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Holding the EU Accountable for Environmental Law Violations: Legitimacy Assets, ‘Complete’ System of Remedies and Unexplored Pathways
No full textWithin the EU, a complex web of legal avenues exists to address breaches of environmental law. This paper critically examines the judicial and non-judicial mechanisms available for litigating such breaches, focusing on the ‘legitimacy assets’ that characterize these mechanisms: independence, accessibility, material scope, and powers. This contribution therefore delves into the action for annulment and the preliminary reference procedure before the Court of Justice of the European Union (CJEU), the internal review procedure foreseen under the Aarhus Regulation, the complaint before the European Ombudsman (EO), the review mechanism of the Aarhus Convention Compliance Committee (ACCC), and the possibility of bringing cases to the European Court of Human Rights (ECtHR). It reveals strong suits and drawbacks for each avenue, ultimately advocating for a renewed attention for the non-judicial mechanisms
Myo-inositol Supplementation to Prevent Pregnancy Complications in Polycystic Ovary Syndrome:A Randomized Clinical Trial
No full textIMPORTANCE: Pregnant individuals with polycystic ovary syndrome (PCOS) present with a higher risk of pregnancy complications, including gestational diabetes, preeclampsia, and preterm birth. Myo-inositol supplementation may reduce these risks. OBJECTIVE: To determine whether daily supplementation with myo-inositol during pregnancy among individuals with PCOS reduces the risk of a composite outcome of gestational diabetes, preeclampsia, and preterm birth. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled, randomized trial was conducted at 13 hospitals in the Netherlands. Pregnant individuals with PCOS who were between 8 and 16 weeks' gestation were enrolled between June 2019 and March 2023. Final follow-up was complete on December 27, 2023. Analyses were conducted July 2024. INTERVENTIONS: Participants were randomized on a 1:1 basis to receive sachets with either myo-inositol, 2 g, with 0.2 mg of folic acid twice daily (n = 230) or matching placebo with 0.2 mg of folic acid only (n = 234) until delivery. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of gestational diabetes, preeclampsia, or preterm birth (before 37 weeks' gestation). RESULTS: Among 464 participants, the mean (SD) age was 31.5 (3.8) years; 18 participants (3.9%) reported Asian race and 395 (86.1%) reported White race. The prevalence of biochemical hyperandrogenism was higher at baseline in the myo-inositol group than the placebo group (29.0% [53 of 180] vs 18.5% [37 of 193]). A primary outcome event occurred in 25.0% (n = 56) of participants in the myo-inositol group and 26.8% (n = 61) in the placebo group (relative risk, 0.93 [95% CI, 0.68-1.28]; P = .67). CONCLUSIONS AND RELEVANCE: Myo-inositol supplementation during pregnancy did not reduce the incidence of a composite of gestational diabetes, preeclampsia, or preterm birth in patients with PCOS. TRIAL REGISTRATION: onderzoekmetmensen.nl Identifier: NL67329.078.18
Varying Levels of Inflammatory Activity in Brain and Body of Patients with Persistent Fatigue and Difficulty Concentrating After COVID-19:A TSPO PET Study
No full textA significant number of patients report persistent fatigue and difficulty concentrating after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a condition known as post-coronavirus disease 2019 (post-COVID) syndrome. The underlying mechanisms for these complaints remain poorly understood. Dysregulated immune and neurologic systems may play a role in the pathophysiology of post-COVID syndrome. A target providing direct information on immune activation is the 18-kDa translocator protein (TSPO), which is upregulated in activated microglia. The PET tracer N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide ([18F]DPA-714) binds with high affinity to TSPO and serves as a biomarker for neuroinflammation. We aimed to assess whole-body inflammatory activity with TSPO PET in individuals with and without persistent severe fatigue and difficulty concentrating 2 y after infection with SARS-CoV-2 as well as its association with complaint severity. Methods: In this cross-sectional cohort study, we evaluated 47 post-COVID individuals, 33 of whom had severe fatigue and difficulty concentrating (age, 50 ± 8 y; 27 ± 9 mo after initial infection) and 14 who did not have these complaints (age, 47 ± 9 y; 25 ± 10 mo after initial infection). All individuals were high-affinity binders according to their TSPO genotype and completed whole-body 60-min dynamic [18F]DPA-714 PET with arterial sampling, MRI, genotyping, and questionnaires. Tracer binding was quantified using binding potential for cerebral regions and inhibitory constant or total distribution volume for extracerebral regions. Parameters were compared between 33 individuals with persistent complaints (severe fatigue and difficulty concentrating) and 14 without, and associations between parameters were assessed. Results: We found globally increased cerebral [18F]DPA-714 binding in some individuals reporting persistent complaints when compared with individuals without these complaints. No group-level differences were found in extracerebral binding. Large variability in cerebral and extracerebral binding was observed among individuals. Cerebral and extracerebral binding levels were not correlated with each other or with complaint severity. Conclusion: Increased specific [18F]DPA-714 binding was found in some individuals with post-COVID syndrome, indicating the presence of an inflammatory subtype and further supporting the role of neuroinflammation in subtypes of post-COVID syndrome.</p
Mapping the Processes of Pharmacist Therapeutic Reasoning:A Scoping Review and Development of the Pharmacist Therapeutic Reasoning Model
No full textBackground: Pharmacists make complex therapeutic decisions. Yet the reasoning processes that result in these choices, therapeutic reasoning (TR), are poorly defined. Existing models of clinical reasoning often overlook how pharmacists weigh risks and benefits of treatment options. Aim: To develop a conceptual model that characterizes the processes, subprocesses, and cognitive strategies used during pharmacist TR based on current literature. Methods: A scoping review was conducted in February 2024 to identify studies describing pharmacist or pharmacy student reasoning during therapeutic decision-making. Data were extracted by two researchers using a standardized form and inductively analyzed. Codes were thematically organized based on shared properties: discrete knowledge, reasoning connections, or modifying influences. Theory use was assessed using the Continuum of Theory Talk framework. Results: Ten studies met inclusion criteria representing diverse contexts, scope, and reasoning stimuli. A total of 109 unique codes were identified and synthesized into a conceptual pharmacist therapeutic reasoning model (Pharm-TRv1). It consists of three knowledge domains (drug, disease, and patient information), three core reasoning processes connecting these domains (drug–patient, drug–disease, patient–disease), and three to four related subprocesses. The model includes five influencing factors: two external (decision context and entry and exit from reasoning) and three internal cognitive modifiers (metacognition, closing a knowledge gap, and reflection). Conclusion: Pharm-TRv1 provides a foundational model of pharmacist therapeutic reasoning grounded in current literature. It offers a structured way to describe, teach, and study how pharmacists evaluate treatment options. Future research should further explore specific processes and subprocesses, validate the model, and explore broader theoretical perspectives
Patterns of Post-Concussive Symptoms Following Mild Traumatic Brain Injury:Longitudinal Data in Children and Adults to Examine Sex Differences Across the Life Span
No full textOBJECTIVE: To examine sex- and age-related differences in patterns of post-concussive symptoms (PCS), across cognitive, somatic, emotional, and behavioral domains, and their recovery within the first 6 months after mild traumatic brain injury (mTBI), and their relation to participation. SETTING: Data were collected from patients visiting the emergency departments of 14 hospitals in the Netherlands. PARTICIPANTS: Two hundred 8 to 17-year-old children with mTBI and their caregivers, and 186 adults with mTBI. DESIGN: Data were collected in 2 prospective cohort studies, with assessments at 2 weeks and 6 months post-injury. Data were analyzed using Multivariate Latent Class Growth Analysis to detect latent PCS patterns (classes), multivariate logistic regressions to assess age and sex differences between classes, and Kruskal-Wallis tests to investigate class differences in participation. MAIN MEASURES: PCS were assessed with the Health and Behavior Inventory (children) and the Rivermead Post-Concussion Symptoms Questionnaire (adults). Participation (being involved in daily life situations) was assessed with the Child and Adolescent Scale of Participation (children) and the Utrecht Scale for Evaluation and Rehabilitation-Participation (adults). RESULTS: Three distinct classes with unique PCS recovery trajectories were found across samples (children/caregiver, adults). In child-reported PCS, sex differences were found, driven by higher levels of somatic and emotional PCS in females. No sex differences were found in caregiver reports or in adult reports. Age differences were found in the caregiver report for the child sample, with higher ages found in the class showing decreasing somatic symptoms over time, and in the adult sample, where younger individuals were more often in the class with recovered PCS. Classes differed in their levels of participation in all samples. DISCUSSION: Findings highlight the heterogeneity of PCS across the lifespan as well as the variation of discrepancies in sex- and age-related findings. Taking age and sex differences into account increases our understanding of recovery patterns after mTBI and allow identification of at-risk individuals and better-tailored interventions
Corporate tourism threatens protected areas
No full textRapidly expanding tourism infrastructure within protected areas—particularly new camps, lodges, and hotels—undermines biodiversity conservation and Indigenous peoples’ rights. The Ritz-Carlton, Masai Mara Safari Camp in Kenya’s Maasai Mara National Reserve, a United Nations Educational, Scientific, and Cultural Organization (UNESCO) tentative site and home to the Great Wildebeest Migration Route, exemplifies this threat
Routine RNA-based analysis of potential splicing variants facilitates genomic diagnostics and reveals limitations of in silico prediction tools
No full textDNA variants affecting pre-mRNA splicing are an important cause of genetic disorders and remain challenging to interpret without experimental data. Although variant classification guidelines recommend experimental characterization of variant splicing effects, the added value of routine diagnostic investigation of patient mRNA splicing has not been systematically described. Here, we assessed the utility of pre-mRNA splicing analysis in a diagnostic setting for 202 suspected splice-altering variants from individuals referred for genetic testing. Pre-mRNA splicing was assessed in patient cells by RT-PCR, followed by agarose gel electrophoresis and Sanger sequencing and/or exon trapping assays. An effect on pre-mRNA splicing was demonstrated in 63% (n = 128/202) of the tested variants. Among the 177 variants initially classified as variants of uncertain significance (VUS), 54% (n = 96/177) were reclassified based on pre-mRNA splicing analysis, including 48% (n = 85/177) that were upgraded to likely pathogenic or pathogenic. We benchmarked the splice prediction algorithms SpliceAI, SQUIRLS, SPiP, and Pangolin, the tools integrated in Alamut on this clinically relevant and experimentally validated dataset, and the CAGI6 splicing VUS dataset and found variable performance dependent on variant type and location. No single tool classified all variants equally well. We describe several examples of hard-to-predict effects and unexpected results highlighting the limitations of prediction tools, including a not previously described variant type affecting U12-splice site subtype. In summary, we provide a framework for RNA-based analysis in a molecular diagnostic setting, demonstrate the added value of routine testing of RNA from individuals with suspected splice-altering variants, and highlight the limitations of in silico prediction tools.</p
Response to comment on "The usefulness of the modified steep ramp test as a practical exercise test for preoperative risk assessment in patients scheduled for pancreatic surgery"
No full textThe role of systemic and nervous system factors in patients with shoulder pain:a perspective review
No full textBackgroundPersistent shoulder pain is often driven by inflammatory conditions, including tendinopathy, bursitis, and frozen shoulder. Treatment remains uncertain, but targeting underlying mechanisms like inflammation, metabolic factors, and nervous system disturbances may be more effective.ObjectiveThis perspective review summarizes these underlying mechanisms' roles in patients with inflammatory-driven shoulder pain and potential effective treatments for these mechanisms.ResultsLiterature links inflammatory-driven shoulder pain to low-grade inflammation, obesity, hypertension, diabetes mellitus, and/or autonomic and central nervous system disturbances, which are interconnected. Both acute and chronic inflammation are evident in tissue around the shoulder joint, potentially compromising treatment outcomes and predisposing tissue to hyperresponsiveness. Persistent inflammation can disrupt endocrine and nervous system functions, leading to additional health issues. Metabolic factors, characterized by low-grade inflammation, increase the risk for developing inflammatory-driven shoulder pain. Patients with inflammatory-driven shoulder pain often exhibit autonomic and somatosensory dysregulation. The autonomic nervous system's involvement in the inflammatory pathway can be influenced by or influence inflammation when dysregulation precedes shoulder pain development. Its pathways overlap with pain processing, potentially affecting each other. Prolonged stress (mental or biological) can lead to a maladaptive state and trigger somatosensory dysregulation. Interventions targeting these mechanisms go beyond the joint and include pain neuroscience education, exercise therapy, graded motor imagery, stress management, lifestyle interventions, and combinations of these. However, evidence specific to shoulder pain is limited.ConclusionFuture research should prioritize understanding these underlying mechanisms in patients with inflammatory-driven musculoskeletal shoulder pain and evaluating targeted interventions' effects on shoulder disabilities
Smart dendrimer nanogels boost mRNA-based cancer therapy via synergistic glycolysis inhibition and immune activation
No full textCancer mRNA vaccine has emerged as a promising immunotherapy approach. However, development of functional vehicles for safe and efficient mRNA delivery into immune cells (e.g., dendritic cells, DCs) remains to be challenging, and most of the mRNA-based vaccines just act on immune cells for improved anticancer immunity without additional input to tackle cancer cells, ultimately limiting the anticancer efficacy. Herein, we report the development of pH-responsive dual-action dendrimer nanogels (DNGs) to deliver gp100 mRNA as a potential nanovaccine. Mannose-conjugated generation 3 poly(amidoamine) dendrimers were crosslinked through dual functional polyethylene glycol with both ends of aldehyde groups to form pH-responsive DNGs. The DNGs with a size of 45.7 nm show excellent colloidal stability and cytocompatibility and allow dual-actions for DC-targeted mRNA delivery and cancer cell glycolysis inhibition. In a subcutaneous mouse melanoma model, the DNG/mRNA vaccine exerted glycolytic inhibition effect and triggered robust antitumor immune responses to suppress the tumor growth, especially in combination with anti-PD-L1 antibody-mediated immune checkpoint blockade. Meanwhile, the local vaccination of the vaccine enabled effective tumor occurrence prevention. Such a DNGbased mRNA vaccine with dual actions on both DCs and cancer cells may be applied for improved immunotherapy of other cancer types