Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Climatic stability and geological history shape global centers of neo- and paleoendemism in seed plants.

Assessing the distribution of geographically restricted and evolutionarily unique species and their underlying drivers is key to understanding biogeographical processes and critical for global conservation prioritization. Here, we quantified the geographic distribution and drivers of phylogenetic endemism for ~320,000 seed plants worldwide and identified centers and drivers of evolutionarily young (neoendemism) and evolutionarily old endemism (paleoendemism). Tropical and subtropical islands as well as tropical mountain regions displayed the world's highest phylogenetic endemism. Most tropical rainforest regions emerged as centers of paleoendemism, while most Mediterranean-climate regions showed high neoendemism. Centers where high neo- and paleoendemism coincide emerged on some oceanic and continental fragment islands, in Mediterranean-climate regions and parts of the Irano-Turanian floristic region. Global variation in phylogenetic endemism was well explained by a combination of past and present environmental factors (79.8 to 87.7% of variance explained) and most strongly related to environmental heterogeneity. Also, warm and wet climates, geographic isolation, and long-term climatic stability emerged as key drivers of phylogenetic endemism. Neo- and paleoendemism were jointly explained by climatic and geological history. Long-term climatic stability promoted the persistence of paleoendemics, while the isolation of oceanic islands and their unique geological histories promoted neoendemism. Mountainous regions promoted both neo- and paleoendemism, reflecting both diversification and persistence over time. Our study provides insights into the evolutionary underpinnings of biogeographical patterns in seed plants and identifies the areas on Earth with the highest evolutionary and biogeographical uniqueness-key information for setting global conservation priorities.

Fifteen-minute consultation: Group A streptococcal pharyngitis, diagnosis and treatment in children.

Group A streptococcus (GAS) is the most common bacterial cause of pharyngitis in children. GAS causes significant suppurative and non-suppurative complications including invasive GAS disease and acute rheumatic fever. This article describes the current epidemiology and clinical presentation of GAS pharyngitis and explores how diagnostic and treatment decisions differ globally. Several key decision support tools are discussed including international guidelines, clinical decision scores and laboratory tests along with the evidence for treatment choice and duration. With recent international reports describing an increase in GAS infections, clinicians should be familiar with their local GAS pharyngitis guidelines and the rationale for diagnosis and treatment of this common childhood illness.

Group A Streptococcus Primary Peritonitis in Children, New Zealand.

Group A Streptococcus (GAS) primary peritonitis is a rare cause of pediatric acute abdomen (sudden onset of severe abdominal pain); only 26 pediatric cases have been reported in the English language literature since 1980. We discuss 20 additional cases of pediatric primary peritonitis caused by GAS among patients at Starship Children's Hospital, Auckland, New Zealand, during 2010-2022. We compare identified cases of GAS primary peritonitis to cases described in the existing pediatric literature. As rates of rates of invasive GAS increase globally, clinicians should be aware of this cause of unexplained pediatric acute abdomen.

Boxwood phyllosphere fungal and bacterial communities and their differential responses to film-forming anti-desiccants.

BACKGROUND: Anti-desiccant is a class of agrochemicals widely used to protect plants from water stresses, rapid temperature variations, heat and sunburn, frost and freeze damages, transplant shock, and pathogen and pest attack. Although anti-desiccants are generally considered non-toxic to organisms, it is unclear whether they may impact the phyllosphere microbial communities. In this study, three film-forming anti-desiccant products, TransFilm, Vapor Gard, and Wilt-Pruf were applied to the canopy of two boxwood cultivars 'Vardar Valley' and 'Justin Brouwers' on April 13 and August 26, 2021. Shoot samples were collected from boxwood plants treated with each of the three products, as well as nontreated control on June 16, August 26 (before the second treatment), and October 18. Microbial and plant genomic DNA was isolated together and 16S rRNA gene and the extended internal transcribed spacer regions were amplified with PCR and sequenced on a Nanopore MinION platform for bacterial and fungal identification. RESULTS: Bacterial communities were more diverse than fungal communities. At the phylum level, the boxwood phyllosphere was dominated by Proteobacteria and Ascomycota; at the genus level, Methylobacterium and Shiraia were the most abundant bacteria and fungi, respectively. Among the three film-forming anti-desiccants, Vapor Gard and Wilt-Pruf had more impact than TransFilm on the microbial communities. Specifically, broader impacts were observed on fungal than bacterial community composition and structure, with most affected fungi being suppressed while bacteria promoted. CONCLUSION: This study addressed several major knowledge gaps regarding boxwood phyllosphere microbiota and the impact of anti-desiccants on plant microbiome. We identified diverse microbial communities of boxwood, a major evergreen woody crop and an iconic landscape plant. We also found differential effects of three film-forming anti-desiccants on the composition and structure of bacterial and fungal communities. These findings advanced our understanding of the associated microbiome of this landmark plant, enabling growers to fully utilize the potentials of microbiome and three anti-desiccants in improving boxwood health and productivity.

The contribution of plant life and growth forms to global gradients of vascular plant diversity.

Plant life and growth forms (shortened to 'plant forms') represent key functional strategies of plants in relation to their environment and provide important insights into the ecological constraints acting on the distribution of biodiversity. Despite their functional importance, how the spectra of plant forms contribute to global gradients of plant diversity is unresolved. Using a novel dataset comprising > 295 000 species, we quantify the contribution of different plant forms to global gradients of vascular plant diversity. Furthermore, we establish how plant form distributions in different biogeographical regions are associated with contemporary and paleoclimate conditions, environmental heterogeneity and phylogeny. We find a major shift in representation of woody perennials in tropical latitudes to herb-dominated floras in temperate and boreal regions, following a sharp latitudinal gradient in plant form diversity from the tropics to the poles. We also find significant functional differences between regions, mirroring life and growth form responses to environmental conditions, which is mostly explained by contemporary climate (18-87%), and phylogeny (6-62%), with paleoclimate and heterogeneity playing a lesser role (< 23%). This research highlights variation in the importance of different plant forms to diversity gradients world-wide, shedding light on the ecological and evolutionary pressures constraining plant-trait distributions.

Global models and predictions of plant diversity based on advanced machine learning techniques.

Despite the paramount role of plant diversity for ecosystem functioning, biogeochemical cycles, and human welfare, knowledge of its global distribution is still incomplete, hampering basic research and biodiversity conservation. Here, we used machine learning (random forests, extreme gradient boosting, and neural networks) and conventional statistical methods (generalized linear models and generalized additive models) to test environment-related hypotheses of broad-scale vascular plant diversity gradients and to model and predict species richness and phylogenetic richness worldwide. To this end, we used 830 regional plant inventories including c. 300 000 species and predictors of past and present environmental conditions. Machine learning showed a superior performance, explaining up to 80.9% of species richness and 83.3% of phylogenetic richness, illustrating the great potential of such techniques for disentangling complex and interacting associations between the environment and plant diversity. Current climate and environmental heterogeneity emerged as the primary drivers, while past environmental conditions left only small but detectable imprints on plant diversity. Finally, we combined predictions from multiple modeling techniques (ensemble predictions) to reveal global patterns and centers of plant diversity at multiple resolutions down to 7774 km2 . Our predictive maps provide accurate estimates of global plant diversity available at grain sizes relevant for conservation and macroecology.

Fetal Loss and Preterm Birth Caused by Intraamniotic Haemophilus influenzae Infection, New Zealand.

Invasive Haemophilus influenzae infection during pregnancy can cause preterm birth and fetal loss, but the mechanism is unclear. We investigated 54 cases of pregnancy-associated invasive H. influenzae disease in 52 unique pregnancies in the Auckland region of New Zealand during October 1, 2008‒September 30, 2018. Intraamniotic infection was identified in 36 (66.7%) of 54 cases. Outcome data were available for 48 pregnancies. Adverse pregnancy outcomes, defined as fetal loss, preterm birth, or the birth of an infant requiring intensive/special care unit admission, occurred in 45 (93.8%) of 48 (pregnancies. Fetal loss occurred in 17 (35.4%) of 48 pregnancies, before 24 weeks' gestation in 13 cases, and at >24 weeks' gestation in 4 cases. The overall incidence of pregnancy-associated invasive H. influenzae disease was 19.9 cases/100,000 births, which exceeded the reported incidence of pregnancy-associated listeriosis in New Zealand. We also observed higher rates in younger women and women of Maori ethnicity.

Temporal stability of the hemodynamic response function across the majority of human cerebral cortex.

The hemodynamic response function (HRF) measured with functional magnetic resonance imaging is generated by vascular and metabolic responses evoked by brief (<4 s) stimuli. It is known that the human HRF varies across cortex, between subjects, with stimulus paradigms, and even between different measurements in the same cortical location. However, our results demonstrate that strong HRFs are remarkably repeatable across sessions separated by time intervals up to 3 months. In this study, a multisensory stimulus was used to activate and measure the HRF across the majority of cortex (>70%, with lesser reliability observed in some areas of prefrontal cortex). HRFs were measured with high spatial resolution (2-mm voxels) in central gray matter to minimize variations caused by partial-volume effects. HRF amplitudes and temporal dynamics were highly repeatable across four sessions in 20 subjects. Positive and negative HRFs were consistently observed across sessions and subjects. Negative HRFs were generally weaker and, thus, more variable than positive HRFs. Statistical measurements showed that across-session variability is highly correlated to the variability across events within a session; these measurements also indicated a normal distribution of variability across cortex. The overall repeatability of the HRFs over long time scales generally supports the long-term use of event-related functional magnetic resonance imaging protocols.

Biodiversity data integration-the significance of data resolution and domain.

Recent years have seen an explosion in the availability of biodiversity data describing the distribution, function, and evolutionary history of life on earth. Integrating these heterogeneous data remains a challenge due to large variations in observational scales, collection purposes, and terminologies. Here, we conceptualize widely used biodiversity data types according to their domain (what aspect of biodiversity is described?) and informational resolution (how specific is the description?). Applying this framework to major data providers in biodiversity research reveals a strong focus on the disaggregated end of the data spectrum, whereas aggregated data types remain largely underutilized. We discuss the implications of this imbalance for the scope and representativeness of current macroecological research and highlight the synergies arising from a tighter integration of biodiversity data across domains and resolutions. We lay out effective strategies for data collection, mobilization, imputation, and sharing and summarize existing frameworks for scalable and integrative biodiversity research. Finally, we use two case studies to demonstrate how the explicit consideration of data domain and resolution helps to identify biases and gaps in global data sets and achieve unprecedented taxonomic and geographical data coverage in macroecological analyses.

Retinotopic variations of the negative blood-oxygen-level dependent hemodynamic response function in human primary visual cortex.

Functional magnetic resonance imaging (fMRI) measures blood-oxygen-level-dependent (BOLD) contrast that is generally assumed to be linearly related to excitatory neural activity. The positive hemodynamic response function (pHRF) is the positive BOLD response (PBR) evoked by a brief neural stimulation; the pHRF is often used as the impulse response for linear analysis of neural excitation. Many fMRI studies have observed a negative BOLD response (NBR) that is often associated with neural suppression. However, the temporal dynamics of the NBR evoked by a brief stimulus, the negative HRF (nHRF), remains unclear. Here, a unilateral visual stimulus was presented in a slow event-related design to elicit both pHRFs in the stimulus representation (SR), and nHRFs elsewhere. The observed nHRFs were not inverted versions of the pHRF previously reported. They were characterized by a stronger initial negative response followed by a significantly later positive peak. In contralateral primary visual cortex (V1), these differences varied with eccentricity from the SR. Similar nHRFs were observed in ipsilateral V1 with less eccentricity variation. Experiments with the blocked version of the same stimulus confirmed that brain regions presenting the unexpected nHRF dynamics correspond to those presenting a strong NBR. These data demonstrated that shift-invariant temporal linearity did not hold for the NBR while confirming that the PBR maintained rough linearity. Modeling indicated that the observed nHRFs can be created by suppression of both blood flow and oxygen metabolism. Critically, the nHRF can be misinterpreted as a pHRF due to their similarity, which could confound linear analysis for event-related fMRI experiments.NEW & NOTEWORTHY We investigate dynamics of the negative hemodynamic response function (nHRF), the negative blood-oxygen-level-dependent (BOLD) response (NBR) evoked by a brief stimulus, in human early visual cortex. Here, we show that the nHRFs are not inverted versions of the corresponding pHRFs. The nHRF has complex dynamics that varied significantly with eccentricity. The results also show shift-invariant temporal linearity does not hold for the NBR.

The Utility of Rapid Group A Streptococcus Molecular Testing Compared with Throat Culture for the Diagnosis of Group A Streptococcal Pharyngitis in a High-Incidence Rheumatic Fever Population.

Group A streptococcus (GAS) causes significant morbidity and mortality in New Zealand and is responsible for invasive disease and immune sequelae, including acute rheumatic fever (ARF). Early treatment of GAS pharyngitis reduces the risk of ARF. In settings with a high burden of GAS disease, a rapid GAS pharyngitis diagnostic test with a strong negative predictive value is needed to enable prompt and accurate treatment. This prospective study compares the Xpert Xpress Strep A molecular test (Cepheid) to throat culture and a second molecular method, the BioGX group A streptococcus-open system reagent (OSR) for BD Max for the diagnosis of GAS pharyngitis. Throat swabs were collected from the emergency department and wards of Middlemore Hospital, New Zealand. The BioGX group A streptococcus OSR for BD Max contributes to the composite gold standard of throat culture or both molecular methods positive. Basic demographic, clinical, and laboratory data were collected. Two hundred five out of two hundred fourteen swabs were suitable for analysis. Of those, 28/205 (13.7%) were GAS culture positive, 45/205 (22%) Xpert Xpress Strep A positive, and 38/205 (18.5%) BioGX positive. Compared to culture, the sensitivity, specificity, and positive and negative predictive values of the Xpert Xpress Strep A molecular test were 100%, 90.4%, 62.2%, and 100%, respectively. Compared to the composite gold standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 100%, 95.8%, 84.4%, and 100%, respectively. Seventeen samples were Xpert Xpress positive but culture negative; 6 of these 17 swabs represent true positives with evidence of recent GAS infection. Ten samples were culture negative but both Xpert Xpress and BioGX positive. The Xpert Xpress Strep A molecular test is highly sensitive with a strong negative predictive value and rapid turnaround time. It can be safely introduced as a first-line test for throat swabs in a high-incidence ARF population.

Natural history of Tay-Sachs disease in sheep.

Tay-Sachs disease (TSD) is a fatal neurodegenerative disease caused by a deficiency of the enzyme ß-N-acetylhexosaminidase A (HexA). TSD naturally occurs in Jacob sheep is the only experimental model of TSD. TSD in sheep recapitulates neurologic features similar to juvenile onset and late onset TSD patients. Due to the paucity of human literature on pathology of TSD, a better natural history in the sheep TSD brain, which is on the same order of magnitude as a child's, is necessary for evaluating therapy and characterizing the pathological events that occur. To provide clinicians and researchers with a clearer understanding of longitudinal pathology in patients, we compare spectrum of clinical signs and brain pathology in mildly symptomatic (3-months), moderately symptomatic (6-months), or severely affected TSD sheep (humane endpoint at ~9-months of age). Increased GM2 ganglioside in the CSF of TSD sheep and a TSD specific biomarker on MRS (taurine) correlate with disease severity. Microglial activation and reactive astrocytes were observed globally on histopathology in TSD sheep with a widespread reduction in oligodendrocyte density. Myelination is reduced primarily in the forebrain illustrated by loss of white matter on MRI. GM2 and GM3 ganglioside were increased and distributed differently in various tissues. The study of TSD in the sheep model provides a natural history to shed light on the pathophysiology of TSD, which is of utmost importance due to novel therapeutics being assessed in human patients.

Caregiver experiences of developmental screening.

BACKGROUND: The American Academy of Pediatrics (AAP) has called for a universal system of developmental screening and surveillance to enhance early detection and intervention for children. While the need and potential impact of universal screening is well documented, recent reports show that screening rates have not reached expected goals and gaps remain in terms of effective follow-up and referral to early intervention (EI) services. Few studies have explored parent and child experiences of developmental screening, which would aid researchers, practitioners and policymakers in improving early detection and referral to EI. The purpose of this qualitative study was to understand the experiences of caregivers and children who received developmental screening across different service sectors, including the type of screening received, location of screening, experiences during the screening process and the follow-up interventions received following screening. METHODS: Individual interviews were conducted with 31 caregivers. A descriptive qualitative design allowed for the exploration of caregiver experiences with developmental screening. Thematic analysis was utilized to categorize caregiver reflections prior to, during and following developmental screening events. RESULTS: Analysis revealed five themes that described caregivers' experiences with screening and assessment for their child: (1) parent's goals of screening; (2) screening preparation and support; (3) parent/child response to screening; (4) result reporting and follow-up; (5) overall satisfaction with screening process. Each theme was composed of several subthemes. CONCLUSIONS: Caregivers see the importance of developmental screening, caregivers and children respond well to screening delivered by various providers in multiple settings and caregivers find the information gleaned from screening events important in planning for their child's developmental trajectory. Key places where improvements can be made to further bolster parental engagement and satisfaction include screening preparation and follow-up.

More than BOLD: Dual-spin populations create functional contrast.

PURPOSE: Functional MRI contrast has generally been associated with changes in transverse relaxivity caused by blood oxygen concentration, the so-called blood oxygen level dependent contrast. However, this interpretation of fMRI contrast has been called into question by several recent experiments at high spatial resolution. Experiments were conducted to examine contrast dependencies that cannot be explained only by differences in relaxivity in a single-spin population. METHODS: Measurements of functional signal and contrast were obtained in human early visual cortex during a high-contrast visual stimulation over a large range of TEs and for several flip angles. Small voxels (1.5 mm) were used to restrict the measurements to cortical gray matter in early visual areas identified using retinotopic mapping procedures. RESULTS: Measurements were consistent with models that include 2 spin populations. The dominant population has a relatively short transverse lifetime that is strongly modulated by activation. However, functional contrast is also affected by volume changes between this short-lived population and the longer-lived population. CONCLUSION: Some of the previously observed "nonclassical" behaviors of functional contrast can be explained by these interacting dual-spin populations.

Comparing VA and Community-Based Care: Trends in Sleep Studies Following the Veterans Choice Act.

BACKGROUND: To address concerns about access to care, the Veterans Access, Choice, and Accountability Act of 2014 was enacted to make care available in the community when Veterans Health Administration (VA) care was unavailable or not timely. This paper examined VA referrals for diagnostic sleep studies from federal fiscal year (FY) 2015-2018. DESIGN: Sleep studies completed between FY2015 and 2018 for Veterans tested within VA facilities (VAF) or referred to VA community care (VACC) providers were identified using VA administrative data files. Sleep studies were divided into laboratory and home studies. KEY RESULTS: The number of sleep studies conducted increased over time; the proportion of home studies increased in VAF (32 to 47%). Veterans were more likely to be referred for a sleep study to VACC if they lived in a rural or highly rural area (ORs = 1.47 and 1.55, respectively), and had public or public and private insurance (ORs = 2.01 and 1.35), and were less likely to be referred to VACC if they were age 65+ (OR = 0.72) and were in the highest utilization risk based on Nosos score (OR = 0.78). Regression analysis of sleep study type revealed that lab studies were much more likely for VACC referrals (OR = 3.16), for persons living in rural areas (OR = 1.21), with higher comorbidity scores (OR = 1.28) and for ages 44-54, 55 to 64, and 65+ (ORs = 1.12, 1.28, 1.45, respectively) compared to younger Veterans. Veterans with some or full VA copayments (ORs = 0.91 and 0.86, respectively), and overweight Veterans (OR = 0.94) were less likely to have lab studies. CONCLUSIONS: The number of sleep studies performed on Veterans increased from 2015 to 2018. Access to sleep studies improved through a combination of providing care through the Veteran Choice Program, predominantly used by rural Veterans, and increased use of home sleep studies by VA.

Island disharmony revisited using orchids as a model group.

One central concept in island biology is that island assemblages form subsets of the mainland species pool, being disproportionately rich or poor in certain taxonomic groups. This unbalanced composition, termed 'disharmony', is generally explained using a taxon-centred approach, linking the over- or under-representation of taxa to their colonisation abilities. However, islands may also harbour 'functionally' disharmonic flora, being disproportionately rich or poor in species with certain traits, which may offer greater insights into the processes driving island colonisation. Here, we use orchids as a model to illustrate key processes involved in the formation of functionally disharmonic island floras, including filtering effects (for example biotic interactions), and speciation. Our synthesis is based on a comprehensive orchid dataset of 27 637 species and combines both a literature review and simple exploratory analyses to show that orchids are significantly under-represented on islands relative to mainland regions and that insular orchids display shifts in functional traits, from the shortening of nectar spurs to facilitate ornithophily to changes in colour associated with generalist insect pollinators. We highlight that taxa are simply coarse proxies and that we need to consider species traits and interactions to gain a full understanding of the processes constraining plant assembly on islands.

Catheter-based retrograde coronary sinus infusion is a practical delivery technique for introducing biological molecules into the cardiac system.

OBJECTIVES: To demonstrate coronary sinus (CS) retrograde catheterization as a practicable technique for delivering biologics into the heart. BACKGROUND: There are many options to deliver biologics into the heart. However, there is no single optimal technique when considering safety, biologic retention, and reproducibility. Retrograde delivery has the potential to address many of these concerns. This study evaluated retrograde CS infusion of luciferase-expressing plasmid in a porcine model using the Advance® CS Coronary Sinus Infusion Catheter and bioluminescence imaging to track the expression of the infused biological markers. METHODS: Plasmid was delivered retrograde into the CS in one of three infusion volumes. Twenty-four hours post-infusion, hearts were excised and underwent bioluminescence imaging to characterize the expression of the infusates. Heart and lung biopsies were also assessed for luciferase expression using RT-qPCR. RESULTS: Retrograde infusion was safe and successful in all nine test subjects. Luciferase detection was inconsistent in the low volume group. Bioluminescence was confined predominantly along the posterolateral left ventricle for medium volume infusions and was more broadly dispersed along the anterior side of the heart for high volume infusions. Tissue mRNA analysis corroborated the bioluminescence results, with the highest concentration of luciferase expression localized in the left ventricle. CONCLUSIONS: Retrograde CS infusion is a promising technique for delivering biological molecules to the heart. Specifically, this study demonstrated that the low pressure coronary venous system accommodates a wide range of infusion volumes and that biological infusates can be maintained in situ following the resumption of coronary venous flow.

Genetic Analysis of 400 Patients Refines Understanding and Implicates a New Gene in Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Genetic variation in complement genes is a predisposing factor for atypical hemolytic uremic syndrome (aHUS), a life-threatening thrombotic microangiopathy, however interpreting the effects of genetic variants is challenging and often ambiguous. METHODS: We analyzed 93 complement and coagulation genes in 400 patients with aHUS, using as controls 600 healthy individuals from Iowa and 63,345 non-Finnish European individuals from the Genome Aggregation Database. After adjusting for population stratification, we then applied the Fisher exact, modified Poisson exact, and optimal unified sequence kernel association tests to assess gene-based variant burden. We also applied a sliding-window analysis to define the frequency range over which variant burden was significant. RESULTS: We found that patients with aHUS are enriched for ultrarare coding variants in the CFH, C3, CD46, CFI, DGKE, and VTN genes. The majority of the significance is contributed by variants with a minor allele frequency of <0.1%. Disease-related variants tend to occur in specific complement protein domains of FH, CD46, and C3. We observed no enrichment for multiple rare coding variants in gene-gene combinations. CONCLUSIONS: In known aHUS-associated genes, variants with a minor allele frequency >0.1% should not be considered pathogenic unless valid enrichment and/or functional evidence are available. VTN, which encodes vitronectin, an inhibitor of the terminal complement pathway, is implicated as a novel aHUS-associated gene. Patients with aHUS are not enriched for multiple rare variants in complement genes. In aggregate, these data may help in directing clinical management of aHUS.

Characterization of the hemodynamic response function across the majority of human cerebral cortex.

A brief (<4 s) period of neural activation evokes a stereotypical sequence of vascular and metabolic events to create the hemodynamic response function (HRF) measured using functional magnetic resonance imaging (fMRI). Linear analysis of fMRI data requires that the HRF be treated as an impulse response, so the character and temporal stability of the HRF are critical issues. Here, a simple audiovisual stimulus combined with a fast-paced task was used to evoke a strong HRF across a majority, ∼77%, of cortex during a single scanning session. High spatiotemporal resolution (2-mm voxels, 1.25-s acquisition time) was used to focus HRF measurements specifically on the gray matter for whole brain. The majority of activated cortex responds with positive HRFs, while ∼27% responds with negative (inverted) HRFs. Spatial patterns of the HRF response amplitudes were found to be similar across subjects. Timing of the initial positive lobe of the HRF was relatively stable across the cortical surface with a mean of 6.1 ±â€¯0.6 s across subjects, yet small but significant timing variations were also evident in specific regions of cortex. The results provide guidance for linear analysis of fMRI data. More importantly, this method provides a means to quantify neurovascular function across most of the brain, with potential clinical utility for the diagnosis of brain pathologies such as traumatic brain injury.