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Linkage studies have identified a locus on chromosome 3 as reading disabilities ( RD) and speech and sound disorder ( SSD) susceptibility region, with both RD and SSD sharing similar phonological processing and phonological memory difficulties. One gene in this region, roundabout homolog 1 ( ROBO1), has been indicated as a RD candidate and has shown significant association with measures of phonological memory in a population-based sample. In this study, we conducted a family-based association analysis using two independent samples collected in Toronto and Calgary, Canada. Using the two samples, we tested for association between ROBO1 single nucleotide polymorphisms ( SNPs) and RD, along with quantitative measures for reading, spelling and phonological memory. One SNP, rs331142, which was selected based on its correlation with ROBO1 expression in brain tissue, was found to be significantly associated with RD in the Toronto sample with over transmission of the minor C allele ( P = 0.001), correlated with low expression. This SNP is located ∼200 bp from a putative enhancer and results for a marker within the enhancer, rs12495133, showed evidence for association with the same allele in both the Toronto and Calgary samples ( P = 0.005 and P = 0.007). These results support previous associations between ROBO1 and RD, as well as correlation with low gene expression, suggesting a possible mechanism of risk conferred by this gene. [ABSTRACT FROM AUTHOR]

Twin studies have provided evidence for shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) and specific reading disabilities (RD), with this overlap being highest for the inattentive symptom dimension of ADHD. Previously, we found evidence for association of the dopamine receptor D1 gene (DRD1) with ADHD, and with the inattentive symptom dimension in particular. This, combined with evidence for working memory (WM) deficits in individuals with RD or ADHD, and the importance of D1 receptors in attentional processes and WM function, suggests that DRD1 may be a common genetic influence underlying both disorders. Here, in a study of 232 families ascertained through probands with reading problems, we tested for association of the DRD1 gene with RD, as a categorical trait, and with quantitative measures of key reading component skills, WM ability, and inattentive symptoms. Although no associations were found with RD, or with reading component skills or verbal WM, we found evidence for association with inattentive behaviour. Specifically, DRD1 Haplotype 3, the haplotype previously found to be associated with inattentive symptoms in ADHD, is also associated with parent- and teacher-reported symptoms of inattention in this sample selected for reading problems (P=0.023 and 0.004, respectively). Together, the replicated finding of Haplotype 3 association with inattentive symptoms in two independent study samples strongly supports a role for DRD1 in attentional ability. Furthermore, the association of DRD1 with inattention, but not with RD, or the other reading and reading-related phenotypes analysed, suggests that DRD1 contributes uniquely to inattention, without overlap for reading ability.Molecular Psychiatry (2007) 12, 776–785; doi:10.1038/sj.mp.4001972; published online 20 February 2007 [ABSTRACT FROM AUTHOR]

Dyslexia has been linked to a number of chromosomal regions including 15q. Recently a gene, EKN1, with unknown function in the linked region, was identified via a translocation breakpoint. This gene was further supported as a susceptibility locus by association studies in a Finnish sample. We investigated the possibility of this locus as a susceptibility gene contributing to dyslexia, analyzed as a categorical trait, and analyzed key reading phenotypes as quantitative traits using six polymorphisms including the two previously reported to be associated with dyslexia. In our sample of 148 families identified through a proband with reading difficulties, we found significant evidence for an association to dyslexia analyzed as a categorical trait and found evidence of association to the reading and related processes of phonological awareness, word identification, decoding, rapid automatized naming, language ability, and verbal short-term memory. However, association was observed with different alleles and haplotypes than those reported to be associated in a Finnish sample. These findings provide support for EKN1 as a risk locus for dyslexia and as contributing to reading component processes and reading-related abilities. Based on these findings, further studies of this gene in independent samples are now required to determine the relationship of this gene to dyslexia.Molecular Psychiatry (2004) 9, 1111-1121. doi:10.1038/sj.mp.4001543 Published online 13 July 2004 [ABSTRACT FROM AUTHOR]

Background Suturing requires repeated practice with guidance to prevent skill deterioration; however, guidance is often limited by expert availability. There is evidence that augmented reality (AR) may assist procedural skill acquisition among learners. This study examines the use of an AR suture guidance application to assist the independent practice of suturing. Methodology A novel suture guidance application was designed for the Microsoft HoloLens. The guidance system included a calibration system and holograms that projected over a suture pad in a stepwise manner. To assess the application, 30 medical students were recruited and randomly assigned to two groups. The control group (n = 16) was given 30 minutes of independent suture practice, while the experimental group (n = 14) utilized the suture guidance application. Both groups completed a pre- and post-test wound closure assessment. After the post-test, the control group trialed the suture guidance application. All participants completed a feedback survey on the application. Statistical analysis was completed using Stata (StataCorp., College Station, TX, USA) with paired Student's t-tests and Welch's t-tests with a significance of 95%. Results Both groups demonstrated a significant improvement in total time and time per stitch during the post-test. Additionally, comparing pre- and post-test assessments in the experimental group revealed a significant improvement in the total number of stitches (p = 0.007), the ratio of bisecting stitches (p = 0.02), and the symmetry of stitch bite (p = 0.03). The feedback survey supported the application for guiding suture placement and spacing. Participants identified limitations in the hologram stability and neck positioning. Conclusions This study suggests the potential to use AR to facilitate the independent practice of wound closure within simulation environments., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2024, Lovett et al.)

Introduction: Hospitalized children diagnosed with SARS-CoV-2-related conditions are at risk for new or persistent symptoms and functional impairments. Our objective was to analyze post-hospital symptoms, healthcare utilization, and outcomes of children previously hospitalized and diagnosed with acute SARS-CoV-2 infection or Multisystem Inflammatory Syndrome in Children (MIS-C)., Methods: Prospective, multicenter electronic survey of parents of children <18 years of age surviving hospitalization from 12 U.S. centers between January 2020 and July 2021. The primary outcome was a parent report of child recovery status at the time of the survey (recovered vs. not recovered). Secondary outcomes included new or persistent symptoms, readmissions, and health-related quality of life. Multivariable backward stepwise logistic regression was performed for the association of patient, disease, laboratory, and treatment variables with recovered status., Results: The children [ n  = 79; 30 (38.0%) female] with acute SARS-CoV-2 (75.7%) or MIS-C (24.3%) had a median age of 6.5 years (interquartile range 2.0-13.0) and 51 (64.6%) had a preexisting condition. Fifty children (63.3%) required critical care. One-third [23/79 (29.1%)] were not recovered at follow-up [43 (31, 54) months post-discharge]. Admission C-reactive protein levels were higher in children not recovered vs. recovered [5.7 (1.3, 25.1) vs. 1.3 (0.4, 6.3) mg/dl, p  = 0.02]. At follow-up, 67% overall had new or persistent symptoms. The most common symptoms were fatigue (37%), weakness (25%), and headache (24%), all with frequencies higher in children not recovered. Forty percent had at least one return emergency visit and 24% had a hospital readmission. Recovered status was associated with better total HRQOL [87 (77, 95) vs. 77 (51, 83), p  = 0.01]. In multivariable analysis, lower admission C-reactive protein [odds ratio 0.90 (95% confidence interval 0.82, 0.99)] and higher admission lymphocyte count [1.001 (1.0002, 1.002)] were associated with recovered status., Conclusions: Children considered recovered by their parents following hospitalization with SARS-CoV-2-related conditions had less symptom frequency and better HRQOL than those reported as not recovered. Increased inflammation and lower lymphocyte count on hospital admission may help to identify children needing longitudinal, multidisciplinary care., Clinical Trial Registration: ClinicalTrials.gov (NCT04379089)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MP-E declared a past co-authorship with the author LD to the handling editor., (© 2024 Fink, Alcamo, Lovett, Hartman, Williams, Garcia, Rasmussen, Pal, Drury, MackDiaz, Ferrazzano, Dervan, Appavu, Snooks, Stulce, Rubin, Pate, Toney, Robertson, Wainwright, Roa, Schober and Slomine.)

The Clinical Frailty Scale (CFS) is incorporated into our institution's comprehensive geriatric assessment (CGA). CGAs and CFS scoring are completed by junior medical trainees on the Geriatric consult service. The agreement between CFS score assignment by junior trainees and Geriatrics trained individuals in this setting is unknown. Importantly, these scores assign a frailty level that impacts care pathways. We conducted a retrospective chart review from April-June 2019. A Geriatric medicine subspecialty resident assigned retrospective CFS scores based on data from the CGA. We compared scores to determine the level of agreement using the Cohen and Conger's Kappa inter-rater agreement metric and assessed whether patient characteristics influenced the likelihood of agreement between raters using a generalized linear model. Medical students assessed 43% (46/108) of patients (n = 13), and 57% (62/108) were assessed by PGY1s (n = 10). Inter-rater agreement measures showed substantial agreement overall and for PGY1s, but dropped to a moderate agreement for medical students. The retrospective inter-rater agreement of the CFS showed substantial agreement overall and decreased when limited to medical students, highlighting the need for interventions to improve the understanding of frailty early in medical training.

Background: Many people are turning to online pharmacies for medication purchases leading to a growing number of legal and illegal online pharmacies (IOPs). With a growing number of IOPs, consumers are more likely to receive substandard or falsified medications when purchasing medications online., Objectives: This study aims to identify the number of verified , not recommended , and not verified pharmacy websites consumers see using different keywords and medications on an Internet browser based off the National Association Boards of Pharmacy's (NABP) list of verified and not recommended websites. It also aims to compare which keywords result in more not recommended pharmacy websites compared with verified pharmacy websites for consumers over time., Design and Methods: We created an Internet browser extension compatible with different Internet browsers to quickly identify which search results are verified , not recommended , and not verified based on NABP lists. We then utilized an application programming interface to automatically search different key terms and classify the search results as verified , not recommended , and not verified over a 4-week data collection period for analysis., Results: A total of 131 key terms were used for the search. There was an average signal determining the number of verified and not recommended search results compared with not verified results of 4.3% over the 4-week data collection period. There was about a 3:1 ratio of not recommended to verified search results noted. Top signal and not recommended search result producing keywords contained words such as "shipped" and "cheap.", Conclusion: The Internet browser extension will aid in making it easier to identify which search results are safe and which are not safe when searching to purchase medications online. This study has set the premise on expanding how to use an Internet pharmacy extension to combat IOPs, improve patient safety, and increase safe access to medications., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background and Purpose: Despite the availability of a variety of treatment options, many asthma patients have poorly controlled disease with frequent exacerbations. Proteinase-activated receptor-2 (PAR2) has been identified in preclinical animal models as important to asthma initiation and progression following allergen exposure. Proteinase activation of PAR2 raises intracellular Ca 2+ , inducing MAPK and β-arrestin signalling in the airway, leading to inflammatory and protective effects. We have developed C391, a potent PAR2 antagonist effective in blocking peptidomimetic- and trypsin-induced PAR2 signalling in vitro as well as reducing inflammatory PAR2-associated pain in vivo. We hypothesized that PAR2 antagonism by C391 would attenuate allergen-induced acutely expressed asthma indicators in murine models., Experimental Approach: We evaluated the ability of C391 to alter Alternaria alternata-induced PAR2 signalling pathways in vitro using a human airway epithelial cell line that naturally expresses PAR2 (16HBE14o-) and a transfected embryonic cell line (HEK 293). We next evaluated the ability for C391 to reduce A. alternata-induced acutely expressed asthma indicators in vivo in two murine strains., Key Results: C391 blocked A. alternata-induced, PAR2-dependent Ca 2+ and MAPK signalling in 16HBE14o- cells, as well as β-arrestin recruitment in HEK 293 cells. C391 effectively attenuated A. alternata-induced inflammation, mucus production, mucus cell hyperplasia and airway hyperresponsiveness in acute allergen-challenged murine models., Conclusions and Implications: To our best knowledge, this is the first demonstration of pharmacological intervention of PAR2 to reduce allergen-induced asthma indicators in vivo. These data support further development of PAR2 antagonists as potential first-in-class allergic asthma drugs., (© 2021 The British Pharmacological Society.)

Objectives: Survivors of the PICU face long-term morbidities across health domains. In this study, we detail active PICU follow-up programs (PFUPs) and identify perceptions and barriers about development and maintenance of PFUPs., Methods: A web link to an adaptive survey was distributed through organizational listservs. Descriptive statistics characterized the sample and details of existing PFUPs. Likert responses regarding benefits and barriers were summarized., Results: One hundred eleven respondents represented 60 institutions located in the United States (n = 55), Canada (n = 3), Australia (n = 1), and the United Kingdom (n = 1). Details for 17 active programs were provided. Five programs included broad PICU populations, while the majority were neurocritical care (53%) focused. Despite strong agreement on the need to assess and treat morbidity across multiple health domains, 29% were physician only programs, and considerable variation existed in services provided by programs across settings. More than 80% of all respondents agreed PFUPs provide direct benefits and are essential to advancing knowledge on long-term PICU outcomes. Respondents identified "lack of support" as the most important barrier, particularly funding for providers and staff, and lack of clinical space, though successful programs overcome this challenge using a variety of funding resources., Conclusions: Few systematic multidisciplinary PFUPs exist despite strong agreement about importance of this care and direct benefit to patients and families. We recommend stakeholders use our description of successful programs as a framework to develop multidisciplinary models to elevate continuity across inpatient and outpatient settings, improve patient care, and foster collaboration to advance knowledge., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: Neuromonitoring is the use of continuous measures of brain physiology to detect clinically important events in real-time. Neuromonitoring devices can be invasive or non-invasive and are typically used on patients with acute brain injury or at high risk for brain injury. The goal of this study was to characterize neuromonitoring infrastructure and practices in North American pediatric intensive care units (PICUs)., Methods: An electronic, web-based survey was distributed to 70 North American institutions participating in the Pediatric Neurocritical Care Research Group. Questions related to the clinical use of neuromonitoring devices, integrative multimodality neuromonitoring capabilities, and neuromonitoring infrastructure were included. Survey results were presented using descriptive statistics., Results: The survey was completed by faculty at 74% (52 of 70) of institutions. All 52 institutions measure intracranial pressure and have electroencephalography capability, whereas 87% (45 of 52) use near-infrared spectroscopy and 40% (21/52) use transcranial Doppler. Individual patient monitoring decisions were driven by institutional protocols and collaboration between critical care, neurology, and neurosurgery attendings. Reported device utilization varied by brain injury etiology. Only 15% (eight of 52) of institutions utilized a multimodality neuromonitoring platform to integrate and synchronize data from multiple devices. A database of neuromonitoring patients was maintained at 35% (18 of 52) of institutions. Funding for neuromonitoring programs was variable with contributions from hospitals (19%, 10 of 52), private donations (12%, six of 52), and research funds (12%, six of 52), although 73% (40 of 52) have no dedicated funds., Conclusions: Neuromonitoring indications, devices, and infrastructure vary by institution in North American pediatric critical care units. Noninvasive modalities were utilized more liberally, although not uniformly, than invasive monitoring. Further studies are needed to standardize the acquisition, interpretation, and reporting of clinical neuromonitoring data, and to determine whether neuromonitoring systems impact neurological outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Sarcopenia is an important modifiable risk factor in patients being considered for elective knee or hip replacement as it may be associated with a higher risk of post-operative joint replacement complications. Our objectives are to determine the prevalence of patients with osteoarthritis at risk of sarcopenia by using the SARC-F tool, and whether risk of sarcopenia is associated with referral to an orthopaedic surgeon., Methods: We conducted a retrospective review of patients who were 60 years or older assessed at four Canadian musculoskeletal assessment centres. Patients completed the SARC-F as part of their assessment. Multivariable logistic regression analyses were conducted to determine association between risk of sarcopenia and the odds of referral to an orthopedic surgeon for surgical consultation., Results: 3,697 patients were included and 67.8% (2,508/3,697) were at risk of sarcopenia. Prevalence was highest in those assessed for hip replacement at 72.3% (635/878). Patients at risk of sarcopenia were more likely to be referred to an orthopaedic surgeon (OR 1.299; SD 1.074-1.571)., Conclusions: Patients with osteoarthritis assessed for joint replacement are at high risk of sarcopenia, particularly individuals undergoing potential hip replacement. Patients at risk of sarcopenia are more likely to be referred to orthopaedic surgery for surgical consultation., Competing Interests: CONFLICT OF INTEREST DISCLOSURES The authors declare that no conflicts of interest exist., (© 2021 Author(s). Published by the Canadian Geriatrics Society.)

Purpose: Intracranial pressure (ICP) > 20 mmHg is associated with worse outcomes in children. The gold standard for monitoring ICP is invasive, has complications such as bleeding and infection, and may not be available in resource limited areas. Ultrasound of the optic nerve sheath diameter (ONSD) has been studied as a noninvasive way to evaluate for elevated ICP in adults. Its utility in pediatrics remains unclear., Methods: A prospective study was performed in a pediatric intensive care unit in children ≤ 18 years old. ONSD ultrasound was performed using a 13-6 MHz linear probe with the patient's invasively measured ICP simultaneously recorded. Linear mixed effects models were used to evaluate the association between ONSD and ICP., Results: One hundred thirty-six measurements were obtained from 16 patients. ONSD was not significantly associated with ICP (p = 0.51). A ROC curve assessing ONSD to determine elevated ICP > 20 mmHg had an area under the curve of 0.52 (95%CI = 0.32-0.72). There was no difference in measurements obtained between the left and right ONSD at the same time (p = 0.82)., Conclusions: In conclusion, this study demonstrated no association between ONSD measurement and invasively monitored ICP in critically ill children.

Background: Mastery learning assumes that given enough time and appropriate instructional strategies, most trainees will be able to achieve proficiency. Expert-level performance requires numerous hours of intensive and focus practice. We aimed to study whether it was possible for surgical trainees to achieve expert-derived proficiency level in laparoscopic suturing using the Advanced Training in Laparoscopic Suturing (ATLAS) curriculum over a short period of time., Study Design: A multicenter IRB approved prospective study included surgery residents and minimally invasive fellows. Participants underwent weekly supervised instruction and assessments of ATLAS skills and self-directed practice between sessions over 12 weeks. Participants were asked to practice until they achieved previously established proficiency benchmarks of expert laparoscopic surgeons., Results: Fifteen participants, PGY2 to PGY6, from 3 institutions practiced on the ATLAS curriculum. Three participants were able to achieve proficiency on the entire curriculum, with a cumulative practice time varying between 3.4 and 7.6 hours. Individual tasks had varying degrees of difficulty ranging from 85% proficiency on task 1 to 33.3% proficiency for task 6. Using a mixed-method model, the mean cumulative hours of practice to reach the benchmark threshold was estimated for each task and varied from 4.5 to 13.2 hours. The improved performance was associated with higher PGY level and proficiency in FLS., Conclusions: This study demonstrates that it is possible for some senior surgical trainees to achieve proficiency in an expert-level laparoscopic suturing curriculum. This study establishes a learning curve for each ATLAS individual task. Some learners may not be able to achieve proficiency on the entire curriculum over a short period of practice. Additional studies are needed to assess how to shorten the learning curve with effective instructional methods such as expert-guided training with immediate feedback., (Copyright © 2020 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Age-related hearing loss (ARHL) is a threat to future human wellbeing. Multiple factors contributing to the terminal auditory decline have been identified; but a unified understanding of ARHL - or the homeostatic maintenance of hearing before its breakdown - is missing. We here present an in-depth analysis of homeostasis and ageing in the antennal ears of the fruit fly Drosophila melanogaster. We show that Drosophila, just like humans, display ARHL. By focusing on the phase of dynamic stability prior to the eventual hearing loss we discovered a set of evolutionarily conserved homeostasis genes. The transcription factors Onecut (closest human orthologues: ONECUT2, ONECUT3), Optix (SIX3, SIX6), Worniu (SNAI2) and Amos (ATOH1, ATOH7, ATOH8, NEUROD1) emerged as key regulators, acting upstream of core components of the fly's molecular machinery for auditory transduction and amplification. Adult-specific manipulation of homeostatic regulators in the fly's auditory neurons accelerated - or protected against - ARHL.

Bacillus anthracis is the causative agent of anthrax, a disease of livestock, wildlife, and humans. Here, we present the draft genome sequences of five historical B. anthracis strains that were preserved as lyophilates in glass vials for decades., (Copyright © 2020 Sommer et al.)

Hair cells in the auditory organ of the vertebrate inner ear are the sensory receptors that convert acoustic stimuli into electrical signals that are conveyed along the auditory nerve to the brainstem. Hair cells are highly susceptible to ototoxic drugs, infection, and acoustic trauma, which can cause cellular degeneration. In mammals, hair cells that are lost after damage are not replaced, leading to permanent hearing impairments. By contrast, supporting cells in birds and other non-mammalian vertebrates regenerate hair cells after damage, which restores hearing function. The cellular mechanisms that regulate hair cell regeneration are not well understood. We investigated the role of vascular endothelial growth factor (VEGF) during regeneration of auditory hair cells in chickens after ototoxic injury. Using RNA-Seq, immunolabeling, and in situ hybridization, we found that VEGFA, VEGFC, VEGFR1, VEGFR2, and VEGFR3 were expressed in the auditory epithelium, with VEGFA expressed in hair cells and VEGFR1 and VEGFR2 expressed in supporting cells. Using organotypic cultures of the chicken cochlear duct, we found that blocking VEGF receptor activity during hair cell injury reduced supporting cell proliferation as well as the numbers of regenerated hair cells. By contrast, addition of recombinant human VEGFA to organ cultures caused an increase in both supporting cell division and hair cell regeneration. VEGF's effects on supporting cells were preserved in isolated supporting cell cultures, indicating that VEGF can act directly upon supporting cells. These observations demonstrate a heretofore uncharacterized function for VEGF signaling as a critical positive regulator of hair cell regeneration in the avian inner ear., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The causes that individuals attribute to reading outcomes shape future behaviors, including engagement or persistence with learning tasks. Although previous reading motivation research has examined differences between typical and struggling readers, there may be unique dynamics related to varying levels of reading and attention skills. Using latent profile analysis, we found 4 groups informed by internal attributions to ability and effort. Reading skills, inattention, and hyperactivity/impulsivity were investigated as functional correlates of attribution profiles. Participants were 1,312 youth (8-15 years of age) of predominantly African American and Hispanic racial/ethnic heritage. More adaptive attribution profiles had greater reading performance and lower inattention. The reverse was found for the least adaptive profile with associations to greater reading and attention difficulties. Distinct attribution profiles also existed across similar-achieving groups. Understanding reading-related attributions may inform instructional efforts in reading. Promoting adaptive attributions may foster engagement with texts despite learning difficulties and, in turn, support reading achievement., Competing Interests: Disclosure statement No potential conflict of interest was reported by the authors.

Human vestibular sensory epithelia in explant culture were incubated in gentamicin to ablate hair cells. Subsequent transduction of supporting cells with ATOH1 using an Ad-2 viral vector resulted in generation of highly significant numbers of cells expressing the hair cell marker protein myosin VIIa. Cells expressing myosin VIIa were also generated after blocking the Notch signalling pathway with TAPI-1 but less efficiently. Transcriptomic analysis following ATOH1 transduction confirmed up-regulation of 335 putative hair cell marker genes, including several downstream targets of ATOH1 . Morphological analysis revealed numerous cells bearing dense clusters of microvilli at the apical surfaces which showed some hair cell-like characteristics confirming a degree of conversion of supporting cells. However, no cells bore organised hair bundles and several expected hair cell markers genes were not expressed suggesting incomplete differentiation. Nevertheless, the results show a potential to induce conversion of supporting cells in the vestibular sensory tissues of humans., Competing Interests: RT, AF, UP, YA, JH, ML, AF No competing interests declared, (© 2018, Taylor et al.)