Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model.

Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome. We examined widespread alterations in functional connectivity following TBI using simultaneous widefield mesoscale GCaMP7c calcium imaging and electrocorticography (ECoG) in mice injured using the controlled cortical impact (CCI) model of TBI. Combining CCI with widefield cortical imaging provides us with unprecedented access to characterize network connectivity changes throughout the entire injured cortex over time. Our data demonstrate that CCI profoundly disrupts functional connectivity immediately after injury, followed by partial recovery over 3 weeks. Examining discrete periods of locomotion and stillness reveals that CCI alters functional connectivity and reduces theta power only during periods of behavioral stillness. Together, these findings demonstrate that TBI causes dynamic, behavioral state-dependent changes in functional connectivity and ECoG activity across the cortex.

Deep behavioural phenotyping of the Q175 Huntington disease mouse model: effects of age, sex, and weight.

BACKGROUND: Huntington disease (HD) is a neurodegenerative disorder with complex motor and behavioural manifestations. The Q175 knock-in mouse model of HD has gained recent popularity as a genetically accurate model of the human disease. However, behavioural phenotypes are often subtle and progress slowly in this model. Here, we have implemented machine-learning algorithms to investigate behaviour in the Q175 model and compare differences between sexes and disease stages. We explore distinct behavioural patterns and motor functions in open field, rotarod, water T-maze, and home cage lever-pulling tasks. RESULTS: In the open field, we observed habituation deficits in two versions of the Q175 model (zQ175dn and Q175FDN, on two different background strains), and using B-SOiD, an advanced machine learning approach, we found altered performance of rearing in male manifest zQ175dn mice. Notably, we found that weight had a considerable effect on performance of accelerating rotarod and water T-maze tasks and controlled for this by normalizing for weight. Manifest zQ175dn mice displayed a deficit in accelerating rotarod (after weight normalization), as well as changes to paw kinematics specific to males. Our water T-maze experiments revealed response learning deficits in manifest zQ175dn mice and reversal learning deficits in premanifest male zQ175dn mice; further analysis using PyMouseTracks software allowed us to characterize new behavioural features in this task, including time at decision point and number of accelerations. In a home cage-based lever-pulling assessment, we found significant learning deficits in male manifest zQ175dn mice. A subset of mice also underwent electrophysiology slice experiments, revealing a reduced spontaneous excitatory event frequency in male manifest zQ175dn mice. CONCLUSIONS: Our study uncovered several behavioural changes in Q175 mice that differed by sex, age, and strain. Our results highlight the impact of weight and experimental protocol on behavioural results, and the utility of machine learning tools to examine behaviour in more detailed ways than was previously possible. Specifically, this work provides the field with an updated overview of behavioural impairments in this model of HD, as well as novel techniques for dissecting behaviour in the open field, accelerating rotarod, and T-maze tasks.

Advanced glycated end-products inhibit dilation through constitutive endothelial RAGE and Nox1/4 in rat isolated skeletal muscle arteries.

OBJECTIVE: This study investigated the actions of advanced glycated end-products (AGE), their receptors (RAGE), and NAD(P)H oxidase (Nox) subtypes 1, 2, and 4 on mechanisms of endothelium-dependent dilation of the rat cremaster muscle artery (CMA). METHODS: Immunofluorescence studies were used to examine expression of RAGE in rat arteries. ROS accumulation was measured using luminescence and fluorescence assays. Functional studies were performed using pressure myography. RESULTS: High levels of RAGE expression were shown in the endothelial cells of the CMA, compared with low endothelial expression in middle cerebral and mesenteric arteries and the aorta. Exogenous AGE (in vitro glycated bovine serum albumin) stimulated H2O2 accumulation in CMA, which was prevented by the RAGE antagonist FPS-ZM1, the NAD(P)H oxidase (Nox) inhibitor apocynin and inhibited by the Nox1/4 inhibitor setanaxib, but not the Nox2 inhibitor GSK2795039. In functional studies, AGE inhibited vasodilation of CMA stimulated by acetylcholine, sodium nitroprusside, and the BKCa activator NS1619, but not adenosine-induced dilation. FPS-ZM1, apocynin, and setanaxib prevented the inhibitory effects of AGE on responses to acetylcholine and NS-1619. CONCLUSION: These observations suggest RAGE are constitutively expressed in the endothelium of the rat CMA and may be activated by AGE to stimulate Nox1/4 and ROS formation with resulting inhibition of NO and BKCa-mediated endothelium-dependent dilation.

A three-dimensional virtual mouse generates synthetic training data for behavioral analysis.

We developed a three-dimensional (3D) synthetic animated mouse based on computed tomography scans that is actuated using animation and semirandom, joint-constrained movements to generate synthetic behavioral data with ground-truth label locations. Image-domain translation produced realistic synthetic videos used to train two-dimensional (2D) and 3D pose estimation models with accuracy similar to typical manual training datasets. The outputs from the 3D model-based pose estimation yielded better definition of behavioral clusters than 2D videos and may facilitate automated ethological classification.

Magnetic Resonance Imaging Indirect Signs for Anterior Instability of the Lateral Meniscus in Pediatric and Adolescent Patients.

BACKGROUND: Anterior instability (AI) of the LM is potentially debilitating in young patients. The use of magnetic resonance imaging (MRI) to diagnose AI is limited due to the lack of reliable and accurate MRI findings. The ability to identify AI preoperatively would potentially improve the diagnosis and treatment of this pathology. This study presents a novel MRI finding ("phantom sign") for the detection of AI of the LM and demonstrates its reliability and accuracy. METHODS: Three independent blinded reviewers performed retrospective review of preoperative MRI for all patients who underwent LM repair between July 1, 2019, and March 31, 2022, at a single center. Positive phantom sign was defined as abnormal signal intensity on MRI of the anterior horn of the LM on the coronal sequence at the anterior tibial insertion of the anterior cruciate ligament (ACL). Preoperative MRI was also evaluated for other signs of LM anterior instability. Intrarater and inter-rater reliability was assessed for rater scoring of presence of pathology on MRI. Predictive ability of each imaging finding with at least good (ICC 0.6 or above) reliability was also evaluated based on documented intraoperative findings. RESULTS: Fifty-five preoperative MRIs of arthroscopically treated LM tears were reviewed. Median age was 15 years (range 6 to 20), and 21 patients (38.2%) were female. Twenty-seven patients (49.1%) had a discoid meniscus. LM AI was present on arthroscopy for 25 knees (45.45%), and among these, 21 had discoid morphology. Interrater reliability was substantial for phantom sign (ICC 0.71, 97.5% CI: 0.55-0.82), posterior displacement (ICC 0.71, 97.5% CI: 0.55-0.82), and posterior "megahorn" (ICC 0.76, 97.5% CI: 0.62-0.85). On predictive analysis, phantom signs were 98% sensitive and 76.7% specific for LM AI. Posterior displacement and posterior megahorn were specific for AI (both 93.34%), though with limited sensitivity (32% and 28.6%, respectively). CONCLUSIONS: Phantom sign is a reliable and sensitive MRI finding for anterior instability, even in the absence of frank displacement on preoperative MRI. A positive finding should prompt a thorough arthroscopic evaluation of the anterior horn of the LM. LEVEL OF EVIDENCE: Level III-case control study.

Retrieval of renal function after renal artery stenting improves event-free survival in a subgroup analysis of the Cardiovascular Outcomes in Renal Atherosclerotic Lesions trial.

OBJECTIVE: The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, a multicenter randomized controlled trial with 947 patients, concluded that there was no benefit of renal artery stenting (RAS) over medical therapy. However, patients with chronic kidney disease (CKD) were not analyzed separately in the CORAL trial. CKD is a risk factor for cardiovascular and renal morbidity. We hypothesized that improved renal function after RAS would be associated with increased long-term survival and a lower risk of cardiovascular and renal events in patients with CKD. METHODS: This post hoc analysis of the CORAL trial included 842 patients with CKD stages 2 to 4 at baseline who were randomized to optimal medical therapy alone (OMT; n = 432) or RAS plus OMT (RAS + OMT; n = 410). Patients were categorized as responders or nonresponders based on the change in the estimated glomerular filtration rate (eGFR) from baseline to last follow-up (median, 3.6 years; interquartile range, 2.6-4.6 years). Responders were defined by a 20% or greater increase in eGFR from baseline; all others were designated as nonresponders. Event-free survival was defined as freedom from death and multiple cardiovascular and renal complications. Event-free survival was analyzed using the Kaplan-Meier method and log-rank test. Multivariable Cox proportional hazards regression analysis was used to identify independent predictors of event-free survival. RESULTS: The RAS + OMT group had a higher proportion of patients with improved renal function (≥20% increase in eGFR over baseline), compared with the OMT group (25.6% vs 17.1%; P = .003). However, event-free survival was no different for the two cohorts (P = .18 by the log-rank test). Multivariable Cox proportional hazards regression analysis identified four variables that independently correlated with event-free survival for the stented cohort. Higher preoperative eGFR (hazard ratio, 0.98; 95% confidence interval [CI], 0.96-0.99; P = .002) and being a responder to stenting (hazard ratio, 0.49; 95% CI, 0.26-0.95; P = .033) increased event-free survival, whereas a history of congestive heart failure (hazard ratio, 2.52; 95% CI, 1.46-4.35; P < .001) and a higher preoperative systolic BP (hazard ratio, 1.02; 95% CI, 1.01-1.03; P = .002) decreased event-free survival. Within the stented group, 105 of 410 patients (25.6%) were responders. Event-free survival was superior for responders, compared with nonresponders (P = .009 by log-rank test). The only independent preoperative negative predictor of improved renal function after stenting was diabetes (odds ratio, 0.37; 95% CI, 0.16-0.84; P = .017), which decreased the probability of improved renal function after RAS + OMT. A subset of patients (23.4%) after RAS had worsened renal function, but OMT alone produced an equivalent incidence of worsened renal function. An increased urine albumin/creatinine ratio was an independent predictor of worsened renal function after RAS. CONCLUSIONS: CORAL participants who demonstrated improved kidney function after RAS + OMT demonstrated improved event-free survival. This finding reinforces the need for predictors of outcome to guide patient selection for RAS.

Degendering Parents on Birth Certificates.

Birth certificates typically designate parents as "mothers" or "fathers," although some US states offer nongendered designations. The authors argue that gendered characterizations offer scant legal or moral value and that states should move to degender parental status on birth certificates but retain that information in registrations of birth. Registrations of birth identify the person giving birth to a child, when, and where, and they report demographic and health information useful for civic and public health purposes. Birth certificates typically report a child's name, sex, date and location of birth, and parentage so far as known. As documents establishing parents' standing in relation to children and vice versa, as well as age and presumptive citizenship, birth certificates add no legal or moral value by gendering parents. Gendering parents on birth certificates obliges the state to rely on exclusionary criteria of "mother" and "father." By contrast, degendering parental status withdraws the need for such criteria and confers benefits on people with transgender and nonbinary identities, as well as undercutting any problematic presumption that parents have responsibilities to their children qua mother or qua father.

Altered cortical processing of sensory input in Huntington disease mouse models.

Huntington disease (HD), a hereditary neurodegenerative disorder, manifests as progressively impaired movement and cognition. Although early abnormalities of neuronal activity in striatum are well established in HD models, there are fewer in vivo studies of the cortex. Here, we record local field potentials (LFPs) in YAC128 HD model mice versus wild-type mice. In multiple cortical areas, limb sensory stimulation evokes a greater change in LFP power in YAC128 mice. Mesoscopic imaging using voltage-sensitive dyes reveals more extensive spread of evoked sensory signals across the cortical surface in YAC128 mice. YAC128 layer 2/3 sensory cortical neurons ex vivo show increased excitatory events, which could contribute to enhanced sensory responses in vivo. Cortical LFP responses to limb stimulation, visual and auditory input are also significantly increased in zQ175 HD mice. Results presented here extend knowledge of HD beyond ex vivo studies of individual neurons to the intact cortical network.

Podocalyxin is required for maintaining blood-brain barrier function during acute inflammation.

Podocalyxin (Podxl) is broadly expressed on the luminal face of most blood vessels in adult vertebrates, yet its function on these cells is poorly defined. In the present study, we identified specific functions for Podxl in maintaining endothelial barrier function. Using electrical cell substrate impedance sensing and live imaging, we found that, in the absence of Podxl, human umbilical vein endothelial cells fail to form an efficient barrier when plated on several extracellular matrix substrates. In addition, these monolayers lack adherens junctions and focal adhesions and display a disorganized cortical actin cytoskeleton. Thus, Podxl has a key role in promoting the appropriate endothelial morphogenesis required to form functional barriers. This conclusion is further supported by analyses of mutant mice in which we conditionally deleted a floxed allele of Podxl in vascular endothelial cells (vECs) using Tie2Cre mice (PodxlΔTie2Cre). Although we did not detect substantially altered permeability in naïve mice, systemic priming with lipopolysaccharide (LPS) selectively disrupted the blood-brain barrier (BBB) in PodxlΔTie2Cre mice. To study the potential consequence of this BBB breach, we used a selective agonist (TFLLR-NH2) of the protease-activated receptor-1 (PAR-1), a thrombin receptor expressed by vECs, neuronal cells, and glial cells. In response to systemic administration of TFLLR-NH2, LPS-primed PodxlΔTie2Cre mice become completely immobilized for a 5-min period, coinciding with severely dampened neuroelectric activity. We conclude that Podxl expression by CNS tissue vECs is essential for BBB maintenance under inflammatory conditions.

Effects of tracker location on the accuracy and precision of the Gazepoint GP3 HD for spectacle wearers.

Remote view eye-tracking systems are prone to errors when used on spectacle wearers due to reflections from the lenses and frame that result in inaccurate tracking. Traditionally, these trackers are situated below a computer monitor and the viewer's eye moments are recorded while they view the screen. Reflections may be influenced by the pantoscopic tilt of the spectacles, whereby the tilt angle causes incident light to be reflected to the camera. To overcome this problem, we propose mounting the tracker above the monitor to avoid these reflections and test the accuracy and precision of subjects with single vision spectacles, multifocals, and no correction, using both mounting positions. Experimental results showed that this alternate position had overall worse accuracy (4.06° ± 0.13) and precision (0.67° ± 0.05) compared to the standard configuration (2.15° ± 0.06 vs. 0.50° ± 0.03), with more invalid readings (5.91 vs. 19.19%) for single vision lens wearers. Multifocals performed better for the top-mounting position for the top portion of the monitor, suggesting higher-order aberrations from the bottom portion of the lens negatively impact data quality. Higher pantoscopic tilt angles displayed an improved accuracy for this alternate position (r(9) = - 0.69, p = 0.02), with superior accuracy for tilt angles greater than 14° compared to the standard configuration. This study quantifies the impact of spectacle wear on eye-tracking performance and suggests other alternate mounting positions may be viable in certain situations.

Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease.

Nontypeable Haemophilus influenzae (NTHi) exclusively colonize and infect humans and are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD). In vitro and animal models do not accurately capture the complex environments encountered by NTHi during human infection. We conducted whole-genome sequencing of 269 longitudinally collected cleared and persistent NTHi from a 15-y prospective study of adults with COPD. Genome sequences were used to elucidate the phylogeny of NTHi isolates, identify genomic changes that occur with persistence in the human airways, and evaluate the effect of selective pressure on 12 candidate vaccine antigens. Strains persisted in individuals with COPD for as long as 1,422 d. Slipped-strand mispairing, mediated by changes in simple sequence repeats in multiple genes during persistence, regulates expression of critical virulence functions, including adherence, nutrient uptake, and modification of surface molecules, and is a major mechanism for survival in the hostile environment of the human airways. A subset of strains underwent a large 400-kb inversion during persistence. NTHi does not undergo significant gene gain or loss during persistence, in contrast to other persistent respiratory tract pathogens. Amino acid sequence changes occurred in 8 of 12 candidate vaccine antigens during persistence, an observation with important implications for vaccine development. These results indicate that NTHi alters its genome during persistence by regulation of critical virulence functions primarily by slipped-strand mispairing, advancing our understanding of how a bacterial pathogen that plays a critical role in COPD adapts to survival in the human respiratory tract.

Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis.

BACKGROUND: The post-thrombotic syndrome frequently develops in patients with proximal deep-vein thrombosis despite treatment with anticoagulant therapy. Pharmacomechanical catheter-directed thrombolysis (hereafter "pharmacomechanical thrombolysis") rapidly removes thrombus and is hypothesized to reduce the risk of the post-thrombotic syndrome. METHODS: We randomly assigned 692 patients with acute proximal deep-vein thrombosis to receive either anticoagulation alone (control group) or anticoagulation plus pharmacomechanical thrombolysis (catheter-mediated or device-mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration, with or without stenting). The primary outcome was development of the post-thrombotic syndrome between 6 and 24 months of follow-up. RESULTS: Between 6 and 24 months, there was no significant between-group difference in the percentage of patients with the post-thrombotic syndrome (47% in the pharmacomechanical-thrombolysis group and 48% in the control group; risk ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.11; P=0.56). Pharmacomechanical thrombolysis led to more major bleeding events within 10 days (1.7% vs. 0.3% of patients, P=0.049), but no significant difference in recurrent venous thromboembolism was seen over the 24-month follow-up period (12% in the pharmacomechanical-thrombolysis group and 8% in the control group, P=0.09). Moderate-to-severe post-thrombotic syndrome occurred in 18% of patients in the pharmacomechanical-thrombolysis group versus 24% of those in the control group (risk ratio, 0.73; 95% CI, 0.54 to 0.98; P=0.04). Severity scores for the post-thrombotic syndrome were lower in the pharmacomechanical-thrombolysis group than in the control group at 6, 12, 18, and 24 months of follow-up (P<0.01 for the comparison of the Villalta scores at each time point), but the improvement in quality of life from baseline to 24 months did not differ significantly between the treatment groups. CONCLUSIONS: Among patients with acute proximal deep-vein thrombosis, the addition of pharmacomechanical catheter-directed thrombolysis to anticoagulation did not result in a lower risk of the post-thrombotic syndrome but did result in a higher risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute and others; ATTRACT ClinicalTrials.gov number, NCT00790335 .).

Final Two-Year Outcomes for the Sentry Bioconvertible Inferior Vena Cava Filter in Patients Requiring Temporary Protection from Pulmonary Embolism.

PURPOSE: To report final 2-year outcomes with the Sentry bioconvertible inferior vena cava (IVC) filter in patients requiring temporary protection against pulmonary embolism (PE). MATERIALS AND METHODS: In a prospective multicenter trial, the Sentry filter was implanted in 129 patients with documented deep vein thrombosis (DVT) and/or PE (67.5%) or who were at temporary risk of developing DVT/PE (32.6%). Patients were monitored and bioconversion status ascertained by radiography, computed tomography (CT), and CT venography through 2 years. RESULTS: The composite primary 6-month endpoint of clinical success was achieved in 97.4% (111/114) of patients. The rate of new symptomatic PE was 0% (n = 126) through 1 year and 2.4% (n = 85) through the second year of follow-up, with 2 new nonfatal cases at 581 and 624 days that were adjudicated as not related to the procedure or device. Two patients (1.6%) developed symptomatic caval thrombosis during the first month and underwent successful interventions without recurrence. No other filter-related symptomatic complications occurred through 2 years. There was no filter tilting, migration, embolization, fracture, or caval perforation and no filter-related deaths through 2 years. Filter bioconversion was successful for 95.7% (110/115) of patients at 6 months, 96.4% (106/110) of patients at 12 months, and 96.5% (82/85) of patients at 24 months. Through 24 months of follow-up, there was no evidence of late-stage IVC obstruction or thrombosis after filter bioconversion or of thrombogenicity associated with retracted filter arms. CONCLUSIONS: The Sentry IVC filter provided safe and effective protection against PE, with a high rate of intended bioconversion and a low rate of device-related complications, through 2 years of follow-up.

Trauma Service Utilization Increases Cost But Does Not Add Value for Minimally Injured Patients.

OBJECTIVE: Trauma care provides value to the critically injured. Our aim was to assess whether trauma team involvement adds value to the care of minimally injured patients and to define its costs. METHODS: Minimally injured patients admitted to a trauma center were propensity matched and compared by involvement versus no involvement of the trauma service (TS). Demographics, injury severity, complications, length of emergency department stay, mortality, and hospital costs and charges were studied. RESULTS: A total of 1253 patients were enrolled, with 308 propensity matched to the following groups: TS (n = 102) and no TS (n = 206). TS demonstrated a 30% increase in total charges and costs with no difference in complications. TS did demonstrate decreased time in the emergency department but had an increased delay to operation. Findings were similar when stratified for only lower extremity injuries. CONCLUSIONS: TS involvement for minimally injured patients does not increase value. Reducing TS involvement while avoiding trauma undertriage may reduce costs to the healthcare system without affecting outcomes.

Gestation as mothering.

Some commentators maintain that gestational surrogates are not 'mothers' in a way capable of grounding a claim to motherhood. These commentators find that the practices that constitute motherhood do not extend to gestational surrogates. We argue that gestational surrogates should be construed as mothers of the children they bear, even if they fully intend to surrender those children at birth to the care of others. These women stand in a certain relationship to the expected children: they live in changed moral circumstances by reason of their pregnancy, and they engage in the practices said to define motherhood in the post-birth context. By contrast, ovum donors and embryo donors are not similarly 'mothers' because they do not find themselves involved in these circumstances. Not all women involved in three-parent in vitro fertilization qualify as mothers either. Given this analysis of mothering, we note that transmen who gestate children are engaged in mothering activity even if they otherwise function as a father to those children. By itself, this defence of the maternity of gestational surrogates does not confer moral title to the children they bear; gestation would not by itself override the contractual arrangements gestational surrogates have made regarding the disposition of their children. This interpretation of gestational surrogates as mothers does, however, undercut cultural understandings of these women as mere 'vessels', devoid of entitlement to respect as persons and parents. We also consider the meaning of mothering for 'brain-dead' women kept alive to give birth and for the prospect of extracorporeal gestation.

The Laminin Interactome: A Multifactorial Laminin-Binding Strategy by Nontypeable Haemophilus influenzae for Effective Adherence and Colonization.

Laminin is a well-defined component of the airway basement membrane (BM). Efficient binding of laminin via multiple interactions is important for nontypeable Haemophilus influenzae (NTHi) colonization in the airway mucosa. In this study, we identified elongation factor thermo-unstable (EF-Tu), l-lactate dehydrogenase (LDH), protein D (PD), and peptidoglycan-associated lipoprotein P6 as novel laminin-binding proteins (Lbps) of NTHi. In parallel with other well-studied Lbps (protein 4 [P4], protein E [PE], protein F [PF], and Haemophilus adhesion and penetration protein [Hap]), EF-Tu, LDH, PD, and P6 exhibited interactions with laminin, and mediated NTHi laminin-dependent adherence to pulmonary epithelial cell lines. More importantly, the NTHi laminin interactome consisting of the well-studied and novel Lbps recognized laminin LG domains from the subunit α chains of laminin-111 and -332, the latter isoform of which is the main laminin in the airway BM. The NTHi interactome mainly targeted multiple heparin-binding domains of laminin. In conclusion, the NTHi interactome exhibited a high plasticity of interactions with different laminin isoforms via multiple heparin-binding sites.

Persistence of Moraxella catarrhalis in Chronic Obstructive Pulmonary Disease and Regulation of the Hag/MID Adhesin.

BACKGROUND: Persistence of bacterial pathogens in the airways has profound consequences on the course and pathogenesis of chronic obstructive pulmonary disease (COPD). Patients with COPD continuously acquire and clear strains of Moraxella catarrhalis, a major pathogen in COPD. Some strains are cleared quickly and some persist for months to years. The mechanism of the variability in duration of persistence is unknown. METHODS: Guided by genome sequences of selected strains, we studied the expression of Hag/MID, hag/mid gene sequences, adherence to human cells, and autoaggregation in longitudinally collected strains of M. catarrhalis from adults with COPD. RESULTS: Twenty-eight of 30 cleared strains of M. catarrhalis expressed Hag/MID whereas 17 of 30 persistent strains expressed Hag/MID upon acquisition by patients. All persistent strains ceased expression of Hag/MID during persistence. Expression of Hag/MID in human airways was regulated by slipped-strand mispairing. Virulence-associated phenotypes (adherence to human respiratory epithelial cells and autoaggregation) paralleled Hag/MID expression in airway isolates. CONCLUSIONS: Most strains of M. catarrhalis express Hag/MID upon acquisition by adults with COPD and all persistent strains shut off expression during persistence. These observations suggest that Hag/MID is important for initial colonization by M. catarrhalis and that cessation of expression facilitates persistence in COPD airways.

ReVac: a reverse vaccinology computational pipeline for prioritization of prokaryotic protein vaccine candidates.

BACKGROUND: Reverse vaccinology accelerates the discovery of potential vaccine candidates (PVCs) prior to experimental validation. Current programs typically use one bacterial proteome to identify PVCs through a filtering architecture using feature prediction programs or a machine learning approach. Filtering approaches may eliminate potential antigens based on limitations in the accuracy of prediction tools used. Machine learning approaches are heavily dependent on the selection of training datasets with experimentally validated antigens (positive control) and non-protective-antigens (negative control). The use of one or few bacterial proteomes does not assess PVC conservation among strains, an important feature of vaccine antigens. RESULTS: We present ReVac, which implements both a panoply of feature prediction programs without filtering out proteins, and scoring of candidates based on predictions made on curated positive and negative control PVCs datasets. ReVac surveys several genomes assessing protein conservation, as well as DNA and protein repeats, which may result in variable expression of PVCs. ReVac's orthologous clustering of conserved genes, identifies core and dispensable genome components. This is useful for determining the degree of conservation of PVCs among the population of isolates for a given pathogen. Potential vaccine candidates are then prioritized based on conservation and overall feature-based scoring. We present the application of ReVac, applied to 69 Moraxella catarrhalis and 270 non-typeable Haemophilus influenzae genomes, prioritizing 64 and 29 proteins as PVCs, respectively. CONCLUSION: ReVac's use of a scoring scheme ranks PVCs for subsequent experimental testing. It employs a redundancy-based approach in its predictions of features using several prediction tools. The protein's features are collated, and each protein is ranked based on the scoring scheme. Multi-genome analyses performed in ReVac allow for a comprehensive overview of PVCs from a pan-genome perspective, as an essential pre-requisite for any bacterial subunit vaccine design. ReVac prioritized PVCs of two human respiratory pathogens, identifying both novel and previously validated PVCs.

Reduced late mismatch negativity and auditory sustained potential to rule-based patterns in schizophrenia.

Complex rule-based auditory processing is abnormal in individuals with long-term schizophrenia (SZ), as demonstrated by reduced mismatch negativity (MMN) to deviants in rule-based patterns and reduced auditory sustained potential (ASP) that appears when grouping tones together. Together, this suggests deficits later in the auditory processing hierarchy in Sz. Here, MMN and ASP were elicited by deviations from a complex zig-zag pitch pattern that cannot be predicted by simple linear rules. Twenty-seven SZ and 26 matched healthy controls (HC) participated. Frequent groups of patterns contained eight tones that zig-zagged in a two-up one-down pitch-based paradigm. There were two deviant patterns: the final tone was either higher in pitch than expected (creating a jump in pitch) or was repeated. Simple MMN to pitch-deviants among repetitive tones was measured for comparison. Sz exhibited a smaller pitch MMN compared to HC as expected. HC produced a late MMN in response to the repeat and jump-deviant and a larger ASP to the standard group of tones, all of which were significantly blunted in SZ. In Sz, the amplitude of the late complex MMN was related to neuropsychological functioning, whereas ASP was not. ASP and late MMN did not significantly correlate in HC or in Sz, suggesting that they are not dependent on one another and may originate within distinct processing streams. Together, this suggests multiple deficits later in the auditory sensory-perceptual hierarchy in Sz, with impairments evident in both segmentation and deviance detection abilities.

Relationship of mildly increased albuminuria and coronary artery revascularization outcomes in patients with diabetes.

BACKGROUND: The aim of this study was to examine the relationship of albuminuria to cardiovascular disease outcomes in diabetic patients undergoing treatment for stable coronary artery disease. METHODS AND RESULTS: We analyzed data from 2176 participants of the Bypass Angioplasty Revascularization Investigation in type-2 diabetes (BARI-2D) trial, a randomized clinical trial comparing Percutaneous coronary intervention/Coronary artery bypass grafting (PCI/CABG) to medical therapy for people with diabetes. The population was stratified by baseline spot urine albumin-creatinine ratio (uACR) into normal (uACR <10 mg/g), mildly (uACR ≥10 mg/g < 30 mg/g), moderately (uACR ≥30 mg/g < 300 mg/g) and severely increased (uACR ≥300 mg/g) groups, and outcomes compared between groups. Death, myocardial infarction (MI) and/or stroke were experienced by 489 patients at a mean follow-up of 4.3 ± 1.5 years. Compared with normal uACR, mildly increased uACR was associated with a 1.4 times (P = 0.042) increase in all-cause mortality. Additionally, nonwhites with type-II diabetes and stable coronary artery disease who had mildly increased albuminuria had a Hazard ratio (HR) of 3.3 times (P = 0.028) for cardiovascular death, 3.1 times for (P = 0.002) all-cause mortality, and two times for (P = 0.015) MI during follow-up. CONCLUSIONS: Mildly increased albuminuria is a significant predictor of all-cause mortality in those with type-II diabetes mellitus and stable coronary artery disease, as well as for cardiovascular events those who are nonwhites.