Hospitalization for permanent pacemaker implantation in the context of isolated sinus node dysfunction is associated with increased mortality compared with an outpatient strategy.

BACKGROUND: Permanent pacemaker (PPM) implantation is a well-established treatment for symptomatic sinus node dysfunction (SND). The optimal timing of this intervention is unclear, with atrioventricular blocks often prioritized in resource stressed waiting lists due to mortality concerns. METHODS: Mortality data was compared between patients receiving elective outpatient (OP) PPM implantation, and those presenting to hospital for urgent inpatient (IP) management for symptomatic SND. Survival analysis was conducted using Kaplan-Meier plots and compared using the log-rank test. Univariable and multivariable Cox regression, as well as propensity score matching analyses were performed to assess the prognostic effect on 30-day and 1-year all-cause mortality of inpatient implant. RESULTS: Of the 1269 patients identified with isolated SND, 740 (58%) had PPMs implanted on an OP and 529 (42%) on an IP basis. Mortality was significantly worse in patients where management was driven by hospital admission on an urgent basis (Log-Rank χ2 = 21.6, p < 0.001) and remained an independent predictor of 1-year all-cause mortality (HR 3.40, 95% CI 1.97-5.86, p < 0.001) on multivariable analysis. CONCLUSIONS: SND is predominantly a disease associated with ageing and comorbid populations, where avoidance of deconditioning, hospitalization acquired infections, and polypharmacy is advantageous. Admission avoidance is therefore the preferable strategy.

A prospective, multicenter, clinical Study to evaluate the Safety, Pharmacokinetics, and Efficacy of Bleed Outcomes, with HemoRel-A® in severe Hemophilia A Patients.

PURPOSE: To evaluate efficacy for an on-demand treatment of acute bleeding events, pharmacokinetics, safety, and tolerability of HemoRel-A® in severe hemophilia A. METHODS: A total of 44 male subjects with severe hemophilia A with an annualized bleed rate of 12 while on-demand treatment with factor VIII (FVIII) were enrolled in the study and received HemoRel-A® for bleed treatment. The efficacy of HemoRel-A® was evaluated based on a four-point scale (excellent, good, moderate, or none). Six-point pharmacokinetic (PK) assessment was performed following a single dose of 50 IU/kg in 12 subjects after a 7-day wash-out period. Safety evaluations were performed at each visit and inhibitor testing was performed in all patients at screening and end of study. RESULTS: Forty-four male subjects received at least a single dose of the study medication and were included in the intent-to-treat (ITT) analysis and safety outcome. In 23 (7.52%) out of the 306 bleeding events, HemoRel-A® efficacy was rated as excellent, in 272 (88.89 %) bleeds it was rated as good, and in 11 (3.68%) bleeding events it was rated as moderate. No failure of efficacy was noted in any of the bleeding events. Thus overall out of 306 bleeding events, 295 (96.41%) showed excellent or good efficacy. Pharmacokinetic assessment based on plasma FVIII activity measured by the chromogenic assay in 12 patients showed comparative results similar to FVIII preparations. A total of 12 adverse events (AEs) were reported in this study. There was no inhibitor development in this previously treated patients (PTP) cohort. CONCLUSION: HemoRel-A® was established to be efficacious and safe in the treatment of acute bleeding events in subjects with severe hemophilia A. TRIAL REGISTRATION NUMBER: CTRI/2018/05/013790. Registration date: 9th May 2018.

Randomized Comparative Clinical Study of First Global Omalizumab Biosimilar with Innovator Product in Moderate to Severe Persistent Asthma.

PURPOSE OF STUDY: Omalizumab the first anti-IgE antibody is proven with several real-world studies and meta-analyses as important adjuvant in severe allergic asthma. This study was undertaken for the first omalizumab biosimilar to establish clinical biosimilarity and interchangeability with originator product. MATERIALS AND METHODS: In this randomized, double-blind comparative study 105 subjects (70 subjects in the study group and 35 subjects in the reference group) were dosed up to week 16 as double blind phase and responders entered open label phase till week 24. All responders at week 16 received study product in open-label phase of the study as per their dosing schedule till week 24. The additional efficacy assessment visit was performed till week 24. Safety follow up visit was performed in responders at week 26. The pharmacokinetic (PK) and pharmacodynamic (PD) assessment was planned in 48 subjects after first dose of omalizumab. RESULTS: In double blind phase, 4 (5.80%) asthma exacerbations were reported in study arm compared to 1 (2.86%) asthma exacerbation in reference arm with no statistically significant difference (p>0.05). The time to first asthma exacerbation was 53 days in study arm compared to 62 days in reference arm. In study and reference arm, the mean change from baseline in forced expiratory volume in one second (FEV1%) was 7.51 and 5.98 at week 4; and 12.30 and 8.94 at week 16 respectively while mean change from baseline in forced expiratory volume in one second/forced vital capacity (FEV1/FVC%) was 4.20 and 4.06 at week 4 and 6.77 and 7.10 at week 16 respectively (no statistically significant difference, p>0.05). At week 16, 4 (5.80%) subjects in study arm had 50-75% inhaled corticosteroids (ICS) dose reduction compared to 2 (5.71%) subjects in reference arm. The proportion of subjects with meaningful improvement in Asthma Quality of Life Questionnaire (AQLQ) (improvement in overall AQLQ score ≥0.5), mean change in overall Asthma Control Questionnaire (ACQ) score and proportion of responders based on Global evaluation of treatment effectiveness (GETE) assessment also was similar at 16 weeks. A total of 101 adverse events were reported out of which 63 were reported in the study or biosimilar arm and 38 were reported in the reference or innovator arm. Two serious adverse events (SAEs) were reported, one in each arm. No deaths occurred during this study and the safety observations are consistent with the known safety profile of omalizumab. All the samples analysed in this study were negative for anti-omalizumab antibodies. There was no significant difference in the PK and PD evaluation. CONCLUSION: The evaluation of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity was concluded to show no meaningful clinical difference of the biosimilar omalizumab with the reference product.

Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease.

Crizanlizumab is an anti-P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, nonrandomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of crizanlizumab 5.0 mg/kg (N = 45) and 7.5 mg/kg (N = 12) in patients with SCD with a history of VOCs. The median treatment duration was 104.7 and 85.7 weeks in the 5.0 and 7.5 mg/kg groups, respectively. For both doses, serum crizanlizumab concentrations rose to near maximum levels shortly after infusion, and near complete and sustained ex vivo P-selectin inhibition was observed. Grade ≥3 adverse events (AEs) occurred in 48.9% and 33.3% of patients in the 5.0 and 7.5 mg/kg groups, respectively; only 1 event was deemed treatment-related (7.5 mg/kg group). No treatment-related serious AEs occurred. One infusion-related reaction was recorded (5.0 mg/kg, grade 2 "pain during infusion"), which resolved without treatment withdrawal. Infections occurred in 57.8% and 41.7% of patients in the 5.0 and 7.5 mg/kg groups, respectively; none were drug-related. No treatment-related bleeding events were reported. No patients developed immunogenicity. The median (range) absolute reduction from baseline in the annualized rate of VOCs leading to a health care visit was -0.88 (-14.7 to 13.3) and -0.93 (-2.0 to 0.4) in the 5.0 and 7.5 mg/kg groups, respectively. Results here demonstrate the PK/PD properties of crizanlizumab in patients with SCD and the potential sustained efficacy and long-term safety of the drug after >12 months' treatment. This trial was registered at www.clinicaltrials.gov as #NCT03264989.

Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study.

Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.

Randomised, Double-blind, Comparative Clinical Study of New Ranibizumab Biosimilar in Neovascular (Wet) Age-Related Macular Degeneration.

PURPOSE: The study was undertaken for regulatory purposes to establish clinical biosimilarity and interchangeability of a ranibizumab biosimilar with reference product. PATIENTS AND METHODS: A total of 159 subjects with neovascular (wet) age-related macular degeneration (AMD) were dosed with ranibizumab. Initial double blind period of 16 weeks was followed by open-label phase till week 24. Efficacy assessment was performed at weeks 1, 4, 8, 12, 16, 20 and 24 based on best corrected visual acuity. Change in central macular thickness was assessed by optical coherence tomography from baseline to week 24. Immunogenicity assessment was done in both arms at baseline, week 16 and week 24. Safety evaluation included clinical and ophthalmic examination, adverse events, vital signs, laboratory parameters and immunogenicity in both treatment arms. RESULTS: In the biosimilar test arm, 104 (98.11%) and 105 (99.06%) patients lost fewer than 15 letters in visual acuity at week 16 and week 24, respectively, compared with 53 (100%) at both follow-ups in reference arm. In the test arm, 27 (25.47%) and 34 (32.08%) patients gained at least 15 letters in visual acuity till week 16 and week 24 respectively, compared with 17 (32.08%) and 23 (43.30%) in the reference arm. In the test arm, mean change in central macular thickness at 24 weeks was -89.93 µm against -64.42 µm in the reference arm. Difference was statistically not significant for any endpoint at 16 and 24 weeks for the primary and secondary endpoints. CONCLUSION: The evaluation of efficacy, safety and immunogenicity was concluded to show no meaningful clinical difference for biosimilar ranibizumab with the reference product.

Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Chemotherapy-Induced Neutropenia in Adults With Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Plinabulin is a novel, non-granulocyte colony-stimulating factor (GCSF) small molecule with both anticancer and neutropenia-prevention effects. OBJECTIVE: To assess the efficacy and safety of plinabulin compared with pegfilgrastim for the prevention of chemotherapy-induced neutropenia following docetaxel chemotherapy in patients with non-small lung cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, open-label, phase 2 clinical trial of 4 treatment arms that was conducted in 19 cancer treatment centers in the United States, China, Russia, and Ukraine. Participants were adult patients with non-small cell lung cancer whose cancer had progressed after platinum-based chemotherapy. Data were collected from April 2017 through March 2018 and analyzed from August 2019 through February 2020. INTERVENTIONS: All patients received docetaxel 75 mg/m2 on day 1 and were randomly assigned to 1 of 3 doses of plinabulin (5, 10, or 20 mg/m2) on day 1 or to pegfilgrastim 6 mg on day 2. Patients were treated every 21 days for 4 chemotherapy cycles. MAIN OUTCOMES AND MEASURES: The primary end point was the determination of the recommended phase 3 dose of plinabulin based on the days of severe neutropenia during chemotherapy cycle 1. Daily complete blood cell counts and absolute neutrophil counts were drawn during times of anticipated neutropenia during cycle 1. RESULTS: Of the 55 patients randomized and evaluated, the mean (SD) age was 61.3 (10.2) years, and 38 (69.1%) were men. With each escalation of the plinabulin dose, the incidence of any grade of neutropenia decreased. There were no significant differences in mean (SD) days of severe neutropenia among those treated with pegfilgrastim (0.15 [0.38] days) when dosed at day 2 vs plinabulin 20 mg/m2 (0.36 [0.93] days; P = .76) when dosed at day 1, and no safety signals were detected. CONCLUSIONS AND RELEVANCE: Single dose-per-cycle plinabulin has a similar neutropenia protection benefit as pegfilgrastim. Plinabulin 40 mg fixed dose, which is pharmacologically equivalent to 20 mg/m2, will be compared with pegfilgrastim 6 mg in the phase 3 portion of this trial. Noninferior days of severe neutropenia will be the primary end point, and bone pain reduction, thrombocytopenia reduction, and quality of life maintenance will be secondary end points. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03102606.

The observation of magnetic excitations in a single layered and a bilayered brownmillerite.

We describe the results of an inelastic neutron scattering measurement of the magnetic excitations in SrCaGaMnO(5+δ), a quasi-two-dimensional compound whose structure consists of layers of MnO(6) octahedra separated by layers of GaO(4) tetrahedra (the brownmillerite structure), and Ca(2.5)Sr(0.5)Mn(2)GaO(8), a bilayered brownmillerite. In both materials, a band of magnetic scattering appears below the magnetic ordering temperature which can be associated with magnon excitations. Our measurements allow us to provide an estimate for the intraplane exchange constant in both materials, which we find to be 3.4(4) meV for SrCaGaMnO(5+δ) and 2.2(4) meV for Ca(2.5)Sr(0.5)Mn(2)GaO(8).

Using virtual reality technology for aircraft visual inspection training: presence and comparison studies.

The aircraft maintenance industry is a complex system consisting of several interrelated human and machine components. Recognizing this, the Federal Aviation Administration (FAA) has pursued human factors related research. In the maintenance arena the research has focused on the aircraft inspection process and the aircraft inspector. Training has been identified as the primary intervention strategy to improve the quality and reliability of aircraft inspection. If training is to be successful, it is critical that we provide aircraft inspectors with appropriate training tools and environment. In response to this need, the paper outlines the development of a virtual reality (VR) system for aircraft inspection training. VR has generated much excitement but little formal proof that it is useful. However, since VR interfaces are difficult and expensive to build, the computer graphics community needs to be able to predict which applications will benefit from VR. To address this important issue, this research measured the degree of immersion and presence felt by subjects in a virtual environment simulator. Specifically, it conducted two controlled studies using the VR system developed for visual inspection task of an aft-cargo bay at the VR Lab of Clemson University. Beyond assembling the visual inspection virtual environment, a significant goal of this project was to explore subjective presence as it affects task performance. The results of this study indicated that the system scored high on the issues related to the degree of presence felt by the subjects. As a next logical step, this study, then, compared VR to an existing PC-based aircraft inspection simulator. The results showed that the VR system was better and preferred over the PC-based training tool.

3-D eye movement analysis.

This paper presents a novel three-dimensional (3-D) eye movement analysis algorithm for binocular eye tracking within virtual reality (VR). The user's gaze direction, head position, and orientation are tracked in order to allow recording of the user's fixations within the environment. Although the linear signal analysis approach is itself not new, its application to eye movement analysis in three dimensions advances traditional two-dimensional approaches, since it takes into account the six degrees of freedom of head movements and is resolution independent. Results indicate that the 3-D eye movement analysis algorithm can successfully be used for analysis of visual process measures in VR. Process measures not only can corroborate performance measures, but also can lead to discoveries of the reasons for performance improvements. In particular, analysis of users' eye movements in VR can potentially lead to further insights into the underlying cognitive processes of VR subjects.