Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.

Separating the wheat from the chaff: systematic identification of functionally relevant noncoding variants in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations ('the wheat' from 'the chaff') will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools-genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)-that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.

Multidisciplinary approach in the management of absolute trismus with bilateral temporomandibular joint replacements for a patient with juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is an exclusion diagnosis that gathers together all forms of arthritis that begin before the age of 16 years, persist for more than 6 weeks and are of unknown origin. We present the case of a 42 year old woman with a 20 year history of absolute trismus, secondary to bilateral temporomandibular joint (TMJ) ankylosis caused by JIA. The trismus resulted in grossly compromised oral hygiene and limited the patient to a semi-solid diet. JIA also affected her neck leading to a severe cervico-thoracic kyphosis. The patient who had been wheelchair bound developed severe lymphoedema of both lower limbs, complicating the pre-operative work up further. This particularly challenging case required input from specialists in anaesthetics, neurosurgery, special care dentistry, intensive care and maxillofacial surgery. Treatment consisted of ankylosis release, dental clearance and bilateral alloplastic replacement of her TMJs with custom implants. A full range of hinge movement and good functional outcome was achieved. This case presents the multidisciplinary approach to a severely compromised patient and illustrates the pre-, intra- and postoperative management of bilateral TMJ ankylosis with bespoke implants.

Interprofessional care for temporomandibular joint disorders: the patient's perspective.

The Indiana University School of Dentistry TMJ Institute is a multidisciplinary clinic designed to support the management of patients with challenging temporomandibular disorders. Professionals across dentistry, medicine, physical therapy, and social work collaborate to create a customised, interprofessional consensus to patient care. Compared with traditional, siloed healthcare models, are patients diagnosed with TMJ dysfunction satisfied with the quality of care received from an interprofessional approach? The objective of this study is to determine the level of patient satisfaction at the Institute using a 5-Point Likert scale patient questionnaire. A total of 93 questionnaires were distributed and 84 were collected. A total of 43% of patients travelled over 50 miles to be seen at the Institute. 'Strongly agree' was the most selected response for each prompt. The exception was whether patients preferred to meet with each clinician individually, to which 'strongly disagree' or 'disagree' was the most popular response, indicating that an interprofessional approach was preferred. The results and comments provided by patients revealed that most patients diagnosed with TMJ dysfunction were highly satisfied with the interprofessional approach used at the TMJ Institute. Our study suggests that positive patient satisfaction is an important factor in assessing the quality and efficacy of interprofessional, patient-centred clinic models.

Feedlot operators' and cow-calf producers' perspectives on the economic value of health-preconditioned weaner calves in South Africa.

Health preconditioning programmes have recently gained increased attention in South Africa. Uncertainty remains about whether South African feedlot operators and cow-calf producers perceive health preconditioning as an economic value-added management practice. Results indicated that most feedlot operators were willing to pay average price premiums of R0.58/kg, R0.83/kg and R1.02/kg for a basic, intermediate and comprehensive health preconditioning programme, respectively. Cow-calf producers were willing to accept average price premiums of R0.49/kg, R0.72/kg and R0.83/kg for the programmes. The findings provide information that could contribute to potential market development for health-preconditioned weaners in developing countries and could significantly aid in improving efficiency and herd health within beef industries worldwide.

Myofibroma of the body of mandible: A case report of a solitary lesion.

Myofibromas are rare benign lesions and are often found as solitary entities. The treatment of the lesion is complete excision and the recurrence is rare. A 56-year-old female presented to the Oral and Maxillofacial Surgery clinic for further evaluation and management of a solitary lesion of the right body of the mandible that was first noticed incidentally by her referring dentist. An incisional biopsy was first performed in the clinic with the diagnosis of myofibroma. The patient was then treated with complete excision of the lesion and extraction of the adjacent teeth. The final biopsy report confirmed the initial diagnosis of myofibroma. Intraosseous solitary lesion of the mandible is a rare lesion with a handful of reported cases. Uniquely, the diagnosis of myofibroma in this 56-year-old is the oldest reported case of myofibroma. There are distinct histopathological features of the lesion that distinguishes this entity from other closely resembling lesions.

Role of alloplastic reconstruction of the temporomandibular joint in the juvenile idiopathic arthritis population.

We present outcomes following total joint replacement of the temporomandibular joint (TMJ) in adolescent and young adult patients with juvenile idiopathic arthritis (JIA), and discuss a multidisciplinary treatment model. A retrospective review was performed of patients presenting to the University of North Carolina Oral and Maxillofacial Surgery Service (Chapel Hill, NC) from 2016- 2018 who underwent unilateral or bilateral total replacement of the TMJ for a diagnosis of end-stage joint disease secondary to JIA. Inclusion criteria included diagnosis by a rheumatologist, presentation to our department in adolescence (under 18 years of age), surgical intervention in adolescence or young adulthood (under 25 years of age), and documentation of preoperative and postoperative pain, maximum incisal opening (MIO), and quality of life measures. A database was created and data were then analysed both qualitatively and quantitatively. Five patients met the inclusion criteria. All achieved MIO of more than 35mm with a mean improvement of 24mm, and were able to tolerate a regular diet. All preoperative pain had essentially been eliminated. All patients reported a considerable improvement in quality of life. To our knowledge, this is the first report to document a series of paediatric and young adult patients with JIA who required total replacement of the joint for end-stage joint disease. To our knowledge, it is also the first to describe the use of a collaborative clinic of oral and maxillofacial surgeons, neuroradiologists, dental radiologists, orofacial pain specialists, paediatric rheumatologists, and paediatric nurse practitioners, to care for these patients.

Inducibility of class II major histocompatibility complex antigens by interferon gamma is associated with reduced tumorigenicity in C3H mouse fibroblasts transformed by v-Ki-ras.

Paired lines of C3H mouse fibroblasts transformed with murine sarcoma virus (Kirsten strain) were prepared that express high or low levels of class II major histocompatibility complex antigen after treatment with interferon gamma (IFN-gamma). Here, we described a comparison of the tumorigenicity of these lines in euthymic syngeneic and thymus-deficient nu/nu mice and in mice depleted of IFN-gamma. The class II-inducible cells are clearly less tumorigenic than the noninducible cells in syngeneic mice, but of similar tumorigenicity in nu/nu mice and in mice treated with antibodies to deplete IFN-gamma. We propose that in this system, IFN-gamma induction of class II antigens on the tumor cell surface operates to limit tumor growth; ras expression, which inhibits induction of class II antigens, prevents this and so allows tumor growth.

Teledentistry Knowledge and Attitudes: Perspectives on the role of dental hygienists.

Purpose. The first statewide teledentistry (TD) Summit in North Carolina (NC) was convened by the University of North Carolina (UNC) at Chapel Hill in 2018. The purpose of this analysis is to compare Summit participants' understanding of TD, its benefits, challenges, solutions and the role of dental hygienists, pre- and post-Summit.Methods. Summit invitees included leaders in related policy, education, advocacy, legislation, technology and UNC dental hygiene and dental students. Descriptive analyses and exact McNemar's matched pair tests compared proportions of participants' responses to pre- and post-Summit surveys.Results. Response rates were pre-Summit 75.3% (n= 58) and post-Summit 70.1% (n= 47); matched pre-post survey pairs (n=42). Pre-Summit respondents reported their primary role in administration (48.0%), teaching and mentoring (21.0%), patient care (12.0%) or as a student (19.0%). Among respondents, overall self-reported TD knowledge increased from 38.1% to 92.9%, p< 0.001. Their reported extent TD should be developed in NC increased from 78.6% to 95.2%, p = 0.07; the extent hygienists should have a role in TD services increased from 83.3% to 88.1%, p = 0.73. The most frequently mentioned challenge was state practice acts requiring direct supervision of dental hygienists, limiting their TD use in community settings, which increased in the pre- to post-surveys from 33.3% to 59.5% respectively, p = 0.01.Conclusion. Among attendees at the statewide TD Summit, self-reported knowledge was high and attitudes favorable for moving forward with TD in NC. However, state dental practice act barriers restricting dental hygienist participation in TD was the first challenge respondents thought needed to be addressed.

Responding to a pandemic: Development of the Carolina Dentistry Virtual Oral Health Care Helpline.

BACKGROUND: A virtual oral health care help line was established to provide consultation and triage for people with dental questions and concerns. Its goal during a pandemic was to keep patients from seeking unnecessary in-person care from emergency departments and urgent care clinics, especially when dental practices were closed or limited to providing essential urgent and emergency oral health care. METHODS: The Adams School of Dentistry, University of North Carolina at Chapel Hill, developed the Carolina Dentistry Virtual Oral Health Care Helpline using a quality improvement framework with faculty and staff member feedback. The process included establishing infrastructure (phone, video, protocols, referrals, documentation), personnel (scheduling, training, calibration), and internal and external communication. The authors collected retrospective information for descriptive evaluation of the first month's operations. RESULTS: There were 337 telephone calls answered, of which 65 (19%) were administrative and 272 (81%) were related to dental concerns. Dental pain (54%) was the most prevalent reason for calling. Triage and Providers referred 107 of 175 callers (61%) to the school's urgent care center. Of the 79 callers who received teleconsultations from virtual providers, 33 (42%) did not require additional follow-up, and 7 (9%) needed a follow-up phone call. Overall, 4 people were referred to community clinics, and 4 were referred to the emergency department. CONCLUSIONS: The Helpline was launched quickly and improved through quality improvement cycles, and it provided a needed community dental service. The process resolved some patient concerns without their seeking urgent or emergency care. PRACTICAL IMPLICATIONS: The pandemic has increased teledentistry practice. The authors describe establishing a dental school's virtual oral health Helpline, which provides a framework for dental practices seeking to use this patient communication modality.

Ultra-high resolution array painting facilitates breakpoint sequencing.

OBJECTIVE: To describe a considerably advanced method of array painting, which allows the rapid, ultra-high resolution mapping of translocation breakpoints such that rearrangement junction fragments can be amplified directly and sequenced. METHOD: Ultra-high resolution array painting involves the hybridisation of probes generated by the amplification of small numbers of flow-sorted derivative chromosomes to oligonucleotide arrays designed to tile breakpoint regions at extremely high resolution. RESULTS AND DISCUSSION: How ultra-high resolution array painting of four balanced translocation cases rapidly and efficiently maps breakpoints to a point where junction fragments can be amplified easily and sequenced is demonstrated. With this new development, breakpoints can be mapped using just two array experiments: the first using whole-genome array painting to tiling resolution large insert clone arrays, the second using ultra-high-resolution oligonucleotide arrays targeted to the breakpoint regions. In this way, breakpoints can be mapped and then sequenced in a few weeks.

Ultrasound versus magnetic resonance imaging of the temporomandibular joint in juvenile idiopathic arthritis: a systematic review.

A systematic review of published articles on ultrasound (US) and magnetic resonance imaging (MRI) of the temporomandibular joint (TMJ) in juvenile idiopathic arthritis (JIA) was performed to answer the question "What is the sensitivity and specificity of US as compared to MRI in diagnosing acute and chronic joint changes in patients with JIA?" The most recent evidence was sought in published articles via a search of the PubMed, Ovid, and Embase databases. Article appraisal was performed by two reviewers. Nineteen articles reporting prospective or ambispective studies comparing US to MRI in TMJ imaging were found. Six of these articles were specific to JIA patients. The heterogeneity of these articles made comparison difficult. Of the acute and chronic changes assessed (disk displacement, joint effusion, bony deformity), only joint effusion was appropriately assessed by multiple authors, with US having a sensitivity of 0-72% and specificity of 70-83% as compared to MRI. There was a paucity of studies specific to JIA, with many studying adult, non-rheumatic patients. This systematic review found that dynamic imaging with high-resolution US improves sensitivity and specificity compared to static, low-resolution US. Additionally, there is evidence to suggest that US imaging following a baseline MRI can increase US sensitivity and specificity and may have a future role in disease surveillance.

Body mass index (BMI), postoperative appearance satisfaction, and sexual function in breast cancer survivorship.

PURPOSE: We sought to explore the correlation between BMI and postoperative sexual function, body image, and breast-specific sensuality before and after breast cancer surgery. METHODS: A cross-sectional survey of patients at least 1 year from surgery employed the Female Sexual Function Index (FSFI) and investigator-generated questions. Patients who underwent lumpectomy (L), mastectomy (M), and mastectomy with reconstruction (MR) were compared across three BMI groups: normal weight, overweight, and obese. RESULTS: Two hundred fifty-five patients underwent lumpectomy (L, n = 174), mastectomy (M, n = 22), or mastectomy with reconstruction (MR, n = 59). Median age was 57 (range 30-93) and median BMI was 28 (range 19-45). Obese and overweight women reported more appearance dissatisfaction (18.1 and 13.0%) than normal weight women (4.1%) (p = 0.01). Lower satisfaction was associated with increasing BMI within the MR group (p = 0.05). The obese group's median FSFI score met criteria for sexual dysfunction (25.90, range 11.30-33.10). More overweight women reported their chest played an important role in intimacy before and after surgery, but a postoperative decline in the importance of this role was observed in all groups. CONCLUSIONS: Greater post-treatment BMI is inversely related to postoperative appearance satisfaction, particularly in those undergoing mastectomy with reconstruction. The role of the breast in intimacy is greatest in overweight women, but decreases postoperatively in all BMI groups. IMPLICATIONS FOR CANCER SURVIVORS: Postoperative appearance satisfaction and sexual function seems to be correlated to post-treatment BMI, which highlights the need to encourage perioperative weight management for improved survivorship outcomes.

Radioimmunoassay for measurement of thyroglobulin in human serum.

A specific and reproducible double antibody radioimmunoassay for the measurement of thyroglobulin (HTg) in human serum has been developed. Since antithyroglobulin autoantibodies combine with the [(131)I] HTg tracer, antibody-positive sera were rejected for measurement. Specificity is demonstrated in that thyroid analogous such as thyroxine (T(4)), triiodothyronine (T(2)) monoiodotyrosine (MIT) and diiodotyrosine (DIT) did not crossreact. Sera previously reacted with anti-HTg-Sepharose contained no immunoassayable HTg. Finally, sera obtained from patients after total thyroid ablation for thyroid carcinoma did not contain demonstrable HTg. The sensitivity of the assay is 1.6 ng/ml, and HTg was detectable in 74% of 95 normal subjects. The mean concentration was 5.1 ng/ml +/-0.49 SEM (range <1.6-20.7 ng/ml). Day to day variation in HTg levels is large in some euthyroid subjects and nearly absent in others. HTg was detectable in 90% of the sera obtained in 23 pregnant women at delivery in whom a mean concentration of 10.1 ng/ml +/-1.3 SEM was observed. The mean level for the corresponding newborn infants at birth was 29.3 ng/ml +/-4.7 SEM a value significantly higher than the mean maternal HTg concentration (P <0.01). A group of 17 thyrotoxic individuals all had elevated HTg levels; the mean for this group was 344.8 ng/ml +/-90.7 SEM. In the acute phase of subacute thyroiditis HTg was also elevated in all of 12 patients, and the mean for this group was 136.8 ng/ml +/-74.6 SEM.

Effect of 1- and 10-day administration of tepoxalin on minimum alveolar concentration of isoflurane and sevoflurane in dogs.

Analgesics given preoperatively have the potential to decrease the amount of inhalant anesthetics required intraoperatively (i.e., to decrease the minimum alveolar concentration, or MAC, for the inhalant). Tepoxalin is an NSAID approved for the treatment of arthritis in dogs in the United States and, hence, could be administered to patients undergoing anesthesia. In this study, administration of a single dose or a 10-day course of tepoxalin did not affect the MAC for isoflurane or sevoflurane.

Auditory prediction errors as individual biomarkers of schizophrenia.

Schizophrenia is a complex psychiatric disorder, typically diagnosed through symptomatic evidence collected through patient interview. We aim to develop an objective biologically-based computational tool which aids diagnosis and relies on accessible imaging technologies such as electroencephalography (EEG). To achieve this, we used machine learning techniques and a combination of paradigms designed to elicit prediction errors or Mismatch Negativity (MMN) responses. MMN, an EEG component elicited by unpredictable changes in sequences of auditory stimuli, has previously been shown to be reduced in people with schizophrenia and this is arguably one of the most reproducible neurophysiological markers of schizophrenia. EEG data were acquired from 21 patients with schizophrenia and 22 healthy controls whilst they listened to three auditory oddball paradigms comprising sequences of tones which deviated in 10% of trials from regularly occurring standard tones. Deviant tones shared the same properties as standard tones, except for one physical aspect: 1) duration - the deviant stimulus was twice the duration of the standard; 2) monaural gap - deviants had a silent interval omitted from the standard, or 3) inter-aural timing difference, which caused the deviant location to be perceived as 90° away from the standards. We used multivariate pattern analysis, a machine learning technique implemented in the Pattern Recognition for Neuroimaging Toolbox (PRoNTo) to classify images generated through statistical parametric mapping (SPM) of spatiotemporal EEG data, i.e. event-related potentials measured on the two-dimensional surface of the scalp over time. Using support vector machine (SVM) and Gaussian processes classifiers (GPC), we were able classify individual patients and controls with balanced accuracies of up to 80.48% (p-values = 0.0326, FDR corrected) and an ROC analysis yielding an AUC of 0.87. Crucially, a GP regression revealed that MMN predicted global assessment of functioning (GAF) scores (correlation = 0.73, R2 = 0.53, p = 0.0006).

Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects.

OBJECTIVE: To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA). METHODS: In this open-label, randomized, 2-part, 2-period crossover study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within prespecified bounds of (0.80, 1.25). RESULTS: The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/ SIMVA and EZE + SIMVA were generally well tolerated. CONCLUSIONS: The lowest and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dosages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tablet across the clinical dose range.

Nitric oxide-mediated regulation of chemosensitivity in cancer cells.

BACKGROUND: Hypoxia in tumors is associated with malignant progression, metastatic spread, and increased resistance to radiotherapy and chemotherapy. Molecular O(2) is required for the cellular production of nitric oxide (NO) by the enzyme NO synthase (NOS), and NO may block components of the adaptive response to hypoxia. Hence, we hypothesized that hypoxia increases drug resistance in tumor cells by inhibiting endogenous NO production. METHODS: Human breast carcinoma (MDA-MB-231) and mouse melanoma (B16F10) cells were pre-exposed to 20% O(2), 5% O(2), or 1% O(2), incubated with a pharmacologic inhibitor of endogenous NO production, and then treated with chemotherapeutic agents. Resistance was assessed by colony-formation assays, and western blot analysis was used to measure NOS protein levels. All P values were two-sided. RESULTS: Incubation of MDA-MB-231 tumor cells in 1% O(2) maximally increased their resistance to doxorubicin and 5-fluorouracil by 8.5-fold (P =.002) and 2.3-fold (P =.002), respectively, compared with incubation in 20% O(2). B16F10 mouse melanoma cells preincubated in 1% O(2) (versus 20% O(2)) for 12 hours exhibited a twofold increase in resistance to doxorubicin (P<.001). The rapid acquisition of drug resistance after exposure to 1% O(2) could be mimicked by incubating the MDA-MB-231 cells for 12 hours with the NOS inhibitor N(G)-monomethyl-Larginine (fivefold increase; P<.001). Conversely, replacement of NO activity by use of the NO-mimetic glyceryl trinitrate (GTN) and diethylenetriamine NO adduct produced statistically significant attenuations in the development of resistance of 59% (P<.001) and 40% (P<.001), respectively, in MDA-MB-231 cells. Treatment of B16F10 cells with GTN produced a 58% reduction in resistance (P<.001). MDA-MB-231 cells expressed all three isoforms of the NOS enzyme at levels that were not altered by exposure to hypoxia. CONCLUSIONS: NO mediates chemosensitivity in tumor cells, and hypoxia-induced drug resistance appears to result, in part, from downstream suppression of endogenous NO production. These results raise the possibility that administration of small doses of NO mimetics could be used as an adjuvant in chemotherapy.