Parker Hannifin (Germany)

Abstract Background/Aims The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the European Alliance of Associations for Rheumatology (EULAR) developed recommendation sets for psoriatic arthritis (PsA) treatment based on current evidence. All biologic disease-modifying anti-rheumatic drugs (bDMARDs) are equally recommended for peripheral arthritis. Different treatments exist for relevant skin and axial involvement. Interleukin 17 (IL-17) inhibitors (i) and IL-12/23i are recommended over tumour necrosis factor inhibitors (TNFi) for PsA with significant skin involvement. IL-12/23i are not recommended with axial manifestations. PRO-SPIRIT is the first large sample prospective multi-national observational PsA study. The objective of this study was to report the real-world treatment patterns reflecting PsA recommendations using results from the PRO-SPIRIT study. Methods PRO-SPIRIT enrolled adults with PsA from 2019 to 2022 who initiated or switched to approved biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARD). Treatment groups included TNFi, IL-17Ai, IL-12/23i, IL-23i, Janus kinase (JAKi), and phosphodiesterase-4 (PDE4i). Mode of action (MoA) was at the discretion of the treating physician. Patient demographic, disease activity, treatment characteristics, and clinical and patient-reported outcomes were collected at baseline (BL). Descriptive results are presented. Missing BL values were imputed. Results Analysis includes 1,192 patients with PsA treated by different MoA. Patients with arthritis (defined by swollen joint count (SJC) and tender joint count (TJC) ≥5) were equally distributed across treatment classes except for a lower percentage in PDE4i. Patients receiving IL-17Ai commonly presented with joint, skin, and nail involvement. Patients with higher skin (body surface area (BSA) ≥3%) and nail involvement were more commonly treated by IL-17Ai and IL-23i, less so with JAKi. Patients receiving JAKi presented with more joint and axial, and less skin involvement. After IL-23i, PDE4i had the second highest proportion of patients with nail involvement. PDE4i patients were low and reported less active domain affectation in general. Line of therapy results showed more patients treated with IL-12/23i, JAKi, and IL-17Ai after prior b/tsDMARDs treatment. Conclusion In general, patients had polyarticular disease at BL. Pts with skin and nail involvement were more commonly treated with IL-17Ai and IL-23i over TNFi and JAKi. Patients with axial manifestations were more commonly treated with IL-17Ai and JAKi over IL-12/23i and IL-23i. Findings add to the evidence on real-world PsA treatment patterns and recommendations sets for guiding individualised PsA treatment. Disclosure W. Tillett: Honoraria; AbbVie, Amgen, Celgene, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and UCB Pharma. M. Nisar: Honoraria; AbbVie, Bristol Myers Squibb, Celgene, Chugai, Eli Lilly and Company, Merck Sharp and Dohme, Novartis, Pfizer, Roche, and UCB Pharma. V. Chandran: Grants/research support; AbbVie, and is a consultant for: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, and UCB Pharma. K. Ng: Shareholder/stock ownership; Employee and shareholder of Eli Lilly and Company. M. Ngantcha: Shareholder/stock ownership; Employee and shareholder of Eli Lilly and Company. C. Laedermann: Shareholder/stock ownership; Employee and shareholder of Eli Lilly and Company. S. Moyano: Shareholder/stock ownership; Employee and shareholder of Eli Lilly and Company. R. Alten: Grants/research support; AbbVie, Bristol Myers Squibb, Eli Lilly and Company, Galapagos NV, Gilead Sciences, Janssen, Novartis, Pfizer, and UCB Pharma. L. Kristensen: Consultancies; AbbVie, Amgen, Biogen, Bristol Myers Squibb, Eli Lilly and Company, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and UCB Pharma. Grants/research support; AbbVie, Biogen, Eli Lilly and Company, Gilead Sciences, Janssen, Novartis, Pfizer, and UCB Pharma.

SUMMARYDefining consequential differences in intestinal epithelial stem cells in healthy humans versus those with inflammatory bowel disease (Crohn’s disease and ulcerative colitis) is essential for the development of much needed therapies to restore the epithelial barrier and maintain its fidelity. Employing single cell transcriptomic/epigenomic approaches and colonoid models from children and adults with Crohn’s disease led us to identify an inflammatory secretory progenitor (ISP) cell state present almost exclusively in patients with Crohn’s disease compared to control subjects. ISPs exhibit gene expression profiles consistent with normal secretory progenitor cells but concomitantly express a suite of distinguishing pro-inflammatory genes. Mechanistically, ISPs exhibit open chromatin and gene expression of ISP signature genes. While these ISP-specific genes are not expressed in intestinal stem cells, their chromatin is accessible in Crohn’s disease stem cells suggesting that ISP genes are epigenetically poised in stem cells and are transcriptionally activated in ISP cells in the presence of inflammatory stimuli. Consistently, Crohn’s disease colonoids exhibit sustained ISP gene expression that can be elicited further with pro-inflammatory cytokines or via co-culture with pro-inflammatory macrophages. In summary, we define differences in the epithelial stem and progenitor compartment of patients with Crohn’s disease suggesting aberrant stem cell differentiation and inflammatory gene expression arises during disease.HIGHLIGHTSWe identify an inflammatory secretory progenitor cell state in endoscopically non-inflamed tissue from pediatric and adult patients with Crohn’s disease.Crohn’s disease epithelial stem and progenitor cells display increased chromatin accessibility preceding the emergence of inflammatory secretory progenitor cell states.Crohn’s disease colonoids from non-inflamed regions contain inflammatory secretory progenitor cells in the absence of inflammatory stimuliInflammatory secretory progenitor cells expand in colonoid culture in response to cytokine stimulation or co-culture with pro-inflammatory macrophages

The intrinsic electronic properties of donor (D) and acceptor (A) materials in coupling with morphological features dictate the output in organic solar cells (OSCs). New physical properties of intimate eutectic mixing are used in nonfullerene-acceptor-based D-A1 -A2 ternary blends to fine-tune the bulk heterojunction thin film morphology as well as their electronic properties. With enhanced thin film crystallinity and improved carrier transport, a significant JSC amplification is achieved due to the formation of eutectic fibrillar lamellae and reduced defects state density. Material wise, aligned cascading energy levels with much larger driving force, and suppressed recombination channels confirm efficient charge transfer and transport, enabling an improved power conversion efficiency (PCE) of 17.84%. These results reveal the importance of utilizing specific material interactions to control the crystalline habit in blended films to form a well-suited morphology in guiding superior performances, which is of high demand in the next episode of OSC fabrication toward 20% PCE.

Background: Self-reported dietary data may not accurately represent usual dietary intake. Grocery purchase records provide an objective measure of diet, but little research has explored whether the diet quality of grocery purchases reflects individual-level diet quality and whether it differentiates between groups with known differences in dietary quality. This study evaluated whether there are sociodemographic differences in the dietary quality of grocery purchases akin to those observed in existing individual-level national data. Hypothesis: The diet quality of grocery purchases will reflect trends observed with individual-level diet quality. Methods: Grocery purchasing data from 3,961 households in the nationally-representative Food Acquisition and Purchase Study (FoodAPS) were used. Dietary data was collected using hand scanners over 7-days, and demographic data was self-reported. The Healthy Eating Index (HEI) 2015 was used to determine grocery purchase quality, and multivariable-adjusted regression with Tukey adjustment or planned contrasts were used to determine whether HEI-15 scores differed according to food insecurity, Supplemental Nutrition Assistance Program (SNAP) participation, obesity within a household, race/ethnicity, and interactions between these variables. FoodAPS sample weights and Taylor series linearization method for variance estimation accounted for the complex sample design. Results: Primary respondents were, on average, 50.6 years, non-Hispanic White (70.3%), female (70.2%) and had attended some college (57.8%). The mean HEI-15 score was 54.7; 14.0% of households were food insecure and 12.7% received SNAP benefits. HEI-15 scores differed across all sociodemographic predictors (p<0.05). Additionally, interactions (p<0.1) were detected between SNAP participation and (1) food insecurity and (2) obesity within the household as well as race/ethnicity and obesity within the household. Food secure, non-SNAP households had higher HEI-15 scores than food insecure, SNAP participating households (53.9±0.5 vs. 50.3±0.7, p=0.007) in models adjusted for age, income, smoking, and education. Similarly, non-SNAP households without obesity present had significantly higher HEI-15 scores than all other households. Obesity presence within a household was associated with lower HEI-15 scores in non-Hispanic White (50.8±0.5 vs. 52.5±0.7, p=0.046), and Black households (48.8±1.5 vs. 53.1±1.4, p=0.018), but not Hispanic households (54.4±1.0 vs. 52.2±1.2, p=0.21). Conclusions: Disparities in the diet quality of grocery purchases reflect individual-level trends and vary based on sociodemographic factors. This analysis highlights the interrelationships between SNAP, food insecurity, race/ethnicity, and obesity within a household, demonstrating how the co-occurrence of risk factors may modify associations with diet quality.

PurposeSystemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival.Patients and MethodsStandard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors.ResultsA total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel.ConclusionThese data show no overall evidence of improved survival with Cel. Preplanned subgroup analyses provide hypotheses for future studies.

The rotating bending fatigue strength of gas nitrided JIS-SCM435 steel was evaluated to find the thickness that gives the highest bending fatigue strength. Four specimens were used that had different compound layer thicknesses composed of γ' (-Fe4N) phase: 0, 2, 10, and 20 μm. The composition of γ' phase was more than 70% of the volume of the compound layer in the specimens. The increment of the fatigue strength at 105–107 cycles was remarkably high when the compound layer thickness was from 0 to 10 μm and gradually increased from 10 to 20 μm. The increment of the fatigue strength was caused by the increment of the γ' phase thickness and the compressive residual stress depth as the compound layer thickness increased. The gradually increasing fatigue strength of more than 10 μm thickness was responsible for the porous layer thickness increasing and the compressive residual stress reducing on the surface as the compound layer thickness increased. These findings show that the fatigue strength of gas-nitrided JIS-SCM435 steel composed of γ' phase depends on not only the compound layer thickness but also the porous layer thickness and the compressive residual stress of the compound layer.

The 2014 PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) study[1][1] compared the effectiveness of a novel combination of neprilysin (an endopeptidase) inhibitor sacubitril and angiotensin II receptor antagonist

Objectives: The interdigitating technique in aortic arch reconstruction in hypoplastic left heart syndrome and variants (HLHS) is very effective to minimize the recoarctation rate. Little is known on the aortic arch’s growth characteristics and the resulting clinical impact. Methods: 139 patients with HLHS underwent staged palliation between 2007 and 2014. 72 patients who underwent Norwood arch reconstruction with the interdigitating technique were included. Dimensions of the ascending aorta (AA), transverse arch (TA), isthmus (IA) and descending aorta (DA) in pre-stage II (P1, n=50) and pre-Fontan (P2, n=21) angiograms were measured and geometry and growth characteristics of the aortic arches were analyzed. Correlations between the aortic dimensions and clinical outcomes were assessed. Results: There were significant increases in diameters in all segments between P1 and P2 (p < .0005). The z-scores in AA, TA and IA were unchanged between P1 and P2 (p = .931/.425/.121), but increased significantly in DA at P2 (p = .039). The percent increase in diameters were comparable among 4 segments (mean, 146% in IA, 144 in DA, p=.648). There were correlations in dimensions and z-scores between P1 and P2 in AA (p = .029/.013) and TA (p = .001/ < .0005), but no correlations were found in IA (p = .140/.747) and DA (p = .075/.432). The most significant tapering in the arch dimension occurred between TA and IA in both time points (P1, 67.3% vs. P2, 61.1%, p=.303). The reverse coarctation index (TA/IA ratio) at P1 (r = .381, p = .042), but not coarctation index (CoAI, IA/DA ratio) at P1 (p = .774) had a significant correlation with post-stage II ventricular function. Balloon dilatation for recoarctation was needed in 2 (2.7%) patients prior to stage II palliation. CoAI at P1 was a predictor for ventricular dysfunction at latest follow-up (p=.017). Conclusions: Aortic arch growth after interdigitating reconstruction in HLHS is substantial and relatively constant. The isthmus growth is proportional to other segments. Overall reintervention rate for recoarctation is exceptionally low. CoAI prior to stage II palliation may be associated with long-term ventricular function.

Background: We determined whether exercise performance and lower extremity microcirculation were associated with endothelial cell inflammation, oxidative stress, and apoptosis, and with circulating biomarkers of inflammation and antioxidant capacity. Methods: One hundred sixty symptomatic patients with PAD were characterized on the endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells. Patients were further evaluated on circulating inflammatory and vascular biomarkers, physical examination, medical history, exercise performance measured during treadmill evaluation by peak walking time (PWT), and claudication onset time (COT), and lower extremity microcirculation measured by calf muscle hemoglobin oxygen saturation (StO 2 ) during treadmill exercise. Results: In the multivariate regression model for PWT, the significant independent variables included ankle-brachial index (p<0.001), age (p=0.017), hydroxyl radical antioxidant capacity (HORAC) (p=0.008), and endothelial cell NF-κB activity (p=0.015). In the multivariate regression model for COT, the significant independent variable was endothelial cell NF-κB activity (p=0.013). In the multivariate analyses for the average rate of decline in calf muscle StO 2 during exercise, the significant independent variables included body mass index (p<0.001) and HORAC (p=0.024). Conclusions: Endothelial cell inflammation and circulating biomarkers of inflammation and antioxidant capacity are significant factors for exercise performance and microcirculation of the ischemic calf musculature during exercise. The clinical implication is that interventions designed to alleviate endothelial cell inflammation and circulating inflammatory biomarkers, such as antioxidant therapy, may improve exercise performance of symptomatic patients with PAD.