Novel Independent Trans- and Cis-Genetic Variants Associated with CYP2D6 Expression and Activity in Human Livers.

Cytochrome P450 2D6 (CYP2D6) is a critical hepatic drug-metabolizing enzyme in humans, responsible for metabolizing approximately 20%-25% of commonly used medications such as codeine, desipramine, fluvoxamine, paroxetine, and tamoxifen. The CYP2D6 gene is highly polymorphic, resulting in substantial interindividual variability in its catalytic function and the pharmacokinetics and therapeutic outcomes of its substrate drugs. Although many functional CYP2D6 variants have been discovered and validated, a significant portion of the variability in the expression and activity of CYP2D6 remains unexplained. In this study, we performed a genome-wide association study (GWAS) to identify novel variants associated with CYP2D6 protein expression in individual human livers, followed by a conditional analysis to control for the effect of functional CYP2D6 star alleles. We also examined their impact on hepatic CYP2D6 activity. Genotyping on a genome-wide scale was achieved using the Illumina Multi-Ethnic Genotyping Array (MEGA). A data-independent acquisition (DIA)-based proteomics method was used to quantify CYP2D6 protein concentrations. CYP2D6 activity was determined by measuring the dextromethorphan O-demethylation in individual human liver s9 fractions. The GWAS identified 44 single nuclear polymorphisms (SNPs) that are significantly associated with CYP2D6 protein expressions with a P value threshold of 5.0 × 10-7 After the conditional analysis, five SNPs, including the cis-variants rs1807493 and rs1062753 and the trans-variants rs4073010, rs729559, and rs80274432, emerged as independent variants significantly correlated with hepatic CYP2D6 protein expressions. Notably, four of these SNPs, except for rs80274432, also exhibited a significant association with CYP2D6 activities in human livers, suggesting their potential as novel and independent cis- and trans-variants regulating CYP2D6. SIGNIFICANT STATEMENT: Using individual human livers, we identified four novel cis- and trans-pQTLs/aQTLs (protein quantitative trait loci/activity quantitative trait loci) of Cytochrome P450 2D6 (CYP2D6) that are independent from known functional CYP2D6 star alleles. This study connects the CYP2D6 gene expression and activity, enhancing our understanding of the genetic variants associated with CYP2D6 protein expression and activity, potentially advancing our insight into the interindividual variability in CYP2D6 substrate medication response.

Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d.

Natural killer T (NKT) cells detect lipids presented by CD1d. Most studies focus on type I NKT cells that express semi-invariant αß T cell receptors (TCR) and recognize α-galactosylceramides. However, CD1d also presents structurally distinct lipids to NKT cells expressing diverse TCRs (type II NKT cells), but our knowledge of the antigens for type II NKT cells is limited. An early study identified a nonlipidic NKT cell agonist, phenyl pentamethyldihydrobenzofuransulfonate (PPBF), which is notable for its similarity to common sulfa drugs, but its mechanism of NKT cell activation remained unknown. Here, we demonstrate that a range of pentamethylbenzofuransulfonates (PBFs), including PPBF, activate polyclonal type II NKT cells from human donors. Whereas these sulfa drug-like molecules might have acted pharmacologically on cells, here we demonstrate direct contact between TCRs and PBF-treated CD1d complexes. Further, PBF-treated CD1d tetramers identified type II NKT cell populations expressing αßTCRs and γδTCRs, including those with variable and joining region gene usage (TRAV12-1-TRAJ6) that was conserved across donors. By trapping a CD1d-type II NKT TCR complex for direct mass-spectrometric analysis, we detected molecules that allow the binding of CD1d to TCRs, finding that both selected PBF family members and short-chain sphingomyelin lipids are present in these complexes. Furthermore, the combination of PPBF and short-chain sphingomyelin enhances CD1d tetramer staining of PPBF-reactive T cell lines over either molecule alone. This study demonstrates that nonlipidic small molecules, which resemble sulfa drugs implicated in systemic hypersensitivity and drug allergy reactions, are targeted by a polyclonal population of type II NKT cells in a CD1d-restricted manner.

Inequalities in accelerated cognitive decline: Resolving observational window bias using nested non-linear regression.

INTRODUCTION: Limited observational windows lead to conflicting results in studies examining educational differences in Alzheimer's disease and related dementias (ADRD) risk, due to observational window bias relative to onset of accelerated cognitive decline. This study tested a novel model to address observational window bias and tested for the presence and sources of disparities in accelerated cognitive declines due to ADRD. METHODS: The sample examined 167,314 cognitive assessments from 32,441 Health and Retirement Study participants. We implemented a parametric non-linear nested longitudinal regression and reported multivariable-adjusted nodal incidence ratios (aNIR). RESULTS: University degrees were associated with lower incidence (aNIR = 0.253, 95% confidence interval [CI] = [0.221 to 0.289], p < 0.001), while black participants had a higher incidence (aNIR = 1.995, [1.858 to 2.141], p < 0.001) of accelerated cognitive decline, adjusting for demographic, sociobehavioral, and medical risk factors. Sex-stratified analyses identified diminished educational returns for women and increased incidence among minoritized women. DISCUSSION: Addressing observational window bias reveals large social inequalities in the onset of accelerated cognitive declines indicative of ADRD. HIGHLIGHTS: This study identifies observational window bias as a source of conflicting results among previous studies of educational achievement in Alzheimer's disease and related dementias (ADRD) disparities. The study locates preclinical accelerated cognitive decline, which is indicative of ADRD while occurring 10+ years prior to symptom onset, as a site to study ADRD disparities that mitigates observational window bias. A novel method, nested non-linear regression, is developed to test for differences in the onset of accelerated cognitive decline. Educational and racial/ethnic disparities are demonstrated in the onset of accelerated cognitive decline, as are their intersecting differences with sex/gender.

Sleep strengthens resting-state functional communication between brain areas involved in the consolidation of problem-solving skills.

Sleep consolidates procedural memory for motor skills, and this process is associated with strengthened functional connectivity in hippocampal-striatal-cortical areas. It is unknown whether similar processes occur for procedural memory that requires cognitive strategies needed for problem-solving. It is also unclear whether a full night of sleep is indeed necessary for consolidation to occur, compared with a daytime nap. We examined how resting-state functional connectivity within the hippocampal-striatal-cortical network differs after offline consolidation intervals of sleep, nap, or wake. Resting-state fMRI data were acquired immediately before and after training on a procedural problem-solving task that requires the acquisition of a novel cognitive strategy and immediately prior to the retest period (i.e., following the consolidation interval). ROI to ROI and seed to whole-brain functional connectivity analyses both specifically and consistently demonstrated strengthened hippocampal-prefrontal functional connectivity following a period of sleep versus wake. These results were associated with task-related gains in behavioral performance. Changes in functional communication were also observed between groups using the striatum as a seed. Here, we demonstrate that at the behavioral level, procedural strategies benefit from both a nap and a night of sleep. However, a full night of sleep is associated with enhanced functional communication between regions that support problem-solving skills.

SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore.

Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens, resulting in mitochondrial membrane potential (ΔΨm) dissipation, loss of ATP production, and cell death. Several genetic candidates have been proposed to form the PTP complex, however, the core component is unknown. We identified a necessary and conserved role for spastic paraplegia 7 (SPG7) in Ca(2+)- and ROS-induced PTP opening using RNAi-based screening. Loss of SPG7 resulted in higher mitochondrial Ca(2+) retention, similar to cyclophilin D (CypD, PPIF) knockdown with sustained ΔΨm during both Ca(2+) and ROS stress. Biochemical analyses revealed that the PTP is a heterooligomeric complex composed of VDAC, SPG7, and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca(2+)- and ROS-induced ΔΨm depolarization and cell death. This study identifies an ubiquitously expressed IMM integral protein, SPG7, as a core component of the PTP at the OMM and IMM contact site.

Exploration of machine learning methods to predict systemic lupus erythematosus hospitalizations.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a heterogeneous disease characterized by disease flares which can require hospitalization. Our objective was to apply machine learning methods to predict hospitalizations for SLE from electronic health record (EHR) data. METHODS: We identified patients with SLE in a longitudinal EHR-based cohort with ≥2 outpatient rheumatology visits between 2012 and 2019. We applied multiple machine learning methods to predict hospitalizations with a primary diagnosis code for SLE, including decision tree, random forest, naive Bayes, logistic regression, and an ensemble method. Candidate predictors were derived from structured EHR features, including demographics, laboratory tests, medications, ICD-9/10 codes for SLE manifestations, and healthcare utilization. We used two approaches to assess these variables over longitudinal follow-up, including the incorporation of lagged features to capture changes over time of clinical data. The performance of each model was evaluated by overall accuracy, the F statistic, and the area under the receiver operator curve (AUC). RESULTS: We identified 1996 patients with SLE. 4.6% were hospitalized for SLE in their most recent year of follow-up. Random forest models had highest performance in predicting SLE hospitalizations, with AUC 0.751 and AUC 0.772 for two approaches (averaging and progressive), respectively. The leading predictors of SLE hospitalizations included dsDNA positivity, C3 level, blood cell counts, and inflammatory markers as well as age and albumin. CONCLUSION: We have demonstrated that machine learning methods can predict SLE hospitalizations. We identified key predictors of these events including known markers of SLE disease activity; further validation in external cohorts is warranted.

Teaching undergraduate physical chemistry lab with kinetic analysis of COVID-19 in the United States.

A physical chemistry lab for undergraduate students described in this report is about applying kinetic models to analyze the spread of COVID-19 in the United States and obtain the reproduction numbers. The susceptible-infectious-recovery (SIR) model and the SIR-vaccinated (SIRV) model are explained to the students and are used to analyze the COVID-19 spread data from U.S. Centers for Disease Control and Prevention (CDC). The basic reproduction number R 0 and the real-time reproduction number R t of COVID-19 are extracted by fitting the data with the models, which explains the spreading kinetics and provides a prediction of the spreading trend in a given state. The procedure outlined here shows the differences between the SIR model and the SIRV model. The SIRV model considers the effect of vaccination which helps explain the later stages of the ongoing pandemic. The predictive power of the models is also shown giving the students some certainty in the predictions they made for the following months.

A micro-CT-based standard brain atlas of the bumblebee.

In recent years, bumblebees have become a prominent insect model organism for a variety of biological disciplines, particularly to investigate learning behaviors as well as visual performance. Understanding these behaviors and their underlying neurobiological principles requires a clear understanding of brain anatomy. Furthermore, to be able to compare neuronal branching patterns across individuals, a common framework is required, which has led to the development of 3D standard brain atlases in most of the neurobiological insect model species. Yet, no bumblebee 3D standard brain atlas has been generated. Here we present a brain atlas for the buff-tailed bumblebee Bombus terrestris using micro-computed tomography (micro-CT) scans as a source for the raw data sets, rather than traditional confocal microscopy, to produce the first ever micro-CT-based insect brain atlas. We illustrate the advantages of the micro-CT technique, namely, identical native resolution in the three cardinal planes and 3D structure being better preserved. Our Bombus terrestris brain atlas consists of 30 neuropils reconstructed from ten individual worker bees, with micro-CT allowing us to segment neuropils completely intact, including the lamina, which is a tissue structure often damaged when dissecting for immunolabeling. Our brain atlas can serve as a platform to facilitate future neuroscience studies in bumblebees and illustrates the advantages of micro-CT for specific applications in insect neuroanatomy.

Examining emotional intelligence in older adults with chronic pain: a factor analysis approach.

OBJECTIVE: The current study explored whether the three-factor structure of an emotional intelligence measure (attention to emotions, clarity in understanding emotions, and emotion regulation) developed in a sample of college students would replicate in a sample of older adults with chronic pain. METHOD: Confirmatory and exploratory factor analyses were conducted to examine the factor structure of the 30-item Trait Meta-Mood Scale among 340 older adults with knee osteoarthritis. RESULTS: Confirmatory factor analyses indicated that the original three-factor model of emotional intelligence did not fit well with the data for older adults. Exploratory factor analyses revealed a four-factor model of emotional intelligence: (1) confusion, (2) acceptance, (3) rejection, and (4) insight. Correlations between the original and new subscales were explored. CONCLUSION: While the newly derived emotional intelligence scales resembled the original conceptualization of emotional intelligence proposed by Salovey, Mayer, Goldman, Turvey, and Palfai (1995), the current study highlights the differences in emotional intelligence likely representative of older adults with chronic pain.

Sleep Spindle-dependent Functional Connectivity Correlates with Cognitive Abilities.

EEG studies have shown that interindividual differences in the electrophysiological properties of sleep spindles (e.g., density, amplitude, duration) are highly correlated with trait-like "reasoning" abilities (i.e., "fluid intelligence"; problem-solving skills; the ability to employ logic or identify complex patterns), but not interindividual differences in STM or "verbal" intellectual abilities. Previous simultaneous EEG-fMRI studies revealed brain activations time-locked to spindles. Our group has recently demonstrated that the extent of activation in a subset of these regions was related to interindividual differences in reasoning intellectual abilities, specifically. However, spindles reflect communication between spatially distant and functionally distinct brain areas. The functional communication among brain regions related to spindles and their relationship to reasoning abilities have yet to be investigated. Using simultaneous EEG-fMRI sleep recordings and psychophysiological interaction analysis, we identified spindle-related functional communication among brain regions in the thalamo-cortical-BG system, the salience network, and the default mode network. Furthermore, the extent of the functional connectivity of the cortical-striatal circuitry and the thalamo-cortical circuitry was specifically related to reasoning abilities but was unrelated to STM or verbal abilities, thus suggesting that individuals with higher fluid intelligence have stronger functional coupling among these brain areas during spontaneous spindle events. This may serve as a first step in further understanding the function of sleep spindles and the brain network functional communication, which support the capacity for fluid intelligence.

Insecticide exposure during brood or early-adult development reduces brain growth and impairs adult learning in bumblebees.

For social bees, an understudied step in evaluating pesticide risk is how contaminated food entering colonies affects residing offspring development and maturation. For instance, neurotoxic insecticide compounds in food could affect central nervous system development predisposing individuals to become poorer task performers later-in-life. Studying bumblebee colonies provisioned with neonicotinoid spiked nectar substitute, we measured brain volume and learning behaviour of 3 or 12-day old adults that had experienced in-hive exposure during brood and/or early-stage adult development. Micro-computed tomography scanning and segmentation of multiple brain neuropils showed exposure during either of the developmental stages caused reduced mushroom body calycal growth relative to unexposed workers. Associated with this was a lower probability of responding to a sucrose reward and lower learning performance in an olfactory conditioning test. While calycal volume of control workers positively correlated with learning score, this relationship was absent for exposed workers indicating neuropil functional impairment. Comparison of 3- and 12-day adults exposed during brood development showed a similar degree of reduced calycal volume and impaired behaviour highlighting lasting and irrecoverable effects from exposure despite no adult exposure. Our findings help explain how the onset of pesticide exposure to whole colonies can lead to lag-effects on growth and resultant dysfunction.

Pattern Recognition to Objectively Differentiate the Etiology of Cognitive Decline: Analysis of the Impact of Stroke and Alzheimer's Disease.

BACKGROUND: Undetected Alzheimer's disease (AD) and stroke neuropathology is believed to account for a large proportion of decline in cognitive performance that is attributed to normal aging. This study examined the amount of variance in age-related cognitive change that is accounted for by AD and stroke using a novel pattern recognition protocol. METHOD: Secondary analyses of data collected for the Health and Retirement Study (N = 17,579) were used to objectively characterize patterns of cognitive decline associated with AD and stroke. The rate of decline in episodic memory and orientation was the outcome of interest, while algorithms indicative of AD and stroke pathology were the predictors of interest. RESULTS: The average age of the sample was 67.54 ± 10.45 years at baseline, and they completed, on average, 14.20 ± 3.56 years of follow-up. After adjusting for demographics, AD and stroke accounted for approximately half of age-associated decline in cognition (51.07-55.6% for orientation and episodic memory, respectively) and explained variance attributed to random slopes in longitudinal multilevel models. DISCUSSION: The results of this study suggested that approximately half of the cognitive decline usually attributed to normal aging are more characteristic of AD and stroke.

Cholesteryl 6-O-acyl-α-glucosides from diverse Helicobacter spp. signal through the C-type lectin receptor Mincle.

Helicobacter spp. are Gram-negative bacteria that cause a spectrum of disease in the gut, biliary tree and liver. Many Helicobacter spp. produce a range of cholesteryl α-glucosides that have the potential to act as pathogen associated molecular patterns. We report a highly stereoselective α-glucosylation of cholesterol using 3,4,6-tri-O-acetyl-2-O-benzyl-d-glucopyranosyl N-phenyl-2,2,2-trifluoroacetimidate, which allowed the synthesis of cholesteryl α-glucoside (αCG) and representative Helicobacter spp. cholesteryl 6-O-acyl-α-glucosides (αCAGs; acyl = C12:0, 14:0, C16:0, C18:0, C18:1). All αCAGs, irrespective of the nature of their acyl chain composition, strongly agonised signalling through the C-type lectin receptor Mincle from human and mouse to similar degrees. By contrast, αCG only weakly signalled through human Mincle, and did not signal through mouse Mincle. These results provide a molecular basis for understanding of the immunobiology of non-pylori Helicobacter infections in humans and other animals.

The impact of social interactions and pain on daily positive and negative affect in adults with osteoarthritis of the knee.

This study utilized experience sampling methodology (ESM) to examine the relationship of social interactions with daily pain and mood symptoms in people with osteoarthritis (OA) of the knee. Two hundred sixty-eight adults with physician-diagnosed OA of the knee underwent a baseline in-person interview and subsequent week-long ESM protocol to assess their daily activity patterns, pain, and mood via phone interview four times a day. A coding system was developed to assess presence and type of social interactions based on subject self-report of activity patterns. Multilevel modeling was used to examine between- and within-subject variation in outcomes based on both global and momentary measures of social activities, pain, and mood, while controlling for key demographic and potentially confounding variables. Positive associations were demonstrated between the ratio of positive to negative affect and both global (ß = 0.49, p < .001) and momentary, especially positive (ß = 0.24, p < .05), social activity patterns. Additionally, the association between negative affect and pain (ß = -0.07, p < .01) was attenuated in those with more baseline social interactions. Social interaction has the potential to influence mood in adults with OA of the knee, both on a global scale, and through daily variations in interactions. These interactions seem to be directly related to mood, as well as the apparently attenuating the relationship between pain and depression. Daily social interactions showed a robust positive association with contemporaneous positive affect.

Effect of GAD1 genotype status on auditory attention and acute nicotine administration in healthy volunteers.

OBJECTIVE: The effects of GABA modulating drugs and nicotine, the prototypical nicotinic cholinergic agonist, on attention have been investigated using subcomponents of the P300 event-related potentials (ERP), which index involuntary (P3a) and voluntary attention (P3b). However, investigations into how such pharmacologic effects interact with genetic features in the GABA system remain unclear. This study examined the moderating effects of a single nucleotide polymorphism (rs7557793) in the glutamic acid decarboxylase 67 (GAD1) gene, which is implicated in the conversion of glutamate to GABA, on P300-indices of auditory attentional processing; the influence of nicotine administration was also assessed. METHODS: The effects of GAD1 genotype (TT/CC/CT) were examined on the P3a/b in response to an auditory selective attention task in healthy, nonsmoking male volunteers (N = 126; 18-40 years). Participants responded to rare target stimuli (P3b-eliciting) and ignored frequent nontarget stimuli as well as rare distractor stimuli (P3a-eliciting). In a subsample (N = 59), P3a/b profiles to acute nicotine (vs. placebo) administration were examined as a function of GAD1 genotype. As a secondary aim, earlier sensory processes were assessed with N200 ERP subcomponents elicited by novel (N2a) and target (N2b) auditory stimuli. RESULTS: GAD1 allelic variation moderated early sensory processes, enhancing N2a amplitudes in CT versus TT carriers. Further, TT homozygotes exhibited larger P3b amplitudes than CC homozygotes in the placebo versus nicotine condition. Regardless of genotype, nicotine versus placebo moderated the N200 ERP. CONCLUSION: These findings expand our knowledge regarding the attentional effects of GAD1 genetic variants in relation to nicotine.

Global Versus Momentary Osteoarthritis Pain and Emotional Distress: Emotional Intelligence as Moderator.

Background: Pain and emotional well-being are complexly associated both globally and in the moment. Emotional regulation strategies may contribute to that complexity by shaping the pain-well-being association. Purpose: Using emotional intelligence (EI) as an integrative conceptual framework, this study probed the role of emotional regulation in the associations of osteoarthritis pain with emotional well-being in varying time frames. Perceived attention to, clarity, and regulation of emotions were examined as predictors of well-being, and as moderators of the well-being-pain association, at global and momentary (within-day) levels. Methods: In a microlongitudinal study, 218 older adults with physician-diagnosed knee osteoarthritis self-reported global pain, depressive symptoms, and EI (mood attention, clarity, and repair). Momentary pain and positive and negative affect were then assessed four times daily for 7 days. EI subscales were examined as moderators of the pain-well-being association at global and momentary levels, controlling demographics and general health. Results: Global and momentary pain were positively associated with mood clarity and negatively with attention, but not with repair. Clarity and repair negatively predicted depression, and buffered effects of pain on depression. Momentary negative affect was negatively predicted by mood clarity and repair; again, clarity and mood repair buffered effects of momentary pain on negative affect. Only mood repair predicted positive affect, with no interactions emerging. Conclusions: Attention to mood states exacerbates the experience of pain in both short and long terms. In contrast, both mood clarity and ability to repair moods appear important to both momentary and longer-term emotional well-being.

Effect of Simulated Climate Warming on the Ectomycorrhizal Fungal Community of Boreal and Temperate Host Species Growing Near Their Shared Ecotonal Range Limits.

Ectomycorrhizal (ECM) fungi can influence the establishment and performance of host species by increasing nutrient and water absorption. Therefore, understanding the response of ECM fungi to expected changes in the global climate is crucial for predicting potential changes in the composition and productivity of forests. While anthropogenic activity has, and will continue to, cause global temperature increases, few studies have investigated how increases in temperature will affect the community composition of ectomycorrhizal fungi. The effects of global warming are expected to be particularly strong at biome boundaries and in the northern latitudes. In the present study, we analyzed the effects of experimental manipulations of temperature and canopy structure (open vs. closed) on ectomycorrhizal fungi identified from roots of host seedlings through 454 pyrosequencing. The ecotonal boundary site selected for the study was between the southern boreal and temperate forests in northern Minnesota, USA, which is the southern limit range for Picea glauca and Betula papyrifera and the northern one for Pinus strobus and Quercus rubra. Manipulations that increased air and soil temperature by 1.7 and 3.4 °C above ambient temperatures, respectively, did not change ECM richness but did alter the composition of the ECM community in a manner dependent on host and canopy structure. The prediction that colonization of boreal tree species with ECM symbionts characteristic of temperate species would occur was not substantiated. Overall, only a small proportion of the ECM community appears to be strongly sensitive to warming.

Domperidone is Commonly Prescribed With QT-Interacting Drugs: Review of a Community-based Practice and a Postmarketing Adverse Drug Event Reporting Database.

INTRODUCTION: Domperidone, a peripheral D2 dopamine receptor antagonist, has efficacy for treatment of nausea, dyspepsia, and gastroparesis. Domperidone prolongs the QT interval (QTc), and may cause life-threatening arrhythmias. METHODS: Electronic medical records for all patients receiving domperidone in the NorthShore University HealthSystem from January 1, 2008 to December 1, 2013 were reviewed. All concomitant medications were noted. The coadministration of QT-interacting medications was determined. Electrocardiogram (EKG) evaluation before and during domperidone therapy was noted. A query of the FDA Adverse Event Reporting System (FAERS) database was also performed. Individual reports from the FAERS Web site from January 2008 to June 2014 were downloaded and analyzed. The database was queried for all reports of adverse events with domperidone. Coadministration of QT-interacting medications was noted. Cardiac events that potentially were related to prolongation of the QTc were examined. RESULTS: In total, 108 of 155 patients (69.7%) were coprescribed QT-interacting drugs along with domperidone. Fifty-nine of 155 patients (38.1%) underwent a baseline EKG and 9 (15.3%) had prolongation of the QTc at initiation. Forty patients (25.8%) had a follow-up EKG and 13 (32.5%) had prolongation of the QTc. All 13 were coprescribed QT-interacting medications. On the FAERS, 221 nonfatal cardiac events were reported in domperidone patients; of these, 162 (73.3%) occurred in patients receiving QT-interacting medications. Coprescription occurred in 53 of 151 deaths (35.1%) and in 16 of 61 cardiac arrests (26.2%). CONCLUSIONS: Coprescribing of QT-prolonging medications and inconsistent EKG monitoring occur in patients receiving domperidone, placing these patients at risk for arrhythmias.

Endemism and functional convergence across the North American soil mycobiome.

Identifying the ecological processes that structure communities and the consequences for ecosystem function is a central goal of ecology. The recognition that fungi, bacteria, and viruses control key ecosystem functions has made microbial communities a major focus of this field. Because many ecological processes are apparent only at particular spatial or temporal scales, a complete understanding of the linkages between microbial community, environment, and function requires analysis across a wide range of scales. Here, we map the biological and functional geography of soil fungi from local to continental scales and show that the principal ecological processes controlling community structure and function operate at different scales. Similar to plants or animals, most soil fungi are endemic to particular bioregions, suggesting that factors operating at large spatial scales, like dispersal limitation or climate, are the first-order determinants of fungal community structure in nature. By contrast, soil extracellular enzyme activity is highly convergent across bioregions and widely differing fungal communities. Instead, soil enzyme activity is correlated with local soil environment and distribution of fungal traits within the community. The lack of structure-function relationships for soil fungal communities at continental scales indicates a high degree of functional redundancy among fungal communities in global biogeochemical cycles.