Individual differences in the sensitivity to serotonergic drugs: a pharmacobehavioural approach using rats selected on the basis of their response to novelty

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FOLFIRINOX chemotherapy modulates the peripheral immune landscape in pancreatic cancer:Implications for combination therapies and early response prediction

Background: FOLFIRINOX chemotherapy has improved outcomes for pancreatic cancer patients, but poor long-term survival outcomes and high toxicity remain challenges. This study investigates the impact of FOLFIRINOX on plasma proteins and peripheral immune cells to guide immune-based combination therapies and, ideally, to identify a potential biomarker to predict early disease progression during FOLFIRINOX. Methods: Blood samples were collected from 86 pancreatic cancer patients before and two weeks after the first FOLFIRINOX cycle and subjected to comprehensive immune cell and proteome profiling. Principal Component Analysis and Linear Mixed Effect Regression models were used for data analysis. FOLFIRINOX efficacy was radiologically evaluated after the fourth cycle. Results: One cycle of FOLFIRINOX diminished tumour-cell-related pathways and enhanced pathways related to immune activation, illustrated by an increase in pro-inflammatory IL–18, IL–15, and TNFRSF4. Similarly, FOLFIRINOX promoted the activation of CD4 + and CD8 + T cells, the proliferation of NK(T), and the activation of antigen-presenting cells. Furthermore, high pre-treatment levels of VEGFA and PRDX3 and an elevation in FCRL3 levels after one cycle predicted early progression under FOLFIRINOX. Finally, patients with progressive disease exhibited high levels of inhibitory markers on B cells and CD8 + T cells, while responding patients exhibited high levels of activation markers on CD4 + and CD8 + T cell subsets. Conclusion: FOLFIRINOX has immunomodulatory effects, providing a foundation for clinical trials exploring immune-based combination therapies that harness the immune system to treat pancreatic cancer. In addition, several plasma proteins hold potential as circulating predictive biomarkers for early prediction of FOLFIRINOX response in patients with pancreatic cancer.</p

Donor Fecal Microbiota Transplantation Alters Gut Microbiota and Metabolites in Obese Individuals With Steatohepatitis

The intestinal microbiota has been linked to the development and prevalence of steatohepatitis in humans. Interestingly, steatohepatitis is significantly lower in individuals taking a plant-based, low-animal-protein diet, which is thought to be mediated by gut microbiota. However, data on causality between these observations in humans is scarce. In this regard, fecal microbiota transplantation (FMT) using healthy donors is safe and is capable of changing microbial composition in human disease. We therefore performed a double-blind randomized controlled proof-of-principle study in which individuals with hepatic steatosis on ultrasound were randomized to two study arms: lean vegan donor (allogenic n = 10) or own (autologous n = 11) FMT. Both were performed three times at 8-week intervals. A liver biopsy was performed at baseline and after 24 weeks in every subject to determine histopathology (Nonalcoholic Steatohepatitis Clinical Research Network) classification and changes in hepatic gene expression based on RNA sequencing. Secondary outcome parameters were changes in intestinal microbiota composition and fasting plasma metabolomics. We observed a trend toward improved necro-inflammatory histology, and found significant changes in expression of hepatic genes involved in inflammation and lipid metabolism following allogenic FMT. Intestinal microbial community structure changed following allogenic FMT, which was associated with changes in plasma metabolites as well as markers of .Conclusion:Allogenic FMT using lean vegan donors in individuals with hepatic steatosis shows an effect on intestinal microbiota composition, which is associated with beneficial changes in plasma metabolites and markers of steatohepatitis.Peer reviewe

Patient safety culture measurement in general practice. Clinimetric properties of 'SCOPE'

<p>Abstract</p> <p>Background</p> <p>A supportive patient safety culture is considered to be an essential condition for improving patient safety. Assessing the current safety culture in general practice may be a first step to target improvements. To that end, we studied internal consistency and construct validity of a safety culture questionnaire for general practice (SCOPE) which was derived from a comparable questionnaire for hospitals (Dutch-HSOPS).</p> <p>Methods</p> <p>The survey was conducted among caregivers of Dutch general practice as part of an ongoing quality accreditation process using a 46 item questionnaire. We conducted factor analyses and studied validity by calculating correlations between the subscales and testing the hypothesis that respondents' <it>patient safety grade </it>of their practices correlated with their scores on the questionnaire.</p> <p>Results</p> <p>Of 72 practices 294 respondents completed the questionnaire. Eight factors were identified concerning <it>handover and teamwork, support and fellowship, communication openness, feedback and learning from error, intention to report events, adequate procedures and staffing, overall perceptions of patient safety </it>and <it>expectations and actions of managers</it>. Cronbach's alpha of the factors rated between 0.64 and 0.85. The subscales intercorrelated moderately, except for the factor about intention to report events. Respondents who graded patient safety highly scored significantly higher on the questionnaire than those who did not.</p> <p>Conclusions</p> <p>The SCOPE questionnaire seems an appropriate instrument to assess patient safety culture in general practice. The clinimetric properties of the SCOPE are promising, but future research should confirm the factor structure and construct of the SCOPE and delineate its responsiveness to changes in safety culture over time.</p

B cell immune profiles in dysbiotic vermiform appendixes of pancreatic cancer patients

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with Klebsiella pneumoniae, Bifidobacterium animalis, and Adlercreutzia equolifaciens, while certain commensals are depleted. Our findings may suggest impaired B cell function within the GALT of PDAC patients, which could potentially be linked to microbial dysbiosis. Additional investigations are imperative to validate our observations and explore these potential targets of future therapies

Effects of patient safety culture interventions on incident reporting in general practice : A cluster randomised trial a cluster randomised trial

Background: A constructive safety culture is essential for the successful implementation of patient safety improvements. Aim: To assess the effect of two patient safety culture interventions on incident reporting as a proxy of safety culture. Design and setting: A three-arm cluster randomised trial was conducted in a mixed method study, studying the effect of administering a patient safety culture questionnaire (intervention I), the questionnaire complemented with a practice-based workshop (intervention II) and no intervention (control) in 30 general practices in the Netherlands. Method: The primary outcome, the number of reported incidents, was measured with a questionnaire at baseline and a year after. Analysis was performed using a negative binomial model. Secondary outcomes were quality and safety indicators and safety culture. Mixed effects linear regression was used to analyse the culture questionnaires. Results: The number of incidents increased in both intervention groups, to 82 and 224 in intervention I and II respectively. Adjusted for baseline number of incidents, practice size and accreditation status, the study showed that practices that additionally participated in the workshop reported 42 (95% confidence interval [CI] = 9.81 to 177.50) times more incidents compared to the control group. Practices that only completed the questionnaire reported 5 (95% CI = 1.17 to 25.49) times more incidents. There were no statistically significant differences in staff perception of patient safety culture at follow-up between the three study groups. Conclusion: Educating staff and facilitating discussion about patient safety culture in their own practice leads to increased reporting of incidents. It is beneficial to invest in a team-wise effort to improve patient safety

Improving Patient Safety Culture in Primary Care: A Systematic Review

Background: Patient safety culture, described as shared values, attitudes and behavior of staff in a health-care organization, gained attention as a subject of study as it is believed to be related to the impact of patient safety improvements. However, in primary care, it is yet unknown, which effect interventions have on the safety culture. Objectives: To review literature on the use of interventions that effect patient safety culture in primary care. Methods: Searches were performed in PubMed, EMBASE, CINAHL, and PsychINFO on March 4, 2013. Terms defining safety culture were combined with terms identifying intervention and terms indicating primary care. Inclusion followed if the intervention effected patient safety culture, and effect measures were reported. Results: The search yielded 214 articles from which two were eligible for inclusion. Both studies were heterogeneous in their interventions and outcome; we present a qualitative summary. One study described the implementation of an electronic medical record system in general practices as part of patient safety improvements. The other study facilitated 2 workshops for general practices, one on risk management and another on significant event audit. Results showed signs of improvement, but the level of evidence was low because of the design and methodological problems. Conclusions: These studies in general practice provide a first understanding of improvement strategies and their effect in primary care. As the level of evidence was low, no clear preference can be determined. Further research is needed to help practices make an informed choice for an intervention

Individual differences in the sensitivity to serotonergic drugs: a pharmacobehavioural approach using rats selected on the basis of their response to novelty. Psychopharmacology 205

Abstract Rationale The mechanisms underlying individual differences in the response to serotonergic drugs are poorly understood. Rat studies may contribute to our knowledge of the neuronal substrates that underlie these individual differences. Objectives A pharmacobehavioural study was performed to assess individual differences in the sensitivity to serotonergic drugs in rats that were selected based on their response to a novel environment. Methods Low responders (LR) and high responders (HR) to novelty rats were tested on the elevated T-maze following systemic injections of increasing doses of various serotonergic agents. The duration of avoidance of the open arms was scored for five trials. Results The duration of avoidance behaviour was larger in saline-treated LR rats compared to saline-treated HR rats. The 5-HT1A agonist 8-OH-DPAT and the 5-HT2 agonists mCPP and DOI decreased the duration of avoidance behaviour in LR rats, but increased it in HR rats. The 5-HT3 agonist SR57227A and the 5-HT releaser/reuptake inhibitor d-fenfluramine increased the duration of avoidance behaviour in both types of rat. However, higher doses of SR57227A were required to alter avoidance behaviour in HR than in LR rats. The onset of the effects of SR57227A, d-fenfluramine and WAY100635 was faster in LR than in HR rats. The described effects were receptor specific. A model explaining the data is presented. Conclusions These data demonstrate that LR and HR rats differ in their sensitivity to serotonergic drugs that act at 5-HT3, 5-HT2 and 5-HT1A receptors. The implications of these individual differences for individual-specific treatment of substance abuse are briefly discussed