BACKGROUND:FIX-HF-5C multicentre, randomized study demonstrated cardiac contractility modulation (CCMTM) improved patient-centred outcomes, including functional capacity, symptom burden, and health-related quality of life. Reductions in cardiovascular death and heart failure hospitalization (HFH) were observed. These event-driven outcomes were not prespecified efficacy endpoints and were not incorporated into overall assessment of treatment benefit. Comprehensive clinical benefit of CCM therapy was re-analyzed by a win-ratio method that integrated event-driven clinical endpoints with patient-centred outcomes. METHODS:The hierarchical win-ratio prioritized cardiovascular mortality, HFH, and patient-centred outcomes comprising equally weighted components of peak oxygen consumption, Minnesota Living with Heart Failure Questionnaire score, 6-minute walk distance, and NYHA functional class. Sub-group analyses were performed in patients with NYHA Class III versus IV. RESULTS:In the primary analysis of 160 randomized patients (6364 patient pairs), the overall win ratio was 2.48 (95% CI 1.76 to 3.64; P < .001), corresponding to a 71% pairwise comparative probability of clinical benefit with CCM versus OMT. Event-driven clinical endpoints accounted for 22% of total wins while 56.2% came from patient-centric endpoints. CCM consistently outperformed OMT across all hierarchies. Sensitivity analyses yielded similar findings with win ratios favouring CCM (range: 1.52 to 2.42). Treatment effects were consistent across NYHA class III and IV subgroups. CONCLUSIONS:The win-ratio re-analysis supports and extends the original study results demonstrating a consistent clinical benefit of CCM therapy over OMT across a hierarchical framework integrating event-driven clinical endpoints with patient-centred functional outcomes. The findings, while clinically highly encouraging, are hypothesis-generating and warrant validation in future confirmatory studies.
Objective: To assess the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients with a probable or definite ALS diagnosis were randomized to receive twice daily oral doses (for 12 weeks) of Usnoflast (25 mg, 50 mg, or 75 mg) or placebo. The primary outcome was the change in ALS functional rating scale-revised (ALSFRS-R) total score from baseline to week 12. Secondary outcomes were assessment of PK, change in slow vital capacity (SVC) and serum and cerebrospinal fluid (CSF) levels of neurofilament light (NfL) chain from baseline to week 12, and safety up to 12 weeks. Results: Total 24 patients were enrolled; 71% of those who received Usnoflast had the drug above therapeutic concentration in CSF. In the modified intent-to-treat (mITT) population, least square mean changes (ANCOVA) in ALSFRS-R total score from baseline to week 12 were -1.91 for Usnoflast 25 mg, -3.84 for Usnoflast 50 mg, 0.52 for Usnoflast 75 mg, and -2.26 for placebo arm. Though not significant (p > 0.05), compared with placebo, Usnoflast 75 mg demonstrated a difference of 2.78 (mITT) and 3.28 (per-protocol) in ALSFRS-R total score. Statistical non-significant differences were also observed in changes of SVC% and CSF NfL levels. Usnoflast was well-tolerated at tested doses, and there was no treatment-emergent serious adverse event or death during the study duration. Conclusion: Usnoflast 50 and 75 mg doses were well-tolerated in ALS patients, providing rationale for further studies of Usnoflast in ALS.
Patients with heart failure with reduced ejection fraction (HFrEF) experience higher rates of in-hospital and all-cause mortality. On the basis of the VERINA trial, vericiguat is indicated for patients who have had a worsening heart failure (WHF) event despite optimal heart failure (HF) therapy, or for those with tolerability concerns. This multicenter, prospective, single-arm, non-randomized, real-world, descriptive study assessed the efficacy and safety of vericiguat in Indian patients aged ≥18 years with chronic HFrEF who were vericiguat-naïve and started treatment as per the local label. This analysis is based on interim data and the final results may differ. The main endpoint was a composite of cardiovascular (CV) death or first HF hospitalization. Secondary endpoints included each component of the primary outcome, all-cause death, and safety. Dose-titration parameters, including time to reach and duration at various dose levels, were also assessed. A total of 205 patients were enrolled (58.0 ± 13.27 years; 73.7
Chapter 1General introduction endothelial cell damage 27,29,47,57 .When modelling endothelial cell damage or inflammatory responses, standard read-outs are fluorescent staining of endothelial cell markers.However, this does not show the functional differences in the blood vessel such as monocyte adhesion and thrombus formation which will make them more physiologically relevant and can assist in assessing patient specific responses.Furthermore, the demand for standardized quantifiable read-outs is rising 58 .Some BVoC models with blood perfusion assays and monocyte adhesion assays are already in existence [59][60][61][62][63][64] , however standardization, quantification of read-outs, and systematically setting up co-cultures in these models needs to be optimized, making the models and measurements translatable and comparable 58,[65][66][67] .Current blood perfusion models often use fluorescently labelled markers with an end-point fluorescent microscopic measurement of thrombus formation 62,68,69 .Thrombus formation and development in BVoCs are difficult to observe in real time using these assays, furthermore, these fluorescent images give a 2D view of a thrombus.Therefore a non-invasive method of measuring blood clot formation over time, in multiple dimensions, will be an addition in understanding clotting mechanisms 70,71 .Many challenges remain in creating physiologically relevant BVoC models, such as creating BVoC models for vascular disease modelling, which include multiple relevant cell types and with the possibility of relevant and quantifiable read-outs.This thesis aims to contribute to the field of BVoC development by presenting new chip designs, methods for co-culturing cells, and quantifyable read-outs. Thesis outlineThis thesis presents the research towards BVoCs for vascular disease modelling.Using different chip designs and different cell types, we show the ability to create several vessel-on-chip (VoC) models, for different disease types and/or organs with different quantifiable read-outs.Chapter 2 consists of two parts.The first part describes the importance of early involvement of stakeholders in the development of OoCs.It shows the differences in stakeholder opinions, which can be overcome by involvement early in the development process.The next part summarizes the VoC models currently used.Next to that we discuss which quantification possibilities are currently in use in vivo and in vitro and where VoCs are still lacking.
Wetting flows of viscoelastic fluids are encountered in various industrial and biological settings, e.g., dip-coating, deposition of pesticides on plant leaves or ink-jet printing. This thesis explored these viscoelastic wetting flows, specifically focusing on the normal stress effects which are expected to be significant in high shear rate regions in wetting flows. The existing Newtonian results in the literature were not easily generalized to include normal stress, since there was no established thin-film framework based on nonlinear viscoelastic constitutive relations. The goal of this thesis was to fill this gap, and to explore the consequences of viscoelastic normal stresses for classic wetting flows such as dip-coating and contact line motion.We studied the wetting flows with normal stress using systematic expansions of the second-order fluid. We derived the corresponding thin-film equations using the lubrication approximation, which exploits the thinness of the film, to describe the interface profiles and to explore how normal stress changes the wetting behavior. In chapter 1, the long-wave analysis for the second-order fluid was performed using no approximation beyond the slenderness assumption. This resulted in a frame-invariant thin-film equation that contains normal stress, which, subsequently, we used to study the classical Landau-Levich dip-coating problem. We showed how viscoelasticity of the fluid affects the thickness of the deposited film, and resolved the film thinning versus thickening discrepancy present in the literature. In chapter 2, we used the thin-film equation derived from a long-wave expansion of the second-order fluid in chapter 1 to systematically study how contact line motion is affected by the presence of normal stress. The classical Cox-Voinov theory of contact line motion provides a relation between the macroscopically observable contact angle, and the microscopic wetting angle as a function of contact line velocity. Here we investigated how the normal stress modifies wetting dynamics. We found that the normal stress effect is dominant at small scales and that the effect can be incorporated in the Cox-Voinov theory through an apparent microscopic angle, which differs from the true microscopic angle. The theory was applied to the classical problems of drop spreading and dip-coating, which shows how normal stress facilitates advancing and inhibits receding contact line motion. For rapid advancing motion, the apparent microscopic angle can tend to zero in which case the dynamics is described by a new regime that was already anticipated in the literature. The theory will be applicable to a broad range of wetting problems where the flow is (quasi) steady such as for the dewetting of a thin fluid film and drops sliding on a solid substrate. In chapter 3, we extended our theory for viscoelastic contact line motion beyond the lubrication theory. The common approach using the lubrication approximation is intrinsically limited to small interface slopes and therefore only admits solutions at small contact angles. Using a perturbation expansion around corner flow solutions, a generalized lubrication theory can be derived that is valid for arbitrary contact angles. Here we extended this generalized lubrication theory to viscoelastic liquids that exhibit a normal stress effect. These normal stresses were included via the second-order fluid model as in previous chapters, for which we investigated corner flows and established the resulting generalized lubrication theory. Subsequently, we applied this model to advancing and receding contact lines in dip-coating where the plate angle with respect to the liquid bath was also varied along with the contact angle. This final chapter consolidated the results of chapter 2 while also highlighting the relevant dimensionless parameters for viscoelastic contact line motion.
