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This research article examines data from an in-person 2017 survey on LibGuides usage, perceptions, and awareness of health professions students seeking bachelor and graduate-level degrees. Almost 45% ( n  = 20, N  = 45) of participants who visited the library's website at least once per week indicated awareness of library-created LibGuides. Nearly 90% ( n  = 8, N  = 9) of health professions students who had not visited the library's website were unaware of the guides. The statistical analysis shows significant associations between various variables (academic level, library workshop attendance, research guide type usage, research guide page usage) and library guide awareness. The data did not reveal any significant relationships between other variables (undergraduate class level, field of study, and library website visit frequency) and guide awareness. The authors discuss implications for health sciences libraries and suggestions for future research.

First principles modeling of anatase TiO 2 surfaces and their interfacial contacts shows that defect-induced trap states within the band gap arise from intrinsic structural distortions, and these can be corrected by modification with Zr(IV) ions. Experimental testing of these predictions has been undertaken using anatase nanocrystals modified with a range of Zr precursors and characterized using structural and spectroscopic methods. Continuous-wave electron paramagnetic resonance (EPR) spectroscopy revealed that under illumination, nanoparticle-nanoparticle interfacial hole trap states dominate, which are significantly reduced after optimizing the Zr doping. Fabrication of nanoporous films of these materials and charge injection using electrochemical methods shows that Zr doping also leads to improved electron conductivity and mobility in these nanocrystalline systems. The simple methodology described here to reduce the concentration of interfacial defects may have wider application to improving the efficiency of systems incorporating metal oxide powders and films including photocatalysts, photovoltaics, fuel cells, and related energy applications., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

This paper presents diagnostic criteria for vestibular migraine, jointly formulated by the Committee for Classification of Vestibular Disorders of the Bárány Society and the Migraine Classification Subcommittee of the International Headache Society (IHS). It contains a literature update while the original criteria from 2012 were left unchanged. The classification defines vestibular migraine and probable vestibular migraine. Vestibular migraine was included in the appendix of the third edition of the International Classification of Headache Disorders (ICHD-3, 2013 and 2018) as a first step for new entities, in accordance with the usual IHS procedures. Probable vestibular migraine may be included in a later version of the ICHD, when further evidence has accumulated. The diagnosis of vestibular migraine is based on recurrent vestibular symptoms, a history of migraine, a temporal association between vestibular symptoms and migraine symptoms and exclusion of other causes of vestibular symptoms. Symptoms that qualify for a diagnosis of vestibular migraine include various types of vertigo as well as head motion-induced dizziness with nausea. Symptoms must be of moderate or severe intensity. Duration of acute episodes is limited to a window of between 5 minutes and 72 hours.

Leydig cell hypoplasia is a rare autosomal recessive condition caused by mutations in luteinizing hormone/chorionic gonadotropin receptor (LHCGR) genes in which 46, XY patients demonstrate a wide spectrum of disorders/differences of sex development (DSD) phenotypes ranging from normal female external genitalia in severe subtypes to micropenis or hypospadias in patients with less severe presentations. Although most patients with LHCGR defects are diagnosed at puberty, here we describe the prenatal diagnosis of 46, XY DSD due to two likely pathogenic variants in LHCGR , one of which has never been reported., Competing Interests: None., (© 2021 The Authors.)

Objective: To describe rates of cerebrospinal fluid (CSF) rhinorrhea after reconstruction of the IAC with calcium phosphate bone cement during retrosigmoid resections of vestibular schwannomas., Methods: A retrospective chart review of 177 patients who underwent retrosigmoid craniotomy and opening of the internal auditory canal for resection of a vestibular schwannoma between January 2016 and September 2019 at a tertiary referral center. Patients with other cerebellopontine angle tumor histology, neurofibromatosis type II, or those undergoing revision surgeries were excluded., Results: Out of 177 patients, six patients (3.4%) developed postoperative rhinorrhea. Four patients (2.3%) were taken back to the OR for mastoidectomy and repair of CSF leak. Three of these patients were noted to have a CSF leak from the peri-labyrinthine air cells, and one was found to have a leak from the craniotomy site communicating with the mastoid air cells. Two patients were conservatively managed with diuretics and had resolution of their CSF leak. Six patients (3.4%) were readmitted for postoperative infection. Two patients were diagnosed with meningitis (1.1%), one aseptic and one H. Influenza, and three patients developed surgical site infections (1.6%). One patient was empirically treated with antibiotics and ultimately had a negative CSF culture., Conclusions: Our results demonstrate that the use of calcium phosphate bone cement for IAC closure in retrosigmoid resection of vestibular schwannomas is a safe and effective technique with low rates of postoperative CSF rhinorrhea., Competing Interests: The authors disclose no financial disclosures or conflicts of interest., (Copyright © 2021, Otology & Neurotology, Inc.)

Background: Ocrelizumab safety outcomes have been well evaluated in clinical trials and open-label extension (OLE) studies. However, risk factors for infection in patients with multiple sclerosis (MS) receiving ocrelizumab have not been extensively studied in the real-world setting., Objective: The aim of this study was to examine factors determining risk of self-reported infections and antimicrobial use in patients receiving ocrelizumab for MS., Methods: A retrospective, observational cohort study was conducted in patients receiving ocrelizumab at the Royal Melbourne Hospital. Infection type and number were reported by patients, and the associations of potential clinical and laboratory risk factors with self-reported infection and antimicrobial use were estimated using univariate and multivariable logistic regression models., Results: A total of 185 patients were included in the study; a total of 176 infections were reported in 89 patients (46.1%), and antimicrobial use was identified in 47 patients (25.3%). In univariate analyses, a higher serum IgA was associated with reduced odds of infection (OR 0.44, 95% CI 0.25-0.76). In multivariable analyses, older age (OR 0.94, 95% CI 0.88-0.99), higher serum IgA (OR 0.37, 95% CI 0.17-0.80) and higher serum IgG (OR 0.81, 95% CI 0.67-0.99) were associated with reduced odds of infection. Older age (OR 0.85, 95% CI 0.75-0.96) and higher serum IgA (OR 0.23, 95% CI 0.07-0.79) were associated with reduced odds of antimicrobial use, whilst longer MS disease duration (OR 1.22, 95% CI 1.06-1.41) and higher Expanded Disability Status Scale (EDSS) score (OR 1.99, 95% CI 1.02-3.86) were associated with increased odds of antimicrobial use., Conclusions: Higher serum IgA and IgG and older age were associated with reduced odds of infection. Our findings highlight that infection risk is not uniform in patients with MS receiving ocrelizumab and substantiate the need to monitor immunoglobulin levels pre-treatment and whilst on therapy., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Context: It is unclear how fat mass accretion in early life is related to glucose-insulin homeostasis., Objective: Examine associations of fat and fat-free mass accretion from birth to early childhood with glucose-insulin homeostasis in early childhood in a multi-ethnic cohort., Methods: Observational Healthy Start study with data collection from 2010 to 2020. Air displacement plethysmography at birth and 4.8 (SD 0.7) years estimated fat mass percent (FMP, %), fat mass index (FMI, kg/m2), and fat-free mass index (FFMI, kg/m2). General population recruited from academic obstetrics clinics in Denver, Colorado, consisting of 419 mother/offspring dyads. The main outcome measures were fasting glucose, insulin, homeostasis model assessment-2 insulin resistance (HOMA2-IR), and beta-cell function (HOMA2-B) at 4.8 years., Results: Greater fat mass accretion from birth to early childhood was associated with higher fasting glucose (ΔFMP β = 0.20 [95% CI 0.06-0.34], ΔFMI β = 0.90 [0.30-1.50]) in participants of Hispanic, Black, and Other races/ethnicities, while greater fat-free mass accretion was associated with higher fasting glucose in non-Hispanic White participants (ΔFFMI β = 0.76 [0.21-1.32]). Overall, greater fat, but not fat-free, mass accretion was also associated with higher insulin (ΔFMP β = 0.14 [0.09-0.18], ΔFMI 0.71 [0.51-0.92]), HOMA2-IR (FMP β = 0.02 [0.01-0.02], ΔFMI β = 0.09 [0.06-0.12]), and HOMA2-B (ΔFMP β = 0.92 [0.18-1.36], ΔFMI β = 4.76 [2.79-6.73])., Conclusion: Greater fat mass accretion in infancy and childhood is associated with shifts in fasting glucose in children of Hispanic, Black, and Other races/ethnicities at 5 years of age. Body composition beginning in early life is relevant for metabolic health, and precise assessments of adiposity in pediatric research are needed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The COVID-19 pandemic challenges multiple sclerosis services to be innovative in delivering infusible therapies. To reduce time in clinical settings, and potential staff or space losses, we implemented rapid infusion protocols for selected patients., Objective: To analyse the rate of infusion related reactions and patient experience of rapid infusions of natalizumab and ocrelizumab. To document time reduction patients spent in clinical settings during the COVID-19 pandemic., Methods: Patients with prior exposure to at least three natalizumab or two 300mg ocrelizumab infusions were approved for rapid protocols. A retrospective audit and survey were completed., Results: We analysed 269 rapid natalizumab infusions and 100 rapid ocrelizumab infusions. Infusion related reactions during the natalizumab or ocrelizumab infusions occurred in two patients (1.52%) and eight patients (8%), respectively. All infusion related reactions were mild to moderate and did not require infusion discontinuation. No infusion reactions occurred during the post-infusion observation. Patient experience was positive., Conclusion: Frequency or severity of infusion related reactions in rapid infusions were no different compared to published data. In the setting of COVID-19, pandemic rapid infusion protocols could potentially save hospital resources and limit patient exposure to a high-risk clinical setting while still maintaining ongoing treatment of multiple sclerosis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Patients with Multiple Sclerosis (MS) and on disease modifying therapies (DMTs) that can be immunosuppressive or immunomodulatory form a special group where risk of continuation of DMT needs to be taken into account with risk of contracting Covid-19. This concept can pose a degree of anxiety for patients as well as neurologists. We aimed to evaluate patient perspectives regarding the use of Natalizumab and anti-CD20 therapies (Rituximab and Ocrelizumab) in the context of the COVID-19 pandemic., Methods: cross-sectional study conducted via voluntary survey filled in by patients with MS and related disorders receiving their infusional treatment in one MS centre in Australia, exploring their concerns regarding their therapy, their therapy and COVID-19, precautions undertaken in response to the pandemic, and factors impacting their decision-making., Results: 170 patients completed the survey. Of patients on Natalizumab, the majority had either no or mild concern regarding their DMT and COVID-19, and of patients on B-cell depleting therapies, again, the majority had no or mild concern, though a slightly higher proportion had a moderate level of concern. Asked to delineate their concerns, an increased risk of contracting COVID-19 was more commonly conveyed than MS-specific factors or poor outcomes pertaining to COVID-19 if contracted, by patients in both groups. Conversely, being invited to specifically consider the possibility of contracting COVID-19 or experience a relapse of MS, almost half of the cohort rated both of equal of concern. More than half of the cohort were self-isolating more stringently than general government advice and government-related resources followed by information provided by patient's neurologist where the commonest means of information to guide decision making., Conclusions: Whilst a large proportion of patients had some concern regarding the impact of their DMT on COVID-19, whether on their risk of contracting COVID-19 or a theoretical risk for more severe disease, the overall level of concern in most cases was at most mild. Patients on B-cell depleting therapies were more inclined to express a higher level of concern. A similar concern was ascribed to a risk of a relapse or worsening MS symptoms compared to the risk of contracting COVID-19. Such attitudes may underscore a willingness of patients to continue their DMT where benefits outweigh risks during future phases of the COVID-19 pandemic., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A very loud systolic murmur was identified during a pre-operative evaluation of a 51-year-old woman for an elective hysterectomy. The TTE showed a 4.7 cm intracardiac mass obstructing the RVOT. The patient was scheduled instead for resection of the mass. Before anesthesia induction, the surgical team and perfusionist were prepared to initiate CPB in case of circulatory collapse. After induction of general anesthesia, the patient became hypotensive, requiring vasopressor support. She recovered and was then successfully placed on CPB. The mass was removed without incident, and a TEE confirmed resolution of the RVOT obstruction. The patient did well post-operatively., Competing Interests: None

Context: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed nations. There are currently no accurate biomarkers of NAFLD risk in youth., Objective: Identify sex-specific metabolomics biomarkers of NAFLD in a healthy cohort of youth., Design/setting: This prospective study included 395 participants of the EPOCH cohort in Colorado, who were recruited 2006-2009 ("T1 visit") and followed for 5 years ("T2 visit"). We entered 767 metabolites measured at T1 into a reduced rank regression model to identify the strongest determinants of hepatic fat fraction (HFF) at T2, separately for boys and girls. We compared the capacity of metabolites versus conventional risk factors (overweight/obesity, insulin, alanine transaminase, aspartate transaminase) to predict NAFLD (HFF ≥5%) and high HFF (fourth vs first quartile) using area under the receiver operating characteristic curve (AUC)., Results: Prevalence of NAFLD was 7.9% (8.5% of boys, 7.1% of girls). Mean ± SD HFF was 2.5 ± 3.1%. We identified 13 metabolites in girls and 10 metabolites in boys. Metabolites were in lipid, amino acid, and carbohydrate metabolism pathways. At T1, the metabolites outperformed conventional risk factors in prediction of high HFF but not NAFLD. At T2, the metabolites were superior to conventional risk factors as predictors of high HFF (AUC for metabolites vs conventional risk factors for boys: 0.9565 vs 0.8851, P = 0.02; for girls: 0.9450 vs 0.8469, P = 0.02) with similar trends for NAFLD, although the differences were not significant., Conclusions: The metabolite profiles identified herein are superior predictors of high HFF when assessed 5 years prior and concurrently in a general-risk setting., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hypothesis: An augmented reality (AR) platform using a head mounted display (HMD) can successfully display and register virtual computerized tomography (CT) data to corresponding real world anatomy using fiducial markers., Background: AR is a growing field in surgical planning, and has been used by this group to aide in orthopedic surgery applications. Intraoperative AR registration of preoperative CT images could improve identification of critical anatomical structures during lateral skull base surgery., Methods: An AR based HMD platform was created to allow for virtual display and real time manipulation of a temporal bone phantom model. Four fiducial markers were incorporated into this model and used to allow manual alignment of surface markers in real-time. To test the accuracy of this platform virtual lines were created in the AR environment running through the visualized real-world fiducial marker points. Target registration error (TRE) was calculated by measuring the orthogonal distance between these virtual lines and the corresponding virtual fiducial marker for each of the four markers from varying angles. Ten consecutive experiments were performed., Results: The AR based platform successfully displayed CT renderings in the AR environment and allowed real time translation and rotation for manual alignment. A TRE of 10.62 ± 5.90 mm was found., Conclusions: Our results suggest that AR visualization of CT imaging can be registered to patient surface landmarks, but current limitations of AR hardware resulted in TREs too large to be used in the lateral skull base. Future advancements in AR technology will hopefully allow for reduction of registration error.

Scoliosis is a common manifestation of neurofibromatosis type 1, causing significant morbidity. The etiology of dystrophic scoliosis in neurofibromatosis type 1 is not fully understood and therapies are lacking. Somatic mutations in NF1 have been shown in tibial pseudarthrosis providing rationale for similar processes in neurofibromatosis type 1-associated dystrophic scoliosis. Spinal samples from surgical procedures with matched peripheral blood of two individuals with neurofibromatosis type 1 and dystrophic scoliosis were obtained and DNA extracted. Next generation sequencing of various spinal sections as well as the germline/blood sample were performed using a RASopathy gene panel (includes the NF1 gene). Variants were compared between the spinal tissue samples and the germline data. In addition, the next generation sequencing allele frequency data were used to detect somatic loss of heterozygosity. All samples had a detected potentially inactivating NF1 germline mutation. Both individuals demonstrated an allelic imbalance inclusive of NF1 in the next generation sequencing data. In addition, for the same two individuals, there was an increase in the % variant reads for the germline mutation in some of the surgical spinal samples corresponding to the allelic imbalance. Contra analysis did not show any deletion in Chromosome 17 next generation sequencing data. Microarray analysis verified somatic copy neutral loss of heterozygosity for these two individuals for the majority of the chromosome 17 q-arm, inclusive of the NF1 gene. These results suggest that the cause of dystrophic scoliosis is multifactorial and that a somatic NF1 mutation contributes to the etiology.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder associated with unilateral anterolateral bowing with subsequent fracture and nonunion. In infancy, physiologic bowing of the lower leg can be confused with pathologic tibial dysplasia in NF1. Little is known about the bone physiology of the tibiae prior to fracture or predictors of fracture. The aim of this study was to characterize bone quality of bowed tibiae prior to fracture in NF1 using quantitative ultrasound (QUS). Bone quality was assessed on both tibiae (the non-bowed and bowed tibiae) using QUS to measure speed of sound (SOS) at the mid-shaft in 23 individuals with NF1. SOS (m/s) was determined and Z-scores generated using cross-sectional reference data of the same sex and age. The mean difference in SOS Z-scores when comparing the bowed tibia vs the individual's contralateral unaffected tibia was statistically significant with lower mean Z-scores in the bowed tibia (p = 0.001). Radiographs of all individuals with a clinical diagnosis of anterolateral bowing were reviewed, and in 2 individuals the radiographs showed minimal bowing with absence of characteristic cortical thickening and medullary canal narrowing in NF1-related tibial dysplasia, suggesting physiologic bowing. In both individuals, the Z-scores of the bowed leg were not lower than the unaffected leg supporting the suggestion of physiologic bowing rather than pathologic tibial dysplasia. These data show that dysplastic tibiae in NF1 prior to fracture and nonunion have abnormal bone quality with significant decreases in SOS even though radiographically the tibiae show a thickened cortex. These data also suggest that QUS can help distinguish dysplastic bowing vs physiologic bowing in infancy in NF1. QUS is an effective quantitative outcome measure for trials aimed at improving tibial bowing to prevent fracture, and it is a potential aid in diagnosis and clinical management in NF1., (Copyright © 2017 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey-Fineman-Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH., (© 2017 Wiley Periodicals, Inc.)

Objective: The aim of the study was to assess whether the use of carbon dioxide insufflation has any impact on integrity of long saphenous vein comparing 2 types of endoscopic vein harvesting and traditional open vein harvesting., Methods: A total of 301 patients were prospectively randomized into 3 groups. Group 1 control arm of open vein harvesting (n = 101), group 2 closed tunnel (carbon dioxide) endoscopic vein harvesting (n = 100) and Group 3 open tunnel (carbon dioxide) endoscopic vein harvesting (open tunnel endoscopic vein harvesting) (n = 100). Each group was assessed to determine the systemic level of partial arterial carbon dioxide, end-tidal carbon dioxide, and pH. Three blood samples were obtained at baseline, 10 minutes after start of endoscopic vein harvesting, and 10 minutes after the vein was retrieved. Vein samples were taken immediately after vein harvesting without further surgical handling to measure the histological level of endothelial damage. A modified validated endothelial scoring system was used to compare the extent of endothelial stretching and detachment., Results: The level of end-tidal carbon dioxide was maintained in the open tunnel endoscopic vein harvesting and open vein harvesting groups but increased significantly in the closed tunnel endoscopic vein harvesting group (P = 0.451, P = 0.385, and P < 0.001). Interestingly, partial arterial carbon dioxide also did not differ over time in the open tunnel endoscopic vein harvesting group (P = 0.241), whereas partial arterial carbon dioxide reduced significantly over time in the open vein harvesting group (P = 0.001). A profound increase in partial arterial carbon dioxide was observed in the closed tunnel endoscopic vein harvesting group (P < 0.001). Consistent with these patterns, only the closed tunnel endoscopic vein harvesting group demonstrated a sudden drop in pH over time (P < 0.001), whereas pH remained stable for both open tunnel endoscopic vein harvesting and open vein harvesting groups (P = 0.105 and P = 0.869, respectively). Endothelial integrity was better preserved in the open vein harvesting group compared with open tunnel endoscopic vein harvesting or closed tunnel endoscopic vein harvesting groups (P = 0.012) and was not affected by changes in carbon dioxide or low pH. Significantly greater stretching of the endothelium was observed in the open tunnel endoscopic open tunnel endoscopic vein harvesting group compared with the other groups (P = 0.003)., Conclusions: This study demonstrated that the different vein harvesting techniques impact on endothelial integrity; however, this does not seem to be related to the increase in systemic absorption of carbon dioxide or to the pressurized endoscopic tunnel. The open tunnel endoscopic harvesting technique vein had more endothelial stretching compared with the closed tunnel endoscopic technique; this may be due to manual dissection of the vein. Further research is required to evaluate the long-term clinical outcome of these vein grafts.

O -GlcNAc is a regulatory post-translational modification of nucleocytoplasmic proteins that has been implicated in multiple biological processes, including transcription. In humans, single genes encode enzymes for its attachment ( O -GlcNAc transferase (OGT)) and removal ( O -GlcNAcase (OGA)). An X-chromosome exome screen identified a missense mutation, which encodes an amino acid in the tetratricopeptide repeat, in OGT (759G>T (p.L254F)) that segregates with X-linked intellectual disability (XLID) in an affected family. A decrease in steady-state OGT protein levels was observed in isolated lymphoblastoid cell lines from affected individuals, consistent with molecular modeling experiments. Recombinant expression of L254F-OGT demonstrated that the enzyme is active as both a glycosyltransferase and an HCF-1 protease. Despite the reduction in OGT levels seen in the L254F-OGT individual cells, we observed that steady-state global O -GlcNAc levels remained grossly unaltered. Surprisingly, lymphoblastoids from affected individuals displayed a marked decrease in steady-state OGA protein and mRNA levels. We observed an enrichment of the OGT-containing transcriptional repressor complex mSin3A-HDAC1 at the proximal promoter region of OGA and correspondingly decreased OGA promoter activity in affected cells. Global transcriptome analysis of L254F-OGT lymphoblastoids compared with controls revealed a small subset of genes that are differentially expressed. Thus, we have begun to unravel the molecular consequences of the 759G>T (p.L254F) mutation in OGT that uncovered a compensation mechanism, albeit imperfect, given the phenotype of affected individuals, to maintain steady-state O -GlcNAc levels. Thus, a single amino acid substitution in the regulatory domain (the tetratricopeptide repeat domain) of OGT, which catalyzes the O -GlcNAc post-translational modification of nuclear and cytosolic proteins, appears causal for XLID., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

A subset of neurofibromatosis type 1 patients develop tibial dysplasia, which can lead to pseudarthrosis. The tissue from the tibial pseudarthrosis region commonly has a somatic second hit in NF1: single-nucleotide variants, small deletions, or loss of heterozygosity (LOH). We used exome next-generation sequencing (NGS) variant frequency data (allelic imbalance analysis) to detect somatic LOH in pseudarthrosis tissue from three individuals with clinically and diagnostically confirmed neurofibromatosis type 1, and verified the results with microarray. The variant files were parsed and plotted using python scripts, and the NGS variant frequencies between the affected tissue and blood sample were compared. Individuals without somatic single-nucleotide variants or small insertions/deletions were tested for somatic LOH using the NGS variant allele frequencies. One individual's NGS data indicated no LOH in chromosome 17. The other two individuals demonstrated somatic LOH inclusive of NF1: one had an LOH region of approximately one million bases and Contra (NGS copy number program) indicated a somatic deletion and the other individual had LOH for most of chromosome 17q and Contra indicated no copy number change (microarray data verified this sample as copy neutral somatic LOH). Both LOH and copy number variation detected by NGS data correlated with microarray data, demonstrating the somatic LOH second hit can be detected directly from the NGS data., (Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate safety and efficacy of a single intratympanic injection of OTO-104, sustained-exposure dexamethasone, in patients with unilateral Ménière's disease., Study Design: Randomized, double-blind, placebo-controlled, Phase 2b study over 5 months., Setting: Fifty-two academic and community otolaryngology centers., Patients: One hundred fifty four patients (77 per group) aged 18 to 85 years inclusive., Intervention: Single intratympanic injection of OTO-104 (12 mg dexamethasone) or placebo., Main Outcome Measures: Efficacy (vertigo) and safety (adverse events, otoscopy, audiometry, tympanometry)., Results: Primary endpoint (change from baseline in vertigo rate at Month 3) was not statistically significant (placebo [-43%], OTO-104 [-61%], P = 0.067). Improvements with OTO-104 were observed in prospectively defined secondary endpoints number of days with definitive vertigo, (Month 2 [P = 0.035], Month 3 [P = 0.030]), vertigo severity (Months 2-3, P = 0.046) and daily vertigo counts (Month 2, P = 0.042), and in some Short Form-36 (SF-36) subscales (Month 2 bodily pain P = 0.039, vitality P = 0.045, social functioning P = 0.025). No difference in tinnitus loudness or tinnitus handicap inventory (THI-25) was observed. OTO-104 was well tolerated; no negative impact on safety compared with placebo. Persistent tympanic membrane perforation was observed in two OTO-104 treated patients at study end., Conclusion: OTO-104 was well-tolerated, did not significantly affect change from baseline in vertigo rate, but did reduce number definitive vertigo days, vertigo severity, and average daily vertigo count compared with placebo during Month 3. Results provide insight into analyzing for a vertigo treatment effect and support advancing OTO-104 into Phase 3 clinical trials for the treatment of Ménière's disease symptoms.

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes 2 categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low-to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 min and 12h. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 min to 24h., (Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Patología Cérvico-Facial. All rights reserved.)

This paper describes the diagnostic criteria for vestibular paroxysmia (VP) as defined by the Classification Committee of the Bárány Society. The diagnosis of VP is mainly based on the patient history and requires: A) at least ten attacks of spontaneous spinning or non-spinning vertigo; B) duration less than 1 minute; C) stereotyped phenomenology in a particular patient; D) response to a treatment with carbamazepine/oxcarbazepine; and F) not better accounted for by another diagnosis. Probable VP is defined as follows: A) at least five attacks of spinning or non-spinning vertigo; B) duration less than 5 minutes; C) spontaneous occurrence or provoked by certain head-movements; D) stereotyped phenomenology in a particular patient; E) not better accounted for by another diagnosis.Ephaptic discharges in the proximal part of the 8th cranial nerve, which is covered by oligodendrocytes, are the assumed mechanism. Important differential diagnoses are Menière's disease, vestibular migraine, benign paroxysmal positional vertigo, epileptic vestibular aura, paroxysmal brainstem attacks (in multiple sclerosis or after brainstem stroke), superior canal dehiscence syndrome, perilymph fistula, transient ischemic attacks and panic attacks. Current areas of uncertainty in the diagnosis of VP are: a) MRI findings of vascular compression which are not diagnostic of the disease or predictive for the affected side because they are also observed in about 30% of healthy asymptomatic subjects; and b) response to treatment with carbamazepine/oxcarbazepine supports the diagnosis but there are so far no randomized controlled trials for treatment of VP.

Aims: Heart failure remains a leading cause of morbidity, hospitalizations, and deaths. We previously showed that overexpression of the enzyme ribonucleotide reductase (RNR) in cardiomyocytes increased levels of the myosin activator, 2-deoxy-ATP, catalysed enhanced contraction, and improved cardiac performance in rodent hearts. Here we used a swine model of myocardial infarction (MI) to test preliminarily a novel gene therapy for heart failure based on delivery of the human RNR enzyme complex under the control of a cardiac-specific promoter via an adeno-associated virus serotype 6 vector--designated as BB-R12., Methods and Results: We induced heart failure following MI in Yucatan minipigs by balloon occlusion of the left anterior descending artery. Two weeks, later, pigs received BB-R12 at one of three doses via antegrade coronary infusion. At 2 months post-treatment, LVEF and systolic LV dimension (measured by echocardiography) improved significantly in the high-dose group, despite further deterioration in the saline controls. Haemodynamic parameters including LV end-diastolic pressure, +dP/dt, and -dP/dt all trended towards improvement in the high-dose group. We observed no difference in the histopathological appearance of hearts or other organs from treated animals vs. controls, nor did we encounter any safety or tolerability concerns following BB-R12 delivery., Conclusion: These pilot results suggest cardiac-specific gene therapy using BB-R12 may reverse cardiac dysfunction by myosin activation in a large-animal heart failure model with no observed safety concerns. Thus further research into the therapeutic potential of BB-R12 for patients with chronic heart failure appears warranted., (© 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.)

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 minutes and 12 hours. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 minutes to 24 hours.

Hypothesis: We investigated if current-generation computed tomographic (CT) scanners have the resolution required to objectively detect bone structure defects as small as 0.1 mm. In addition, we propose that our method is able to predict a possible dehiscence in a semicircular canal., Background: In semicircular canal dehiscence (SCD), the bone overlying the superior canal (SC) is partially absent, causing vertigo, autophony, hyperacusis or hearing loss. Diagnosis of SCD is typically based on multi-slice computed tomography (MSCT) images combined with the consideration of clinical signs and symptoms. Recent studies have shown that MSCT tends to overestimate the size of dehiscences and may skew the diagnosis towards dehiscence when a thin bone layer remains. Evaluations of CT scans for clinical application are typically observer based., Methods: We developed a method of objectively evaluating the resolution of CT scanners. We did this for 2 types of computed tomography: MSCT, and cone beam computed tomography (CBCT), which have been reported to have a higher resolution for temporal bone scans. For the evaluation and comparison of image accuracy between different CT scanners and protocols, we built a bone cement phantom containing small, well-defined structural defects (diameter, 0.1-0.4 mm). These small inhomogeneities could reliably be detected by comparing the variances of radiodensities of a region of interest (i.e., a region containing a hole) with a homogenous region. The Fligner-Killeen test was used to predict the presence or absence of a hole (p ≥ 0.05). For our second goal, that is, to see how this technique could be applied to the detection of a possible dehiscence in a SC, a cadaveric head specimen was used to create an anatomic model for a borderline SCD; the SC was drilled to the point of translucency. After semi-automatically fitting the location of the canal, our variance-based approach allowed a clear, significant detection of the thin remaining bone layer., Results: Our approach of statistical noise analysis on bone cement phantoms allowed us to distinguish real irregularities from measured image noise or reconstruction errors. We have shown that with computed tomography, an approach comparing radiodensity variance in regions of interest is capable of detecting inhomogeneities down to 0.1 mm (p ≤ 0.0001)., Conclusion: Our analysis of data from the cadaveric head specimen demonstrates that this approach can be used to objectively detect thin layers of bone overlying an SC. This should provide the basis for using this approach for a semi-automated, objective detection of SCD.

We present here the characteristics of an in situ forming hydrogel prepared from carboxymethyl chitosan and oxidized carboxymethyl cellulose for interventional therapies. Gelation, owing to the formation of Schiff bases, occurred both with and without the presence of a radiographic contrast agent. The hydrogel exhibited a highly porous internal structure (pore diameter 17±4 μm), no cytotoxicity to human umbilical vein endothelial cells, hemocompatibility with human blood, and degradability in lysozyme solutions. Drug release from hydrogels loaded with a sclerosant, tetracycline, was measured at pH 7.4, 6 and 2 at 37°C. The results showed that tetracycline was more stable under acidic conditions, with a lower release rate observed at pH 6. An anticancer drug, doxorubicin, was loaded into the hydrogel and a cumulative release of 30% was observed over 78 h in phosphate-buffered saline at 37°C. Injection of the hydrogel precursor through a 5-F catheter into a fusiform aneurysm model was feasible, leading to complete filling of the aneurysmal sac, which was visualized by fluoroscopy. The levels of occlusion by hydrogel precursors (1.8% and 2.1%) and calibrated microspheres (100-300 μm) in a rabbit renal model were compared. Embolization with hydrogel precursors was performed without clogging and the hydrogel achieved effective occlusion in more distal arteries than calibrated microspheres. In conclusion, this hydrogel possesses promising characteristics potentially beneficial for a wide range of vascular intervention procedures that involve embolization and drug delivery., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

This paper presents diagnostic criteria for vestibular migraine, jointly formulated by the Committee for Classification of Vestibular Disorders of the Bárány Society and the Migraine Classification Subcommittee of the International Headache Society (IHS). The classification includes vestibular migraine and probable vestibular migraine. Vestibular migraine will appear in an appendix of the third edition of the International Classification of Headache Disorders (ICHD) as a first step for new entities, in accordance with the usual IHS procedures. Probable vestibular migraine may be included in a later version of the ICHD, when further evidence has been accumulated. The diagnosis of vestibular migraine is based on recurrent vestibular symptoms, a history of migraine, a temporal association between vestibular symptoms and migraine symptoms and exclusion of other causes of vestibular symptoms. Symptoms that qualify for a diagnosis of vestibular migraine include various types of vertigo as well as head motion-induced dizziness with nausea. Symptoms must be of moderate or severe intensity. Duration of acute episodes is limited to a window of between 5 minutes and 72 hours.

Aims: Transforming growth factor-β (TGF-β) signaling is critical for the differentiation of smooth muscle cells (SMCs) into quiescent cells expressing a full repertoire of contractile proteins. Heterozygous mutations in TGF-β receptor type II (TGFBR2) disrupt TGF-β signaling and lead to genetic conditions that predispose to thoracic aortic aneurysms and dissections (TAADs). The aim of this study is to determine the molecular mechanism by which TGFBR2 mutations cause TAADs., Methods and Results: Using aortic SMCs explanted from patients with TGFBR2 mutations, we show decreased expression of SMC contractile proteins compared with controls. Exposure to TGF-β1 fails to increase expression of contractile genes in mutant SMCs, whereas control cells further increase expression of these genes. Analysis of fixed and frozen aortas from patients with TGFBR2 mutations confirms decreased in vivo expression of contractile proteins relative to unaffected aortas. Fibroblasts explanted from patients with TGFBR2 mutations fail to transform into mature myofibroblasts with TGF-β1 stimulation as assessed by expression of contractile proteins., Conclusions: These data support the conclusion that heterozygous TGFBR2 mutations lead to decreased expression of SMC contractile protein in both SMCs and myofibroblasts. The failure of TGFBR2-mutant SMCs to fully express SMC contractile proteins predicts defective contractile function in these cells and aligns with a hypothesis that defective SMC contractile function contributes to the pathogenesis of TAAD.

Osteoarthritis (OA) has historically been classified as 'primary' where no discernible cause was evident and 'secondary' where a triggering factor was apparent. Irrespective of the triggering events, late-stage OA is usually characterized by articular cartilage attrition and consequently the anatomical basis for disease has been viewed in terms of cartilage. However, the widespread application of magnetic resonance imaging in early OA has confirmed several different anatomical abnormalities within diseased joints. A key observation has been that several types of primary or idiopathic OA show ligament-related pathology at the time of clinical presentation, so these categories of disease are no longer idiopathic - at least from the anatomical perspective. There is also ample evidence for OA initiation in other structures including menisci and bones in addition to articular cartilage. Therefore, a new classification for OA is proposed, which is based on the anatomical sites of earliest discernible joint structural involvement. The major proposed subgroups within this classification are ligament-, cartilage-, bone-, meniscal- and synovial-related, in addition to disease that is mixed pattern or multifocal in origin. We show how such a structural classification for OA provides a useful reference framework for staging the magnitude of disease. For late-stage or end-stage/whole organ disease, the final common pathway of these different scenarios, joint replacement strategies are likely to remain the only viable option. However, for younger subjects in particular, near the time of clinical disease onset, this scheme has implications for therapy targeted to specific anatomical locations. Thus, in the same way that tumours can be classified and staged according to their tissue of origin and extent of involvement, OA can likewise be anatomically classified and staged. This has implications for therapeutic strategies including regenerative medicine therapy development.

Objectives: Introduce a novel method for objectively evaluating attentional bias to peripheral facial deformities using an established metric of attention., Methods: The SMI eye-tracker system (SensoMotoric Inc., Boston, MA) was used to record the eye movement patterns, called scanpaths, of eight naïve observers gazing at pictures of faces with or without peripheral surgical deformities. The scanpaths of observers gazing on those novel faces were compared, and the fixation durations for different facial regions were compared between faces., Results: There were statistically significant differences in the mean fixation times between the faces considered normal and those considered abnormal (those with an obvious defect). When multivariate analysis of variance was performed with dependent variables total fixation time, fixation time in central triangle, and fixation time in the defect region and the independent variable face, all four tests were highly statistically significant. When univariate analysis of variance was performed to test the hypothesis that defect fixation times varied by face, the results were highly statistically significant (F = 8.79, P = .0003)., Conclusions: Observers gazing on faces typically focus their attention on discriminating features, such as eyes, nose, and mouth. The well-established method of eye movement recordings was applied in a novel way to provide quantitative data showing changes in observer gaze patterns to focus on deformities. These gaze patterns are a direct reflection of observer attention. This is the first objective method to quantify the amount of distraction caused by peripheral facial deformities and may provide insight into the perception of facial deformity.

In the superior canal dehiscence syndrome, patients can have sound- or pressure-induced vertigo and oscillopsia. They may also present conductive hearing loss or higher than normal bone conduction thresholds. Clinical manifestations are due to the effect of a third mobile window in the inner ear created by the dehiscence. Diagnosis is based on clinical manifestations, vertical and rotatory nystagmus induced by sound and pressure reflecting SSC stimulation, reduced threshold and increased amplitude of vestibular evoked myogenic potentials (VEMP) and temporal bone CT scan images showing the SSC dehiscence. Characteristic eye movements can be recorded with the scleral search coil technique.

We conducted a retrospective review to assess outcomes of therapy in patients with newly diagnosed Wegener granulomatosis (WG) using methotrexate (MTX) for mild to moderate disease and short-term treatment with cyclophosphamide (CYC) followed by MTX for severe disease. Patients with WG were included if their initial plan of therapy and subsequent care were directly supervised by the Cleveland Clinic Center for Vasculitis Care and Research. Severe disease (immediately life-threatening or involving critical organs) was initially treated with CYC and glucocorticoids. Mild to moderate disease was initially treated with MTX and glucocorticoids if serum creatinine was less than 2 mg/dL. Following initial improvement of severe disease, treatment was changed to MTX if serum creatinine was originally less than 2 mg/dL or had diminished to less than 2 mg/dL. Disease activity was determined at each visit and later converted to a Birmingham Vasculitis Activity Score, as modified for Wegener granulomatosis (BVAS/WG). Laboratory monitoring of disease and treatment toxicity was initially weekly and never less than monthly.Eighty-two (32%) of 253 patients with WG referred to the Center for Vasculitis Care and Research met eligibility criteria. Ineligible patients did not have new-onset disease or were not able to be followed principally in our center. Seventy percent of patients (57/82) initially had severe disease and received a short course of CYC for remission induction. In over half of these patients, illness was judged to be severe because of pulmonary hemorrhage; rapidly progressive glomerulonephritis, including need for dialysis; or neurologic abnormalities. All patients improved: remission was achieved in 50% (41/82) of patients within 6 months and in 72% (59/82) within 12 months. Sustained remission (BVAS/WG = 0 for at least 6 consecutive months) was ultimately achieved in 78% (64/82) of patients. Among the 75 (91%) patients who achieved remission of any duration, 45% relapsed within 1 year and 66% relapsed within 2 years following remission. Eighty-two percent of relapsed patients achieved subsequent remissions after additional treatment. About three-quarters of relapses were mild and promptly responded to treatment. Seventeen percent of patients developed serious infections. CYC-associated cystitis or bladder cancer did not occur in any patients. At least 1 form of permanent morbidity from WG alone was noted in 74.0% of patients. Three patients (3.7%) died over a median follow-up period of 4.5 years; no deaths were due to active disease. Although treatment was primarily directed toward achieving clinical improvement and not calculated to achieve marked lymphopenia, patients in whom treatment produced lymphocyte counts of 1000/mm was associated with a hazard ratio for relapse of 3.0, although the latter difference was not statistically significant. In patients with WG, a strategy that limits or avoids CYC therapy produced a frequency of remission comparable to that achieved with conventional CYC protocols, excellent survival, and avoidance of long-term CYC toxicity. However, relapses were common and incremental permanent morbidity occurred in most patients. While not a goal of therapy, when treatment produced marked lymphopenia, prolonged remissions were more likely.