The association between reasons for first using cannabis, later pattern of use, and risk of first-episode psychosis: the EU-GEI case-control study.

BACKGROUND: While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis. METHODS: We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case-control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case-control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case-control status. RESULTS: Controls (86.1%) and FEPp (75.63%) were most likely to report 'because of friends' as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: 'to feel better' as their RFUC (χ2 = 50.97; p < 0.001). RFUC 'to feel better' was associated with being a FEPp (OR 1.74; 95% CI 1.03-2.95) while RFUC 'with friends' was associated with being a control (OR 0.56; 95% CI 0.37-0.83). The path model indicated an association between RFUC 'to feel better' with heavy cannabis use and with FEPp-control status. CONCLUSIONS: Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use 'to feel better'. People who reported their reason for first using cannabis to 'feel better' were more likely to progress to heavy use and develop a psychotic disorder than those reporting 'because of friends'.

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Do AKT1, COMT and FAAH influence reports of acute cannabis intoxication experiences in patients with first episode psychosis, controls and young adult cannabis users?

Epidemiological and biological evidence support the association between heavy cannabis use and psychosis. However, it is unclear which cannabis users are susceptible to its psychotogenic effect. Therefore, understanding genetic factors contributing to this relationship might prove an important strategy to identify the mechanisms underlying cannabis-associated psychotic experiences. We aimed to determine how variation in AKT1, COMT and FAAH genotypes, and their interaction with three different groups (first episode psychosis (FEP) patients (n = 143), controls (n = 92) and young adult (YA) cannabis users n = 485)) influenced cannabis experiences, in those who had used cannabis at least once. We investigated the role of AKT1 (rs2494732), COMT Val158Met (rs4680) and FAAH (rs324420) on cannabis experiences by combining data from a large case-control study of FEP patients, with a naturalistic study of YA cannabis users (n = 720). Outcome measures were cannabis-induced psychotic-like experiences (cPLEs) and euphoric experiences (cEEs). We used linear mixed effects models to assess the effects of each genotype and their interaction with group, adjusting for age, sex, ethnicity, age of first cannabis use, years of use and frequency. cPLEs were more frequent in FEP patients than controls and YA cannabis users. cEEs were more prevalent in YA cannabis users than FEP patients or controls. Variation in AKT1, COMT or FAAH was not associated with cPLEs/cEEs. There was no interaction between genotype and group (FEP cases, controls and YA cannabis users) on cPLEs/cEEs. In conclusion, AKT1, COMT or FAAH did not modulate specific psychotomimetic response to cannabis and did not interact with group, contrary to previous research.

The use of a thromboelastometry-based algorithm reduces the need for blood product transfusion during orthotopic liver transplantation: A randomised controlled study.

BACKGROUND: Orthotopic liver transplantation is associated with a risk of bleeding. Coagulation in cirrhotic patients is difficult to assess with standard coagulation tests because of rebalanced coagulation. This can be better assessed by thromboelastometry which can detect coagulation impairments more specifically in such patients. OBJECTIVES: Our first objective was to compare the number of units of blood products transfused during liver transplantation when using an algorithm based on standard coagulation tests or a thromboelastometry-guided transfusion algorithm. DESIGN: Randomised controlled trial. SETTING: Single-centre tertiary care hospital in France, from December 2014 to August 2016. PARTICIPANTS: A total of 81 adult patients undergoing orthotopic liver transplantation were studied. Patients were excluded if they had congenital coagulopathies. INTERVENTION: Transfusion management during liver transplantation was guided either by a standard coagulation test algorithm or by a thromboelastometry-guided algorithm. Transfusion, treatments and postoperative outcomes were compared between groups. MAIN OUTCOME MEASURES: Total number of transfused blood product units during the operative period (1 U is one pack of red blood cells (RBCs), fresh frozen plasma (FFP) or platelets). RESULTS: Median [interquartile range] intra-operative transfusion requirement was reduced in the thromboelastometry group (3 [2 to 4] vs. 7 [4 to 10] U, P = 0.005). FFP and tranexamic acid were administered less frequently in the thromboelastometry group (respectively 15 vs. 46.3%, P = 0.002 and 27.5 vs. 58.5%, P = 0.005), whereas fibrinogen was more often infused in the thromboelastometry group (72.5 vs. 29.3%, P < 0.001). Median transfusions of FFP (3 [2 to 6] vs. 4 [2 to 7] U, P = 0.448), RBCs (3 [2 to 5] vs. 4 [2 to 6] U, P = 0.330) and platelets (1 [1 to 2] vs. 1 [1 to 2] U, P = 0.910) were not different between groups. In the postoperative period, RBC or platelet transfusion, the need for revision surgery or occurrence of haemorrhage were not different between groups. CONCLUSION: A transfusion algorithm based on thromboelastometry assessment of coagulation reduced the total number of blood product units transfused during liver transplantation, particularly FFP administration. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02352181.

Effects of continuation, frequency, and type of cannabis use on relapse in the first 2 years after onset of psychosis: an observational study.

BACKGROUND: Although cannabis use after a first episode of psychosis has been associated with relapse, little is known about the determinants of this most preventable risk factor for relapse of psychosis. Here we aimed to study whether the effects on outcome vary depending on the type of cannabis consumed and usage pattern. METHODS: In this observational study, we prospectively recruited and followed up patients aged 18-65 years who presented with their first episode of psychosis to psychiatric services in south London, London, UK. Relapse of psychosis within 2 years after onset of psychosis was defined as risk of subsequent admission to hospital. We classified patients into different patterns of cannabis use based on continuity of use after onset of psychosis, potency of cannabis consumed, and frequency of use after the onset of their illness. We used multiple regression analyses (logistic or binominal) to compare the different cannabis use groups and propensity score analysis to validate the results. FINDINGS: Between April 12, 2002, and July 26, 2013, 256 patients presented with a first episode of psychosis. We did follow-up assessments for these patients until September, 2015. Simple analyses showed that former regular users of cannabis who stopped after the onset of psychosis had the most favourable illness course with regards to relapse. In multiple analysis, continued high-frequency users (ie, daily use in all 24 months) of high-potency (skunk-like) cannabis had the worst outcome, indexed as an increased risk for a subsequent relapse (odds ratio [OR] 3·28; 95% CI 1·22-9·18), more relapses (incidence rate ratio 1·77; 95% CI 0·96-3·25), fewer months until a relapse occurred (b -0·22; 95% CI -0·40 to -0·04), and more intense psychiatric care (OR 3·16; 95% CI 1·26-8·09) after the onset of psychosis. INTERPRETATION: Adverse effects associated with continued use of cannabis after the onset of a first episode of psychosis depend on the specific patterns of use. Possible interventions could focus on persuading cannabis-using patients with psychosis to reduce use or shift to less potent forms of cannabis. FUNDING: National Institute for Health Research (NIHR).

Substance use, medication adherence and outcome one year following a first episode of psychosis.

Both substance use and poor medication adherence are associated with poor outcome in psychosis. To clarify the contributions of substance use and poor medication adherence to poor outcome in the year following a first episode of psychosis, 205 patients were evaluated for use of tobacco, alcohol, cannabis and stimulants at their psychosis onset, and in a 1-year follow-up. Data on medication adherence and symptom remission were also collected. Patients had high rates of overall substance use before (37-65%) and after psychosis onset (45-66%). 44% showed poor medication adherence and 55% did not reach remission from psychosis. Nicotine dependence and cannabis use after psychosis onset significantly predicted both poor medication adherence and non-remission, and poor medication adherence mediated the effects of these substances on non-remission. In conclusion, medication adherence lies on the causal pathway between nicotine dependence and cannabis on the one hand and non-remission on the other.

The RS685012 Polymorphism of ACCN2, the Human Ortholog of Murine Acid-Sensing Ion Channel (ASIC1) Gene, is Highly Represented in Patients with Panic Disorder.

Panic disorder (PD) is a disabling anxiety disorder that is characterized by unexpected, recurrent panic attacks, associated with fear of dying and worrying about possible future attacks or other behavioral changes as a consequence of the attacks. The acid-sensing ion channels (ASICs) are a family of proton-sensing channels expressed throughout the nervous system. Their activity is linked to a variety of behaviors including fear, anxiety, pain, depression, learning, and memory. The human analog of ASIC1a is the amiloride-sensitive cation channel 2 (ACCN2). Adenosine A2A receptors are suggested to play an important role in different brain circuits and pathways involved in anxiety reactions. In this work we aimed to evaluate the distribution of ACCN2 rs685012 and ADORA2A rs2298383 polymorphisms in PD patients compared with healthy subjects. We found no association between ADORA2A polymorphism and PD. Instead, the C mutated allele for ACCN2 rs685012 polymorphism was significantly more frequent in patients than in controls. On the contrary, the TT homozygous wild-type genotype and also the ACCN2 TT/ADORA2A CT diplotype were significantly more represented in controls. These results are suggestive for a role of ACCN2 rs685012 polymorphism in PD development in Caucasian people.

Accuracy of invasive arterial pressure monitoring in cardiovascular patients: an observational study.

INTRODUCTION: Critically ill patients and patients undergoing high-risk and major surgery, are instrumented with intra-arterial catheters and invasive blood pressure is considered the "gold standard" for arterial pressure monitoring. Nonetheless, artifacts due to inappropriate dynamic response of the fluid-filled monitoring systems may lead to clinically relevant differences between actual and displayed pressure values. We sought to analyze the incidence and causes of resonance/underdamping phenomena in patients undergoing major vascular and cardiac surgery. METHODS: Arterial pressures were measured invasively and, according to the fast-flush Gardner's test, each patient was attributed to one of two groups depending on the presence (R-group) or absence (NR-group) of resonance/underdamping. Invasive pressure values were then compared with the non-invasive ones. RESULTS: A total of 11,610 pulses and 1,200 non-invasive blood pressure measurements were analyzed in 300 patients. Ninety-two out of 300 (30.7%) underdamping/resonance arterial signals were found. In these cases (R-group) systolic invasive blood pressure (IBP) average overestimation of non-invasive blood pressure (NIBP) was 28.5 (15.9) mmHg (P <0.0001) while in the NR-group the overestimation was 4.1(5.3) mmHg (P < 0.0001). The mean IBP-NIBP difference in diastolic pressure in the R-group was -2.2 (10.6) mmHg and, in the NR-group -1.1 (5.8) mmHg. The mean arterial pressure difference was 7.4 (11.2) mmHg in the R-group and 2.3 (6.4) mmHg in the NR-group. A multivariate logistic regression identified five parameters independently associated with underdamping/resonance: polydistrectual arteriopathy (P = 0.0023; OR = 2.82), history of arterial hypertension (P = 0.0214; OR = 2.09), chronic obstructive pulmonary disease (P = 0.198; OR = 2.61), arterial catheter diameter (20 vs. 18 gauge) (P < 0.0001; OR = 0.35) and sedation (P = 0.0131; OR = 0.5). The ROC curve for the maximal pressure-time ratio, showed an optimum selected cut-off point of 1.67 mmHg/msec with a specificity of 97% (95% CI: 95.13 to 99.47%) and a sensitivity of 77% (95% CI: 67.25 to 85.28%) and an area under the ROC curve by extended trapezoidal rule of 0.88. CONCLUSION: Physicians should be aware of the possibility that IBP can be inaccurate in a consistent number of patients due to underdamping/resonance phenomena. NIBP measurement may help to confirm/exclude the presence of this artifact avoiding inappropriate treatments.

FloTrac/Vigileo(TM) (third generation) and MostCare(®)/PRAM versus echocardiography for cardiac output estimation in vascular surgery.

OBJECTIVE: To compare the FloTrac/Vigileo(TM) cardiac output (COFT/V) and the MostCare(®)/PRAM cardiac output (COMC/P) versus transthoracic echocardiographic cardiac output estimation (reference method; CO(ECHO)). DESIGN: Prospective observational study. SETTING: Single center, Cardio-Thoracic and Vascular Surgery/Intensive Care Unit. PARTICIPANTS: Patients undergoing elective vascular surgery. INTERVENTIONS: Cardiac output measurement with two pulse contour methods: the FloTrac/Vigileo(TM) and the MostCare(®)/PRAM before (T1) and after (T2) fluid loading versus echocardiography (reference method). MEASUREMENTS AND MAIN RESULTS: One hundred fifty-six CO measurements were performed in 26 patients. The data showed poor agreement between CO(ECHO) and CO(FT/V): r(2) = 0.29 (T1) and 0.27 (T2); bias -0.37 (T1) and -0.40 (T2) L/min; limits of agreement from -3.10 to 2.42 (T1) and from -3.0 to 2.2 (T2) L/min. The percentage error was 51.7% (T1) and 49.3% (T2). Conversely, COMC/P resulted in agreement with echocardiography: r(2) = 0.76 (T1) and 0.80 (T2); bias -0.01 (T1) and -0.06 (T2) L/min; limits of agreement from -1.13 to 1.11 (T1) and from -0.90 to 0.80 (T2) L/min, with a PE of 22.4% (T1) and of 17.0% (T2). CONCLUSIONS: In patients undergoing vascular surgery, the FloTrac/Vigileo(TM) did not demonstrate that it was a reliable system for CO monitoring when compared with echocardiography-derived CO. However, MostCare(®)/PRAM was shown to estimate CO with a good level of agreement with echocardiographic measures.

Dynamic response of liquid-filled catheter systems for measurement of blood pressure: precision of measurements and reliability of the Pressure Recording Analytical Method with different disposable systems.

PURPOSE: We aimed to compare the effects of a blood pressure transducer system specifically manufactured to limit underdamping artifacts with those of a standard system on hemodynamic parameter estimation and accuracy. MATERIALS AND METHODS: Forty-three consecutive patients undergoing vascular surgery at the University of Florence, Italy, were included. Arterial blood pressure signal was simultaneously registered with 2 MostCare monitors, connected to the artery either by a standard transducer or a specific transducer manufactured to avoid underdamping artifacts (Resonance Over-Shoot Eliminator [R.O.S.E.]; Becton Dickinson, Becton Drive, NJ). Patients were divided into 2 groups: absence (C group) or presence (R group) of underdamping/resonance artifacts of blood pressure signal. Systolic blood pressure, cardiac index, maximal pressure/time ratio (dP/dt(MAX)), and cardiac cycle efficiency were recorded every 30 seconds for 30 minutes. A total of 2675 measurements were performed with 34.9% incidence of underdamping/resonance artifacts. RESULTS: All hemodynamic parameters showed clinically acceptable differences in the C group; in contrast, the results differed greatly in the R group between standard and R.O.S.E. transducer (systolic blood pressure bias, 16.7 mm Hg; cardiac index bias, 0.24 L min(-1) m(-2); dP/dt(MAX) bias, 0.92 mm Hg/ms; cardiac cycle efficiency bias, 0.018 units). CONCLUSIONS: Underdamping/resonance artifacts frequently affect blood pressure measurement in operating rooms and intensive care units and cause severe overestimation of systolic blood pressure and incorrect estimation of hemodynamic parameters when the pulse contour method is used.