The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent ...findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology.
Eye-tracking data were collected from 486 6-to-30-year-old autistic (N = 282) and non-autistic control (N = 204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL).
The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline.
The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons.
Biological motion preference elicits small-to-medium-sized case-control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear.
Despite international guidelines, cognitive behavioural therapy for early psychosis (CBTep) is still under-used in daily clinical practice, mainly due to the lack of specific skills among mental ...health professionals. The aim of the study was to evaluate the feasibility and efficacy of a CBTep training course and to investigate the impact of trainees’ variables on the level of skills acquisition. An intensive and graded CBTep training programme consisting of 112 hours of plenary lectures, 30 hours of group supervision and 3 months of practical training was offered to mental health professionals of 65 Italian community Mental Health Centers (CMHCs). CBT expert psychologists were used as the comparison group. Participants underwent pre-planned exams to test the level of skills acquisition and were requested to complete a satisfaction survey. The vast majority of participants (93%) completed the training with medium–high evaluation scores and reported to be highly satisfied with the course. CMHCs staff members achieved high scores in the examinations and no major differences between them and CBT expert psychologists were found in most of the final exam scores. Our results support the feasibility and the efficacy of the training to build specific CBTep capacity in a large cohort of professionals working in Italian Generalist Mental Health Services.
Backgroud: Vascular inflammation is a hallmark of atherosclerosis and arterial and venous thromboembolic disease. Arterial hypertension is a highly significant risk factor for death and ...cardiovascular disease. High levels of angiotensin II (ATII) cause arterial hypertension by a complex inflammatory pathway requiring leukocyte recruitment and reactive oxygen species production within the vessel wall. Interactions of platelets, leukocytes and the vessel wall play pivotal roles in activating coagulation and precipitating thrombosis. Platelets provide a pro-coagulant surface for amplified thrombin generation in hemostasis and thrombosis, and play important roles in vascular inflammation by preserving vascular integrity. They also promote leukocyte recruitment in wire injury and angiogenesis models through glycoprotein Ib alpha (GPIbalpha) interacting with the integrin alphaMbeta2 (CD11b/CD18 or Mac-1) on leukocytes and regulate monocyte and neutrophil activation. How platelets, coagulation factors, leukocytes and the vessel wall cooperate to promote vascular inflammation in arterial hypertension is unclear.
Objective: The aim of this work was to explore the roles of TF, FXI, FXII, thrombin and platelet GPIbalpha on inflammatory monocyte-driven vascular dysfunction and arterial hypertension in ATII infused mice and rats as well as in 5/6 nephrectomized (5/6Nx) rats.
Methods: FXII-/-, FXI-/-, and hIL-4R/Ibalpha mice and 5/6NX rats were used for this study. Mice and rats where treated with ATII (1 mg×kg-1 ×d-1 for 7 days) using osmotic minipumps. Blood pressure was recorded using tail cuff measurement and telemetry carotid implants. To assess vasodilator properties, isolated aortic segments were mounted to force transducers in organ chambers to test their response to acetylcholine (ACh) and glyceryl trinitrate (GTN). ROS production was quantified within the aorta using dihydroethidium-derived fluorescence. Thrombin generation in platelet rich plasma (PRP) was measured using calibrated automated thrombography.
Results: ATII induces an upregulation of tissue factor, thrombin-dependent endothelial cell VCAM-1 expression and integrin alpha4- and platelet-dependent leukocyte adhesion to arterial conductance vessels. Depletion of platelets using an anti-GPIbalpha antibody as well as injection of anti-Mac-1 directed against the CD11b/CD18 integrin on leukocytes similarly prevented leukocyte rolling and adhesion. Reduced vascular recruitment of leukocytes was paralleled by diminished vascular ROS production assessed by the superoxide-sensitive dye dihydroethidium. ATII-induced vascular dysfunction unexpectedly involved the activation of FXI but not FXII. Moreover, inhibition of FXI synthesis attenuates blood pressure increase in response to ATII. The platelet FXI receptor GPIbalpha supports the upregulation of thrombin feedback activation in ATII-treated mice. Blockade of TF during ATII administration attenuated both endothelial dysfunction (acetylcholine concentration-relaxation curves) and smooth muscle dysfunction as demonstrated by improved vascular relaxation in response to the endothelium independent vasodilator glyceryl trinitrate and reduced ROS within the vessel wall. Five/6Nx rats had endothelial dysfunction that was prevented by FXI Antisense oligonucleotide. Thrombin-induced thrombin generation was increased in PRP of 5/6 Nx rats and markedly diminished by FXI Antisense oligonucleotide, mimicking the results from ATII-infused mice.
Conclusion: Our results reveal a critical role of platelet GPIbalpha to promote localized thrombin amplification and a FXI-thrombin feedback loop in ATII-induced vascular inflammation. Importantly, pharmacologic inhibition of FXI synthesis is sufficient to prevent thrombin propagation on platelets, to reduce vessel wall leukocyte infiltration, and to diminish ATII-induced endothelial dysfunction and arterial hypertension in mice and rats.Targeting FXI could be a novel therapeutic possibility to interrupt this heterotypic cellular coagulation-inflammatory circuit.
Monia:Isis Pharmaceuticals: Employment.
how best to manage patients with colorectal cancer and synchronous liver metastasis is still controversial, with specific concerns of increased risk of postoperative complications following combined ...resection. We aimed at analyzing the influence of combined liver resection on the risk of anastomotic leak (AL) following colorectal resection.
we reviewed the iCral prospectively maintained database to compare the relative risk of AL of patients undergoing colorectal resection for cancer to that of patients receiving simultaneous liver and colorectal resection for cancer with isolated hepatic metastases. The incidence of AL was the primary outcome of the analysis. Perioperative details and postoperative complications were also appraised.
out of a total of 996 patients who underwent colorectal resection for cancer, 206 receiving isolated colorectal resection were compared with a matched group of 53 patients undergoing simultaneous liver and colorectal resection. Combined surgery had greater operative time and resulted in longer postoperative hospitalization compared to colorectal resection alone. The proportion of overall morbidity following combined resection was significantly higher than after isolated colorectal resection (56.6% vs. 37.9%, p = 0.021). Overall, the two groups of patients did not differ neither on the rate of major postoperative complications, nor in terms of AL (9.4% vs. 6.3%, p = 0.381). At specific multivariate analysis, the duration of surgery was the only risk factor independently associated with the likelihood of AL.
combining hepatic with colorectal resection for the treatment of synchronous liver metastasis from colorectal cancer does not increase significantly the incidence of AL.
•Over the last decade there has been a growing interest in performing simultaneous resection of colorectal cancer with synchronous metastases confined to the liver.•Despite some concerns have been raised regarding a higher risk of postoperative morbidity, clinical evidence focusing on specific surgical-related morbidity is still scarce.•This study aims at comparing the relative risk of anastomotic failure in patients receiving isolated colorectal resection vs. patients undergoing colorectal resection in combination with liver metastasis resection.•By comparing well-matched groups of patients, this analysis demonstrates that simultaneous colorectal and liver resection does not confer a significantly higher risk of anastomotic leakage as compared to colorectal resection alone.
The extension of indications for procedures in a Day Surgery (DS) setting has led to changes in the anesthetic and surgical treatment of Inguinal Hernias (IH). According to the recommendations of the ...European Hernia Society, the treatment of IH in DS units should be performed under Monitored Anesthesia Care (MAC).
960 patients underwent IH repairs over a period of 24 months. The patients were randomly divided into two groups: R (remifentanil) and F (fentanyl); the group F was considered as a control group. The exclusion criteria in both group were: morbid obesity (BMI>40 or BMI>35 in association with high blood pressure or diabetes); coagulopathy; OSAS (obstructive sleep apnea syndrome) with AHI >10; cardiovascular, respiratory, renal, hepatic or metabolic disease; history of substances abuse; GERD-related esophagitis (gastro-esophageal reflux disease); chronic analgesic use; allergy to local anesthetic and ASA>III. Patients reported their level of pain on a verbal numeric scale (VNS), with scores ranging from 0 to 10. For each patient systolic and diastolic blood pressure (SBP and DBP), mean arterial pressure (MAP), heart rate (HR) and peripheral oxygen saturation (SpO2) were recorded. The results are presented as the mean value ± standard deviations; statistical analysis was performed using Student's t-test.
Amongst the 960 procedures, complications or side effects related to the anesthetic techniques didn't occur; no procedure-related complications requiring mechanical ventilation support were reported. Our research focused on evaluating remifentanil effectiveness in pain control and its impact on hemodynamic stability and respiratory function. There was a significant difference between the two groups with regard to the VNS.
Remifentanil, is an excellent drug for pain control during intra-operative procedures, that allows an optimal hemodynamic stability for IH repairs in a DS setting, due to its pharmacokinetic and pharmacodynamic properties and few adverse effects.
PCSK9 binds to the low density lipoprotein receptor (LDLR) and leads to LDLR degradation and inhibition of plasma LDL cholesterol clearance. Consequently, the role of PCSK9 in modulating circulating ...LDL makes it a promising therapeutic target for treating hypercholesterolemia and coronary heart disease. Although the C-terminal domain of PCSK9 is not involved in LDLR binding, the location of several naturally occurring mutations within this region suggests that it has an important role for PCSK9 function. Using a phage display library, we identified an anti-PCSK9 Fab (fragment antigen binding), 1G08, with subnanomolar affinity for PCSK9. In an assay measuring LDL uptake in HEK293 and HepG2 cells, 1G08 Fab reduced 50% the PCSK9-dependent inhibitory effects on LDL uptake. Importantly, we found that 1G08 did not affect the PCSK9-LDLR interaction but inhibited the internalization of PCSK9 in these cells. Furthermore, proteolysis and site-directed mutagenesis studies demonstrated that 1G08 Fab binds a region of β-strands encompassing Arg-549, Arg-580, Arg-582, Glu-607, Lys-609, and Glu-612 in the PCSK9 C-terminal domain. Consistent with these results, 1G08 fails to bind PCSK9ΔC, a truncated form of PCSK9 lacking the C-terminal domain. Additional studies revealed that lack of the C-terminal domain compromised the ability of PCSK9 to internalize into cells, and to inhibit LDL uptake. Together, the present study demonstrate that the PCSK9 C-terminal domain contribute to its inhibition of LDLR function mainly through its role in the cellular uptake of PCSK9 and LDLR complex. 1G08 Fab represents a useful new tool for delineating the mechanism of PCSK9 uptake and LDLR degradation.
Backround. Low-dose total body irradiation (TBI)-based nonmyeloablative conditioning regimens are widely used in acute myeloid leukemia (AML) patients in first or second complete remission (CR) at ...the time of transplantation. With these regimens the burden for tumor eradication relies mostly on immune-mediated graft-versus-leukemia (GVL) effects that can be impacted by donor type. Here we assessed the impact of donor type in a large cohort of AML patients transplanted in CR after low-dose TBI-based nonmyeloablative conditioning regimens.
Methods. Inclusion criteria included >= 18 years of age, de novo or secondary AML in CR1 or CR2, transplantation between 2004 and 2015, conditioning with fludarabine + 2 Gy TBI with or without pre- or post-transplant cyclophosphamide, no in vitro or in vivo T cell depletion of the graft (besides post-transplant cyclophosphamide), and either an HLA-matched sibling donor (MSD), a 10/10 HLA-matched unrelated donor (MUD), an HLA-haplo-identical donor (Haplo) or a single or double umbilical cord blood (CBT).
Results. Data from 1357 patients receiving grafts from MSD (n=594), MUD (n=442), Haplo (n=77) or given single or double CBT (n=244) were included. The proportion of patients transplanted in CR1 was 87%, 80%, 66% and 60% in MSD, MUD, Haplo and CBT groups, respectively (P<0.001) while median patient age at transplantation was 58, 63, 57 and 55 years, respectively (P<0.001). The proportion of patients with secondary AML was 16%, 22%, 21% and 20% in MSD, MUD, Haplo and CBT groups (P=0.04). Median follow-up was 49, 25, 17 and 48 months, respectively (P<0.001). Graft rejection occurred in 2% of each MSD and MUD recipients, 7% of haplo patients and 8% of CBT recipients (P<0.001). Grade III-IV acute GVHD was more frequent in CBT (16%) than in MUD (9%), haplo (8%) or MSD (7%) recipients (P<0.001). In contrast, chronic GVHD was less frequent in CBT (27%) and in haplo (30%) patients than in MSD (50%) and MUD (52%) recipients (P<0.001). Two-year OS and GRFS were 60% and 30% in MSD patients, 56% and 41% in CBT recipients, 54% and 24% in MUD recipients, and 42% and 35% in haplo patients, respectively (P=0.02 for OS and P=0.03 for GRFS ; Figure 1). Two-year incidences of relapse and nonrelapse mortality (NRM) were 33% and 12% in MSD patients, 29% and 20% in MUD recipients, 34% and 17% in CBT recipients, and 37% and 21% in haplo patients, respectively (P=0.7 for relapse and P<0.001 for NRM). In multivariate analyses, in comparison to MSD patients, each other donor type was associated with a significantly higher NRM. Interestingly, CBT was associated with a higher incidence of grade III-IV acute GVHD (HR 2.9, P=0.001) but a lower incidence of chronic GVHD (HR=0.4, P<0.001) than MSD resulting in a significantly worse GVHD-free relapse free survival (GRFS) the first 100 days (HR=1.5, P=0.02) but significantly better GRFS beyond day 100 (HR=0.6, P=0.001). Finally, there was a suggestion for lower OS in haplo patients (HR 1.5, P=0.08). Factors associated with worse OS included intermediate and adverse-risk cytogenetics and secondary AML. AML relapse, GVHD and infections were the primary causes of death of 24%, 6% and 4% of MSD recipients, 21%, 7% and 7% of MUD recipients, 22%, 5% and 14% of haplo recipients, and 25%, 8% and 5% of CBT recipients, respectively.
Conclusions. In this large cohort of AML patients transplanted in CR following low-dose TBI-based nonmyeloablative conditioning regimen there were no significant differences in OS and LFS between MSD, MUD and UCB while there was a suggestion for lower LFS and OS with haplo due to a higher incidence of death from infection. Since this regimen relies nearly exclusively on GVL effects for tumor eradication, our data suggest that the intensity of GVL effects is comparable with these four donor types. Further studies including more haplo patients are needed to confirm these results.
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Savani:Jazz Pharmaceuticals: Speakers Bureau. Mohty:Sanofi: Honoraria, Speakers Bureau.
Background: Post-transplant Cyclophosphamide (PT-Cy) is being used successfully in the setting of unmanipulated haploidentical transplant as graft versus host disease (GVHD) prophylaxis. Experience ...with the application of PT-Cy for prevention of GVHD post allogeneic stem cell transplantation (HSCT) from matched sibling donors (MSD) or unrelated donor (UD) is rather limited and it involves mainly single center experience and small numbers of patients.
Methods: Study aim was to evaluate the yield of PT-Cy as GVHD prophylaxis post HSCT from MSD and UD transplants for acute leukemia. We analyzed 423 patients (pts) with acute leukemia who received PT-CY alone or in combination to other drugs as GVHD prophylaxis and reported to the ALWP of the EBMT. 78 pts received PT-Cy alone (group 1); 204 received PT-CY in combination with one immunosuppressive (IS) drug -cyclosporine A (CSA) or and methotrexate (MTX) or mycophenolate mofetil (MMF)(group 2), while 141 pts received PT-Cy in combination with 2 IS drugs- CSA+MTX or CSA+MMF (group 3). Transplants were performed from 2007-2015 and median follow up is 16 months.
Results: There were some differences among groups: pts in group 1 were younger (median age 37 years, p<0.001) were transplanted in more recent year (2014, p<0.001), with a MSD (80%, p<0.001), and CMV positive donor (73%, p=0.008), received more frequently a reduced intensity conditioning (RIC) (56%, p<0.001) and bone marrow (BM) as source of stem cells (74%, p<0.001), with no ATG (100%, p<0.001). Probability of OS at 2 year was 50%, 52.2% and 62.4%, for the 3 groups, respectively, p=0.06.
Overall the cumulative incidence (CI) of grade II-IV acute GVHD was 27.9%, and the CI of chronic GVHD was 33.4%, and 16.5% the CI of extensive cGVHD. The CI of relapse at 2 years was 33.5% and non-relapse mortality (NRM) 18.5%, disease recurrence and GVHD were the most common causes of death in the whole cohort.
At 2 years the probability of leukemia free survival (LFS) and overall survival (OS) was 48% and 55%.
In multivariate analysis, the addition of IS to the PT-CY did not impact the risk of acute GVHD. Diagnosis of ALL (HR 0.57, p<0.001), unrelated donor (HR 1.65, p=0.02), RIC regimen (HR 1.72, p=0.01) and donor CMV positive (HR 1.77, p=0.01) were associated with the risk of grade II-IV acute GVHD. The use of PBSC (HR 2.41, p=0.01) and the absence of ATG (HR 1.69, p=0.03) were independently associated with an higher risk of chronic GVHD (p=0.005). In comparison to PT-Cy alone the addition of 1 or 2 IS drugs as GVHD prophylaxis were associated with reduced risk of extensive chronic GVHD (PT Cy+ 1 drug, HR 0.25, p=0.02, PT Cy+ 2 drugs, HR 0.77, p=0.01) as well the use of BM (HR 0.21, p<0.001) and the use of ATG (HR 0.22, p<0.001). Notably, the addition of 1 or 2 IS drugs to PT-CY did not impact the risk of relapse. Advance disease status (HR 2.42, p<0.001), was the only factor associated with increased risk of relapse. As for NRM addition of CSA+MTX or CSA+MMF to the PT-Cy (HR 0.35, p=0.04), diagnosis of AML (HR 0.35, p=0.001), and disease status at transplant (HR 2.94, p<0.001), and patients CMV serology (HR 2.04, p=0.04), influenced the NRM.
Factors associated with increased OS were the use of PT-Cy in combination with CSA+MTX or CSA+MMF (HR 0.49, p=0.02), diagnosis of AML (HR 0.59, p=0.001), and disease status at HSCT ((CR1 vs CR2 HR 0.58, p=0.02), (CR1 vs advanced disease (HR 0.40, p<0.001)).
Conclusions: PT-CY is effective GVHD prophylaxis in MSD and MUD HSCT for acute leukemia. The addition of IS drugs CSA+MTX or CSA+MMF to the PT-Cy shapes its effect and further decrease the risk of severe chronic GVHD, reducing transplant related mortality and improving overall survival.
Mohty:Sanofi: Honoraria, Speakers Bureau.
Patient satisfaction with services is an important outcome variable that is increasingly used in mental health service evaluation. This study includes 404 people with schizophrenia in five European ...sites and addresses five questions focused on site, service, and patient characteristics as variables that might explain service satisfaction, using the Verona Service Satisfaction Scale. Patient satisfaction differed significantly across sites (highest in Copenhagen, lowest in London). In all sites, patients were least satisfied with involvement of relatives in care and information about illness. A multiple regression model showed that lower levels of total service satisfaction were associated with living in London or Santander, being retired/unemployed, having more hospital admissions, having more severe psychopathology, having more unmet needs, or having lower satisfaction with life. This model explained 31 percent of variance in service satisfaction. Our data show that service satisfaction can be seen as a result of (1) the ability of the service to provide a standard of care above a certain quality threshold, and (2) the perception of each patient that the care received has been tailored to the patient's own problems.
"Salsiccia Sarda" is catalogued as a ready-to-eat food (RTE) for which actual European Legislation proposes microbiological criteria for L. monocytogenes. This study evaluates the influence of water ...activity (aw) on L. monocytogenes growth in 180 "Salsiccia Sarda" samples. A challenge test was performed to determine the L. monocytogenes growth potential (delta). The highest values of delta were detected in samples with limited values of a.sub.w, showing that this product is frequently around the limits for the growth of this pathogen. Our results provide some critical information about process parameter combinations that could lead to greater safety of this product and better L. monocytogenes control. Keywords: Challenge test, growth potential, legislation, Listeria monocytogenes, ready to eat meat products, "Salsiccia Sarda", water activity
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