ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

© 2015 Springer-Verlag Berlin Heidelberg.Rationale: Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. Objectives: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Methods: Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. Results: Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r 2∈=∈0.68, p∈=∈0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters. Conclusions: The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials

Interspecific Proteomic Comparisons Reveal Ash Phloem Genes Potentially Involved in Constitutive Resistance to the Emerald Ash Borer

The emerald ash borer (Agrilus planipennis) is an invasive wood-boring beetle that has killed millions of ash trees since its accidental introduction to North America. All North American ash species (Fraxinus spp.) that emerald ash borer has encountered so far are susceptible, while an Asian species, Manchurian ash (F. mandshurica), which shares an evolutionary history with emerald ash borer, is resistant. Phylogenetic evidence places North American black ash (F. nigra) and Manchurian ash in the same clade and section, yet black ash is highly susceptible to the emerald ash borer. This contrast provides an opportunity to compare the genetic traits of the two species and identify those with a potential role in defense/resistance. We used Difference Gel Electrophoresis (DIGE) to compare the phloem proteomes of resistant Manchurian to susceptible black, green, and white ash. Differentially expressed proteins associated with the resistant Manchurian ash when compared to the susceptible ash species were identified using nano-LC-MS/MS and putative identities assigned. Proteomic differences were strongly associated with the phylogenetic relationships among the four species. Proteins identified in Manchurian ash potentially associated with its resistance to emerald ash borer include a PR-10 protein, an aspartic protease, a phenylcoumaran benzylic ether reductase (PCBER), and a thylakoid-bound ascorbate peroxidase. Discovery of resistance-related proteins in Asian species will inform approaches in which resistance genes can be introgressed into North American ash species. The generation of resistant North American ash genotypes can be used in forest ecosystem restoration and urban plantings following the wake of the emerald ash borer invasion

Negative Impacts of Human Land Use on Dung Beetle Functional Diversity

The loss of biodiversity caused by human activity is assumed to alter ecosystem functioning. However our understanding of the magnitude of the effect of these changes on functional diversity and their impact on the dynamics of ecological processes is still limited. We analyzed the functional diversity of copro-necrophagous beetles under different conditions of land use in three Mexican biosphere reserves. In Montes Azules pastures, forest fragments and continuous rainforest were analyzed, in Los Tuxtlas rainforest fragments of different sizes were analyzed and in Barranca de Metztitlán two types of xerophile scrub with different degrees of disturbance from grazing were analyzed. We assigned dung beetle species to functional groups based on food relocation, beetle size, daily activity period and food preferences, and as measures of functional diversity we used estimates based on multivariate methods. In Montes Azules functional richness was lower in the pastures than in continuous rainforest and rainforest fragments, but fragments and continuous forest include functionally redundant species. In small rainforest fragments (<5 ha) in Los Tuxtlas, dung beetle functional richness was lower than in large rainforest fragments (>20 ha). Functional evenness and functional dispersion did not vary among habitat types or fragment size in these reserves. In contrast, in Metztitlán, functional richness and functional dispersion were different among the vegetation types, but differences were not related to the degree of disturbance by grazing. More redundant species were found in submontane than in crassicaule scrub. For the first time, a decrease in the functional diversity in communities of copro-necrophagous beetles resulting from changes in land use is documented, the potential implications for ecosystem functioning are discussed and a series of variables that could improve the evaluation of functional diversity for this biological group is proposed

Barriers and facilitators of effective self-management in asthma: systematic review and thematic synthesis of patient and healthcare professional views

Self-management is an established, effective approach to controlling asthma, recommended in guidelines. However, promotion, uptake and use among patients and health-care professionals remain low. Many barriers and facilitators to effective self-management have 25 been reported, and views and beliefs of patients and health care professionals have been explored in qualitative studies. We conducted a systematic review and thematic synthesis of qualitative research into self-management in patients, carers and health care professionals regarding self-management of asthma, to identify perceived barriers and facilitators associated with reduced effectiveness of asthma self-management interventions. Electronic databases and guidelines were searched systematically for qualitative literature that explored factors relevant to facilitators and barriers to uptake, adherence, or outcomes of self-management in patients with asthma. Thematic synthesis of the 56 included studies identified 11 themes: 1) partnership between patient and health care professional; 2) issues around medication; 3) education about asthma and its management; 4) health beliefs; 5) self-management interventions; 6) co-morbidities 7) mood disorders and anxiety; 8) social support; 9) non-pharmacological methods; 10) access to healthcare; 11) professional factors. From this, perceived barriers and facilitators were identified at the level of individuals with asthma (and carers), and health-care professionals. Future work addressing the concerns and beliefs of adults, adolescents and children (and carers) with asthma, effective communication and partnership, tailored support and education (including for ethnic minorities and at risk groups), and telehealthcare may improve how self-management is recommended by professionals and used by patients. Ultimately, this may achieve better outcomes for people with asthma

Use of non-steroidal anti-inflammatory drugs and risk of breast cancer: The Spanish Multi-Case-control (MCC) study

Background: The relationship between non-steroidal anti-inflammatory drug (NSAID) consumption and breast cancer has been repeatedly studied, although the results remain controversial. Most case-control studies reported that NSAID consumption protected against breast cancer, while most cohort studies did not find this effect. Most studies have dealt with NSAIDs as a whole group or with specific drugs, such aspirin, ibuprofen, or others, but not with NSAID subgroups according to the Anatomical Therapeutic Chemical Classification System; moreover, scarce attention has been paid to their effect on different tumor categories (i.e.: ductal/non-ductal, stage at diagnosis or presence of hormonal receptors). Methods: In this case-control study, we report the NSAID – breast cancer relationship in 1736 breast cancer cases and 1895 healthy controls; results are reported stratifying by the women’s characteristics (i.e.: menopausal status or body mass index category) and by tumor characteristics. Results: In our study, NSAID use was associated with a 24 % reduction in breast cancer risk (Odds ratio [OR] = 0.76; 95 % Confidence Interval [CI]: 0.64–0.89), and similar results were found for acetic acid derivatives, propionic acid derivatives and COXIBs, but not for aspirin. Similar results were found in postmenopausal and premenopausal women. NSAID consumption also protected against hormone + or HER2+ cancers, but not against triple negative breast cancers. The COX-2 selectivity showed an inverse association with breast cancer (i.e. OR < 1), except in advanced clinical stage and triple negative cancers. Conclusion: Most NSAIDs, but not aspirin, showed an inverse association against breast cancer; this effect seems to be restricted to hormone + or HER2+ cancers. Keywords: Breast cancer, Non-steroidal anti-inflammatory drug, Hormone receptor positive breast cancer, HER2 positive breast cancer, Triple negative breast cance

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3&nbsp;years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0&nbsp;years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores &gt;2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores &gt;2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score &gt;2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores &gt;2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores &gt;2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007

Postoperative outcomes in oesophagectomy with trainee involvement

BACKGROUND: The complexity of oesophageal surgery and the significant risk of morbidity necessitates that oesophagectomy is predominantly performed by a consultant surgeon, or a senior trainee under their supervision. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on postoperative outcomes in an international multicentre setting. METHODS: Data from the multicentre Oesophago-Gastric Anastomosis Study Group (OGAA) cohort study were analysed, which comprised prospectively collected data from patients undergoing oesophagectomy for oesophageal cancer between April 2018 and December 2018. Procedures were grouped by the level of trainee involvement, and univariable and multivariable analyses were performed to compare patient outcomes across groups. RESULTS: Of 2232 oesophagectomies from 137 centres in 41 countries, trainees were involved in 29.1 per cent of them (n = 650), performing only the abdominal phase in 230, only the chest and/or neck phases in 130, and all phases in 315 procedures. For procedures with a chest anastomosis, those with trainee involvement had similar 90-day mortality, complication and reoperation rates to consultant-performed oesophagectomies (P = 0.451, P = 0.318, and P = 0.382, respectively), while anastomotic leak rates were significantly lower in the trainee groups (P = 0.030). Procedures with a neck anastomosis had equivalent complication, anastomotic leak, and reoperation rates (P = 0.150, P = 0.430, and P = 0.632, respectively) in trainee-involved versus consultant-performed oesophagectomies, with significantly lower 90-day mortality in the trainee groups (P = 0.005). CONCLUSION: Trainee involvement was not found to be associated with significantly inferior postoperative outcomes for selected patients undergoing oesophagectomy. The results support continued supervised trainee involvement in oesophageal cancer surgery

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead