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bstract
We revisit the generation of a matter-antimatter asymmetry in the minimal extension of the Standard Model with two singlet heavy neutral leptons (HNL) that can explain neutrino masses. We ...derive an accurate analytical approximation to the solution of the complete linearized set of kinetic equations, which exposes the non-trivial parameter dependencies in the form of parameterization-independent CP invariants. The identification of various washout regimes relevant in different regions of parameter space sheds light on the relevance of the mass corrections in the interaction rates and clarifies the correlations of baryogenesis with other observables. In particular, by requiring that the measured baryon asymmetry is reproduced, we derive robust upper or lower bounds on the HNL mixings depending on their masses, and constraints on their flavour structure, as well as on the CP-violating phases of the PMNS mixing matrix, and the amplitude of neutrinoless double-beta decay. We also find certain correlations between low and high scale CP phases. Especially emphasizing the testable part of the parameter space we demonstrate that our findings are in very good agreement with numerical results. The methods developed in this work can help in exploring more complex scenarios.
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bstract
We consider the generation of a baryon asymmetry in an extension of the Standard Model with two singlet Majorana fermions that are degenerate above the electroweak phase transition. The ...model can explain neutrino masses as well as the observed matter-antimatter asymmetry, for masses of the heavy singlets below the electroweak scale. The only physical CP violating phases in the model are those in the PMNS mixing matrix, i.e. the Dirac phase and a Majorana phase that enter light neutrino observables. We present an accurate analytic approximation for the baryon asymmetry in terms of CP flavour invariants, and derive the correlations with neutrino observables. We demonstrate that the measurement of CP violation in neutrino oscillations as well as the mixings of the heavy neutral leptons with the electron, muon and tau flavours suffice to pin down the matter-antimatter asymmetry from laboratory measurements.
Summary Introduction Treatment response in randomized clinical trials (RCT) of osteoarthritis (OA) has been assessed by multiple primary and secondary outcomes, including pain, function, patient and ...clinician global measures of status and response to treatment, and various composite and responder measures. Identifying outcome measures with greater responsiveness to treatment is important to increase the assay sensitivity of RCTs. Objective To assess and compare the responsiveness of different outcome measures used in placebo-controlled RCTs of OA. Search strategy The Resource for Evaluating Procedures and Outcomes of Randomized Trials database includes placebo-controlled clinical trials of pharmacologic treatments (oral, topical, or transdermal) for OA identified from a systematic literature search of RCTs published or publicly available before August 5, 2009, which was conducted using PubMed, the Cochrane collaboration, publicly-available websites, and reference lists of retrieved publications. Data collection and analysis Data collected included: (1) pain assessed with single-item ratings and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale; (2) patient and clinician global measures of status, improvement, and treatment response; (3) function assessed by the WOMAC function subscale; (4) stiffness assessed by the WOMAC stiffness subscale; and (5) the WOMAC and Lequesne Algofunctional Index composite outcomes. Measures were grouped according to the total number of response categories (i.e., <10 categories or ≥10 categories). The treatment effect (difference in mean change from baseline between the placebo and active therapy arms) and standardized effect size (SES) were estimated for each measure in a meta-analysis using a random effects model. Results There were 125 RCTs with data to compute the treatment effect for at least one measure; the majority evaluated non-steroidal anti-inflammatory drugs (NSAIDs), followed by opioids, glucosamine and/or chondroitin, and acetaminophen. In general, the patient-reported pain outcome measures had comparable responsiveness to treatment as shown by the estimates of treatment effects and SES. Treatment effects and SESs were generally higher for patient-reported global measures compared with clinician-rated global measures but generally similar for the WOMAC and Lequesne composite measures. Conclusions Comparing different outcome measures using meta-analysis and selecting those that have the greatest ability to identify efficacious treatments may increase the efficiency of clinical trials of treatments for OA. Improvements in the quality of the reporting of clinical trial results are needed to facilitate meta-analyses to evaluate the responsiveness of outcome measures and to also address other issues related to assay sensitivity.
An essential component of the interpretation of results of randomized clinical trials of treatments for chronic pain involves the determination of their clinical importance or meaningfulness. This ...involves two distinct processes—interpreting the clinical importance of individual patient improvements and the clinical importance of group differences—which are frequently misunderstood. In this article, we first describe the essential differences between the interpretation of the clinical importance of patient improvements and of group differences. We then discuss the factors to consider when evaluating the clinical importance of group differences, which include the results of responder analyses of the primary outcome measure, the treatment effect size compared to available therapies, analyses of secondary efficacy endpoints, the safety and tolerability of treatment, the rapidity of onset and durability of the treatment benefit, convenience, cost, limitations of existing treatments, and other factors. The clinical importance of individual patient improvements can be determined by assessing what patients themselves consider meaningful improvement using well-described methods. In contrast, the clinical meaningfulness of group differences must be determined by a multi-factorial evaluation of the benefits and risks of the treatment and of other available treatments for the condition in light of the primary goals of therapy. Such determinations must be conducted on a case-by-case basis, and are ideally informed by patients and their significant others, clinicians, researchers, statisticians, and representatives of society at large.
The objective of the present research was to develop a single measure of the major symptoms of both neuropathic and non-neuropathic pain that can be used in studies of epidemiology, natural history, ...pathophysiologic mechanisms, and treatment response. We expanded and revised the Short-form McGill Pain Questionnaire1Copyright: SF-MPQ, R. Melzack; SF-MPQ-2, R. Melzack and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT).1 (SF-MPQ) pain descriptors by adding symptoms relevant to neuropathic pain and by modifying the response format to a 0–10 numerical rating scale to provide increased responsiveness in longitudinal studies and clinical trials. The reliability, validity, and subscale structure of the revised SF-MPQ (SF-MPQ-21) were examined in responses from 882 individuals with diverse chronic pain syndromes and in 226 patients with painful diabetic peripheral neuropathy who participated in a randomized clinical trial. The data suggest that the SF-MPQ-2 has excellent reliability and validity, and the results of both exploratory and confirmatory factor analyses provided support for four readily interpretable subscales—continuous pain, intermittent pain, predominantly neuropathic pain, and affective descriptors. These results provide a basis for use of the SF-MPQ-2 in future clinical research, including clinical trials of treatments for neuropathic and non-neuropathic pain conditions.
There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite ...previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.
A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy ...had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo (“assay sensitivity”). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.
Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning ...of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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