Chapter 1: The Astrobiology Primer 3.0.

The Astrobiology Primer 3.0 (ABP3.0) is a concise introduction to the field of astrobiology for students and others who are new to the field of astrobiology. It provides an entry into the broader materials in this supplementary issue of Astrobiology and an overview of the investigations and driving hypotheses that make up this interdisciplinary field. The content of this chapter was adapted from the other 10 articles in this supplementary issue and thus represents the contribution of all the authors who worked on these introductory articles. The content of this chapter is not exhaustive and represents the topics that the authors found to be the most important and compelling in a dynamic and changing field.

Chapter 5: Major Biological Innovations in the History of Life on Earth.

All organisms living on Earth descended from a single, common ancestral population of cells, known as LUCA-the last universal common ancestor. Since its emergence, the diversity and complexity of life have increased dramatically. This chapter focuses on four key biological innovations throughout Earth's history that had a significant impact on the expansion of phylogenetic diversity, organismal complexity, and ecospace habitation. First is the emergence of the last universal common ancestor, LUCA, which laid the foundation for all life-forms on Earth. Second is the evolution of oxygenic photosynthesis, which resulted in global geochemical and biological transformations. Third is the appearance of a new type of cell-the eukaryotic cell-which led to the origin of a new domain of life and the basis for complex multicellularity. Fourth is the multiple independent origins of multicellularity, resulting in the emergence of a new level of complex individuality. A discussion of these four key events will improve our understanding of the intertwined history of our planet and its inhabitants and better inform the extent to which we can expect life at different degrees of diversity and complexity elsewhere.

A population-based, electronic health record-guided approach to improve the quality of dementia care.

BACKGROUND: The quality of care of the 6.5 million Americans living with dementia has been suboptimal, leading to worse outcomes and higher costs. Few health systems have formal systems in place to guide the care of these patients. To help improve the care of persons living with dementia, we developed and preliminarily evaluated the effectiveness of electronic health record (EHR)-generated recommendations for patients with dementia. METHODS: This quality improvement study was conducted from October 2020 through June 2022 at a single academic healthcare system and included patients identified as having dementia on their problem list and their physicians. Ten (seven outpatient and three inpatient) algorithms based on clinical logic and evidence were embedded in an EHR system to generate specific recommendations based on combinations of utilization, diagnosis, and medications. The number of each type of recommendation generated, and orders for each type of recommendation were recorded, as well as physician's perceptions of this approach. RESULTS: Three thousand six hundred and nine recommendations on 763 patients were triggered by the algorithms in the outpatient setting, and 185 referrals were placed. The most common recommendations were for ongoing care through the UCLA Alzheimer's and Dementia Care program, Palliative Care, the Extensivist Clinic, Urogynecology, and Clinical Pharmacy. The most commonly acted upon by providers were recommendations for referral to Pharmacists and the UCLA Alzheimer's and Dementia Care program. The most common reason for not responding to specific recommendations was that these were not perceived as relevant to the patient. Compared to general medicine physicians, geriatricians felt more comfortable managing dementia care without a referral to a service (23% (95% CI 15%-34%) versus 3% (95% CI 0%-17%), p = 0.012) and less commonly felt the recommendation was appropriate (1% (95% CI 0%-7%) versus 13% (95% CI 4%-30%), p = 0.02). CONCLUSIONS: EHR-generated algorithms can help guide patients with dementia to appropriate clinical services.

Polypharmacy in the Hospitalized Older Adult: Considerations for Safe and Effective Treatment.

Care for the hospitalized older adult is made more complex by polypharmacy that can increase the risks of adverse drug events. This article reviews polypharmacy in the hospitalized older adult from their admission to hospitalization and transition of care as well as highlighting principles to reduce polypharmacy and tools for deprescribing during hospitalization. We review common reasons for admission and how these conditions may be particularly affected by or contribute to polypharmacy in older adults.

Impact of a "Chart Closure" Hard Stop Alert on Prescribing for Elevated Blood Pressures Among Patients With Diabetes: Quasi-Experimental Study.

BACKGROUND: University of California at Los Angeles Health implemented a Best Practice Advisory (BPA) alert for the initiation of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) for individuals with diabetes. The BPA alert was configured with a "chart closure" hard stop, which demanded a response before closing the chart. OBJECTIVE: The aim of the study was to evaluate whether the implementation of the BPA was associated with changes in ACEI and ARB prescribing during primary care encounters for patients with diabetes. METHODS: We defined ACEI and ARB prescribing opportunities as primary care encounters in which the patient had a diabetes diagnosis, elevated blood pressure in recent encounters, no active ACEI or ARB prescription, and no contraindications. We used a multivariate logistic regression model to compare the change in the probability of an ACEI or ARB prescription during opportunity encounters before and after BPA implementation in primary care sites that did (n=30) and did not (n=31) implement the BPA. In an additional subgroup analysis, we compared ACEI and ARB prescribing in BPA implementation sites that had also implemented a pharmacist-led medication management program. RESULTS: We identified a total of 2438 opportunity encounters across 61 primary care sites. The predicted probability of an ACEI or ARB prescription increased significantly from 11.46% to 22.17% during opportunity encounters in BPA implementation sites after BPA implementation. However, in the subgroup analysis, we only observed a significant improvement in ACEI and ARB prescribing in BPA implementation sites that had also implemented the pharmacist-led program. Overall, the change in the predicted probability of an ACEI or ARB prescription from before to after BPA implementation was significantly greater in BPA implementation sites compared with nonimplementation sites (difference-in-differences of 11.82; P<.001). CONCLUSIONS: A BPA with a "chart closure" hard stop is a promising tool for the treatment of patients with comorbid diabetes and hypertension with an ACEI or ARB, especially when implemented within the context of team-based care, wherein clinical pharmacists support the work of primary care providers.

De novo origins of multicellularity in response to predation.

The transition from unicellular to multicellular life was one of a few major events in the history of life that created new opportunities for more complex biological systems to evolve. Predation is hypothesized as one selective pressure that may have driven the evolution of multicellularity. Here we show that de novo origins of simple multicellularity can evolve in response to predation. We subjected outcrossed populations of the unicellular green alga Chlamydomonas reinhardtii to selection by the filter-feeding predator Paramecium tetraurelia. Two of five experimental populations evolved multicellular structures not observed in unselected control populations within ~750 asexual generations. Considerable variation exists in the evolved multicellular life cycles, with both cell number and propagule size varying among isolates. Survival assays show that evolved multicellular traits provide effective protection against predation. These results support the hypothesis that selection imposed by predators may have played a role in some origins of multicellularity.

sRNA-pathway genes regulating myxobacterial development exhibit clade-specific evolution.

Small non-coding RNAs (sRNAs) control bacterial gene expression involved in a wide range of important cellular processes. In the highly social bacterium Myxococcus xanthus, the sRNA Pxr prevents multicellular fruiting-body development when nutrients are abundant. Pxr was discovered from the evolution of a developmentally defective strain (OC) into a developmentally proficient strain (PX). In OC, Pxr is constitutively expressed and blocks development even during starvation. In PX, one mutation deactivates Pxr allowing development to proceed. We screened for transposon mutants that suppress the OC defect and thus potentially reveal new Pxr-pathway components. Insertions significantly restoring development were found in four genes-rnd, rnhA, stkA and Mxan_5793-not previously associated with an sRNA activity. Phylogenetic analysis suggests that the Pxr pathway was constructed within the Cystobacterineae suborder both by co-option of genes predating the Myxococcales order and incorporation of a novel gene (Mxan_5793). Further, the sequence similarity of rnd, rnhA and stkA homologs relative to M. xanthus alleles was found to decrease greatly among species beyond the Cystobacterineae suborder compared to the housekeeping genes examined. Finally, ecological context differentially affected the developmental phenotypes of distinct mutants, with implications for the evolution of development in variable environments.

Primary care provider adherence to an alert for intensification of diabetes blood pressure medications before and after the addition of a "chart closure" hard stop.

Objective: To evaluate provider responses to a narrowly targeted "Best Practice Advisory" (BPA) alert for the intensification of blood pressure medications for persons with diabetes before and after implementation of a "chart closure" hard stop, which is non-interruptive but demands an action or dismissal before the chart can be closed. Materials and Methods: We designed a BPA that fired alerts within an electronic health record (EHR) system during outpatient encounters for patients with diabetes when they had elevated blood pressures and were not on angiotensin receptor blocking medications. The BPA alerts were implemented in eight primary care practices within UCLA Health. We compared data on provider responses to the alerts before and after implementing a "chart closure" hard stop, and we conducted chart reviews to adjudicate each alert's appropriateness. Results: Providers responded to alerts more often after the "chart closure" hard stop was implemented (P < .001). Among 284 alert firings over 16 months, we judged 107 (37.7%) to be clinically unnecessary or inappropriate based on chart review. Among the remainder, which represent clear opportunities for treatment, providers ordered the indicated medication more often (41% vs 75%) after the "chart closure" hard stop was implemented (P = .001). Discussion: The BPA alerts for diabetes and blood pressure control achieved relatively high specificity. The "chart closure" hard stop improved provider attention to the alerts and was effective at getting patients treated when they needed it. Conclusion: Targeting specific omitted medication classes can produce relatively specific alerts that may reduce alert fatigue, and using a "chart closure" hard stop may prompt providers to take action without excessively disrupting their workflow.

Divergence of functional effects among bacterial sRNA paralogs.

BACKGROUND: Non-coding small RNAs (sRNAs) regulate a variety of important biological processes across all life domains, including bacteria. However, little is known about the functional evolution of sRNAs in bacteria, which might occur via changes in sRNA structure and/or stability or changes in interactions between sRNAs and their associated regulatory networks, including target mRNAs. The sRNA Pxr functions as a developmental gatekeeper in the model cooperative bacterium Myxococcus xanthus. Specifically, Pxr prevents the initiation of fruiting body development when nutrients are abundant. Previous work has shown that Pxr appears to have a recent origin within a sub-clade of the myxobacteria, which allowed us to infer the most recent common ancestor of pxr and examine the divergence of Pxr since its origin. RESULTS: To test for inter-specific divergence in functional effects, extant pxr homologs from several species and their inferred ancestor were introduced into an M. xanthus deletion mutant lacking pxr. Both the inferred ancestral pxr and all extant alleles from species containing only one copy of pxr were found to control development in M. xanthus in a qualitatively similar manner to the native M. xanthus allele. However, multiple paralogs present in Cystobacter species exhibited divergent effects, with two paralogs controlling M. xanthus development but two others failing to do so. These differences may have occurred through changes in gene expression caused by apparent structural differences in the sRNA variants encoded by these paralogs. CONCLUSIONS: Taken together, our results suggest that Pxr plays a common fundamental role in developmental gene regulation across diverse species of myxobacteria but also that the functional effects of some Pxr variants may be evolving in some lineages.

Chimaeric load among sympatric social bacteria increases with genotype richness.

The total productivity of social groups can be determined by interactions among their constituents. Chimaeric load--the reduction of group productivity caused by antagonistic within-group heterogeneity--may be common in heterogeneous microbial groups due to dysfunctional behavioural interactions between distinct individuals. However, some instances of chimaerism in social microbes can increase group productivity, thus making a general relationship between chimaerism and group-level performance non-obvious. Using genetically similar strains of the soil bacterium Myxococcus xanthus that were isolated from a single centimetre-scale patch of soil, we tested for a relationship between degree of chimaerism (genotype richness) and total group performance at social behaviours displayed by this species. Within-group genotype richness was found to correlate negatively with total group performance at most traits examined, including swarming in both predatory and prey-free environments and spore production during development. These results suggest that interactions between such neighbouring strains in the wild will tend to be mutually antagonistic. Negative correlations between group performance and average genetic distance among group constituents at three known social genes were not found, suggesting that divergence at other loci that govern social interaction phenotypes is responsible for the observed chimaeric load. The potential for chimaeric load to result from co-aggregation among even closely related neighbours may promote the maintenance and strengthening of kin discrimination mechanisms, such as colony-merger incompatibilities observed in M. xanthus. The findings reported here may thus have implications for understanding the evolution and maintenance of diversity in structured populations of soil microbes.

A recent evolutionary origin of a bacterial small RNA that controls multicellular fruiting body development.

In animals and plants, non-coding small RNAs regulate the expression of many genes at the post-transcriptional level. Recently, many non-coding small RNAs (sRNAs) have also been found to regulate a variety of important biological processes in bacteria, including social traits, but little is known about the phylogenetic or mechanistic origins of such bacterial sRNAs. Here we propose a phylogenetic origin of the myxobacterial sRNA Pxr, which negatively regulates the initiation of fruiting body development in Myxococcus xanthus as a function of nutrient level, and also examine its diversification within the Myxococcocales order. Homologs of pxr were found throughout the Cystobacterineae suborder (with a few possible losses) but not outside this clade, suggesting a single origin of the Pxr regulatory system in the basal Cystobacterineae lineage. Rates of pxr sequence evolution varied greatly across Cystobacterineae sub-clades in a manner not predicted by overall genome divergence. A single copy of pxr was found in most species with 17% of nucleotide positions being polymorphic among them. However three tandem paralogs were present within the genus Cystobacter and these alleles together exhibited an elevated rate of divergence. There appears to have been strong selection for maintenance of a predicted stem-loop structure, as polymorphisms accumulated preferentially at loop or bulge regions or as complementary substitutions within predicted stems. All detected pxr homologs are located in the intergenic region between the σ(54)-dependent response regulator nla19 and a predicted NADH dehydrogenase gene, but other neighboring gene content has diversified.

A comparison of long-standing implantable cardioverter-defibrillator patients with and without appropriate therapy for ventricular arrhythmias: impact of a widening QRS.

AIMS: The comparison of patients with long-standing implantable cardioverter-defibrillators (ICDs) who have had or never have had appropriate therapy for ventricular arrhythmias may offer insight into potential risk factors that may improve patient selection. METHODS AND RESULTS: Records from patients in the Columbia Presbyterian device clinic whose original ICD was implanted before 31 December 2004 were analysed. The patients were divided into those who had never received appropriate therapy for ventricular arrhythmias (Group A, n = 188), and those who had received appropriate therapy (Group B, n = 173). The subset of patients with consistent follow-up greater than 5 years was then analysed (Group A, n = 140; Group B, n = 158). Demographic, clinical, echocardiographic, and electrocardiographic data were collected. There were no significant differences in age, sex, or type of heart disease between the groups. There were more patients in Group B vs. A who had ICDs implanted for secondary prevention (70.3 vs. 55.7%, P < 0.05). The mean QRS width was similar at implant but increased significantly in Group B vs. A on pre-ICD discharge electrocardiograms (134.1 ± 35.0 vs. 125.1 ± 36.2 ms, P < 0.05). Congestive heart failure class, comorbidities, use of antiarrhythmic agents, or left ventricular ejection fraction were not discriminators between Groups A and B. CONCLUSION: In this study of patients with long-standing ICDs, the only discriminating factors for appropriate shocks were implant for secondary prevention or increasing QRS width, suggesting electrical factors are the best predictors of ultimate ICD discharges.

A comparison of atrial arrhythmias after heart or double-lung transplantation at a single center: insights into the mechanism of post-operative atrial fibrillation.

OBJECTIVES: We compared the incidence of atrial arrhythmias in double-lung transplant patients versus heart transplant patients to gain insight into factors that contribute to post-operative atrial fibrillation (AF). BACKGROUND: Atrial fibrillation is a common complication after thoracic surgery. Pulmonary vein isolation is an effective treatment for AF. Heart or double-lung transplantation surgery both involve pulmonary vein isolation because of suture lines. METHODS: We reviewed the records of 174 consecutive heart transplant patients and 122 double-lung transplant patients at the Columbia Presbyterian Medical Center between January 2005 and June 2008. Electrocardiograms during atrial arrhythmia episodes were reviewed by an electrophysiologist. Clinical variables, biopsy results, immunosuppressive regimens, and echocardiographic measurements were collected from the perioperative time period and at the time of arrhythmia occurrence. RESULTS: In the heart transplant group, 8 (4.6%) patients had AF (group A). In the lung transplant group, 23 (18.9%) patients had AF (group B; p < 0.001). The incidence of AF in a comparison group of 131 patients with normal left ventricular function who underwent coronary artery bypass graft surgery was 19.8%. Immunosuppressive regimens and clinical variables were similar for both groups. Echocardiographic data revealed no significant cardiac abnormalities in 74% of group B compared with 25% of group A (p < 0.05), and 78% of biopsy results in group B were normal, whereas only 25% of group A results were normal (p < 0.05). CONCLUSIONS: In heart transplant recipients, AF is uncommon and occurs in the setting of myocardial dysfunction and graft rejection. In contrast, AF is more common after lung transplantation despite the absence of graft rejection and cardiac dysfunction. Pulmonary vein isolation alone cannot explain the discrepancy in AF incidence between heart transplant recipients and double-lung transplant recipients. Cardiac autonomic denervation may have a protective effect for heart transplant patients in the post-operative setting.

Molecular evidence for broad-scale distributions in bdelloid rotifers: everything is not everywhere but most things are very widespread.

The Baas-Becking's hypothesis, also known by the term 'everything is everywhere' (EisE), states that microscopic organisms such as bacteria and protists are globally distributed and do not show biogeographical patterns, due to their high dispersal potential. We tested the prediction of the EisE hypothesis on bdelloid rotifers, microscopic animals similar to protists in size and ecology that present one of the best cases among animals for the plausibility of global dispersal. Geographical range sizes and patterns of isolation by distance were estimated for global collections of the genera Adineta and Rotaria, using different taxonomic units: (i) traditional species based on morphology, (ii) the most inclusive monophyletic lineages from a cytochrome oxidase I phylogeny comprising just a single traditional species, and (iii) genetic clusters indicative of independently evolving lineages. Although there are cases of truly cosmopolitan distribution, even at the most finely resolved taxonomic level, most genetic clusters are distributed at continental or lower scales. Nevertheless, although 'everything is not everywhere', bdelloid rotifers do display broad distributions typical of those of other microscopic organisms. Broad dispersal and large population sizes might be factors lessening the evolutionary cost of long-term abstinence from sexual reproduction in this famous group of obligate parthenogens.