Profiles of mathematical deficits in children with dyslexia.

Despite a high rate of concurrent mathematical difficulties among children with dyslexia, we still have limited information regarding the prevalence and severity of mathematical deficits in this population. To address this gap, we developed a comprehensive battery of cognitive tests, known as the UCSF Mathematical Cognition Battery (MCB), with the aim of identifying deficits in four distinct mathematical domains: number processing, arithmetical procedures, arithmetic facts retrieval, and geometrical abilities. The mathematical abilities of a cohort of 75 children referred to the UCSF Dyslexia Center with a diagnosis of dyslexia, along with 18 typically developing controls aged 7 to 16, were initially evaluated using a behavioral neurology approach. A team of professional clinicians classified the 75 children with dyslexia into five groups, based on parents' and teachers' reported symptoms and clinical history. These groups included children with no mathematical deficits and children with mathematical deficits in number processing, arithmetical procedures, arithmetic facts retrieval, or geometrical abilities. Subsequently, the children underwent evaluation using the MCB to determine concordance with the clinicians' impressions. Additionally, neuropsychological and cognitive standardized tests were administered. Our study reveals that within a cohort of children with dyslexia, 66% exhibit mathematical deficits, and among those with mathematical deficits, there is heterogeneity in the nature of these deficits. If these findings are confirmed in larger samples, they can potentially pave the way for new diagnostic approaches, consistent subtype classification, and, ultimately personalized interventions.

Auditory Verb Generation Performance Patterns Dissociate Variants of Primary Progressive Aphasia.

Primary progressive aphasia (PPA) is a clinical syndrome in which patients progressively lose speech and language abilities. Three variants are recognized: logopenic (lvPPA), associated with phonology and/or short-term verbal memory deficits accompanied by left temporo-parietal atrophy; semantic (svPPA), associated with semantic deficits and anterior temporal lobe (ATL) atrophy; non-fluent (nfvPPA) associated with grammar and/or speech-motor deficits and inferior frontal gyrus (IFG) atrophy. Here, we set out to investigate whether the three variants of PPA can be dissociated based on error patterns in a single language task. We recruited 21 lvPPA, 28 svPPA, and 24 nfvPPA patients, together with 31 healthy controls, and analyzed their performance on an auditory noun-to-verb generation task, which requires auditory analysis of the input, access to and selection of relevant lexical and semantic knowledge, as well as preparation and execution of speech. Task accuracy differed across the three variants and controls, with lvPPA and nfvPPA having the lowest and highest accuracy, respectively. Critically, machine learning analysis of the different error types yielded above-chance classification of patients into their corresponding group. An analysis of the error types revealed clear variant-specific effects: lvPPA patients produced the highest percentage of "not-a-verb" responses and the highest number of semantically related nouns (production of baseball instead of throw to noun ball); in contrast, svPPA patients produced the highest percentage of "unrelated verb" responses and the highest number of light verbs (production of take instead of throw to noun ball). Taken together, our findings indicate that error patterns in an auditory verb generation task are associated with the breakdown of different neurocognitive mechanisms across PPA variants. Specifically, they corroborate the link between temporo-parietal regions with lexical processing, as well as ATL with semantic processes. These findings illustrate how the analysis of pattern of responses can help PPA phenotyping and heighten diagnostic sensitivity, while providing insights on the neural correlates of different components of language.

The Practical Haplotype Graph, a platform for storing and using pangenomes for imputation.

MOTIVATION: Pangenomes provide novel insights for population and quantitative genetics, genomics and breeding not available from studying a single reference genome. Instead, a species is better represented by a pangenome or collection of genomes. Unfortunately, managing and using pangenomes for genomically diverse species is computationally and practically challenging. We developed a trellis graph representation anchored to the reference genome that represents most pangenomes well and can be used to impute complete genomes from low density sequence or variant data. RESULTS: The Practical Haplotype Graph (PHG) is a pangenome pipeline, database (PostGRES & SQLite), data model (Java, Kotlin or R) and Breeding API (BrAPI) web service. The PHG has already been able to accurately represent diversity in four major crops including maize, one of the most genomically diverse species, with up to 1000-fold data compression. Using simulated data, we show that, at even 0.1× coverage, with appropriate reads and sequence alignment, imputation results in extremely accurate haplotype reconstruction. The PHG is a platform and environment for the understanding and application of genomic diversity. AVAILABILITY AND IMPLEMENTATION: All resources listed here are freely available. The PHG Docker used to generate the simulation results is https://hub.docker.com/ as maizegenetics/phg:0.0.27. PHG source code is at https://bitbucket.org/bucklerlab/practicalhaplotypegraph/src/master/. The code used for the analysis of simulated data is at https://bitbucket.org/bucklerlab/phg-manuscript/src/master/. The PHG database of NAM parent haplotypes is in the CyVerse data store (https://de.cyverse.org/de/) and named/iplant/home/shared/panzea/panGenome/PHG_db_maize/phg_v5Assemblies_20200608.db. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The resilience of the developing reading system: multi-modal evidence of incident and recovery after a pediatric stroke.

Decades of neuroscientific findings have elucidated the highly specialized brain areas involved in reading, especially along the ventral occipitotemporal stream where the critical step of recognizing words occurs. We report on a 14-year-old female with temporary dyslexia after a left ventral occipitotemporal ischemic stroke. Our longitudinal multimodal findings show that the resolution of the reading impairment was associated with heightened activity in the left posterior superior and inferior temporal gyri. Our findings highlight the role of the left inferior temporal gyrus in reading and the importance of perilesional and ipsilateral cortical areas for functional recovery after childhood stroke.

Neural dynamics of semantic categorization in semantic variant of primary progressive aphasia.

Semantic representations are processed along a posterior-to-anterior gradient reflecting a shift from perceptual (e.g., it has eight legs) to conceptual (e.g., venomous spiders are rare) information. One critical region is the anterior temporal lobe (ATL): patients with semantic variant primary progressive aphasia (svPPA), a clinical syndrome associated with ATL neurodegeneration, manifest a deep loss of semantic knowledge. We test the hypothesis that svPPA patients perform semantic tasks by over-recruiting areas implicated in perceptual processing. We compared MEG recordings of svPPA patients and healthy controls during a categorization task. While behavioral performance did not differ, svPPA patients showed indications of greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. These findings suggest a pervasive reorganization of brain networks in response to ATL neurodegeneration: the loss of this critical hub leads to a dysregulated (semantic) control system, and defective semantic representations are seemingly compensated via enhanced perceptual processing.

Regional and hemispheric susceptibility of the temporal lobe to FTLD-TDP type C pathology.

Post-mortem studies show that focal anterior temporal lobe (ATL) neurodegeneration is most often caused by frontotemporal lobar degeneration TDP-43 type C pathology. Clinically, these patients are described with different terms, such as semantic variant primary progressive aphasia (svPPA), semantic dementia (SD), or right temporal variant frontotemporal dementia (FTD) depending on whether the predominant symptoms affect language, semantic knowledge for object or people, or socio-emotional behaviors. ATL atrophy presents with various degrees of lateralization, with right-sided cases considered rarer even though estimation of their prevalence is hampered by the paucity of studies on well-characterized, pathology-proven cohorts. Moreover, it is not clear whether left and right variants show a similar distribution of atrophy within the ATL cross-sectionally and longitudinally. Here we study the largest cohort to-date of pathology-proven TDP-43-C cases diagnosed during life as svPPA, SD or right temporal variant FTD. We analyzed clinical, cognitive, and neuroimaging data from 30 cases, a subset of which was followed longitudinally. Guided by recent structural and functional parcellation studies, we constructed four bilateral ATL regions of interest (ROIs). The computation of an atrophy lateralization index allowed the comparison of atrophy patterns between the two hemispheres. This led to an automatic, imaging-based classification of the cases as left-predominant or right-predominant. We then compared the two groups in terms of regional atrophy patterns within the ATL ROIs (cross-sectionally) and atrophy progression (longitudinally). Results showed that 40% of pathology proven cases of TDP-43-C diagnosed with a temporal variant presented with right-lateralized atrophy. Moreover, the findings of our ATL ROI analysis indicated that, irrespective of atrophy lateralization, atrophy distribution within both ATLs follows a medial-to-lateral gradient. Finally, in both left and right cases, atrophy appeared to progress to the contralateral ATL, and from the anterior temporal pole to posterior temporal and orbitofrontal regions. Taken together, our findings indicate that incipient right predominant ATL atrophy is common in TDP-43-C pathology, and that distribution of damage within the ATLs appears to be the same in left- and right- sided variants. Thus, regardless of differences in clinical phenotype and atrophy lateralization, both temporal variants of FTD should be viewed as a spectrum presentation of the same disease.

Dopamine receptor D4 (DRD4) polymorphisms with reduced functional potency intensify atrophy in syndrome-specific sites of frontotemporal dementia.

OBJECTIVE: We aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration. METHODS: 337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures. RESULTS: DRD4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity. CONCLUSIONS: We conclude that DRD4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD.

Impacts of Crop Variety and Time of Inoculation on the Susceptibility and Tolerance of Winter Wheat to Wheat streak mosaic virus.

Plant genotype, age, size, and environmental factors can modify susceptibility and tolerance to disease. Understanding the individual and combined impacts of these factors is needed to define improved disease management strategies. In the case of Wheat streak mosaic virus (WSMV) in winter wheat, yield losses and plant susceptibility have been found to be greatest when the crop is exposed to the virus in the fall in the central and southern Great Plains. However, the seasonal dynamics of disease risk may be different in the northern Great Plains, a region characterized by a relatively cooler fall conditions, because temperature is known to modify plant-virus interactions. In a 2-year field study conducted in south-central Montana, we compared the impact of fall and spring WSMV inoculations on the susceptibility, tolerance, yield, and grain quality of 10 winter wheat varieties. Contrary to previous studies, resistance and yields were lower in the spring than in the fall inoculation. In all, 5 to 7% of fall-inoculated wheat plants were infected with WSMV and yields were often similar to uninoculated controls. Spring inoculation resulted in 45 to 57% infection and yields that were 15 to 32% lower than controls. Although all varieties were similarly susceptible to WSMV, variations in tolerance (i.e., yield losses following exposure to the virus) were observed. These results support observations that disease risk and impacts differ across the Great Plains. Possible mechanisms include variation in climate and in the genetic composition of winter wheat and WSMV across the region.

Relative Susceptibility Among Alternative Host Species Prevalent in the Great Plains to Wheat streak mosaic virus.

Wild grasses, crops, and grassy weeds are known to host Wheat streak mosaic virus (WSMV) and its vector, the wheat curl mite (WCM). Their relative importance as a source of WSMV was evaluated. A survey of small-grain fields throughout Montana was conducted between 2008 and 2009. Cheatgrass was the most prevalent grassy weed and the most frequent viral host, with 6% infection by WSMV in 2008 (n = 125) and 15% in 2009 (n = 358). By mechanically inoculating plants with WSMV in the greenhouse, the highest susceptibility was found in rye brome (52.1%), jointed goatgrass (80.9%), and wild oat (53.9%. Quackgrass, not previously reported as a host, was susceptible to WSMV (12.7%). Mite transmission efficiency from susceptible grass species was lower than from wheat, and grass species must be a host for both WSMV and the WCM to serve as a virus source. WCM transmission was more efficient than mechanical transmission. Overall, results indicate that grass species can serve as a viral reservoir, regional variation in a weed species' susceptibility to WSMV cannot explain geographic variation in epidemic intensity, and crop species and closely related weeds (e.g., jointed goatgrass) remain the best reservoirs for both WSMV and the WCM.

Reducing antibiotic use in children: a randomized trial in 12 practices.

OBJECTIVE: To test whether an educational outreach intervention for families and physicians, based on the Centers for Disease Control and Prevention (CDC) principles of judicious antibiotic use, decreases antimicrobial drug prescribing for children younger than 6 years old. Setting. Twelve practices affiliated with 2 managed care organizations (MCOs) in eastern Massachusetts and northwest Washington State. Patients. All enrolled children younger than 6 years old. METHODS: Practices stratified by MCO and size were randomized to intervention or control groups. The intervention included 2 meetings of the practice with a physician peer leader, using CDC-endorsed summaries of judicious prescribing recommendations; feedback on previous prescribing rates were also provided. Parents were mailed a CDC brochure on antibiotic use, and supporting materials were displayed in waiting rooms. Automated enrollment, ambulatory visit, and pharmacy claims were used to determine rates of antibiotic courses dispensed (antibiotics/person-year) during baseline (1996-1997) and intervention (1997-1998) years. The primary analysis (for children 3 to <36 months and 36 to <72 months) assessed the impact of the intervention among children during the intervention year, controlling for covariates including patient age and baseline prescription rate. Confirmatory analyses at the practice level were also performed. RESULTS: The practices cared for 14 468 and 13 460 children in the 2 study years, respectively; 8815 children contributed data in both years. Sixty-two percent of antibiotic courses were dispensed for otitis media, 6.5% for pharyngitis, 6.3% for sinusitis, and 9.2% for colds and bronchitis. Antibiotic dispensing for children 3 to <36 months old decreased 0.41 antibiotics per person-year (18.6%) in intervention compared with 0.33 (11.5%) in control practices. Among children 36 to <72 months old, the rate decreased by 0.21 antibiotics per person-year (15%) in intervention and 0.17 (9.8%) in control practices. Multivariate analysis showed an adjusted intervention effect of 16% in the younger and 12% in the older age groups. The direction and approximate magnitude of effect were confirmed in practice-level analyses. CONCLUSIONS: A limited simultaneous educational outreach intervention for parents and providers reduced antibiotic use among children in primary care practices, even in the setting of substantial secular trends toward decreased prescribing. Future efforts to promote judicious prescribing should continue to build on growing public awareness of antibiotic overuse.

Synergism between transcription factors TFE3 and Smad3 in transforming growth factor-beta-induced transcription of the Smad7 gene.

Activation of transforming growth factor-beta (TGF-beta) receptors triggers phosphorylation of Smad2 and Smad3. After binding to Smad4, the complex enters the nucleus and interacts with other transcription factors to activate gene transcription. Unlike other Smads, Smad7 inhibits phosphorylation of Smad2 and Smad3, and its transcription is induced by TGF-beta, suggesting a negative feedback loop. Here, we show that TFE3 and Smad3 synergistically mediate TGF-beta-induced transcription from the Smad7 promoter by binding to an E-box and two adjacent Smad binding elements (SBEs), respectively. A precise 3-base pair spacer between one SBE and the E-box is essential. Previously, we showed that a similar arrangement between a SBE and an E-box of an element is essential for TGF-beta-dependent transcription of the plasminogen activator inhibitor-1 gene (PAI-1) and that TGF-beta-induced phosphorylation of Smad3 triggers its association with TFE3. Thus, TFE3-Smad3 response elements may represent a common target for TGF-beta-induced gene expression.

Congenital cutaneous candidiasis: clinical presentation, pathogenesis, and management guidelines.

We describe a term infant with congenital cutaneous candidiasis (CCC), and review all cases in the English literature that reported birth weight and outcome. Presence of an intrauterine foreign body was a predisposing factor for development of CCC and subsequent preterm birth. The most common presentation of CCC in neonates weighing >1000 g was a generalized eruption of erythematous macules, papules, and/or pustules that sometimes evolved to include vesicles and bullae. Extremely low birth weight, premature neonates weighing <1000 g most often presented with a widespread desquamating and/or erosive dermatitis (10 of 15 [67%]), and were at greater risk for systemic infection with Candida spp (10 of 15 [67%]) and death (6 of 15 [40%] than those weighing >1000 g (5 of 48 [10%]; 4 of 48 [8%], respectively). Systemic antifungal therapy is recommended for neonates with burn-like dermatitis attributable to Candida spp, or positive blood, urine, and/or cerebrospinal fluid cultures. Systemic treatment also should be considered for all infants with CCC who have respiratory distress in the immediate neonatal period and/or laboratory signs of sepsis such as an elevated leukocyte count with an increase in immature forms or persistent hyperglycemia and glycosuria.

Specificity in transforming growth factor beta-induced transcription of the plasminogen activator inhibitor-1 gene: interactions of promoter DNA, transcription factor muE3, and Smad proteins.

Transforming growth factor beta (TGF-beta) regulates a broad range of biological processes, including cell growth, development, differentiation, and immunity. TGF-beta signals through its cell surface receptor serine kinases that phosphorylate Smad2 or Smad3 proteins. Because Smad3 and its partner Smad4 bind to only 4-bp Smad binding elements (SBEs) in DNA, a central question is how specificity of TGF-beta-induced transcription is achieved. We show that Smad3 selectively binds to two of the three SBEs in PE2.1, a TGF-beta-inducible fragment of the plasminogen activator inhibitor-1 promoter, to mediate TGF-beta-induced transcription; moreover, a precise 3-bp spacer between one SBE and the E-box, a binding site for transcription factor muE3 (TFE3), is essential for TGF-beta-induced transcription. Whereas an isolated Smad3 MH1 domain binds to TFE3, TGF-beta receptor-mediated phosphorylation of full-length Smad3 enhances its binding to TFE3. Together, these studies elucidate an important mechanism for specificity in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene.

Managed care and the infectious diseases specialist.

There is growing demand to contain health care costs and to reassess the value of medical services. The traditional hospital, academic, and research roles of the infectious disease (ID) specialist are threatened, yet there is an increasing need for expertise because of growing antimicrobial resistance and emerging pathogens. Opportunities exist to develop and expand services for the care of patients infected with human immunodeficiency virus and in infection control, epidemiology, outcomes research, outpatient intravenous therapy, and resource management. It is important for ID physicians to appreciate the principles involved in managed care and the areas in which ID services can be valuable. To be effective, physicians need to know about tools such as practice guidelines, physician profiling, outcomes monitoring, computerized information management, risk sharing, networking, and marketing, as well as related legal issues. With a positive attitude toward learning, application, and leadership, ID physicians can redefine their role and expand their services through managed care.

Outpatient parenteral antibiotic therapy. Management of serious infections. Part II: Amenable infections and models for delivery. Health maintenance organization.

HMOs can provide economical outpatient parenteral antibiotic therapy that takes advantage of existing nursing and physician staff as well as centralized pharmacy services. Reimbursement problems are nonexistent. Treatment is possible in the home or clinic. In the model presented, the therapeutic program is initiated and supervised by infectious disease specialists.

Development and validation of an immunization tracking system in a large health maintenance organization.

Practitioners seeing individual patients and those charged with improving immunization practices in that population need accurate information on the epidemiology of immunizations within the population. To meet this need, we have developed a computer-based record of data required by the National Childhood Vaccine Injury Act of 1986 for all immunizations given to 350,000 enrollees in a large health maintenance organization. In the first eight months of operation, 102,271 immunizations representing 11 separate antigens given to 65,676 enrollees were entered into the database. Comparison of immunizations given and recorded in the medical record with the database shows that the system has high sensitivity, specificity, and positive predictive value, but a relatively low negative predictive value. The database is being used for analysis of current immunization practices for Haemophilus influenzae b vaccine and for research on adverse outcomes of childhood immunizations.

Development of an immunization tracking system in a large health maintenance organization. Group Health Cooperative of Puget Sound.

We have successfully developed a mainframe system for tracking all immunizations administered to enrollees in a large HMO. This system will provide comprehensive immunization records on a population of over 350,000 patients. Data required by the National Childhood Vaccine Injury Act of 1986 are locally entered into terminals, and records of immunization are stored in a database. Preliminary results show that data entry times are practical, but that improvement in data quality is needed. This immunization tracking system will be used for research, and as the foundation of an immunization reminder system under development.