Oxidation state of a polyurethane membrane after plasma etching

Low moduli cell culture substrates can be used to apply dynamic mechanical strain to cells, by surface deformation. Understanding the surface interaction with cells is critical to improving cell adhesion and normal growth. A medical grade polyurethane (PU), Chronoflex AL 80A, was modified by oxygen plasma etching and characterised by X-ray photoelectron spectroscopy. Etching resulted in increased cross-linking at the isocyanate bond and formation of new oxygen moieties. The model, derived from patent data and XPS data of the unetched PU, indicated that the additional oxygen was likely to be hydroxyl and carbonyl groups. Etched membranes enhanced protein adhesion, resulting in full surface coverage compared to unetched PU. The etched PU supported cell adhesion and spreading, while the unetched PU was not conducive to monolayer formation

Physiological parameter response to variation of mental workload

Previous studies have examined how individual physiological measures respond to changes in mental demand and subjective reports of mental workload. This study explores the response of multiple physiological parameters, measured simultaneously and quantifies the added value of each of the measures when estimating the level of demand. The study presented was conducted in laboratory conditions and required participants to perform a custom-designed visual-motor task that imposed varying levels of demand. The data collected consisted of: physiological measurements (heart inter-beat intervals, breathing rate, pupil diameter, facial thermography); subjective ratings of workload from the participants (ISA and NASA-TLX); and the performance measured within the task. Facial thermography and pupil diameter were demonstrated to be good candidates for non-invasive mental workload measurements; for 7 out of 10 participants, pupil diameter showed a strong correlation (with R values between 0.61 and 0.79 at a significance value of 0.01) with mean ISA normalized values. Facial thermography measures added on average 47.7% to the amount of variability in task performance explained by a regression model. As with the ISA ratings, the relationship between the physiological measures and performance showed strong inter-participant differences, with some individuals demonstrating a much stronger relationship between workload and performance measures than others. The results presented in this paper demonstrate that physiological monitoring can be used for non-invasive real-time measurement of workload, assuming models have been appropriately trained on previously recorded data from the user population. Facial thermography combined with measurement of pupil diameter are strong candidates for real-time monitoring of workload due to the availability and non-intrusive nature of current technology. The study also demonstrates the importance of identifying whether an individual is one who demonstrates a strong relationship between physiological measures and experienced workload measures before physiological measures are applied uniformly. This is a feasible proposition in a setting such as aircraft cockpits, where pilots are drawn from a relatively small, targeted and managed population

The use of decellularised animal tissue to study disseminating cancer cells

Since the establishment of cell culture, common practice has been to grow adherent cells in 2D monolayers. Although cells behave completely differently when grown under these artificial conditions, the ease of 2D culturing has meant that this practice still prevails, and adopting conditions that more closely reflect the natural microenvironment has been met with substantial inertia. The alternative, animal models that mimic natural human physiology, are less accessible, strictly regulated and require licences and expensive facilities. Although transition from 2D to 3D cell culturing is gathering momentum, there is a clear need for alternative culturing methods that more closely resemble in vivo conditions. Here, we show that decellularised organs gleaned from discarded animal carcasses are ideal biomimetic scaffolds to support secondary tumour initiation in vitro. Further, we describe how to decellularise tissue and perform basic histochemistry and immunofluorescence procedures for cell and matrix detection. Cancer cell behaviour on this matrix is followed by way of an example. Because integration into the traditional work flow is easy and inexpensive, we hope this article will encourage other researchers to adopt this approach

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Comparison of glutaraldehyde and procyanidin cross-linked scaffolds for soft tissue engineering

Soft tissue injuries are among the most difficult orthopaedic conditions to treat, and regenerative medicine holds the promise of better treatments of these injuries. There is therefore a requirement for substrates and porous scaffolds which provide an appropriate chemical and mechanical environment for cell attachment, growth, proliferation and differentiation. In this study, cross-linked porous gelatin-chitosan (Gel/Chi) scaffolds with high porosity (> 90%) were fabricated and their internal morphology, pore sizes and porosities were characterized using scanning electron microscopy (SEM), micro computed tomography (micro-CT) and mercury intrusion porosimetry. The cross-linking agents chosen for this study were Procyanidin (PA), chosen for its biocompatibility, and glutaraldehyde (GA), chosen for comparison as a highly effective cross-linker. Concentrations of these cross-linkers varied from 0.1% to 1% (w/v) and controls had the same gelatin-chitosan blend but were untreated. It was found that the water absorption of cross-linked scaffolds decreased as the cross-linker concentration increased and in vitro collagenase degradation test showed both cross-linkers increased the biostability of the scaffolds. Scaffolds were also tested under compressive load to investigate their resistance to deformation. The results indicated that both cross-linkers increase the stiffness of the scaffolds both initially and at higher strains, but GA cross-linked scaffolds had a higher compressive stiffness than scaffolds cross-linked with PA for a given concentration. Results from cyclic compression and stress relaxation tests showed that PA cross-linked scaffolds recover more rapidly after deformation. 3T3 fibroblasts were cultured on the scaffolds to assess cytotoxicity and biocompatibility. The results indicated that PA was non-cytotoxic and promoted the attachment and proliferation of the seeded cells, while fewer cells were seen on GA cross-linked scaffolds, indicating that the GA had conferred some cytotoxicity. PA cross-linked Gel/Chi porous scaffolds show promise as three dimentional porous scaffolds in tissue engineering, as porous substrates for biomimetic culture environments, and for regenerative medicine applications, due to their excellent biocompatibility and easily adaptable mechanical properties, as well as their lower cost compared to collagen and fibrin based substrates

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

BackgroundSparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis.MethodsPROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850.FindingsBetween Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals.InterpretationOver 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine