Evaluating generalizability of artificial intelligence models for molecular datasets.

Deep learning has made rapid advances in modeling molecular sequencing data. Despite achieving high performance on benchmarks, it remains unclear to what extent deep learning models learn general principles and generalize to previously unseen sequences. Benchmarks traditionally interrogate model generalizability by generating metadata based (MB) or sequence-similarity based (SB) train and test splits of input data before assessing model performance. Here, we show that this approach mischaracterizes model generalizability by failing to consider the full spectrum of cross-split overlap, i.e., similarity between train and test splits. We introduce Spectra, a spectral framework for comprehensive model evaluation. For a given model and input data, Spectra plots model performance as a function of decreasing cross-split overlap and reports the area under this curve as a measure of generalizability. We apply Spectra to 18 sequencing datasets with associated phenotypes ranging from antibiotic resistance in tuberculosis to protein-ligand binding to evaluate the generalizability of 19 state-of-the-art deep learning models, including large language models, graph neural networks, diffusion models, and convolutional neural networks. We show that SB and MB splits provide an incomplete assessment of model generalizability. With Spectra, we find as cross-split overlap decreases, deep learning models consistently exhibit a reduction in performance in a task- and model-dependent manner. Although no model consistently achieved the highest performance across all tasks, we show that deep learning models can generalize to previously unseen sequences on specific tasks. Spectra paves the way toward a better understanding of how foundation models generalize in biology.

Evolution of Disparities in Outpatient Ophthalmic Care at a Tertiary Care Center in California at the Beginning of and One Year into the COVID-19 Public Health Emergency.

PURPOSE: To compare disparities in outpatient ophthalmic care during early and later periods of the COVID-19 public health emergency. METHODS: This cross-sectional study compared non-peri-operative outpatient ophthalmology visits by unique patients at an adult ophthalmology practice affiliated with a tertiary-care academic medical center in the Western US during three time periods: pre-COVID (3/15/19-4/15/19), early-COVID (3/15/20-4/15/20), and late-COVID (3/15/21-4/15/21). Differences in participant demographics, barriers to care, visit modality (telehealth, in person), and subspeciality of care were studied using unadjusted and adjusted models. RESULTS: There were 3095, 1172 and 3338 unique patient-visits during pre-COVID, early-COVID and late-COVID (overall age 59.5 ± 20.5 years, 57% female, 41.8% White, 25.9% Asian, 16.1% Hispanic). There were disparities in patient age (55.4 ± 21.8 vs. 60.2 ± 19.9 years), race (21.9% vs. 26.9% Asian), ethnicity (18.3% Hispanic vs. 15.2% Hispanic), and insurance (35.9% vs. 45.1% Medicare) as well as changes in modality (14.2% vs. 0% telehealth) and subspecialty (61.6% vs. 70.1% internal exam specialty) in early-COVID vs. pre-COVID (p < .05 for all). In late-COVID, only insurance (42.7% vs. 45.1% Medicare) and modality of care (1.8% vs. 0% telehealth) persisted as differences compared to pre-COVID. CONCLUSIONS: There were disparities in patients receiving outpatient ophthalmology care during early-COVID that returned close to pre-COVID baseline one year later. These results suggest that there has not been a lasting positive or negative disruptive effect of the COVID-19 pandemic on disparities in outpatient ophthalmic care.

Genome-wide detection of somatic mosaicism at short tandem repeats.

Motivation: Somatic mosaicism, in which a mutation occurs post-zygotically, has been implicated in several developmental disorders, cancers, and other diseases. Short tandem repeats (STRs) consist of repeated sequences of 1-6bp and comprise more than 1 million loci in the human genome. Somatic mosaicism at STRs is known to play a key role in the pathogenicity of loci implicated in repeat expansion disorders and is highly prevalent in cancers exhibiting microsatellite instability. While a variety of tools have been developed to genotype germline variation at STRs, a method for systematically identifying mosaic STRs (mSTRs) is lacking. Results: We introduce prancSTR, a novel method for detecting mSTRs from individual high-throughput sequencing datasets. Unlike many existing mosaicism detection methods for other variant types, prancSTR does not require a matched control sample as input. We show that prancSTR accurately identifies mSTRs in simulated data and demonstrate its feasibility by identifying candidate mSTRs in whole genome sequencing (WGS) data derived from lymphoblastoid cell lines for individuals sequenced by the 1000 Genomes Project. Our analysis identified an average of 76 and 577 non-homopolymer and homopolymer mSTRs respectively per cell line as well as multiple cell lines with outlier mSTR counts more than 6 times the population average, suggesting a subset of cell lines have particularly high STR instability rates. Availability: prancSTR is freely available at https://github.com/gymrek-lab/trtools. Documentation: Detailed documentation is available at https://trtools.readthedocs.io/.

Plant-derived single domain COVID-19 antibodies.

Data show a decrease in the risk of hospitalization and death from COVID-19. To date, global vaccinations for SARS-CoV-2 protections are underway, but additional treatments are urgently needed to prevent and cure infection among naïve and even vaccinated people. Neutralizing monoclonal antibodies are very promising for prophylaxis and therapy of SARS-CoV-2 infections. However, traditional large-scale methods of producing such antibodies are slow, extremely expensive and possess a high risk of contamination with viruses, prions, oncogenic DNA and other pollutants. The present study is aimed at developing an approach of producing monoclonal antibodies (mAbs) against SARS-CoV-2 spike (S) protein in plant systems which offers unique advantages, such as the lack of human and animal pathogens or bacterial toxins, relatively low-cost manufacturing, and ease of production scale-up. We selected a single N-terminal domain functional camelid-derived heavy (H)-chain antibody fragments (VHH, AKA nanobodies) targeted to receptor binding domain of SARS-CoV-2 spike protein and developed methods of their rapid production using transgenic plants and plant cell suspensions. Isolated and purified plant-derived VHH antibodies were compared with mAbs produced in traditional mammalian and bacterial expression systems. It was found that plant generated VHH using the proposed methods of transformation and purification possess the ability to bind to SARS-CoV-2 spike protein comparable to that of monoclonal antibodies derived from bacterial and mammalian cell cultures. The results of the present studies confirm the visibility of producing monoclonal single-chain antibodies with a high ability to bind the targeted COVID-19 spike protein in plant systems within a relatively shorter time span and at a lower cost when compared with traditional methods. Moreover, similar plant biotechnology approaches can be used for producing monoclonal neutralizing antibodies against other types of viruses.

Hierarchical modeling of elastic moduli of equine hoof wall.

This study predicts analytically effective elastic moduli of substructures within an equine hoof wall. The hoof wall is represented as a composite material with a hierarchical structure comprised of a sequence of length scales. A bottom-up approach is employed. Thus, the outputs from a lower spatial scale serve as the inputs for the following scale. The models include the Halpin-Tsai model, composite cylinders model, a sutured interface model, and classical laminate theory. The length scales span macroscale, mesoscale, sub-mesoscale, microscale, sub-microscale, and nanoscale. The macroscale represents the hoof wall, consisting of tubules within a matrix at the mesoscale. At the sub-mesoscale, a single hollow tubule is reinforced by a tubule wall made of lamellae; the surrounding intertubular material also has a lamellar structure. The lamellae contain sutured and layered cells at the microscale. A single cell is made of crystalline macrofibrils arranged in an amorphous matrix at the sub-microscale. A macrofibril contains aligned crystalline rod-like intermediate filaments at the nanoscale. Experimentally obtained parameters are used in the modeling as inputs for geometry and nanoscale properties. The predicted properties of the hoof wall material agree with experimental measurements at the mesoscale and macroscale. We observe that the hierarchical structure of the hoof wall leads to a decrease in the elastic modulus with increasing scale, from the nanoscale to the macroscale. Such behavior is an intrinsic characteristic of hierarchical biological materials. This study can serve as a framework for designing impact-resistant hoof-inspired materials and structures.

Concentration-Dependent Global Quantitative Proteome Response of Staphylococcus epidermidis RP62A Biofilms to Subinhibitory Tigecycline.

Staphylococcus epidermidis is a leading cause of biofilm-associated infections on implanted medical devices. During the treatment of an infection, bacterial cells inside biofilms may be exposed to sublethal concentrations of the antimicrobial agents. In the present study, the effect of subinhibitory concentrations of tigecycline (TC) on biofilms formed by S. epidermidis strain RP62A was investigated using a quantitative global proteomic technique. Sublethal concentrations of TC [1/8 (T1) and 1/4 minimum inhibitory concentration (MIC) (T2)] promoted biofilm production in strain RP62A, but 1/2 MIC TC (T3) significantly inhibited biofilm production. Overall, 413, 429, and 518 proteins were differentially expressed in biofilms grown with 1/8 (T1), 1/4 (T2), and 1/2 (T3) MIC of TC, respectively. As the TC concentration increased, the number of induced proteins in each Cluster of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway increased. The TC concentration dependence of the proteome response highlights the diverse mechanisms of adaptive responses in strain RP62A biofilms. In both COG and KEGG functional analyses, most upregulated proteins belong to the metabolism pathway, suggesting that it may play an important role in the defense of strain RP62A biofilm cells against TC stress. Sub-MIC TC treatment of strain RP62A biofilms led to significant changes of protein expression related to biofilm formation, antimicrobial resistance, virulence, quorum sensing, ABC transporters, protein export, purine/pyrimidine biosynthesis, ribosomes, and essential proteins. Interestingly, in addition to tetracycline resistance, proteins involved in resistance of various antibiotics, including aminoglycosides, antimicrobial peptides, ß-lactams, erythromycin, fluoroquinolones, fusidic acid, glycopeptides, lipopeptides, mupirocin, rifampicin and trimethoprim were differentially expressed. Our study demonstrates that global protein expression profiling of biofilm cells to antibiotic pressure may improve our understanding of the mechanisms of antibiotic resistance in biofilms.

Neurobehavioral and neurochemical effects of perinatal arsenite exposure in Sprague-Dawley rats.

Exposure to relatively high levels of inorganic arsenic (iAs) is associated with detrimental effects on human health, including cancer and diabetes. The effects of lower-level exposures are less clear, and gaps in the literature exist as to the effects of iAs exposure on neurodevelopment. The current study assessed the effects of perinatal iAs exposure on rodent neurodevelopment and behavior. Pregnant Sprague-Dawley (SD) rats were exposed to arsenite (AsIII) via oral gavage on gestational days (GD) 6 through 21, and pups were directly dosed via gavage on postnatal days (PND) 1 through 21. Dams and offspring received the same doses: 0.00, 0.10, 1.50, or 3.75 mg/kg/day. Male and female offspring underwent a battery of behavioral assessments from weaning until PND 180. Brain arsenic levels increased in a dose-dependent manner at both PND 1 and 21. Results from the behavioral tests show that pre- and postnatal AsIII exposure did not adversely affect offspring weight gain, adolescent motor and cognitive functions, or adult motor and cognitive functions in the SD rat. There were no differences in concentration of several brain proteins associated with blood-brain barrier permeability, dopamine functions, and inflammation.

Prenatal imaging features and perinatal outcomes of foetal volvulus-A literature review.

OBJECTIVE: To conduct a review of the literature on foetal volvulus with emphasis on prenatal imaging, pregnancy characteristics and clinical outcomes. METHODS: A review of all published cases of foetal volvulus diagnosed prenatally and indexed in Medline, EBSCOhost, CINAHL, SOCIndex and Healthy Policy Reference Centre. Studies without antenatal sonographic signs of foetal volvulus and without a postpartum surgical diagnosis were excluded. Data were analysed for frequencies and distributions and tested for statistical significance. RESULTS: Eighty-eight cases of foetal volvulus were identified from 58 published case reports/series. The most common ultrasound findings were dilated bowel/stomach (77.3%), polyhydramnios (30.7%) and whirlpool/snail sign (28.4%). Median gestation at diagnosis was 31.9 weeks (IQR 27-34) and mean gestation at delivery was 34.5 weeks (SD 2.8). Underlying aetiology included intestinal malrotation (15.9%), cystic fibrosis (14.8% of all cases, 32.5% of tested cases) and abnormal mesenteric fixation (12.5%). Complications included intestinal atresia (36.4%) and foetal anaemia (9.1%). The overall perinatal mortality rate was 14.5%. CONCLUSION: Foetal volvulus is a rare condition with high rates of preterm birth and perinatal mortality. Intestinal malrotation and cystic fibrosis are common predisposing causes, although the majority are idiopathic. Bowel and/or gastric dilatation is by far the most common sonographic finding.

Can neonatal pneumothorax be successfully managed in regional Australia?

INTRODUCTION: There is a lack of data reflecting the trend of neonatal pneumothorax in regional Australia. The aim of this study is to review the incidence and characteristics of neonates diagnosed with pneumothorax in Central Queensland, analyse outcomes in terms of the ability of local hospitals to manage this condition, and describe predictors for severe disease requiring transfer to a tertiary centre. Thus the role of regional health services in managing this condition will be reviewed. METHODS: This was a retrospective observational study of all neonates born between 1 January 2008 and 31 December 2015 coded by hospital records with a diagnosis of neonatal pneumothorax in Central Queensland. Data for sex and birth gestation for all Central Queensland births of the same period were also obtained. Descriptive statistics were calculated for birth weight and gestation, and Apgar scores. Frequencies were calculated for sex, length of admission, age of diagnosis and risk factors including meconium aspiration syndrome (MAS), prolonged rupture of membranes (PROM) and positive pressure ventilation (PPV). The primary outcome measure was successful treatment at a Central Queensland hospital versus requirement for transfer to tertiary hospital or death prior to transfer. Statistical significance was calculated for binary and continuous variables. RESULTS: During the study period, there were 31 cases of pneumothorax amongst 17 640 deliveries recorded by three Central Queensland hospitals, with a significant bias towards males (84%) amongst pneumothorax cases (p<0.001). Median gestational age was comparable between the Central Queensland population and the pneumothorax cohort. Diagnosis of pneumothorax was usually made within 48 hours of birth (87.1%). PPV was present in two-thirds of the pneumothorax cohort whilst MAS and PROM were less common. No significant relationship was found between type of pneumothorax and gender, birth weight, MAS, PROM, caesarean section or PPV. The majority of cases were successfully treated locally (67.7%) and with oxygen alone (64.5%). Other treatment modalities included surfactant use, thoracocentesis, chest tube insertion and PPV. Patients with bilateral pneumothorax or pneumomediastinum had poorer outcomes (p=0.04). Overall local outcomes were good, with only one perinatal death prior to discharge or transfer. CONCLUSION: Neonatal pneumothorax is effectively managed in the regional hospitals studied in keeping with contributions of regional paediatricians and rural generalists. Compared with unilateral pneumothorax, bilateral pneumothorax or pneumomediastinum were associated with transfer to tertiary centre. There were no clear predictors for bilateral pneumothorax.

Pharmacokinetics of inhaled nanotherapeutics for pulmonary delivery.

Pulmonary delivery of lipid-based nanotherapeutics by inhalation presents an advantageous alternative to oral and intravenous routes of administration that avoids enzymatic degradation in gastrointestinal tract and hepatic first pass metabolism and also limits off-target adverse side effects upon heathy tissues. For lung-related indications, inhalation provides localized delivery in order to enhance therapeutic efficacy at the site of action. Optimization of physicochemical properties, selected drug and inhalation format can greatly influence the pharmacokinetic behavior of inhaled nanoparticle systems and their payloads. The present review analyzes a wide range of nanoparticle systems, their formulations and consequent effect on pharmacokinetic distribution of delivered active components after inhalation.

Gamification improves melanoma visual identification among high school students: Results from a randomized study.

Identification of melanoma or worrisome moles is often taught as an important part of routine skin checks. We sought to evaluate the efficacy of gamified education vs. traditional ABCDEs education on melanoma identification and self-confidence in identifying worrisome moles. We report that in our cohort (n = 271), participants randomized to the gamified intervention were more likely to correctly identify melanoma and non-melanoma skin lesions than those randomized to the ABCDE control cohort (74.2% vs 63.5% correct, P < .0001) and perceived confidence in self-identifying worrisome lesions was slightly higher in the gamified group than the traditional group, though the trend was not significant. These novel findings have significant implications on improved ways to educate young patients on the visual identification of melanoma and worrisome moles.

Isolation of Cerebral Capillaries from Fresh Human Brain Tissue.

Understanding blood-brain barrier function under physiological and pathophysiological conditions is critical for the development of new therapeutic strategies that hold the promise to enhance brain drug delivery, improve brain protection, and treat brain disorders. However, studying the human blood-brain barrier function is challenging. Thus, there is a critical need for appropriate models. In this regard, brain capillaries isolated from human brain tissue represent a unique tool to study barrier function as close to the human in vivo situation as possible. Here, we describe an optimized protocol to isolate capillaries from human brain tissue at a high yield and with consistent quality and purity. Capillaries are isolated from fresh human brain tissue using mechanical homogenization, density-gradient centrifugation, and filtration. After the isolation, the human brain capillaries can be used for various applications including leakage assays, live cell imaging, and immune-based assays to study protein expression and function, enzyme activity, or intracellular signaling. Isolated human brain capillaries are a unique model to elucidate the regulation of the human blood-brain barrier function. This model can provide insights into central nervous system (CNS) pathogenesis, which will help the development of therapeutic strategies for treating CNS disorders.

Preventing P-gp Ubiquitination Lowers Aß Brain Levels in an Alzheimer's Disease Mouse Model.

One characteristic of Alzheimer's disease (AD) is excessive accumulation of amyloid-ß (Aß) in the brain. Aß brain accumulation is, in part, due to a reduction in Aß clearance from the brain across the blood-brain barrier. One key element that contributes to Aß brain clearance is P-glycoprotein (P-gp) that transports Aß from brain to blood. In AD, P-gp protein expression and transport activity levels are significantly reduced, which impairs Aß brain clearance. The mechanism responsible for reduced P-gp expression and activity levels is poorly understood. We recently demonstrated that Aß40 triggers P-gp degradation through the ubiquitin-proteasome pathway. Consistent with these data, we show here that ubiquitinated P-gp levels in brain capillaries isolated from brain samples of AD patients are increased compared to capillaries isolated from brain tissue of cognitive normal individuals. We extended this line of research to in vivo studies using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576) that were treated with PYR41, a cell-permeable, irreversible inhibitor of the ubiquitin-activating enzyme E1. Our data show that inhibiting P-gp ubiquitination protects the transporter from degradation, and immunoprecipitation experiments confirmed that PYR41 prevented P-gp ubiquitination. We further found that PYR41 treatment prevented reduction of P-gp protein expression and transport activity levels and substantially lowered Aß brain levels in hAPP mice. Together, our findings provide in vivo proof that the ubiquitin-proteasome system mediates reduction of blood-brain barrier P-gp in AD and that inhibiting P-gp ubiquitination prevents P-gp degradation and lowers Aß brain levels. Thus, targeting the ubiquitin-proteasome system may provide a novel therapeutic approach to protect blood-brain barrier P-gp from degradation in AD and other Aß-based pathologies.

Aging, motor function, and sensitivity to calcium channel blockers: An investigation using chronic methylmercury exposure.

Methylmercury (MeHg) neurotoxicity is thought to be mediated, in part, by dysregulation of calcium (Ca(2+)) homeostasis, a mechanism that may also slowly and progressively degrade neuronal function during normal aging. Longitudinal studies of MeHg exposure provide a powerful approach to studying neural and behavioral mechanisms by which both MeHg toxicity and aging affect motor function. Wheel-running and rotarod performance were assessed in two age groups of BALB/c mice chronically exposed to 0 or 1.2mg/kg/day MeHg and 0 or 20mg/kg/day nimodipine, a 1,4-dihyrdopyridine L-type calcium channel blocker (CCB), for approximately 8.5 months. Adults began exposure on postnatal day (PND) 72 and retired breeders on PND 296. A log-survivor bout analysis partitioned wheel-running into bouts that identified motor (within-bout rates) and motivational (bout-initiation rates) influences. Retired breeders ran farther, because of a higher bout-initiation rates, but performed more poorly on the rotarod than younger adults, a difference unaffected by nimodipine. MeHg produced relatively age-independent deficits in wheel-running and rotarod performance, whereas nimodipine afforded greater protection to adult mice than to retired breeders. Rotarod performance and within-bout response rate were more sensitive to and more reliable predictors of MeHg toxicity than bout-initiation rate, which was least affected by MeHg exposure. Thus the motivation to run was unimpaired as the ability to do so declined. While chronic MeHg exposure produced functionally similar behavior deficits between age groups, the age-dependent neuroprotection by nimodipine supports the notion that underlying neurobiological systems mediated by Ca(2+) signaling, are differentially affected in older adults.

A bout analysis reveals age-related methylmercury neurotoxicity and nimodipine neuroprotection.

Age-related deficits in motor and cognitive functioning may be driven by perturbations in calcium (Ca(2+)) homeostasis in nerve terminals, mechanisms that are also thought to mediate the neurotoxicity of methylmercury (MeHg). Calcium-channel blockers (CCBs) protect against MeHg toxicity in adult mice, but little is known about their efficacy in other age groups. Two age groups of BALB/c mice were exposed to 0 or 1.2mg/kg/day MeHg and 0 or 20mg/kg/day of the CCB nimodipine for approximately 8.5 months. Adults began exposure on postnatal day (PND) 72 and the retired breeders on PND 296. High-rate operant behavior was maintained under a percentile schedule, which helped to decouple response rate from reinforcer rate. Responding was analyzed using a log-survivor bout analysis approach that partitioned behavior into high-rate bouts separated by pauses. MeHg-induced mortality did not depend on age but nimodipine neuroprotection was age-dependent, with poorer protection occurring in older mice. Within-bout response rate (a marker of sensorimotor function) was more sensitive to MeHg toxicity than bout-initiation rate (a marker of motivation). Within-bout rate declined almost 2 months prior to overt signs of toxicity for the MeHg-only retired breeders but not adults, suggesting greater delay to toxicity in younger animals. Motor-based decrements also appeared in relatively healthy adult MeHg+NIM animals. Aging appeared to alter the processes underlying Ca(2+) homeostasis thereby diminishing protection by nimodipine, even in mice that have not reached senescence. The study of MeHg exposure presents an experimental model by which to study potential mechanisms of aging.

Carbapenems versus alternative antibiotics for the treatment of bloodstream infections caused by Enterobacter, Citrobacter or Serratia species: a systematic review with meta-analysis.

OBJECTIVES: This systematic review and meta-analysis compared effects of different antibiotics on mortality in patients with bloodstream infections caused by Enterobacteriaceae with chromosomal AmpC ß-lactamase. METHODS: Databases were systematically searched for studies reporting mortality in patients with bloodstream infections caused by AmpC producers treated with carbapenems, broad-spectrum ß-lactam/ß-lactamase inhibitors (BLBLIs), quinolones or cefepime. Pooled ORs for mortality were calculated for cases that received monotherapy with these agents versus carbapenems. REGISTRATION: PROSPERO international prospective register of systematic reviews (CRD42014014992; 18 November 2014). RESULTS: Eleven observational studies were included. Random-effects meta-analysis was performed on studies reporting empirical and definitive monotherapy. In unadjusted analyses, no significant difference in mortality was found between BLBLIs versus carbapenems used for definitive therapy (OR 0.87, 95% CI 0.32-2.36) or empirical therapy (OR 0.48; 95% CI 0.14-1.60) or cefepime versus carbapenems as definitive therapy (OR 0.61; 95% CI 0.27-1.38) or empirical therapy (0.60; 95% CI 0.17-2.20). Use of a fluoroquinolone as definitive therapy was associated with a lower risk of mortality compared with carbapenems (OR 0.39; 95% CI 0.19-0.78). Three studies with patient-level data were used to adjust for potential confounders. The non-significant trends favouring non-carbapenem options in these studies were diminished after adjustment for age, sex and illness severity scores, suggestive of residual confounding. CONCLUSIONS: Despite limitations of available data, there was no strong evidence to suggest that BLBLIs, quinolones or cefepime were inferior to carbapenems. The reduced risk of mortality observed with quinolone use may reflect less serious illness in patients, rather than superiority over carbapenems.

Examination of clozapine and haloperidol in improving ketamine-induced deficits in an incremental repeated acquisition procedure in BALB/c mice.

RATIONALE: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, causes locomotor hyperactivity, aberrant prepulse inhibition and impaired reversal learning among other deficits. There are numerous clinical and pre-clinically uses of NMDAR antagonists and a growing need to characterize their neurobehavioral effects. OBJECTIVES: The present study was designed to characterize 1) ketamine's effect on incremental repeated acquisition (IRA), a procedure that taps multiple neurobehavioral functions and has performance measures correlated with IQ in humans, and 2) the extent to which clozapine (CLZ) and haloperidol (HAL) block ketamine's detrimental effects. METHODS AND RESULTS: In experiment 1 (Exp. 1), BALB/c mice nose-poked under an IRA procedure for sucrose pellets. Systemic ketamine (1-30 mg/kg) dose-dependently decreased measures of cognitive and motor function. CLZ pretreatment (CLZ 0.1-4.0 mg/kg) dose-dependently attenuated ketamine-induced (30 mg/kg) deficits; the effective dose range of CLZ was 0.3-1.0 mg/kg. HAL pretreatment (0.01-0.1 mg/kg) did not attenuate any ketamine-induced deficits. In experiment 2 (Exp. 2), BALB/c mice lever-pressed under an IRA procedure for sweetened condensed milk. Ketamine (30 mg/kg) produced a global impairment in the IRA procedure and CLZ pretreatment (0.3-1.0 mg/kg) dose-dependently attenuated that impairment; motor-based performance recovered to a greater extent than cognitive performance. When tested alone, these doses of CLZ had little effect on IRA performance. CONCLUSIONS: These findings support the notion that CLZ is more effective than HAL at blocking ketamine-induced deficits. The IRA procedure may be beneficial for distinguishing the efficacy of drugs that seek to alleviate deficits in complex behavior that result from acute NMDAR antagonism.

Spatial discrimination reversal and incremental repeated acquisition in adolescent and adult BALB/c mice.

Adolescence is characterized by neural and behavior development that includes increases in novel experiences and impulsive choice. Experimental rodent models can characterize behavior phenotypes that typify adolescence. The present experiment was designed to characterize differences between adolescent (post-natal day (PND) 34-60) and adult (PND 70-96) BALB/c mice using a response-initiated spatial discrimination reversal (SDR) and incremental repeated acquisition of response chains (IRA) procedures. During SDR, adolescents omitted more trials and were slower to initiate trials than adults, but the age groups did not differ on accuracy and perseveration measures. During IRA, adolescents displayed poorer overall performance (measured by progress quotient), lower accuracy at individual chain links, and completed fewer long response chains (>3 links) than adults. In both procedures (SDR and IRA), the poorer performance of adolescents appeared to be related to the use of a response device that was spatially removed from reinforcer delivery. These results indicate that SDR and IRA performance can be established during the brief rodent adolescent period but that these two age groups' performances differ. We hypothesize that adolescent behavior is more sensitive than adult behavior to the spatiotemporal distance between response device and location of reinforcer delivery.

Defining "therapeutically inconsequential" head computed tomographic findings in patients with blunt head trauma.

STUDY OBJECTIVE: Many injuries detected by computed tomographic (CT) imaging of blunt head trauma patients are considered "therapeutically inconsequential." We estimate the prevalence of these findings and determine how frequently affected patients had "important neurosurgical outcomes," defined as either a directed intervention or a poor Glasgow Outcome Scale score. METHODS: We prospectively enrolled all blunt head trauma patients undergoing emergency head CT imaging at 18 centers participating in the National Emergency X-radiography Utilization Study II (NEXUS). From these cases, we identified all patients whose official CT reading met predefined criteria for "therapeutically inconsequential" injuries. We obtained detailed follow-up information on all such patients at 6 sites, including the need for neurosurgical intervention and Glasgow Outcome Scale scores. Among patients having "important neurosurgical outcomes," we assessed the frequency of 2 potential clinical identifiers: altered mental status and coagulopathy. RESULTS: "Therapeutically inconsequential" head CT findings were present in 155 of 8,374 subjects (1.85%; 95% confidence interval 1.57% to 2.16%). Sites participating in the follow-up study enrolled 81 of these patients, of whom 10 (12%) had "important neurosurgical outcomes." Follow-up information was available for 9 patients, all of whom had abnormal mental status at CT scanning. Coagulopathy was also present in 5 of 7 patients for whom coagulation status was known. CONCLUSION: "Therapeutically inconsequential" findings are identified in less than 2% of blunt head trauma patients who undergo CT scanning. A small proportion of these patients have an "important neurosurgical outcome," but it appears that such patients may be identified clinically by the presence of abnormal mental status or coagulopathy.