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Patients with high bleeding risk (HBR) are often treated with abbreviated dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) to reduce bleeding risk, however this strategy is associated with an increase in ischemic events, especially if the acute PCI result is suboptimal. We compared clinical outcomes among patients with HBR treated with 1-month DAPT who underwent intravascular ultrasound (IVUS)- or optical coherence tomography (OCT)-guided PCI versus those who underwent angiography-guided PCI without intravascular imaging. The Onyx ONE Clear study includes patients with HBR from the Onyx ONE US/Japan and Onyx ONE randomized studies who were treated with the Resolute Onyx zotarolimus-eluting stent. The primary endpoint was the composite of cardiac death (CD) or myocardial infarction (MI) between 1 month and 2 years after PCI. Propensity-score adjustments and matching were performed for differences in baseline and procedural characteristics between groups. Among the 1507 patients in Onyx ONE Clear, 271 (18.0 %) had IVUS or OCT used during PCI (Imaging-guided group) and 1236 (82.0 %) underwent Angiography-guided PCI (Angio-guided group). Imaging-guided patients were less likely to present with atrial fibrillation, acute coronary syndrome, and left ventricle ejection fraction ≤35 %. Conversely, Imaging-guided patients were more likely to have complex (ACC/AHA type B2/C), longer, and heavily calcified lesions. Between 1 month and 2 years, the composite rate of CD or MI was similar between Imaging-guided and Angio-guided patients (9.9 % vs. 12.4 %, P = 0.33). There was also no difference between groups after adjustment; (P = 0.56). However, CD was significantly lower among Imaging-guided patients (2.7 % vs. 6.1 %, P = 0.048). There were no between-group differences in MI or stent thrombosis. Propensity score matching results were similar. Despite higher lesion complexity, using intravascular imaging guidance for PCI between 1-month and 2-years follow-up had comparable outcomes with angiographic guidance alone in patients with HBR treated with 1-month DAPT. (ClinicalTrials.gov : Identifier: NCT03647475 and NCT03344653). BARC: Bleeding Academic Research Consortium; DAPT: dual antiplatelet therapy; DES: drug-eluting stent; HBR: high bleeding risk; IVUS: intravascular ultrasound; OCT: optical coherence tomography; SAPT: single antiplatelet therapy. • Balancing ischemic and bleeding risks after PCI remains challenging in HBR patients. • Imaging-guided HBR patients had more complex legions. • Outcomes were similar using imaging vs. angio-guided PCI. [ABSTRACT FROM AUTHOR]

Although efficacy of ustekinumab (UST) has been demonstrated through randomized trials, data from real-life prospective cohorts are still limited. Our aim was to evaluate clinical efficacy, drug sustainability, dose intensification and results from therapeutic drug monitoring in UST treated patients with Crohn's disease (CD) using a prospective, nationwide, multicenter cohort. Patients from 10 Inflammatory Bowel Disease centers were enrolled between 2019 January and 2020 May. Patient demographics, disease phenotype, treatment history, clinical disease activity (Crohn's Disease Activity Index(CDAI), Harvey Bradshaw Index(HBI)), biomarkers, and serum drug levels were obtained. Evaluations were performed at week8 (post-induction), w16–20, w32–36, and w52–56 follow-up visits. A total of 142 patients were included [57.4% female; complex disease behavior (B2/B3):48%, previous anti-TNF exposition:97%]. Clinical response and remission rates after induction(w8) were 78.1% and 57.7% using CDAI, and 82.5% and 51.8% based on HBI scores. The one-year clinical remission rate was 58%/57.3%(CDAI/HBI). Composite clinical and biomarker remission (CDAI<150 and C-reactive protein<10 mg/L) rates were 35.4%; 33.3%; 38.6% and 36.6% at w8/w16–20/w32–36 and w52–56. Drug sustainability was 81.9%(standard deviation(SD): 3.4) at 1 year(1y). Probability of dose intensification was high and introduced early, 42.2%(SD:4.2) at ~w32 and 51.9%(SD:4.4%) at 1y. Ustekinumab showed favorable drug sustainability and clinical efficacy in a patient population with severe disease phenotype and previous anti-tumor necrosis factor (anti-TNF) failure, however frequent dose intensification was required. [ABSTRACT FROM AUTHOR]

Malawi has not yet transitioned from the use of wood to more sustainable and efficient means of energy production. This aggravates the already dire problem of deforestation and contributes to severe fuelwood scarcity. The rural sellers of fuelwood, whose livelihoods depend upon access to the commodity, are particularly incentivized to find means of stabilizing their supply. Although agroforestry fuelwood technology (AFT) options such as private and communal woodlots are available for increasing sustainable supplies, Malawians largely have not adopted them. This study investigates the use of agroforestry in general, and AFT in particular, by rural fuelwood sellers in Malawi through analysis of survey results gathered during a large-scale agroforestry extension effort. The findings indicate that fuelwood sellers are 125% and 43% more likely to use AFT than the general population in the North and South regions of the country, respectively. Moreover, binary regression showed that the use of AFT in particular was directly related to the ability to sell fuelwood in the South (i.e., increasing its likelihood by 4.5 times). Based on the findings, the authors propose that for Malawi and similarly situated countries, household composition should be considered in policy and extension recommendations. Communal woodlots may be promoted for the general population in patrilocal areas with high numbers of female-headed households or particularly weak tenure scenarios, while individual woodlots within broader agroforestry prescriptions may be preferred for male-headed households. For both situations, the role of agroforestry in improving environmental conditions and thereby increasing future output levels should be emphasized. • Fuelwood sellers are 125% & 43% more likely to use agroforestry than others in the North & South Malawi • Tenure scenarios, gender, and perceptions of agroforestry fuelwood technology's environmental benefits affect its adoption • Individual woodlots within broader agroforestry prescriptions may be preferred by male-headed households • It may be beneficial to promote communal woodlots to female headed households [ABSTRACT FROM AUTHOR]

Cardiac imaging procedures are a cornerstone of the diagnosis and management of patients with cardiac disease. The optimal management of the patient with stable ischemic heart disease or ischemic heart failure often rests on the totality of symptom burden, patient risk, and disease severity, whether assessed anatomically or functionally. Recent trials have demonstrated the power of flow measurements to direct revascularization as well as the strengths and limitations of ischemia and viability/hibernation imaging as markers of risk to direct interventions. They have also highlighted the challenges in evaluating imaging or functional testing to direct therapies, because imaging does not directly affect outcome itself, rather it affects the management decisions that may result in a positive outcome. Ongoing studies with randomized designs, such as FAME 3 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation), ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), and AIMI-HF (Alternative Imaging Modalities in Ischemic Heart Failure) (IMAGE-HF [Imaging Modalities to Assist with Guiding Therapy in The Evaluation of Patients with Heart Failure]), will provide the highest level of evidence to support practice changes that may further clarify the role of cardiac imaging in the evaluation of these patients and result in improved patient outcomes. [ABSTRACT FROM AUTHOR]

Background There is no data on the impact of coronary computed tomography angiography (coronary CTA), as an addition to angiography, on the outcomes of percutaneous coronary interventions (PCI) in bifurcation lesions. Methods Patients with stable coronary artery disease scheduled for elective bifurcation PCI were randomized 1:1 to planning the procedure based on coronary CTA and angiography (CTA group) or angiography alone (CA group). The primary efficacy endpoint was the immediate angiographic result. Secondary efficacy endpoints were: a) procedural characteristics and b) postprocedural fractional flow reserve (FFR) in the side branch (SB) in a subgroup of patients. Safety outcomes were: a) periprocedural myocardial infarction, b) contrast use and c) radiation dose. Results PCI of 45 lesions in the CTA group and 47 lesions in the CA group was performed. Postprocedural lumen diameters in the main branch (MB) and SB, frequency of SB compromise or occlusion and mean SB FFR values were not different between study groups. Two or more stents were implanted less frequently in the CTA group than in the CA group (18% vs. 43%, p = 0.01). This difference was driven by less frequent MB 2-stent overlap in the CTA group (7 vs. 21%, p = 0.046) and numerically less SB stenting (11% vs. 21%, p = 0.07). Proximal optimization technique was used more frequently in the CTA group (44% vs. 21%, p = 0.018). Conclusions CTA-assisted bifurcation PCI leads to similar immediate results compared with angiography alone, however is associated with higher use of single-stent procedures with proximal optimization, less frequent 2-stent overlap and less SB stenting. [ABSTRACT FROM AUTHOR]

Background: In patients with coronary artery disease, clinical outcome depends on the extent of reversible myocardial ischemia. Whether the outcome also depends on the severity of the stenosis as determined by fractional flow reserve (FFR) remains unknown.Objectives: This study sought to investigate the relationship between FFR values and vessel-related clinical outcome.Methods: We prospectively studied major adverse cardiovascular events (MACE) at 2 years in 607 patients in whom all stenoses were assessed by FFR and who were treated with medical therapy alone. The relationship between FFR and 2-year MACE was assessed as a continuous function. Logistic and Cox proportional hazards regression models were used to calculate the average decrease in the risk of MACE per 0.05-U increase in FFR.Results: MACE occurred in 272 (26.5%) of 1,029 lesions. Target lesions with diameter stenosis ≥70% were more often present in the MACE group (p < 0.01). Median FFR was significantly lower in the MACE group versus the non-MACE group (0.68 [interquartile range: 0.54 to 0.77] vs. 0.80 [interquartile range: 0.70 to 0.88]; p < 0.01). The cumulative incidence of MACE significantly increased with increasing FFR quartiles. An average decrease in MACE per 0.05-unit increase in FFR was statistically significant even after adjustment for all clinical and angiographic features (odds ratio: 0.81; 95% confidence interval: 0.76 to 0.86]). The strongest increase in MACE occurred for FFR values between 0.80 and 0.60. In multivariable Cox regression analysis, FFR was significantly associated with MACE up to 2 years (hazard ratio: 0.87; 95% confidence interval: 0.83 to 0.91]).Conclusions: In patients with stable coronary disease, stenosis severity as assessed by FFR is a major and independent predictor of lesion-related outcome. (FAME II - Fractional Flow Reserve [FFR] Guided Percutaneous Coronary Intervention [PCI] Plus Optimal Medical Treatment [OMT] Verses OMT; NCT01132495). [ABSTRACT FROM AUTHOR]

Pressure wire-based fractional flow reserve is considered the standard of reference for evaluation of the ischemic potential of coronary stenoses and the expected benefit from revascularization. Accordingly, its application in daily practice or for research purposes has to be as standardized as possible to avoid technical or operator-related artifacts in pressure recordings. This document proposes a standardized way of acquiring, recording, interpreting, and archiving the pressure tracings for daily practice and for the purpose of clinical research involving a core laboratory. Proposed standardized steps enhance the uniformity of clinical practices and data interpretation. [ABSTRACT FROM AUTHOR]

Objectives This study sought to assess the impact of a wide range of mean right atrial pressure (P ra ) on fractional flow reserve (FFR) measurements. Background FFR invasively assesses the ischemic potential of coronary stenoses. FFR is calculated as the ratio of mean distal coronary pressure (P d ) to mean aortic pressure (P a ) during maximal hyperemia. The P ra is considered to have little impact if it is within normal range, so it is neglected in the formula. Methods In 1,676 stenoses of 1,235 patients undergoing left-right heart catheterization for ischemic (642 [52%]) or valvular heart disease (593 [48%]), the authors compared the FFR values calculated without accounting for P ra (FFR= P d /P a ) to the corresponding myocardial fractional flow reserve (FFR myo ) values accounting for P ra (FFR myo = P d − P ra /P a − P ra ). Results The median P ra was 7 (interquartile range [IQR]: 5 to 10) mm Hg with a maximum of 27 mm Hg. The correlation and agreement between FFR and FFR myo was excellent (R 2 = 0.987; slope 1.096 ± 0.003). The median FFR (0.85; IQR: 0.78 to 0.91) was slightly but statistically significantly higher than the median FFR myo (0.83; IQR: 0.76 to 0.90; p < 0.001) with a median difference of 0.01 (IQR: 0.01 to 0.02). Values of FFR above the cutoff of 0.80 provided an FFR myo ≤0.80 in 110 (9%) stenoses. No FFR value above 0.80 provided an FFR myo ≤0.75. Conclusions The difference between FFR and FFR myo was minimal even in patients with markedly increased P ra . FFR values above the gray zone (i.e., >0.80) did not yield values below the gray zone (i.e., ≤0.75) in any case, which suggests that the impact of right atrial pressure on FFR measurement is indeed negligible. [ABSTRACT FROM AUTHOR]

Localization of sound source azimuth within horizontal plane uses interaural time differences (ITDs) between sounds arriving through the left and right ear. In mammals, ITDs are processed primarily in the medial superior olive (MSO) neurons. These are the first binaural neurons in the auditory pathway. The MSO neurons are notable because they possess high time precision in the range of tens of microseconds. Several theories and experimental studies explain how neurons are able to achieve such precision. In most theories, neuronal coincidence detection processes the ITDs and encodes azimuth in ascending neurons of the auditory pathway using modalities that are more tractable than the ITD. These modalities have been described as firing rate codes, place codes (labeled line codes) and similarly. In this theoretical model it is described how the ITD is processed by coincidence detection and converted into spikes by summing the postsynaptic potentials. Particular postsynaptic conductance functions are used in order to obtain an analytical solution in a closed form. Specifically, postsynaptic response functions are derived from the exponential decay of postsynaptic conductances and the MSO neuron is modeled as a simplified version of the Spike Response Model (SRM 0 ) which uses linear summations of the membrane responses to synaptic inputs. For plausible ratios of time constants, an analytical solution used to describe properties of coincidence detection window is obtained. The parameter space is then explored in the vicinity of the analytical solution. The variation of parameters does not change the solution qualitatively. [ABSTRACT FROM AUTHOR]

Objectives The present study sought to establish the dosage of intracoronary (IC) adenosine associated with minimal side effects and above which no further increase in flow can be expected. Background Despite the widespread adoption of IC adenosine in clinical practice, no wide-ranging, dose-response study has been conducted. A recurring debate still exists regarding its optimal dose. Methods In 30 patients, Doppler-derived flow velocity measurements were obtained in 10 right coronary arteries (RCAs) and 20 left coronary arteries (LCAs) free of stenoses >20% in diameter. Flow velocity was measured at baseline and after 8 ml bolus administrations of arterial blood, saline, contrast medium, and 9 escalating doses of adenosine (4 to 500 μg). The hyperemic value was expressed in percent of the maximum flow velocity reached in a given artery (Q/Q max , %). Results Q/Q max did not increase significantly beyond dosages of 60 μg for the RCA and 160 μg for LCA. Heart rate did not change, whereas mean arterial blood pressure decreased by a maximum of 7% (p < 0.05) after bolus injections of IC adenosine. The incidence of transient A-V blocks was 40% after injection of 100 μg in the RCA and was 15% after injection of 200 μg in the LCA. The duration of the plateau reached 12 ± 13 s after injection of 100 μg in the RCA and 21 ± 6 s after the injection of 200 μg in the LCA. A progressive prolongation of the time needed to return to baseline was observed. Hyperemic response after injection of 8 ml of contrast medium reached 65 ± 36% of that achieved after injection of 200 μg of adenosine. Conclusions This wide-ranging, dose-response study indicates that an IC adenosine bolus injection of 100 μg in the RCA and 200 μg in the LCA induces maximum hyperemia while being associated with minimal side effects. [ABSTRACT FROM AUTHOR]

Until recently, our understanding of coronary artery disease (CAD) has been largely based on a purely anatomical approach as derived from the invasive angiogram. The confirmation of the diagnosis of “significant” CAD, the assessment of its extent, the risk stratification of patients, the therapeutic decisions, the definition of study end-points, and the validation of non-invasive testing, all mainly relied on “eyeballing” the angiogram, i.e. a subjective evaluation of the presence of at least 50% (or 70%) diameter stenosis.With the development of invasive, wire-based, means to quantify coronary pressure and flow with high spatial resolution, one realized that purely angiographic metrics correlated poorly with functional information. Currently, it is admitted that both anatomical and functional information are needed to define CAD and to optimize its management. In the present review, we summarize the main characteristics of invasive functional indices of ischemia and perfusion. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to develop a new model for assessment of stenosis severity in a bifurcation lesion including its core. The diagnostic performance of this model, powered by 3-dimensional quantitative coronary angiography to predict the functional significance of obstructive bifurcation stenoses, was evaluated using fractional flow reserve (FFR) as the reference standard. Background Development of advanced quantitative models might help to establish a relationship between bifurcation anatomy and FFR. Methods Patients who had undergone coronary angiography and interventions in 5 European cardiology centers were randomly selected and analyzed. Different bifurcation fractal laws, including Murray, Finet, and HK laws, were implemented in the bifurcation model, resulting in different degrees of stenosis severity. Results A total of 78 bifurcation lesions in 73 patients were analyzed. In 51 (65%) bifurcations, FFR was measured in the main vessel. A total of 34 (43.6%) interrogated vessels had an FFR ≤0.80. Correlation between FFR and diameter stenosis was poor by conventional straight analysis (ρ = −0.23, p < 0.001) but significantly improved by bifurcation analyses: the highest by the HK law (ρ = −0.50, p < 0.001), followed by the Finet law (ρ = −0.49, p < 0.001), and the Murray law (ρ = −0.41, p < 0.001). The area under the receiver-operating characteristics curve for predicting FFR ≤0.80 was significantly higher by bifurcation analysis compared with straight analysis: 0.72 (95% confidence interval: 0.61 to 0.82) versus 0.60 (95% confidence interval: 0.49 to 0.71; p = 0.001). Applying a threshold of ≥50% diameter stenosis, as assessed by the bifurcation model, to predict FFR ≤0.80 resulted in 23 true positives, 27 true negatives, 17 false positives, and 11 false negatives. Conclusions The new bifurcation model provides a comprehensive assessment of bifurcation anatomy. Compared with straight analysis, identification of lesions with preserved FFR values in obstructive bifurcation stenoses was improved. Nevertheless, accuracy was limited by using solely anatomical parameters. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The aim of this study was to determine the impact of downstream coronary stenosis in the left anterior descending coronary artery (LAD) or left circumflex coronary artery (LCx) on the assessment of fractional flow reserve (FFR) across an intermediate left main coronary artery (LMCA) stenosis in humans with the pressure wire positioned in the nondiseased downstream vessel. BACKGROUND: Accurate assessment of intermediate LMCA disease is critical for guiding decisions regarding revascularization. In theory, FFR across an intermediate LMCA stenosis will be affected by downstream disease, even if the pressure wire is positioned in the nondiseased downstream vessel. METHODS: After percutaneous coronary intervention of the LAD, LCx, or both, an intermediate LMCA stenosis was created with a deflated balloon catheter. FFR was measured in the LAD and LCx coronary arteries before and after creation of downstream stenosis by inflating an angioplasty balloon within the newly placed stent. The true FFR (FFRtrue) of the LMCA, measured in the nondiseased downstream vessel in the absence of stenosis in the other vessel, was compared with the apparent FFR (FFRapp) measured in the presence of stenosis. RESULTS: In 25 patients, 91 pairs of measurements were made, 71 with LAD stenosis and 20 with LCx stenosis. FFRtrue of the LMCA was significantly lower than FFRapp (0.81 ± 0.08 vs. 0.83 ± 0.08, p < 0.001), although the numerical difference was small. This difference correlated with the severity of the downstream disease (r 0.35, p < 0.001). In all cases in which FFRapp was >0.85, FFRtrue was >0.80. CONCLUSIONS: In most cases, downstream disease does not have a clinically significant impact on the assessment of FFR across an intermediate LMCA stenosis with the pressure wire positioned in the nondiseased vessel. [ABSTRACT FROM AUTHOR]

Fractional flow reserve (FFR) has never been investigated in patients with aortic stenosis (AS). From 2002 to 2010, we identified 106 patients with AS and coronary artery disease with at least one intermediate lesion treated according to FFR guidance. We matched 212 contemporary control patients with AS in which revascularization was decided on angiography only. More patients in the FFR-guided group underwent percutaneous coronary intervention (24% vs 13%; p = 0.019), whereas there was a trend toward less coronary artery bypass grafting (CABG) performed. After FFR, the number of diseased vessels was downgraded within the FFR-guided group (from 1.85 ± 0.97 to 1.48 ± 1; p <0.01) and compared with the angio-guided group (1.48 ± 1 vs 1.8 ± 0.97; p <0.01). Less aortic valve replacement was reported in the FFR-guided group (46% vs 57%; p = 0.056). In patients who underwent CABG, less venous conduits (0.5 ± 0.69 vs 0.73 ± 0.76; p = 0.05) and anastomoses (0.61 ± 0.85 vs 0.94 ± 1; p = 0.032) were necessary in the FFR-guided group. Up to 5 years, we found no difference in major adverse cardiac events (38% vs 39%; p = 0.98), overall death (32% vs 31%; p = 0.68), nonfatal myocardial infarction (2% vs 2%; p = 0.79), and revascularization (8% vs 7%; p = 0.76) between the 2 groups. In conclusion, FFR guidance impacts the management of selected patients with moderate or severe AS and coronary artery disease by resulting into deferral of aortic valve replacement, more patients treated with percutaneous coronary intervention, and in patients treated with CABG, into less venous grafts and anastomoses without increasing adverse event rates up to 5 years. [ABSTRACT FROM AUTHOR]

GeoGOBLIN, a novel environmental impact and land balance assessment tool, builds upon the GOBLIN biophysical land use emissions model for Ireland, offering enhanced resolution and system-level detail. It combines remotely sensed data and national agricultural census data to model climate change, air quality, and eutrophication emissions at the catchment level. Integration of the CBM-CFS3 forest carbon modelling framework (utilised in Ireland's National Inventory Report) increases alignment with national emissions reporting. GeoGOBLIN disaggregates emissions by life cycle assessment impact categories, making it a valuable tool for policymakers and researchers evaluating environmental and economic trade-offs associated with land-use scenarios. Illustrative scenarios demonstrate GeoGOBLIN's ability to assess the multifaceted impacts of alternative land uses, supporting informed decision-making for sustainable land use, food production, and a circular bioeconomy. • Land balance model for the assessment of environmental impacts from land use/cover change at the catchment level. • Spatially specific land cover and environmental impact assessment. • Assessment of multiple life cycle impact categories at the catchment level. • Rules based assessment for scenario result prioritization. [ABSTRACT FROM AUTHOR]

• Aortic dissection need to be considered as a cause of acute coronary syndrome before rushing into invasive treatments. • Screening for other diseases that may affect body vasculature should be assessed; IgG4-RD can cause aortitis and aortic dissection. • Histopathology findings are never diagnostic alone for IgG4-RD and must be interpreted in the context of clinical, serologic and radiologic data. Occlusion of the right coronary artery is a relatively rare complication of type A aortic dissection and an example of type 2 myocardial infarction (MI) as well but when it occurs, it may have a fatal result for the patient. Aortic pseudoaneurysms are local type A dissections with a restricted extent in which the majority of the aortic wall has been breached and luminal blood is held in only by a thin rim of the remaining wall, mainly purely the adventitia. They typically occur from iatrogenic trauma by interventional procedures or previous cardiac surgery. We present a case of a 56 years old patient who suffered an acute functional MI due to such pseudoaneurysm formed in the context of an undiagnosed aortitis. The etiology remained unclear until the surgical aortic prosthesis was deemed necessary, finding chronic IgG4 infiltrates in the aortic tissue. To our knowledge, this is the first case of IgG4-related aortitis causing functional MI and cardiogenic shock. [ABSTRACT FROM AUTHOR]

Background: The neuroplastic pathway, which includes cyclic adenosine monophosphate response element-binding protein 1 (CREB1), brain-derived neurotrophic factor (BDNF), and its receptor (neurotrophic tyrosine kinase receptor, type 2 [NTRK2]), plays a crucial role in the adaptation of brain to stress, and thus variations of these genes are plausible risk factors for depression. Methods: A population-based sample was recruited, subsets of which were interviewed and underwent functional magnetic resonance imaging. We investigated the association of nine polymorphisms throughout the CREB1-BDNF-NTRK2 pathway with lifetime depression, rumination, current depression severity, negative life events, and sad face emotion processing in a three-level design. Results: In the population study, BDNF-rs6265 and CREB1-rs2253206 major alleles were significantly associated with rumination and through rumination with current depression severity. However, childhood adversity increased the risk of lifetime depression in the minor allele carriers of BDNF-rs6265 and CREB1-rs2253206 and in alleles of six other single nucleotide polymorphisms (SNPs). We validated our findings in the interviewed subjects using structural equation modeling. Finally, using functional magnetic resonance imaging, we found that viewing sad faces evoked greater activity in depression-related areas in healthy control subjects possessing the minor alleles of BDNF-rs6265 and CREB1-rs2253206. Conclusions: Genetic variation associated with reduced function in the CREB1-BDNF-NTRK2 pathway has multiple, sometimes opposing, influences on risk mechanisms of depression, but almost all the SNPs studied amplified the effect of childhood adversity. The use of cognitive and neural intermediate phenotypes together with a molecular pathway approach may be critical to understanding how genes influence risk of depression. [ABSTRACT FROM AUTHOR]

Abstract: In animal models endogenous cannabinoids have an inhibitory effect on trigeminovascular activation through the cannabinoid receptor 1 (CB1), although there is no evidence of the potential role of CB1 in human migraine. In this study we applied single marker association and haplotypic trend regression analysis to investigate the relationship between the CB1 gene (CNR1) and headache with migraine symptoms (nausea, photophobia and disability, measured by the ID-migraine questionnaire). We identified our controls (CO=684) as those who have not reported ID-migraine symptoms at all and defined migraine headache sufferers (M =195) as those who reported all three symptoms. The CNR1 was covered by 10 SNPs located throughout the gene based on haplotype tagging (htSNP) and previous literature. Our results demonstrated a significant haplotypic effect of CNR1 on migraine headaches (p =0.008, after permutation p =0.017). This effect was independent of reported depression or drug/alcohol abuse although using neuroticism in the analysis as covariant slightly decreased this association (p =0.027, permutated p =0.052). These results suggest a significant effect of CNR1 on migraine headaches that might be related to the alteration of peripheral trigeminovascular activation. In addition, this is the first study to demonstrate the effectiveness of using trait components combinations to define extreme phenotypes with haplotype analysis in genetic association studies for migraine. However, further studies are needed to elucidate the role of CNR1 and the cannabinoid system in migraine. [Copyright &y& Elsevier]