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Objective: The goal of this work is to describe the first experience in the UK with the slim pre-curved perimodiolar electrode Nucleus CI532 in a continuous series of patients in terms of surgical and clinical reliability and early performance outcomes.Method: In this retrospective review we describe the complication rate (including electrode array tip fold-over), NRT thresholds, hearing preservation, power efficiency and CI performance outcomes in a continuous series of 40 cochlear implants CI532 performed between October 2016 and November 2017 in 17 adults and 13 children with severe to profound hearing loss.Results: Preliminary data from these groups reveals some low-frequency hearing preservation in the CI532 group although none of the patients were conventional hearing preservation candidates. NRT thresholds, power efficiency, and BKB sentences in quiet were measured at 3 and 6 months post activation. There were no significant differences in these results. The average BKB score in quiet increases from 22% pre-operatively to 58% at 3 months and 70% at 6 months. In addition, although hearing preservation was not an objective, low-frequency thresholds were preserved in 20% of cases at 3 and 6 months post-operatively. Complications were observed in 5 cases, one case with non-device related aerocoele and four related to the device array: two cases of tip roll over, one case of the electrode array being placed extra-cochlea, and one case with the electrode buckling into the middle ear. The last 2 cases were dealt with per-operatively.Discussion: Our preliminary results with the CI532 implant indicate that it may be reliably placed with standard surgical techniques but care is needed during the deployment of the electrode. Further initial data suggest that switch on and early electrophysiological measures are comparable to the existing CI 512 device. However whilst preliminary, our data suggest that it may be possible to use this electrode for hearing preservation. However, further studies are required to determine its definitive advantage over other electrode designs.Conclusion: CI532 is a reliable device offering good initial results and could be an option for hearing preservation although further studies are required. [ABSTRACT FROM AUTHOR]

Summary: Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant‐eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment‐emergent adverse events. In summary, these findings suggest a benefit of D‐RVd front‐line therapy among Black and White patients and underscore the importance of equitable treatment access for all patients. [ABSTRACT FROM AUTHOR]

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC 50 s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg). A multi-parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases. [ABSTRACT FROM AUTHOR]

Summary: Patients with multiple myeloma are at increased risk of vascular thromboembolic events (VTEs). This post hoc analysis evaluated VTEs in the randomised phase 2 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) that investigated lenalidomide/bortezomib/dexamethasone (RVd) ± daratumumab (D). Patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation (ASCT) received D‐RVd/RVd induction, high‐dose therapy and ASCT, D‐RVd/RVd consolidation and up to 2 years of lenalidomide maintenance therapy ± D. VTE prophylaxis was recommended (at least aspirin, ≥162 mg daily) in accordance with International Myeloma Working Group guidelines. In the safety population (D‐RVd, n = 99; RVd, n = 102), VTEs occurred in 10.1% of D‐RVd patients and 15.7% of RVd patients; grade 2–4 VTEs occurred in 9.1% and 14.7%, respectively. Median time to the first onset of VTE was longer for D‐RVd versus RVd patients (305 days vs 119 days). Anti‐thrombosis prophylaxis use was similar between arms (D‐RVd, 84.8% vs RVd, 83.3%); among patients with VTEs, prophylaxis use at time of first VTE onset was 60.0% for D‐RVd and 68.8% for RVd. In summary, the addition of daratumumab to RVd did not increase the incidence of VTEs, but the cumulative VTE incidence was relatively high in this cohort and anti‐thrombotic prophylaxis use was suboptimal. [ABSTRACT FROM AUTHOR]

Background: There is limited real-world evidence that describes patients with newly diagnosed multiple myeloma (NDMM) treated with the bortezomib, lenalidomide, and dexamethasone (VRd) triplet regimen. We evaluated patient characteristics and treatment outcomes among nontransplanted NDMM patients who received VRd as their first line of therapy (LOT) in US oncology practice settings.Methods: This retrospective observational cohort study evaluated patients from the Flatiron MM Core Registry who received VRd as first LOT between November 1, 2015, and February 28, 2021. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. Associations between patient demographic and clinical characteristics and PFS were evaluated using a multivariable Cox proportional hazards model.Results: A total of 2342 eligible patients with VRd as first LOT were identified (mean age, 67.0 years). Among all identified patients, 64.3% were ≥ 65 years of age, 25.5% were elderly (≥75 years), and 47.9% were frail. Among patients with available data, 21.2% had high-risk cytogenetics, and the majority had International Staging System (ISS) stage I/II disease (71.8%), and Eastern Cooperative Oncology Group performance status (ECOG PS) score 0/1 (81.2%). Median duration of therapy was 5.5 months. With median follow-up of 21.0 months, median PFS and time-to-next-treatment were 26.5 and 16.1 months, respectively. Higher risk of disease progression or death was seen in patients categorized as elderly (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.13-1.66 vs patients < 65 years), having high-risk cytogenetics (HR = 1.44; 95% CI: 1.19-1.75 vs standard risk), having ISS disease stages II and III (HR = 1.31; 95% CI: 1.06-1.63 and HR = 1.37; 95% CI: 1.10-1.70 versus stage I, respectively), and having worse ECOG PS score (≥2) (HR = 1.49; 95% CI: 1.22-1.81 versus functionally active patients).Conclusions: The majority of patients treated with VRd in this study were ≥ 65 years of age, were ISS stage I/II, had an ECOG PS score of 0/1, and had standard cytogenetic risk. Median PFS observed in real-world practice was notably shorter than that observed in the SWOG S0777 clinical trial. In nontransplanted patients treated with VRd as first LOT, a higher risk of disease progression or death was associated with older age, having high-risk cytogenetics, worse disease stage, and worse ECOG PS score. [ABSTRACT FROM AUTHOR]

Objective and importance Patients who have undergone solid organ transplantation and continuing immunosuppressant medication are at a higher risk of wound problems and infections following cochlear implantation. This risk is theoretically even further increased in multi-organ transplant recipients due to the increased doses of immunosuppressive medications that these patients are administered. Clinical presentation and intervention Here, we present the first reported case of successful cochlear implantation in a patient who had previously undergone successful combined liver and kidney transplant. She had no significant complications from the surgery and had good audiological outcomes 3 months post-operatively. Conclusion As we continue our advances in the use of cochlear implant technology, our report adds to the growing evidence of its benefits in transplant recipients. However, there are important pre- and peri-operative considerations in this group of patients which can improve safety and outcome. [ABSTRACT FROM AUTHOR]

Dienes readily undergo Diels–Alder reaction with CH2&z.dbnd6;C(NO2)SO2Ph (2a), CH2&z.dbnd6;C(NO2)CO2Et (2b), and CH2&z.dbnd6;C(NO2)COPh (2c), all observed in situ by 1H NMR. The cycloadducts of 2a undergo SRN1 reactions. [Copyright &y& Elsevier]

Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Abstract: 2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (K i =1.2nM) that exhibits robust efficacy in canine anticoagulation and thrombosis models upon oral administration. [Copyright &y& Elsevier]