Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations

It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations.      

Modulation of level response areas and stimulus selectivity of neurons in cat primary auditory cortex

Sounds commonly occur in sequences, such as in speech. It is therefore important to understand how the occurrence of one sound affects the response to a subsequent sound. We approached this question by determining how a conditioning stimulus alters the response areas of single neurons in the primary auditory cortex (AI) of barbiturate-anesthetized cats. The response areas consisted of responses to stimuli that varied in level at the two ears and delivered at the characteristic frequency of each cell. A binaural conditioning stimulus was then presented > or =50 ms before each of the stimuli comprising the level response area. An effective preceding stimulus alters the shape and severely reduces the size and response magnitude of the level response area. This ability of the preceding stimulus depends on its proximity in the level domain to the level response area, not on its absolute level or on the size of the response it evokes. Preceding stimuli evoke a nonlinear inhibition across the level response area that results in an increased selectivity of a cortical neuron for its preferred binaural stimuli. The selectivity of AI neurons during the processing of a stream of acoustic stimuli is likely to be restricted to a portion of their level response areas apparent in the tone-alone condition. Thus rather than being static, level response areas are fluid; they can vary greatly in extent, shape and response magnitude. The dynamic modulation of the level response area and level selectivity of AI neurons might be related to several tasks confronting the central auditory system.     

Associations between interpersonal violence victimisation and concussions among US college students

Interpersonal violence is common on college campuses and is associated with many adverse health outcomes; however, it remains unknown whether experiencing interpersonal violence victimisation is associated with concussions. The aim of this study was to estimate the associations between interpersonal violence, including emotional abuse, physical abuse and sexual assault, and concussions among a large, diverse sample of college students. We analysed cross-sectional data from the 2018–2019 national (US) Healthy Minds Study (N = 1,478). Multiple logistic regression analyses were conducted to estimate the association between interpersonal violence victimisation (any violence victimisation, emotional abuse, physical abuse and sexual assault) and concussion history (any concussion, diagnosed concussion and undiagnosed concussion), while adjusting for potential confounders. Analyses were conducted among the overall sample and separately by male and female participants. Results showed patterns of significant associations between interpersonal violence victimisation and concussions among the overall sample and among male and female participants. Among the overall sample, any interpersonal violence victimisation (adjusted odds ratio [AOR] 1.45, 95% confidence interval [CI] 1.13–1.88), emotional abuse (AOR 1.36, 95% CI 1.06–1.76), physical abuse (AOR 1.61, 95% CI 1.07–2.44) and sexual assault (AOR 2.17, 95% CI 1.44–3.26) were associated with higher odds of any concussion history. Sexual assault victimisation had the strongest association with any concussion history among male (AOR 1.96, 95% CI 1.04–3.71) and female (AOR 2.96, 95% CI 1.62–5.43) participants. These results expand on prior interpersonal violence and concussion research by showing an association with multiple victimisation measures among a large and diverse sample of college students. Medical professionals should screen for concussions among college students who experience emotional abuse, physical abuse and sexual assault to provide appropriate guidance. Information on the symptoms of concussions should be incorporated into campus violence awareness and prevention efforts.     

Correction to: Middle School Effects of the Dating Matters® Comprehensive Teen Dating Violence Prevention Model on Physical Violence,Bullying, and Cyberbullying: A Cluster-Randomized Controlled Trial

Prevention Science - The article “Middle School Effects of the Dating Matters® Comprehensive Teen Dating Violence Prevention Model on Physical Violence, Bullying, and Cyberbullying: a...     

Migration Patterns for Revision Total Hip Arthroplasty in the United States as Reported in the American Joint Replacement Registry

BackgroundRevision total hip arthroplasty (revTHA) is associated with higher rates of complications and greater costs than primary procedures. The aim of this study is to evaluate the effect of hospital size, teaching status, and indication for revTHA, on migration patterns in patients older than 65 years old.MethodsAll THAs and revTHAs reported to the American Joint Replacement Registry from 2012 to 2018 were included and merged with the Centers for Medicare and Medicaid Services database. Migration rate was defined as a patient’s THA and revTHA procedures that were performed at separate institutions by different surgeons. Migratory patterns were recorded based on hospital size, teaching status, and indication for revTHA. Analyses were performed by statisticians.ResultsThe number of linked procedures included was 11,906. Migration rates in revTHA due to infection were higher for small hospitals than large hospitals (46.6% vs 28.6%, P < .0001). Migration rates were higher comparing non-teaching with teaching hospitals (55% vs 34%, P < .0001). This difference was significant for periprosthetic fractures (70.6% vs 37.2%, P = .005), instability (56.5% vs 35.5%, P = .04), and mechanical complications (88.9% vs 34.7%, P < .05). Most patients migrated to medium or large hospitals rather than small hospitals (89% vs 11%, P < .0001) and to teaching rather than non-teaching institutions (82% vs 18%, P < .0001).ConclusionHospital size and teaching status significantly affected migration patterns for revTHA. Migration rates were significantly higher in small non-teaching hospitals in revTHA due to infection, periprosthetic fracture, instability, and mechanical complications. Over 80% of patients migrated to larger teaching hospitals.     

A functional three-dimensional microphysiological human model of myeloma bone disease

Human myeloma bone disease (MBD) occurs when malignant plasma cells migrate to the bone marrow and commence inimical interactions with stromal cells, disrupting the skeletal remodeling process. The myeloma cells simultaneously suppress osteoblastic bone formation while promoting excessive osteoclastic resorption. This bone metabolism imbalance produces osteolytic lesions that cause chronic bone pain and reduce trabecular and cortical bone structural integrity, and often culminate in pathological fractures. Few bone models exist that enable scientists to study MBD and the effect therapies have on restoring the bone metabolism imbalance. The purpose of this research was to develop a well characterized three-dimensional (3D) bone organoid that could be used to study MBD and current or potential treatment options. First, bone marrow stromal cell–derived osteoblasts (OBs) mineralized an endosteal-like extracellular matrix (ECM) over 21 days. Multiple analyses confirmed the generation of hydroxyapatite (HA)-rich bone-like tissue fragments that were abundant in alkaline phosphatase, calcium, and markers of osteoblastic gene expression. On day 22, bone marrow macrophage (BMM)–derived osteoclasts (OCs) were introduced to enhance the resorptive capability of the model and recapitulate the balanced homeostatic nature of skeletal remodeling. Tartrate-resistant acid phosphatase 5b (TRAcP-5b), type I collagen C-telopeptide (CTX-1), and gene expression analysis confirmed OC activity in the normal 3D organoid (3D in vitro model of normal bonelike fragments [3D-NBF]). On day 30, a human multiple myeloma (MM)–derived plasmacytoma cell line was introduced to the 3D-NBF to generate the 3D-myeloma bone disease organoid (3D-MBD). After 12 days, the 3D-MBD had significantly reduced total HA, increased TRAcP-5b levels, increases levels of CTX-1, and decreased expression of osteoblastic genes. Therapeutic intervention with pharmaceutical agents including an immunomodulatory drug, a bisphosphonate, and monoclonal restored HA content and reduced free CTX-1 in a dose-dependent manner. This osteogenically functional model of MBD provides a novel tool to study biological mechanisms guiding the disease and to screen potential therapeutics. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Outcomes of gastrostomy placement with and without concomitant tracheostomy among ventilator dependent children

IntroductionSimultaneous gastrostomy tube (GT) and tracheostomy placement in young children offers potential benefit in limiting anesthetic exposure, but it is unknown whether combining these procedures introduces additional morbidity. This study compared outcomes after combined GT and tracheostomy placement versus GT placement alone among similar ventilator-dependent patients.MethodsVentilator-dependent children <2-years-old who underwent GT placement alone (MV-GT), simultaneous GT and tracheostomy placement (GT+T), and GT placement alone with a pre-existing tracheostomy (T-GT) were identified using 2012–2018 NSQIP-Pediatric Participant User Files. Multiple logistic regression models were used to compare outcomes while adjusting for other group differences.ResultsAmong 1100 children, 351 underwent MV-GT, 494 GT+T, and 255 T-GT. Major complications occurred in 23.6%, 17.0%, and 14.5% of the respective groups (p = 0.01). Major complications with GT+T were similar to T-GT (adjusted odds ratio [aOR]=1.19, 95%CI:0.78–1.83, p = 0.4) and lower than MV-GT (aOR=0.67, 95%CI:0.47–0.95, p = 0.02). Severe complications including mortality, cardiac arrest, and stroke were similar between the three groups (p = 0.8).ConclusionsChildren <2-years-old undergoing GT+T did not experience higher post-operative complications compared to children undergoing T-GT or MV-GT. Utilizing GT+T to limit anesthetic exposure may be reasonable within this high-risk population.Type of StudyTreatment StudyLevel of EvidenceLevel III     

Measuring patient perceptions of surgeon communication performance in the treatment of thyroid nodules and thyroid cancer using the communication assessment tool

BackgroundThyroid surgeons are offering their patients less aggressive diagnostic and therapeutic management strategies for thyroid nodules and low-risk thyroid cancer in an effort to decrease overdiagnosis and overtreatment of indolent disease. Explaining the rationale for less aggressive management plans requires physicians to be effective communicators. We aimed to assess the communication skills of thyroid surgeons with the Makoul Communication Assessment Tool and to identify risk factors for poor communication.MethodsNew adult patients with thyroid nodules or thyroid cancer presenting to a single tertiary-referral endocrine surgery clinic were enrolled from July 2018 through December 2019. Patients were administered the Communication Assessment Tool immediately after their clinical encounter. Outlier communication scores were identified, and clinical characteristics were compared between outlier and nonoutlier groups.ResultsA total of 107 patients completed the Communication Assessment Tool. Mean (standard deviation) total and top box scores were 67 (6) and 86% (29%), respectively. Twenty-five patients (23%) were in the low-outlier group, defined by a total score below 67.5/70 or top box score below 82.25%. Other race and non-Hispanic patients (versus white race) were more likely low outliers (odds ratio 3.58, P = .048). The lowest scoring Communication Assessment Tool item overall was “the doctor encouraged me to ask questions” (78.5% top box).ConclusionWe found communication to be perceived as excellent in the majority of patients; however, an opportunity for improvement was identified in 29% of participants. Significant differences in race and ethnicity between low outlier and nonoutlier communication score patients were observed, which warrants additional investigation. These findings support the utility of the Communication Assessment Tool in studying the effectiveness of communication improvement initiatives.