Quasispecies Made Simple

Quasispecies are clouds of genotypes that appear in a population at mutation–selection balance. This concept has recently attracted the attention of virologists, because many RNA viruses appear to generate high levels of genetic variation that may enhance the evolution of drug resistance and immune escape. The literature on these important evolutionary processes is, however, quite challenging. Here we use simple models to link mutation–selection balance theory to the most novel property of quasispecies: the error threshold—a mutation rate below which populations equilibrate in a traditional mutation–selection balance and above which the population experiences an error catastrophe, that is, the loss of the favored genotype through frequent deleterious mutations. These models show that a single fitness landscape may contain multiple, hierarchically organized error thresholds and that an error threshold is affected by the extent of back mutation and redundancy in the genotype-to-phenotype map. Importantly, an error threshold is distinct from an extinction threshold, which is the complete loss of the population through lethal mutations. Based on this framework, we argue that the lethal mutagenesis of a viral infection by mutation-inducing drugs is not a true error catastophe, but is an extinction catastrophe

From Bad to Good: Fitness Reversals and the Ascent of Deleterious Mutations

Deleterious mutations are considered a major impediment to adaptation, and there are straightforward expectations for the rate at which they accumulate as a function of population size and mutation rate. In a simulation model of an evolving population of asexually replicating RNA molecules, initially deleterious mutations accumulated at rates nearly equal to that of initially beneficial mutations, without impeding evolutionary progress. As the mutation rate was increased within a moderate range, deleterious mutation accumulation and mean fitness improvement both increased. The fixation rates were higher than predicted by many population-genetic models. This seemingly paradoxical result was resolved in part by the observation that, during the time to fixation, the selection coefficient (s) of initially deleterious mutations reversed to confer a selective advantage. Significantly, more than half of the fixations of initially deleterious mutations involved fitness reversals. These fitness reversals had a substantial effect on the total fitness of the genome and thus contributed to its success in the population. Despite the relative importance of fitness reversals, however, the probabilities of fixation for both initially beneficial and initially deleterious mutations were exceedingly small (on the order of 10(−5) of all mutations)

Medication Reconciliation of Medically-Complex Emergency Department Patients by Second-Year Professional Pharmacy Students

ABSTRACT: Background: There is a high potential for medication discrepancies to occur during patient care transitions. However, health professionals must find ways to reduce these and improve patient care, such as with medication reconciliation. This intervention is used to identify a patient’s most accurate medication list by comparing the medical record to another list obtained from the patient, hospital, or other provider. Pharmacists have a major role in this process because of their medicinal expertise, but paying them is expensive, so using students may be more cost-effective. Research has examined fourth-year professional pharmacy students (P4s) performing medication reconciliation during their advanced pharmacy practice experiences; however, no research currently exists that explores the use of P2 students to determine their efficacy. Objectives: The primary objective of this study is to determine the effect of P2 students on medication reconciliation for high-risk patients undergoing care transitions within the emergency department compared to the efforts of P4s as described in the literature. The secondary objective is to determine the impact on 30-day readmission rates. Methodology: This is a historical-controlled, prospective, observational study. Data collection will occur August 2015 through April 2016 at Grandview Medical Center and Miami Valley Hospital in Dayton, Ohio. A sample size of at least 34 subjects is required to obtain statistical significance. Subjects will be selected by purposive sampling based on inclusion and exclusion criteria. P2 students will perform medication reconciliation and complete a reporting form providing information on medication discrepancies, interventions, and re-admission dates. Analysis: Researchers will use descriptive statistics, such as mean, mode, and standard deviation, to report each set of data based on normality. One-sample t-tests will also be used to compare P2 data with pre-existing P4 data found in the literature

Does hormone replacement therapy prevent cognitive decline in postmenopausal women?

Q: Evidence-based answer: NO. Hormone replacement therapy (HRT) does not prevent cognitive decline in postmenopausal women—and in fact, it may slightly increase risk (strength of recommendation, A; systematic review, meta-analysis of randomized controlled trials [RCTs], and individual RCT).Madeline Gates, MD; Melissa Beagle, MD, MPH; Lauren Bull, MD; Roxanne Radi, MD, MPH; Corey Lyon, DO (University of Colorado, Family Medicine Residency), Kristen DeSanto, MSLS, MS, RD (University of Colorado, Health Sciences Library), Rick Guthmann, MD, MPH (Advocate Health Care Illinois Masonic Medical Center Program)Includes bibliographical reference

Medication Reconciliation of Medically-Complex Emergency Department Patients by Second-Year Professional Pharmacy Students

Background: There is a high potential for medication discrepancies to occur during patient care transitions. However, health professionals must find ways to reduce these and improve patient care, such as with medication reconciliation. This intervention is used to identify a patient’s most accurate medication list by comparing the medical record to another list obtained from the patient, hospital, or other provider. Pharmacists have a major role in this process because of their medicinal expertise, but paying them is expensive, so using students may be more cost-effective. Research has examined fourth-year professional pharmacy students (P4s) performing medication reconciliation during their advanced pharmacy practice experiences; however, no research currently exists that explores the use of P2 students to determine their efficacy. Objectives: The primary objective of this study is to determine the effect of P2 students on medication reconciliation for high-risk patients undergoing care transitions within the emergency department compared to the efforts of P4s as described in the literature. The secondary objective is to determine the impact on 30-day readmission rates. Methodology: This is a historical-controlled, prospective, observational study. Data collection will occur August 2015 through April 2016 at Miami Valley Hospital in Dayton, Ohio. A sample size of at least 34 subjects is required to obtain statistical significance. Subjects will be selected by purposive sampling based on inclusion and exclusion criteria. P2 students will perform medication reconciliation and complete a reporting form providing information on medication discrepancies, interventions, and re-admission dates. Analysis: Researchers will use descriptive statistics, such as mean, mode, and standard deviation, to report each set of data based on normality. One-sample t-tests will also be used to compare P2 data with pre-existing P4 data found in the literature

Long wavelength TCF-based fluorescent probe for the detection of alkaline phosphatase in live cells

A long wavelength TCF-based fluorescent probe (TCF-ALP) was developed for the detection of alkaline phosphatase (ALP). ALP-mediated hydrolysis of the phosphate group of TCF-ALP resulted in a significant fluorescence “turn on” (58-fold), which was accompanied by a colorimetric response from yellow to purple. TCF-ALP was cell-permeable, which allowed it to be used to image ALP in HeLa cells. Upon addition of bone morphogenic protein 2, TCF-ALP proved capable of imaging endogenously stimulated ALP in myogenic murine C2C12 cells. Overall, TCF-ALP offers promise as an effective fluorescent/colorimetric probe for evaluating phosphatase activity in clinical assays or live cell systems

The Ascent of the Abundant: How Mutational Networks Constrain Evolution

Evolution by natural selection is fundamentally shaped by the fitness landscapes in which it occurs. Yet fitness landscapes are vast and complex, and thus we know relatively little about the long-range constraints they impose on evolutionary dynamics. Here, we exhaustively survey the structural landscapes of RNA molecules of lengths 12 to 18 nucleotides, and develop a network model to describe the relationship between sequence and structure. We find that phenotype abundance—the number of genotypes producing a particular phenotype—varies in a predictable manner and critically influences evolutionary dynamics. A study of naturally occurring functional RNA molecules using a new structural statistic suggests that these molecules are biased toward abundant phenotypes. This supports an “ascent of the abundant” hypothesis, in which evolution yields abundant phenotypes even when they are not the most fit

Utilization and Harmonization of Adult Accelerometry Data: Review and Expert Consensus.

PURPOSE: This study aimed to describe the scope of accelerometry data collected internationally in adults and to obtain a consensus from measurement experts regarding the optimal strategies to harmonize international accelerometry data. METHODS: In March 2014, a comprehensive review was undertaken to identify studies that collected accelerometry data in adults (sample size, n ≥ 400). In addition, 20 physical activity experts were invited to participate in a two-phase Delphi process to obtain consensus on the following: unique research opportunities available with such data, additional data required to address these opportunities, strategies for enabling comparisons between studies/countries, requirements for implementing/progressing such strategies, and value of a global repository of accelerometry data. RESULTS: The review identified accelerometry data from more than 275,000 adults from 76 studies across 36 countries. Consensus was achieved after two rounds of the Delphi process; 18 experts participated in one or both rounds. The key opportunities highlighted were the ability for cross-country/cross-population comparisons and the analytic options available with the larger heterogeneity and greater statistical power. Basic sociodemographic and anthropometric data were considered a prerequisite for this. Disclosure of monitor specifications and protocols for data collection and processing were deemed essential to enable comparison and data harmonization. There was strong consensus that standardization of data collection, processing, and analytical procedures was needed. To implement these strategies, communication and consensus among researchers, development of an online infrastructure, and methodological comparison work were required. There was consensus that a global accelerometry data repository would be beneficial and worthwhile. CONCLUSIONS: This foundational resource can lead to implementation of key priority areas and identification of future directions in physical activity epidemiology, population monitoring, and burden of disease estimates.This work, and authors involved in this work were supported by the UK Medical Research Council (grants MC_UU_12015/3 and MRC Centenary Award to KWi, SB); the British Heart Foundation (grant FS/12/58/29709 to KWi); the Australian Heart Foundation (grant PH 12B 7054 to GNH); the Australian National Health and Medical Research Council (Fellowship to NO; Program grant to NO; NHMRC Centre for Research Excellence Grant in the Translational Science of Sedentary Behaviour APP1041056 to GNH, NO, DD); an Australian Postgraduate Award (to SS); The Coca-Cola Company, Body Media, U.S. National Institutes of Health, and Technogym (to SB); MRC, Chartered Society of Physiotherapy, EPSRC, Greater Manchester Academic Health Science Network (to MG); Australian Research Council (Future Fellowship: FT100100918 to DD).This is the final published version. It first appeared at http://dx.doi.org/10.1249/MSS.000000000000066

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant