Inventory of personal factors influencing conditioned pain modulation in healthy people: a systematic literature review

Background: Conditioned pain modulation (CPM) is believed to play an important role in the development and exacerbation of chronic pain, because dysfunction of CPM is associated with a shift in balance between pain facilitation and pain inhibition. In many patients with central sensitization, CPM is less efficacious. Besides that, efficacy of CPM is highly variable in healthy people. Consequently, it seems that several individual variables may influence CPM. A systematic review examining personal factors influencing CPM was conducted. Methods: This systematic review follows the PRISMA guidelines. Pubmed and Web of Science were searched using different synonyms of CPM. Full-text clinical reports addressing the influence of personal factors on CPM in healthy adults were included. Checklists for RCTs and case-control studies provided by the Dutch Institute for Healthcare Improvement (CBO) and the Dutch Cochrane Centre were utilized to assess methodological quality. Levels of evidence and strength of conclusion were assigned using the CBO guidelines. Results: Forty-six articles were identified that reported the influence of personal factors on CPM. Quality assessment revealed 10 studies with a methodological quality less than 50% wherefore they were excluded (21.8%), resulting in a general total methodological quality score of 72.5%. Overall younger adult age, male gender, ovulatory phase, positive expectations, attention to the conditioning stimulus, and carrier of the 5-HTTLPR long allele result in better CPM. Conclusion: It is advised for future studies to take these factors into account. Further research regarding the influence of oral contraceptives, catastrophizing, information about conditioning stimulation, distraction, physical activity, and genetics on CPM magnitude is required

Clinical pharmacokinetics of antipsychotics in pediatric populations:a scoping review focusing on dosing regimen

Introduction:Achieving optimal clinical responses and minimizing side effects through precision dosing of antipsychotics in children and adolescents with psychiatric disorders remains a challenge. Identifying patient characteristics (covariates) that affect pharmacokinetics can inform more effective dosing strategies and ultimately improve patient outcomes. This review aims to provide greater insight into the impact of covariates on the clinical pharmacokinetics of antipsychotics in pediatric populations. Areas covered: A comprehensive literature search was conducted, and the main findings regarding the effects of the covariates on the pharmacokinetics of antipsychotics in children and adolescents are presented. Expert opinion: Our study highlights significant covariates, including age, sex, weight, CYP2D6 phenotype, co-medication, and smoking habits, which affect the pharmacokinetics of antipsychotics. However, the findings were generally limited by the small sample sizes of naturalistic, open-label, observational studies, and the homogeneous subgroups. Dosing based on weight and preemptive genotyping could prove beneficial for optimizing the dosing regimen in pediatric populations. Future research is needed to refine dosing recommendations and establish therapeutic reference ranges critical for precision dosing and Therapeutic Drug Monitoring (TDM). The integration of individual patient characteristics with TDM can further optimize the efficacy and safety of antipsychotics for each patient.</p

Large cell neuroendocrine carcinoma with a solitary brain metastasis and low Ki-67:a unique subtype

INTRODUCTION: Stage IV large cell neuroendocrine carcinoma (LCNEC) of the lung generally presents as disseminated and aggressive disease with a Ki-67 proliferation index (PI) 40-80%. LCNEC can be subdivided in two main subtypes: the first harboring TP53/RB1 mutations (small cell lung carcinoma (SCLC)-like), the second with mutations in TP53 and STK11/KEAP1 (non-small cell lung carcinoma (NSCLC)-like). Here we evaluated 11 LCNEC patients with only a solitary brain metastasis and evaluate phenotype, genotype and follow-up. METHODS: Eleven LCNEC patients with solitary brain metastases were analyzed. Clinical characteristics and survival data were retrieved from medical records. Pathological analysis included histomorphological analysis, immunohistochemistry (pRB and Ki-67 PI) and next generation sequencing (TP53, RB1, STK11, KEAP1 and MEN1). RESULTS: All patients had N0 or N1 disease. Median overall survival (OS) was 12 months (95% confidence interval (CI) 5.5-18.5 months). Mean Ki-67 PI was 59% (range 15-100%). In 6/11 LCNEC Ki-67 PI was ≤40%. OS was longer for Ki-67 ≤40% compared to >40% (17 months (95% CI 11-23 months) vs. 5 months (95% CI 0.7-9 months), p=0.007). Two patients were still alive at follow-up after 86 and 103 months, both had Ki-67 ≤40%. 8/11 patients could be subclassified and both SCLC-like (n=6) and NSCLC-like (n=2) subtype were present. No MEN1 mutation was found. CONCLUSION: Stage IV LCNEC with a solitary brain metastasis and N0/N1 disease show in the majority of cases Ki-67 PI ≤40% and prolonged survival, distinguishing them from general LCNEC. This unique subgroup can be both of the SCLC-like and NSCLC-like subtype

Clusters with random size: maximum likelihood versus weighted estimation

Abstract: There are many contemporary designs that do not use a random sample of a fixed, a priori determined size. In case of informative cluster sizes, the cluster size is influenced by the the cluster&apos;s data, but here we cope with some issues that even occur when the cluster size and the data are unrelated. First, fitting models to clusters of varying sizes is often more complicated than when all cluster have the same size. Secondly, in such cases, there usually is no so-called complete sufficient statistic

In-depth molecular analysis of combined and co-primary pulmonary large cell neuroendocrine carcinoma and adenocarcinoma

Up to 14% of large cell neuroendocrine carcinomas (LCNECs) are diagnosed in continuity with nonsmall cell lung carcinoma. In addition to these combined lesions, 1% to 7% of lung tumors present as co-primary tumors with multiple synchronous lesions. We evaluated molecular and clinicopathological characteristics of combined and co-primary LCNEC-adenocarcinoma (ADC) tumors. Ten patients with LCNEC-ADC (combined) and five patients with multiple synchronous ipsilateral LCNEC and ADC tumors (co-primary) were included. DNA was isolated from distinct tumor parts, and 65 cancer genes were analyzed by next generation sequencing. Immunohistochemistry was performed including neuroendocrine markers, pRb, Ascl1 and Rest. Pure ADC (N = 37) and LCNEC (N = 17) cases were used for reference. At least 1 shared mutation, indicating tumor clonality, was found in LCNEC- and ADC-parts of 10/10 combined tumors but only in 1/5 co-primary tumors. A range of identical mutations was observed in both parts of combined tumors: 8/10 contained ADC-related (EGFR/KRAS/STK11 and/or KEAP1), 4/10 RB1 and 9/10 TP53 mutations. Loss of pRb IHC was observed in 6/10 LCNEC- and 4/10 ADC-parts. The number and intensity of expression of Ascl1 and neuroendocrine markers increased from pure ADC (low) to combined ADC (intermediate) and combined and pure LCNEC (high). The opposite was true for Rest expression. In conclusion, all combined LCNEC-ADC tumors were clonally related indicating a common origin. A relatively high frequency of pRb inactivation was observed in both LCNEC- and ADC-parts, suggesting an underlying role in LCNEC-ADC development. Furthermore, neuroendocrine differentiation might be modulated by Ascl1(+) and Rest(-) expression

Research challenges for cultural ecosystem services and public health in (peri-)urban environments

Urbanization is a global trend, and consequently the quality of urban environments is increasingly important for human health and wellbeing. Urban life-style is typically associated with low physical activity and sometimes with high mental stress, both contributing to an increasing burden of diseases. Nature-based solutions that make effective use of ecosystem services, particularly of cultural ecosystem services (CES), can provide vital building blocks to address these challenges. This paper argues that, the salutogenic, i.e. health-promoting effects of CES have so far not been adequately recognised and deserve more explicit attention in order to enhance decision making around health and wellbeing in urban areas. However, a number of research challenges will need to be addressed to reveal the mechanisms, which underpin delivery of urban CES. These include: causal chains of supply and demand, equity, and equality of public health benefits promoted. Methodological challenges in quantifying these are discussed. The paper is highly relevant for policy makers within and beyond Europe, and also serves as a review for current researchers and as a roadmap to future short- and long-term research opportunities. Highlights • Concerns positive public health impacts of urban nature's cultural ecosystem services (CES). • Discusses global development trends' implications for the provision and demand of CES. • Discusses current research and key research questions for a new research agenda

Crisis-induced disruptions in place-based social-ecological research ‐ an opportunity for redirection

Place-based research faces multiple threats, including both natural and global health hazards and political conflicts, which may disrupt fieldwork. The current COVID-19 pandemic shows how these threats can drastically affect social-ecological research activities given its engagement with different local stakeholders, disciplines, and knowledge systems. The crisis reveals the need for adaptive research designs while also providing an opportunity for a structural shift towards a more sustainable and inclusive research landscape

Crisis-induced disruptions in place-based social-ecological research ‐ an opportunity for redirection

Place-based research faces multiple threats, including both natural and global health hazards and political conflicts, which may disrupt fieldwork. The current COVID-19 pandemic shows how these threats can drastically affect social-ecological research activities given its engagement with different local stakeholders, disciplines, and knowledge systems. The crisis reveals the need for adaptive research designs while also providing an opportunity for a structural shift towards a more sustainable and inclusive research landscape

High quality of SARS-CoV-2 molecular diagnostics in a diverse laboratory landscape through supported benchmark testing and External Quality Assessment

A two-step strategy combining assisted benchmark testing (entry controls) and External Quality Assessments (EQAs) with blinded simulated clinical specimens to enhance and maintain the quality of nucleic acid amplification testing was developed. This strategy was successfully applied to 71 diagnostic laboratories in The Netherlands when upscaling the national diagnostic capacity during the SARS-CoV-2 pandemic. The availability of benchmark testing in combination with advice for improvement substantially enhanced the quality of the laboratory testing procedures for SARS-CoV-2 detection. The three subsequent EQA rounds demonstrated high quality testing with regard to specificity (99.6% correctly identified) and sensitivity (93.3% correctly identified). Even with the implementation of novel assays, changing workflows using diverse equipment and a high degree of assay heterogeneity, the overall high quality was maintained using this two-step strategy. We show that in contrast to the limited value of Cq value for absolute proxies of viral load, these Cq values can, in combination with metadata on strategies and techniques, provide valuable information for laboratories to improve their procedures. In conclusion, our two-step strategy (preparation phase followed by a series of EQAs) is a rapid and flexible system capable of scaling, improving, and maintaining high quality diagnostics even in a rapidly evolving (e.g. pandemic) situation.</p

High quality of SARS-CoV-2 molecular diagnostics in a diverse laboratory landscape through supported benchmark testing and External Quality Assessment

A two-step strategy combining assisted benchmark testing (entry controls) and External Quality Assessments (EQAs) with blinded simulated clinical specimens to enhance and maintain the quality of nucleic acid amplification testing was developed. This strategy was successfully applied to 71 diagnostic laboratories in The Netherlands when upscaling the national diagnostic capacity during the SARS-CoV-2 pandemic. The availability of benchmark testing in combination with advice for improvement substantially enhanced the quality of the laboratory testing procedures for SARS-CoV-2 detection. The three subsequent EQA rounds demonstrated high quality testing with regard to specificity (99.6% correctly identified) and sensitivity (93.3% correctly identified). Even with the implementation of novel assays, changing workflows using diverse equipment and a high degree of assay heterogeneity, the overall high quality was maintained using this two-step strategy. We show that in contrast to the limited value of Cq value for absolute proxies of viral load, these Cq values can, in combination with metadata on strategies and techniques, provide valuable information for laboratories to improve their procedures. In conclusion, our two-step strategy (preparation phase followed by a series of EQAs) is a rapid and flexible system capable of scaling, improving, and maintaining high quality diagnostics even in a rapidly evolving (e.g. pandemic) situation.</p