Multiple Sources of Uncertainty Confound Inference of Historical Human Generation Times.

Wang et al. (2023) recently proposed an approach to infer the history of human generation intervals from changes in mutation profiles over time. As the relative proportions of different mutation types depend on the ages of parents, binning variants by the time they arose allows for the inference of changes in average paternal and maternal generation intervals. Applying this approach to published allele age estimates, Wang et al. (2023) inferred long-lasting sex differences in average generation times and surprisingly found that ancestral generation times of West African populations remained substantially higher than those of Eurasian populations extending tens of thousands of generations into the past. Here, we argue that the results and interpretations in Wang et al. (2023) are primarily driven by noise and biases in input data and a lack of validation using independent approaches for estimating allele ages. With the recent development of methods to reconstruct genome-wide gene genealogies, coalescence times, and allele ages, we caution that downstream analyses may be strongly influenced by uncharacterized biases in their output.

Demes: a standard format for demographic models.

Understanding the demographic history of populations is a key goal in population genetics, and with improving methods and data, ever more complex models are being proposed and tested. Demographic models of current interest typically consist of a set of discrete populations, their sizes and growth rates, and continuous and pulse migrations between those populations over a number of epochs, which can require dozens of parameters to fully describe. There is currently no standard format to define such models, significantly hampering progress in the field. In particular, the important task of translating the model descriptions in published work into input suitable for population genetic simulators is labor intensive and error prone. We propose the Demes data model and file format, built on widely used technologies, to alleviate these issues. Demes provide a well-defined and unambiguous model of populations and their properties that is straightforward to implement in software, and a text file format that is designed for simplicity and clarity. We provide thoroughly tested implementations of Demes parsers in multiple languages including Python and C, and showcase initial support in several simulators and inference methods. An introduction to the file format and a detailed specification are available at https://popsim-consortium.github.io/demes-spec-docs/.

Efficient ancestry and mutation simulation with msprime 1.0.

Stochastic simulation is a key tool in population genetics, since the models involved are often analytically intractable and simulation is usually the only way of obtaining ground-truth data to evaluate inferences. Because of this, a large number of specialized simulation programs have been developed, each filling a particular niche, but with largely overlapping functionality and a substantial duplication of effort. Here, we introduce msprime version 1.0, which efficiently implements ancestry and mutation simulations based on the succinct tree sequence data structure and the tskit library. We summarize msprime's many features, and show that its performance is excellent, often many times faster and more memory efficient than specialized alternatives. These high-performance features have been thoroughly tested and validated, and built using a collaborative, open source development model, which reduces duplication of effort and promotes software quality via community engagement.

Conflict Management Education for Anesthesiology Residents: Bridging the Gap in Interpersonal and Communication Skills Competency.

Effective communication and conflict management are important skills for anesthesiologists and are designated by the Accreditation Council for Graduate Medical Education (ACGME) as elements of the "interpersonal and communication skill" competency (ACGME Anesthesiology Milestone Project 2020). However, structured conflict management education for anesthesiology residents remains limited. To address this gap, we developed and implemented a conflict management session incorporating didactics and application exercises using role-play and high-fidelity simulation (SIM) for anesthesiology residents (postgraduate years 3 and 4) at a tertiary academic medical institution. These sessions were well-received, and both role-play and SIM appear to help residents learn conflict management skills.

The NR4A agonist, Cytosporone B, attenuates pro-inflammatory mediators in human colorectal cancer tissue ex vivo.

Inflammation is a pivotal pathological factor in colorectal cancer (CRC) initiation and progression, and modulating this inflammatory state has the potential to ameliorate disease progression. NR4A receptors have emerged as key regulators of inflammatory pathways that are important in CRC. Here, we have examined the effect of NR4A agonist, Cytosporone B (CsnB), on colorectal tissue integrity and its effect on the inflammatory profile in CRC tissue ex vivo. Here, we demonstrate concentrations up 100 µM CsnB did not adversely affect tissue integrity as measured using transepithelial electrical resistance, histology and crypt height. Subsequently, we reveal through the use of a cytokine/chemokine array, ELISA and qRT-PCR analysis that multiple pro-inflammatory mediators were significantly increased in CRC tissue compared to control tissue, which were then attenuated with the addition of CsnB (such as IL-1ß, IL-8 and TNFα). Lastly, stratification of the data revealed that CsnB especially alters the inflammatory profile of tumours derived from males who had not undergone chemoradiotherapy. Thus, this study demonstrates that NR4A agonist CsnB does not adversely affect colon tissue structure or functionality and can attenuate the pro-inflammatory state of human CRC tissue ex vivo.

Design and Implementation of an Innovative, Longitudinal Wellness Curriculum in an Anesthesiology Residency Program.

Burnout is a serious problem that anesthesiologists face during training and in practice. To mitigate it, experts advocate for strategies focused on enhancing individual resilience in addition to organizational change in health care systems. To catalyze this change, wellness-focused education must incorporate foundational knowledge about the science of well-being and impart skills to empower trainees to lead change in the future. We developed and implemented a longitudinal, developmental 3-year curriculum in a large anesthesiology residency program that included strategies to strengthen community-building, enhance meaning from a career in medicine, and incorporated topics focused on career and leadership development.

Efficiently Summarizing Relationships in Large Samples: A General Duality Between Statistics of Genealogies and Genomes.

As a genetic mutation is passed down across generations, it distinguishes those genomes that have inherited it from those that have not, providing a glimpse of the genealogical tree relating the genomes to each other at that site. Statistical summaries of genetic variation therefore also describe the underlying genealogies. We use this correspondence to define a general framework that efficiently computes single-site population genetic statistics using the succinct tree sequence encoding of genealogies and genome sequence. The general approach accumulates sample weights within the genealogical tree at each position on the genome, which are then combined using a summary function; different statistics result from different choices of weight and function. Results can be reported in three ways: by site, which corresponds to statistics calculated as usual from genome sequence; by branch, which gives the expected value of the dual site statistic under the infinite sites model of mutation, and by node, which summarizes the contribution of each ancestor to these statistics. We use the framework to implement many currently defined statistics of genome sequence (making the statistics' relationship to the underlying genealogical trees concrete and explicit), as well as the corresponding branch statistics of tree shape. We evaluate computational performance using simulated data, and show that calculating statistics from tree sequences using this general framework is several orders of magnitude more efficient than optimized matrix-based methods in terms of both run time and memory requirements. We also explore how well the duality between site and branch statistics holds in practice on trees inferred from the 1000 Genomes Project data set, and discuss ways in which deviations may encode interesting biological signals.

The Effects of the Marine-Derived Polysaccharides Laminarin and Chitosan on Aspects of Colonic Health in Pigs Challenged with Dextran Sodium Sulphate.

This study examined the effects of dietary supplementation with laminarin or chitosan on colonic health in pigs challenged with dextran sodium sulphate (DSS). Weaned pigs were assigned to: (1) a basal diet (n = 22); (2) a basal diet + laminarin (n = 10); and (3) a basal diet + chitosan (n = 10). On d35, the basal group was split, creating four groups: (1) the basal diet (control); (2) the basal diet + DSS; (3) the basal diet + laminarin + DSS; and (4) the basal diet + chitosan + DSS. From d39-42, the pigs were orally challenged with DSS. On d44, colonic tissue/digesta samples were collected. The basal DSS group had reduced growth, higher pathology score and an increased expression of MMP1, IL13 and IL23 compared with the controls (p < 0.05); these parameters were similar between the DSS-challenged groups (p > 0.05). In the basal DSS group, the relative abundance of beneficial taxa including Prevotella and Roseburia were reduced while Escherichia/Shigella were increased, compared with the controls (p < 0.05). The relative abundance of Escherichia/Shigella was reduced and the molar proportions of acetate were increased in the laminarin DSS group compared with the basal DSS group (p < 0.01), suggesting that laminarin has potential to prevent pathogen proliferation and enhance the volatile fatty acid profile in the colon in a porcine model of colitis.

The Effect of Increasing Inclusion Levels of a Fucoidan-Rich Extract Derived from Ascophyllum nodosum on Growth Performance and Aspects of Intestinal Health of Pigs Post-Weaning.

This study examines the effects of increasing dietary inclusion levels of fucoidan, from a 44% fucoidan extract on the growth performance and intestinal health of pigs post-weaning (PW). Seventy-two newly weaned pigs (8.4 kg (SD 1.06)) were assigned to: (T1) basal diet (BD); (T2) BD + 125 ppm fucoidan; (T3) BD + 250 ppm fucoidan (8 pens/treatment). The appropriate quantity of a 44% fucoidan extract was included to achieve these inclusion levels. Faecal scores were recorded daily. On d15 PW, samples were collected from the intestinal tract from 1 pig/pen from the BD and BD + 250 ppm fucoidan groups. Pigs supplemented with 250 ppm fucoidan had improved faecal scores and increased concentrations of total volatile fatty acids and propionate in the colon (p < 0.05). The fucoidan-rich extract reduced the expression of CLDN5 (duodenum), SCL5A1/SGLT1 and SI (jejunum) and TJP1, FABP2, and SLC5A1 (ileum) (p < 0.05). The extract reduced the relative abundance of Prevotella and Lachnospiraceae (p < 0.05) and increased the abundance of Helicobacter (p < 0.01) in the caecum. However, no negative impact on growth performance or small intestinal morphology was observed. Thus, the inclusion of 250 ppm fucoidan improves faecal consistency without affecting growth performance and therefore warrants further investigation as a supplement for the prevention of PW diarrhoea under more challenging commercial conditions.

Polygenic Adaptation to an Environmental Shift: Temporal Dynamics of Variation Under Gaussian Stabilizing Selection and Additive Effects on a Single Trait.

Predictions about the effect of natural selection on patterns of linked neutral variation are largely based on models involving the rapid fixation of unconditionally beneficial mutations. However, when phenotypes adapt to a new optimum trait value, the strength of selection on individual mutations decreases as the population adapts. Here, I use explicit forward simulations of a single trait with additive-effect mutations adapting to an "optimum shift." Detectable "hitchhiking" patterns are only apparent if (i) the optimum shifts are large with respect to equilibrium variation for the trait, (ii) mutation rates to large-effect mutations are low, and (iii) large-effect mutations rapidly increase in frequency and eventually reach fixation, which typically occurs after the population reaches the new optimum. For the parameters simulated here, partial sweeps do not appreciably affect patterns of linked variation, even when the mutations are strongly selected. The contribution of new mutations vs. standing variation to fixation depends on the mutation rate affecting trait values. Given the fixation of a strongly selected variant, patterns of hitchhiking are similar on average for the two classes of sweeps because sweeps from standing variation involving large-effect mutations are rare when the optimum shifts. The distribution of effect sizes of new mutations has little effect on the time to reach the new optimum, but reducing the mutational variance increases the magnitude of hitchhiking patterns. In general, populations reach the new optimum prior to the completion of any sweeps, and the times to fixation are longer for this model than for standard models of directional selection. The long fixation times are due to a combination of declining selection pressures during adaptation and the possibility of interference among weakly selected sites for traits with high mutation rates.

Intensive care unit providers more quickly and accurately assess risk of multiple harms using an engineered safety display.

Project Emerge took a systems engineering approach to reduce avoidable harm in the intensive care unit. We developed a socio-technology solution to aggregate and display information relevant to preventable patient harm. We compared providers' efficiency and ability to assess and assimilate data associated with patient-safety practice compliance using the existing electronic health record to Emerge, and evaluated for speed, accuracy, and the number of mouse clicks required. When compared to the standard electronic health record, clinicians were faster (529 ± 210 s vs 1132 ± 344 s), required fewer mouse clicks (42.3 ± 15.3 vs 101.3 ± 33.9), and were more accurate (24.8 ± 2.7 of 28 correct vs 21.2 ± 2.9 of 28 correct) when using Emerge. All results were statistically significant at a p-value < 0.05 using Wilcoxon signed-rank test (n = 18). Emerge has the potential to make clinicians more productive and patients safer by reducing the time and errors when obtaining information to reduce preventable harm.

Genetic architecture and selective sweeps after polygenic adaptation to distant trait optima.

Understanding the genetic basis of phenotypic adaptation to changing environments is an essential goal of population and quantitative genetics. While technological advances now allow interrogation of genome-wide genotyping data in large panels, our understanding of the process of polygenic adaptation is still limited. To address this limitation, we use extensive forward-time simulation to explore the impacts of variation in demography, trait genetics, and selection on the rate and mode of adaptation and the resulting genetic architecture. We simulate a population adapting to an optimum shift, modeling sequence variation for 20 QTL for each of 12 different demographies for 100 different traits varying in the effect size distribution of new mutations, the strength of stabilizing selection, and the contribution of the genomic background. We then use random forest regression approaches to learn the relative importance of input parameters in determining a number of aspects of the process of adaptation, including the speed of adaptation, the relative frequency of hard sweeps and sweeps from standing variation, or the final genetic architecture of the trait. We find that selective sweeps occur even for traits under relatively weak selection and where the genetic background explains most of the variation. Though most sweeps occur from variation segregating in the ancestral population, new mutations can be important for traits under strong stabilizing selection that undergo a large optimum shift. We also show that population bottlenecks and expansion impact overall genetic variation as well as the relative importance of sweeps from standing variation and the speed with which adaptation can occur. We then compare our results to two traits under selection during maize domestication, showing that our simulations qualitatively recapitulate differences between them. Overall, our results underscore the complex population genetics of individual loci in even relatively simple quantitative trait models, but provide a glimpse into the factors that drive this complexity and the potential of these approaches for understanding polygenic adaptation.

Efficient pedigree recording for fast population genetics simulation.

In this paper we describe how to efficiently record the entire genetic history of a population in forwards-time, individual-based population genetics simulations with arbitrary breeding models, population structure and demography. This approach dramatically reduces the computational burden of tracking individual genomes by allowing us to simulate only those loci that may affect reproduction (those having non-neutral variants). The genetic history of the population is recorded as a succinct tree sequence as introduced in the software package msprime, on which neutral mutations can be quickly placed afterwards. Recording the results of each breeding event requires storage that grows linearly with time, but there is a great deal of redundancy in this information. We solve this storage problem by providing an algorithm to quickly 'simplify' a tree sequence by removing this irrelevant history for a given set of genomes. By periodically simplifying the history with respect to the extant population, we show that the total storage space required is modest and overall large efficiency gains can be made over classical forward-time simulations. We implement a general-purpose framework for recording and simplifying genealogical data, which can be used to make simulations of any population model more efficient. We modify two popular forwards-time simulation frameworks to use this new approach and observe efficiency gains in large, whole-genome simulations of one to two orders of magnitude. In addition to speed, our method for recording pedigrees has several advantages: (1) All marginal genealogies of the simulated individuals are recorded, rather than just genotypes. (2) A population of N individuals with M polymorphic sites can be stored in O(N log N + M) space, making it feasible to store a simulation's entire final generation as well as its history. (3) A simulation can easily be initialized with a more efficient coalescent simulation of deep history. The software for recording and processing tree sequences is named tskit.

Label-Free Imaging and Optical Characterization of Tissues Based on Autofluorescence.

Attaining capability of label-free optical characterization of tissues will offer methodological advancement and possibilities for early clinical detection, which is of paramount importance in treating patients under clinical setups, for example, cancer. Here, we demonstrate the potential of autofluorescence exhibited by tissues as an enabling microscopic strategy to achieve high-resolution imagery data offering a wealth of clinically relevant information including possibility of three-dimensional rendering. Furthermore, we elucidate the use of analytic tools to extract numerical read-outs from such data with further implications in histopathology, pharmaceutics, toxicology, and screening purposes. This study summarizes the results obtained through a systematic autofluorescence-based investigation on murine and porcine gut tissues with an example of applying the technique in nanotoxicology. The study provides with a methodological roadmap toward developing a fast, effective, and robust platform enabling in-depth optical characterization of tissues.

Interprofessional Care and Teamwork in the ICU.

OBJECTIVES: We describe the importance of interprofessional care in modern critical care medicine. This review highlights the essential roles played by specific members of the interprofessional care team, including patients and family members, and discusses quality improvement initiatives that require interprofessional collaboration for success. DATA SOURCES: Studies were identified through MEDLINE search using a variety of search phrases related to interprofessional care, critical care provider types, and quality improvement initiatives. Additional articles were identified through a review of the reference lists of identified articles. STUDY SELECTION: Original articles, review articles, and systematic reviews were considered. DATA EXTRACTION: Manuscripts were selected for inclusion based on expert opinion of well-designed or key studies and review articles. DATA SYNTHESIS: "Interprofessional care" refers to care provided by a team of healthcare professionals with overlapping expertise and an appreciation for the unique contribution of other team members as partners in achieving a common goal. A robust body of data supports improvement in patient-level outcomes when care is provided by an interprofessional team. Critical care nurses, advanced practice providers, pharmacists, respiratory care practitioners, rehabilitation specialists, dieticians, social workers, case managers, spiritual care providers, intensivists, and nonintensivist physicians each provide unique expertise and perspectives to patient care, and therefore play an important role in a team that must address the diverse needs of patients and families in the ICU. Engaging patients and families as partners in their healthcare is also critical. Many important ICU quality improvement initiatives require an interprofessional approach, including Awakening and Breathing Coordination, Delirium, Early Exercise/Mobility, and Family Empowerment bundle implementation, interprofessional rounding practices, unit-based quality improvement initiatives, Patient and Family Advisory Councils, end-of-life care, coordinated sedation awakening and spontaneous breathing trials, intrahospital transport, and transitions of care. CONCLUSIONS: A robust body of evidence supports an interprofessional approach as a key component in the provision of high-quality critical care to patients of increasing complexity and with increasingly diverse needs.

Evidence of directional and stabilizing selection in contemporary humans.

Modern molecular genetic datasets, primarily collected to study the biology of human health and disease, can be used to directly measure the action of natural selection and reveal important features of contemporary human evolution. Here we leverage the UK Biobank data to test for the presence of linear and nonlinear natural selection in a contemporary population of the United Kingdom. We obtain phenotypic and genetic evidence consistent with the action of linear/directional selection. Phenotypic evidence suggests that stabilizing selection, which acts to reduce variance in the population without necessarily modifying the population mean, is widespread and relatively weak in comparison with estimates from other species.

Identifying Information Resources for Patients in the Intensive Care Unit and Their Families.

BACKGROUND: Providing information to patients in intensive care units and their families is challenging. Patients often are admitted unexpectedly and experience stress and uncertainty. One source of stress has been identified as unclear, uncoordinated, or inconsistent communication and information. Despite the need for information, no centrally located, easily accessible, standardized intensive care unit education content exists. OBJECTIVE: To identify educational content for patients in the intensive care unit and their families across 4 different hospitals, develop a general content database, and organize the general content into a framework for education of patients and their families. METHODS: Educational content for patients in the intensive care units of 4 participating hospitals was collected and a gap analysis was performed. RESULTS: Key content format and categories were identified. Educational content was organized into an information pathway divided into 3 phases: intensive care unit arrival; understanding the intensive care unit and partnering in care; and intensive care unit transitions. The gap analysis revealed substantial variation in content format and categories. CONCLUSIONS: Structuring a digital learning center using different stages of the patient's stay in the intensive care unit and placing resources in the context of an information pathway can help coordinate education for these patients and their families, and creates a consistent communication guide for clinicians as well. The optimal digital format should be considered in designing the learning center.

Preventing Harm in the ICU-Building a Culture of Safety and Engaging Patients and Families.

OBJECTIVE: Preventing harm remains a persistent challenge in the ICU despite evidence-based practices known to reduce the prevalence of adverse events. This review seeks to describe the critical role of safety culture and patient and family engagement in successful quality improvement initiatives in the ICU. We review the evidence supporting the impact of safety culture and provide practical guidance for those wishing to implement initiatives aimed at improving safety culture and more effectively integrate patients and families in such efforts. DATA SOURCES: Literature review using PubMed including evaluation of key studies assessing large-scale quality improvement efforts in the ICU, impact of safety culture on patient outcomes, methodologies for quality improvement commonly used in healthcare, and patient and family engagement. Print and web-based resources from leading patient safety organizations were also searched. STUDY SELECTION: Our group completed a review of original studies, review articles, book chapters, and recommendations from leading patient safety organizations. DATA EXTRACTION: Our group determined by consensus which resources would best inform this review. DATA SYNTHESIS: A strong safety culture is associated with reduced adverse events, lower mortality rates, and lower costs. Quality improvement efforts have been shown to be more effective and sustainable when paired with a strong safety culture. Different methodologies exist for quality improvement in the ICU; a thoughtful approach to implementation that engages frontline providers and administrative leadership is essential for success. Efforts to substantively include patients and families in the processes of quality improvement work in the ICU should be expanded. CONCLUSIONS: Efforts to establish a culture of safety and meaningfully engage patients and families should form the foundation for all safety interventions in the ICU. This review describes an approach that integrates components of several proven quality improvement methodologies to enhance safety culture in the ICU and highlights opportunities to include patients and families.

Tandem duplications lead to novel expression patterns through exon shuffling in Drosophila yakuba.

One common hypothesis to explain the impacts of tandem duplications is that whole gene duplications commonly produce additive changes in gene expression due to copy number changes. Here, we use genome wide RNA-seq data from a population sample of Drosophila yakuba to test this 'gene dosage' hypothesis. We observe little evidence of expression changes in response to whole transcript duplication capturing 5' and 3' UTRs. Among whole gene duplications, we observe evidence that dosage sharing across copies is likely to be common. The lack of expression changes after whole gene duplication suggests that the majority of genes are subject to tight regulatory control and therefore not sensitive to changes in gene copy number. Rather, we observe changes in expression level due to both shuffling of regulatory elements and the creation of chimeric structures via tandem duplication. Additionally, we observe 30 de novo gene structures arising from tandem duplications, 23 of which form with expression in the testes. Thus, the value of tandem duplications is likely to be more intricate than simple changes in gene dosage. The common regulatory effects from chimeric gene formation after tandem duplication may explain their contribution to genome evolution.