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Mol Ecol ; 30(4): 1086-1101, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33404162


Rapid evolutionary processes can produce drastically different outcomes when studied in panmictic population models vs. spatial models. One such process is gene drive, which describes the spread of "selfish" genetic elements through a population. Engineered gene drives are being considered for the suppression of disease vectors or invasive species. While laboratory experiments and modelling in panmictic populations have shown that such drives can rapidly eliminate a population, it remains unclear if these results translate to natural environments where individuals inhabit a continuous landscape. Using spatially explicit simulations, we show that the release of a suppression drive can result in what we term "chasing" dynamics, in which wild-type individuals recolonize areas where the drive has locally eliminated the population. Despite the drive subsequently reconquering these areas, complete population suppression often fails to occur or is substantially delayed. This increases the likelihood that the drive is lost or that resistance evolves. We analyse how chasing dynamics are influenced by the type of drive, its efficiency, fitness costs, and ecological factors such as the maximal growth rate of the population and levels of dispersal and inbreeding. We find that chasing is more common for lower efficiency drives when dispersal is low and that some drive mechanisms are substantially more prone to chasing behaviour than others. Our results demonstrate that the population dynamics of suppression gene drives are determined by a complex interplay of genetic and ecological factors, highlighting the need for realistic spatial modelling to predict the outcome of drive releases in natural populations.

Z Evid Fortbild Qual Gesundhwes ; 156-157: 82-88, 2020 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-32861613


INTRODUCTION: Patient involvement in health research is an integral part of health care in many countries. It promotes the relevance and quality of research and increases the meaningfulness of research results. Meanwhile, the value of patient involvement has also been recognised in Germany. The lack of a common understanding of patient involvement and appropriate methods make implementation difficult. In Germany, patients are still rarely involved in the planning and conduct of health research. Vulnerable patient groups such as the elderly and the very old are considered particularly challenging for researchers in active patient involvement due to their special needs, which is why they are often neglected. Especially nursing home residents suffer from a variety of health impairments which are accompanied by a high number of prescription drugs and adverse events and can therefore make patient involvement more difficult. The present project aims to test the method of patient advisory boards for the involvement of nursing home residents. Using the design of a clinical trial to optimise medication for nursing home residents as a case study, we will assess the feasibility of the method for this target group. We will also install a patient advocate as moderator of the advisory board. The study plan is described in the present study protocol. METHODS: Two patient advisory boards with nursing home residents will be established. With a patient advocate acting as moderator, the essential elements of a clinical trial to optimise medication will be discussed and passed on to the study planning team via the patient advocate. The overall topic of the clinical trial is the optimisation of medication in cardiovascular disease. The nursing home residents are informed about the contents and ideas of the study to be planned and the interests of the researchers, respectively, and will discuss the proposals of the study planning team. Nursing home residents', the patient advocate's and the researchers' expectations and experiences will be examined in individual interviews. DISCUSSION: The study will provide a potentially suitable method to involve nursing home residents in the research process. The jointly developed study design will be incorporated into a new project proposal. The results will be used to inform the development of a German handbook on active public and patient involvement.

Comitês Consultivos , Casas de Saúde , Participação do Paciente , Idoso , Alemanha , Humanos
Z Evid Fortbild Qual Gesundhwes ; 155: 56-63, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32798190


Usually, patients participating in clinical trials have a passive role as test persons. This creates a risk that patients' needs and interests are not reflected in clinical research. The aim of the present paper is to give an introduction to patient involvement in clinical research. It is based on an exploratory literature research and our own experiences with patient involvement. By actively involving patients in the design, conduct and translation of clinical trials, research and healthcare can be better tailored to meet the patients' needs. Patient involvement has the potential to enhance the quality and relevance of research, support patient empowerment and contribute to the democratisation of research processes. There are different methods to involve patients in research, which are often differentiated as consultation, cooperation and user-led research. Methods, time of involvement and persons to be involved should be chosen to fit the aims of the involvement. While cultural, practical and personal barriers could hinder patient involvement, there are several strategies that enable effective involvement: defining the aims of the involvement, clarifying motivation and expectations as well as roles and the form of cooperation, offering training, planning sufficient resources, involving patients from the start and communicating the benefits of involvement.

Motivação , Participação do Paciente , Alemanha , Humanos , Projetos de Pesquisa
BMC Biol ; 18(1): 27, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164660


BACKGROUND: CRISPR gene drive systems allow the rapid spread of a genetic construct throughout a population. Such systems promise novel strategies for the management of vector-borne diseases and invasive species by suppressing a target population or modifying it with a desired trait. However, current homing-type drives have two potential shortcomings. First, they can be thwarted by the rapid evolution of resistance. Second, they lack any mechanism for confinement to a specific target population. In this study, we conduct a comprehensive performance assessment of several new types of CRISPR-based gene drive systems employing toxin-antidote (TA) principles, which should be less prone to resistance and allow for the confinement of drives to a target population due to invasion frequency thresholds. RESULTS: The underlying principle of the proposed CRISPR toxin-antidote gene drives is to disrupt an essential target gene while also providing rescue by a recoded version of the target as part of the drive allele. Thus, drive alleles tend to remain viable, while wild-type targets are disrupted and often rendered nonviable, thereby increasing the relative frequency of the drive allele. Using individual-based simulations, we show that Toxin-Antidote Recessive Embryo (TARE) drives targeting an haplosufficient but essential gene (lethal when both copies are disrupted) can enable the design of robust, regionally confined population modification strategies with high flexibility in choosing promoters and targets. Toxin-Antidote Dominant Embryo (TADE) drives require a haplolethal target gene and a germline-restricted promoter, but they could permit faster regional population modification and even regionally confined population suppression. Toxin-Antidote Dominant Sperm (TADS) drives can be used for population modification or suppression. These drives are expected to spread rapidly and could employ a variety of promoters, but unlike TARE and TADE, they would not be regionally confined and also require highly specific target genes. CONCLUSIONS: Overall, our results suggest that CRISPR-based TA gene drives provide promising candidates for flexible ecological engineering strategies in a variety of organisms.

Antídotos/farmacologia , Antitoxinas/farmacologia , Sistemas CRISPR-Cas , Tecnologia de Impulso Genético/métodos , Genes Essenciais , Haploinsuficiência , Modelos Genéticos
Syst Rev ; 5: 18, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26831725


BACKGROUND: Steroids are often combined with local anesthetic (LA) and injected to reduce pain associated with various chronic non-cancer pain (CNCP) complaints. The biological rationale behind injection of a steroid solution is unclear, and it is uncertain whether the addition of steroids offers any additional benefits over injection of LA alone. We propose to conduct a systematic review and meta-analysis to summarize the evidence for using steroids and LA vs. LA alone in the treatment of CNCP. METHODS: An experienced librarian will perform a comprehensive search of EMBASE, MEDLINE, and the Cochrane Central Registry of Controlled Trials (CENTRAL) databases with search terms for clinical indications, LA, and steroid agents. We will review bibliographies of all relevant published reviews in the last 5 years for additional studies. Eligible trials will be published in English and randomly allocate patients with CNCP to treatment with steroid and LA injection therapy or injection with LA alone. We will use the guidelines published by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to inform the outcomes that we collect and present. Teams of reviewers will independently and in duplicate assess trial eligibility, abstract data, and assess risk of bias among eligible trials. We will prioritize intention to treat analysis and, when possible, pool outcomes across trials using random effects models. We will report our findings as risk differences, weighted mean differences, or standardized mean differences for individual outcomes. Further, to ensure interpretability of our results, we will present risk differences and measures of relative effect for pain reduction based on anchor-based minimally important clinical differences. We will conduct a priori defined subgroup analyses and use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to evaluate the certainty of the evidence on an outcome-by-outcome basis. DISCUSSION: Our review will evaluate both the effectiveness and the adverse events associated with steroid plus LA vs. LA alone for CNCP, evaluate the quality of the evidence using the GRADE approach, and prioritize patient-important outcomes guided by IMMPACT recommendations. Our results will facilitate evidence-based management of patients with chronic non-cancer pain and identify key areas for future research. TRIAL REGISTRATION: PROSPERO CRD42015020614.

Corticosteroides , Anestésicos Locais , Dor Crônica/tratamento farmacológico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto