Indirect effects shape species fitness in coevolved mutualistic networks.

Ecological interactions are one of the main forces that sustain Earth's biodiversity. A major challenge for studies of ecology and evolution is to determine how these interactions affect the fitness of species when we expand from studying isolated, pairwise interactions to include networks of interacting species1-4. In networks, chains of effects caused by a range of species have an indirect effect on other species they do not interact with directly, potentially affecting the fitness outcomes of a variety of ecological interactions (such as mutualism)5-7. Here we apply analytical techniques and numerical simulations to 186 empirical mutualistic networks and show how both direct and indirect effects alter the fitness of species coevolving in these networks. Although the fitness of species usually increased with the number of mutualistic partners, most of the fitness variation across species was driven by indirect effects. We found that these indirect effects prevent coevolving species from adapting to their mutualistic partners and to other sources of selection pressure in the environment, thereby decreasing their fitness. Such decreases are distributed in a predictable way within networks: peripheral species receive more indirect effects and experience higher reductions in fitness than central species. This topological effect was also evident when we analysed an empirical study of an invasion of pollination networks by honeybees. As honeybees became integrated as a central species within networks, they increased the contribution of indirect effects on several other species, reducing their fitness. Our study shows how and why indirect effects can govern the adaptive landscape of species-rich mutualistic assemblages.

COVID-19 needs no passport: the interrelationship of the COVID-19 pandemic along the U.S.-Mexico border.

OBJECTIVES: To investigate the impact of the COVID-19 pandemic along the U.S.-Mexico border region and evaluate the relationship of COVID-19 related mortality, socioeconomic status, and vaccination. METHODS: We used indirect standardization to age-adjust mortality rates and calculate standardized mortality ratios [SMR] in both countries. To examine the impact of socioeconomic factors, we calculated the Human Development Index (HDI) by county/municipality. We performed linear regression to understand the relationship between mortality, vaccination, and HDI. We used choropleth maps to visualize the trends seen in the region. RESULTS: Between January 22nd, 2020 and December 1st, 2021, surges of cases and deaths were similar in dyad cities along the U.S.-Mexico border visualizing the interconnectedness of the region. Mortality was higher in U.S. counties along the border compared to the national average (SMR 1.17, 95% CI 1.15-1.19). In Mexico, border counties had a slightly lower mortality to the national average (SMR 0.94, 95% CI 0.93-0.95). In U.S. border states, SMR was shown to negatively correlate with human development index (HDI), a socioeconomic proxy, resulting in a higher SMR in the border region compared to the rest of the counties. Conversely in Mexican border states, there was no association between SMR and HDI. Related to vaccination, U.S. counties along the border were vaccinated at a greater percentage than non-border counties and vaccination was negatively correlated with HDI. In Mexico, states along the border had a higher ratio of vaccinations per person than non-border states. CONCLUSIONS: The U.S.-Mexico border is a divide of incredible importance not only to immigration but as a region with unique social, economic, environmental, and epidemiological factors that impact disease transmission. We investigated how the COVID-19 pandemic followed trends of previously studied diseases in the corridor such as tuberculosis, HIV, and influenza H1N1. These data state how targeted intervention along the U.S.-Mexico border region is a necessity when confronting COVID-19 and have implications for future control of infectious diseases in the region.

Integrating data types to estimate spatial patterns of avian migration across the Western Hemisphere.

For many avian species, spatial migration patterns remain largely undescribed, especially across hemispheric extents. Recent advancements in tracking technologies and high-resolution species distribution models (i.e., eBird Status and Trends products) provide new insights into migratory bird movements and offer a promising opportunity for integrating independent data sources to describe avian migration. Here, we present a three-stage modeling framework for estimating spatial patterns of avian migration. First, we integrate tracking and band re-encounter data to quantify migratory connectivity, defined as the relative proportions of individuals migrating between breeding and nonbreeding regions. Next, we use estimated connectivity proportions along with eBird occurrence probabilities to produce probabilistic least-cost path (LCP) indices. In a final step, we use generalized additive mixed models (GAMMs) both to evaluate the ability of LCP indices to accurately predict (i.e., as a covariate) observed locations derived from tracking and band re-encounter data sets versus pseudo-absence locations during migratory periods and to create a fully integrated (i.e., eBird occurrence, LCP, and tracking/band re-encounter data) spatial prediction index for mapping species-specific seasonal migrations. To illustrate this approach, we apply this framework to describe seasonal migrations of 12 bird species across the Western Hemisphere during pre- and postbreeding migratory periods (i.e., spring and fall, respectively). We found that including LCP indices with eBird occurrence in GAMMs generally improved the ability to accurately predict observed migratory locations compared to models with eBird occurrence alone. Using three performance metrics, the eBird + LCP model demonstrated equivalent or superior fit relative to the eBird-only model for 22 of 24 species-season GAMMs. In particular, the integrated index filled in spatial gaps for species with over-water movements and those that migrated over land where there were few eBird sightings and, thus, low predictive ability of eBird occurrence probabilities (e.g., Amazonian rainforest in South America). This methodology of combining individual-based seasonal movement data with temporally dynamic species distribution models provides a comprehensive approach to integrating multiple data types to describe broad-scale spatial patterns of animal movement. Further development and customization of this approach will continue to advance knowledge about the full annual cycle and conservation of migratory birds.

Activity Monitoring for Toxicity Detection and Management in Patients Undergoing Chemoradiation for Gastrointestinal Malignancies.

PURPOSE: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation. MATERIALS AND METHODS: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling. RESULTS: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31). CONCLUSION: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations.

Anesthetic management of a parturient with Marfan syndrome scheduled for cesarean section: case report and review of literature / Manejo anestésico de una parturienta con síndrome de Marfan programada para cesárea: informe de un caso y revisión de la literatura

Abstract: Introduction: Marfan syndrome is an inherited disorder that affects connective tissue. Case: We report the anesthetic management of a parturient with Marfan syndrome scheduled for an elective C-section. Successful use of a combined spinal-epidural technique was used to provide neuraxial anesthesia; however, she presented an unfavorable evolution due to maternal sepsis. Likewise, a literature review of combined spinal-epidural anesthesia for C-sections in Marfan syndrome pregnant women was performed. Conclusion: Anesthetic management of parturients affected by Marfan syndrome during the cesarean section can be challenging. Strict blood pressure control during the intraoperative period has cornerstone importance. Likewise, neuraxial techniques have a significant percentage of failure in these patients.

Resumen: Introducción: El síndrome de Marfan es un desorden hereditario que afecta el tejido conectivo. Caso: Reportamos el manejo anestésico de una parturienta con síndrome de Marfan programada para una cesárea electiva. Para administrar anestesia neuroaxial se utilizó un bloqueo combinado espinal-epidural; sin embargo, la paciente presentó una evolución desfavorable debido a sepsis materna. Asimismo, se realizó una revisión de la literatura del uso de esta técnica anestésica para cesárea en gestantes con síndrome de Marfan. Conclusión: El manejo anestésico de parturientas afectadas por este síndrome puede ser complicado. El control estricto de la presión arterial durante el intraoperatorio tiene importancia fundamental. Además, las técnicas neuroaxiales tienen un porcentaje significativo de fallo en estas pacientes.

Synthesis, Antitrypanosomal and Antimycobacterial Activities of Coumarin N-acylhydrazonic Derivatives.

BACKGROUND: Near to 5-7 million people are infected with T. cruzi in the world, and about 10,000 people per year die of problems associated with this disease. METHODS: Herein, the synthesis, antitrypanosomal and antimycobacterial activities of seventeen coumarinic N-acylhydrazonic derivatives have been reported. RESULTS: These compounds were synthesized using methodology with reactions global yields ranging from 46%-70%. T. cruzi in vitro effects were evaluated against trypomastigote and amastigote, forming M. tuberculosis activity towards H37Rv sensitive strain and resistant strains. DISCUSSION: Against T. cruzi, the more active compounds revealed only moderate activity IC50/96h~20 µM for both trypomastigotes and amastigotes intracellular forms. (E)-2-oxo-N'- (3,4,5-trimethoxybenzylidene)-2H-chromene-3-carbohydrazide showed meaningful activity in INH resistant/RIP resistant strain. CONCLUSION: These compound acting as multitarget could be good leads for the development of new trypanocidal and bactericidal agents.

Genetic correlations and ecological networks shape coevolving mutualisms.

Ecological interactions shape the evolution of multiple species traits in populations. These traits are often linked to each other through genetic correlations, affecting how each trait evolves through selection imposed by interacting partners. Here, we integrate quantitative genetics, coevolutionary theory and network science to explore how trait correlations affect the coevolution of mutualistic species not only in pairs of species but also in species-rich networks across space. We show that genetic correlations may determine the pace of coevolutionary change, affect species abundances and fuel divergence among populations of the same species. However, this trait divergence promoted by genetic correlations is partially buffered by the nested structure of species-rich mutualisms. Our study, therefore, highlights how coevolution and its ecological consequences may result from conflicting processes at different levels of organisation, ranging from genes to communities.

Trait-based climate vulnerability of native rodents in southwestern Mexico.

AIM: Incorporate species' trait information together with climate projections for associated habitat to assess the potential vulnerability of rodent taxa to climate change. LOCATION: Oaxaca State, Mexico. METHODS: We used a trait-based approach together with climate exposure models to evaluate the vulnerability of rodent species to projected climate conditions in the study region. Vulnerability was estimated based on three factors: (a) Level of climatic exposure that species are projected to experience across their current statewide range; (b) inherent species-specific sensitivity to stochastic events; and (c) species' capacity to cope with climate change effects. We defined species as inherently sensitive if they had any of the following: restricted geographic distribution in Mexico; narrow altitudinal range; low dispersal ability; or long generation length. RESULTS: Vulnerability varied depending on the climate change scenario applied. Under the MPI general circulation model and current emissions trends, by 2099, all species evaluated were projected to have some level of threat (vulnerable for at least one factor), with 4 out of 55 species vulnerable for all three factors, 29 for two factors, and 22 for one factor. Six out of ten rodent species endemic to Oaxaca were vulnerable for two or more factors. We found that species with narrow and restricted-range distributions combined with low adaptive capacity were projected to be particularly vulnerable. MAIN CONCLUSIONS: By including species-specific trait information in climate exposure assessments, researchers can contextualize and enhance their understanding about how climate change is likely to affect individual taxa in an area of interest. As such, studies like this one provide more relevant threat assessment information than exposure analyses alone and serve as a starting point for considering how climatic changes interact with an array of other variables to affect native species across their range.

Understanding the Role of Values in Health Policy Decision-Making From the Perspective of Policy-Makers and Stakeholders: A Multiple-Case Embedded Study in Chile and Colombia.

BACKGROUND: Chile and Colombia are examples of Latin American countries with health systems shaped by similar values. Recently, both countries have crafted policies to regulate the participation of private for-profit insurance companies in their health systems, but through very different mechanisms. This study asks: what values are important in the decision-making processes that crafted these policies? And how and why are they used? METHODS: An embedded multiple-case study design was carried out for 2 specific decisions in each country: (1) in Chile, the development of the Universal Plan of Explicit Entitlements -AUGE/GES - and mandating universal coverage of treatments for high-cost diseases; and (2) in Colombia, the declaration of health as a fundamental right and a mechanism to explicitly exclude technologies that cannot be publicly funded. We interviewed key informants involved in one or more of the decisions and/or in the policy analysis and development process that contributed to the eventual decision. The data analysis involved a constant comparative approach and thematic analysis for each case study. RESULTS: From the 40 individuals who were invited, 28 key informants participated. A tension between 2 important values was identified for each decision (eg, solidarity vs. individualism for the AUGE/GES plan in Chile; human dignity vs. sustainability for the declaration of the right to health in Colombia). Policy-makers used values in the decisionmaking process to frame problems in meaningful ways, to guide policy development, as a pragmatic instrument to make decisions, and as a way to legitimize decisions. In Chile, values such as individualism and free choice were incorporated in decision-making because attaining private health insurance was seen as an indicator of improved personal economic status. In Colombia, human dignity was incorporated as the core value because the Constitutional Court asserted its importance in its use of judicial activism as a check on the power of the executive and legislative branches. CONCLUSION: There is an opportunity to open further exploration of the role of values in different health decisions, political sectors besides health, and even other jurisdictions.

Genetic architecture underlying changes in carotenoid accumulation during the evolution of the blind Mexican cavefish, Astyanax mexicanus.

Carotenoids are lipid-soluble yellow to orange pigments produced by plants, bacteria, and fungi. They are consumed by animals and metabolized to produce molecules essential for gene regulation, vision, and pigmentation. Cave animals represent an interesting opportunity to understand how carotenoid utilization evolves. Caves are devoid of light, eliminating primary production of energy through photosynthesis and, therefore, limiting carotenoid availability. Moreover, the selective pressures that favor carotenoid-based traits, like pigmentation and vision, are relaxed. Astyanax mexicanus is a species of fish with multiple river-adapted (surface) and cave-adapted populations (i.e., Tinaja, Pachón, Molino). Cavefish exhibit regressive features, such as loss of eyes and melanin pigment, and constructive traits, like increased sensory neuromasts and starvation resistance. Here, we show that, unlike surface fish, Tinaja and Pachón cavefish accumulate carotenoids in the visceral adipose tissue. Carotenoid accumulation is not observed in Molino cavefish, indicating that it is not an obligatory consequence of eye loss. We used quantitative trait loci mapping and RNA sequencing to investigate genetic changes associated with carotenoid accumulation. Our findings suggest that multiple stages of carotenoid processing may be altered in cavefish, including absorption and transport of lipids, cleavage of carotenoids into unpigmented molecules, and differential development of intestinal cell types involved in carotenoid assimilation. Our study establishes A. mexicanus as a model to study the genetic basis of natural variation in carotenoid accumulation and how it impacts physiology.

Evaluation of oxidative stress-related genetic variants for predicting stroke in patients with sickle cell anemia.

Overt stroke in adults with sickle cell anemia (SCA) continues to be a major cause of morbidity and mortality, while no evidence-based strategy for prevention has been reached so far. Although transcranial Doppler ultrasonography represents the most important tool for identifying young patients with SCA at risk of primary stroke, strategies for stroke prediction in adulthood remain challenging. Emerging data suggest that oxidative stress may exert a pivotal role in the pathogenesis of ischemic brain injury. Combining these pieces of evidences with the well-known genetic contribution to the development of stroke in SCA, we hypothesized that genetic variants related to the biology of oxidative stress could be used to identify adult patients at higher risk of stroke. Overall, 499 unrelated patients with SCA aged >18 years were genotyped for SOD2 Val16Ala (rs4880), GPX3 T-568C (rs8177404), GPX3 T-518C (rs8177406), GPX3 T-65C (rs8177412), and CAT01 C-262 T (rs1001179) polymorphisms, along with α-thalassemia status and ß-globin gene haplotypes. Of these, only the SOD2 Val16Ala polymorphism was associated with stroke. SOD2 Val16Ala polymorphism was independently associated with risk of stroke (odds ratio: 1.98; 95% confidence interval [CI]: 1.18-3.32; P = .009) and with the long-term cumulative incidence of stroke (hazard ratio: 2.24, 95% CI: 1.3-3.9; P = .004). In summary, we provide evidence that oxidative stress-related genetic variants, in particular, the SOD2 Val16Ala polymorphism, may represent a simple and inexpensive alternative for identifying patients at risk of stroke.

Population Structure and Genetic Diversity among Isolates of Coccidioides posadasii in Venezuela and Surrounding Regions.

Coccidioides posadasii is a pathogenic fungus that causes coccidioidomycosis in many arid regions of the Americas. One of these regions is bordered by the Caribbean Sea, and the surrounding landscape may play an important role in the dispersion of C. posadasii across South America through southeastern Mexico, Honduras, Guatemala, and Venezuela. Comparative phylogenomic analyses of C. posadasii reveal that clinical strains from Venezuela are genetically distinct from the North American populations found in (i) Arizona and (ii) Texas, Mexico, and the rest of South America (TX/MX/SA). We find evidence for admixture between the Venezuela and the North American populations of C. posadasii in Central America. Additionally, the proportion of Venezuelan alleles in the admixed population decreases as latitude (and distance from Venezuela) increases. Our results indicate that the population in Venezuela may have been subjected to a recent bottleneck and shows a strong population structure. This analysis provides insight into potential for Coccidioides spp. to invade new regions.IMPORTANCE Valley Fever is a fungal disease caused by two species of fungi: Coccidioides immitis and C. posadasii These fungi are found throughout the arid regions of North and South America; however, our understanding of genetic diversity and disease in South America is limited. In this report, we analyze 10 new genomes of Coccidioides posadasii from regions bordering the Caribbean Sea. We show that these populations are distinct and that isolates from Venezuela are likely a result of a recent bottleneck. These data point to patterns that might be observed when investigating recently established populations.

Developing evidence briefs for policy: a qualitative case study comparing the process of using a guidance-contextualization workbook in Peru and Uganda.

BACKGROUND: Translating research evidence from global guidance into policy can help strengthen health systems. A workbook was developed to support the contextualization of the WHO's 'Optimizing health worker roles to improve maternal and newborn health' (OptimizeMNH) guidance. This study evaluated the use of the workbook for the development of evidence briefs in two countries - Peru and Uganda. Findings surrounding contextual factors, steps in the process and evaluation of the workbook are presented. METHODS: A qualitative embedded case study was used. The case was the process of using the workbook to support the contextualization of global health systems guidance, with local evidence, to develop evidence briefs. Criterion sampling was used to select the countries, participants for interviews and documents included in the study. A template-organizing style and constant comparison were used for data analysis. RESULTS: A total of 19 participant-observation sessions and 8 interviews were conducted, and 50 documents were reviewed. Contextual factors, including the cadres, or groups, of health workers available in each country, the way the problem and its causes were framed, potential policy options to address the problem, and implementation considerations for these policy options, varied substantially between Peru and Uganda. However, many similarities were found in the process of using the workbook. Overall, the workbook was viewed positively and participants in both countries would use it again for other topics. CONCLUSIONS: Organizations that produce global guidance, such as WHO, need to consider institutionalizing the application of the workbook into their guidance development processes to help users at the national/subnational level create actionable and context-relevant policies. Feedback mechanisms also need to be established so that the evidence briefs and health policies arising from global guidance are tracked and the findings coming out of such guideline contextualization processes can be taken into consideration during future guidance development and research priority-setting.

A Comparison of Pediatric and Adult Safety Studies for Antipsychotic and Antidepressant Drugs Submitted to the United States Food and Drug Administration.

OBJECTIVE: To examine the differences in the adverse drug reaction (ADR) profile of antipsychotic and antidepressant agents between pediatric and adult patients in studies submitted to the Food and Drug Administration (FDA) during the drug development process. STUDY DESIGN: Clinical trials in adult and pediatric patients were conducted by sponsors as part of the drug development programs for antipsychotic and antidepressant agents, and ADR information was collected as part of those trials and submitted to the FDA. Data collection was conducted by reviewing publicly available FDA-authored reviews and FDA-approved product labels for 10 drugs with an antipsychotic or an antidepressant indication from 2007 to 2017. RESULTS: There were 308 drug and ADR combinations for the 10 drugs and drug combinations with 113 (36.7%) having a significantly different incidence in pediatric patients compared with adults. Sixty-eight (60.2%) of these ADRs had a significantly higher incidence in pediatric patients than in adults. Sedation was higher in 6 of the 10 drugs and drug combinations with risk differences ranging from 9.6 to 36.6%. CONCLUSIONS: This analysis indicates that there were significant differences between the pediatric and adult safety profiles of antipsychotic and antidepressant drugs. Sedation was the major ADR associated with the use of atypical antipsychotic drugs in pediatric patients. Clinicians caring for children should consider the ADR profile when prescribing antipsychotics and antidepressants in pediatric patients.

The importance of productivity and seasonality for structuring small rodent diversity across a tropical elevation gradient.

Photosynthetic productivity is a key determinant of the abundance and distribution of biodiversity around the world. The effect of this productivity on the distribution patterns of mammals is frequently invoked; however, it is seldom measured directly. In this study, we used Sherman live traps set in dry and rainy seasons across a 2300-m elevation gradient in southwestern Mexico to assess small rodent species distributions, and to relate these patterns to habitat structure, climate, and a well-accepted measure of photosynthetic productivity: the normalized difference vegetation index (NDVI). While habitat structure and climate helped explain some of the patterns observed, NDVI proved to be the most important contributing variable for most of the distribution models. We also found that partitioning the gradient-distribution model by trapping season revealed strong differences in terms of the effect of NDVI and the other explanatory variables. For example, lower elevations were associated with seasonal and year-round reductions in rodent diversity and were composed almost exclusively of granivore-based species assemblages. By contrast, the middle and upper elevations were more species rich, less affected by seasonality, and characterized by omnivorous species. Our results suggest that the positive productivity-diversity relationship found may be due, at least in part, to increased food resources and niche opportunities at more productive elevations. Increased diversity at the higher elevations may also be partially due to reductions in competition that result from productivity increases, as well as from the broader spectrum of feeding guild representation that it and the lack of seasonality allow.

Population structure and genetic diversity among isolates of coccidioides posadasii in Venezuela and surrounding regions

Coccidioides posadasii is a pathogenic fungus that causes coccidioidomycosis in many arid regions of the Americas. One of these regions is bordered by the Caribbean Sea, and the surrounding landscape may play an important role in the dispersion of C. posadasii across South America through southeastern Mexico, Honduras, Guatemala, and Venezuela. Comparative phylogenomic analyses of C. posadasii reveal that clinical strains from Venezuela are genetically distinct from the North American populations found in (i) Arizona and (ii) Texas, Mexico, and the rest of South America (TX/MX/SA). We find evidence for admixture between the Venezuela and the North American populations of C. posadasii in Central America. Additionally, the proportion of Venezuelan alleles in the admixed population decreases as latitude (and distance from Venezuela) increases. Our results indicate that the population in Venezuela may have been subjected to a recent bottleneck and shows a strong population structure. This analysis provides insight into potential for Coccidioides spp. to invade new regions. IMPORTANCE Valley Fever is a fungal disease caused by two species of fungi: Coccidioides immitis and C. posadasii. These fungi are found throughout the arid regions of North and South America; however, our understanding of genetic diversity and disease in South America is limited. In this report, we analyze 10 new genomes of Coccidioides posadasii from regions bordering the Caribbean Sea. We show that these populations are distinct and that isolates from Venezuela are likely a result of a recent bottleneck. These data point to patterns that might be observed when investigating recently established populations.

The geographic mosaic of coevolution in mutualistic networks.

Ecological interactions shape adaptations through coevolution not only between pairs of species but also through entire multispecies assemblages. Local coevolution can then be further altered through spatial processes that have been formally partitioned in the geographic mosaic theory of coevolution. A major current challenge is to understand the spatial patterns of coadaptation that emerge across ecosystems through the interplay between gene flow and selection in networks of interacting species. Here, we combine a coevolutionary model, network theory, and empirical information on species interactions to investigate how gene flow and geographical variation in selection affect trait patterns in mutualistic networks. We show that gene flow has the surprising effect of favoring trait matching, especially among generalist species in species-rich networks typical of pollination and seed dispersal interactions. Using an analytical approximation of our model, we demonstrate that gene flow promotes trait matching by making the adaptive landscapes of different species more similar to each other. We use this result to show that the progressive loss of gene flow associated with habitat fragmentation may undermine coadaptation in mutualisms. Our results therefore provide predictions of how spatial processes shape the evolution of species-rich interactions and how the widespread fragmentation of natural landscapes may modify the coevolutionary process.

Prescription Drug Shortages: Implications for Ambulatory Pediatrics.

OBJECTIVE: To describe contemporary drug shortages affecting general ambulatory pediatrics. STUDY DESIGN: Data from January 2001 to December 2015 were obtained from the University of Utah Drug Information Service. Two pediatricians reviewed drug shortages and identified agents used in ambulatory pediatrics. Shortage data were analyzed by the type of drug, formulation, reason for shortage, duration, marketing status, if a pediatric friendly-formulation was available, or if it was a single-source product. The availability of an alternative, and whether that alternative was affected by a shortage, also was noted. RESULTS: Of 1883 products in shortage during the study period, 314 were determined to be used in ambulatory pediatrics. The annual number of new pediatric shortages decreased initially but then increased to a high of 38 in 2011. Of the 314 pediatric shortages, 3.8% were unresolved at the end of the study. The median duration of resolved shortages was 7.6 months. The longest shortage was for ciprofloxacin 500-mg tablets. The most common class involved was infectious disease drugs. Pediatric-friendly dosage forms were affected in 19.1% of shortages. An alternative agent was available for 86% drugs; however, 29% of these also were affected. The most common reason for shortage was manufacturing problems. CONCLUSIONS: Drug shortages affected a substantial number of agents used in general ambulatory pediatrics. Shortages for single-source products are a concern if a suitable alternative is unavailable. Providers working in the ambulatory setting must be aware of current shortages and implement mitigation strategies to optimize patient care.

Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.