning at a relatively young age is increasingly common among youth. Contributing factors include perceptions of Eastern European sport programs, a parent's desire to give his or her child an edge, labeling youth as talented at an early age, pursuit of scholarships and professional contracts, the sporting goods and services industry, and expertise research. The factors interact with the demands of sport systems. Limiting experiences to a single sport is not the best path to elite status. Risks of early specialization include social isolation, overdependence, burnout, and perhaps risk of overuse injury. Commitment to a single sport at an early age immerses a youngster in a complex world regulated by adults, which is a setting that facilitates manipulation - social, dietary, chemical, and commercial. Youth sport must be kept in perspective. Participants, including talented young athletes, are children and adolescents with the needs of children and adolescents.


Personal choice or evidence-based nursing intervention: nurses' decision-making about influenza vaccination.
Nursing interventions are actions taken by nurses to enhance patient outcomes. Little is known about nursing interventions such as influenza vaccination in which the nurse's decision to adopt a health behavior impacts patient outcomes. There is strong evidence that immunization of health care workers (HCWs) against influenza is effective in preventing the spread of this disease and lowers mortality among patients. Yet, worldwide influenza vaccination rates among HCWs are low, with nurse vaccination rates among the lowest. To understand the factors influencing nurses' decision-making about personally receiving immunization against influenza. A qualitative descriptive design in which data were collected using semistructured interviews was used. Participants were 14 RNs who indicated on a prior survey that they were uncertain about, or would not receive an influenza vaccine during the next vaccination season. Data were analyzed using content analysis. The overarching theme is that influenza immunization is a low priority for nurses. Subthemes include a sense of good health, skepticism of the vaccine's value, fear of vaccine side effects, hand washing as prevention, and inconvenient immunization locations. The nurse participants in this study viewed influenza vaccination as a personal health choice, not as an evidence-based nursing intervention. As a result, the decision to decline influenza vaccination was made in the context of personal health choice and/or risk of injury or illness to the nurse. Patient safety outcomes were not expressed as a factor in making the decision to decline influenza vaccination.


Extracts of Opuntia humifusa Fruits Inhibit the Growth of AGS Human Gastric Adenocarcinoma Cells.
Opuntia humifusa (OHF) has been used as a nutraceutical source for the prevention of chronic diseases. In the present study, the inhibitory effects of ethyl acetate extracts of OHF on the proliferation of AGS human gastric cancer cells and the mode of action were investigated. To elucidate the antiproliferative mechanisms of OHF in cancer cells, the expression of genes related to apoptosis and cell cycle arrest were determined with real-time PCR and western blot. The cytotoxic effect of OHF on AGS cells was observed in a dose-dependent manner. Exposure to OHF (100 μg/mL) significantly induced (P<0.05) the G1 phase cell cycle arrest. Additionally, the apoptotic cell population was greater (P<0.05) in OHF (200 μg/mL) treated AGS cells when compared to the control. The expression of genes associated with cell cycle progression (Cdk4, Cdk2, and cyclin E) was significantly downregulated (P<0.05) by the OHF treatment. Moreover, the expression of Bax and caspase-3 in OHF treated cells was higher (P<0.05) than in the control. These findings suggest that OHF induces the G1 phase cell cycle arrest and activation of mitochondria-mediated apoptosis pathway in AGS human gastric cancer cells.


Scoring predictive models using a reduced representation of proteins: model and energy definition.
Reduced representations of proteins have been playing a keyrole in the study of protein folding. Many such models are available, with different representation detail. Although the usefulness of many such models for structural bioinformatics applications has been demonstrated in recent years, there are few intermediate resolution models endowed with an energy model capable, for instance, of detecting native or native-like structures among decoy sets. The aim of the present work is to provide a discrete empirical potential for a reduced protein model termed here PC2CA, because it employs a PseudoCovalent structure with only 2 Centers of interactions per Amino acid, suitable for protein model quality assessment. All protein structures in the set top500H have been converted in reduced form. The distribution of pseudobonds, pseudoangle, pseudodihedrals and distances between centers of interactions have been converted into potentials of mean force. A suitable reference distribution has been defined for non-bonded interactions which takes into account excluded volume effects and protein finite size. The correlation between adjacent main chain pseudodihedrals has been converted in an additional energetic term which is able to account for cooperative effects in secondary structure elements. Local energy surface exploration is performed in order to increase the robustness of the energy function. The model and the energy definition proposed have been tested on all the multiple decoys' sets in the Decoys'R'us database. The energetic model is able to recognize, for almost all sets, native-like structures (RMSD less than 2.0 A). These results and those obtained in the blind CASP7 quality assessment experiment suggest that the model compares well with scoring potentials with finer granularity and could be useful for fast exploration of conformational space. Parameters are available at the url: http://www.dstb.uniud.it/~ffogolari/download/.


Activation of left posterior cingulate gyrus by the auditory presentation of threat-related words: an fMRI study.
This study investigated the cortical response to hearing threat-related and neutral words using functional magnetic resonance imaging (fMRI) in 16 coronal planes. Right-handed volunteers listened to (i) neutral words alternating with no words as the control condition, and (ii) neutral words alternating with threat-related words as the experimental condition. Threat-related words compared to neutral words activated left posterior cingulate gyrus in eight of 10 subjects with activation most prominent in the retrosplenial region. Patterns of activation produced by neutral words compared to no words included bilateral temporal and frontal regions but not posterior cingulate. The retrosplenial cingulate region has recently been implicated in episodic memory processes. We discuss the possible role of the posterior cingulate cortex in processes involving emotion and memory and in anxiety disorders.


Investigation of the association between mitochondrial DNA and p53 gene mutations in transitional cell carcinoma of the bladder.
Bladder carcinoma is the most common malignancy of the urinary tract. The major aim of the present study is to investigate the association between mitochondrial DNA (mtDNA) and p53 gene mutations in bladder carcinoma. A total of 30 patients with transitional cell carcinoma and 27 controls were recruited for the study. Bladder cancer tissues were obtained by radical cystectomy or transurethral resection. Genomic DNA was extracted from peripheral blood. mtDNA and p53 genes were amplified by polymerase chain reaction and sequenced directly. A total of 37 polymorphisms were identified, among which, 2 mutations were significant in the patient group, and 1 mutation was significant in the control group. Additionally, 5 different moderate positive correlations between mtDNA mutations and 3 different positive correlations between p53 gene and mtDNA mutations were detected. The high incidence of mtDNA and p53 gene mutations in bladder cancer suggests that these genes could be important in carcinogenesis.


Precious African American memories, post-racial dreams & the American nation.
This interdisciplinary essay explores a fundamental paradox at the heart of American race relations since the 1960s: "the changing same." The more things change; the more they remain the same. Combining historical and social-scientific evidence with autobiographical reflections, this discussion critically probes the paradoxical decline and persistence of two dimensions of our enduring racial quagmire: racial inequality and white supremacy. The essay argues that these powerful and interrelated elements of America's continuing racial dilemma demand a massive democratic movement to alleviate both at once. This wide-ranging struggle to realize the promise of American democracy requires more than just a revitalized African American Freedom Struggle that is both intraracial and interracial. Progress toward resolving the seemingly intractable problem of racial inequality in the United States demands far more than intensified efforts to alleviate economic inequality; it requires alleviating white supremacy as well.


Attendees' feedback on king abdulaziz medical city pilot chronic kidney disease education class.
Despite similar or better patient outcomes, peritoneal dialysis and pre-emptive kidney transplantation are underutilized in Saudi Arabia. Moreover, most patients with end-stage renal disease begin dialysis in unplanned fashion necessitating the commencement of dialysis using central venous catheter access. We aimed to investigate if early patient education can help in overcoming these barriers. The study is a survey-based study at King Abdulaziz Medical City, Riyadh Dialysis Center. In January 2017, we started a monthly Chronic Kidney Disease Education Class in our center. Since then, 14 classes have taken place attended by 54 patients referred from outpatient nephrology clinics with chronic kidney disease (CKD) stages IV and V. The mean age was 51.6 years (16-85); 32 of the attendees were male and 22 were female. The class consisted of a slide informative presentation, a display of educational materials, and interactions with a multidisciplinary team from dialysis, transplantation, vascular access, and dietician services. A feedback survey was given to attendees at the conclusion of the class covering three domains; speakers, the program, and their personal reflections. Feedback options were laid out as "excellent, very good, good, fair, and poor." All class attendees responded to the questionnaire (100% response rate). The overall class evaluation was positive with the majority of attendees giving "excellent" rating for the speakers and the educational materials covered. Most thought that the class made them understand CKD nature better and helped them choose the right modality of renal replacement therapy. This initiative proves the feasibility of a sustained and attendee-gratifying education class to inform patients with advanced CKD about different options of renal replacement therapy and the need for timely preparation. To objectively measure the class's effect, the next phase of this review will define the ultimate outcome of each of its attendees.


Dolutegravir Plus Two Nucleoside Reverse Transcriptase Inhibitors versus Efavirenz Plus Two Nucleoside Reverse Transcriptase Inhibitors As Initial Antiretroviral Therapy for People with HIV: A Systematic Review.
Dolutegravir (DTG) is a once-daily unboosted second-generation integrase-inhibitor that along with two nucleoside reverse transcriptase inhibitors is one of several regimens recommended by the United States, United Kingdom and European Union for first-line antiretroviral treatment of people with HIV infection. Our objective was to review the evidence for the efficacy and safety of DTG-based first-line regimens compared to efavirenz (EFV)-based regimens. We conducted a systematic review. We comprehensively searched a range of databases as well as conference abstracts and a trials registry. We used Cochrane methods in screening and data collection and assessed each study's risk of bias with the Cochrane tool. We meta-analyzed data using a fixed-effects model. We used GRADE to assess evidence quality. From 492 search results, we identified two randomized controlled trials, reported in five peer-reviewed articles and one conference abstract. One trial tested two DTG-based regimens (DTG + abacavir (ABC) + lamivudine (3TC) or DTG + tenofovir + emtricitabine) against an EFV-based regimen (EFV+ ABC+3TC). The other trial tested DTG+ABC+3TC against EFV+ABC+3TC. In meta-analysis, DTG-containing regimens were superior to EFV-containing regimens at 48 weeks and at 96 weeks (RR = 1.10, 95% CI 1.04-1.16; and RR = 1.12, 95% CI 1.04-1.21, respectively). In one trial, the DTG-containing regimen was superior at 144 weeks (RR = 1.13, 95% CI 1.02-1.24). DTG-containing regimens were superior in reducing treatment discontinuation compared to those containing EFV at 96 weeks and at 144 weeks (RR = 0.27, 95% CI 0.15-0.50; and RR = 0.28, 95% CI 0.16-0.48, respectively). Risk of serious adverse events was similar in each regimen at 96 weeks (RR = 1.15, 95% CI 0.80-1.63) and 144 weeks (RR = 0.93, 95% CI 0.68-1.29). Risk of bias was moderate overall, as was GRADE evidence quality. DTG-based regimens should be considered in future World Health Organization guidelines for initial HIV treatment.


Advancing oral medicine through informatics and information technology: a proposed framework and strategy.
The implementation of information technology in healthcare is a significant focus for many nations around the world. However, information technology support for clinical care, research and education in oral medicine is currently poorly developed. This situation hampers our ability to transform oral medicine into a 'learning healthcare discipline' in which the divide between clinical practice and research is diminished and, ultimately, eliminated. This paper reviews the needs of and requirements for information technology support of oral medicine and proposes an agenda designed to meet those needs. For oral medicine, this agenda includes analyzing and reviewing current clinical and documentation practices, working toward progressively standardizing clinical data, and helping define requirements for oral medicine systems. IT professionals can contribute by conducting baseline studies about the use of electronic systems, helping develop controlled vocabularies and ontologies, and designing, implementing, and evaluating novel systems centered on the needs of clinicians, researchers and educators. Successfully advancing IT support for oral medicine will require close coordination and collaboration among oral medicine professionals, information technology professionals, system vendors, and funding agencies. If current barriers and obstacles are overcome, practice and research in oral medicine stand ready to derive significant benefits from the application of information technology.


Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. It has an excessive desmoplastic stroma that can limit the intratumoral delivery of chemotherapy drugs, and protect tumor cells against radiotherapy. Therefore, both stromal and tumor compartments need to be addressed in order to effectively treat PDAC. We hereby co-deliver a sonic hedgehog inhibitor, cyclopamine (CPA), and a cytotoxic chemotherapy drug paclitaxel (PTX) with a polymeric micelle formulation (M-CPA/PTX). CPA can deplete the stroma-producing cancer-associated fibroblasts (CAFs), while PTX can inhibit tumor proliferation. Here we show that in clinically relevant PDAC models, M-CPA effectively modulates stroma by increasing microvessel density, alleviating hypoxia, reducing matrix stiffness while maintaining the tumor-restraining function of extracellular matrix. M-CPA/PTX also significantly extends animal survival by suppressing tumor growth and lowering the percentages of poorly to moderately differentiated tumor phenotypes. Our study suggests that using multifunctional nanoparticles to simultaneously target stromal and tumor compartments is a promising strategy for PDAC therapy.


Comparative genomic and phylogenetic analysis of a toxigenic clinical isolate of Corynebacterium diphtheriae strain B-D-16-78 from Malaysia.
In this study, we report the comparative genomics and phylogenetic analysis of Corynebacterium diphtheriae strain B-D-16-78 that was isolated from a clinical specimen in 2016. The complete genome of C. diphtheriae strain B-D-16-78 was sequenced using PacBio Single Molecule, Real-Time sequencing technology and consists of a 2,474,151-bp circular chromosome with an average GC content of 53.56%. The core genome of C. diphtheriae was also deduced from a total of 74 strains with complete or draft genome sequences and the core genome-based phylogenetic analysis revealed close genetic relationship among strains that shared the same MLST allelic profile. In the context of CRISPR-Cas system, which confers adaptive immunity against re-invading DNA, 73 out of 86 spacer sequences were found to be unique to Malaysian strains which harboured only type-II-C and/or type-I-E-a systems. A total of 48 tox genes which code for the diphtheria toxin were retrieved from the 74 genomes and with the exception of one truncated gene, only nucleotide substitutions were detected when compared to the tox gene sequence of PW8. More than half were synonymous substitution and only two were nonsynonymous substitutions whereby H24Y was predicted to have a damaging effect on the protein function whilst T262V was predicted to be tolerated. Both toxigenic and non-toxigenic toxin-gene bearing strains have been isolated in Malaysia but the repeated isolation of toxigenic strains with the same MLST profile suggests the possibility of some of these strains may be circulating in the population. Hence, efforts to increase herd immunity should be continued and supported by an effective monitoring and surveillance system to track, manage and control outbreak of cases.


Essential roles for the FE65 amyloid precursor protein-interacting proteins in brain development.
Targeted deletion of two members of the FE65 family of adaptor proteins, FE65 and FE65L1, results in cortical dysplasia. Heterotopias resembling those found in cobblestone lissencephalies in which neuroepithelial cells migrate into superficial layers of the developing cortex, aberrant cortical projections and loss of infrapyramidal mossy fibers arise in FE65/FE65L1 compound null animals, but not in single gene knockouts. The disruption of pial basal membranes underlying the heterotopias and poor organization of fibrillar laminin by isolated meningeal fibroblasts from double knockouts suggests that FE65 proteins are involved in basement membrane assembly. A similar phenotype is observed in triple mutant mice lacking the APP family members APP, APLP1 and APLP2, all of which interact with FE65 proteins, suggesting that this phenotype may be caused by decreased transmission of an APP-dependent signal through the FE65 proteins. The defects observed in the double knockout may also involve the family of Ena/Vasp proteins, which participate in actin cytoskeleton remodeling and interact with the WW domains of FE65 proteins.


Vascular complications following bladder drained, simultaneous pancreas-kidney transplantation: the University of Miami experience.
Vascular complications remain a significant nonimmunologic source of pancreas allograft loss. From February 1993 through January 1998, we performed 98 simultaneous pancreas-kidney transplantations (SPK) using pancreatic exocrine bladder drainage in patients with type 1 insulin-dependent diabetes mellitus and end-stage renal disease. They originally received quadruple immunosuppression, and since May 1997 triple immunosuppression protocol (tacrolimus, mycophenolate mofetil, and steroids). The patients' mean age was 37 years (range 24-53 years), including 50 women and 48 men with a mean follow-up of 42 months. The overall rate of vascular complications was 6% (5 patients). The vascular complications were as follows: late thrombosis of the Y with persistent pancreas allograft function (n = 1), rupture of a pseudoaneurysm of the superior mesenteric artery (PSMA) with an arteriovenous fistula (AVF) (n = 1), thrombosis of the splenic vein (SV) (n = 3), complete thrombosis of the superior mesenteric vein (SMV) and splenic vein (n = 1). The patient with PSMA underwent surgical correction of the AVF and PSMA with preservation of the allograft pancreas function. The other patient with late thrombosis of the Y-graft required no treatment. All 3 patients with SV thrombosis were systemically heparinized followed by oral anticoagulation. The patient with complete thrombosis required surgical thrombectomy of the SMV and SV followed by heparinization and oral anticoagulation. All 6 patients including the 4 with thrombosis had preservation of the pancreas function. Serial pancreas ultrasound showed resolution and improvement with recanalization of the splenic vein and superior mesenteric vein in those patients with thrombosis. We describe our vascular experience with salvage of the pancreatic allograft function. Surgery seems to be the best treatment option in the case of AVF or complete thrombosis of the allograft. Intravenous heparin followed by oral anticoagultion could be a conservative approach for SV thrombosis.


A comparative analysis of multi-level computer-assisted decision making systems for traumatic injuries.
This paper focuses on the creation of a predictive computer-assisted decision making system for traumatic injury using machine learning algorithms. Trauma experts must make several difficult decisions based on a large number of patient attributes, usually in a short period of time. The aim is to compare the existing machine learning methods available for medical informatics, and develop reliable, rule-based computer-assisted decision-making systems that provide recommendations for the course of treatment for new patients, based on previously seen cases in trauma databases. Datasets of traumatic brain injury (TBI) patients are used to train and test the decision making algorithm. The work is also applicable to patients with traumatic pelvic injuries. Decision-making rules are created by processing patterns discovered in the datasets, using machine learning techniques. More specifically, CART and C4.5 are used, as they provide grammatical expressions of knowledge extracted by applying logical operations to the available features. The resulting rule sets are tested against other machine learning methods, including AdaBoost and SVM. The rule creation algorithm is applied to multiple datasets, both with and without prior filtering to discover significant variables. This filtering is performed via logistic regression prior to the rule discovery process. For survival prediction using all variables, CART outperformed the other machine learning methods. When using only significant variables, neural networks performed best. A reliable rule-base was generated using combined C4.5/CART. The average predictive rule performance was 82% when using all variables, and approximately 84% when using significant variables only. The average performance of the combined C4.5 and CART system using significant variables was 89.7% in predicting the exact outcome (home or rehabilitation), and 93.1% in predicting the ICU length of stay for airlifted TBI patients. This study creates an efficient computer-aided rule-based system that can be employed in decision making in TBI cases. The rule-bases apply methods that combine CART and C4.5 with logistic regression to improve rule performance and quality. For final outcome prediction for TBI cases, the resulting rule-bases outperform systems that utilize all available variables.


Demonstration of a specific site of covalent labeling of the human motilin receptor using a biologically active photolabile motilin analog.
The motilin receptor belongs to a group of class I G protein-coupled receptors that also includes the growth hormone secretagogue and ghrelin receptors. These represent clinically useful targets for pharmacotherapy. Their potentially unique structures and the molecular basis of their binding are not yet clear. We previously reported the initial affinity labeling of a region within this receptor (a cyanogen bromide fragment extending from the first to the second extracellular loop) using a position 1 photolabile motilin analog. To extend our understanding of the molecular basis of motilin binding, we have developed an additional radioiodinatable motilin analog probe having site of covalent attachment in position 5. This was a full agonist that bound to the motilin receptor specifically and with high affinity, and that efficiently established a single covalent bond to its receptor. Sequential chemical and enzymatic cleavage of labeled wild-type and mutant motilin receptor constructs established that the region of labeling was within the third extracellular loop. This was further localized to Phe(332) using radiochemical Edman degradation sequencing. These data provide the first spatial approximation constraint that can be used in the docking of this peptide ligand to its receptor. We hope that a series of such constraints can be determined to provide adequate structural information to begin to elucidate the conformation of this agonist-bound receptor and to ultimately be useful in the rational design of drugs acting at this important target.


Lung cancer incidence among American Indians and Alaska Natives in the United States, 1999-2004.
Lung cancer incidence rates among American Indians and Alaska Natives (AI/ANs) in the United States have not been described well, primarily because of race misclassification and, until the 1990s, incomplete coverage of their population by cancer registries. Smoking, the predominant cause of lung cancer, is particularly prevalent among this population. Data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results Program were combined to estimate age-adjusted incidence rates of lung cancer during 1999 through 2004. Cases were linked to Indian Health Service (IHS) registration databases to identify AI/ANs whose race may have been misclassified. Age-adjusted rates were calculated for Contract Health Service Delivery Area (CHSDA) counties and for all counties by IHS region, and comparisons were made between AI/ANs and non-Hispanic whites (NHWs). Among populations living in CHSDA counties, NHWs overall had higher rates of lung cancer than AI/ANs. However, the rates (per 100,000 population) among AI/ANs varied substantially between IHS regions from 14.9 (Southwest) to 87.1 (Southern Plains), 93.2 (Alaska), and 104.3 (Northern Plains). Approximately 41.6% of AI/AN lung cancer cases were diagnosed before age 65 years compared with approximately 29.8% of NHW lung cancer cases. The overall percentage stage distribution was not different between AI/ANs and NHWs. Squamous cell carcinomas were slightly more common and adenocarcinomas were less common among AI/ANs than among NHWs. Lung cancer rates were not decreasing for AI/ANs as they were for NHWs. Data from this study clarified the need for culturally appropriate tobacco prevention and control policies and resources for AI/ANs in all regions, and especially in the Plains and Alaska.


Suppression of T and B lymphocyte activation by a Yersinia pseudotuberculosis virulence factor, yopH.
The acquired immune responses are crucial to the survival of Yersinia-infected animals. Mice lacking T cells are sensitive to Yersinia infection, and a humoral response to Yersinia can be protective. Diverse mechanisms for Yersinia to impair and evade the host innate immune defense have been suggested, but the effects of Yersinia on lymphocytes are not known. Here, we demonstrate that after a transient exposure to Y. pseudotuberculosis, T and B cells are impaired in their ability to be activated through their antigen receptors. T cells are inhibited in their ability to produce cytokines, and B cells are unable to upregulate surface expression of the costimulatory molecule, B7.2, in response to antigenic stimulation. The block of lymphocyte activation results from the inhibition of early phosphorylation events of the antigen receptor signaling complex. Through the use of Y. pseudotuberculosis mutants, we show that the inhibitory effect in both T cells and B cells is dependent on the production of Yersinia outermembrane protein (Yop) H, a tyrosine phosphatase. Our results suggest a mechanism by which the pathogenic bacteria may modulate a wide range of T and B cell-mediated immune responses.


Synchronous and asynchronous electrically evoked motor activities during wind-up stimulation are differentially modulated following an acute spinal transection.
In this study, we used a novel technique to study reflex wind-up when the spinal cord is intact and following an acute spinal transection. Specifically, we evaluated reflex responses evoked by a series of 10 electrical pulses to the tibial or superficial peroneal nerves in 9 decerebrate adult cats, before and after an acute spinal transection. Electromyograms were recorded in four hindlimb muscles (lateral gastrocnemius, tibialis anterior, semitendinosus, and sartorius) to evaluate reflex amplitude, duration, and the temporal summation of reflex responses, so-called wind-up. We identified two distinct reflex responses evoked by electrical stimulation of the tibial or superficial peroneal nerves on the basis of their pattern of change following acute spinal transection, a short-latency (∼10 ms) compound action potential (CAP) that was followed by a burst of sustained activity (SA). Wind-up of CAP and SA amplitudes was clearly present when the spinal cord was intact but was drastically reduced after acute spinalization in some muscles. Moreover, CAP and SA reflex responses were differentially modified by the acute spinalization. When the effects of acute spinal transection were significant, CAP responses were increased after acute spinalization, whereas SA responses were reduced, suggesting that the two signals are regulated by different neuronal mechanisms. The present results provide the first assessment of reflex wind-up before and after an acute spinal transection in the same animals and indicate that different reflex components must be considered separately when evaluating changes in neuronal excitability following SCI.


Thought suppression and suicidal ideation: preliminary evidence in support of a robust association.
The suppression of unwanted thoughts appears to contribute to the development and maintenance of emotional disorders. This report tested the thought suppression paradigm in relation to suicidal ideation. Based on the ironic process theory, we hypothesized that the suppression of unwanted thoughts, especially suicidal thoughts, would associate with a higher frequency and a greater intensity of suicidal ideation. Study 1 examined cross-sectional associations between self-reported thought suppression and the frequency of suicidal ideation in a nonclinical sample of 166 undergraduate students. Study 2 extended cross-sectional findings in an inpatient sample of 71 suicidal adolescents. Study 3 examined prospective associations between suicidal thought suppression and increases in self-reported suicidal ideation over a 4-week period in a separate nonclinical sample of 118 undergraduate students. Findings across studies support a robust association between thought suppression and suicidal ideation, even controlling for general depressive symptoms. Participants in Studies 1 and 2 who endorsed greater tendencies toward suppression of thoughts, especially suicidal thoughts (Study 2), displayed higher concurrent levels of suicidal ideation. Participants in Study 3 who endorsed greater baseline tendencies toward suppression of suicidal thoughts displayed an increase in the severity of suicidal ideation over time. Suppression of suicidal thoughts may represent 1 mechanism contributing to the persistence of suicidal ideation. Clinicians may wish to explore patients' reactions to suicidal ideation and consider acceptance-oriented strategies among patients who attempt to control unwanted suicidal thoughts.


Alternative serotype adenovirus vaccine vectors elicit memory T cells with enhanced anamnestic capacity compared to Ad5 vectors.
The failure of the adenovirus serotype 5 (Ad5) vector-based human immunodeficiency virus type 1 (HIV-1) vaccine in the STEP study has led to the development of adenovirus vectors derived from alternative serotypes, such as Ad26, Ad35, and Ad48. We have recently demonstrated that vaccines using alternative-serotype Ad vectors confer partial protection against stringent simian immunodeficiency virus (SIV) challenges in rhesus monkeys. However, phenotypic differences between the T cell responses elicited by Ad5 and those of alternative-serotype Ad vectors remain unexplored. Here, we report the magnitude, phenotype, functionality, and recall capacity of memory T cell responses elicited in mice by Ad5, Ad26, Ad35, and Ad48 vectors expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP). Our data demonstrate that memory T cells elicited by Ad5 vectors were high in magnitude but exhibited functional exhaustion and decreased anamnestic potential following secondary antigen challenge compared to Ad26, Ad35, and Ad48 vectors. These data suggest that vaccination with alternative-serotype Ad vectors offers substantial immunological advantages over Ad5 vectors, in addition to circumventing high baseline Ad5-specific neutralizing antibody titers.


Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis.
Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.


Chondrogenic and gliogenic subpopulations of neural crest play distinct roles during the assembly of epibranchial ganglia.
In vertebrates, the sensory neurons of the epibranchial (EB) ganglia transmit somatosensory signals from the periphery to the CNS. These ganglia are formed during embryogenesis by the convergence and condensation of two distinct populations of precursors: placode-derived neuroblasts and neural crest- (NC) derived glial precursors. In addition to the gliogenic crest, chondrogenic NC migrates into the pharyngeal arches, which lie in close proximity to the EB placodes and ganglia. Here, we examine the respective roles of these two distinct NC-derived populations during development of the EB ganglia using zebrafish morphant and mutants that lack one or both of these NC populations. Our analyses of mutant and morphant zebrafish that exhibit deficiencies in chondrogenic NC at early stages reveal a distinct requirement for this NC subpopulation during early EB ganglion assembly and segmentation. Furthermore, restoration of wildtype chondrogenic NC in one of these mutants, prdm1a, is sufficient to restore ganglion formation, indicating a specific requirement of the chondrogenic NC for EB ganglia assembly. By contrast, analysis of the sox10 mutant, which lacks gliogenic NC, reveals that the initial assembly of ganglia is not affected. However, during later stages of development, EB ganglia are dispersed in the sox10 mutant, suggesting that glia are required to maintain normal EB ganglion morphology. These results highlight novel roles for two subpopulations of NC cells in the formation and maintenance of EB ganglia: chondrogenic NC promotes the early-stage formation of the developing EB ganglia while glial NC is required for the late-stage maintenance of ganglion morphology.


Restoration of rivers used for timber floating: effects on riparian plant diversity.
Fluvial processes such as flooding and sediment deposition play a crucial role in structuring riparian plant communities. In rivers throughout the world, these processes have been altered by channelization and other anthropogenic stresses. Yet despite increasing awareness of the need to restore natural flow regimes for the preservation of riparian biodiversity, few studies have examined the effects of river restoration on riparian ecosystems. In this study, we examined the effects of restoration in the Ume River system, northern Sweden, where tributaries were channelized to facilitate timber floating in the 19th and early 20th centuries. Restoration at these sites involved the use of heavy machinery to replace instream boulders and remove floatway structures that had previously lined stream banks and cut off secondary channels. We compared riparian plant communities along channelized stream reaches with those along reaches that had been restored 3-10 years prior to observation. Species richness and evenness were significantly increased at restored sites, as were floodplain inundation frequencies. These findings demonstrate how river restoration and associated changes in fluvial disturbance regimes can enhance riparian biodiversity. Given that riparian ecosystems tend to support a disproportionate share of regional species pools, these findings have potentially broad implications for biodiversity conservation at regional or landscape scales.


Systemic neurotransplantation--a problem-oriented systematic review.
Systemic neurotransplantation (SNT) was introduced in the laboratory in 2000 and currently it is being widely examined in animal models of neurological disorders. The aim of this systematic review was to evaluate the current state of knowledge in the field of experimental SNT and the premise for the introduction of clinical trials. PubMed was searched and 60 articles utilizing an SNT approach were found and subjected to analysis. The time window for cell transplantation was addressed in only two studies, with contradictory results. Immunosuppression was applied in 25% of studies. No study addressed the justification for immunosuppression. Bone marrow was the most frequent source of grafted cells, followed by cord blood and then by cells of embryonic origin. Studies investigating dose-dependency revealed no satisfactory results with transplantation of less than 10(6) cells/animal; the efficient dose most frequently ranged from 10(6)-10(7) cells/animal (mice and rats). The behavioral effects of cell transplantation were assessed in 75% of all studies; significant improvement was achieved in 95% of them. Morphological effect was evaluated in half of the studies; significant positive effect was achieved in 73% of them. Experimental attempts to elucidate the mechanisms mediating cell-dependent effect were not undertaken in half of the studies. In the other half, the most frequent mechanisms were growth factors, neurogenesis and immunomodulation. SNT still seems to be at the very initial stage of development. Many critical factors have not been sufficiently addressed in laboratory studies and they must be clarified before the introduction of clinical trials.


First Report of Ascochyta Blight Caused by QoI-Resistant Isolates of Ascochyta rabiei in Chickpea Fields of Nebraska and South Dakota.
Ascochyta blight, caused by Ascochyta rabiei, is a serious disease of chickpea (Cicer arietinum) and fungicide applications are used to manage the disease in the North Central plains (4). During the 2010 growing season, a commercial field near Stanley, SD was treated with pyraclostrobin (Headline, BASF, NC) and called a management failure by the grower. Similarly, limited efficacy of pyraclostrobin was observed in an ascochyta research trial near Scott's Bluff, NE. In both locations, symptoms and signs consistent with A. rabiei infection existed on leaves, stems, and pods; namely, circular brown lesions with concentric rings of dark brown pycnidia. Symptomatic samples were collected, disinfected with 95% ethanol for 1 min, rinsed with sterile water, placed in 0.5% NaOCl for 1 min, and rinsed again with sterile water for 1 min (4). Samples were air dried, placed on potato dextrose agar (PDA) plates for 3 to 7 days, and colonies with morphological characteristics typical of A. rabiei were single-spored and transferred to new PDA plates and incubated for 7 to 14 days. Three and six putative A. rabiei isolates were obtained from South Dakota and Nebraska samples, respectively. Morphological characteristics were consistent with A. rabiei; cultures were brown with concentric rings of dark, pear-shaped pycnidia with an ostiole, and conidia were hyaline, single-celled, and oval-shaped (2). Comparison of the internal transcribed spacer (ITS) region amplified from the genomic DNA of 3-day-old liquid cultures using ITS4/ITS5 primers by BLASTN searches using the nr database in GenBank (Accession Number FJ032643) also confirmed isolates to be A. rabiei. Mismatch amplification mutation assay (MAMA) PCR was used for detection of sensitive and resistant isolates to QoI fungicides (1). Confirmation of the presence of the G143A mutation was carried out by cloning an mRNA fragment of the cytochrome b gene using cDNA synthesized from total RNA of A. rabiei and CBF1/CBR2 (1,3). Total RNA was extracted from 3-day-old liquid cultures and it was used instead of genomic DNA for this PCR to avoid large intronic regions commonly present in mitochondrial genes. The G143A mutation has previously been correlated with resistance to QoI fungicides in other fungal plant pathogens (3). Also, these isolates were determined to be QoI-resistant in vitro by PDA amended with a discriminatory dose of 1 μg/ml of azoxystrobin (4). To our knowledge, this is the first report of QoIresistant A. rabiei isolates causing infections on chickpeas in South Dakota and Nebraska. QoI-resistant isolates were reported in North Dakota and Montana in 2005 and 2007, respectively (4). Of nearly 300 isolates collected from these states from 2005 and 2007, approximately 65% were determined to be QoI resistant (4). The widespread occurrence of QoIresistant isolates and reduction of fungicide performance in fields led the North Dakota State University Cooperative Extension Service to actively discourage the use of QoI fungicides on chickpeas in North Dakota and Montana (4). It is likely that similar recommendations will need to be adopted in South Dakota and Nebraska for profitable chickpea production. References: (1) J. A. Delgado, 2012 Ph.D. Diss. Department of Plant Pathology, North Dakota State University. (2) R. M. Harveson et al. 2011. Online. Plant Health Progress doi:10.1094/PHP-2011-0103-01-DG. (3) Z. Ma et al. Pestic. Biochem. Physiol. 77:66, 2003. (4) K. A. Wise et al. Plant Dis. 93:528, 2009.


Corrected QT Interval Prolongation in Psychopharmacological Treatment and Its Modulation by Genetic Variation.
Several antipsychotics and antidepressants have been associated with electrocardiogram alterations, the most clinically relevant of which is the heart rate-corrected QT interval (QTc) prolongation, a risk factor for sudden cardiac death. Genetic variants influence drug-induced QTc prolongation and can provide valuable information for precision medicine. The effect of genetic variants on QTc prolongation as well as the possible interaction between polymorphisms and risk medications in determining QTc prolongation were investigated. Medications were classified according to their known risk of inducing QTc prolongation (high-to-moderate, low, and no risk). QTc duration and risk of QTc > median value were investigated in a sample of 77 patients with mood or psychotic disorders being treated with antidepressants and antipsychotics, and who had at least 1 ECG recording. A secondary analysis considered QTc percentage change in patients (n = 25) with 2 ECG recordings. Single-nucleotide polymorphisms previously associated with QTc prolongation during treatment with psychotropic medications were investigated. No association survived after multiple-testing correction. The best results for modulation of QTc duration were identified for rs10808071 (the ABCB1 gene, nominal p = 0.007) when at least 1 medication with a moderate-to-high risk was prescribed, and for rs12029454 (the NOS1AP gene) in patients taking at least 1 medication with a cardiovascular risk (nominal p = 0.008). In the secondary analysis, rs2072413 (the KCNH2 gene) was the top finding for the modulation of QTc percentage change (nominal p = 0.001) when 1 drug with a moderate-to-high risk was added compared to baseline. Despite the limited power of this study, our results suggest that ABCB1, NOS1AP, and KCNH2 may play a role in QTc duration/prolongation during treatment with psychotropic drugs.


Soluble nonclassical HLA generated by the metalloproteinase pathway.
Soluble human leukocyte antigens (HLA-A, -B, and -C) proteins can be generated by a membrane-bound metalloproteinase (MPase). The MPase-mediated pathway produces soluble nonconformed HLA proteins susceptible to further degradation, and also HLA proteins with high affinity peptides stable at physiologic temperatures. Accessibility of classical HLA to the MPase cleavage inversely correlates with stability of heavy chain (HC) interactions with beta2-microglobulin (beta(2)m). Whether a MPase is involved in release of soluble nonclassical HLA or CD1 proteins is unknown. We have investigated this question with transfectants expressing full-length HLA proteins. Native surface HLA-E and -G complexes, similar to HLA-A2, were unstable at low pH and dissociated giving rise to beta(2)m-free HC. Furthermore, HLA-E and -G proteins, similar to HLA-A2, were readily released from cell surface into supernatants as soluble 37-kilodalton beta(2)m-free HC. However, the stability of surface CD1d complexes was not affected by pH changes and no soluble CD1d was detected. Because beta(2)m-free CD1d HC were expressed on cells, the lack of cleaved soluble products cannot be explained by high stability of native complexes. Instead, absence of a CD1d-specific MPase in these cells or its impaired interactions with substrate HC may be responsible.


The effect of weight on the efficacy and safety of C1 esterase inhibitor concentrate for the treatment of acute hereditary angioedema.
Despite the worldwide obesity epidemic, there have been very few studies investigating the influence of body weight on treatment dosing and outcomes in patients with hereditary angioedema (HAE). The purpose of this analysis was to determine whether the standard weight-based dosing recommendation of C1 esterase inhibitor (C1-INH) concentrate (20 IU/kg) is adequate in HAE patients with a high body mass index (BMI). Data from patients treated for HAE attacks with 20 IU/kg of C1-INH concentrate were retrospectively analyzed from the open-label IMPACT2 study (International Multicenter Prospective Angioedema C1-INH Trial). Patients were categorized according to BMI as being normal body weight, overweight, or obese. Efficacy end points were time to onset of symptom relief and time to complete resolution of symptoms. The safety profile was evaluated according to adverse events occurring within 7 to 9 days of treatment. Of 57 patients, 24 (42%) were of normal body weight, 20 (35%) were overweight, and 13 (23%) were obese. Median (95% CI) time to onset of symptom relief was 0.37 hour (0.29-0.57) in normal-weight patients, 0.48 hour (0.39-0.53) in overweight patients, and 0.58 hour (0.41-0.94) in obese patients. Median time (95% CI) to complete resolution of symptoms was 15.2 hours (9.3-23.2) in normal-weight patients, 22.6 hours (11.3-44.6) in overweight patients, and 11.0 hours (5.6-23.6) in obese patients (differences not significant). There were no relevant differences in the incidence of adverse events in normal-weight patients (54%), overweight patients (30%), and obese patients (54%). Treatment of HAE attacks with weight-based doses of C1-INH concentrate provided reliable treatment response, regardless of body weight, in these patients with HAE.


Translational research in oncology: key bottlenecks and new paradigms.
Translational research is about transforming progress in basic research into products that benefit patients. Here I discuss some of the key obstacles to effective translational research in oncology that have previously received limited attention. Basic research often does not go far enough for straightforward clinical translation, and long-term, high-risk endeavours to fill these key gaps have not been adequately addressed either by industry or by the culture of investigator-initiated research. These key gaps include the identification of causative oncogenic mutations and new approaches to regulating currently undruggable targets such as tumour suppressor genes. Even where an inhibitor of a key target has been identified, new approaches to clinical development are needed. The current approach of treating broad populations of patients based primarily on primary cancer site is not well suited to the development of molecularly targeted drugs. Although developing drugs with predictive diagnostics makes drug development more complex, it can improve the success rate of development, as well as provide benefit to patients and the economics of healthcare. I review here some prospective Phase III designs that have been developed for transition from the era of correlative science to one of reliable predictive and personalised oncology.


Growth factors and early mesoderm morphogenesis: insights from the sea urchin embryo.
The early morphogenesis of the mesoderm is critically important in establishing the body plan of the embryo. Recent research has led to a better understanding of the mechanisms that underlie this process, and growth factor signaling pathways have emerged as key regulators of the directional movements of mesoderm cells during gastrulation. In this review, we undertake a comparative analysis of the various essential functions of growth factor signaling pathways in regulating early mesoderm morphogenesis, with an emphasis on recent advances in the sea urchin embryo. We focus on the roles of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) pathways in the migration of primary mesenchyme cells and the formation of the embryonic endoskeleton. We compare the functions of VEGF and FGF in sea urchins with the roles that these and other growth factors play in regulating mesoderm migration during gastrulation in Drosophila and vertebrates.


Postsurgical paracicatricial cutaneous satellitosis of giant cell tumour of the tendon sheath, localized type.
Tenosynovial giant cell tumour (localized type) is a tumour of tendon sheaths and interphalangeal joints, affecting the digits and arising from the synovium. It is characterized by a proliferation of mononuclear cells and osteoclast-like polykaryocytes. Its propagation to the skin is an exceptional event, which can take place either in localized form in the fingertips (localized type) or in the rare diffuse form called giant cell tumour of the tendon sheath (diffuse type). We report here a case of giant cell tumour with cutaneous satellites, which appeared close to and around the surgical scar following the excision of the primary lesion, in a 9-year-old boy. In the cutaneous satellites, a few signs of transformation could be observed, consisting of the lack of stroma and pronounced cellularity characterized by sheets of rounded synovial-like cells admixed with multinucleated giant cells and xanthoma cells. No relapse was observed 1 year after a plastic surgery procedure (complete replacement of the involved skin). Diffuse lesions usually represent a diagnostic problem in comparison with their localized counterparts. The malignant transformation of an originally typical tenosynovial giant cell tumour is a rare but well-documented event. Our case seems to represent a typical example because the pronounced cellularity might wrongly lead to a diagnosis of malignancy.


Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: in vitro, in vivo, and crystallographic results.
The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first committed step in its biosynthesis, condensation of two farnesyl diphosphate (FPP) molecules to dehydrosqualene, catalyzed by the enzyme dehydrosqualene synthase (CrtM). The most active compounds are phosphonoacetamides that have low nanomolar K(i) values for CrtM inhibition and are active in whole bacterial cells and in mice, where they inhibit S. aureus disease progression. We also report the X-ray crystallographic structure of the most active compound, N-3-(3-phenoxyphenyl)propylphosphonoacetamide (IC(50) = 8 nM, in cells), bound to CrtM. The structure exhibits a complex network of hydrogen bonds between the polar headgroup and the protein, while the 3-phenoxyphenyl side chain is located in a hydrophobic pocket previously reported to bind farnesyl thiodiphosphate (FsPP), as well as biphenyl phosphonosulfonate inhibitors. Given the good enzymatic, whole cell, and in vivo pharmacologic activities, these results should help guide the further development of novel antivirulence factor-based therapies for S. aureus infections.


Lactococcus garvieae infection in the giant freshwater prawn Macrobranchium rosenbergii confirmed by polymerase chain reaction and 16S rDNA sequencing.
An epizootic bacterial infection in the giant freshwater prawn Macrobranchium rosenbergii occurred in Taiwan from May to June 1999. The cumulative mortality was approximately 30 to 75%. The diseased prawns showed opaque and whitish muscles and were approximately 2 mo old with total lengths from 5 to 6 cm. Histopathologically, they showed marked edema and necrotic lesions with inflammation in the muscles and hepatopancreas. Bacteria isolated using brain heart infusion medium or tryptic soy agar were Gram-positive and ovoid. Three isolates from diseased prawns at different farms were tested using the API 20 Strepsystem and conventional tests and identified as Lactococcus garvieae. Experimental infections with these isolates gave gross signs and histopathological changes similar to those seen in the naturally infected prawns. The LD50 value of isolate MR1 was 6.6 x 10(5) colony forming units/prawn. Identification of MR1 was confirmed by a PCR assay for L. garvieae that gave the expected amplicon of 1100 bp. In addition, its 16S rDNA sequence (GenBank accession number AF283499) gave 99% sequence identity to Enterococcus seriolicida (synonym L. garvieae; GenBank accession number AF061005). This is the first report of confirmed L. garvieae infection in prawn aquaculture.


Public Veterinary Medicine: Public Health Rabies virus variants identified in Nuevo Leon State, Mexico, from 2008 to 2015.
To identify rabies virus variants (RVVs) isolated from bats and terrestrial mammals in Nuevo Leon between 2008 and 2015 and Coahuila in 2006. RVVs isolated from 15 bats and terrestrial mammals in Nuevo Leon and from a cow (Bos taurus) in Coahuila, along with 46 reference rabies virus sequences. Antigenic characterization of the 16 isolates was performed with an indirect fluorescent antibody technique. Genomic sequencing of the nucleoprotein gene in the 16 isolates was performed with a reverse transcription PCR assay. Phylogenetic reconstruction of the 62 sequences was performed by means of Bayesian inference. 9 isolates from bats and 1 isolate from a domestic cat that became infected as a result of contact with a Mexican free-tailed bat all clustered in the lineage associated with Lasiurus spp in the Americas or the lineage associated with Tadarida brasiliensis mexicana. An isolate from a domestic dog was identified as a variant associated with the dog-coyote lineage. The RVV isolated from a fox clustered in an Arizona fox lineage. The 3 RVVs from skunks (Mephitis macroura) were placed in a lineage with variants isolated from spotted skunks (Spilogale putorius). The RVV isolated from the cow was clustered in a lineage associated with foxes in Texas and separate from the lineage for the fox from Nuevo Leon. Results reinforced the need for Mexico to implement rabies surveillance and monitoring programs for bats and wild-living terrestrial carnivores.


The role of selective attention in visual awareness of stimulus features: electrophysiological studies.
Attention and awareness are closely related, but the nature of their relationship is unclear. The present study explores the timing and temporal evolution of their interaction with event-related potentials. The participants attended to specific conjunctions of spatial frequency and orientation in masked (unaware) and unmasked (aware) visual stimuli. A correlate of awareness appeared 100-200 msec from stimulus onset similarly to both attended and unattended features. Selection negativity (SN), a correlate of attentional selection, emerged in response to both masked and unmasked stimuli after 200 msec. This double dissociation between correlates of awareness and SN suggests that the electrophysiological processes associated with feature-based attentional selection and visual awareness of features can be dissociated from each other at early stages of processing. In a passive task, requiring no attention to the stimuli, early electrophysiological responses (before 200 msec) related to awareness were attenuated, suggesting that focal attention modulates visual awareness earlier than does selective feature-based attention.


25 years after Vi typhoid vaccine efficacy study, typhoid affects significant number of population in Nepal.
Salmonella Typhi, first isolated in 1884, results in infection of the intestines and can end in death and disability. Due to serious adverse events post vaccination, whole cell killed vaccines have been replaced with new generation vaccines. The efficacy of Vi polysaccharide (ViPS) vaccine, a new generation, single-dose intramuscular typhoid vaccine was assessed in Nepal in 1987. However, despite the availability of ViPS vaccine for more than 25 years, Nepal has one of the highest incidence of typhoid fever. Therefore we collected information from hospitals in the Kathmandu Valley from over the past five years. There were 9901 enteric fever cases between January 2008 and July 2012. 1,881 of these were confirmed typhoid cases from five hospitals in the Kathmandu district. Approximately 70% of the cases involved children under 15 years old. 1281 cases were confirmed as S. Paratyphi. Vaccines should be prioritized for control of typhoid in conjunction with improved water and sanitation conditions in Nepal and in endemic countries of Asia and Africa.


Adaptation of the MISSCARE Survey to the Maternity Care Setting.
Missed nursing care is an important measure of nursing care quality that is sensitive to nurse staffing and is associated with patient outcomes in medical-surgical and pediatric inpatient settings. Missed nursing care during labor and birth has not been studied, yet childbirth represents the most common reason for hospitalization in the United States. The Missed Nursing Care (MISSCARE) Survey, a measure of medical-surgical nursing quality with substantial evidence for validity and reliability, was adapted to maternity nursing care using data from focus groups of labor nurses, physicians, and new mothers and an online survey of labor nurses. Content validity was evaluated via participant feedback, and exploratory factor analysis was performed to identify the factor structure of the instrument. The modified version, the Perinatal Missed Care Survey, appears to be a feasible and promising instrument with which to evaluate missed nursing care of women during labor and birth in hospitals.


Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice.
The adapter protein SLP-76 is expressed in T lymphocytes and hematopoietic cells of the myeloid lineage, and is known to be a substrate of the protein tyrosine kinases that are activated after ligation of the T-cell antigen receptor. Transient overexpression of SLP-76 in a T-cell line potentiates transcriptional activation after T-cell receptor ligation, while loss of SLP-76 expression abrogates several T-cell receptor-dependent signaling pathways. Mutant mice that lack SLP-76 manifest a severe block at an early stage of thymocyte development, implicating SLP-76 in signaling events that promote thymocyte maturation. While it is clear that SLP-76 plays a key role in development and activation of T lymphocytes, relatively little is understood regarding its role in transducing signals initiated after receptor ligation in other hematopoietic cell types. In this report, we describe fetal hemorrhage and perinatal mortality in SLP-76-deficient mice. Although megakaryocyte and platelet development proceeds normally in the absence of SLP-76, collagen-induced platelet aggregation and granule release is markedly impaired. Furthermore, treatment of SLP-76-deficient platelets with collagen fails to elicit tyrosine phosphorylation of phospholipase C-gamma2 (PLC-gamma2), suggesting that SLP-76 functions upstream of PLC-gamma2 activation. These data provide one potential mechanism for the fetal hemorrhage observed in SLP-76-deficient mice and reveal that SLP-76 expression is required for optimal receptor-mediated signal transduction in platelets as well as T lymphocytes.


Insulin for type 2 diabetes: choosing a second-line insulin regimen.
Guidance has been published on the choice of initial insulin regimen for patients with type 2 diabetes [NPH (isophane) insulin or a long-acting insulin analogue] but not on how to choose a second regimen when glycaemic control becomes unsatisfactory. To develop pragmatic clinical guidance for choosing a second-line insulin regimen tailored to the individual needs of patients with type 2 diabetes after failure of first-line insulin therapy. Formulation of a consensus by expert panel based on published evidence and best clinical practice, taking into account patient preferences, lifestyle and functional capacity. Six patient-dependent factors relevant to the choice of second-line insulin regimen and three alternative insulin regimens (twice-daily premixed, basal-plus and basal-bolus) were identified. The panel recommended one or more insulin regimens compatible with each factor, emphasising the fundamental importance of a healthy lifestyle that includes exercise and weight reduction. These recommendations were incorporated into an algorithm to provide pragmatic guidance for clinicians. The three alternative insulin regimens offer different benefits and drawbacks and it is important to make the right choice to optimise outcomes for patients.


Pacific Islanders' perspectives on heart failure management.
To identify the health beliefs, attitudes, practices, and social and family relations important in heart failure treatment among Pacific Islanders. Four focus groups were convened with 36 Native Hawaiians and Samoans with heart failure and their family caregivers. Thematic data analysis was used to categorize data into four domains: health beliefs and attitudes, preferred health practices, social support systems, and barriers to heart failure care. Common coping styles and emotional experiences of heart failure in this population included avoidance or denial of illness, hopelessness and despair, and reliance on spiritual/religious beliefs as a means of support. Among study participants, more Samoans preferred to be treated by physicians whereas more Native Hawaiians preferred traditional Hawaiian methods of healing. Two types of social support (informational and tangible-instrumental) were identified as important in heart failure care. Barriers to heart failure care included poor knowledge of heart failure, lack of trust in physicians' care, poor physician-patient relations, finances, dietary changes, and competing demands on time. The recruitment, retention, and adherence of Pacific Islanders to heart failure interventions is affected by an array of psychosocial and socio-cultural factors. Interventions might be improved by offering participants accurate and detailed information about heart failure and its treatment, engaging the extended family in providing necessary supports, and providing tools to facilitate physician-patient relationships, among others, within the context of a larger socio-cultural system.


Long-term outcomes for mothers who have or have not held their stillborn baby.
to investigate long-term outcomes of mothers who have or have not held their stillborn baby, and predictors of having held the baby. postal questionnaires. a nation-wide cohort study of mothers who gave birth to a singleton stillborn baby in Sweden in 1991. 314 out of 380 women answered the questionnaire and 309 reported whether or not they had held their baby. scales measuring anxiety, depression and well-being. 126 (68%) mothers of 185 babies stillborn after 37 gestational weeks had held their baby and 82 (68%) mothers of 120 babies stillborn at gestational weeks 28-37 had also done so. Compared with mothers who agreed completely with the statement that staff gave enough support to hold the baby, mothers who did not agree were less likely to have held their baby [relative risk (RR) 4.1; 95% confidence interval (CI) 2.7-6.1], and mothers with a low level of education were less likely to have held their baby than mothers with a higher level of education (RR 2.2; 95% CI 1.3-3.8). Mothers who had not held their babies born after 37 gestational weeks had an increased risk of headache (RR 4.3; 95% CI 1.1-16.5), and they were less satisfied with their sleep (RR 2.7; 95% CI 1.5-5.0). The increased risk of long-term outcomes associated with not holding, compared with holding, a stillborn baby were less pronounced for women who gave birth at gestational week 28-37 compared with women who gave birth after 37 gestational weeks. in this cohort, we found an overall beneficial effect of having held a stillborn baby born after 37 gestational weeks, whereas findings for having held a stillborn baby born at gestational weeks 28-37 are uncertain. The attitude of staff influenced whether or not the mother held her stillborn baby. if the mother is guided by staff in a sensitive way to hold her stillborn term baby, the experience will possibly be beneficial for her in the long term.


Identification of imprinted genes subject to parent-of-origin specific expression in Arabidopsis thaliana seeds.
Epigenetic regulation of gene dosage by genomic imprinting of some autosomal genes facilitates normal reproductive development in both mammals and flowering plants. While many imprinted genes have been identified and intensively studied in mammals, smaller numbers have been characterized in flowering plants, mostly in Arabidopsis thaliana. Identification of additional imprinted loci in flowering plants by genome-wide screening for parent-of-origin specific uniparental expression in seed tissues will facilitate our understanding of the origins and functions of imprinted genes in flowering plants. cDNA-AFLP can detect allele-specific expression that is parent-of-origin dependent for expressed genes in which restriction site polymorphisms exist in the transcripts derived from each allele. Using a genome-wide cDNA-AFLP screen surveying allele-specific expression of 4500 transcript-derived fragments, we report the identification of 52 maternally expressed genes (MEGs) displaying parent-of-origin dependent expression patterns in Arabidopsis siliques containing F1 hybrid seeds (3, 4 and 5 days after pollination). We identified these MEGs by developing a bioinformatics tool (GenFrag) which can directly determine the identities of transcript-derived fragments from (i) their size and (ii) which selective nucleotides were added to the primers used to generate them. Hence, GenFrag facilitates increased throughput for genome-wide cDNA-AFLP fragment analyses. The 52 MEGs we identified were further filtered for high expression levels in the endosperm relative to the seed coat to identify the candidate genes most likely representing novel imprinted genes expressed in the endosperm of Arabidopsis thaliana. Expression in seed tissues of the three top-ranked candidate genes, ATCDC48, PDE120 and MS5-like, was confirmed by Laser-Capture Microdissection and qRT-PCR analysis. Maternal-specific expression of these genes in Arabidopsis thaliana F1 seeds was confirmed via allele-specific transcript analysis across a range of different accessions. Differentially methylated regions were identified adjacent to ATCDC48 and PDE120, which may represent candidate imprinting control regions. Finally, we demonstrate that expression levels of these three genes in vegetative tissues are MET1-dependent, while their uniparental maternal expression in the seed is not dependent on MET1. Using a cDNA-AFLP transcriptome profiling approach, we have identified three genes, ATCDC48, PDE120 and MS5-like which represent novel maternally expressed imprinted genes in the Arabidopsis thaliana seed. The extent of overlap between our cDNA-AFLP screen for maternally expressed imprinted genes, and other screens for imprinted and endosperm-expressed genes is discussed.


Salmonellosis in songbirds in the Canadian Atlantic provinces during winter-summer 1997-98.
From winter 1997 to summer 1998, an epizootic of salmonellosis affected several species of songbirds over a large area of the eastern North American continent. This article describes the details of this epizootic in the Canadian Atlantic provinces, based on laboratory examination of dead affected birds and on suspected but unconfirmed cases of salmonellosis reported by members of the public. The common redpoll (Carduelis flammea) was the species most often affected, followed by pine siskins (C. pinus), purple finches (Carpodacus purpureus), evening grosbeaks (Coccothraustes vespertinus), and American goldfinches (Carduelis tristis). A poor body condition and necrotizing and fibrinopurulent esophagitis and ingluvitis were the most common gross lesions in these birds. Thirty-four of 35 isolates of Salmonella recovered from these birds were identified as phage type 40. Despite the magnitude of this and previous epizootics of salmonellosis among North American songbirds, the sources of these epizootics and the precise influence of environmental factors on their occurrence remain poorly understood.


Genetic architecture, biochemical underpinnings and ecological impact of floral UV patterning.
Floral attraction traits can significantly affect pollinator visitation patterns, but adaptive evolution of these traits may be constrained by correlations with other traits. In some cases, molecular pathways contributing to floral attraction are well characterized, offering the opportunity to explore loci potentially underlying variation among individuals. Here, we quantify the range of variation in floral UV patterning (i.e. UV 'bulls-eye nectar guides) among crop and wild accessions of Brassica rapa. We then use experimental crosses to examine the genetic architecture, candidate loci and biochemical underpinnings of this patterning as well as phenotypic manipulations to test the ecological impact. We find qualitative variation in UV patterning between wild (commonly lacking UV patterns) and crop (commonly exhibiting UV patterns) accessions. Similar to the majority of crops, recombinant inbred lines (RILs) derived from an oilseed crop × WI fast-plant® cross exhibit UV patterns, the size of which varies extensively among genotypes. In RILs, we further observe strong statistical-genetic and QTL correlations within petal morphological traits and within measurements of petal UV patterning; however, correlations between morphology and UV patterning are weak or nonsignificant, suggesting that UV patterning is regulated and may evolve independently of overall petal size. HPLC analyses reveal a high concentration of sinapoyl glucose in UV-absorbing petal regions, which, in concert with physical locations of UV-trait QTLs, suggest a regulatory and structural gene as candidates underlying observed quantitative variation. Finally, insects prefer flowers with UV bulls-eye patterns over those that lack patterns, validating the importance of UV patterning in pollen-limited populations of B. rapa.


KEYLINK: towards a more integrative soil representation for inclusion in ecosystem scale models. I. review and model concept.
The relatively poor simulation of the below-ground processes is a severe drawback for many ecosystem models, especially when predicting responses to climate change and management. For a meaningful estimation of ecosystem production and the cycling of water, energy, nutrients and carbon, the integration of soil processes and the exchanges at the surface is crucial. It is increasingly recognized that soil biota play an important role in soil organic carbon and nutrient cycling, shaping soil structure and hydrological properties through their activity, and in water and nutrient uptake by plants through mycorrhizal processes. In this article, we review the main soil biological actors (microbiota, fauna and roots) and their effects on soil functioning. We review to what extent they have been included in soil models and propose which of them could be included in ecosystem models. We show that the model representation of the soil food web, the impact of soil ecosystem engineers on soil structure and the related effects on hydrology and soil organic matter (SOM) stabilization are key issues in improving ecosystem-scale soil representation in models. Finally, we describe a new core model concept (KEYLINK) that integrates insights from SOM models, structural models and food web models to simulate the living soil at an ecosystem scale.


The evolutionary paths towards complexity: a metabolic perspective.
As sessile organisms, land plants have exploited their metabolic systems to produce a panoply of structurally and functionally diverse natural chemicals and polymers to adapt to challenging ecosystems. Many of these core and specialized metabolites confer chemical shields against a multitude of abiotic stresses, while others play important roles in plants' interactions with their biotic environments. Plant specialized metabolites can be viewed as complex traits in the sense that the biosynthesis of these molecules typically requires multistep metabolic pathways comprising numerous specific enzymes belonging to diverse protein fold families. Resolving the evolutionary trajectories underlying the emergence of these specialized metabolic pathways will impact a fundamental question in biology – how do complex traits evolve in a Darwinian fashion? Here, I discuss several general patterns observed in rapidly evolving specialized metabolic systems in plants, and surmise mechanistic features at enzyme, pathway and organismal levels that rationalize the remarkable malleability of these systems through stepwise evolution. Future studies, focused on fine sampling of metabolic enzymes and pathways in phylogenetically related plant species, or employing directed evolution strategies in synthetic systems, will significantly broaden our perspective on how biological complexity arises at the metabolic level.


Repetitive arm functional tasks after stroke (RAFTAS): a pilot randomised controlled trial.
Repetitive functional task practise (RFTP) is a promising treatment to improve upper limb recovery following stroke. We report the findings of a study to determine the feasibility of a multi-centre randomised controlled trial to evaluate this intervention. A pilot randomised controlled trial recruited patients with new reduced upper limb function within 14 days of acute stroke from three stroke units. Participants were randomised to receive a four week upper limb RFTP therapy programme consisting of goal setting, independent activity practise, and twice weekly therapy reviews in addition to usual post stroke rehabilitation, or usual post stroke rehabilitation. The recruitment rate; adherence to the RFTP therapy programme; usual post stroke rehabilitation received; attrition rate; data quality; success of outcome assessor blinding; adverse events; and the views of study participants and therapists about the intervention were recorded. Fifty five eligible patients were identified, 4-6 % of patients screened at each site. Twenty four patients participated in the pilot study. Two study sites met the recruitment target of 1-2 participants per month. The median number of face to face therapy sessions received was 6 [IQR 3-8]. The median number of daily repetitions of activities recorded was 80 [IQR 39-80]. Data about usual post stroke rehabilitation were available for 18/24 (75 %). Outcome data were available for 22/24 (92 %) at one month and 20/24 (83 %) at three months. Outcome assessors were unblinded to participant group allocation for 11/22 (50 %) at one month and 6/20 (30 %) at three months. Four adverse events were considered serious as they resulted in hospitalisation. None were related to study treatment. Feedback from patients and therapists about the RFTP programme was mainly positive. A multi-centre randomised controlled trial to evaluate an upper limb RFTP therapy programme provided early after stroke is feasible and acceptable to patients and therapists, but there are issues which need to be addressed when designing a Phase III study. A Phase III study will need to monitor and report not only recruitment and attrition but also adherence to the intervention, usual post stroke rehabilitation received, and outcome assessor blinding. International Standard Randomised Controlled Trials Number (ISRCTN) 58527251.


High-resolution manometric evaluation of the effects of cisapride and metoclopramide hydrochloride administered orally on lower esophageal sphincter pressure in awake dogs.
To evaluate the effects of cisapride and metoclopramide hydrochloride administered orally on the lower esophageal sphincter (LES) resting pressure in awake healthy dogs. 6 adult Beagles. Each dog was evaluated after administration of a single dose of cisapride (0.5 mg/kg), metoclopramide (0.5 mg/kg), or placebo (empty gelatin-free capsule) in 3 experiments performed at 3-week intervals. To measure LES pressure, a high-resolution manometry catheter equipped with 40 pressure sensors spaced 10 mm apart was used. For each experiment, LES pressure was recorded during a 20-minute period with a virtual electronic sleeve emulation before treatment (baseline) and at 1, 4, and 7 hours after drug or placebo administration. A linear mixed-effects model was used to test whether the 3 treatments affected LES pressure differently. In the cisapride, metoclopramide, and placebo experiments, median baseline LES pressures were 29.1, 30.5, and 29.0 mm Hg, respectively. For the cisapride, metoclopramide, and placebo treatments, median LES pressures at 1 hour after administration were 44.4, 37.8, and 36.6 mm Hg, respectively; median LES pressures at 4 hours after administration were 50.7, 30.6, and 31.1 mm Hg, respectively; and median LES pressures at 7 hours after administration were 44.3, 28.5, and 33.3 mm Hg, respectively. The LES pressures differed significantly only between the placebo and cisapride treatments. Results suggested that orally administered cisapride may be of benefit in canine patients for which an increase in LES pressure is desirable, whereas orally administered metoclopramide did not affect LES resting pressures in dogs.


National trends in heart failure mortality in men and women, United Kingdom, 2000-2017.
To understand gender differences in the prognosis of women and men with heart failure, we compared mortality, cause of death and survival trends over time. We analysed UK primary care data for 26 725 women and 29 234 men over age 45 years with a new diagnosis of heart failure between 1 January 2000 and 31 December 2017 using the Clinical Practice Research Datalink, inpatient Hospital Episode Statistics and the Office for National Statistics death registry. Age-specific overall survival and cause-specific mortality rates were calculated by gender and year. During the study period 15 084 women and 15 822 men with heart failure died. Women were on average 5 years older at diagnosis (79.6 vs. 74.8 years). Median survival was lower in women compared to men (3.99 vs. 4.47 years), but women had a 14% age-adjusted lower risk of all-cause mortality [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.84-0.88]. Heart failure was equally likely to be cause of death in women and men (HR 1.03, 95% CI 0.96-1.12). There were modest improvements in survival for both genders, but these were greater in men. The reduction in mortality risk in women was greatest for those diagnosed in the community (HR 0.83, 95% CI 0.80-0.85). Women are diagnosed with heart failure older than men but have a better age-adjusted prognosis. Survival gains were less in women over the last two decades. Addressing gender differences in heart failure diagnostic and treatment pathways should be a clinical and research priority.


Dab2, a negative regulator of DC immunogenicity, is an attractive molecular target for DC-based immunotherapy.
Dab2 is an adapter protein involved in receptor-mediated signaling, endocytosis, cell adhesion, hematopoietic cell differentiation, and angiogenesis. It plays a pivotal role in controlling cellular homeostasis. In the immune system, the Dab2 is a Foxp3 target gene and is required for regulatory T (Treg) cell function. Dab2 expression and its biological function in dendritic cells (DCs) have not been described. In this study, we found that Dab2 was significantly induced during the development of mouse bone marrow (BM)-derived DCs (BMDCs) and human monocyte-derived DCs (MoDCs). Even in a steady state, Dab2 was expressed in mouse splenic DCs (spDCs). STAT5 activation, Foxp3 expression, and hnRNPE1 activation mediated by PI3K/Akt signaling were required for Dab2 expression during GM-CSF-derived BMDC development regardless of TGF-β signaling. Dab2-silencing was accompanied by enhanced IL-12 and IL-6 expression, and an improved capacity of DC for antigen uptake, migration and T cell stimulation, which generated strong CTL in vaccinated mice. Vaccination with Dab2-silenced DCs inhibited tumor growth more effectively than did vaccination with wild type DCs. Dab2-overexpression abrogated the efficacy of the DC vaccine in DC-based tumor immunotherapy. These data strongly suggest that Dab2 might be an intrinsic negative regulator of the immunogenicity of DCs, thus might be an attractive molecular target to improve DC vaccine efficacy.


Eating habits and sleep patterns of adolescents with depression symptoms in Mumbai, India.
Adolescents with depression engage in unhealthy eating habits and irregular sleep patterns and are often at an increased risk for weight-related problems. Improvement in these lifestyle behaviours may help to prevent depression, but knowledge about the associations between depression, sleep, eating habits and body weight among adolescents in India is limited. This cross-sectional study investigated the prevalence of depression and its association with sleep patterns, eating habits and body weight status among a convenience sample of 527 adolescents, ages 10-17 years in Mumbai, India. Participants completed a survey on sleep patterns such as sleep duration, daytime sleepiness and sleep problems and eating habits such as frequency of breakfast consumption, eating family meals and eating out. Depression was assessed using the Patient Health Questionnaire modified for Adolescents (PHQ-A). Anthropometric measurements were also taken. Within this sample, 25% had moderate to severe depression (PHQ-A ≥ 10) and 46% reported sleeping less than 6 h > thrice a week. Adolescents with moderate to severe depression had significantly higher body mass index than those with minimal depression (26.2 ± 6.6 vs. 20.2 ± 4.8 kg/m2 ). The odds of having clinically significant depression (PHQ-A ≥ 10) was 4.5 times higher in adolescents who had family meals ≤ once a week, 1.6 times higher among those who were sleeping <6 h and 2.3 times higher among participants having trouble falling to sleep more than thrice a week. The findings indicated that a significant proportion of adolescents had depression symptoms; improving sleep and eating habits may present potential targets for interventions.


What information is important for accredited exercise physiologists to facilitate change in clients living with type 2 diabetes mellitus?
Accredited Exercise Physiologists (AEPs) prescribe exercise and physical activity interventions for people living with type 2 diabetes mellitus (T2DM). During initial consultations, AEPs face the challenge of collecting enough information to facilitate behaviour change and adherence to treatment recommendations. The objective of this research is to explore the initial consultation practices of AEPs with clients living with T2DM and resultant recommendations provided to clients to promote long-term adherence. This study was an exploratory descriptive qualitative study. Twenty-one AEPs who currently practice in the Townsville Region participated in focus groups or semi-structured interviews. Data were analysed using a thematic and triangulation approach. Results revealed that an interview style consultation is standard practice, which varied based on experience of the AEP. Interviewing techniques facilitating behaviour change were under-utilised, especially among less-experienced AEPs who focused on the medical information. Assessment of the psychosocial wellbeing of the client living with T2DM by AEPs was limited. AEPs recommended that group exercise sessions yielded greater success for clients adopting physical activity. It is recommended that new graduate AEPs develop greater confidence in strategies of gathering information to facilitate behaviour change in clients with T2DM. A mentorship program could ensure the continued development of new graduate AEPs through the transfer of knowledge and skills.