Target achievement and cardiovascular event rates with Lomitapide in homozygous Familial Hypercholesterolaemia

Background Homozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Lomitapide reduces low-density lipoprotein cholesterol (LDL-C) levels; however, the probable impact on LDL-C goals and CV events is unknown. Methods We used data collected in the first 26 weeks of the lomitapide pivotal phase 3 study (NCT00730236) to evaluate achievement of European Atherosclerosis Society (EAS) LDL-C targets. We used publicly available data reporting major adverse CV events (MACE) rates from other cohorts of HoFH patients to compare event rates for an equivalent number of patient years of exposure (98) in the lomitapide extension trial (NCT00943306). Results Twenty-nine patients were included in the phase 3 study. During the first 26 weeks, 15 (51%) and eight (28%) reached LDL-C targets of 100 mg/dL and 70 mg/dL, respectively, at least once. Fourteen (74%) and 11 (58%) of the 19 patients who remained in the extension study after week 126 reached LDL-C targets of 100 mg/dL and 70 mg/dL at least once during the entire study period. Only two MACE were reported in the lomitapide trials (one cardiac death and one coronary artery bypass graft (CABG)) – equivalent to 1.7 events per 1000 patient months of treatment. MACE rates were 21.7, 9.5 and 1.8 per 1000 patient-months respectively in cohorts of HoFH patients pre- and post-mipomersen, and receiving evolocumab. On treatment LDL-C levels were 166, 331 and 286 mg/dL for lomitapide, mipomersen and evolocumab, respectively. Conclusions Approximately three quarters and half of patients who took lomitapide for at least 2 years reached LDL-C goals of 100 mg/dL and 70 mg/dL, respectively. There were fewer major CV events per 1000 patient months of treatment in patients taking lomitapide, mipomersen or evolocumab than reported in the mipomersen cohort prior to starting mipomersen. These results support the hypothesis that novel lipid-lowering therapies may reduce CV events in HoFH patients by lowering LDL-C further. Trial registration NCT00730236 (registered 8 Aug 2008) and NCT00943306 (registered 22 July 2009)

Cortisol awakening response over the course of humanitarian aid deployment: A prospective cohort study

Alastair Ager - ORCID 0000-0002-9474-3563 https://orcid.org/0000-0002-9474-3563Added VoR 2021-01-05Background: Internationally deployed humanitarian aid (HA) workers are routinely confronted with potentially traumatic stressors. However, it remains unknown whether HA deployment and related traumatic stress are associated with long-term changes in hypothalamic-pituitary-adrenal (HPA) axis function. Therefore, we investigated whether cortisol awakening response (CAR) decreased upon deployment and whether this was moderated by previous and recent trauma exposure and parallel changes in symptom severity and perceived social support.Methods: In this prospective study, n=86 HA workers (68% females) completed questionnaires regarding trauma exposure, posttraumatic stress disorder (PTSD), anxiety and depressive symptoms and perceived social support, as well as salivary cortisol assessments at awakening and 30 minutes post-awakening at before, early and 3-6 months post-deployment.Results: Linear mixed models showed significantly decreased CAR (b(SE)=-.036(.011), p=.002) and awakening cortisol over time (b(SE)=-.007(.003), p=.014). The extent of awakening cortisol change was significantly moderated by interactions between previous and recent trauma exposure. Also, a steeper awakening cortisol decrease was significantly associated with higher mean anxiety and PTSD symptoms across assessments. No significant effects were found for social support.Conclusions: We observed attenuated CAR and awakening cortisol upon HA deployment, with a dose-response effect between trauma exposure before and during the recent deployment on awakening cortisol. Awakening cortisol change was associated with PTSD and anxiety symptom levels across assessments. Our findings support the need for organizational awareness that work-related exposures may have long-lasting biological effects. Further research assessing symptoms and biological measures in parallel is needed to translate current findings into guidelines on the individual level.This work was funded by the US Centers for Disease Control and Prevention and the Antares Foundation through a cooperative agreement [Grant Number: 5U01EH000217]; The first author Yulan Qing is financially supported by the Chinese Scholarship Council Grant for her Ph.D. (NO. 201504910771). Additionally, Mirjam van Zuiden was supported by a Veni grant from the Netherlands organization for Health research and Development (ZonMw, grant no. 91617037). The funding source had no role in the design or execution of the research.https://doi.org/10.1080/20008198.2020.181664911pubpub

Psychological Distress, Depression, Anxiety, and Burnout among International Humanitarian Aid Workers: A Longitudinal Study

Background International humanitarian aid workers providing care in emergencies are subjected to numerous chronic and traumatic stressors. Objectives To examine consequences of such experiences on aid workers' mental health and how the impact is influenced by moderating variables. Methodology We conducted a longitudinal study in a sample of international non-governmental organizations. Study outcomes included anxiety, depression, burnout, and life and job satisfaction. We performed bivariate regression analyses at three time points. We fitted generalized estimating equation multivariable regression models for the longitudinal analyses. Results Study participants from 19 NGOs were assessed at three time points: 212 participated at pre-deployment; 169 (80%) post-deployment; and 154 (73%) within 3-6 months after deployment. Prior to deployment, 12 (3.8%) participants reported anxiety symptoms, compared to 20 (11.8%) at post-deployment (p-_=-_00027); 22 (10.4%) reported depression symptoms, compared to 33 (19.5%) at post-deployment (p-_=-_00117) and 31 (20.1%) at follow-up (p-_=-_.00083). History of mental illness (adjusted odds ratio [AOR] 4.2; 95% confidence interval [CI] 145-1250) contributed to an increased risk for anxiety. The experience of extraordinary stress was a contributor to increased risk for burnout depersonalization (AOR 1.5; 95% CI 1.17-1.83). Higher levels of chronic stress exposure during deployment were contributors to an increased risk for depression (AOR 11; 95% CI 102-1.20) comparing post- versus pre-deployment, and increased risk for burnout emotional exhaustion (AOR 1.1; 95% CI 1.04-1.19). Social support was associated with lower levels of depression (AOR 09; 95% CI 084-095), psychological distress (AOR-_=-_0.9; [CI] 0.85-0.97), burnout lack of personal accomplishment (AOR 095; 95% CI 091-098), and greater life satisfaction (p-_=-_0.0213). Conclusions When recruiting and preparing aid workers for deployment, organizations should consider history of mental illness and take steps to decrease chronic stressors, and strengthen social support networks.sch_iih7pub4233pub

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Decreased awakening cortisol over the course of humanitarian aid deployment is associated with stress-related symptoms: A prospective cohort study

Ager, Alastair - ORCID 0000-0002-9474-3563 https://orcid.org/0000-0002-9474-3563Item not available in this repository.Background: Internationally deployed humanitarian aid (HA) workers are at risk for traumatic and chronic stress, and consequently stress-related psychopathology. Therefore, HA deployment may lead to long-term changes in neuroendocrine stress reactivity. Objective: We investigated whether awakening cortisol changed upon deployment, and whether this was associated with lifetime childhood and adulthood traumatic stressors, current deployment-related traumatic and chronic stressors and within-person changes in stress-related symptomatology upon deployment. Method: From a prospective study among expatriate HA workers (n = 214) from 19 international NGOs, we included n = 86 participants (68% females, 33 ± 8 years) who completed questionnaires and cortisol assessments at three points: pre-deployment, early post-deployment and 3–6 months post-deployment. At each assessment, cortisol parameters were calculated from two saliva samples: at awakening and 30 minutes post-awakening. Results: Linear mixed models showed significant decreased awakening cortisol over time (bs: −.036 [SE = .011] to −.008 [SE = .003], all ps < .007). Cortisol was significantly predicted by three-way interactions between lifetime stressors, deployment stressors and time, with the smallest decrease over time in those with limited lifetime and current stressors (all ps < .05). The change in cortisol was no longer significant upon inclusion of stress-related symptoms in the model. Moreover, a sharper cortisol decrease was significantly associated with higher anxiety (p = .004) and PTSD symptoms (p = .049) across assessments. Conclusions: This is the first study indicating decreased awakening cortisol after HA deployment. The exact decrease within participants depended on the amount of lifetime and current stressors. Importantly, when taking changes in stress-related symptomatology into account, we found these accounted for the attenuated awakening cortisol.https://doi.org/10.1080/20008198.2019.161383410pubpubSup

A systematic review of the effectiveness of mental health promotion interventions for young people in low and middle income countries.

BACKGROUND: This systematic review provides a narrative synthesis of the evidence on the effectiveness of mental health promotion interventions for young people in low and middle-income countries (LMICs). Commissioned by the WHO, a review of the evidence for mental health promotion interventions across the lifespan from early years to adulthood was conducted. This paper reports on the findings for interventions promoting the positive mental health of young people (aged 6-18 years) in school and community-based settings. METHODS: Searching a range of electronic databases, 22 studies employing RCTs (N = 11) and quasi-experimental designs conducted in LMICs since 2000 were identified. Fourteen studies of school-based interventions implemented in eight LMICs were reviewed; seven of which included interventions for children living in areas of armed conflict and six interventions of multicomponent lifeskills and resilience training. Eight studies evaluating out-of-school community interventions for adolescents were identified in five countries. Using the Effective Public Health Practice Project (EPHPP) criteria, two reviewers independently assessed the quality of the evidence. RESULTS: The findings from the majority of the school-based interventions are strong. Structured universal interventions for children living in conflict areas indicate generally significant positive effects on students' emotional and behavioural wellbeing, including improved self-esteem and coping skills. However, mixed results were also reported, including differential effects for gender and age groups, and two studies reported nonsignficant findings. The majority of the school-based lifeskills and resilience programmes received a moderate quality rating, with findings indicating positive effects on students' self-esteem, motivation and self-efficacy. The quality of evidence from the community-based interventions for adolescents was moderate to strong with promising findings concerning the potential of multicomponent interventions to impact on youth mental health and social wellbeing. CONCLUSIONS: The review findings indicate that interventions promoting the mental health of young people can be implemented effectively in LMIC school and community settings with moderate to strong evidence of their impact on both positive and negative mental health outcomes. There is a paucity of evidence relating to interventions for younger children in LMIC primary schools. Evidence for the scaling up and sustainability of mental health promotion interventions in LMICs needs to be strengthened