Delayed tranexamic acid after traumatic brain injury impedes learning and memory: Early tranexamic acid is favorable but not in sham animals.

BACKGROUND: Early but not late tranexamic acid (TXA) after TBI preserves blood-brain-barrier integrity, but it is unclear if and how dose timing affects cognitive recovery beyond hours postinjury. We hypothesized that early (1 hour post-TBI) but not late (24 hours post-TBI) TXA administration improves cognitive recovery for 14 days. METHODS: CD1 male mice (n = 25) were randomized to severe TBI (injury [I], by controlled cortical impact) or sham craniotomy (S) followed by intravenous saline at 1 hour (placebo [P1]) or 30 mg/kg TXA at 1 hour (TXA1) or 24 hours (TXA24). Daily body weights, Garcia Neurological Test scores, brain/lung water content, and Morris water maze exercises quantifying swimming traffic in the platform quadrant (zone [Z] 1) and platform area (Z5) were recorded for up to 14 days. RESULTS: Among injured groups, I-TXA1 demonstrated fastest weight gain for 14 days and only I-TXA1 showed rapid (day 1) normalization of Garcia Neurological Test ( p = 0.01 vs. I-P1, I-TXA24). In cumulative spatial trials, compared with I-TXA1, I-TXA24 hindered learning (distance to Z5 and % time in Z1, p < 0.05). Compared with I-TXA1, I-TXA24 showed poorer memory with less Z5 time (0.51 vs. 0.16 seconds, p < 0.01) and Z5 crossing frequency. Unexpectedly, TXA in uninjured animals (S-TXA1) displayed faster weight gain but inferior learning and memory. CONCLUSION: Early TXA appears beneficial for cognitive and behavioral outcomes following TBI, although administration 24 hours postinjury consistently impairs cognitive recovery. Tranexamic acid in sham animals may lead to adverse effects on cognition.

Time-dependent homeostatic mechanisms underlie brain-derived neurotrophic factor action on neural circuitry.

Plasticity and homeostatic mechanisms allow neural networks to maintain proper function while responding to physiological challenges. Despite previous work investigating morphological and synaptic effects of brain-derived neurotrophic factor (BDNF), the most prevalent growth factor in the central nervous system, how exposure to BDNF manifests at the network level remains unknown. Here we report that BDNF treatment affects rodent hippocampal network dynamics during development and recovery from glutamate-induced excitotoxicity in culture. Importantly, these effects are not obvious when traditional activity metrics are used, so we delve more deeply into network organization, functional analyses, and in silico simulations. We demonstrate that BDNF partially restores homeostasis by promoting recovery of weak and medium connections after injury. Imaging and computational analyses suggest these effects are caused by changes to inhibitory neurons and connections. From our in silico simulations, we find that BDNF remodels the network by indirectly strengthening weak excitatory synapses after injury. Ultimately, our findings may explain the difficulties encountered in preclinical and clinical trials with BDNF and also offer information for future trials to consider.

Provider Perceptions of Oxygenation Strategies for Critically Ill Trauma Patients With and Without Moderate-to-Severe Traumatic Brain Injury.

BACKGROUND: Hypoxia and hyperoxia (pulse oximetry [SpO2] > 96%) are associated with increased mortality in critically ill patients. However, provider practices regarding oxygenation in traumatic brain injury (TBI) patients are unknown. This study assesses views on oxygenation of critically ill trauma patients with and without TBI and how this varies between Neurological ICU (NeuroICU) and Surgical-Trauma ICU (STICU) providers. METHODS: This is a cross-sectional survey of Level I trauma center's NeuroICU and STICU providers. We used Likert scales, yes-no questions, and multiple-choice case-based scenarios to characterize provider views on oxygenation with descriptive statistics to characterize responses. Significant differences regarding TBI and non-TBI patients or NeuroICU and STICU providers were determined using Fisher's exact test and a P-value of .05. RESULTS: A total of 83 providers initiated the survey, and 53 providers completed it. Most providers identified a threshold SpO2 < 92% for the administration of supplemental oxygen in critically ill TBI patients. A total of 9% of providers "somewhat or completely agreed" that they were more likely to give supplemental oxygen to a critically ill trauma patient with TBI than one without TBI and the same SpO2. A total of 48% of providers selected an SpO2 < 90% as the point at which supplemental oxygen should be initiated in patients without TBI, compared to 27% of providers in patients with TBI (P < .01). This threshold for supplemental oxygen use varied by provider type for non-TBI patients, but not for TBI patients (30% NeuroICU and 69% STICU providers selected SpO2 < 90% in non-TBI, P < .05; 30% NeuroICU and 35% STICU providers selected SpO2 < 90% in TBI, P = .85). CONCLUSIONS: Critical care providers at UCHealth University of Colorado Hospital approach the oxygenation of critically ill trauma patients with and without TBI differently. Specifically, critical care respondents accepted a different lower oxygen saturation threshold for TBI and non-TBI patients. NeuroICU and STICU respondents differed in their threshold for the down-titration of supplemental oxygen. Targeted education for critical care providers may reduce these discrepancies and optimize oxygen use.

Serum C-terminal telopeptide of Type-I collagen (CTx) concentration and myocardial hyperechogenicity in cats with hypertrophic cardiomyopathy.

Objective: This study sought to determine the serum concentrations of C-terminal telopeptide of Type-I collagen (CTx), a marker of collagen degradation, in a hospital population of cats with hypertrophic cardiomyopathy (HCM). The study also evaluated the prevalence of myocardial hyperechogenicity of the left ventricle (LV) in the same cats. Animals and procedure: Cats brought to a university veterinary cardiology service entered the study when they had an echocardiographic diagnosis of HCM; echocardiographically normal cats served as controls. Serum CTx concentrations were assessed using ELISA. Results: There was no difference in serum CTx concentrations between cats with HCM and controls (HCM: median 0.248 ng/mL, controls: median 0.253 ng/mL; P = 0.4). Significantly more cats with HCM (60%) showed echocardiographic LV myocardial hyperechogenicity compared to normal controls (17%; P = 0.0057), but serum CTx concentrations were not different between these 2 groups. Conclusion and clinical relevance: These results indicate that, as in human patients with HCM and in contrast to earlier feline studies, there was no evidence of enhanced collagen degradation indicated by serum CTx concentrations in cats with HCM compared to normal controls.

Concentration sérique de télopeptide C-terminal du collagène de Type I (CTx) et hyperéchogénicité myocardique chez des chats atteints de cardiomyopathie hypertrophique. Objectif: Le premier objectif de cette étude était d'évaluer le taux sérique d'un marqueur de dégradation de collagène, soit le télopeptide C-terminal du collagène de Type-I (CTx), chez les chats atteints de cardiomyopathie hypertrophique (CMH). Le deuxième objectif était d'évaluer la prévalence de l'hyperéchogénicité du myocarde du ventricule gauche chez ces mêmes chats. Animaux et procédures: Les chats participant à l'étude avaient été présentés pour soins à un service de cardiologie vétérinaire universitaire, et ces chats avaient un diagnostic échocardiographique soit de CMH, soit d'aucune lésion cardiaque (groupe témoin). Le taux sérique de CTx a été évalué de façon immuno-enzymatique par ELISA. Résultats: Les résultats n'ont démontré aucune différence entre le taux sérique de CTx chez les chats atteint de CMH et le taux sérique de CTx chez les chats sans lésion cardiaque (CMH : médiane, 0,248 ng/mL; groupe témoin : médiane, 0,253 ng/mL; P = 0,4). Plus de chats atteints de CMH (60 %) que de chats dans le groupe témoin (17 %) ont démontré une hyperéchogénicité du myocarde du ventricule gauche à l'échocardiographie (P = 0,0057), quoique les taux sériques de CTx n'étaient pas différents entre ces 2 groupes. Conclusion et signification clinique: Ces résultats n'indiquent aucune augmentation de la dégradation de collagène chez les chats atteints de CMH, ce qui s'apparente aux résultats provenant d'études antérieures de la CMH chez l'humain mais non pas à ceux provenant d'études de la CMH féline.(Traduit par les auteurs).

Protocol and statistical analysis plan for the PREOXI trial of preoxygenation with noninvasive ventilation vs oxygen mask.

Background: Hypoxemia is a common and life-threatening complication during emergency tracheal intubation of critically ill adults. The administration of supplemental oxygen prior to the procedure ("preoxygenation") decreases the risk of hypoxemia during intubation. Research Question: Whether preoxygenation with noninvasive ventilation prevents hypoxemia during tracheal intubation of critically ill adults, compared to preoxygenation with oxygen mask, remains uncertain. Study Design and Methods: The PRagmatic trial Examining OXygenation prior to Intubation (PREOXI) is a prospective, multicenter, non-blinded randomized comparative effectiveness trial being conducted in 7 emergency departments and 17 intensive care units across the United States. The trial compares preoxygenation with noninvasive ventilation versus oxygen mask among 1300 critically ill adults undergoing emergency tracheal intubation. Eligible patients are randomized in a 1:1 ratio to receive either noninvasive ventilation or an oxygen mask prior to induction. The primary outcome is the incidence of hypoxemia, defined as a peripheral oxygen saturation <85% between induction and 2 minutes after intubation. The secondary outcome is the lowest oxygen saturation between induction and 2 minutes after intubation. Enrollment began on 10 March 2022 and is expected to conclude in 2023. Interpretation: The PREOXI trial will provide important data on the effectiveness of noninvasive ventilation and oxygen mask preoxygenation for the prevention of hypoxemia during emergency tracheal intubation. Specifying the protocol and statistical analysis plan prior to the conclusion of enrollment increases the rigor, reproducibility, and interpretability of the trial. Clinical trial registration number: NCT05267652.

Hyperoxia is associated with a greater risk for mortality in critically ill traumatic brain injury patients than in critically ill trauma patients without brain injury.

OBJECTIVE: The role of hyperoxia in patients with traumatic brain injury (TBI) remains controversial. The objective of this study was to determine the association between hyperoxia and mortality in critically ill TBI patients compared to critically ill trauma patients without TBI. DESIGN: Secondary analysis of a multicenter retrospective cohort study. SETTING: Three regional trauma centers in Colorado, USA, between October 1, 2015, and June 30, 2018. PATIENTS: We included 3464 critically injured adults who were admitted to an intensive care unit (ICU) within 24 h of arrival and qualified for inclusion into the state trauma registry. We analyzed all available SpO2 values during the first seven ICU days. The primary outcome was in-hospital mortality. Secondary outcomes included the proportion of time spent in hyperoxia (defined as SpO2 > 96%) and ventilator-free days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In-hospital mortality occurred in 163 patients (10.7%) in the TBI group and 101 patients (5.2%) in the non-TBI group. After adjusting for ICU length of stay, TBI patients spent a significantly greater amount of time in hyperoxia versus non-TBI patients (p = 0.024). TBI status significantly modified the effect of hyperoxia on mortality. At each specific SpO2 level, the risk of mortality increases with increasing FiO2 for both patients with and without TBI. This trend was more pronounced at lower FiO2 and higher SpO2 values, where a greater number of patient observations were obtained. Among patients who required invasive mechanical ventilation, TBI patients required significantly more days of ventilation to day 28 than non-TBI patients. CONCLUSIONS: Critically ill trauma patients with a TBI spend a greater proportion of time in hyperoxia compared to those without a TBI. TBI status significantly modified the effect of hyperoxia on mortality. Prospective clinical trials are needed to better assess a possible causal relationship.

Facial typicality and attractiveness reflect an ideal dimension of face structure.

Face perception and recognition are important processes for social interaction and communication among humans, so understanding how faces are mentally represented and processed has major implications. At the same time, faces are just some of the many stimuli that we encounter in our everyday lives. Therefore, more general theories of how we represent objects might also apply to faces. Contemporary research on the mental representation of faces has centered on two competing theoretical frameworks that arose from more general categorization research: prototype-based face representation and exemplar-based face representation. Empirically distinguishing between these frameworks is difficult and neither one has been ruled out. In this paper, we advance this area of research in three ways. First, we introduce two additional frameworks for mental representation of categories, varying abstraction and ideal representation, which have not been applied to face perception and recognition before. Second, we fit formal computational models of all four of these theories to human perceptual judgments of the typicality and attractiveness (a strong correlate of typicality) of 100 young adult Caucasian female faces, with the models expressed within a face space derived from facial similarity judgments via multidimensional scaling. Third, we predict the perceived typicality and attractiveness of the faces using these models and compare the predictive performance of each to the empirical data. We found that of all four models, the ideal representation model provided the best account of perceived typicality and attractiveness for the present set of faces, although all models showed discrepancies from the empirical data. These findings demonstrate the relevance of mental categorization processes for representing faces.

Overlooked Symptoms in Autoimmune Hepatitis Negatively Impact Many Facets of Life.

BACKGROUND: Significant reduction in quality of life among patients with autoimmune hepatitis (AIH) patients has been observed in several studies. While acute symptoms associated with AIH have been well described, little is known about the overall impact of living with AIH on patients' quality of life. The aim of this qualitative descriptive study was to describe the impact of AIH and associated symptoms on quality of life from the perspectives of patients living with AIH. METHODS: Patients from Autoimmune Hepatitis Association support groups were recruited to participate in one of five online focus groups conducted between August and September 2020. After enrollment, patients were asked to complete a brief demographic and disease history questionnaire. A single moderator conducted interviews with each group guided by seven questions focused on the impact of AIH on the participants' quality of life. Each session was recorded, transcribed, and verified. Content analysis was used to summarize the participants' responses. RESULTS: The participants' discussed three overarching topics: (a) symptoms of AIH and medication side effects, (b) the impact the disease and symptoms/side effects on five domains of quality of life (work life, relationships with friends and family, social life, leisure activities, and diet and exercise) and (c) interactions with healthcare providers and recommendations for future research. CONCLUSIONS: Living with AIH can have profound effects on patients' quality of life in several domains. Healthcare providers and the AIH research community should focus on developing further strategies that can improve the quality of life in persons suffering from AIH.

Acquired Systolic Dysfunction and Subsequent Congestive Heart Failure Following Treatment of Hypoadrenocorticism in Two Dogs.

Acquired cardiomyopathies have been described in human patients with hypoadrenocorticism. Several mechanisms have been described to explain the cardiac effects of primary adrenal insufficiency, but, clinically, these manifestations may be underappreciated in dogs. In humans, there is an infrequently described, reversible dilated cardiomyopathy in patients with hypoadrenocorticism. Two dogs were presented to a single referral center for evaluation of weakness or collapse and were subsequently diagnosed with hypoadrenocorticism after a full diagnostic workup. Following the diagnosis of hypoadrenocorticism and administration of glucocorticoids and desoxycorticosterone pivalate, both dogs developed left-sided congestive heart failure and had systolic dysfunction diagnosed by echocardiogram. Both dogs were euthanized; one because of recurrent congestive heart failure and another because of a concern for poor long-term prognosis and decreased quality of life. The purpose of this case report is to document multiple cases of hypoadrenocorticism-associated systolic dysfunction and subsequent cardiogenic pulmonary edema in dogs.

Concussion Prone Scenarios: A Multi-Dimensional Exploration in Impact Directions, Brain Morphology, and Network Architectures Using Computational Models.

While individual susceptibility to traumatic brain injury (TBI) has been speculated, past work does not provide an analysis considering how physical features of an individual's brain (e.g., brain size, shape), impact direction, and brain network features can holistically contribute to the risk of suffering a TBI from an impact. This work investigated each of these features simultaneously using computational modeling and analyses of simulated functional connectivity. Unlike the past studies that assess the severity of TBI based on the quantification of brain tissue damage (e.g., principal strain), we approached the brain as a complex network in which neuronal oscillations orchestrate to produce normal brain function (estimated by functional connectivity) and, to this end, both the anatomical damage location and its topological characteristics within the brain network contribute to the severity of brain function disruption and injury. To represent the variations in the population, we analyzed a publicly available database of brain imaging data and selected five distinct network architectures, seven different brain sizes, and three uniaxial head rotational conditions to study the consequences of 74 virtual impact scenarios. Results show impact direction produces the most significant change in connections across brain areas (structural connectome) and the functional coupling of activity across these brain areas (functional connectivity). Axial rotations were more injurious than those with sagittal and coronal rotations when the head kinematics were the same for each condition. When the impact direction was held constant, brain network architecture showed a significantly different vulnerability across axial and sagittal, but not coronal rotations. As expected, brain size significantly affected the expected change in structural and functional connectivity after impact. Together, these results provided groupings of predicted vulnerability to impact-a subgroup of male brain architectures exposed to axial impacts were most vulnerable, while a subgroup of female brain architectures was the most tolerant to the sagittal impacts studied. These findings lay essential groundwork for subject-specific analyses of concussion and provide invaluable guidance for designing personalized protection equipment.

Brain architecture-based vulnerability to traumatic injury.

The white matter tracts forming the intricate wiring of the brain are subject-specific; this heterogeneity can complicate studies of brain function and disease. Here we collapse tractography data from the Human Connectome Project (HCP) into structural connectivity (SC) matrices and identify groups of similarly wired brains from both sexes. To characterize the significance of these architectural groupings, we examined how similarly wired brains led to distinct groupings of neural activity dynamics estimated with Kuramoto oscillator models (KMs). We then lesioned our networks to simulate traumatic brain injury (TBI) and finally we tested whether these distinct architecture groups' dynamics exhibited differing responses to simulated TBI. At each of these levels we found that brain structure, simulated dynamics, and injury susceptibility were all related to brain grouping. We found four primary brain architecture groupings (two male and two female), with similar architectures appearing across both sexes. Among these groupings of brain structure, two architecture types were significantly more vulnerable than the remaining two architecture types to lesions. These groups suggest that mesoscale brain architecture types exist, and these architectural differences may contribute to differential risks to TBI and clinical outcomes across the population.

Scene saliencies in egocentric vision and their creation by parents and infants.

Across the lifespan, humans are biased to look first at what is easy to see, with a handful of well-documented visual saliences shaping our attention (e.g., Itti & Koch, 2001). These attentional biases may emerge from the contexts in which moment-tomoment attention occurs, where perceivers and their social partners actively shape bottom-up saliences, moving their bodies and objects to make targets of interest more salient. The goal of the present study was to determine the bottom-up saliences present in infant egocentric images and to provide evidence on the role that infants and their mature social partners play in highlighting targets of interest via these saliences. We examined 968 unique scenes in which an object had purposefully been placed in the infant's egocentric view, drawn from videos created by one-year-old infants wearing a head camera during toy-play with a parent. To understand which saliences mattered in these scenes, we conducted a visual search task, asking participants (n = 156) to find objects in the egocentric images. To connect this to the behaviors of perceivers, we then characterized the saliences of objects placed by infants or parents compared to objects that were otherwise present in the scenes. Our results show that body-centric properties, such as increases in the centering and visual size of the object, as well as decreases in the number of competing objects immediately surrounding it, both predicted faster search time and distinguished placed and unplaced objects. The present results suggest that the bottom-up saliences that can be readily controlled by perceivers and their social partners may most strongly impact our attention. This finding has implications for the functional role of saliences in human vision, their origin, the social structure of perceptual environments, and how the relation between bottom-up and top-down control of attention in these environments may support infant learning.

Age-specific impacts of nicotine and withdrawal on hippocampal neuregulin signalling.

Smoking remains the leading cause of preventable death in the United States, with 87% of smokers starting before the age of 18. Age of initiation is a major predictive factor for smoking frequency and successful smoking cessation. People who initiate smoking during adolescences are 2.33 times more likely to become heavy smokers and half as likely to quit compared with smokers who started during adulthood. Additionally, schizophrenia, a disease state linked to altered neurodevelopment during adolescence, is a major predictive factor for smoking status. Smoking rates among people suffering from schizophrenia are between 60% and 90%. Interestingly, the Neuregulin Signalling Pathway (NSP), which plays an important role in neurodevelopment, is implicated in both schizophrenia and nicotine use disorder. Specifically, SNPS in neuregulin 3 (Nrg3) and Erb-B2 Receptor Tyrosine Kinase 4 (ErbB4) have been associated with smoking cessation outcomes and schizophrenia. Here, we examine the effects of chronic nicotine (18 mg/kg/day) and 24-h withdrawal on NSP gene expression in the hippocampus of adult (20-week-old) and adolescent (4-week-old) mice. We show that withdrawal from chronic nicotine decreased the expression of Erbb4 mRNA in the hippocampus of the adult mice but increased the expression of cytosolic Erbb4 protein in adolescent mice. Nrg3 mRNA and protein expression was not altered by chronic nicotine or withdrawal in the adult or adolescent cohorts, but Nrg3 mRNA and synaptosomal protein expression was lower in the adult withdrawal group when compared with their adolescent counterparts. These results highlight the age-specific effects of nicotine withdrawal on the NSP and may contribute to the lower quit rate and higher cigarette consumption of smokers who initiation during adolescences.

Pseudomonas aeruginosa Alters Peptidoglycan Composition under Nutrient Conditions Resembling Cystic Fibrosis Lung Infections.

Epidemic strains of Pseudomonas aeruginosa are highly virulent opportunistic pathogens with increased transmissibility and enhanced antimicrobial resistance. Understanding the cellular mechanisms behind this heightened virulence and resistance is critical. Peptidoglycan (PG) is an integral component of P. aeruginosa cells that is essential to its survival and a target for antimicrobials. Here, we examined the global PG composition of two P. aeruginosa epidemic strains, LESB58 and LESlike1, and compared them to the common laboratory strains PAO1 and PA14. We also examined changes in PG composition when the strains were cultured under nutrient conditions that resembled cystic fibrosis lung infections. We identified 448 unique muropeptides and provide the first evidence for stem peptides modified with O-methylation, meso-diaminopimelic acid (mDAP) deamination, and novel substitutions of mDAP residues within P. aeruginosa PG. Our results also present the first evidence for both d,l- and l,d-endopeptidase activity on the PG sacculus of a Gram-negative organism. The PG composition of the epidemic strains varied significantly when grown under conditions resembling cystic fibrosis (CF) lung infections, showing increases in O-methylated stem peptides and decreases in l,d-endopeptidase activity as well as an increased abundance of de-N-acetylated sugars and l,d-transpeptidase activity, which are related to bacterial virulence and antibiotic resistance, respectively. We also identified strain-specific changes where LESlike1 increased the addition of unique amino acids to the terminus of the stem peptide and LESB58 increased amidase activity. Overall, this study demonstrates that P. aeruginosa PG composition is primarily influenced by nutrient conditions that mimic the CF lung; however, inherent strain-to-strain differences also exist. IMPORTANCE Using peptidoglycomics to examine the global composition of the peptidoglycan (PG) allows insights into the enzymatic activity that functions on this important biopolymer. Changes within the PG structure have implications for numerous physiological processes, including virulence and antimicrobial resistance. The identification of highly unique PG modifications illustrates the complexity of this biopolymer in Pseudomonas aeruginosa. Analyzing the PG composition of clinical P. aeruginosa epidemic strains provides insights into the increased virulence and antimicrobial resistance of these difficult-to-eradicate infections.

Effects of dexmedetomidine and its reversal with atipamezole on echocardiographic measurements and circulating cardiac biomarker concentrations in normal cats.

OBJECTIVE: To investigate the effects of dexmedetomidine (DXM) and its subsequent reversal with atipamezole (APM) on the echocardiogram and circulating concentrations of cardiac biomarkers in cats. ANIMALS: 14 healthy cats. PROCEDURES: Cats underwent echocardiography and measurements of circulating cTn-I and NT-proBNP concentrations before (PRE) and during (INTRA) DXM sedation (40 µg/kg IM) and 2 to 4 (2H POST) and 24 (24H POST) hours after reversal with APM. RESULTS: Administering DXM significantly decreased heart rate, right ventricular and left ventricular (LV) outflow tract velocities, and M-mode-derived LV free-wall thickness; increased LV end systolic diameter and volume; and caused valvar regurgitation. While sedative effects resolved within 25 minutes of APM reversal, the evolution of echocardiographic changes was mixed: LV ejection fraction and mitral valvar regurgitation score were different at 2H POST than at both INTRA and PRE (partial return toward baseline), LV end-diastolic volume was different PRE to INTRA and INTRA to 2H POST but not different PRE to 2H POST (full return toward baseline), and M-mode-derived LV free-wall thickness was significantly different from PRE to INTRA and PRE to 2H POST (no return toward baseline). Serum cTn-I and plasma NT-proBNP concentrations increased significantly with DXM, which remained significant 2H POST. CLINICAL RELEVANCE: Administration of DXM and APM reversal produced changes in echocardiographic results and in circulating cTn-I and NT-proBNP concentrations. Understanding these changes could help veterinarians differentiate drug effects from cardiac disease.

WT1 complete gonadal dysgenesis with membranoproliferative glomerulonephritis: case series and literature review.

BACKGROUND: Intronic WT1 mutations are usually causative of Frasier syndrome with focal segmental glomerulosclerosis as the characteristic nephropathy. Membranoproliferative glomerulonephritis is not commonly associated with disorders of sex development but has been recently identified as a WT1-associated nephropathy, but usually in cases of exonic mutations in either isolated Wilms tumor or Denys-Drash syndrome. METHODS: The clinical and genetic data from 3 individuals are reported. RESULTS: This report describes the kidney manifestations in 3 individuals from 2 unrelated families with Frasier syndrome intronic WT1 mutations, noting that 2 of the 3 individuals have histologically confirmed membranoproliferative glomerulonephritis. CONCLUSIONS: These case reports support expansion of the clinical spectrum of the kidney phenotypes associated with Frasier syndrome providing evidence of an association between WT1 mutation and an immune complex-related membranoproliferative glomerulonephritis. A higher resolution version of the Graphical abstract is available as Supplementary information.

The practice of genomic medicine: A delineation of the process and its governing principles.

Genomic medicine, an emerging medical discipline, applies the principles of evolution, developmental biology, functional genomics, and structural genomics within clinical care. Enabling widespread adoption and integration of genomic medicine into clinical practice is key to achieving precision medicine. We delineate a biological framework defining diagnostic utility of genomic testing and map the process of genomic medicine to inform integration into clinical practice. This process leverages collaboration and collective cognition of patients, principal care providers, clinical genomic specialists, laboratory geneticists, and payers. We detail considerations for referral, triage, patient intake, phenotyping, testing eligibility, variant analysis and interpretation, counseling, and management within the utilitarian limitations of health care systems. To reduce barriers for clinician engagement in genomic medicine, we provide several decision-making frameworks and tools and describe the implementation of the proposed workflow in a prototyped electronic platform that facilitates genomic care. Finally, we discuss a vision for the future of genomic medicine and comment on areas for continued efforts.

Tbx5a and Tbx5b paralogues act in combination to control separate vectors of migration in the fin field of zebrafish.

The T-box containing family member, TBX5, has been shown to play important functional roles in the pectoral appendages of a variety of vertebrate species. While a single TBX5 gene exists in all tetrapods studied to date, the zebrafish genome retains two paralogues, designated as tbx5a and tbx5b, resulting from a whole genome duplication in the teleost lineage. Zebrafish deficient in tbx5a lack pectoral fin buds, whereas zebrafish deficient in tbx5b exhibit misshapen pectoral fins, showing that both paralogues function in fin development. The mesenchymal cells of the limb/fin bud are derived from the Lateral Plate Mesoderm (LPM). Previous fate mapping work in zebrafish has shown that wildtype (wt) fin field cells are initially located adjacent to somites (s)1-4. The wt fin field cells migrate in opposing diagonal directions placing the limb bud between s2-3 and lateral to the main body. To better characterize tbx5 paralogue functions in zebrafish, time-lapse analyses of the migrations of fin bud precursors under conditions of tbx5a knock-down, tbx5b knock-down and double-knock-down were performed. Our data suggest that zebrafish tbx5a and tbx5b have functionally separated migration direction vectors, that when combined recapitulate the migration of the wt fin field. We and others have shown that loss of Tbx5a function abolishes an fgf24 signaling cue resulting in fin field cells failing to converge in an Antero-Posterior (AP) direction and migrating only in a mediolateral (ML) direction. We show here that loss of Tbx5b function affects initial ML directed movements so that fin field cells fail to migrate laterally but continue to converge along the AP axis. Furthermore, fin field cells in the double Tbx5a/Tbx5b knock-down zebrafish do not engage in directed migrations along either the ML or AP axis. Therefore, these two paralogues may be acting to instruct separate vectors of fin field migration in order to direct proper fin bud formation.

No evidence for language benefits in infant relational learning.

Recent studies have found that infants show relational learning in the first year. Like older children, they can abstract relations such as same or different across a series of exemplars. For older children, language has a major impact on relational learning: labeling a shared relation facilitates learning, while labeling component objects can disrupt learning. Here we ask: Does language influence relational learning at 12 months? Experiment 1 (n = 64) examined the influence of a relational label on learning. Prior to the study, the infants saw three pairs of objects, all labeled "These are same" or "These are different". Experiment 2 (n = 48) examined the influence of object labels prior to the study, with three objects labeled (e.g., "This is a cup, this is a tower."). We compared the present results with those of Ferry et al. (2015), where infants abstracted same and different relations after undergoing a similar paradigm without prior labels. If the effects of language mirror those in older children, we would expect that infants given relational labels (Experiment 1) will be helped in abstracting same and different compared to infants not given labels and that infants given object labels (Experiment 2) will be hindered relative to those not given labels. We found no evidence for either prediction. In Experiment 1, infants who had heard relational labels did not benefit compared to infants who had received no labels (Ferry et al., 2015). In Experiment 2, infants who had heard object labels showed the same patterns as those in Ferry et al. (2015), suggesting that object labels had no effect. This finding is important because it highlights a key difference between the relational learning abilities of infants and those seen in older children, pointing to a protracted process by which language and relational learning become entwined.

A multicenter cluster randomized, stepped wedge implementation trial for targeted normoxia in critically ill trauma patients: study protocol and statistical analysis plan for the Strategy to Avoid Excessive Oxygen (SAVE-O2) trial.

BACKGROUND: Targeted normoxia (SpO2 90-96% or PaO2 60-100 mmHg) may help to conserve oxygen and improve outcomes in critically ill patients by avoiding potentially harmful hyperoxia. However, the role of normoxia for critically ill trauma patients remains uncertain. The objective of this study is to describe the study protocol and statistical analysis plan for the Strategy to Avoid Excessive Oxygen for Critically Ill Trauma Patients (SAVE-O2) clinical trial. METHODS: Design, setting, and participants: Protocol for a multicenter cluster randomized, stepped wedge implementation trial evaluating the effectiveness of a multimodal intervention to target normoxia in critically ill trauma patients at eight level 1 trauma centers in the USA. Each hospital will contribute pre-implementation (control) and post-implementation (intervention) data. All sites will begin in the control phase with usual care. When sites reach their randomly assigned time to transition, there will be a one-month training period, which does not contribute to data collection. Following the 1-month training period, the site will remain in the intervention phase for the duration of the trial. MAIN OUTCOME MEASURES: The primary outcome will be supplemental oxygen-free days, defined as the number of days alive and not on supplemental oxygen. Secondary outcomes include in-hospital mortality to day 90, hospital-free days to day 90, ventilator-free days (VFD) to day 28, time to room air, Glasgow Outcome Score (GOS), and duration of time receiving supplemental oxygen. DISCUSSION: SAVE-O2 will determine if a multimodal intervention to improve compliance with targeted normoxia will safely reduce the need for concentrated oxygen for critically injured trauma patients. These data will inform military stakeholders regarding oxygen requirements for critically injured warfighters, while reducing logistical burden in prolonged combat casualty care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04534959 . Registered September 1, 2020.