Non-Locality and Theories of Causation

The aim of the paper is to investigate the characterization of an unambiguous notion of causation linking single space-llike separated events in EPR-Bell frameworks. This issue is investigated in ordinary quantum mechanics, with some hints to no collapse formulations of the theory such as Bohmian mechanics.Comment: Presented at the NATO Advanced Research Workshop on Modality, Probability and Bell's Theorems, Cracow, Poland, August 19-23, 200

Comparison of the structure and activity of glycosylated and asglycosylated human carboxylesterase 1

Human Carboxylesterase 1 (hCES1) is the key liver microsomal enzyme responsible for detoxification and metabolism of a variety of clinical drugs. To analyse the role of the single N-linked glycan on the structure and activity of the enzyme, authentically glycosylated and aglycosylated hCES1, generated by mutating asparagine 79 to glutamine, were produced in human embryonic kidney cells. Purified enzymes were shown to be predominantly trimeric in solution by analytical ultracentrifugation. The purified aglycosylated enzyme was found to be more active than glycosylated hCES1 and analysis of enzyme kinetics revealed that both enzymes exhibit positive cooperativity. Crystal structures of hCES1 a catalytically inactive mutant (S221A) and the aglycosylated enzyme were determined in the absence of any ligand or substrate to high resolutions (1.86 Å, 1.48 Å and 2.01 Å, respectively). Superposition of all three structures showed only minor conformational differences with a root mean square deviations of around 0.5 Å over all Cα positions. Comparison of the active sites of these un-liganded enzymes with the structures of hCES1-ligand complexes showed that side-chains of the catalytic triad were pre-disposed for substrate binding. Overall the results indicate that preventing N-glycosylation of hCES1 does not significantly affect the structure or activity of the enzyme

A Post Hoc Analysis of KidneyIntelX and Cardiorenal Outcomes in Diabetic Kidney Disease

KidneyIntelX, a bioprognostic test for assessing risk of CKD progression, risk stratified individuals for kidney, heart failure, and death outcomes in the Canagliflozin Cardiovascular Assessment Study.Individuals scored as high risk seemed to derive more of benefit from treatment with canagliflozin versus placebo.These findings may serve to increase adoption of underutilized therapies for cardiorenal risk reduction in patients with diabetic kidney disease

Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by deficiency of frataxin protein, with the primary sites of pathology being the large sensory neurons of the dorsal root ganglia and the cerebellum. FRDA is also often accompanied by severe cardiomyopathy and diabetes mellitus. Frataxin is important in mitochondrial iron–sulfur cluster (ISC) biogenesis and low-frataxin expression is due to a GAA repeat expansion in intron 1 of the FXN gene. FRDA cells are genomically unstable, with increased levels of reactive oxygen species and sensitivity to oxidative stress. Here we report the identification of elevated levels of DNA double strand breaks (DSBs) in FRDA patient and YG8sR FRDA mouse model fibroblasts compared to normal fibroblasts. Using lentivirus FXN gene delivery to FRDA patient and YG8sR cells, we obtained long-term overexpression of FXN mRNA and frataxin protein levels with reduced DSB levels towards normal. Furthermore, γ-irradiation of FRDA patient and YG8sR cells revealed impaired DSB repair that was recovered on FXN gene transfer. This suggests that frataxin may be involved in DSB repair, either directly by an unknown mechanism, or indirectly via ISC biogenesis for DNA repair enzymes, which may be essential for the prevention of neurodegeneration.Ataxia UK, FARA Australasia and FARA US

Clinical utility of KidneyIntelX in early stages of diabetic kidney disease in the CANVAS trial

Introduction: KidneyIntelX is a composite risk score, incorporating biomarkers and clinical variables for predicting progression of diabetic kidney disease (DKD). The utility of this score in the context of sodium glucose co-transporter 2 inhibitors and how changes in the risk score associate with future kidney outcomes are unknown. Methods: We measured soluble tumor necrosis factor receptor (TNFR)-1, soluble TNFR-2, and kidney injury molecule 1 on banked samples from CANagliflozin cardioVascular Assessment Study (CANVAS) trial participants with baseline DKD (estimated glomerular filtration rate [eGFR] 30-59 mL/min/1.73 m2 or urine albumin- to-creatinine ratio [UACR] ≥30 mg/g) and generated KidneyIntelX risk scores at baseline and years 1, 3, and 6. We assessed the association of baseline and changes in Kidney- IntelX with subsequent DKD progression (composite outcome of an eGFR decline of ≥5 mL/min/year [using the 6-week eGFR as the baseline in the canagliflozin group], ≥40% sustained decline in the eGFR, or kidney failure). Results: We included 1,325 CANVAS participants with concurrent DKD and available baseline plasma samples (mean eGFR 65 mL/min/1.73 m2 and median UACR 56 mg/g). During a mean follow-up of 5.6 years, 131 participants (9.9%) experienced the composite kidney outcome. Using risk cutoffs from prior validation studies, KidneyIntelX stratified patients to low- (42%), intermediate- (44%), and high-risk (15%) strata with cumulative incidence for the outcome of 3%, 11%, and 26% (risk ratio 8.4; 95% confidence interval [CI]: 5.0, 14.2) for the high-risk versus low-risk groups. The differences in eGFR slopes for canagliflozin versus placebo were 0.66, 1.52, and 2.16 mL/min/1.73 m2 in low, intermediate, and high KidneyIntelX risk strata, respectively. KidneyIntelX risk scores declined by 5.4% (95% CI: -6.9, -3.9) in the canagliflozin arm at year 1 versus an increase of 6.3% (95% CI: 3.8, 8.7) in the placebo arm (p < 0.001). Changes in the KidneyIntelX score at year 1 were associated with future risk of the composite outcome (odds ratio per 10 unit decrease 0.80; 95% CI: 0.77, 0.83; p < 0.001) after accounting for the treatment arm, without evidence of effect modification by the baseline KidneyIntelX risk stratum or by the treatment arm. Conclusions: KidneyIntelX successfully risk-stratified a large multinational external cohort for progression of DKD, and greater numerical differences in the eGFR slope for canagliflozin versus placebo were observed in those with higher baseline KidneyIntelX scores. Canagliflozin treatment reduced KidneyIntelX risk scores over time and changes in the KidneyIntelX score from baseline to 1 year associated with future risk of DKD progression, independent of the baseline risk score and treatment arm

Nature contact and general health: testing multiple serial mediation pathways with data from adults in 18 countries

This is the final version. Available on open access from Elsevier via the DOI in this record. Data availability: A subset of the data is available at: (Elliott, LR, White, MP. 2022. BlueHealth International Survey Dataset, 2017-2018. [data collection]. UK Data Service. SN: 8874, doi: 10.5255/UKDA-SN-8874-2).The role of neighbourhood nature in promoting good health is increasingly recognised in policy and practice, but consistent evidence for the underlying mechanisms is lacking. Heterogeneity in exposure methods, outcome measures, and population characteristics, little exploration of recreational use or the role of different types of green or blue space, and multiple separate mediation models in previous studies have limited our ability to synthesise findings and draw clear conclusions. We examined multiple pathways linking different types of neighbourhood nature with general health using a harmonised international sample of adults. Using cross-sectional survey data from 18 countries (n = 15,917), we developed a multigroup path model to test theorised pathways, controlling for sociodemographic variables. We tested the possibility that neighbourhood nature (e.g. greenspace, inland bluespace, and coastal bluespace) would be associated with general health through lower air pollution exposure, greater physical activity attainment, more social contact, and higher subjective well-being. However, our central prediction was that associations between different types of neighbourhood nature and general health would largely be serially mediated by recent visit frequency to corresponding environment types, and, subsequently, physical activity, social contact, and subjective well-being associated with these frequencies. Several subsidiary analyses assessed the robustness of the results to alternative model specifications as well as effect modification by sociodemographics. Consistent with this prediction, there was statistical support for eight of nine potential serial mediation pathways via visit frequency which held for a range of alternative model specifications. Effect modification by financial strain, sex, age, and urbanicity altered some associations but did not necessarily support the idea that nature reduced health inequalities. The results demonstrate that across countries, theorised nature-health linkages operate primarily through recreational contact with natural environments. This provides arguments for greater efforts to support use of local green/blue spaces for health promotion and disease prevention.European Union Horizon 202

Multicentric phase II trial of gemcitabine plus epirubicin plus paclitaxel as first-line chemotherapy in metastatic breast cancer

In this phase II, multicentre trial, patients with metastatic breast cancer (MBC) were treated with a combination of gemcitabine, epirubicin and paclitaxel (GET). The primary objective of this study was to determine the tolerability and activity in terms of complete responce (CR) and overall response rate of the GET combination in this patient population. Patients with no prior treatment for MBC, and at least one bidimensionally measurable lesion received gemcitabine 1000 mg m(-2) intravenously (i.v.) over 30 min on days 1 and 4, followed by epirubicin i.v. at 90 mg m(-2) on day 1, and paclitaxel 175 mg m(-2) over 3 h on day 1, every 21 days, up to eight courses. From May 1999 to June 2000, 48 patients were enrolled from seven Italian institutions. A total of 297 chemotherapy courses were administered with a median of six cycles patient(-1) (range 1-8). Seven patients (15%) obtained CR and 27 patients (56%) had partial responce, for an overall response rate of 71% (95%; CI: 58.3-83.7). After a median follow-up of 23.7 months (range 7.0-34.4), median progression-free survival was 10.5 months (95%; CI: 9.2-11.7), and median overall survival 25.9 months. The main haematological toxicity consisted of grade 3 or 4 neutropenia that occurred in 62% of cycles (22% grade 4 and 40% grade 3). The GET combination is active and well tolerated as first-line chemotherapy for MBC

Research Note: Residential distance and recreational visits to coastal and inland blue spaces in eighteen countries

This is the final version. Available on open access from Elsevier via the DOI in this recordData availability: The data used in this research will be open access in the future under the BlueHealth project's participation in the EU Open Data Pilot (Openaire).Varied categorisations of residential distance to bluespace in population health studies make comparisons difficult. Using survey data from eighteen countries, we modelled relationships between residential distance to blue spaces (coasts, lakes, and rivers), and self-reported recreational visits to these environments at least weekly, with penalised regression splines. We observed exponential declines in visit probability with increasing distance to all three environments and demonstrated the utility of derived categorisations. These categories may be broadly applicable in future research where the assumed underlying mechanism between residential distance to a blue space and a health outcome is direct recreational contact.European Union Horizon 202

Associations between green/blue spaces and mental health across 18 countries

This is the final version. Available on open access from Nature Research via the DOI in this record.Data availability: All data for the BlueHealth International Survey will be made open access in 2025 in accordance with an embargo agreement by research partners. For queries about the specifc data and analysis, including r script, used in the present manuscript please contact the corresponding author.Living near, recreating in, and feeling psychologically connected to, the natural world are all associated with better mental health, but many exposure-related questions remain. Using data from an 18-country survey (n = 16,307) we explored associations between multiple measures of mental health (positive well-being, mental distress, depression/anxiety medication use) and: (a) exposures (residential/recreational visits) to different natural settings (green/inland-blue/coastal-blue spaces); and (b) nature connectedness, across season and country. People who lived in greener/coastal neighbourhoods reported higher positive well-being, but this association largely disappeared when recreational visits were controlled for. Frequency of recreational visits to green, inland-blue, and coastal-blue spaces in the last 4 weeks were all positively associated with positive well-being and negatively associated with mental distress. Associations with green space visits were relatively consistent across seasons and countries but associations with blue space visits showed greater heterogeneity. Nature connectedness was also positively associated with positive well-being and negatively associated with mental distress and was, along with green space visits, associated with a lower likelihood of using medication for depression. By contrast inland-blue space visits were associated with a greater likelihood of using anxiety medication. Results highlight the benefits of multi-exposure, multi-response, multi-country studies in exploring complexity in nature-health associations.European Union’ Horizon 202