Introduction Age alone should not preclude systemic therapy in early breast cancer, although older patients often present with comorbidities and increased susceptibility to treatment-related toxicity. Geriatric screening could add information to better individualize their adjuvant treatment. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have demonstrated efficacy as adjuvant therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. However, older adults were underrepresented in pivotal clinical trials. This study aims to evaluate the value of geriatric screening among patients aged ≥70 years receiving adjuvant CDK4/6i, focusing on its association with quality of life, toxicity risk, relative dose intensity (RDI), and clinical outcomes. Materials and methods This is a Swedish multicenter, prospective observational cohort study including approximately 200 patients aged ≥70 years diagnosed with early-stage ER+/HER2- breast cancer starting adjuvant CDK4/6i. Baseline assessments will include the Geriatric 8 (G8) and Vulnerable Elders Survey-13 (VES-13) geriatric screening tools. Quality of life will be evaluated using EORTC QLQ-C30 and ELD14 questionnaires at predefined intervals. Moreover, clinical endpoints include grade ≥3 toxicity (as defined by CTCAE 5.0), CDK4/6i discontinuation, dose modifications, and hospitalization rates. Dose intensity will be assessed via RDI. Long-term outcomes, including breast cancer recurrence and breast cancer-specific survival, and overall survival, will be collected at 3-, 5-, and 10-year follow-up. Discussion Older patients remain underrepresented in clinical trials of adjuvant CDK4/6i, leading to uncertainty regarding real-world benefits and tolerability in this population. International guidelines advocate the integration of geriatric assessment in oncology to support tailored treatment decisions, yet its use remains limited in everyday clinical practice. This study seeks to assess the feasibility and clinical impact of geriatric assessments in routine care of older breast cancer patients receiving adjuvant CDK4/6i. Findings will provide essential data on the relationship between frailty and quality of life, treatment tolerance, dosing, and long-term outcomes, thereby potentially informing future clinical guidelines and improving personalized management for older patients with early breast cancer. Trial registration Registered in clinicaltrials.gov NCT Number: NCT07273357
Purpose: Clinical features of COPD and asthma overlap, complicating differential diagnosis. This study investigated the prevalence of comorbid asthma in COPD patients and its association with patient-related outcomes.Materials and methods: Patients with a doctor’s diagnosis of COPD were randomly selected in two cohorts 2005 (n = 1060) and 2014 (n = 1671), from primary and secondary care in Sweden. Data were collected from medical records and patient questionnaires at baseline and at follow-up (2012 and 2022, respectively). Questionnaires included data on exacerbations. Symptoms were assessed using the clinical COPD questionnaire (CCQ). Comorbid asthma was identified through medical records. Ten-year mortality data were obtained from national registers. Logistic and linear regression assessed associations with patient-reported outcomes; Cox regression was applied for mortality analyses.Results: Comorbid asthma was found in 22% of the 2005 cohort and 9% of the 2014 cohort (p < .001). In both cohorts, it was associated with an increased risk of exacerbations: OR (95% CI) 1.58 (1.07–2.32), p = .02, and 2.20 (1.38–3.52), p < .001, respectively. No associations were found between comorbid asthma and worsening of health status (CCQ). Mortality risk did not differ in the 2005 cohort, HR (95% CI) 0.92 (0.71–1.18), but was lower in the 2014 cohort, HR (95% CI) 0.67 (0.49–0.93), p = .02.Conclusion: Comorbid asthma in COPD has changed from 22 to 9%, potentially due to improved diagnostics. Comorbid asthma remains clinically relevant due to its association with an increased exacerbation risk.
Nonequilibrium Green’s functions provide a powerful framework for studying quantum many-body dynamics including the laser-induced dynamics in solids. The Non-Equilibrium Systems Simulation package (NESSi) offers an efficient platform for such simulations, ranging from perturbative approaches like nonequilibrium GW to nonequilibrium dynamical mean-field theory. However, simulations based on nonequilibrium Green’s functions become computationally demanding when the dynamics span a large temporal range, such as from sub-femtosecond electron dynamics to the picosecond dynamics of collective modes. Due to the memory integral in the Kadanoff-Baym equations, which serve as equations of motion for nonequilibrium Green’s functions, the computational cost scales as O(Nt3) with the number of timesteps Nt, and the memory requirement scales as O(Nt2). In this work, we extend NESSi by incorporating techniques that aim to overcome this bottleneck: (i) By truncating the memory integrals in the KBE to a maximum of Nc timesteps, the computational complexity is reduced to O(NtNc2), and the memory requirement to O(Nc2). Provided that the results converge with respect to the cutoff Nc, memory truncation allows to extend the simulations to significantly longer times. (ii) We introduce functionalities to describe nonequilibrium steady states, i.e. time-translationally invariant nonequilibrium states. Such states are relevant for transport settings, and they provide an approximate description of slowly evolving (prethermal) nonequilibrium states. New Version Program Summary Program Title: NESSi.CPC Library link to program files: https://doi.org/10.17632/973crf9hgd.2Developer’s repository link: https://github.com/nessi-cntr/nessiLicensing provisions: MPL-2.0.Programming language: C++, python.External routines/libraries: cmake, eigen3, fftw3 (optional), hdf5 (optional), mpi (optional), omp (optional).Journal reference of previous version: Comput. Phys. Commun. 257 (2020) 107484 [1].Does the new version supersede the previous version?: Extension of the existing library.Reasons for the new version: Reduce computational and memory cost to extend simulation times and directly simulate nonequilibrium steady states.Summary of revisions: Extension to memory-truncated and steady-state Kadanoff-Baym equations.Nature of problem: Solves equations of motion of time-dependent Green’s functions on the Kadanoff-Baym contour for a memory-truncated self-energy and in the steady state.Solution method: Higher-order solution methods of integral and integro-differential equations on the Kadanoff-Baym contour with memory-truncation in the integral kernel and evaluation of Fourier integrals in the steady state.References[1] M. Schüler, D. Golez, Y. Murakami, N. Bittner, A. Herrmann, H. U. Strand, P. Werner, M. Eckstein, Nessi: The non- equilibrium systems simulation package, Comput. Phys. Commun. 257 (2020) 107484. 10.1016/j.cpc.2020.107484.
Parental antisocial behavior (ASB) is a risk factor for ASB in the next generation. While social and environmental mechanisms contribute to this relationship, research also supports the influence of genetic components. A low resting heart rate (RHR) is moderately heritable and a well-established risk factor that may contribute to the intergenerational transmission of ASB. However, research investigating this relationship is limited. The overarching aim of the current study was to examine the influence of RHR in the intergenerational transmission of ASB from parent to child. Three minutes of RHR was collected on 129 girls and boys at age 9–10 years, alongside maternal ASB. At the age of 14–15 years, data on offspring ASB were collected using the externalizing scale of the Youth Self-Report. Results showed that maternal ASB predicted offspring ASB (B = 2.36, β = 0.36, t = 4.28, p < .001). However, offspring RHR did not mediate or moderate this relationship. Findings indicate that RHR is not a biological marker of risk in the intergenerational transmission of ASB in this community sample, although the results may be influenced by low statistical power.
Abstract Background Endothelial dysfunction profoundly compromises the barrier function that precludes trans-endothelial entry of low-density lipoprotein cholesterol (LDL-C) into the vessel wall. LDL-C retention in the vessel wall is atherogenic and its flux involves several mechanisms including LDL-receptor (LDL-R) mediated transcytosis, a process that is facilitated by inflammatory stressors. In this study, we aimed to investigate the role of interleukin-6 (IL-6) in regulating LDL-R and LDL-C uptake by vascular endothelial cells. Method We used commercially available Human umbilical vein endothelial cells (HUVECs) in this study. Flow cytometry, western blotting, qRT-PCR and ELISA were used to investigate expression of LDL-R and Mylip/IDOL. LDL-C uptake and free cholesterol levels in HUVECs was assessed using flowcytometry and mass-spectrometry respectively. Results We show that HUVECs treated with a combination of IL-6 and soluble IL-6 receptor (sIL-6R) result in a significant reduction in surface expression of LDL-R, an effect that is reversed by soluble gp130Fc – an antagonist of IL-6 trans-singling. Using pharmacological inhibitors and gene silencing techniques, we demonstrate that IL-6 trans-signaling induced downregulation of LDL-R is attained through lysosomal degradation mediated by the E3 ubiquitin ligase Mylip. Conversely, HUVECs treated with IL-6 in combination with sIL-6R exhibit markedly increased uptake of native LDL-C which is also inhibited by sgp130Fc, the actin inhibitor Cytochalasin D and the macropinocytosis inhibitor EIPA. Although stimulation of HUVECs upregulated the expression of scavenger receptors CD36 and CXCL16, their contribution to native LDL-C uptake turned out to be negligible. Conclusion Collectively, this study highlights the role of IL-6 in the regulation of LDL-R expression and cholesterol homeostasis in vascular ECs. IL-6 trans-signaling downregulates LDL-R yet increases LDL-C uptake via an LDL-R–independent, actin-dependent macropinocytosis pathway.
