Development and validation of a clinical respiratory disease scoring system for guiding treatment decisions in veal calves using a Bayesian framework.

Active infectious bovine respiratory disease (BRD) is an infection of the airways that needs to be diagnosed correctly so that appropriate treatment can be initiated. The simplest and most practical test to detect active BRD in dairy calves raised for veal is the detection and interpretation of clinical signs by producers or technicians. However, the clinical scoring system currently available for veal calves lacks sensitivity and specificity, contributing to economic losses and high use of antimicrobials. An accurate and reliable batch-level test to detect active BRD is essential to tailor antimicrobial use and reduce economic losses in veal calves. The objective of this study was therefore to develop and validate a new veal calf respiratory clinical scoring system (VcCRS), including reliable clinical signs (cough, ear droop or head tilt) and increased rectal temperature to detect active BRD in batches of veal calves housed individually, and to describe the accuracy of the scoring system for identifying batches of veal calves to treat. During 2017 to 2018, clinical examination, thoracic ultrasonography (TUS) and a haptoglobin concentration (Hap) were prospectively performed on 800 veal calves housed individually in Québec, Canada. Deep nasopharyngeal swabs were performed on 250 veal calves. A Bayesian latent class model accounting for imperfect accuracy of TUS and Hap was used to obtain weights for the clinical signs and develop the VcCRS. The VcCRS was then validated externally in 3 separate data sets. Finally, the applicability of the VcCRS at batch level was determined. We found that calves with 2 of the following findings-cough, unilateral or bilateral ear droop or head tilt, or increased rectal temperature ≥39.7°C-were considered positive and had a 31% chance of having active BRD. Without at least 2 of these 2 findings, a calf had a 100% chance of not having active BRD. At the batch level, we found that a batch with ≥3 positive calves among 10 calves sampled 2 wk after arrival at the fattening unit had a 94% chance of having an active BRD prevalence ≥10%. A batch with <3 positive calves had a 95% chance of not having an active BRD prevalence ≥10%. In this study, we developed a simple individual and batch-level score that is reliable across examiners and performs effectively in the detection of active BRD in veal calves. The implementation of this VcCRS in the veal calf industry would promote the elaboration of a protocol tailoring antimicrobial use.

Association between transfer of passive immunity and health disorders in multisource commingled dairy calves raised for veal or other purposes: Systematic review and meta-analysis.

Inadequate transfer of passive immunity (ITPI) in newborn dairy calves remains an important risk factor for mortality and morbidity. Most available studies are focused on calves delivered and raised on the same farms. This setting is far different from calves transported and commingled from different farms to be raised as veal or for other purposes. The aim of this systematic review and meta-analysis was to describe the association between ITPI and important health outcomes (mortality, bovine respiratory disease, and diarrhea) in multisource commingled dairy calves raised for veal or other purposes. We searched studies through CAB abstracts (via CAB direct), PubMed, and Web of Science (via ISI) databases until September 2, 2021. Observational studies and randomized trials written in English or French assessing ITPI association with any of the selected outcomes were included. Young dairy calves transported to commercial facilities and explicitly stated as being raised for veal production or not (then considered as "other") were our populations of interest. If raw or adjusted data were available for ≥5 studies for a given outcome of interest, then random effect meta-analysis models were used to investigate ITPI effects on this outcome. Nineteen studies were selected from 6,221 abstracts retrieved in the initial search. We observed significantly higher odds of mortality in calves with ITPI compared with those with successful transfer of passive immunity [odds ratio (OR) = 2.46; 95% confidence interval (CI): 1.43-4.22, n = 8 studies]. Calves with ITPI had higher odds of diarrhea (OR = 3.03; 95% CI: 1.2-7.62, n = 7 studies). A significant publication bias toward publishing studies with positive results was found in studies reporting on bovine respiratory disease (n = 5 studies), which revealed nonsignificant associations after correction of publication bias (OR = 1.40; 95% CI: 0.77-2.6). Heterogeneity could not be thoroughly investigated for mortality and diarrhea due to the limited number of studies. Therefore, the pooled estimates of the random models should be interpreted with caution despite their robustness to sensitivity analyses. In this study, we also observed that multiple definitions for transfer of passive immunity and outcomes were used in the literature. Moreover, the raising system definition was often limited. There seems, therefore, to be a need for standardized definitions of these parameters, as well as a better description of systems used for multisource commingled dairy calves raised for veal production or other production purposes.

Evaluation of inter-rater agreement of the clinical signs used to diagnose bovine respiratory disease in individually housed veal calves.

In dairy calves raised for veal, typical clinical signs of bovine respiratory disease (BRD) are ocular discharge, nasal discharge, ear droop or head tilt, abnormal respiration, cough, and increased rectal temperature. Despite the existence of several clinical scoring systems, there are few studies on the variability of human recognition of individual BRD clinical signs. The objective of this study was therefore to assess the inter-rater agreement of BRD clinical signs in veal calves. We hypothesized that BRD clinical signs were not detected equally between veterinarians, technicians, and producers of the veal industry and that some clinical signs have higher inter-rater agreement than others. During 2017-2018, we prospectively recorded 524 videos of physical examinations of random veal calves from 48 different batches in Québec, Canada. A researcher, not involved in the inter-rater assessment, classified each video as presence/absence of each BRD clinical sign except rectal temperature. For each of the 5 clinical signs, 15 videos with and 15 videos without the clinical signs were randomly selected to avoid kappa paradoxes. Those 30 videos were then presented in a random order to experienced raters of BRD in veal calves: 6 veterinarians, 6 technicians, and 6 producers. The raters assessed the clinical signs using scores based on the Wisconsin and California scoring system with modifications (0 = absent, 1 = mild, 2 = moderate, 3 = severe for nasal discharge, ocular discharge, and ear droop or head tilt; and 0 = absent, 1 = moderate, 2 = severe for abnormal respiration and induced cough). We used median percentage agreement (Pa), median Cohen's kappa (κ), and Gwet's agreement coefficient 1 (AC1) to assess inter-rater agreement. The effect of scale combination was also tested to determine the optimal combination (4-scale 0/1/2/3 vs. 3-scale 0/1/2 vs. 2-scale 0/1,2,3; 0,1/2,3; or 0/1,2). The differences of inter-rater agreement between veterinarians, technicians, and producers were estimated by a Wilcoxon rank-sum test. The 2-scale combination (0,1/2,3 or 0/1,2) had the highest inter-rater agreement for all clinical signs. With this combination, induced cough was the clinical sign with the highest inter-rater agreement (Pa = 0.93; κ = 0.79; AC1 = 0.87) and abnormal respiration was the sign with the lowest inter-rater agreement (Pa = 0.77; κ = 0.20; AC1 = 0.74). According to Pa and AC1 values, the 2-scale inter-rater agreement of the 5 clinical signs was good (value > 0.6). According to κ, only ear droop or head tilt and induced cough had a substantial 2-scale inter-rater agreement (κ > 0.6). In general, the 2-scale inter-rater agreement was better among veterinarians than among technicians and producers, except for the ear droop/head tilt, where agreement was better among producers. We concluded that with severity scores assessed on a scale of 2 (0,1/2,3 or 0/1,2), the inter-rater agreement of BRD clinical signs was variable according to the sign in veal calves. BRD clinical signs were not detected equally between veterinarians, technicians, and producers of the veal industry. Future research could determine if this discrepancy could be improved by standardization training.

Aspergillus fumigatus and aspergillosis: From basics to clinics.

The airborne fungus Aspergillus fumigatus poses a serious health threat to humans by causing numerous invasive infections and a notable mortality in humans, especially in immunocompromised patients. Mould-active azoles are the frontline therapeutics employed to treat aspergillosis. The global emergence of azole-resistant A. fumigatus isolates in clinic and environment, however, notoriously limits the therapeutic options of mould-active antifungals and potentially can be attributed to a mortality rate reaching up to 100 %. Although specific mutations in CYP 51A are the main cause of azole resistance, there is a new wave of azole-resistant isolates with wild-type CYP 51A genotype challenging the efficacy of the current diagnostic tools. Therefore, applications of whole-genome sequencing are increasingly gaining popularity to overcome such challenges. Prominent echinocandin tolerance, as well as liver and kidney toxicity posed by amphotericin B, necessitate a continuous quest for novel antifungal drugs to combat emerging azole-resistant A. fumigatus isolates. Animal models and the tools used for genetic engineering require further refinement to facilitate a better understanding about the resistance mechanisms, virulence, and immune reactions orchestrated against A. fumigatus. This review paper comprehensively discusses the current clinical challenges caused by A. fumigatus and provides insights on how to address them.

Comparison between thoracic ultrasonography and thoracic radiography for the detection of thoracic lesions in dairy calves using a two-stage Bayesian method.

Infectious bronchopneumonia is a lower respiratory tract disease with major economic consequences in dairy calves. Thoracic radiography (TR) and thoracic ultrasonography (TUS) are two imaging diagnostic procedures available in bovine medicine for identifying thoracic lesions. However, no study has investigated whether one of these tests is superior to the other or if they provide comparable results for the detection of thoracic lesions in calves. The objective of this study was therefore to estimate and to compare the performances of TUS and TR for the detection of thoracic lesions in dairy calves. A prospective cross-sectional study was performed in a hospital setting. A total of 50 calves (≥7 days old; ≤100 kg; standing; pCO2 ≥ 53 mmHg; any reason of presentation) were enrolled. Every calf underwent TUS and TR. Only calves with thoracic lesions on TUS and/or TR were controlled by thoracic computed tomography (CT) (the gold standard). Calves without lesions were not controlled by CT. A two-stage Bayesian framework was used. The sensitivities (Se) and specificities (Sp) of both tests individually and used in series or parallel were estimated. The Se and Sp of TUS were 0.81 (95 % BCI (Bayesian Credible Interval): 0.65; 0.92) and 0.90 (95 % BCI: 0.81; 0.96), respectively. The Se and Sp of TR were 0.86 (95 % BCI: 0.62; 0.99) and 0.89 (95 % BCI: 0.67; 0.99), respectively. This study did not reveal any differences between both tests. Using TUS and TR in series was more specific than using both tests in parallel. The performances of TUS alone were not different from the performances of both tests in series or in parallel. In conclusion, TUS and TR were equivalent in detecting thoracic lesions in this study. Using TUS alone allowed an accurate detection of thoracic lesions in dairy calves. Further studies enrolling a larger sample (> 400 calves) and allowing adequate power to be achieved would be necessary to confirm these results.

Hot under the collar: A 14-year association between temperature and violent behavior across 436 U.S. counties.

OBJECTIVES: Violent behavior is influenced by individual and societal characteristics, but the role of environmental factors is less understood. Our aims were to use national-level data to identify the association between criminal behavior and short-term temperature conditions, including the departure of daily temperatures from normal conditions. METHODS: We conducted a multi-stage hierarchical time-series model across 436 U.S. counties and 14-years representing 100.4 million people to investigate the association between daily mean temperature and daily mean temperatures departing from normal conditions with violent and non-violent crime counts. First-stage comparisons were made within counties to control for population and geographic heterogeneities, while a second stage combined estimates. We evaluated differences in risk based on county sociodemographic characteristics and estimated non-linear exposure-response relationships. RESULTS: We observed a total of 9.0 million violent crimes and 20.9 million non-violent property crimes between 2000 through 2013. We estimated that each 10 °C increase in daily temperature or daily departure from long-term normal temperatures were associated with 11.92% (95% PI: 11.57, 12.27) and 10.37% (95% PI: 10.05, 10.69) increase in the risk of violent crime, respectively. Similar, but lower in magnitude trends, were observed for property crime risks. We found that crime risk plateaus and decreases at high daily temperatures, but for temperatures departing from normal, the association with crime increased linearly. Seasonal variations showed that anomalously warm temperatures days during cool months had the greatest risk. CONCLUSIONS: Our study revealed an association between higher temperatures and high departure from normal temperatures with both violent and non-violent crime risk, regardless of community-type. However, our findings on seasonal and daily trends suggest that daily mean temperature may impact crime by affecting routine activities and behavior, as opposed to a temperature-aggression relationship. These results may advance public response and planning to prevent violent behavior.

HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System.

Antiretroviral therapy (ART) has transformed HIV into a chronic condition, lengthening and improving the lives of individuals living with this virus. Despite successful suppression of HIV replication, people living with HIV (PLWH) are susceptible to a growing number of comorbidities, including neuroHIV that results from infection of the central nervous system (CNS). Alterations in the dopaminergic system have long been associated with HIV infection of the CNS. Studies indicate that changes in dopamine concentrations not only alter neurotransmission, but also significantly impact the function of immune cells, contributing to neuroinflammation and neuronal dysfunction. Monocytes/macrophages, which are a major target for HIV in the CNS, are responsive to dopamine. Therefore, defining more precisely the mechanisms by which dopamine acts on these cells, and the changes in cellular function elicited by this neurotransmitter are necessary to develop therapeutic strategies to treat neuroHIV. This is especially important for vulnerable populations of PLWH with chemically altered dopamine concentrations, such as individuals with substance use disorder (SUD), or aging individuals using dopamine-altering medications. The specific neuropathologic and neurocognitive consequences of increased CNS dopamine remain unclear. This is due to the complex nature of HIV neuropathogenesis, and logistical and technical challenges that contribute to inconsistencies among cohort studies, animal models and in vitro studies, as well as lack of demographic data and access to human CNS samples and cells. This review summarizes current understanding of the impact of dopamine on HIV neuropathogenesis, and proposes new experimental approaches to examine the role of dopamine in CNS HIV infection. Graphical abstract HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System. Both substance abuse disorders and the use of dopaminergic medications for age-related diseases are associated with changes in CNS dopamine concentrations and dopaminergic neurotransmission. These changes can lead to aberrant immune function, particularly in myeloid cells, which contributes to the neuroinflammation, neuropathology and dysfunctional neurotransmission observed in dopamine-rich regions in HIV+ individuals. These changes, which are seen despite the use antiretroviral therapy (ART), in turn lead to further dysregulation of the dopamine system. Thus, in individuals with elevated dopamine, the bi-directional interaction between aberrant dopaminergic neurotransmission and HIV infection creates a feedback loop contributing to HIV associated neurocognitive dysfunction and neuroHIV. However, the distinct contributions and interactions made by HIV infection, inflammatory mediators, ART, drugs of abuse, and age-related therapeutics are poorly understood. Defining more precisely the mechanisms by which these factors influence the development of neurological disease is critical to addressing the continued presence of neuroHIV in vulnerable populations, such as HIV-infected older adults or drug abusers. Due to the complexity of this system, understanding these effects will require a combination of novel experimental modalities in the context of ART. These will include more rigorous epidemiological studies, relevant animal models, and in vitro cellular and molecular mechanistic analysis.

Bayesian estimation of sensitivity and specificity of systematic thoracic ultrasound exam for diagnosis of bovine respiratory disease in pre-weaned calves.

Among the different clinical presentations of bovine respiratory disease, active pneumonia, defined as an infection of the lower airway with signs of inflammation, is the most important to diagnose correctly so appropriate treatment can be initiated. Diagnostic tests that accurately identify cases of active pneumonia are lacking; however, thoracic ultrasonography (TUS) seems promising. The primary objective of this study was to estimate the accuracy of TUS compared to reference tests for the diagnosis of active pneumonia in pre-weaned calves, using a latent-class model method (LCM). The tests used for comparison were the Wisconsin Clinical Respiratory Scoring Chart (CRSC, positive if ≥5) and serum haptoglobin concentration (Hap, positive if ≥15 mg/dL). Secondary objectives were to assess the incremental value on TUS accuracy of combining TUS of the right cranial part and caudal parts, and to determine the accuracy of various thresholds for depth of consolidation (≥0 cm, ≥1 cm, or ≥3 cm) for diagnosis of active pneumonia. One population of veal calves (n = 209) and one of dairy calves (n = 301) were enrolled. TUS, CRSC and Hap were all performed on each calf on the same day. TUS was performed by screening the mid to ventral portion of the lung caudal of the heart (the caudal sites), as well as the right parenchyma cranial to the heart (the cranial site). The maximal depth of consolidation (DEPTH) on TUS was recorded and noted separately for caudal and cranial sites. Different TUS cases were defined according to site and DEPTH. The accuracy of TUS was estimated by LCM for three tests conducted in two populations. Prevalence of active pneumonia was low (0.05) in both populations. In general, higher minimal consolidation depth thresholds led to increased TUS specificity (Sp) estimates, with minimal effects on TUS sensitivity (Se). With a TUS DEPTH threshold of ≥3 cm, adding TUS of the cranial site had little effect on accuracy. Using the ≥3 cm threshold with caudal sites only, posterior Se and Sp median estimates of 0.89 (95%BCI: 0.55, 1.0) and 0.95 (95%BCI: 0.92, 0.98), respectively, were obtained. In conclusion, in populations with low active pneumonia prevalence, adding TUS of the cranial site did not enhance the performance of the test. We suggest using a DEPTH threshold of ≥3 cm solely on caudal sites to detect active pneumonia.

Developing a geostatistical simulation method to inform the quantity and placement of new monitors for a follow-up air sampling campaign.

Sampling campaign design is a crucial aspect of air pollution exposure studies. Selection of both monitor numbers and locations is important for maximizing measured information, while minimizing bias and costs. We developed a two-stage geostatistical-based method using pilot NO2 samples from Lanzhou, China with the goal of improving sample design decision-making, including monitor numbers and spatial pattern. In the first step, we evaluate how additional monitors change prediction precision through minimized kriging variance. This was assessed in a Monte Carlo fashion by adding up to 50 new monitors to our existing sites with assigned concentrations based on conditionally simulated NO2 surfaces. After identifying a number of additional sample sites, a second step evaluates their potential placement using a similar Monte Carlo scheme. Evaluations are based on prediction precision and accuracy. Costs are also considered in the analysis. It was determined that adding 28-locations to the existing Lanzhou NO2 sampling campaign captured 73.5% of the total kriged variance improvement and resulted in predictions that were on average within 10.9 µg/m3 of measured values, while using 56% of the potential budget. Additional monitor sites improved kriging variance in a nonlinear fashion. This method development allows for informed sampling design by quantifying prediction improvement (accuracy and precision) against the costs of monitor deployment.

Feasibility of Patient-Reported Outcomes Measurement Information System (PROMIS®) computerized adaptive tests in systemic lupus erythematosus outpatients.

Objective The aims of this study were to assess the feasibility of administering Patient-Reported Outcomes Measurement Information System (PROMIS®) computerized adaptive tests (CATs) to outpatients with systemic lupus erythematosus (SLE). Methods Adults with SLE were recruited during routine outpatient visits at an SLE Center of Excellence. Participants completed 14 PROMIS CATs and provided feedback on their experience. Differences in socio-demographic and clinical characteristics between participants and non-participants were evaluated. Results A total of 204 (86%) of 238 socioeconomically and racially diverse SLE patients completed PROMIS CATs. There were no significant differences between participants and non-participants. Time constraints were cited most frequently as reasons for non-participation. More than 75% of individuals submitted positive comments, including approval of the content and format of questions, and the survey's promotion of self-reflection. A minority of participants cited challenges, most often related to question phrasing (8%) and technical difficulties (6%). Conclusions The administration of PROMIS CATs was feasible and positively received in a diverse cohort of SLE outpatients. Neither socio-demographic nor disease characteristics were significant barriers to successful completion of PROMIS CATs. PROMIS CATs have great potential for efficiently measuring important patient-centered outcomes in routine clinical care of a wide range of SLE patients.

School environmental conditions and links to academic performance and absenteeism in urban, mid-Atlantic public schools.

School facility conditions, environment, and perceptions of safety and learning have been investigated for their impact on child development. However, it is important to consider how the environment separately influences academic performance and attendance after controlling for school and community factors. Using results from the Maryland School Assessment, we considered outcomes of school-level proficiency in reading and math plus attendance and chronic absences, defined as missing 20 or more days, for grades 3-5 and 6-8 at 158 urban schools. Characteristics of the environment included school facility conditions, density of nearby roads, and an index industrial air pollution. Perceptions of school safety, learning, and institutional environment were acquired from a School Climate Survey. Also considered were neighborhood factors at the community statistical area, including demographics, crime, and poverty based on school location. Poisson regression adjusted for over-dispersion was used to model academic achievement and multiple linear models were used for attendance. Each 10-unit change in facility condition index, denoting worse quality buildings, was associated with a decrease in reading (1.0% (95% CI: 0.1-1.9%) and math scores (0.21% (95% CI: 0.20-0.40), while chronic absences increased by 0.75% (95% CI: 0.30-1.39). Each log increase the EPA's Risk Screening Environmental Indicator (RSEI) value for industrial hazards, resulted in a marginally significant trend of increasing absenteeism (p < 0.06), but no association was observed with academic achievement. All results were robust to school-level measures of racial composition, free and reduced meals eligibility, and community poverty and crime. These findings provide empirical evidence for the importance of the community and school environment, including building conditions and neighborhood toxic substance risk, on academic achievement and attendance.

Loss of PRP4K drives anoikis resistance in part by dysregulation of epidermal growth factor receptor endosomal trafficking.

Anoikis acts as a critical barrier to metastasis by inducing cell death upon cancer cell detachment from the extracellular matrix (ECM), thereby preventing tumor cell dissemination to secondary sites. The induction of anoikis requires the lysosomal-mediated downregulation of epidermal growth factor receptors (EGFRs) leading to termination of pro-survival signaling. In this study, we demonstrate that depletion of pre-mRNA splicing factor 4 kinase (PRP4K; also known as PRPF4B) causes dysregulation of EGFR trafficking and anoikis resistance. We also report a novel cytoplasmic localization of PRP4K at the late endosome, and demonstrate both nuclear and cytoplasmic localization in breast, lung and ovarian cancer tissue. Mechanistically, depletion of PRP4K leads to reduced EGFR degradation following cell detachment from the ECM and correlates with increased TrkB, vimentin and Zeb1 expression. As a result, PRP4K loss promotes sustained growth factor signaling and increased cellular resistance to anoikis in vitro and in a novel zebrafish xenotransplantation model of anoikis sensitivity, as well as increased metastasis in a mouse model of ovarian cancer. Thus, PRP4K may serve as a potential biomarker of anoikis sensitivity in ovarian and other epithelial cancers.

A randomised clinical trial of a metaphylactic treatment with tildipirosin for bovine respiratory disease in veal calves.

BACKGROUND: Bovine respiratory disease (BRD) is a major problem in veal calf rearing units. The objective of this randomised clinical trial was to assess the effectiveness of tildipirosin as a metaphylactic treatment in veal calves on the number of BRD treatments, lung consolidation on thoracic ultrasonography (TUS) and average daily gain (ADG). A total of 209 veal calves from a pre-weaning fattening unit were randomly allocated to receive one of two treatments (tildipirosin 4 mg/kg, subcutaneously, n = 109; placebo 0.9% saline, subcutaneously, n = 100) at day 12 after entry in the pre-weaned unit. The calves were followed for a 70-day period. Occurrence of mortality and BRD treatments were recorded during the pre-weaning period. At days 1, 12 and 30, TUS and clinical scores were performed and ADG was measured during the first and second months of feeding. RESULTS: The use of a metaphylactic treatment of tildipirosin 12 days after arrival of the veal calves was not associated with the number of BRD treatments performed by the producer, ultrasonographic lung consolidation or weight gain (P < 0,05). In this cohort of calves, the proportion of calves treated for BRD by the producer was low at 14% (29/209). However, 13% (26/209) of calves included in the study already had ultrasonographic lung consolidation lesions 12 days after their arrival, which was before treatment time, and 27% (56/209) had lung consolidation at day 30. CONCLUSION: In this study population with a low BRD prevalence, we were not able to detect any benefit of tildipirosin as a metaphylactic treatment of BRD at day 12 after arrival based on BRD treatments, TUS, and ADG.

Relationship between M100 Auditory Evoked Response and Auditory Radiation Microstructure in 16p11.2 Deletion and Duplication Carriers.

BACKGROUND AND PURPOSE: Deletion and duplication of chromosome 16p11.2 (BP4-BP5) have been associated with developmental disorders such as autism spectrum disorders, and deletion subjects exhibit a large (20-ms) delay of the auditory evoked cortical response as measured by magnetoencephalography (M100 latency). The purpose of this study was to use a multimodal approach to test whether changes in white matter microstructure are associated with delayed M100 latency. MATERIALS AND METHODS: Thirty pediatric deletion carriers, 9 duplication carriers, and 39 control children were studied with both magnetoencephalography and diffusion MR imaging. The M100 latency and auditory system DTI measures were compared between groups and tested for correlation. RESULTS: In controls, white matter diffusivity significantly correlated with the speed of the M100 response. However, the relationship between structure and function appeared uncoupled in 16p11.2 copy number variation carriers. The alterations to auditory system white matter microstructure in the 16p11.2 deletion only partially accounted for the 20-ms M100 delay. Although both duplication and deletion groups exhibit abnormal white matter microstructure, only the deletion group has delayed M100 latency. CONCLUSIONS: These results indicate that gene dosage impacts factors other than white matter microstructure, which modulate conduction velocity.

Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98-HOXA9-induced myeloid disease.

Acute myeloid leukemia (AML) occurs when multiple genetic aberrations alter white blood cell development, leading to hyperproliferation and arrest of cell differentiation. Pertinent animal models link in vitro studies with the use of new agents in clinical trials. We generated a transgenic zebrafish expressing human NUP98-HOXA9 (NHA9), a fusion oncogene found in high-risk AML. Embryos developed a preleukemic state with anemia and myeloid cell expansion, and adult fish developed a myeloproliferative neoplasm (MPN). We leveraged this model to show that NHA9 increases the number of hematopoietic stem cells, and that oncogenic function of NHA9 depends on downstream activation of meis1, the PTGS/COX pathway and genome hypermethylation through the DNA methyltransferase, dnmt1. We restored normal hematopoiesis in NHA9 embryos with knockdown of meis1 or dnmt1, as well as pharmacologic treatment with DNA (cytosine-5)-methyltransferase (DNMT) inhibitors or cyclo-oxygenase (COX) inhibitors. DNMT inhibitors reduced genome methylation to near normal levels. Strikingly, we discovered synergy when we combined sub-monotherapeutic doses of a histone deacetylase inhibitor plus either a DNMT inhibitor or COX inhibitor to block the effects of NHA9 on zebrafish blood development. Our work proposes novel drug targets in NHA9-induced myeloid disease, and suggests rational therapies by combining minimal doses of known bioactive compounds.

Nested case-control study of selected systemic autoimmune diseases in World Trade Center rescue/recovery workers.

OBJECTIVE: To test the a priori hypothesis that acute and chronic work exposures to the World Trade Center (WTC) site on or after September 11, 2001 were associated with risk of new-onset systemic autoimmune diseases. METHODS: A nested case-control study was performed in WTC rescue/recovery workers who had received a rheumatologist-confirmed systemic autoimmune disease diagnosis between September 12, 2001 and September 11, 2013 (n = 59), each of whom was individually matched to 4 randomly selected controls (n = 236) on the basis of year of hire (±1 year), sex, race, and work assignment (firefighter or emergency medical service). Acute exposure was defined according to the earliest time of arrival (morning of 9/11 versus later) at the WTC site, and chronic exposure was defined as duration (number of months) of WTC site-related work. Rheumatologists were blinded with regard to each subject's exposure status. The conditional odds ratios (CORs) with 95% confidence intervals (95% CIs) for incident autoimmune disease were derived from exact conditional logistic regression models. RESULTS: Rheumatoid arthritis was the most common autoimmune diagnosis (37% of subjects), followed by spondyloarthritis (22%), inflammatory myositis (14%), systemic lupus erythematosus (12%), systemic sclerosis (5%), Sjögren's syndrome (5%), antiphospholipid syndrome (3%), and granulomatosis with polyangiitis (Wegener's) (2%). The COR for incident autoimmune disease increased by 13% (COR 1.13, 95% CI 1.02-1.26) for each additional month worked at the WTC site. These odds were independent of the association between high acute exposure (working during the morning of 9/11) and disease outcome, which conveyed an elevated, but not statistically significant, risk (COR 1.85, 95% CI 0.86-3.89). CONCLUSION: Prolonged work at the WTC site, independent of acute exposure, was an important predictor of post-9/11 systemic autoimmune diseases. The WTC Health Program should expand surveillance efforts for those with extended exposures, as early detection can facilitate early treatment, which has been shown to minimize organ damage and improve quality of life.

Left hemisphere diffusivity of the arcuate fasciculus: influences of autism spectrum disorder and language impairment.

BACKGROUND AND PURPOSE: There has been much discussion whether brain abnormalities associated with specific language impairment and autism with language impairment are shared or are disorder specific. Although white matter tract abnormalities are observed in both specific language impairment and autism spectrum disorders, the similarities and differences in the white matter abnormalities in these 2 disorders have not been fully determined. MATERIALS AND METHODS: Diffusion tensor imaging diffusion parameters of the arcuate fasciculus were measured in 14 children with specific language impairment as well as in 16 children with autism spectrum disorder with language impairment, 18 with autism spectrum disorder without language impairment, and 25 age-matched typically developing control participants. RESULTS: Language impairment and autism spectrum disorder both had (elevating) main effects on mean diffusivity of the left arcuate fasciculus, initially suggesting a shared white matter substrate abnormality. Analysis of axial and radial diffusivity components, however, indicated that autism spectrum disorder and language impairment differentially affect white matter microstructural properties, with a main effect of autism spectrum disorder on axial diffusivity and a main effect of language impairment on radial diffusivity. CONCLUSIONS: Although white matter abnormalities appear similar in language impairment and autism spectrum disorder when examining broad white matter measures, a more detailed analysis indicates different mechanisms for the white matter microstructural anomalies associated with language impairment and autism spectrum disorder.