Primary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival ...with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.
EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140mg/day) or placebo. Final OS and updated safety data are reported.
Minimum follow-up was 42months. Kaplan–Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1months) although the difference did not reach statistical significance stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64–1.12; P=0.24. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation–positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3months for cabozantinib versus 18.9months for placebo HR, 0.60; 95% CI, 0.38–0.94; P=0.03 (not adjusted for multiple subgroup analyses), with corresponding values of 20.2 versus 21.5months (HR, 1.12; 95% CI, 0.70–1.82; P=0.63) in the RET M918T–negative subgroup. Median treatment duration was 10.8months with cabozantinib and 3.4months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.
The secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T–positive tumors may experience a greater treatment benefit with cabozantinib.
NCT00704730
Parkinson's disease or parkinsonism have been described after infections by viruses, such as influenza A, Epstein-Barr virus, varicella zoster, hepatitis C virus, HIV, Japanese encephalitis virus, or ...West Nile virus.1 We report a patient with probable Parkinson's disease, who was diagnosed after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Because of the worsening of tremor in his right extremities, in a follow-up visit on June 29, biperiden was added at a dose of 2 mg daily, and increased to 4 mg daily after 1 week, which resulted in improvement of the tremor. Other researchers have proposed the so-called multiple hit hypothesis, by which the combination of toxic stress and an inhibition of neuroprotective responses can lead to neuronal death.4 Parkinson's disease is often preceded by anosmia, which is a common feature of SARS-CoV-2 infection.5 Immune activation in the olfactory system might eventually lead to the misfolding of α-synuclein and the development of Parkinson's disease.6 This mechanism is supported by post-mortem studies, showing increased levels of TNF,7 IL1, and IL6.8 Moreover, patients with Parkinson's disease had an elevated CSF antibody response to seasonal coronaviruses, compared with age-matched healthy controls.9 In Ashkenazi-Jewish people with Parkinson's disease, about a third are carriers of either a GBA or a LRRK2 mutation.10 A genetic analysis for these mutations and 62 other mutations associated with the disease was negative and our patient had no previous family history of Parkinson's disease.
As clinicians delivering health care, we are very good at treating disease but often not as good at treating the person. The focus of our attention has been on the specific physical condition rather ...than the patient as a whole. Less attention has been given to psychological health and how that can contribute to physical health and disease. However, there is now an increasing appreciation of how psychological health can contribute not only in a negative way to cardiovascular disease (CVD) but also in a positive way to better cardiovascular health and reduced cardiovascular risk. This American Heart Association scientific statement was commissioned to evaluate, synthesize, and summarize for the health care community knowledge to date on the relationship between psychological health and cardiovascular health and disease and to suggest simple steps to screen for, and ultimately improve, the psychological health of patients with and at risk for CVD. Based on current study data, the following statements can be made: There are good data showing clear associations between psychological health and CVD and risk; there is increasing evidence that psychological health may be causally linked to biological processes and behaviors that contribute to and cause CVD; the preponderance of data suggest that interventions to improve psychological health can have a beneficial impact on cardiovascular health; simple screening measures can be used by health care providers for patients with or at risk for CVD to assess psychological health status; and consideration of psychological health is advisable in the evaluation and management of patients with or at risk for CVD.
Giant electrocaloric effect around Tc Rose, Maimon C; Cohen, R E
Physical review letters,
2012-Nov-02, 20121102, Letnik:
109, Številka:
18
Journal Article
Recenzirano
We use molecular dynamics with a first-principles-based shell model potential to study the electrocaloric effect (ECE) in lithium niobate, LiNbO(3), and find a giant electrocaloric effect along a ...line passing through the ferroelectric transition. With an applied electric field, a line of maximum ECE passes through the zero field ferroelectric transition, continuing along a Widom line at high temperatures with increasing fields, and along the instability that leads to homogeneous ferroelectric switching below T(c) with an applied field antiparallel to the spontaneous polarization. This line is defined as the minimum in the inverse capacitance under an applied electric field. We investigate the effects of pressure, temperature and an applied electric field on the ECE. The behavior we observe in LiNbO(3) should generally apply to ferroelectrics; we therefore suggest that the operating temperature for refrigeration and energy scavenging applications should be above the ferroelectric transition region to obtain a large electrocaloric response. The relationship between T(c), the Widom line, and homogeneous switching should be universal among ferroelectrics, relaxors, multiferroics, and the same behavior should be found under applied magnetic fields in ferromagnets.
We report a web-based tool for analysis of experiments using indirect calorimetry to measure physiological energy balance. CalR simplifies the process to import raw data files, generate plots, and ...determine the most appropriate statistical tests for interpretation. Analysis using the generalized linear model (which includes ANOVA and ANCOVA) allows for flexibility in interpreting diverse experimental designs, including those of obesity and thermogenesis. Users also may produce standardized output files for an experiment that can be shared and subsequently re-evaluated using CalR. This framework will provide the transparency necessary to enhance consistency, rigor, and reproducibility. The CalR analysis software will greatly increase the speed and efficiency with which metabolic experiments can be organized, analyzed per accepted norms, and reproduced and will likely become a standard tool for the field. CalR is accessible at https://CalRapp.org/.
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•CalR is a free web tool for analysis of experiments using indirect calorimetry•Imports data, generates plots, and determines the best-fit statistical model•Outputs a standardized CalR file that can be shared, deposited, and re-read by CalR•Increases speed, transparency, and reproducibility of energy balance experiments
Indirect calorimetry is a powerful tool for studying energy balance. These experiments produce rich datasets but are difficult to analyze properly and lack transparency. Mina and colleagues created a rigorous tool, CalR, that takes raw data from indirect calorimeters, allows comprehensive data exploration and reproducible workflows, and provides standardized analyses.
Abstract Posttraumatic stress disorder (PTSD) is an anxiety disorder initiated by exposure to a traumatic event and characterized by intrusive thoughts about the event, attempts to avoid reminders of ...the event, and physiological hyperarousal. In a number of large prospective observational studies, PTSD has been associated with incident cardiovascular disease (CVD) and mortality. Also, in recent years, a number of studies have shown that cardiovascular events can themselves cause PTSD in more than 1 in 8 patients with acute coronary syndrome. Further, a few small studies suggest that PTSD secondary to an acute CVD event then places patients at increased risk for subsequent CVD events and mortality. In this article, we review the evidence for a link between PTSD and CVD, and discuss potential mechanisms for that association as well as future directions for research.
Genetically encoded voltage indicators (GEVIs) can report cellular electrophysiology with high resolution in space and time. Two-photon (2P) fluorescence has been explored as a means to image voltage ...in tissue. Here, we used the 2P electronic excited-state lifetime to probe absolute membrane voltage in a manner that is insensitive to the protein expression level, illumination intensity, or photon detection efficiency. First, we tested several GEVIs for 2P brightness, response speed, and voltage sensitivity. ASAP1 and a previously described citrine-Arch electrochromic Förster resonance energy transfer sensor (dubbed CAESR) showed the best characteristics. We then characterized the voltage-dependent lifetime of ASAP1, CAESR, and ArcLight under voltage-clamp conditions. ASAP1 and CAESR showed voltage-dependent lifetimes, whereas ArcLight did not. These results establish 2P fluorescence lifetime imaging as a viable means of measuring absolute membrane voltage. We discuss the prospects and improvements necessary for applications in tissue.
Background The American College of Surgeons NSQIP offers a Surgical Risk Calculator (SRC) that provides detailed, patient-level, risk assessments for many adverse outcomes to surgeons, patients, and ...the general public. The SRC calculator was designed to help guide discussion and decisions by providing generally applicable (not hospital-specific) information about surgical risk using easily understood and broadly available preoperative variables. Although large, internal evaluations have shown that the SRC has good accuracy (model discrimination and calibration), external validations have been inconsistent and tend to favor a conclusion of inadequate performance. Study Design External studies, attempting to validate the SRC, were examined with respect to 3 design features: sample size (small samples reduce reliability), case-mix homogeneity (homogeneity reduces discrimination); and number of institutions providing data (few institutions reduces generalizability). The impact of each feature was then examined in several sets of simulation studies. Results Each of the 3 design features has the potential to act as an artifactual cause for apparent SRC predictive failure. In addition, demonstrations that SRC estimates are inferior to those from models that use additional (sometimes operation-specific) predictor variables were seen as not relevant with respect to the SRC's intended scope. Conclusions The SRC predictive failures, reported by studies with the described design limitations, should not be misunderstood as disqualifying the SRC as an accurate and appropriate tool for its intended purpose of providing a general purpose risk calculator, applicable across many surgical domains, using easily understood and generally available predictive information.
By 2050, the human population will probably be larger by 2 to 4 billion people, more slowly growing (declining in the more developed regions), more urban, especially in less developed regions, and ...older than in the 20th century. Two major demographic uncertainties in the next 50 years concern international migration and the structure of families. Economies, nonhuman environments, and cultures (including values, religions, and politics) strongly influence demographic changes. Hence, human choices, individual and collective, will have demographic effects, intentional or otherwise.
Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide ...per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab - for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians' understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S.
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