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Bounds and E-values for Marginal Causal Effects
No full textUnmeasured confounding is an important obstacle when estimating causal effects from observational data. Ding and VanderWeele (EPIDEMIOLOGY 2016;27:368) derived bounds for causal effects, based on sensitivity parameters that quantify the maximal strength of unmeasured confounding. These bounds translate to the popular E-value metric, which quantifies the magnitude of unmeasured confounding required to “explain away” an observed association. While Ding and VanderWeele mainly focused on conditional (on measured confounders) causal effects, they also outlined how their method might be used for marginal causal effects. However, this requires specification of the sensitivity parameters at each level of the measured confounders, which is impractical in high-dimensional settings, and it yields overly conservative bounds that lack a natural E-value analog. In this article, we propose novel bounds for marginal causal effects based on Ding and VanderWeele’s sensitivity parameters. The proposed bounds only require the analyst to specify the maximal values of the sensitivity parameters across all levels of the measured confounders, thus substantially reducing dimensionality. Furthermore, the proposed bounds are often narrower than Ding and VanderWeele’s bounds, and they translate naturally into an E-value for marginal causation. We show how the proposed bounds can be estimated using standard regression techniques, and we illustrate through an application to publicly available data, with accompanying R code provided.Unmeasured confounding is an important obstacle when estimating causal effects from observational data. Ding and VanderWeele (EPIDEMIOLOGY 2016;27:368) derived bounds for causal effects, based on sensitivity parameters that quantify the maximal strength of unmeasured confounding. These bounds translate to the popular E-value metric, which quantifies the magnitude of unmeasured confounding required to "explain away" an observed association. While Ding and VanderWeele mainly focused on conditional (on measured confounders) causal effects, they also outlined how their method might be used for marginal causal effects. However, this requires specification of the sensitivity parameters at each level of the measured confounders, which is impractical in high-dimensional settings, and it yields overly conservative bounds that lack a natural E-value analog. In this article, we propose novel bounds for marginal causal effects based on Ding and VanderWeele's sensitivity parameters. The proposed bounds only require the analyst to specify the maximal values of the sensitivity parameters across all levels of the measured confounders, thus substantially reducing dimensionality. Furthermore, the proposed bounds are often narrower than Ding and VanderWeele's bounds, and they translate naturally into an E-value for marginal causation. We show how the proposed bounds can be estimated using standard regression techniques, and we illustrate through an application to publicly available data, with accompanying R code provided.</p
Fabrication and characterization of enteric microneedle patches for oral delivery of small and macromolecule compounds
No full textNeedle patches are commonly used for administration of therapeutics via several routes such as transdermal and buccal delivery. Researchers have further used this strategy for oral delivery of poorly permeable therapeutics by direct injections in the gastrointestinal epithelium, which raises safety concerns about the long-term adverse effects. This study aims to investigate the use of microneedles for oral delivery of compounds with a wide range of molecular weights. For this purpose, we produced fully enteric microneedle patches for unidirectional release by casting. The microneedles presented a length of 175 mu m (minimum mucus thickness in the small intestine) to minimize the risk of epithelial damage. A homogeneous drug distribution in the patches was verified by confocal Raman spectroscopy and fluorescence microscopy. Microneedle patches appeared to increase the force displacement in porcine small intestine compared to negative controls (4.4 +/- 2.1 mN and 1.8 +/- 0.9 mN, respectively), which suggest that microneedles could increase the retention time of oral devices in the gastrointestinal tract. Additionally, the length and integrity of the needles were not affected during the mechanical test studies. In vitro studies at gastric and intestinal pH confirmed successful enteric release and permeation of the drug compounds through biosimilar mucus independently of the molecular weight. The proximity of the patch to the membrane increased the permeation rate, which indicates the potential advantage of microneedles to increase the retention time of more complex devices such as self-unfolding foils, which can ensure drug release in close proximity to the epithelium
Vascular aging mediates the association between atherogenic lipid profiles and depression:survey-weighted evidence from NHANES 2005-2020
No full textBackgroundDyslipidemia and depressive symptoms often co-occur, but the pathway linking atherogenic lipids to mood is unclear. Vascular aging, indexed by aortic stiffness, may mediate this relationship.MethodsWe analyzed nine cycles of the National Health and Nutrition Examination Survey (2005–2020). Adults ≥20 years with complete data on lipids, estimated pulse-wave velocity (ePWV), and the Patient Health Questionnaire-9 (PHQ-9) were included (n = 17,599). Exposures were the atherogenic index of plasma (AIP), triglyceride-to-HDL-cholesterol ratio (TG/HDL-C), and HDL cholesterol. The mediator was ePWV, and the outcome was moderate-to-severe depressive symptoms (PHQ-9 ≥ 10). Survey-weighted regression and mediation models with 5000 bootstraps adjusted for sociodemographic, lifestyle, and clinical covariates.ResultsOverall, 8.7 % had moderate-to-severe depressive symptoms. Higher AIP and TG/HDL-C were associated with greater odds of depression (per SD AIP: adjusted odds ratio [OR], 1.59; 95 % CI, 1.30–1.97; per unit TG/HDL-C: OR, 1.04; 95 % CI, 1.03–1.05), while HDL cholesterol showed inverse association (per mg/dL: adjusted odds ratio [OR], 0.98; 95 % CI, 0.97–0.99). AIP was positively related to ePWV (β, 0.43 m/s; 95 % CI, 0.30–0.56). ePWV was independently associated with depression (OR per 1 m/s, 1.11; 95 % CI, 1.06–1.16). Mediation indicated that ePWV explained 10.4 % of the AIP-depression association, 8.2 % for TG/HDL-C, and 6.4 % for HDL cholesterol in overall study population. Mediation occurred in both sexes, with larger proportions mediated in women.ConclusionsAtherogenic lipid phenotypes were linked to depressive symptoms, with vascular aging explaining part of this association, especially in women. These findings support vascular aging as a pathway connecting dyslipidemia to mood and motivate longitudinal studies targeting lipid quality and large-artery stiffness.BACKGROUND: Dyslipidemia and depressive symptoms often co-occur, but the pathway linking atherogenic lipids to mood is unclear. Vascular aging, indexed by aortic stiffness, may mediate this relationship.METHODS: We analyzed nine cycles of the National Health and Nutrition Examination Survey (2005-2020). Adults ≥20 years with complete data on lipids, estimated pulse-wave velocity (ePWV), and the Patient Health Questionnaire-9 (PHQ-9) were included (n = 17,599). Exposures were the atherogenic index of plasma (AIP), triglyceride-to-HDL-cholesterol ratio (TG/HDL-C), and HDL cholesterol. The mediator was ePWV, and the outcome was moderate-to-severe depressive symptoms (PHQ-9 ≥ 10). Survey-weighted regression and mediation models with 5000 bootstraps adjusted for sociodemographic, lifestyle, and clinical covariates.RESULTS: Overall, 8.7 % had moderate-to-severe depressive symptoms. Higher AIP and TG/HDL-C were associated with greater odds of depression (per SD AIP: adjusted odds ratio [OR], 1.59; 95 % CI, 1.30-1.97; per unit TG/HDL-C: OR, 1.04; 95 % CI, 1.03-1.05), while HDL cholesterol showed inverse association (per mg/dL: adjusted odds ratio [OR], 0.98; 95 % CI, 0.97-0.99). AIP was positively related to ePWV (β, 0.43 m/s; 95 % CI, 0.30-0.56). ePWV was independently associated with depression (OR per 1 m/s, 1.11; 95 % CI, 1.06-1.16). Mediation indicated that ePWV explained 10.4 % of the AIP-depression association, 8.2 % for TG/HDL-C, and 6.4 % for HDL cholesterol in overall study population. Mediation occurred in both sexes, with larger proportions mediated in women.CONCLUSIONS: Atherogenic lipid phenotypes were linked to depressive symptoms, with vascular aging explaining part of this association, especially in women. These findings support vascular aging as a pathway connecting dyslipidemia to mood and motivate longitudinal studies targeting lipid quality and large-artery stiffness.</p
Why and how to act through multiple avatars in virtual reality
No full textIn virtual reality (VR), users typically control one virtual body — their avatar. Previous works enable users to act through multiple avatars simultaneously. These works, though, lack a systematic account of why users want to interact with multiple avatars and do not explain how users can manipulate and generate avatars. To address this, we run six workshops with 12 VR experts and develop a design space that captures four fundamental dimensions for acting through multiple avatars in VR: Appearance, Context, User-Avatar Mapping, and Motion Control. Researchers can use the design space to generate novel interaction opportunities involving multiple avatars or analyze existing work. We then run a usability study with 17 participants to understand the practicalities of an interface that integrates parts of the design space, which reveals conceptual and technical challenges that we address through design recommendations.</p
Paradoxes and dilemmas in local climate missions
No full textThis paper examines local climate missions using paradox theory. We explore how the fundamental paradoxical nature of missions manifests in dilemmas with which mission managers must strategically engage. By studying two local climate missions in Denmark, we identified three dilemmas, their triggers and the mission management’s strategic responses. Importantly, we found that mission resources and place-based leadership are essential in shaping strategic responses to local mission dilemmas. Our findings highlight that paradox theory and its operationalisation are useful for understanding and managing missions as they allow us to better comprehend the potentials and challenges involved in mission work
Visualizing nature:A review of photovoice as a method for understanding environmental change
No full textOriginally developed in the field of public health, the participatory photography research methodology known as “photovoice” has increasingly been used by interdisciplinary environmental scientists. This scoping review assesses this trend, identifying and analyzing 132 relevant journal articles to evaluate how researchers deploy this methodology to understand environmental change processes and perceptions. We find that photovoice has been applied to a range of environmental topics, including environmental health, climate change, water governance, and rural and urban development, complementing a turn towards community-based research methods and co-production of knowledge within the field. We interrogate who is included in photovoice projects and how they were conducted, showing how the original intent of the method - to highlight the perceptions, voices, and experiences of rural women - has been broadened to capture lived experiences of marginalized groups such as resource-dependent, low-income and Indigenous communities. We highlight what we see as the core contribution of this method - understanding alternative epistemologies of environmental change – and argue that photovoice has high potential to capture, explore, and share the views and voices of marginalized people. While we caution that studies should consciously consider the trade-offs involved in this time-consuming and open-ended method, we argue that increasing use of this method can contribute to our understanding of a range of empirical topics as well as fostering epistemological pluralism and insights that can lead to action.</p
Proteomic Alterations and Antimicrobial Effects of Postbiotics from Probiotic Lactic Acid Bacteria and Yeast Against Multidrug-Resistant <i>Salmonella</i> Typhimurium
No full textThe study conducted presents the antimicrobial and antibiofilm properties of postbiotics obtained from Bifidobacterium bifidum, Lactiplantibacillus plantarum, and Saccharomyces cerevisiae against multidrug-resistant Salmonella enterica serotype Typhimurium. Integrated microbiological and proteomic approaches proved that all postbiotics inhibited bacterial growth as well as biofilm formation with high biocompatibility to mammalian cells. Transcriptional and proteomic analyses indicated that exposure to postbiotics modulated major virulence-associated genes and proteins related to motility, adhesion, and stress adaptation. These molecular changes allow the assumption that postbiotics are able to attenuate pathogenicity through multifactorial mechanisms rather than direct bactericidal effects. In summary, this study results in an expression of interest in probiotic-derived postbiotics as safe and stable non-antibiotic agents for the control of multidrugresistant pathogens in biofilm-related infections
Significance and stability of cerebrospinal fluid oligoclonal band patterns in multiple sclerosis
No full textBackgroundImmunoglobulin G (IgG) oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is included in the diagnostic criteria for multiple sclerosis (MS), but their temporal stability and clinical significance remain uncertain. These issues were addressed in a retrospective cohort study.MethodsPatients analyzed for OCBs at a central laboratory were included (n = 16,596). Results and associations between OCBs, age at onset, and disease severity (assessed with the Age-Related Multiple Sclerosis Severity (ARMSS) score and Multiple Sclerosis Severity Score (MSSS)) were assessed.ResultsOCBs were more common in MS (91 %) than in CIS (71 %) and other diseases (10 %) (both p < 0.001) and more frequent in CIS than other diseases (p < 0.001). A single band pattern was more common in CIS (5.8 %) and other diseases (5.6 %) than in MS (2.0 %) (both p < 0.001). In MS and CIS patients with repeated lumbar punctures, changes in OCBs occurred in 29 of 227 patients with MS (13 %) and 5 of 10 patients (50 %) with CIS (p = 0.007); 42 % changed from negative or single band to positive and 59 % from positive to negative or single band. MS patients with OCBs had 3.8 years earlier onset of disease (95 % confidence interval 2.2–5.4) but showed no difference in ARMSS or MSSS.ConclusionIgG OCBs were highly prevalent in MS and CIS; a single band pattern was more prevalent in CIS and other diseases than in MS. Changes in IgG OCB result were uncommon, particularly in MS. The presence of IgG OCBs is associated with lower age of onset but not with severity of MS.Background: Immunoglobulin G (IgG) oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is included in the diagnostic criteria for multiple sclerosis (MS), but their temporal stability and clinical significance remain uncertain. These issues were addressed in a retrospective cohort study. Methods: Patients analyzed for OCBs at a central laboratory were included (n = 16,596). Results and associations between OCBs, age at onset, and disease severity (assessed with the Age-Related Multiple Sclerosis Severity (ARMSS) score and Multiple Sclerosis Severity Score (MSSS)) were assessed. Results: OCBs were more common in MS (91 %) than in CIS (71 %) and other diseases (10 %) (both p < 0.001) and more frequent in CIS than other diseases (p < 0.001). A single band pattern was more common in CIS (5.8 %) and other diseases (5.6 %) than in MS (2.0 %) (both p < 0.001). In MS and CIS patients with repeated lumbar punctures, changes in OCBs occurred in 29 of 227 patients with MS (13 %) and 5 of 10 patients (50 %) with CIS (p = 0.007); 42 % changed from negative or single band to positive and 59 % from positive to negative or single band. MS patients with OCBs had 3.8 years earlier onset of disease (95 % confidence interval 2.2–5.4) but showed no difference in ARMSS or MSSS. Conclusion: IgG OCBs were highly prevalent in MS and CIS; a single band pattern was more prevalent in CIS and other diseases than in MS. Changes in IgG OCB result were uncommon, particularly in MS. The presence of IgG OCBs is associated with lower age of onset but not with severity of MS.</p
Phycocyanin oral delivery system obtained by spray-drying with soy proteins for the treatment of inflammatory bowel diseases:in vivo evaluation
No full textPhycocyanin (PC), a bioactive pigment from Spirulina, exhibits strong antioxidant and anti-inflammatory properties but faces limitations in stability and bioavailability. This study aimed to develop and characterize soy protein-based microparticles (MPs MilcS-PC) using a spray-drying technique to enhance PC's therapeutic potential for inflammatory bowel disease (IBD). Physicochemical characterization (UV–Vis and FT-IR spectroscopy, SEM, XRPD, and DSC) confirmed that PC was effectively encapsulated within the microparticles, improving its solubility and stability. In vitro antioxidant assays demonstrated that MPs MilcS-PC preserved PC's radical scavenging activity. At the same time, dissolution and ex vivo permeation studies revealed a controlled release profile, protecting PC in gastric conditions and enhancing its intestinal permeability. Moreover, biocompatibility tests confirmed the safety of MPs MilcS-PC Fibroblasts, while cytotoxicity assays in Caco-2 cells suggested a dual role in intestinal inflammation management and potential anticancer effects. In vivo, MPs MilcS-PC significantly reduced inflammation in a DNBS-induced colitis rat model, reduced macroscopic damage, and decreased myeloperoxidase activity and IL-6 expression compared to free PC. Bioavailability studies confirmed that encapsulation improved PC absorption. These findings highlight MPs MilcS-PC as a promising delivery system, enhancing PC's stability, bioavailability, and therapeutic efficacy in IBD treatment, encouraging future clinical applications in chronic inflammatory diseases.</p