The Goldilocks Time for Remdesivir - Is Any Indication Just Right?
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ABSTRACT:
SUBMITTER: Heil EL
PROVIDER: S-EPMC8757566 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Magnesium, the most abundant divalent cation in cells, catalyzes RNA cleavage but also promotes RNA folding. Because folding can protect RNA from cleavage, we predicted a 'Goldilocks landscape', with local maximum in RNA lifetime at Mg2+ concentrations required for folding. Here, we use simulation and experiment to discover an innate and sophisticated mechanism of control of RNA lifetime. By simulation we characterized RNA Goldilocks landscapes and their dependence on cleavage and folding parameters. Experiments with yeast tRNAPhe and the Tetrahymena ribozyme P4-P6 domain show that structured RNAs can inhabit Goldilocks peaks. The Goldilocks peaks are tunable by differences in folded and unfolded cleavage rate constants, Mg2+ binding cooperativity, and Mg2+ affinity. Different folding and cleavage parameters produce Goldilocks landscapes with a variety of features. Goldilocks behavior allows ultrafine control of RNA chemical lifetime, whereas non-folding RNAs do not display Goldilocks peaks of protection. In sum, the effects of Mg2+ on RNA persistence are expected to be pleomorphic, both protecting and degrading RNA. In evolutionary context, Goldilocks behavior may have been a selectable trait of RNA in an early Earth environment containing Mg2+ and other metals.
| S-EPMC10164553 | biostudies-literature
Project description:: We present Goldilocks: a Python package providing functionality for collecting summary statistics, identifying shifts in variation, discovering outlier regions and locating and extracting interesting regions from one or more arbitrary genomes for further analysis, for a user-provided definition of interesting.Goldilocks is freely available open-source software distributed under the MIT licence. Source code is hosted publicly at https://github.com/SamStudio8/goldilocks and the package may also be installed using pip install goldilocks. Documentation can be found at https://goldilocks.readthedocs.org: msn@aber.ac.ukSupplementary data are available at Bioinformatics online.
| S-EPMC4920124 | biostudies-literature
Project description:The immune system is a robust and often untapped accomplice of many standard cancer therapies. A majority of tumors exist in a state of immune tolerance where the patient's immune system has become insensitive to the cancer cells. Because of its lymphodepleting effects, chemotherapy has the potential to break this tolerance. To investigate this, we created a mathematical modeling framework of tumor-immune dynamics. Our results suggest that optimal chemotherapy scheduling must balance two opposing objectives: maximizing tumor reduction while preserving patient immune function. Successful treatment requires therapy to operate in a "Goldilocks Window" where patient immune health is not overly compromised. By keeping therapy "just right," we show that the synergistic effects of immune activation and chemotherapy can maximize tumor reduction and control. SIGNIFICANCE: To maximize the synergy between chemotherapy and antitumor immune response, lymphodepleting therapy must be balanced in a "Goldilocks Window" of optimal dosing.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5302/F1.large.jpg.
| S-EPMC6801094 | biostudies-literature
Project description:IntroductionFaculty and residents strive for appropriate autonomy and entrustment. Initial direct supervision of clinical care gradually shifts to increasing levels of resident independence over time. Faculty members are inconsistent in resident supervision leading to missed opportunities for resident independence.MethodsFamily medicine faculty workshop participants completed teaching style self-evaluations prior to discussion of clinical examples with excessive or insufficient autonomy. Participants reviewed real resident feedback examples to increase insight into teaching styles. Participants were presented with cases to discuss varying degrees of resident autonomy and entrustment. Learners committed to one specific behavior to calibrate the degree of autonomy they provide.ResultsOf the faculty, 113 members participated in the workshop with the majority (98%) finding the workshop relevant in helping them to identify strategies for reflecting on their degree of autonomy allowed and to look for appropriate situations for enhancing their resident entrustment.DiscussionThis interactive workshop provided clear ways for addressing the issue of independence versus control in supervision of patient care. It provided a feedback mechanism for educators who provide too much or too little autonomy for the best resident learning. Additionally, this conversation encouraged participants to engage in self-reflection on the autonomy given to their resident.
| S-EPMC7566225 | biostudies-literature
Project description:ObjectivesIt has been reported that job demands affect sleep, but how different levels of job demands affect sleep remains unclear. We examined whether curvilinear relationships exist between job demands and multiple sleep health outcomes.DesignCross-sectional analyses with linear and quadratic effects, using self-administered survey data.SettingA national sample of US adults.ParticipantsWorkers from Midlife in the United States Study (MIDUS2; n = 2927).MeasurementsThe Job Content Questionnaire assessed overall and 5 specific aspects of job demands (intensity, role conflict, work overload, time pressure, and interruptions). Habitual sleep health patterns across 5 dimensions (regularity, satisfaction/quality, daytime alertness, efficiency, and duration) were assessed. Age, sex, race/ethnicity, marital/partnered status, education, job tenure, work hours, body mass index, smoking status, and study sample were covariates.ResultsThere were significant linear and quadratic relationships between job demands and sleep outcomes. Specifically, the linear effects indicated that participants with higher job demands had worse sleep health, such as shorter duration, greater irregularity, greater inefficiency, and more sleep dissatisfaction. The quadratic effects, however, indicated that sleep regularity and efficiency outcomes were the best when participants' job demands were moderate rather than too low or too high. These effects were found for overall job demands as well as for specific aspects of job demands. Stratified analyses further revealed that these curvilinear associations were mainly driven by participants with low job control.ConclusionsModerate levels of job demands, especially if combined with adequate job control, are related to optimal sleep health.
| S-EPMC9991992 | biostudies-literature
Project description:BackgroundThe Goldilocks Work Principle expresses that productive work should be designed to promote workers' health. We recently showed that it is feasible to develop and implement modifications to productive work that change physical behaviors (i.e. sitting, standing and being active) in a direction that may promote health among industrial workers. Therefore, the aim of the present study is to conduct a cluster randomised controlled trial investigating health effects of implementing the Goldilocks Work intervention among industrial workers.MethodsOur implementation plan consists of educating work teams, organizing implementation meetings, and providing feedback to workers. Three meetings with a preselected local workplace group will be scheduled. The first meeting educates the group to use a planning tool by which work can be planned to have 'just right' physical behaviors. The second and third meetings will focus on supporting implementation of the tool in daily work. An expected 28 clusters of work teams across two participating production sites will be randomized to either intervention or control group. Data collection will consist of 1) questionnaires regarding work and musculoskeletal health, 2) wearable sensor measurements of the physical behavior, and 3) assessment of general health indicators, including BMI, blood pressure, and fat percentage. The primary outcome is musculoskeletal health, measured by low back pain intensity, and secondary outcomes are 1) physical behaviors at work, 2) accumulated time in long bouts of sitting, standing, and being active and 3) perceived fatigue and energy during work. Furthermore, implementation and cost of the intervention will be evaluated based on questionnaires and data from the planning tool completed by the workers.DiscussionThis study will evaluate the effectiveness and implementation of a 12 - weeks Goldilocks Work intervention with the aim of improving musculoskeletal health among industrial workers. The cluster randomized controlled study design and the evaluation of the implementation, results and costs of the intervention will make it capable of contributing with valuable evidence of how productive work may be designed to promote industrial workers' health.Trial registrationClinical trial registration was assigned 10-09-2021 (ISRCTN80969503). https://doi.org/10.1186/ISRCTN80969503.
| S-EPMC8867863 | biostudies-literature
Project description: Not available
| S-EPMC5568799 | biostudies-literature
Project description:In the increasingly complex world of modern medicine, relationship-centered, team-based care is important in geriatric cardiology. Palliative cardiovascular care plays a central role in defining the scope and timing of medical therapies and in coordinating symptom-targeted care in line with patient wishes, values, and preferences. Palliative care addresses advance care planning, symptom relief and caregiver/family support and seeks to ameliorate all forms of suffering, including physical, psychological, and spiritual. Although palliative care grew out of the hospice movement and has traditionally been associated with care at the end of life, the current model acknowledges that palliative care can be delivered concurrent with invasive, life-prolonging interventions. As the population ages, patients with serious cardiovascular disease increasingly suffer from noncardiac, multimorbid conditions and become eligible for interventions that palliate symptoms but also prolong life. Management of implanted cardiac support devices at the end of life, whether rhythm management devices or mechanical circulatory support devices, can involve a host of complexities in decisions to deactivate, timing of deactivation and even the mechanics of deactivation. Studies on palliative care interventions have demonstrated clear improvements in quality of life and are more mixed on life prolongation and cost savings. There is and will remain a dearth of clinicians with specialist palliative care training. Therefore, cardiovascular clinicians have a role to play in provision of practical, "primary" palliative care.
| S-EPMC7021658 | biostudies-literature
Project description:Standard curative treatment of early-stage non-small cell lung cancer (NSCLC) involves surgery in combination with postoperative (adjuvant) platinum-based chemotherapy where indicated. Preoperative (neoadjuvant) therapies offer certain theoretical benefits compared with adjuvant approaches, including the ability to assess on-treatment response, reduce the tumor bulk prior to surgery, and enhance tolerability in the preoperative setting. Indeed, the use of neoadjuvant therapies are well established in other cancers such as breast and rectal cancers to debulk the tumor and guide ongoing therapy, and neoadjuvant chemotherapy has similar efficacy but less toxicity in NSCLC. More recently, immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD1)/PD1-ligand 1 (PD-L1) have transformed the treatment of advanced NSCLC; the unique mechanisms of action of ICI offer additional rationale for assessment in the neoadjuvant setting. Preclinical studies in mouse cancer models support the proof of concept of neoadjuvant ICI (NAICI) through improvement of T-cell effector function and long-term memory induction. Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach. However, outstanding issues include defining optimal treatment combinations which balance high efficacy with acceptable toxicity, validating biomarkers to aid in patient selection, and avoiding potential pitfalls such as missing a window for successful surgery, that is, choosing the right drugs, for the right patient, at the right time. Predictive biomarkers to direct selection of therapy are required, and the validation of major pathological response (MPR) as a surrogate for survival will be important in the uptake of the neoadjuvant approach.
| S-EPMC8183290 | biostudies-literature
Project description:To examine predictors of understanding preemptive CYP2D6 pharmacogenomics test results and to identify key features required to improve future educational efforts of preemptive pharmacogenomics testing.One thousand ten participants were surveyed after receiving preemptive CYP2D6 pharmacogenomics test results.Eighty-six percent (n = 869) of patients responded. Of the responders, 98% were white and 55% were female; 57% had 4 years or more of post-secondary education and an average age of 58.9?±?5.5 years. Twenty-six percent said that they only somewhat understood their results and 7% reported they did not understand them at all. Only education predicted understanding. The most common suggestion for improvement was the use of layperson's terms when reporting results. In addition, responders suggested that results should be personalized by referring to medications that they were currently using. Of those reporting imperfect drug adherence, most (91%) reported they would be more likely to use medication as prescribed if pharmacogenomic information was used to help select the drug or dose.Despite great efforts to simplify pharmacogenomic results (or because of them), approximately one-third of responders did not understand their results. Future efforts need to provide more examples and tailor results to the individual. Incorporation of pharmacogenomics is likely to improve medication adherence.Genet Med advance online publication 05 January 2017.
| S-EPMC5498279 | biostudies-literature