A rare presentation of infective endocarditis: Phase 4 block of the left bundle branch as key for the diagnosis. A case report.

Definitive diagnosis of infective endocarditis (IE) is mainly based on microbiological and imaging criteria. In a minority of cases, particularly when perivalvular area is involved, cardiac conduction disorders (CCD) may appear, which implies worse prognosis. In this scenario, different degrees of auriculoventricular block can occur, but development of bundle branch block is rare. Herein, we present a case of IE with negative initial imaging tests, where the occurrence of phase 4 bundle branch block after a sequence of type I second degree AV block was crucial to establish a definitive diagnosis and an optimal therapeutic approach.

Real-World Effectiveness of Upadacitinib for Treatment of Rheumatoid Arthritis in Canadian Patients: Interim Results from the Prospective Observational CLOSE-UP Study.

INTRODUCTION: Upadacitinib (UPA), a selective, reversible, oral Janus kinase (JAK)-1 inhibitor, was approved in 2019 in Canada for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). This phase 4 prospective study aimed to characterise the effectiveness of UPA in the real-world population of patients with RA. METHODS: Adults with RA who initiated treatment with once daily UPA (15 mg) and enrolled in the Canadian Real-Life post-marketing Observational Study assessing the Effectiveness of UPadacitinib for treating rheumatoid arthritis (CLOSE-UP) and who completed a 6-month assessment as of 28 February 2023 were included. The primary endpoint of the CLOSE-UP study is the proportion of patients achieving a Disease Activity Score-28 Joint Count C-reactive protein (DAS28-CRP) < 2.6 at 6 months. Data was collected at routine visits. Data analysed and summarised descriptively for the overall interim population and for subgroups based on prior therapy included remission or low disease activity, patient-reported outcomes (PROs), and adverse events. RESULTS: A total of 392 patients were included in the interim analysis. Overall, 63.5% (191/301) of patients achieved a DAS28-CRP score < 2.6 at month 6, with similar rates observed for all subgroups analysed according to prior therapy including those with prior JAK inhibitor exposure (range 57.4-71.0%), and in patients who received UPA monotherapy (71.6% [48/67]). Early (month 3) and sustained improvements up to 6 months were observed for all PROs. The safety profile was consistent with previous reports. CONCLUSION: Real-world improvements in disease activity and PROs in response to UPA treatment were consistent with clinical trial data across a range of Canadian patients with prior therapy exposure and with UPA monotherapy, with an overall favourable benefit-risk profile. TRIAL REGISTRATION: NCT04574492.

Rate-dependent elevation of the capture threshold after implantation of a leadless pacemaker.

The procedural success in the implantation of cardiac electric devices depends on both the implanted position and the electric performance. The capture threshold and the pacing output affect the estimated battery longevity. In a case with a high capture threshold, recapture and reimplantation of a leadless pacemaker are commonly recommended. We experienced a case with the rate-dependent elevation of the capture threshold following the implantation of a leadless pacemaker. The recognition of the rate-dependency of the capture threshold and the acceptable programming could avoid the unnecessary recapture and reimplantation of that, avoiding the increase of procedural risks.

Real world efficacy and safety of various accelerated deep TMS protocols for major depression.

There is growing interest in accelerated rTMS dosing regimens, wherein multiple sessions of rTMS are applied per day. This Phase IV study evaluated the safety, efficacy, and durability of various accelerated Deep TMS protocols used in clinical practice. Data were aggregated from 111 patients with major depressive disorder (MDD) at 4 sites. Patients received one of several accelerated Deep TMS protocols (2x/day, 3x/day, 5x/day, 10x/day). Self-assessment questionnaires (PHQ-9, BDI-II) and clinician-based rating scales (HDRS-21, MADRS) were collected. On average, accelerated TMS led to an 80.2% response and 50.5% remission rate in the first month based on the most rated scale for each patient. There was no significant difference between protocols (Response: 2x/day:89.6%; 3x/day:75%; 5x/day:81%; 10x/day:67.6%). Response occurred after 10 (3x/day), 20 (5x/day), and 31 sessions (10x/day) on average- all of which occur on day 3-4 of treatment. Of patients with longer term follow up, durability was found in 86.7% (n = 30; 60 days) and 92.9% (n = 14; 180 days). The protocols were well-tolerated with no reported serious adverse events. Accelerated Deep TMS protocols are found to be safe, effective therapeutic options for MDD. They offer treatment resistant patients a treatment option with a rapid onset of action and with long durability.

Antibody responses to an inactivated SARS-CoV-2 vaccine in individuals aged from 50 to 102 years.

Objectives: To assess antibody responses to an inactivated SARS-CoV-2 vaccine in individuals aged 50 and older. Methods: We conducted a post-market cross-sectional seroepidemiology study. We recruited 4,632 vaccinated individuals aged 50 and older, measured their total serum SARS-CoV-2-specific antibody (TA), and collected correlates. The primary outcome was the geometric mean titer (GMT) of TA, and the secondary outcome was the decline of TA with age. Univariate, bivariate, and multivariate analyses were used to examine the associations of the TA GMT with age, and trend analyses were used to test whether their associations were significant. Results: All participants had a detectable TA, which was generally at a low level across all age groups. The TA GMT (95% CI) in AU/mL was 3.05 (2.93, 3.18); the corresponding arithmetic mean (95% CI) was 17.77 (16.13, 19.42) in all participants and 4.33 (3.88, 4.84), 3.86 (3.49, 4.28), 3.24 (2.92, 3.59), 2.77 (2.60, 2.96), and 2.65 (2.48, 2.83) in the age groups of 50-54, 55-59, 60-64, 65-74, and 75 years or older, respectively. The TA GMT decreased with age with a P trend < 0.001. The TA GMT was significantly lower in those with hypertension or diabetes compared to those with neither. Conclusion: The inactivated SARS-CoV-2 vaccine is effective in individuals aged 50 and older. This is the first study that has found an inverse dose-response relationship between ages and the low-level TAs. Older people, especially those with chronic diseases, should get the SARS-CoV-2 vaccine, and their vaccination frequency, dose, and method may need to be different from those of younger people.

Phase 4 clinical trials in the era of the Coronavirus Disease (COVID-19) pandemic and their importance to optimize the COVID-19 vaccination.

Since the appearance of SARS-CoV-2, the scientific community has worked relentlessly to gather enough information about the illness caused by this virus infection. Such great effort has resulted in increased scientific publication, including phase 4 clinical trials addressing the applicability of COVID-19 vaccines. In those trials that investigated the properties of the vaccine among participants with morbidities, mainly immunocompromised individuals, the safety was recommended, but in the presence of immunogenicity, such protection was considered of short and medium terms. It was also observed that a physically active lifestyle might increase the immunogenicity of the COVID-19 vaccination in patients with autoimmune rheumatic diseases and in immunocompromised patients. The coadministration of different types of vaccine such as the combination of the recombinant adenovirus type 5 (AD5)-vectored Convidecia as heterologous reinforcement vs. CoronaVac with homologous reinforcement in adults previously vaccinated with CoronaVac, as well as the coadministration of inactivated COVID-19 vaccine followed by the administration of the tetravalent influenza vaccine (Fragmented, Inactivated) and the pneumococcal vaccine 23 presented satisfactory immunogenicity. However, the heterologous reinforcement had better immunogenicity when compared to the homologous reinforcement. Simultaneous COVID-19 vaccination and vaccines against seasonal influenza did not raise safety issues, producing acceptable levels of adverse reactions and preserving the antibody responses against SARS-CoV-2. In the lot-to-lot consistency evaluation, CoronaVac was seen to induce an immune response considered relatively high, and the lots presented a similar profile of stability and immunogenicity, thus enabling their large-scale distribution. In brief, this article addressed, mainly, the importance of evaluating the immunological response in the COVID-19 vaccination in patients with specific health conditions (e.g., immunocompromised individuals) aiming at enabling adjustments to the vaccine calendar in national vaccination programs.

Post-Approval Research in Drug Development: Priorities and Practices.

A prescriber might ask if a new medication is a good option for use in the patients he or she sees in clinic, with their particular blends of demographic and comorbid clinical characteristics. Is this medicine more effective, safe, tolerable, or affordable than the options used in the past? A payer may ask if the new medication offers a more effective, cost-efficient, or convenient alternative to those treatments already being covered. These are the types of questions that are often difficult to answer on the basis of the clinical trials used to support a medication's initial approval, which are generally designed to evaluate a medication's efficacy, safety, and tolerability in narrowly defined patient populations. Consequently, in order to answer the questions most relevant to key stakeholders (i.e., regulators, patients, and clinicians), it is important to continue to examine a medication's impact and characteristics after it has received regulatory approval. Such studies vary in their purpose, scope, and methodology. In this chapter, we review the types of questions most likely to be investigated after regulatory approval, the methods generally used to investigate them, and the characteristics typically considered when prioritizing the allocation of resources.

Efficacy and Safety of Botulinum Toxin Type A (NABOTA) for Post-stroke Upper Extremity Spasticity: A Multicenter Phase IV Trial.

OBJECTIVE: To evaluate the efficacy and safety of Daewoong botulinum toxin type A (NABOTA) after its launch in South Korea. METHODS: This prospective, multicenter, open-label phase IV clinical trial included 222 patients with stroke. All patients visited the clinic at baseline and at weeks 4, 8, and 12 after injection of upto 360 units of NABOTA into the wrist, elbow, and finger flexor muscles at the first visit. The primary outcome was the change in Modified Ashworth Scale (MAS) score for the wrist flexor muscles between baseline and week 4. The secondary outcomes were the changes in MAS, Disability Assessment Scale (DAS), and Caregiver Burden Scale (CBS) scores between baseline and each visit, and the Global Assessment Scale (GAS) score at week 12. RESULTS: There was a statistically significant decrease in the MAS score for the wrist flexors between baseline and week 4 (-0.97±0.66, p<0.001). Compared with baseline, the MAS, DAS and CBS scores improved significantly during the study period. The GAS was rated as very good or good by 86.8% of physicians and by 60.0% of patients (or caregivers). The incidence of adverse events was 14.4%, which is smaller than that in a previous trial. CONCLUSION: NABOTA showed considerable efficacy and safety in the management of upper limb spasticity in stroke patients.

Paroxysmal Atrioventricular Block: A Rare Cause of Cardiac Arrest.

Paroxysmal atrioventricular block (PAVB) is characterized by a sudden and unanticipated repetitive block of atrial impulses to the ventricles. It is often triggered by supraventricular and ventricular ectopic beats in patients with diseased His-Purkinje system. We present the case of a 69-year-old woman with a history of fascicular block who was admitted with gastrointestinal bleeding. Her hospital course was complicated by cardiac arrest. At the time of the loss of consciousness, telemetry tracings showed sudden onset high-grade second-degree atrioventricular (AV) block with a delayed escape rhythm resulting in a prolonged pause. Adult cardiac life support was necessary along with transvenous pacing until she ultimately underwent the placement of a permanent pacemaker. Thorough evaluation of electrocardiograms (EKGs) and telemetry allowed for accurate diagnoses and appropriate treatment of cardiac arrest secondary to paroxysmal AV block.

Efficacy and Safety of Dupilumab Versus Omalizumab in Chronic Rhinosinusitis With Nasal Polyps and Asthma: EVEREST Trial Design.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma are chronic type 2 inflammatory diseases that are frequently associated with each other. Dupilumab inhibits the dual signaling pathways of interleukin (IL)-4 and IL-13, which are key and central drivers of type 2 inflammation in CRSwNP. Omalizumab blocks the action of immunoglobulin E. Head-to-head studies are required to investigate the comparative efficacy and safety of these interventions. EVEREST (EValuating trEatment RESponses of dupilumab vs omalizumab in Type 2 patients) trial is designed to evaluate whether the efficacy of dupilumab is superior to omalizumab in treating patients with CRSwNP and comorbid asthma (ClinicalTrials.gov Identifiers: NCT04998604). OBJECTIVE: Here, we describe the EVEREST study design to compare the efficacy and safety of dupilumab compared to omalizumab over 24 weeks of treatment in patients with severe CRSwNP and comorbid asthma. METHODS: EVEREST is a global, phase 4 multicenter, randomized (1:1), double-blind, active-controlled trial. Approximately 422 adult patients with severe CRSwNP, symptoms of nasal congestion and loss of smell, and coexisting asthma will be recruited across 15 countries. The primary objective is to assess the efficacy of dupilumab compared to omalizumab in reducing the nasal polyp size and improving the sense of smell. The key secondary objectives are to evaluate the comparative efficacy in improving CRSwNP symptoms (eg, nasal congestion) and lung function. The safety will be evaluated in terms of treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest. CONCLUSIONS: EVEREST is the first head-to-head trial assessing the comparative efficacy and safety of 2 biologics in patients with severe CRSwNP and comorbid asthma. The study will provide evidence to help optimize treatment plans for patients that suffer from severe CRSwNP and comorbid asthma.

Thermal Degradation of Photoluminescence Poly(9,9-dioctylfluorene) Solvent-Tuned Aggregate Films.

The progression of the green emission spectrum during the decomposition of polyfluorenes (PFs) has impeded the development and commercialization of the materials. Herein, we constructed a solvent-tuned aggregated PFO film with the aim of retarding the material's thermal degradation behavior which causes a significant decline in optical properties as a result of phase transformation. The tuning of the aggregate amount and distribution was executed by applying a poor alcohol-based solvent in chloroform. It emerges that at a lower boiling point methanol evaporates quickly, limiting the aggregate propagation in the film which gives rise to a more transparent film. Furthermore, because of the modulated ß-phase conformation, the absorption spectra of PFO films were red-shifted and broadened. The increase in methanol percentage also led to a rise in ß-phase percentage. As for the thermal degradation reactions, both pristine and aggregated PFO films exhibited apparent changes in the UV-Vis spectra and PL spectra. In addition, a 97:3 (chloroform:methanol) aggregated PFO film showed a more defined emission spectrum, which demonstrates that the existence of ß-phase is able to suppress the unwanted green emission.

Preliminary tests of dosimetric quality and projected therapeutic outcomes of multi-phase 4D radiotherapy with proton and carbon ion beams.

Objective. The purpose of this study was to perform preliminary pre-clinical tests to compare the dosimetric quality of two approaches to treating moving tumors with ion beams: synchronously delivering the beam with the motion of a moving planning target volume (PTV) using the recently developed multi-phase 4D dose delivery (MP4D) approach, and asynchronously delivering the ion beam to a motion-encompassing internal tumor volume (ITV) combined with rescanning.Approach. We created 4D optimized treatment plans with proton and carbon ion beams for two patients who had previously received treatment for non-small cell lung cancer. For each patient, we created several treatment plans, using approaches with and without motion mitigation: MP4D, ITV with rescanning, static deliveries to a stationary PTV, and deliveries to a moving tumor without motion compensation. Two sets of plans were optimized with margins or robust uncertainty scenarios. Each treatment plan was delivered using a recently-developed motion-synchronized dose delivery system (M-DDS); dose distributions in water were compared to measurements using gamma index analysis to confirm the accuracy of the calculations. Reconstructed dose distributions on the patient CT were analyzed to assess the dosimetric quality of the deliveries (conformity, uniformity, tumor coverage, and extent of hotspots).Main results. Gamma index analysis pass rates confirmed the accuracy of dose calculations. Dose coverage was >95% for all static and MP4D treatments. The best conformity and the lowest lung doses were achieved with MP4D deliveries. Robust optimization led to higher lung doses compared to conventional optimization for ITV deliveries, but not for MP4D deliveries.Significance. We compared dosimetric quality for two approaches to treating moving tumors with ion beams. Our findings suggest that the MP4D approach, using an M-DDS, provides conformal motion mitigation, with full target coverage and lower OAR doses.

Dosimetric Validation of a System to Treat Moving Tumors Using Scanned Ion Beams That Are Synchronized With Anatomical Motion.

PURPOSE: The purpose of this study was to validate the dosimetric performance of scanned ion beam deliveries with motion-synchronization to heterogenous targets. METHODS: A 4D library of treatment plans, comprised of up to 10 3D sub-plans, was created with robust and conventional 4D optimization methods. Each sub-plan corresponded to one phase of periodic target motion. The plan libraries were delivered to a test phantom, comprising plastic slabs, dosimeters, and heterogenous phantoms. This phantom emulated range changes that occur when treating moving tumors. Similar treatment plans, but without motion synchronization, were also delivered to a test phantom with a stationary target and to a moving target; these were used to assess how the target motion degrades the quality of dose distributions and the extent to which motion synchronization can improve dosimetric quality. The accuracy of calculated dose distributions was verified by comparison with corresponding measurements. Comparisons utilized the gamma index analysis method. Plan quality was assessed based on conformity, dose coverage, overdose, and homogeneity values, each extracted from calculated dose distributions. RESULTS: High pass rates for the gamma index analysis confirmed that the methods used to calculate and reconstruct dose distributions were sufficiently accurate for the purposes of this study. Calculated and reconstructed dose distributions revealed that the motion-synchronized and static deliveries exhibited similar quality in terms of dose coverage, overdose, and homogeneity for all deliveries considered. Motion-synchronization substantially improved conformity in deliveries with moving targets. Importantly, measurements at multiple locations within the target also confirmed that the motion-synchronized delivery system satisfactorily compensated for changes in beam range caused by the phantom motion. Specifically, the overall planning and delivery approach achieved the desired dose distribution by avoiding range undershoots and overshoots caused by tumor motion. CONCLUSIONS: We validated a dose delivery system that synchronizes the movement of the ion beam to that of a moving target in a test phantom. Measured and calculated dose distributions revealed that this system satisfactorily compensated for target motion in the presence of beam range changes due to target motion. The implication of this finding is that the prototype system is suitable for additional preclinical research studies, such as irregular anatomic motion.

A phase 4 study of the safety of the 13-valent pneumococcal conjugate vaccine in children 6 to 17 years of age in India.

PURPOSE: The 13-valent pneumococcal conjugate vaccine (PCV13) was recently approved in India for the prevention of pneumococcal disease in children aged 6 to 17 years based on global data as well as immunogenicity and safety findings from a phase 3 study. The current phase 4 study in India further evaluated the safety profile of PCV13 in this age group to support the positive benefit-risk profile of PCV13. METHODS: Healthy male and female children aged 6 to 17 years in India were administered a single intramuscular injection of PCV13. Through 7 days after PCV13 administration, local reactions and systemic events were recorded daily by caregivers in an electronic diary. Adverse events (AEs) were collected from the provision of informed consent through 28-42 days postvaccination. RESULTS: One hundred subjects enrolled in and completed the study. After PCV13 vaccination, 73.9% and 57.8% of subjects reported local reactions and systemic events, respectively. The majority of reactogenicity events were mild to moderate in severity, with injection site pain and fatigue the most frequently reported local reaction and systemic event, respectively. Six subjects reported 7 AEs, all of which were considered unrelated to PCV13. One subject reported a serious AE (acute hepatitis), which was considered unrelated to PCV13 and ultimately resolved. No subjects withdrew because of AEs, and there were no deaths. CONCLUSION: PCV13 vaccination was well tolerated with an acceptable safety profile in healthy subjects aged 6 to 17 years in India. This work further supports the safety profile of PCV13 for prevention of pneumococcal disease in this age group in India.

Sinonasal cancer in Denmark 2008-2015: a population-based phase-4 cohort study from DAHANCA.

BACKGROUND: Sinonasal cancer is considered a rare disease with poor survival. Its treatment has changed profoundly in recent years, primarily following the introduction of intensity-modulated radiation therapy (IMRT) and minimally invasive endoscopic surgery. Danish national guidelines on treatment of patients diagnosed with sinonasal carcinoma were introduced in 2007. The aim of this phase-4 study was to assess the effect of the implementation of guidelines by describing treatment outcomes in a consecutive nationwide cohort. METHODS: All patients diagnosed with sinonasal carcinoma in Denmark from 2008 to 2015 were identified in the nationwide clinical database, DAHANCA, and were followed until May 2020. Overall survival (OS) was analysed using Kaplan-Meier estimator. Cumulative incidence of locoregional failure (LRF) and disease-specific mortality (DSM) were analysed using the Aalen-Johansen estimator. Competing risks were death from other causes (DSM) and distant failure and death (LRF). Analysis of prognostic factors was performed using Cox proportional hazard analysis. Start of follow-up was time of diagnosis. The results are presented as estimates with 95% confidence intervals (95% CIs). RESULTS: A total of 331 patients were identified. Curatively intended treatment was performed in 264 patients (80%). Non-compliance with treatment guidelines was registered in 24 patients (9%). Non-compliance was associated with LRF (hazard ratio [HR], 2.0 [95% CI: 1.1-3.5]). Among patients qualified for curative treatment, failure occurred in 109 patients (41%), primarily at the primary tumour site (81%). Anatomical tumour site and disease stage were independent prognostic factors. The 5-year OS was 56% in patients treated with curative intent, and a combined treatment strategy showed reduced LRF (HR, 0.53 [95% CI: 0.30-0.92]) in a multivariate analysis. CONCLUSIONS: Guideline compliance and a combined treatment approach reduced the incidence of LRF and thereby increased OS. Our results confirm those of international studies. Treatment of sinonasal carcinoma remains a challenge that requires multidisciplinary team coordination.

Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients.

Virus-specific humoral and cellular immunity act synergistically to protect the host from viral infection. We interrogate the dynamic changes of virological and immunological parameters in 12 patients with symptomatic acute SARS-CoV-2 infection from disease onset to convalescence or death. We quantify SARS-CoV-2 viral RNA in the respiratory tract in parallel with antibodies and circulating T cells specific for various structural (nucleoprotein [NP], membrane [M], ORF3a, and spike) and non-structural (ORF7/8, NSP7, and NSP13) proteins. Although rapid induction and quantity of humoral responses associate with an increase in disease severity, early induction of interferon (IFN)-γ-secreting SARS-CoV-2-specific T cells is present in patients with mild disease and accelerated viral clearance. These findings provide support for the prognostic value of early functional SARS-CoV-2-specific T cells with important implications in vaccine design and immune monitoring.

The PRECIS-2 tool seems not to be useful to discriminate the degree of pragmatism of medicine masked trials from that of open-label trials.

PURPOSE: To assess, with all available trial information, whether the assessment of the PRECIS-2 nine domains could provide a clear distinction between medicine masked pragmatic randomized controlled trials (pRCTs) and open-label pRCTs. METHODS: A search was conducted of participant-level pRCTs on medicines published on 25 influential medical journals in July 2018-December 2019. All pre-licensing (phases 1-3) and cluster pRCTs were excluded. All trials' available reports were searched through the published article information, Google Scholar, and trial websites. Instead of providing a score to each PRECIS-2 domain, these were classified as E (explanatory), N (neutral), or P (pragmatic). RESULTS: Of 128 pRCTs, 18 (14%) were participant-level pRCTs on medicines. The full trial protocol was available for 14 trials; 12 had published the protocol and nine had additional reports published. All trials were prospectively registered, and none was funded by industry. Ten and eight were masked and open-label trials, respectively. Masked pRCTS had 34% of pragmatic and 60% of explanatory domains; open-label pRCTS had 45% pragmatic and 45% explanatory domains. Among the 10 masked trials, only one had a majority of five pragmatic domains; among the eight open-label trials, four had a majority of six or five pragmatic domains. "Follow-up" was considered explanatory in the 18 pRCTs; "primary analysis" was pragmatic in 17 pRCTs. CONCLUSION: The PRECIS-2 tool seems not to be sensitive enough to clearly discriminate between medicine masked pRCTs and open-label pRCTs. When conducting systematic reviews, it is suggested that the PRECIS-2 tool should not be used to support placing masked trials in the pragmatic side of the explanatory/pragmatic continuum.