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Until recently, the evaluation of bone health and fracture risk through imaging has been limited to dual-energy X-ray absorptiometry (DXA) and plain radiographs, with a limited application in the athletic population. Several novel imaging technologies are now available for the clinical assessment of bone health, including bone injury risk and healing progression, with a potential for use in sports medicine. Among these imaging modalities is high-resolution peripheral quantitative computed tomography (HR-pQCT) which is a promising technology that has been developed to examine the bone microarchitecture in both cortical and trabecular bone at peripheral anatomical sites. Technologies that do not expose patients to ionizing radiation are optimal, particularly for athletes who may require frequent imaging. One such alternative is diagnostic ultrasound, which is preferable due to its low cost and lack of radiation exposure. Furthermore, ultrasound, which has not been a common imaging modality for monitoring fracture healing, has been shown to potentially demonstrate earlier signs of union compared to conventional radiographs, including callus mineralization and density at the healing site. Through the use of conventional magnetic resonance imaging (MRI), finite element analysis (FEA) can be used to simulate the structural and mechanical properties of bone. On the other hand, the ultrashort echo time (UTE) MRI can evaluate cortical bone quality by detecting water bound to the organic bone matrix and free water, providing important information about bone porosity. Several novel bone imaging techniques originally developed for osteoporosis assessment have great potential to be utilized to improve the standard of care in bone fracture risk assessment and healing in sports medicine with much greater precision and less adverse radiation exposure.

Bone remodeling is the continual process to renew the adult skeleton through the sequential action of osteoblasts and osteoclasts. Nuclear factor RANK, an osteoclast receptor, and its ligand RANKL, expressed on the surface of osteoblasts, result in coordinated control of bone remodeling. Inflammation, a feature of illness and injury, plays a distinct role in skewing this process toward resorption. It does so via the interaction of inflammatory mediators and their related peptides with osteoblasts and osteoclasts, as well as other immune cells, to alter the expression of RANK and RANKL. Such chemical mediators include TNFα, glucocorticoids, histamine, bradykinin, PGE2, systemic RANKL from immune cells, and interleukins 1 and 6. Conditions, such as periodontal disease and alveolar bone erosion, aseptic prosthetic loosening, rheumatoid arthritis, and some sports related injuries are characterized by the result of this process. A thorough understanding of bone response to injury and disease, and ability to detect such biomarkers, as well as imaging to identify early structural and mechanical property changes in bone architecture, is important in improving management and outcomes of bone related pathology. While gut health and vitamin and mineral availability appear vitally important, nutraceuticals also have an impact on bone health. To date most pharmaceutical intervention targets inflammatory cytokines, although strategies to favorably alter inflammation induced bone pathology are currently limited. Further research is required in this field to advance early detection and treatments.

BACKGROUND: Acute hepatitis C virus (HCV) infection is often asymptomatic; thus, its epidemiology and natural history are difficult to define. METHODS: Acute HCV infection was identified on the basis of HCV seroconversion within 1 year (n=45), new anti-HCV seropositivity with clinical acute hepatitis (n=21), or HCV strain sequencing after an iatrogenic exposure (n=1). Risk factors were assessed with a baseline questionnaire, and participants were followed up prospectively with serial measurement of viral loads. RESULTS: Of 67 persons with acute HCV infection, most were asymptomatic (64%) and injection drug users (66%). Thirteen had an unknown mode of transmission; of these, 11 reported high-risk sexual behavior. Ten acquired acute HCV infection within 3 months of an iatrogenic exposure; 3 had confirmed iatrogenic infection, and 4 had no other risk factors identified. The spontaneous viral clearance rate after 6 months of infection was 18% (95% confidence interval, 11%-31%). The rate of viral clearance varied significantly by sex (34% vs. 3% for women vs. men; P<.001). CONCLUSIONS: High-risk sexual or iatrogenic exposures may be important contemporary risk factors for HCV infection. The spontaneous viral clearance rate (18%) in this contemporary study was similar to that reported for past studies of transfusion-associated HCV infection. Women were more likely to clear acute HCV infection than men. [ABSTRACT FROM AUTHOR]

Background: The potential effectiveness of various donation incentive programs may vary by demographics, first-time or repeat status, and collection site.Study Design and Methods: Attitudes toward future incentives were obtained from a 1998 anonymous survey sent to 92,581 US blood donors. Responses (encouraged, discouraged, no difference) to incentives were compared within demographic groups, donations sites, and between first-time and repeat community whole-blood (WB) donors using chi-square tests and logistic regressions adjusted for sample design.Results: Incentives most likely to encourage donation return among all 45,588 WB respondents were blood credits (61%), cholesterol screening (61%), and prostate-specific antigen (PSA) screening (73% of men). Younger donors (< or = 25 years old) were 4 to 5 times more likely to be encouraged to donate if offered compensatory incentives (tickets to events, discounts or lottery and/or raffle tickets), gifts, or a token of appreciation than were those donors older than 55. This age effect influenced positive attitudes toward incentives in first-time donors and in donors giving at schools, universities, or military sites. Among all donors, up to 7 to 9 percent reported they would be discouraged to return if offered compensatory incentives.Conclusions: Blood credits and cholesterol and PSA screening would be well received at all donation sites. Gifts, compensatory incentives, and tokens of appreciation appeal more to younger donors. These data may allow blood centers to optimize recruitment by tailoring limited incentive resources more effectively. [ABSTRACT FROM AUTHOR]

Category: Bunion Introduction/Purpose: Abnormal motion of the first tarsometatarsal (TMT) joint disrupts the anatomic alignment of the metatarsal head, sesamoid complex and proximal first phalanx. This anatomic disruption combined with the deforming forces of the extensor hallucis longus, adductor tendons, and extensor hallucis brevis result in a hallux valgus deformity. First TMT arthrodesis or the Lapidus procedure has been described as treatment for moderate to severe hallux valgus deformities by correcting hypermobility and restoring anatomic alignment of the first ray. The aim of this study was to evaluate the safety of a percutaneous approach to the Lapidus procedure and its relation to anatomic structures. Methods: A percutaneous, modified Lapidus procedure was performed on 19 embalmed cadaveric feet under fluoroscopic guidance. The specimens were then dissected to identify the extensor hallucis longus (EHL), extensor hallucis brevis (EHB), tibialis anterior (TA), median branch of the superficial peroneal nerve (MBSPN), intermediate branch of the superficial peroneal nerve (IBSPN), deep peroneal neurovascular bundle (DPNVB) and saphenous vein (SV). The structures were localized with reference to percutaneous burr and screw placement during the procedure. Results: The tibialis anterior and intermediate branch of the superficial peroneal nerve were a mean of 3.75 millimeters (mm) and 5.08 mm from the closest burr or screw placement. The extensor hallucis longus and extensor hallucis brevis were at greatest risk under the new approach with mean distances of .92 to 4.08 mm to nearby instrumentation. The extensor hallucis longus or extensor hallucis brevis were either directly pierced or

The article examines the results of two quasi-experimental studies of the implementation and impact of the Literacy Design Collaborative (LDC), an intervention designed to support secondary teachers’ transition to Common Core State Standards in English language arts. The first study examines LDC implementation by eighth-grade social studies and science teachers in districts across Kentucky; the second study is set in sixth-grade advanced reading classes in a large urban district in Florida. Based on teacher surveys, logs, and analysis of classroom artifacts, the LDC was implemented with reasonable fidelity across both studies. Based on available assessment scores, results show statistically significant positive effects in Kentucky for reading but no corollary effect in Florida. There were no significant differences in writing scores in either site. The conclusion shares hypotheses that may explain the differences in results and reflects on implications for evidence-based practice.

During August 2011, influenza A (H3N2) variant [A(H3N2)v] virus infection developed in a child who attended an agricultural fair in Pennsylvania, USA; the virus resulted from reassortment of a swine influenza virus with influenza A(H1N1)pdm09. We interviewed fair attendees and conducted a retrospective cohort study among members of an agricultural club who attended the fair. Probable and confirmed cases of A(H3N2)v virus infection were defined by serology and genomic sequencing results, respectively. We identified 82 suspected, 4 probable, and 3 confirmed case-patients who attended the fair. Among 127 cohort study members, the risk for suspected case status increased as swine exposure increased from none (4%; referent) to visiting swine exhibits (8%; relative risk 2.1; 95% CI 0.2–53.4) to touching swine (16%; relative risk 4.4; 95% CI 0.8–116.3). Fairs may be venues for zoonotic transmission of viruses with epidemic potential; thus, health officials should investigate respiratory illness outbreaks associated with agricultural events.

Background: Rapid growth in the availability of genome-wide transcript abundance levels through gene expression microarrays and RNAseq promises to provide deep biological insights into the complex, genome-wide transcriptional behavior of single-celled organisms. However, this promise has not yet been fully realized. Results: We find that computation of pairwise gene associations (correlation; mutual information) across a set of 2782 total genome-wide expression samples from six diverse bacteria produces unexpectedly large variation in estimates of pairwise gene association – regardless of the metric used, the organism under study, or the number and source of the samples. We pinpoint the cause to sampling bias. In particular, in repositories of expression data (e.g., Gene Expression Omnibus, GEO), many individual genes show small differences in absolute gene expression levels across the set of samples. We demonstrate that these small differences are due mainly to noise instead of signal attributable to environmental or genetic perturbations. We show that downstream analysis using gene expression levels of genes with small differences yields biased estimates of pairwise association.Conclusions: We propose flagging genes with small differences in absolute, RMA-normalized, expression levels (e.g., standard deviation less than 0.5), as potentially yielding biased pairwise association metrics. This strategy has the potential to substantially improve the confidence in genome-wide conclusions about transcriptional behavior in bacterial organisms. Further work is needed to further refine strategies to identify genes with small difference in expression levels prior to computing gene-gene association metrics.

Although nigrostriatal changes are most commonly affiliated with Parkinson’s disease, the role of the cerebellum in Parkinson’s has become increasingly apparent. The present study used lobule-based cerebellar resting state functional connectivity to (1) compare cerebellar-whole brain and cerebellar-cerebellar connectivity in Parkinson’s patients both ON and OFF L-DOPA medication and controls, and to (2) relate variations in cerebellar connectivity to behavioral performance. Results indicated that, when contrasted to the control group, Parkinson’s patients OFF medication had increased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity, whereas Parkinson’s patients ON medication had decreased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity. Moreover, analyses relating levels of cerebellar connectivity to behavioral measures demonstrated that, within each group, increased levels of connectivity were most often associated with improved cognitive and motor performance, but there were several instances where increased connectivity was related to poorer performance. Overall, the present study found medication-variant cerebellar connectivity in Parkinson’s patients, further demonstrating cerebellar changes associated with Parkinson’s disease and the moderating effects of medication.

Perovskite-type BaZr0.1Ce0.7Y0.1M0.1O3-δ (M = Fe, Ni, Co and Yb) (BZCY-M) oxides were synthesized using the conventional solid-state reaction method at 1350-1550 oC in air in order to investigate the effect of dopants on sintering, crystal structure, chemical stability under CO2 and H2S, and electrical transport properties. The formation of the single-phase perovskite-type structure with an orthorhombic space group Imam was confirmed by Rietveld refinement using powder X-ray diffraction (PXRD) for the Fe, Co, Ni and Yb-doped samples. The BZCY-Co and BZCY-Ni oxides show a total electrical conductivity of 0.01 and 8 × 10-3 Scm-1 at 600 oC in wet H2 with an activation energy of 0.36 and 0.41 eV, respectively. Scanning electron microscopy (SEM) and energy-dispersive X-ray analysis (EDX) revealed Ba and Co rich secondary phase at the grain-boundaries, which may explain the enhancement in the total conductivity of the BZCY-Co. However, ex-solution of Ni at higher sintering temperatures, especially at 1550 oC, decreases the total conductivity of the BZCY-Ni material. The Co and Ni dopants act as a sintering aid and form dense pellets at a lower sintering temperature of 1250 oC. The Fe, Co and Ni-doped BZCY-M samples synthesized at 1350 oC show stability in 30 ppm H2S/H2 at 800 oC, and increasing the firing temperature to 1550 oC, enhanced the chemical stability in CO2 / N2 (1: 2) at 25-900 oC. The BZCY-Co and Ni compounds with high conductivity in wet H2 could be considered as possible anodes for intermediate temperature solid oxide fuel cells (IT-SOFCs).

BACKGROUND:Prior to emergence in human populations, zoonoses such as SARS cause occasional infections in human populations exposed to reservoir species. The risk of widespread epidemics in humans can be assessed by monitoring the reproduction number R (average number of persons infected by a human case). However, until now, estimating R required detailed outbreak investigations of human clusters, for which resources and expertise are not always available. Additionally, existing methods do not correct for important selection and under-ascertainment biases. Here, we present simple estimation methods that overcome many of these limitations. METHODS AND FINDINGS:Our approach is based on a parsimonious mathematical model of disease transmission and only requires data collected through routine surveillance and standard case investigations. We apply it to assess the transmissibility of swine-origin influenza A H3N2v-M virus in the US, Nipah virus in Malaysia and Bangladesh, and also present a non-zoonotic example (cholera in the Dominican Republic). Estimation is based on two simple summary statistics, the proportion infected by the natural reservoir among detected cases (G) and among the subset of the first detected cases in each cluster (F). If detection of a case does not affect detection of other cases from the same cluster, we find that R can be estimated by 1-G; otherwise R can be estimated by 1-F when the case detection rate is low. In more general cases, bounds on R can still be derived. CONCLUSIONS:We have developed a simple approach with limited data requirements that enables robust assessment of the risks posed by emerging zoonoses. We illustrate this by deriving transmissibility estimates for the H3N2v-M virus, an important step in evaluating the possible pandemic threat posed by this virus. Please see later in the article for the Editors' Summary.

Analysis of the amplitude of low frequency BOLD signal fluctuations (ALFF) in the resting state has recently been used to study the dynamics of intrinsic neural activity. Several studies have also suggested its potential as a biomarker for neuropsychiatric disease. In the current study, we quantified ALFF to determine changes in intrinsic neural oscillations in patients with Parkinson’s disease (PD) on and off L-DOPA. Twenty-four PD patients and 24 healthy age-matched controls participated in the study. PD patients underwent two resting state fMRI sessions, either ON a controlled dose of L-DOPA or following a placebo pill (OFF). Control participants underwent one test session. We found that there was increased amplitude of low frequency BOLD signal oscillations for PD patients OFF L-DOPA in the primary and secondary motor areas, and in the middle and medial prefrontal cortices. L-DOPA significantly reduced the amplitude of low frequency oscillations within these regions. The degree of ALFF in the premotor cortex predicted patients’ motor performance as measured by the Grooved Pegboard task, such that greater ALFF was associated with poorer performance. These results are in line with the pathophysiology of PD, which shows changes in neural oscillations. Thus, frequency domain analyses of resting state BOLD fMRI signals may provide a useful means to study the pathophysiology of PD and the physiology of the brain’s dopaminergic pathways.

There is a fundamental gap in understanding how brain structural and functional network connectivity are interrelated, how they change with age, and how such changes contribute to older adults’ sensorimotor deficits. Recent neuroimaging approaches including resting state functional connectivity MRI (fcMRI) and diffusion tensor imaging (DTI) have been used to assess brain functional (fcMRI) and structural (DTI) network connectivity, allowing for more integrative assessments of distributed neural systems than in the past. Declines in corpus callosum size and microstructure with advancing age have been well documented, but their contributions to age deficits in unimanual and bimanual function are not well defined. Our recent work implicates age-related declines in callosal size and integrity as a key contributor to unimanual and bimanual control deficits. Moreover, our data provide evidence for a fundamental shift in the balance of excitatory and inhibitory interhemispheric processes that occurs with age, resulting in age differences in the relationship between functional and structural network connectivity. Training studies suggest that the balance of interhemispheric interactions can be shifted with experience, making this a viable target for future interventions.

Background: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions., Methods: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken., Results: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD., Conclusions: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: A child's fear of needles may impact the preferred route of allergy immunotherapy (AIT) when choosing between subcutaneous immunotherapy (allergy shots) or sublingual immunotherapy (SLIT). A survey was conducted to understand caregiver health-seeking behavior for children with allergic rhinitis with or without conjunctivitis (AR/C) and explore if fear of needles impacted AIT decisions., Methods: Caregivers of children ages 5-17 years with AR/C were recruited from the Dynata US research panel to participate in an online survey from May-June 2023. The survey received institutional review board exemption status. SLIT-tablets were described as "under-the-tongue tablets"., Results: About a third (34%) of surveyed caregivers ( n  = 437) reported their child had a severe fear of needles and 47% reported moderate fear. Of surveyed caregivers, 53% and 43% reported they had discussed allergy shots and SLIT-tablets, respectively, with their child's physician. SLIT-tablets were preferred by 84% of caregivers; 6% preferred injections and 10% had no preference. Caregivers of children with a severe fear of needles had the highest preference for SLIT-tablets (95%) vs. injections (2%); 85% and 60% of caregivers of children with moderate and low fear, respectively, preferred SLIT-tablets. Among caregivers of children with a severe fear of needles, a higher percentage agreed that their child would welcome taking SLIT-tablets than that their child would accept taking an ongoing series of allergy shots (93% vs. 43%, respectively)., Conclusions: Most caregivers preferred SLIT-tablets over allergy shots for their child with AR/C. Preference for SLIT-tablets corresponded with the child's degree of fear of needles. Fear of needles should be included in AIT shared decision-making conversations., Competing Interests: KR is a former employee of ALK. MB has served as a consultant or speaker for ALK, Merck, Sanofi, Regeneron, AstraZeneca, GlaxoSmithKline, Proallergy, SoundHealth, Lanier Biotherapeutics, Nectar Allergy, and Bryn Pharma. PG serves as a speaker for ALK and Genentech. HN is an employee of ALK. ES provides consulting services for ALK. DG has nothing to disclose; however, her employer Allergy & Asthma Network has received funding from Sanofi/Regeneron, Genentech, Pfizer, and Novartis for unbranded disease awareness and education., (© 2024 Rance, Blaiss, Gupta, Nolte, Scott and Gardner.)

Background: Expedient diagnosis of incipient dementia is often hindered by time constraints in primary care visits, shortage of dementia specialists, and extended waitlists for comprehensive neuropsychological evaluations., Methods: We developed the Rapid Access Memory Program (RAMP) to improve access of neuropsychological services for older adults presenting to our institutional primary care clinics with concerns of cognitive decline. RAMP provides abbreviated neurocognitive assessment, same-day patient feedback, expedited reporting to referring providers, and is financially self-supported. Here, we describe development of RAMP and clinical outcomes from the first 3 years., Results: Of 160 patients seen, dementia was diagnosed in 30% and Mild Cognitive Impairment in 50%; Alzheimer's disease was the most common suspected etiology. New psychiatric diagnosis was made in about one-third (n = 54). Most frequent recommendations involved medication adjustments (initiating cholinesterase inhibitors, deprescribing anticholinergics), safety (driving, decision-making), and specialist referrals. Additionally, 27 (17%) subsequently enrolled in local research., Conclusions: Results support feasibility and utility of RAMP for connecting older adults in primary care with neuropsychological services., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The trunk axial skeleton develops from paraxial mesoderm cells. Our recent study demonstrated that conditional knockout of the stem cell factor Sall4 in mice by TCre caused tail truncation and a disorganized axial skeleton posterior to the lumbar level. Based on this phenotype, we hypothesized that, in addition to the previously reported role of Sall4 in neuromesodermal progenitors, Sall4 is involved in the development of the paraxial mesoderm tissue. Analysis of gene expression and SALL4 binding suggests that Sall4 directly or indirectly regulates genes involved in presomitic mesoderm differentiation, somite formation and somite differentiation. Furthermore, ATAC-seq in TCre; Sall4 mutant posterior trunk mesoderm shows that Sall4 knockout reduces chromatin accessibility. We found that Sall4-dependent open chromatin status drives activation and repression of WNT signaling activators and repressors, respectively, to promote WNT signaling. Moreover, footprinting analysis of ATAC-seq data suggests that Sall4-dependent chromatin accessibility facilitates CTCF binding, which contributes to the repression of neural genes within the mesoderm. This study unveils multiple mechanisms by which Sall4 regulates paraxial mesoderm development by directing activation of mesodermal genes and repression of neural genes., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Microglia play many critical roles in neural development. Recent single-cell RNA-sequencing studies have found diversity of microglia both across different stages and within the same stage in the developing brain. However, how such diversity is controlled during development is poorly understood. In this study, we first found the expression of the macrophage mannose receptor CD206 in early-stage embryonic microglia on mouse brain sections. This expression showed a sharp decline between E12.5 and E13.5 across the central nervous system. We next tested the roles of the microglia-expressed zinc finger transcription factor SALL1 in this early transition of gene expression. By deleting Sall1 specifically in microglia, we found that many microglia continued to express CD206 when it is normally downregulated. In addition, the mutant microglia continued to show less ramified morphology in comparison with controls even into postnatal stages. Thus, SALL1 is required for early microglia to transition into a more mature status during development., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)

Background: Treatment options for seasonal and perennial allergic rhinitis (SAR/PAR) include pharmacotherapies and allergy immunotherapy. These meta-analyses evaluated the efficacy of pharmacotherapies and sublingual immunotherapy tablets (SLIT-tablets) versus placebo on nasal symptoms associated with SAR and PAR., Methods: Randomized, double-blind, placebo-controlled trials were identified from systematic PubMED/EMBASE searches through 7/18/2019 (PROSPERO protocol CRD42018105632). The primary outcome was mean numerical difference in total nasal symptom score (TNSS; 0-12) between active treatment and placebo at the end of the assessment period. Random-effects meta-analyses estimated the mean difference for each medication group weighted by the inverse of the trial variance. Publication bias assessments and sensitivity analyses were conducted., Results: Rescue symptom-relieving pharmacotherapy was prohibited in most pharmacotherapy trials but was allowed in all SLIT-tablet trials. For adult/adolescent SAR, the mean numerical difference (95% CI) in TNSS versus placebo was: intranasal corticosteroids (INCS)=1.38 (1.18, 1.58; 39 trials); combination intranasal antihistamine/INCS=1.34 (1.15, 1.54; 4 trials); intranasal antihistamines=0.72 (0.56, 0.89; 13 trials); oral antihistamine=0.62 (0.35, 0.90; 18 trials); SLIT-tablets=0.57 (0.41, 0.73; 4 trials); and montelukast=0.48 (0.36, 0.60; 10 trials). For adult/adolescent PAR, mean difference in TNSS versus placebo (95% CI) was: INCS=0.82 (0.66, 0.97; 14 trials); SLIT-tablets=0.65 (0.42, 0.88; 3 trials); and oral antihistamine=0.27 (0.11, 0.42; 3 trials). The number of eligible trials limited meta-analyses for pediatric SAR/PAR., Conclusions: All treatments significantly improved nasal symptoms versus placebo. SLIT-tablets provided improvement in TNSS despite access to rescue symptom-relieving pharmacotherapy. Extensive trial heterogeneity and strong indications of publication bias preclude the comparison of treatment effects among treatment classes.

Anaphylaxis is considered idiopathic when there is no known trigger. The signs and symptoms of idiopathic anaphylaxis (IA) are identical to those of anaphylaxis because of a known cause and can include cutaneous, circulatory, respiratory, gastrointestinal, and neurologic symptoms. Idiopathic anaphylaxis can be a frustrating disease for patients and health care providers. Episodes are unpredictable, and differential diagnosis is challenging. Current anaphylaxis guidelines have little specific guidance regarding differential diagnosis and long-term management of IA. Therefore, the objective of the Idiopathic Anaphylaxis Yardstick is to use published data and the authors' combined clinical experience to provide practical recommendations for the diagnosis and management of patients with IA., (Copyright © 2019 American College of Allergy, Asthma & Immunology. All rights reserved.)

Background: Reliable detection of slowed vertical saccades may help discriminate progressive supranuclear palsy (PSP) from the subset of Parkinson's disease patients who lack tremor (akinetic-rigid or PD-postural instability and gait disorder PIGD subtype), and from age-related oculomotor changes. We investigated the feasibility of a camera-less computerized behavioral saccade latency paradigm previously validated in PD to discriminate probable PSP-Richardson syndrome (PSP-RS) from PD-PIGD and age-matched controls., Methods: In this proof-of-concept case-control study, reflexive saccade latencies were measured in 5 subjects with probable PSP-RS, 5 subjects with PD-PIGD subtype, and 5 age-matched controls using the behavioral paradigm. The battery was repeated approximately one month later. All subjects were examined off levodopa by a movement disorders neurologist and by an ophthalmologist, who also performed a dilated eye exam., Results: Vertical prosaccade latencies were longer in the PSP group (median = 903 ms) relative to PD (median = 268 ms) and control groups (median = 235 ms), with no overlap between groups (100% accuracy). PSP subjects also had larger vertical-horizontal discrepancies than comparison groups. Test-retest reliability for the behavioral saccade measures was good (interclass correlation coefficient = 0.948; 95% confidence interval [0.856, 0.982]), and the measures strongly correlated with clinical ratings., Conclusions: Computerized behavioral measurement of reflexive saccade latency is feasible in PSP, and potentially discriminates probable PSP-RS from the PD-PIGD subtype. Findings from this proof-of-concept study support utility of the approach for obtaining objective saccade metrics in clinical evaluations and for tracking change in future, larger trials of moderately advanced PSP. Future studies should also examine the behavioral paradigm in earlier presentations of PSP and other subtypes of PSP., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)

Purpose of Review: Older adults currently represent the fastest growing demographic of cannabis users, yet few studies have investigated the effects of cannabis use on cognitive functioning in aging. We conducted a systematic review of the recent literature examining cognitive outcomes associated with cannabis use in older adults, with and without neurocognitive disorders, to clarify the potential neuroprotective benefits and risks of cognitive decline in this population., Recent Findings: We identified 26 studies examining cognitive outcomes associated with medical and recreational use of cannabis in healthy aging, dementia, Parkinson's disease, multiple sclerosis, HIV, and pain populations. Although variability in the cannabis products used, outcomes assessed, and study quality limits the conclusions that can be made, modest reductions in cognitive performance were generally detected with higher doses and heavier lifetime use., Summary: This review highlights the need for additional high-quality research using standardized, validated assessments of cannabis exposure and cognitive outcomes. Reliable measures and longitudinal data are necessary to better characterize the effects of cannabis use on cognitive aging, as well as differential effects of recreational and medical cannabis., Competing Interests: Conflict of Interest: Andreana Benitez, Emmi Scott, and Emily Brennan declare that they have no conflicts of interest.

Objective: Few independent studies have examined the psychometric properties of the NIH Toolbox Cognition Battery (NIHTB-CB) in older adults, despite growing interest in its use for clinical purposes. In this paper we report the test-retest reliability and construct validity of the NIHTB-CB, as well as its agreement or concordance with traditional neuropsychological tests of the same construct to determine whether tests could be used interchangeably., Methods: Sixty-one cognitively healthy adults ages 60-80 completed "gold standard" (GS) neuropsychological tests, NIHTB-CB, and brain MRI. Test-retest reliability, convergent/discriminant validity, and agreement statistics were calculated using Pearson's correlations, concordance correlation coefficients (CCC), and root mean square deviations., Results: Test-retest reliability was acceptable (CCC = .73 Fluid; CCC = .85 Crystallized). The NIHTB-CB Fluid Composite correlated significantly with cerebral volumes (r's = |.35-.41|), and both composites correlated highly with their respective GS composites (r's = .58-.84), although this was more variable for individual tests. Absolute agreement was generally lower (CCC = .55 Fluid; CCC = .70 Crystallized) due to lower precision in fluid scores and systematic overestimation of crystallized composite scores on the NIHTB-CB., Conclusions: These results support the reliability and validity of the NIHTB-CB in healthy older adults and suggest that the fluid composite tests are at least as sensitive as standard neuropsychological tests to medial temporal atrophy and ventricular expansion. However, the NIHTB-CB may generate different estimates of performance and should not be treated as interchangeable with established neuropsychological tests.

GABAergic inhibitory neurons in the prefrontal cortex (PFC) play crucial roles in higher cognitive functions. Despite the link between aberrant development of PFC interneurons and a number of psychiatric disorders, mechanisms underlying the development of these neurons are poorly understood. Here we show that the retinoic acid (RA)-degrading enzyme CYP26B1 (cytochrome P450 family 26, subfamily B, member 1) is transiently expressed in the mouse frontal cortex during postnatal development, and that medial ganglionic eminence (MGE)-derived interneurons, particularly in parvalbumin (PV)-expressing neurons, are the main cell type that has active RA signaling during this period. We found that frontal cortex-specific Cyp26b1 knock-out mice had an increased density of PV-expressing, but not somatostatin-expressing, interneurons in medial PFC, indicating a novel role of RA signaling in controlling PV neuron development. The initiation of Cyp26b1 expression in neonatal PFC coincides with the establishment of connections between the thalamus and the PFC. We found that these connections are required for the postnatal expression of Cyp26b1 in medial PFC. In addition to this region-specific role in postnatal PFC that regulates RA signaling and PV neuron development, the thalamocortical connectivity had an earlier role in controlling radial dispersion of MGE-derived interneurons throughout embryonic neocortex. In summary, our results suggest that the thalamus plays multiple, temporally separate roles in interneuron development in the PFC.

The thalamus, a crucial regulator of cortical functions, is composed of many nuclei arranged in a spatially complex pattern. Thalamic neurogenesis occurs over a short period during mammalian embryonic development. These features have hampered the effort to understand how regionalization, cell divisions, and fate specification are coordinated and produce a wide array of nuclei that exhibit distinct patterns of gene expression and functions. Here, we performed in vivo clonal analysis to track the divisions of individual progenitor cells and spatial allocation of their progeny in the developing mouse thalamus. Quantitative analysis of clone compositions revealed evidence for sequential generation of distinct sets of thalamic nuclei based on the location of the founder progenitor cells. Furthermore, we identified intermediate progenitor cells that produced neurons populating more than one thalamic nuclei, indicating a prolonged specification of nuclear fate. Our study reveals an organizational principle that governs the spatial and temporal progression of cell divisions and fate specification and provides a framework for studying cellular heterogeneity and connectivity in the mammalian thalamus.

Background: Peripheral blood stem cells (PBSCs) collected from granulocyte-colony-stimulating factor (G-CSF)-mobilized donors are routinely used for hematopoietic stem cell transplantation. Most PBSC collections worldwide have used the COBE Spectra (COBE) platform that is being replaced by the Spectra Optia (OPTIA). This study compared the PBSC collection performance and safety of the OPTIA using a single-step, continuous mononuclear cell (CMNC) collection procedure and the standard COBE MNC procedure., Study Design and Methods: A prospective, noninferiority, randomized, open-label, crossover, multicenter study was conducted in G-CSF-mobilized donors randomized to undergo MNC collection on Days 5 and 6. The primary endpoint was CD34+ cell collection efficiency (CE1%) with a noninferiority margin of 10%. The secondary endpoint was CD34+ cell CE2%. Product purity and safety were also assessed., Results: Twenty-three healthy donors (87% male) participated in the study. Mean (±SD) CD34+ CE1% was 84.4% (±16.4%) and 66.2% (±15.3%) for the OPTIA and COBE, respectively (p < 0.001 for noninferiority and superiority). Mean (±SD) CD34+ CE2% was 62.4 (±11.6) and 48.4 (±11.2) for the OPTIA and COBE, respectively (p < 0.001 for superiority). Granulocyte and platelet (PLT) contamination were lower in OPTIA-collected products. There were no unexpected adverse events (AEs) and no significant differences in the incidence of AEs between study arms. PLT loss was less with the OPTIA than with the COBE., Conclusion: The OPTIA CMNC collection procedure is safe and effective for the collection of CD34+ cells in G-CSF-mobilized donors and was superior to the COBE for CE1% and CE2%, collecting approximately 19 and 16% higher, respectively., (© 2016 AABB.)

Objective: To calculate the prevalence of urolithiasis in client-owned chelonians examined at a veterinary teaching hospital and to describe the clinical signs, diagnosis, and treatment of urolithiasis in chelonians., Design: Retrospective case series., Animals: 40 client-owned turtles and tortoises with urolithiasis., Procedures: The medical record database of a veterinary teaching hospital was searched from 1987 through 2012 for records of client-owned chelonians with urolithiasis. The prevalence of urolithiasis was calculated for client-owned chelonians examined at the hospital. Signalment and physical examination, hematologic, biochemical, urinalysis, diagnostic imaging, treatment, and necropsy results were described., Results: The mean prevalence of urolithiasis in client-owned chelonians for the study period was 5.1 cases/100 client-owned chelonians examined. Thirty-one of the 40 chelonians were desert tortoises. Only 5 of 40 chelonians had physical examination abnormalities associated with the urogenital tract. Surgery was performed on 17 chelonians; 5 developed postoperative complications, and 4 of those died. Necropsy was performed on 18 chelonians, and urolithiasis contributed to the decision to euthanize or was the cause of death for 9. Uroliths from 13 chelonians were analyzed, and all were composed of 100% urate., Conclusions and Clinical Relevance: Results indicated chelonians with urolithiasis have various clinical signs and physical examination findings that may or may not be associated with the urinary tract. Hematologic, biochemical, and urinalysis findings were nonspecific for diagnosis of urolithiasis. Many chelonians died or were euthanized as a consequence of urolithiasis, which suggested the disease should be identified early and appropriately treated.

Wounds in reptiles are a common reason for presentation to a veterinarian. At this time there is limited information on effective topical medications to aid in wound closure. The objectives of this study were to translate the splinted, full-thickness dermal wound model, validated in mice, to the bearded dragon (Pogona vitticeps) and to determine the effect of topical becaplermin (BP), a platelet-derived growth factor (0.01%), on the rate of wound closure. Ten bearded dragons were anesthetized and two full-thickness cutaneous wounds were made on the dorsum of each lizard. Encircling splints were applied surrounding each wound and subsequently covered by a semi-occlusive dressing. Five lizards had one wound treated with BP and the adjacent wound treated with a vehicle control. Five additional lizards had one wound treated with saline and the second wound treated with a vehicle control. Wounds were imaged daily, and the wound area was measured using digital image analysis. The change in percentage wound closure over 17 days and the time to 50% wound closure was compared among the four treatment groups. There was no significant difference in wound closure rates between BP-treated and saline-treated wounds or in the time to 50% wound closure between any treatments. Vehicle-treated wounds adjacent to saline-treated wounds closed significantly slower than did BP (P < 0.010), saline (P < 0.001), and vehicle-treated wounds adjacent to BP-treated wounds (P < 0.013). Our preliminary study indicates that the splinted wound model, with modifications, may be used to determine wound closure rates in bearded dragons. When compared with saline, BP did not have a significant effect on wound closure rates, while the vehicle alone delayed wound closure. Histologic analysis of experimentally created wounds throughout the wound healing process is needed to further evaluate the effects of these treatments on reptile dermal wound healing.

Objective: To evaluate the long-term protective immunity of a cyprinid herpesvirus 3 (CyHV3) vaccine in naïve koi (Cyprinus carpio koi)., Animals: 72 koi. Procedures-Vaccinated koi (n = 36) and unvaccinated control koi (36) were challenge exposed to a wild-type CyHV3 strain (KHVp8 F98-50) 13 months after vaccination., Results: The CyHV3 vaccine provided substantial protective immunity against challenge exposure. The proportional mortality rate was less in vaccinated koi (13/36 [36%]) than in unvaccinated koi (36/36 [100%]). For koi that died during the experiment, mean survival time was significantly greater in vaccinated than in unvaccinated fish (17 vs 10 days)., Conclusions and Clinical Relevance: The CyHV3 vaccine provided substantial protective immunity against challenge exposure with CyHV3 13 months after vaccination. This provided evidence that koi can be vaccinated annually with the CyHV3 vaccine to significantly reduce mortality and morbidity rates associated with CyHV3 infection.

The Spectra Optia apheresis system is a newer centrifugation-based device that in comparison with the COBE Spectra includes features that enhance procedure automation and usability. In this FDA-approved three-center two-arm observational study we characterized the performance of the Spectra Optia for collection of MNCs and CD34+ cells from nonmobilized and granulocyte-colony stimulating factor (G-CSF) mobilized healthy donors, respectively. There were a total of 15 evaluable subjects in each arm. Key performance indicators included collection efficiency of MNCs/CD34+ cells, product purity and cellular viability. For nonmobilized donors, median MNC collection efficiency, platelet collection efficiency, product hematocrit and granulocyte contamination were 57%, 12%, 4%, and 1.7%, respectively. For mobilized donors, median MNC collection efficiency, CD34+ cell collection efficiency, platelet collection efficiency, product hematocrit and granulocyte contamination were 61%, 77%, 19%, 4%, and 15%, respectively. Average WBC viability in the mobilized products was 99%. There was one severe (grade 3) adverse event related to citrate toxicity. This study demonstrates that the Spectra Optia can be used for safe and efficacious collection of MNCs, and results obtained are in line with expectations on collection efficiency and product characteristics. Adverse events were limited to those that are well documented in the stem-cell mobilization and leukapheresis process. As of the time of this writing, FDA 510(k) approval for use of the Spectra Optia device for MNC collection was achieved in the US based partly on the results of this study., (© 2014 Wiley Periodicals, Inc.)

Objective: To investigate safety and efficacy of a cyprinid herpesvirus type 3 (CyHV3) modified-live virus vaccine for the prevention of koi herpesvirus disease (KHVd)., Animals: 420 healthy koi (Cyprinus carpio koi)., Procedures: Fish were vaccinated with a 1× dose or 10× overdose of CyHV3 modified-live virus vaccine or a placebo through bath exposure in tanks at 22°C. Horizontal transmission of vaccine virus was evaluated by commingling unvaccinated and vaccinated fish. Efficacy was evaluated by challenge exposure of vaccinated and naïve fish to a wild-type virus. Fish that died were submitted for quantitative PCR assay for CyHV3 and histologic evaluation., Results: The CyHV3 vaccine was safe and efficacious, even at a 10× overdose. Vaccine-associated mortality rate was inversely associated with body weight, with a cumulative mortality rate of 9.4% (18/192) in fish weighing ≤ 87 g and no deaths in fish weighing > 87 g (0/48). Horizontal transfer of vaccine virus from vaccinates to naïve fish was negligible. For efficacy, the vaccine provided a significant reduction in mortality rate after challenge exposure to a wild-type virus, with a prevented fraction of 0.83 versus the placebo control fish., Conclusions and Clinical Relevance: KHVd is highly contagious and commonly leads to deaths in 80% to 100% of exposed fish, representing a major threat to koi and common carp populations throughout the world. The CyHV3 modified-live virus vaccine had a favorable safety profile and was an effective vaccine for the control of KHVd in koi weighing > 87 g.

The purpose of this study was to compare and define the normal cross-sectional gross and computed tomographic (CT) anatomy for a species of boney fish to better gain insight into the use of advanced diagnostic imaging for future clinical cases. The pacu (Colossoma macropomum) was used because of its widespread presence in the aquarium trade, its relatively large body size, and its importance in the research and aquaculture settings. Transverse 0.6-mm CT images of three cadaver fish were obtained and compared to corresponding frozen cross sections of the fish. Relevant anatomic structures were identified and labeled at each level; the Hounsfield unit density of major organs was established. The images presented good anatomic detail and provide a reference for future research and clinical investigation.

Viral dermatopathies of fish bear clinical signs similar to those of dermatopathies from other causes. This article offers an overview to approaching dermatologic presentations in fish, with an emphasis on sampling, diagnosis, and management of viral dermatopathies, building on previous publications. It is vital to recognize clinical signs associated with viral dermatopathies because there are currently no treatments available. Avoidance and prevention is the key to controlling viral diseases in fish. Optimizing husbandry practices and providing appropriate quarantine procedures can help prevent viral disease outbreaks in collection and aquaculture stocks., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Myxobolus albi was diagnosed in the cartilage of captive lumpfish (Cyclopterus lumpus) from 2 public aquaria. Eleven fish were affected, with the most common clinical signs being exophthalmos and grossly visible 1- to 2-mm white to tan scleral nodules. Myxozoan cysts were identified in the cartilage of the skull, branchial arch, sclera, vertebrae, tongue, all fin insertions, and the pectoral girdle. Cysts resulted in expansile, deforming, space-occupying lesions, resulting in exophthalmos but often lacking significant tissue damage or inflammation. Once cysts ruptured, free spores elicited a mild to marked inflammatory response. Spores measured 7.5 to 9.0 µm × 3.0 to 6.0 µm and contained 2 pyriform polar capsules oriented at one pole as well as occasional 1-µm-diameter basophilic nuclei. Identification was based on spore morphology together with polymerase chain reaction and sequence comparison of 18S ribosomal DNA. Isolates had 99% similarity to M. albi.

Coronavirus infection of the murine central nervous system (CNS) provides a model for studies of viral encephalitis and demyelinating disease. Mouse hepatitis virus (MHV) neurotropism varies by strain: MHV-A59 causes mild encephalomyelitis and demyelination, while the highly neurovirulent strain JHM.SD (MHV-4) causes fatal encephalitis with extensive neuronal spread of virus. In addition, while neurons are the predominant CNS cell type infected in vivo, the canonical receptor for MHV, the carcinoembryonic antigen family member CEACAM1a, has been demonstrated only on endothelial cells and microglia. In order to investigate whether CEACAM1a is also expressed in other cell types, ceacam1a mRNA expression was quantified in murine tissues and primary cells. As expected, among CNS cell types, microglia expressed the highest levels of ceacam1a, but lower levels were also detected in oligodendrocytes, astrocytes, and neurons. Given the low levels of neuronal expression of ceacam1a, primary neurons from wild-type and ceacam1a knockout mice were inoculated with MHV to determine the extent to which CEACAM1a-independent infection might contribute to CNS infection. While both A59 and JHM.SD infected small numbers of ceacam1a knockout neurons, only JHM.SD spread efficiently to adjacent cells in the absence of CEACAM1a. Quantification of mRNA for the ceacam1a-related genes ceacam2 and psg16 (bCEA), which encode proposed alternative MHV receptors, revealed low ceacam2 expression in microglia and oligodendrocytes and psg16 expression exclusively in neurons; however, only CEACAM2 mediated infection in human 293T cells. Therefore, neither CEACAM2 nor PSG16 is likely to be an MHV receptor on neurons, and the mechanism for CEACAM1a-independent neuronal spread of JHM.SD remains unknown.

In the 1990s, there were two experimental studies that sparked a renewed interest in thermal wave behavior at the macroscale level. Both reported thermal relaxation times of 10 s or higher. However, no further experimental evidence of this behavior has been reported. Due to the extreme significance of these findings, the objectives of this study were to try to reproduce these earlier studies and offer an explanation for the outcome. These two previous studies, one using heterogeneous materials and one using bologna, were repeated following the experimental protocol provided in the studies as closely and as practically as possible. In both cases, the temperature response to a specified boundary condition was recorded. The results from the first set of experiments suggested that the thermal relaxation times presented in the previous study were actually the thermal lag expected from applying Fourier's law, taking into account the uncertainty of the temperature sensor. In the second set of experiments, unlike the distinct jumps in temperature found previously, no indication of wave behavior was found. Here, the explanation for the previous results was more difficult to ascertain. Possible explanations include problems with either the experimental protocol or the temperature sensors used.

Parasitic diseases are common in fish. Diagnosis can be made through gill biopsy, skin cytology, fecal examination, or necropsy. Common parasites include protozoa, helminths, and crustaceans. Determining the cause of death in a fish is important for maintaining the health of other fish in the same environment. Due to rapid autolysis, fish necropsies should be performed promptly after death. Samples should be preserved in 10% neutral buffered formalin. Squash preparations, tissue imprints, microbiology, and virology are also useful in obtaining a diagnosis.

Anesthesia, diagnostic imaging, and surgery of fish have become routine parts of aquatic animal medicine. Anesthesia may be required for simple clinical procedures, diagnostic testing, or more involved surgery. Diagnostic modalities, including radiology, ultrasonography, and endoscopy, can be readily applied to fish and may provide valuable information. Despite some unique challenges, surgery can be performed in fish using basic surgical skills and principles and should be considered as a valid treatment option.

A simple, cost effective, and noninvasive blood perfusion system is tested in animal models. The system uses a small sensor to measure the heat transfer response to a thermal event (convective cooling) imposed on the tissue surface. Heat flux data are compared with a mathematical model of the tissue to estimate both blood perfusion and thermal contact resistance between the tissue and the probe. The perfusion system was evaluated for repeatability and sensitivity using isolated rat liver and exposed rat kidney tests. Perfusion in the isolated liver tests was varied by controlling the flow of the perfusate into the liver, and the perfusion in the exposed kidney tests was varied by temporarily occluding blood flow through the renal artery and vein. The perfusion estimated by the convective perfusion probe was in good agreement with that of the metered flow of the perfusate into the liver model. The liver tests indicated that the probe can be used to detect small changes in perfusion (0.005 ml/ml/s). The probe qualitatively tracked the changes in the perfusion in the kidney model due to occlusion of the renal artery and vein.

Non-invasive blood perfusion measurement systems have been developed and tested in a phantom tissue and an animal model. The probes use a small sensor with a laminated flat thermocouple to measure the heat transfer and temperature response to an arbitrary thermal event (convective or conductive) imposed on the tissue surface. Blood perfusion and thermal contact resistance are estimated by comparing heat flux data with a mathematical model of the tissue. The perfusion probes were evaluated for repeatability and sensitivity using both a phantom tissue test stand and exposed rat liver tests. Perfusion in the phantom tissue tests was varied by controlling the flow of water into the phantom tissue test section, and the perfusion in the exposed liver tests was varied by temporarily occluding blood flow through the portal vein. The phantom tissue tests indicated that the probes can be used to detect small changes in perfusion (0.005 ml/ml/s). The probes qualitatively tracked the changes in the perfusion of the liver model due to occlusion of the portal vein.