Tempo and Mode of Genome Evolution in the Budding Yeast Subphylum.

Budding yeasts (subphylum Saccharomycotina) are found in every biome and are as genetically diverse as plants or animals. To understand budding yeast evolution, we analyzed the genomes of 332 yeast species, including 220 newly sequenced ones, which represent nearly one-third of all known budding yeast diversity. Here, we establish a robust genus-level phylogeny comprising 12 major clades, infer the timescale of diversification from the Devonian period to the present, quantify horizontal gene transfer (HGT), and reconstruct the evolution of 45 metabolic traits and the metabolic toolkit of the budding yeast common ancestor (BYCA). We infer that BYCA was metabolically complex and chronicle the tempo and mode of genomic and phenotypic evolution across the subphylum, which is characterized by very low HGT levels and widespread losses of traits and the genes that control them. More generally, our results argue that reductive evolution is a major mode of evolutionary diversification.

A lethal mitonuclear incompatibility in complex I of natural hybrids.

The evolution of reproductive barriers is the first step in the formation of new species and can help us understand the diversification of life on Earth. These reproductive barriers often take the form of hybrid incompatibilities, in which alleles derived from two different species no longer interact properly in hybrids1-3. Theory predicts that hybrid incompatibilities may be more likely to arise at rapidly evolving genes4-6 and that incompatibilities involving multiple genes should be common7,8, but there has been sparse empirical data to evaluate these predictions. Here we describe a mitonuclear incompatibility involving three genes whose protein products are in physical contact within respiratory complex I of naturally hybridizing swordtail fish species. Individuals homozygous for mismatched protein combinations do not complete embryonic development or die as juveniles, whereas those heterozygous for the incompatibility have reduced complex I function and unbalanced representation of parental alleles in the mitochondrial proteome. We find that the effects of different genetic interactions on survival are non-additive, highlighting subtle complexity in the genetic architecture of hybrid incompatibilities. Finally, we document the evolutionary history of the genes involved, showing signals of accelerated evolution and evidence that an incompatibility has been transferred between species via hybridization.

Predictability and parallelism in the contemporary evolution of hybrid genomes.

Hybridization between species is widespread across the tree of life. As a result, many species, including our own, harbor regions of their genome derived from hybridization. Despite the recognition that this process is widespread, we understand little about how the genome stabilizes following hybridization, and whether the mechanisms driving this stabilization tend to be shared across species. Here, we dissect the drivers of variation in local ancestry across the genome in replicated hybridization events between two species pairs of swordtail fish: Xiphophorus birchmanni × X. cortezi and X. birchmanni × X. malinche. We find unexpectedly high levels of repeatability in local ancestry across the two types of hybrid populations. This repeatability is attributable in part to the fact that the recombination landscape and locations of functionally important elements play a major role in driving variation in local ancestry in both types of hybrid populations. Beyond these broad scale patterns, we identify dozens of regions of the genome where minor parent ancestry is unusually low or high across species pairs. Analysis of these regions points to shared sites under selection across species pairs, and in some cases, shared mechanisms of selection. We show that one such region is a previously unknown hybrid incompatibility that is shared across X. birchmanni × X. cortezi and X. birchmanni × X. malinche hybrid populations.

Taxogenomic analysis of a novel yeast species isolated from soil, Pichia galeolata sp. nov.

A novel budding yeast species was isolated from a soil sample collected in the United States of America. Phylogenetic analyses of multiple loci and phylogenomic analyses conclusively placed the species within the genus Pichia. Strain yHMH446 falls within a clade that includes Pichia norvegensis, Pichia pseudocactophila, Candida inconspicua, and Pichia cactophila. Whole genome sequence data were analyzed for the presence of genes known to be important for carbon and nitrogen metabolism, and the phenotypic data from the novel species were compared to all Pichia species with publicly available genomes. Across the genus, including the novel species candidate, we found that the inability to use many carbon and nitrogen sources correlated with the absence of metabolic genes. Based on these results, Pichia galeolata sp. nov. is proposed to accommodate yHMH446T (=NRRL Y-64187 = CBS 16864). This study shows how integrated taxogenomic analysis can add mechanistic insight to species descriptions.

Postglacial migration shaped the genomic diversity and global distribution of the wild ancestor of lager-brewing hybrids.

The wild, cold-adapted parent of hybrid lager-brewing yeasts, Saccharomyces eubayanus, has a complex and understudied natural history. The exploration of this diversity can be used both to develop new brewing applications and to enlighten our understanding of the dynamics of yeast evolution in the wild. Here, we integrate whole genome sequence and phenotypic data of 200 S. eubayanus strains, the largest collection known to date. S. eubayanus has a multilayered population structure, consisting of two major populations that are further structured into six subpopulations. Four of these subpopulations are found exclusively in the Patagonian region of South America; one is found predominantly in Patagonia and sparsely in Oceania and North America; and one is specific to the Holarctic ecozone. Plant host associations differed between subpopulations and between S. eubayanus and its sister species, Saccharomyces uvarum. S. eubayanus is most abundant and genetically diverse in northern Patagonia, where some locations harbor more genetic diversity than is found outside of South America, suggesting that northern Patagonia east of the Andes was a glacial refugium for this species. All but one subpopulation shows isolation-by-distance, and gene flow between subpopulations is low. However, there are strong signals of ancient and recent outcrossing, including two admixed lineages, one that is sympatric with and one that is mostly isolated from its parental populations. Using our extensive biogeographical data, we build a robust model that predicts all known and a handful of additional regions of the globe that are climatically suitable for S. eubayanus, including Europe where host accessibility and competitive exclusion by other Saccharomyces species may explain its continued elusiveness. We conclude that this industrially relevant species has rich natural diversity with many factors contributing to its complex distribution and natural history.

Evaluation of reticuloruminal temperature for the prediction of clinical mastitis in dairy cows challenged with Streptococcus uberis.

Automated monitoring devices have become increasingly utilized in the dairy industry, especially for monitoring or predicting disease status. While multiple automated monitoring devices have been developed for the prediction of clinical mastitis (CM), limitations in performance or applicability remain. The aims of this study were to (1) detect variations in reticuloruminal temperature (RRT) relative to an experimental intramammary challenge with Streptococcus uberis and (2) evaluate alerts generated automatically based on variation in RRT to predict initial signs of CM in the challenged cows based on severity of clinical signs and the concentration of bacteria (cfu/mL) in the infected quarter separately. Clinically healthy Holstein cows without a history of CM in the 60 d before the experiment (n = 37, parity 1 to 5, ≥120 d in milk) were included if they were microbiologically negative and had a somatic cell count under 200,000 cells/mL based on screening of quarter milk samples 1 wk before challenge. Each cow received an intra-reticuloruminal automated monitoring device before the trial and was challenged with 2,000 cfu of Strep. uberis 0140J in 1 rear quarter. Based on interrupted time series analysis, intramammary challenge with Strep. uberis increased RRT by 0.54°C [95% confidence interval (CI): 0.41, 0.66] at 24 h after the challenge, which remained elevated until the end of the study. Alerts based on RRT correctly classified 78.3% (95% CI: 65.8, 87.9) of first occurrences of CM at least 24 h in advance, with a sensitivity of 70.0% (95% CI: 50.6, 85.3) and a specificity of 86.7% (95% CI: 69.3, 96.2). The accuracy of CM for a given severity score was 90.9% (95% CI: 70.8, 98.9) for mild cases, 85.2% (95% CI: 72.9, 93.4) for moderate cases, and 92.9% (95% CI: 66.1, 99.8) for severe cases. Test characteristics of the RRT alerts to predict initial signs of CM improved substantially after bacterial count in the challenged quarter reached 5.0 log10 cfu/mL, reaching a sensitivity of 73.5% (95% CI: 55.6, 87.1) and a specificity of 87.5% (95% CI: 71.0, 96.5). Overall, the results of this study indicated that RRT was affected by the intramammary challenge with Strep. uberis and the RRT-generated alerts had similar accuracy as reported for other sensors and algorithms. Further research that includes natural infections with other pathogens as well as different variations in RRT to determine CM status is warranted.

Substrate, temperature, and geographical patterns among nearly 2000 natural yeast isolates.

Yeasts have broad importance as industrially and clinically relevant microbes and as powerful models for fundamental research, but we are only beginning to understand the roles yeasts play in natural ecosystems. Yeast ecology is often more difficult to study compared to other, more abundant microbes, but growing collections of natural yeast isolates are beginning to shed light on fundamental ecological questions. Here, we used environmental sampling and isolation to assemble a dataset of 1962 isolates collected from throughout the contiguous United States of America (USA) and Alaska, which were then used to uncover geographic patterns, along with substrate and temperature associations among yeast taxa. We found some taxa, including the common yeasts Torulaspora delbrueckii and Saccharomyces paradoxus, to be repeatedly isolated from multiple sampled regions of the USA, and we classify these as broadly distributed cosmopolitan yeasts. A number of yeast taxon-substrate associations were identified, some of which were novel and some of which support previously reported associations. Further, we found a strong effect of isolation temperature on the phyla of yeasts recovered, as well as for many species. We speculate that substrate and isolation temperature associations reflect the ecological diversity of and niche partitioning by yeast taxa.

Functional and evolutionary characterization of a secondary metabolite gene cluster in budding yeasts.

Secondary metabolites are key in how organisms from all domains of life interact with their environment and each other. The iron-binding molecule pulcherrimin was described a century ago, but the genes responsible for its production in budding yeasts have remained uncharacterized. Here, we used phylogenomic footprinting on 90 genomes across the budding yeast subphylum Saccharomycotina to identify the gene cluster associated with pulcherrimin production. Using targeted gene replacements in Kluyveromyces lactis, we characterized the four genes that make up the cluster, which likely encode two pulcherriminic acid biosynthesis enzymes, a pulcherrimin transporter, and a transcription factor involved in both biosynthesis and transport. The requirement of a functional putative transporter to utilize extracellular pulcherrimin-complexed iron demonstrates that pulcherriminic acid is a siderophore, a chelator that binds iron outside the cell for subsequent uptake. Surprisingly, we identified homologs of the putative transporter and transcription factor genes in multiple yeast genera that lacked the biosynthesis genes and could not make pulcherrimin, including the model yeast Saccharomyces cerevisiae We deleted these previously uncharacterized genes and showed they are also required for pulcherrimin utilization in S. cerevisiae, raising the possibility that other genes of unknown function are linked to secondary metabolism. Phylogenetic analyses of this gene cluster suggest that pulcherrimin biosynthesis and utilization were ancestral to budding yeasts, but the biosynthesis genes and, subsequently, the utilization genes, were lost in many lineages, mirroring other microbial public goods systems that lead to the rise of cheater organisms.

Hemodynamic response to non-pneumatic anti-shock compression garments in patients with renal dysfunction.

BACKGROUND: Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. Chronic exposure to intermittent hemodialysis may be a source of added stress to the cardiovascular system; intradialytic hypotension is a common complication of hemodialysis, and repeated events may lead to hemodynamic stress and ischemic injuries. Administration of non-pneumatic compression stockings to the lower limbs has demonstrated hemodynamic stabilizing effects in other settings and may provide similar benefits in the kidney disease population. Therefore, we conducted this pilot study assessing the feasibility and tolerability of the application of non-pneumatic compression stockings to patients with kidney disease. We also assessed the changes in hemodynamic measurements following the application of the compression stockings to explore the biological feasibility of this being an effective intervention for intradialytic hypotension. METHODS: Fifteen individuals were enrolled in the study (5 healthy, 5 chronic kidney disease patients, and 5 dialysis patients). Outcomes including hemodynamic parameters such as cardiac output, peripheral vascular resistance, and blood pressure were measured using continuous pulse wave analysis. Changes in global longitudinal strain were measured via echocardiography. These outcome measurements were made before and after the application of compression stockings. RESULTS: All study participants tolerated the compression garments well and without complication. Hemodynamic response to lower body compression caused varying effects on cardiac output, mean arterial pressure and global longitudinal strain. Some individuals saw large improvements in hemodynamic parameters while in others the opposite effect was observed. No consistent response was elicited. CONCLUSIONS: Application of compression stockings to patients with renal dysfunction is well-tolerated. However, significant variations in hemodynamic outcomes exist, and may be a barrier for larger scale trials without prior identification of specific patient characteristics indicating likely benefit from the application of external compression. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT02915627, Registration Date: Sept 27, 2016.

An evaluation of the Zambia influenza sentinel surveillance system, 2011-2017.

BACKGROUND: Over the past decade, influenza surveillance has been established in several African countries including Zambia. However, information on the on data quality and reliability of established influenza surveillance systems in Africa are limited. Such information would enable countries to assess the performance of their surveillance systems, identify shortfalls for improvement and provide evidence of data reliability for policy making and public health interventions. METHODS: We used the Centers for Disease Control and Prevention guidelines to evaluate the performance of the influenza surveillance system (ISS) in Zambia during 2011-2017 using 9 attributes: (i) data quality and completeness, (ii) timeliness, (iii) representativeness, (iv) flexibility, (v) simplicity, (vi) acceptability, (vii) stability, (viii) utility, and (ix) sustainability. Each attribute was evaluated using pre-defined indicators. For each indicator we obtained the proportion (expressed as percentage) of the outcome of interest over the total. A scale from 1 to 3 was used to provide a score for each attribute as follows: < 60% (as obtained in the calculation above) scored 1 (weak performance); 60-79% scored 2 (moderate performance); ≥80% scored 3 (good performance). An overall score for each attribute and the ISS was obtained by averaging the scores of all evaluated attributes. RESULTS: The overall mean score for the ISS in Zambia was 2.6. Key strengths of the system were the quality of data generated (score: 2.9), its flexibility (score: 3.0) especially to monitor viral pathogens other than influenza viruses, its simplicity (score: 2.8), acceptability (score: 3.0) and stability (score: 2.6) over the review period and its relatively low cost ($310,000 per annum). Identified weaknesses related mainly to geographic representativeness (score: 2.0), timeliness (score: 2.5), especially in shipment of samples from remote sites, and sustainability (score: 1.0) in the absence of external funds. CONCLUSIONS: The system performed moderately well in our evaluation. Key improvements would include improvements in the timeliness of samples shipments and geographical coverage. However, these improvements would result in increased cost and logistical complexity. The ISSS in Zambia is largely reliant on external funds and the acceptability of maintaining the surveillance system through national funds would require evaluation.

AMON: annotation of metabolite origins via networks to integrate microbiome and metabolome data.

BACKGROUND: Untargeted metabolomics of host-associated samples has yielded insights into mechanisms by which microbes modulate health. However, data interpretation is challenged by the complexity of origins of the small molecules measured, which can come from the host, microbes that live within the host, or from other exposures such as diet or the environment. RESULTS: We address this challenge through development of AMON: Annotation of Metabolite Origins via Networks. AMON is an open-source bioinformatics application that can be used to annotate which compounds in the metabolome could have been produced by bacteria present or the host, to evaluate pathway enrichment of host verses microbial metabolites, and to visualize which compounds may have been produced by host versus microbial enzymes in KEGG pathway maps. CONCLUSIONS: AMON empowers researchers to predict origins of metabolites via genomic information and to visualize potential host:microbe interplay. Additionally, the evaluation of enrichment of pathway metabolites of host versus microbial origin gives insight into the metabolic functionality that a microbial community adds to a host:microbe system. Through integrated analysis of microbiome and metabolome data, mechanistic relationships between microbial communities and host phenotypes can be better understood.

sppIDer: A Species Identification Tool to Investigate Hybrid Genomes with High-Throughput Sequencing.

The genomics era has expanded our knowledge about the diversity of the living world, yet harnessing high-throughput sequencing data to investigate alternative evolutionary trajectories, such as hybridization, is still challenging. Here we present sppIDer, a pipeline for the characterization of interspecies hybrids and pure species, that illuminates the complete composition of genomes. sppIDer maps short-read sequencing data to a combination genome built from reference genomes of several species of interest and assesses the genomic contribution and relative ploidy of each parental species, producing a series of colorful graphical outputs ready for publication. As a proof-of-concept, we use the genus Saccharomyces to detect and visualize both interspecies hybrids and pure strains, even with missing parental reference genomes. Through simulation, we show that sppIDer is robust to variable reference genome qualities and performs well with low-coverage data. We further demonstrate the power of this approach in plants, animals, and other fungi. sppIDer is robust to many different inputs and provides visually intuitive insight into genome composition that enables the rapid identification of species and their interspecies hybrids. sppIDer exists as a Docker image, which is a reusable, reproducible, transparent, and simple-to-run package that automates the pipeline and installation of the required dependencies (https://github.com/GLBRC/sppIDer; last accessed September 6, 2018).

Dynamics of the Electromagnetic Fields Induced by Fast Electron Propagation in Near-Solid-Density Media.

The propagation of fast electron currents in near solid-density media was investigated via proton probing. Fast currents were generated inside dielectric foams via irradiation with a short (∼0.6 ps) laser pulse focused at relativistic intensities (Iλ^{2}∼4×10^{19} W cm^{-2} µm^{2}). Proton probing provided a spatially and temporally resolved characterization of the evolution of the electromagnetic fields and of the associated net currents directly inside the target. The progressive growth of beam filamentation was temporally resolved and information on the divergence of the fast electron beam was obtained. Hybrid simulations of electron propagation in dense media indicate that resistive effects provide a major contribution to field generation and explain well the topology, magnitude, and temporal growth of the fields observed in the experiment. Estimations of the growth rates for different types of instabilities pinpoints the resistive instability as the most likely dominant mechanism of beam filamentation.

Pathogenic budding yeasts isolated outside of clinical settings.

Budding yeasts are distributed across a wide range of habitats, including as human commensals. However, under some conditions, these commensals can cause superficial, invasive, and even lethal infections. Despite their importance to human health, little is known about the ecology of these opportunistic pathogens, aside from their associations with mammals and clinical environments. During a survey of approximately 1000 non-clinical samples across the United States of America, we isolated 54 strains of budding yeast species considered opportunistic pathogens, including Candida albicans and Candida (Nakaseomyces) glabrata. We found that, as a group, pathogenic yeasts were positively associated with fruits and soil environments, whereas the species Pichia kudriavzevii (syn. Candida krusei syn. Issatchenkia orientalis) had a significant association with plants. Of the four species that cause 95% of candidiasis, we found a positive association with soil. These results suggest that pathogenic yeast ecology is more complex and diverse than is currently appreciated and raises the possibility that these additional environments could be a point of contact for human infections.

Complex Ancestries of Lager-Brewing Hybrids Were Shaped by Standing Variation in the Wild Yeast Saccharomyces eubayanus.

Lager-style beers constitute the vast majority of the beer market, and yet, the genetic origin of the yeast strains that brew them has been shrouded in mystery and controversy. Unlike ale-style beers, which are generally brewed with Saccharomyces cerevisiae, lagers are brewed at colder temperatures with allopolyploid hybrids of Saccharomyces eubayanus x S. cerevisiae. Since the discovery of S. eubayanus in 2011, additional strains have been isolated from South America, North America, Australasia, and Asia, but only interspecies hybrids have been isolated in Europe. Here, using genome sequence data, we examine the relationships of these wild S. eubayanus strains to each other and to domesticated lager strains. Our results support the existence of a relatively low-diversity (π = 0.00197) lineage of S. eubayanus whose distribution stretches across the Holarctic ecozone and includes wild isolates from Tibet, new wild isolates from North America, and the S. eubayanus parents of lager yeasts. This Holarctic lineage is closely related to a population with higher diversity (π = 0.00275) that has been found primarily in South America but includes some widely distributed isolates. A second diverse South American population (π = 0.00354) and two early-diverging Asian subspecies are more distantly related. We further show that no single wild strain from the Holarctic lineage is the sole closest relative of lager yeasts. Instead, different parts of the genome portray different phylogenetic signals and ancestry, likely due to outcrossing and incomplete lineage sorting. Indeed, standing genetic variation within this wild Holarctic lineage of S. eubayanus is responsible for genetic variation still segregating among modern lager-brewing hybrids. We conclude that the relationships among wild strains of S. eubayanus and their domesticated hybrids reflect complex biogeographical and genetic processes.

Emerging roles of atypical chemokine receptor 3 (ACKR3) in normal development and physiology.

The discovery that atypical chemokine receptors (ACKRs) can initiate alternative signaling pathways rather than classical G-protein coupled receptor (GPCR) signaling has changed the paradigm of chemokine receptors and their roles in modulating chemotactic responses. The ACKR family has grown over the years, with discovery of new functions and roles in a variety of pathophysiological conditions. However, the extent to which these receptors regulate normal physiology is still continuously expanding. In particular, atypical chemokine receptor 3 (ACKR3) has proven to be an important receptor in mediating normal biological functions, including cardiac development and migration of cortical neurons. In this review, we illustrate the versatile and intriguing role of ACKR3 in physiology.

Young Drug Users: a Vulnerable Population and an Underutilized Resource in HIV/HCV Prevention.

PURPOSE OF REVIEW: The social networks of people who inject drugs (PWID) have long been studied to understand disease transmission dynamics and social influences on risky practices. We illustrate how PWID can be active agents promoting HIV, HCV, and overdose prevention. RECENT FINDINGS: We assessed drug users' connections and interactions with others at risk for HIV/HCV in three cities: New York City (NYC), USA (n = 539); Pereira, Colombia (n = 50); and St. Petersburg, Russia (n = 49). In all three cities, the majority of participants' network members were of a similar age as themselves, yet connections across age groups were also present. In NYC, knowing any opioid user(s) older than 29 was associated with testing HCV-positive. In NYC and St. Petersburg, a large proportion of PWID engaged in intravention activities to support safer injection and overdose prevention; in Pereira, PWID injected, had sex, and interacted with other key groups at risk. People who use drugs can be active players in HIV/HCV and overdose risk- reduction; their networks provide them with ample opportunities to disseminate harm reduction knowledge, strategies, and norms to others at risk. Local communities could augment prevention programming by empowering drug users to be allies in the fight against HIV and facilitating their pre-existing health-protective actions.

Dysregulation of metabolic pathways in a mouse model of allergic asthma.

BACKGROUND: Asthma is a complex lung disease resulting from the interplay of genetic and environmental factors. To understand the molecular changes that occur during the development of allergic asthma without genetic and environmental confounders, an experimental model of allergic asthma in mice was used. Our goals were to (1) identify changes at the small molecule level due to allergen exposure, (2) determine perturbed pathways due to disease, and (3) determine whether small molecule changes correlate with lung function. METHODS: In this experimental model of allergic asthma, matched bronchoalveolar lavage (BAL) fluid and plasma were collected from three groups of C57BL6 mice (control vs sensitized and/or challenged with ovalbumin, n=3-5/group) 6 hour, 24 hour, and 48 hour after the last challenge. Samples were analyzed using liquid chromatography-mass spectrometry-based metabolomics. Airway hyper-responsiveness (AHR) measurements and differential cell counts were performed. RESULTS: In total, 398 and 368 dysregulated metabolites in the BAL fluid and plasma of sensitized and challenged mice were identified, respectively. These belonged to four, interconnected pathways relevant to asthma pathogenesis: sphingolipid metabolism (P=6.6×10-5 ), arginine and proline metabolism (P=1.12×10-7 ), glycerophospholipid metabolism (P=1.3×10-10 ), and the neurotrophin signaling pathway (P=7.0×10-6 ). Furthermore, within the arginine and proline metabolism pathway, a positive correlation between urea-1-carboxylate and AHR was observed in plasma metabolites, while ornithine revealed a reciprocal effect. In addition, agmatine positively correlated with lung eosinophilia. CONCLUSION: These findings point to potential targets and pathways that may be central to asthma pathogenesis and can serve as novel therapeutic targets.

Genome sequence and physiological analysis of Yamadazyma laniorum f.a. sp. nov. and a reevaluation of the apocryphal xylose fermentation of its sister species, Candida tenuis.

Xylose fermentation is a rare trait that is immensely important to the cellulosic biofuel industry, and Candida tenuis is one of the few yeasts that has been reported with this trait. Here we report the isolation of two strains representing a candidate sister species to C. tenuis. Integrated analysis of genome sequence and physiology suggested the genetic basis of a number of traits, including variation between the novel species and C. tenuis in lactose metabolism due to the loss of genes encoding lactose permease and ß-galactosidase in the former. Surprisingly, physiological characterization revealed that neither the type strain of C. tenuis nor this novel species fermented xylose in traditional assays. We reexamined three xylose-fermenting strains previously identified as C. tenuis and found that these strains belong to the genus Scheffersomyces and are not C. tenuis. We propose Yamadazyma laniorum f.a. sp. nov. to accommodate our new strains and designate its type strain as yHMH7 (=CBS 14780 = NRRL Y-63967T). Furthermore, we propose the transfer of Candida tenuis to the genus Yamadazyma as Yamadazyma tenuis comb. nov. This approach provides a roadmap for how integrated genome sequence and physiological analysis can yield insight into the mechanisms that generate yeast biodiversity.

Evaluation of microscopic hematuria and risk of urologic cancer in female patients.

BACKGROUND: Urologic cancer has a lower prevalence in women compared with men; however, there are no differences in the recommended evaluation for women and men with microscopic hematuria. OBJECTIVES: The purpose of this study was to identify risk factors that are associated with urologic cancer in women with microscopic hematuria and to determine the applicability of a hematuria risk score for women. STUDY DESIGN: We conducted a retrospective cohort study within an integrated healthcare system in Southern California. All urinalyses with microscopic hematuria (>3 red blood cells per high-power field) that were performed from 2009-2015 were identified. Women who were referred for urologic evaluation were entered into a prospective database. Clinical and demographic variables that included the presence of gross hematuria in the preceding 6 months were recorded. The cause of the hematuria, benign or malignant, was entered into the database. Cancer rates were compared with the use of chi-square and logistic regression models. Adjusted risk ratios of urologic cancer were estimated with the use of multivariate regression analysis. We also explored the applicability of a previously developed, gender nonspecific, hematuria risk score in this female cohort. RESULTS: A total of 2,705,696 urinalyses were performed in women during the study period, of which 552,119 revealed microscopic hematuria. Of these, 14,539 women were referred for urologic evaluation; clinical data for 3573 women were entered into the database. The overall rate of urologic cancer was 1.3% (47/3573). In women <60 years old, the rate of urologic cancer was 0.6% (13/2053) compared with 2.2% (34/1520) in women ≥60 years old (P<.01). In women who reported a history of gross hematuria, the rate of urologic cancer was 5.8% (20/346) compared with a 0.8% (27/3227) in women with no history of gross hematuria (P<.01). In multivariate analysis, > 60 years old (odds ratio, 3.1; 95% confidence interval, 1.6-5.9), a history of smoking (odds ratio, 3.2; 95% confidence interval, 1.8-5.9), and a history of gross hematuria in the previous 6 months (odds ratio, 6.2; 95% confidence interval, 3.4-11.5) were associated with urologic cancers. A higher microscopic hematuria risk score was associated with an increased risk of cancer in this test cohort (P<.01). Women in the highest risk group had a urologic cancer rate of 10.8% compared with a rate of 0.5% in the lowest risk group. CONCLUSIONS: In this female population, >60 years old and a history of smoking and/or gross hematuria were the strongest predictors of urologic cancer. Absent these risk factors, the rate of urologic cancer did not exceed 0.6%. A higher hematuria risk score correlated significantly with the risk of urologic cancer in this female test cohort.