Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation.

Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.

MARK2 variants cause autism spectrum disorder via the downregulation of WNT/ß-catenin signaling pathway.

Microtubule affinity-regulating kinase 2 (MARK2) contributes to establishing neuronal polarity and developing dendritic spines. Although large-scale sequencing studies have associated MARK2 variants with autism spectrum disorder (ASD), the clinical features and variant spectrum in affected individuals with MARK2 variants, early developmental phenotypes in mutant human neurons, and the pathogenic mechanism underlying effects on neuronal development have remained unclear. Here, we report 31 individuals with MARK2 variants and presenting with ASD, other neurodevelopmental disorders, and distinctive facial features. Loss-of-function (LoF) variants predominate (81%) in affected individuals, while computational analysis and in vitro expression assay of missense variants supported the effect of MARK2 loss. Using proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs), we show that MARK2 loss leads to early neuronal developmental and functional deficits, including anomalous polarity and dis-organization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs). Mark2+/- mice showed abnormal cortical formation and partition and ASD-like behavior. Through the use of RNA sequencing (RNA-seq) and lithium treatment, we link MARK2 loss to downregulation of the WNT/ß-catenin signaling pathway and identify lithium as a potential drug for treating MARK2-associated ASD.

Insurance denials and diagnostic rates in a pediatric genomic research cohort.

PURPOSE: This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials. METHODS: Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage. Diagnostic findings and candidate genetic findings in these groups were determined through review of our internal variant database and patient charts. RESULTS: Of the 801 patients analyzed, 147 had insurance prior-authorization denials on record (18.3%). Exome sequencing and microarray were the most frequently denied genetic tests. Private insurance was significantly more likely to deny testing than public insurance (odds ratio = 2.03 [95% CI = 1.38-2.99] P = .0003). Of the 147 patients with insurance denials, 53.7% had at least 1 diagnostic or candidate finding and 10.9% specifically had a clinically diagnostic finding. Fifty percent of patients with clinically diagnostic results had immediate medical management changes (5.4% of all patients experiencing denials). CONCLUSION: Many patients face a major barrier to genetic testing in the form of lack of insurance coverage. A number of these patients have clinically diagnostic findings with medical management implications that would not have been identified without access to research testing. These findings support re-evaluation of insurance carriers' coverage policies.

An approach to help differentiate postinfarct scar from borderzone tissue using Ripple Mapping during ventricular tachycardia ablation.

BACKGROUND: Ventricular scar is traditionally highlighted on a bipolar voltage (BiVolt) map in areas of myocardium <0.50 mV. We describe an alternative approach using Ripple Mapping (RM) superimposed onto a BiVolt map to differentiate postinfarct scar from conducting borderzone (BZ) during ventricular tachycardia (VT) ablation. METHODS: Fifteen consecutive patients (left ventricular ejection fraction 30 ± 7%) underwent endocardial left ventricle pentaray mapping (median 5148 points) and ablation targeting areas of late Ripple activation. BiVolt maps were studied offline at initial voltage of 0.50-0.50 mV to binarize the color display (red and purple). RMs were superimposed, and the BiVolt limits were sequentially reduced until only areas devoid of Ripple bars appeared red, defined as RM-scar. The surrounding area supporting conducting Ripple wavefronts in tissue <0.50 mV defined the RM-BZ. RESULTS: RM-scar was significantly smaller than the traditional 0.50 mV cutoff (median 4% vs. 12% shell area, p < .001). 65 ± 16% of tissue <0.50 mV supported Ripple activation within the RM-BZ. The mean BiVolt threshold that differentiated RM-scar from BZ tissue was 0.22 ± 0.07 mV, though this ranged widely (from 0.12 to 0.35 mV). In this study, septal infarcts (7/15) were associated with more rapid VTs (282 vs. 347 ms, p = .001), and had a greater proportion of RM-BZ to RM-scar (median ratio 3.2 vs. 1.2, p = .013) with faster RM-BZ conduction speed (0.72 vs. 0.34 m/s, p = .001). Conversely, scars that supported hemodynamically stable sustained VT (6/15) were slower (367 ± 38 ms), had a smaller proportion of RM-BZ to RM-scar (median ratio 1.2 vs. 3.2, p = .059), and slower RM-BZ conduction speed (0.36 vs. 0.63 m/s, p = .036). RM guided ablation collocated within 66 ± 20% of RM-BZ, most concentrated around the RM-scar perimeter, with significant VT reduction (median 4.0 episodes preablation vs. 0 post, p < .001) at 11 ± 6 months follow-up. CONCLUSION: Postinfarct scars appear significantly smaller than traditional 0.50 mV cut-offs suggest, with voltage thresholds unique to each patient.

POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum.

POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.

Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes.

PURPOSE: This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program. METHODS: Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes. RESULTS: Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases). CONCLUSION: Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from >1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

TAB2 variants cause cardiovascular heart disease, connective tissue disorder, and developmental delay.

Congenital heart defects (CHD) are the most commonly occurring birth defect and can occur in isolation or with additional clinical features comprising a genetic syndrome. Autosomal dominant variants in TAB2 are recognized by the American Heart Association as causing nonsyndromic CHD, however, emerging data point to additional, extra-cardiac features associated with TAB2 variants. We identified 15 newly reported individuals with pathogenic TAB2 variants and reviewed an additional 24 subjects with TAB2 variants in the literature. Analysis showed 64% (25/39) of individuals with disease resulting from TAB2 single nucleotide variants (SNV) had syndromic CHD or adult-onset cardiomyopathy with one or more extra-cardiac features. The most commonly co-occurring features with CHD or cardiomyopathy were facial dysmorphism, skeletal and connective tissue defects and most subjects with TAB2 variants present as a connective tissue disorder. Notably, 53% (8/15) of our cohort displayed developmental delay and we suspect this may be a previously unappreciated feature of TAB2 disease. We describe the largest cohort of subjects with TAB2 SNV and show that in addition to heart disease, features across multiple systems are present in most TAB2 cases. In light of our findings, we recommend that TAB2 be included on the list of genes that cause syndromic CHD, adult-onset cardiomyopathy, and connective tissue disorder.

22q11.2 duplications: Expanding the clinical presentation.

22q11.2 duplication syndrome has a frequency of ~1/700 in the intellectual disability population. Despite this frequency, there is limited information on the variable clinical presentation. Although the phenotype and incidence of congenital anomalies are well described for 22q11.2 deletion syndrome, they are not as well understood for individuals with 22q11.2 duplication syndrome. This study is a single-center, retrospective review of patients diagnosed with 22q11.2 duplication syndrome designed to categorize the variable phenotype seen in these individuals. The data suggest that the incidence of congenital anomalies may be higher than previously reported for this syndrome. Affected individuals are at increased risk for a variety of problems including gastrointestinal complications, endocrine dysfunction, ophthalmologic abnormalities, palatal anomalies, congenital heart disease, musculoskeletal differences, and neurologic abnormalities. Individuals with 22q11.2 duplication syndrome would benefit from care coordinated by a multidisciplinary team and managed according to the 22q11.2 deletion syndrome guidelines.

BAILA: A Randomized Controlled Trial of Latin Dancing to Increase Physical Activity in Spanish-Speaking Older Latinos.

BACKGROUND: Latinos are the fastest growing minority group of the older adult population. Although physical activity (PA) has documented health benefits, older Latinos are less likely to engage in leisure time PA than older non-Latino whites. Dance, popular among Latinos, holds promise as a culturally relevant form of PA. PURPOSE: To describe self-reported and device-assessed changes in PA as a result of a randomized controlled trial of BAILAMOS, a 4-month Latin dance program with a 4-month maintenance program, versus a health education control group. METHODS: Adults, aged 55+, Latino/Hispanic, Spanish speaking, with low PA levels at baseline, and risk for disability were randomized to the dance program (n = 167) or health education condition (n = 166). Data were analyzed using multilevel modeling with full information maximum likelihood. RESULTS: A series of multilevel models revealed significant time × group interaction effects for moderate-to-vigorous physical activity (MVPA), dance PA, leisure PA, and total PA. Exploring the interaction revealed the dance group to significantly increase their MVPA, dance PA, leisure PA, and total PA at months 4 and 8. Household PA and activity counts from accelerometry data did not demonstrate significant interaction effects. CONCLUSIONS: The study supports organized Latin dance programs to be efficacious in promoting self-reported PA among older Latinos. Efforts are needed to make dancing programs available and accessible, and to find ways for older Latinos to add more PA to their daily lives. CLINICAL TRIAL INFORMATION: NCT01988233.

Evaluation and Potential Uses of Site Investigation Soil Contamination Data Submitted to Uk Local Government.

There has been considerable brownfield development in the UK since 2000 due to increasing demand for new housing, combined with local opposition to building on greenbelt land. To facilitate this, extensive site investigations have been carried out and the reports submitted to local government as part of the planning process. This research investigates whether this largely untapped resource of site investigation data can be used to improve understanding of potentially toxic elements (PTE) and persistent organic pollutants (POP) at a local scale. The PTE/POP data were extracted from 1707 soil samples across 120 brownfield sites in an urban/suburban region. The samples were analysed to determine the effect of site location, historical use and site age on PTE/POP concentrations. Box plots indicating statistical results together with GIS maps of PTE/POP sample data provided the optimal visualisation of results. The dataset was shown to be a valuable resource, although further exploitation would be enhanced by digitisation of the submitted data. The paper explores potential applications of this data, including background concentrations and anthropogenic enrichment factors for PTE/POP. The results were summarised in a table for the PTE/POP and a preliminary risk assessment process chart to inform developers/regulators on potential PTE/POP levels on brownfield sites on a local scale. This information could focus design and resources for developers for site investigations and risk assessments and improve planning and regulatory guidance. The lack of predictability in PTE/POP results across sites have emphasised the ongoing need for intrusive site investigation on new brownfield developments.

An Exploratory Study of a New Vancomycin Eye Drops Formulation for Extemporaneous Compounding.

Purpose: Compounded eye drop solutions of vancomycin hydrochloride have important clinical applications, such as postoperative antimicrobial prophylaxis and bacterial keratitis. There exists a plethora of data to support the use of various liquid vehicles to compound vancomycin hydrochloride eye drops. However, there are a number of limitations for implementation, especially the frequent shortage or discontinuation of the vehicle products. This study was designed to investigate the use of an OTC eye wash product as the evergreen vehicle and to evaluate the physical and chemical stability of the new formulation. Methods: The Advance Eye Relief® eye wash and vancomycin hydrochloride for injection vials were used to prepare 10 and 50 mg/mL vancomycin eye drop solutions. The solutions were packaged in Steri-Droppers® bottles and stored in a freezer for 14 days followed by 28 days in refrigeration. The 14-day period of freezing was included to allow time for sterility testing. At pre-determined stability time points, samples were taken for visual inspection, pH and osmolality measurement, and analysis by a stability-indicating high performance liquid chromatography (HPLC) method. Results: Freshly prepared vancomycin eye drops were clear, colorless, and free of particulates. The pH readings were 7.03 and 6.28 for the 10 and 50 mg/mL solutions, respectively. The osmolality of both solutions were within the range of 300-330 mOsmol/kg and considered isotonic. Initial drug concentrations of all samples were confirmed by HPLC to be within 100%-103% of the label claims. Throughout the stability study period, there were no significant changes in the appearance, pH, or osmolality of any samples. The HPLC results also confirmed that the drug concentrations in all stability samples were within 98%-101% of the initial time zero values and no significant degradation product peaks were observed. Conclusion: A new compounded vancomycin eye drop formulation was developed to mitigate vehicle sourcing issues. This eye drop formulation was easy to prepare, exhibited satisfactory properties for ophthalmic applications, and remained stable chemically and physically when stored for 14 days in freezer followed by 28 days in refrigerator.

Nager syndrome in patient lacking acrofacial dysostosis: Expanding the phenotypic spectrum of SF3B4-related disease.

Nager syndrome epitomizes the acrofacial dysostoses, which are characterized by craniofacial and limb defects. The craniofacial defects include midfacial retrusion, downslanting palpebral fissures, prominent nasal bridge, and micrognathia. Limb malformations typically include hypoplasia or aplasia of radial elements including the thumb. Nager syndrome is caused by haploinsufficiency of SF3B4, encoding a spliceosomal protein called SAP49. Here, we report a patient with a loss of function variant in SF3B4 without acrofacial dysostosis or limb defects, whose reason for referral was developmental and growth delay. This patient is evidence of a broader phenotypic spectrum associated with SF3B4 variants than previously appreciated.

Asbestos contamination on brownfield development sites in the UK.

The development of brownfield sites in the UK requires site investigation for contamination as part of the regulatory planning process. This site investigation includes the collection of soil samples that are analysed for asbestos contamination. This research project analyses this untapped resource of brownfield asbestos data, using site investigation data submitted to a local Borough Council, in Surrey, UK. Over 100 site investigation reports were collected. This paper presents the trends in asbestos testing from 2001 to 2019 and data on the location, concentration, form and type of asbestos found in this Borough. The rate of asbestos detection has increased significantly, reflecting improvements in asbestos measuring techniques, to a rate of 22% for all samples tested between 2016 and 2019. The concentrations of asbestos found were very low, with 74% of samples having concentrations below the limit of detection of the laboratory and were predominantly of fibrous form. A significant proportion of samples contained more carcinogenic amphibole type. Most of the asbestos was found in the top 1 m of Made Ground soil. Site history was found to be important with gas works having the highest asbestos detection rate, though a detection rate of 10% was found in soil samples on former residential sites. This information is important to inform and update risk assessment for site workers and site remediation in relation to asbestos. Hence based upon these results, a qualitative risk chart for asbestos is presented to provide guidance and in-sight into asbestos on brownfield sites for local authorities and developers.

Experimental Evidence for Sex Differences in Sexual Variety Preferences: Support for the Coolidge Effect in Humans.

We examined sex differences in preferences for sexual variety and novelty to determine whether the Coolidge effect plays a role in human sexuality. In two experimental studies that employed different manipulations, we found converging evidence that men showed a greater preference for variety in potential short-term mates than did women. In the first study, men (n = 281) were more likely than women (n = 353) to select a variety of mates when given the opportunity to distribute chances to have sex with different individuals in hypothetical situations. This sex difference was evident regardless of the targets' attractiveness and age. Further, men found it more appealing if their committed romantic/sexual partners frequently changed their physical appearance, while women reported that they modified their physical appearance more frequently than did men, potentially appealing to male desires for novelty. In the second study, when participants were given a hypothetical dating task using photographs of potential short-term mates, men (n = 40) were more likely than women (n = 56) to select a novel person to date. Collectively, these findings lend support to the idea that sex differences in preferences for sexual variety and novelty are a salient sex-specific evolved component of the repertoire of human mating strategies.

Fit and Strong! Plus: Twelve and eighteen month follow-up results for a comparative effectiveness trial among overweight/obese older adults with osteoarthritis.

This comparative effectiveness trial compared the longer-term effectiveness (12 and 18 months) of the standard Fit & Strong! physical activity program to Fit & Strong! Plus, which combined physical activity and dietary weight loss. Outcomes were weight, diet quality, physical activity, osteoarthritis symptoms, performance measures, and anxiety/depression. In this study, 413 overweight/obese participants with OA, ≥60 years old and primarily African American, were randomly assigned to Fit & Strong! (F&S!) or Fit & Strong! Plus (F&S! Plus), with outcomes assessed at 2, 6, 12, and 18 months. 356 (86%) participants completed the 18-month visit. Compared with participants randomized to standard F&S!, F&S! Plus participants maintained longer-term benefits at 12 months in weight (mean change ± SE: -1.7 ± 0.3 kg for F&S! Plus vs -0.9 ± 0.3 kg for F&S!, p = 0.049), BMI (-0.6 ± 0.1 vs -0.3 ± 0.1 kg/m2, p = 0.04), waist circumference (-2.7 ± 0.6 vs -0.4 ± 0.6 cm, p = 0.004), and lower extremity strength (1.6 ± 0.2 vs 1.0 ± 0.2 chair stands, p = 0.046). At 18 months, F&S! Plus participants showed improved lower extremity strength (1.4 ± 0.2 vs. 0.7 ± 0.2 chair stands, p = 0.045. African American older adults in the F&S! Plus arm showed sustained modest improvements in weight, waist circumference, and lower extremity strength at 12 months and in lower extremity strength at 18 months compared to F&S!. Implications for the translation of evidence-based programs into community settings to support healthy behaviors in older adults are discussed.

Evaluation of trauma resources in rural northern Alberta identifies opportunities for improvement.

Background: The care of rural trauma patients in northern Alberta can be extremely challenging because of the vast geographic area, the limited access to health care facilities and the lack of adequate resources to manage severe injuries. Identifying gaps in equipment and personnel in rural centres can provide opportunities for improving the care of injured patients in these environments. We conducted a survey based on Canadian Accreditation Council quality indicators to evaluate trauma infrastructure and human resources in rural centres across northern Alberta. Methods: A standardized survey was developed to assess the availability of trauma-specific equipment and personnel across the prehospital and emergency department (ED) settings. The survey was distributed to 50 peripheral hospitals biannually from January 2017 to September 2018. Two-tailed paired t tests were used to evaluate changes in survey responses; a p value of less than 0.05 was considered statistically significant. Results: The survey response rate was 100%. By the end of the study period, there were significant improvements in the number of providers (p = 0.04), nurses (p = 0.01) and dedicated trauma resuscitation bays (p = 0.04) in the ED for managing injured patients. There were also significant increases in the availability of equipment, including advanced airway management tools (p = 0.02), rapid infusion devices (p = 0.02) and warmers (p = 0.04). Access to x-ray equipment (p = 0.03) and computed tomography (CT) scanners (p = 0.04) as well as equipment to support telehealth and teleconferencing (p = 0.04) increased during the study period. Access to, and supply of, blood products also increased significantly (p = 0.02) during the study period. Conclusion: Our study demonstrates that the trauma resources of rural health care centres may be evaluated in a standardized fashion centres, and the results point to opportunities to remedy gaps in equipment and personnel. Our methods may be applied to any trauma network that serves geographically large areas with a sparse distribution of health care facilities, to provide critical information for the optimization of resources in rural trauma.

Contexte: Les soins aux patients victimes de traumatismes en région rurale dans le nord de l'Alberta peuvent être très difficiles en raison de la superficie de la région, de l'accès limité aux établissements de santé et du manque de ressources pour soigner adéquatement les blessures graves. En repérant les lacunes en équipement et en personnel dans les établissements en région rurale, on peut créer des occasions d'améliorer les soins aux patients blessés dans ces milieux. Nous avons mené un sondage fondé sur les indicateurs de qualité du Conseil d'accréditation canadien pour évaluer les infrastructures et les ressources humaines en traumatologie dans les établissements des régions rurales du nord de l'Alberta. Méthodes: Un sondage standardisé a été créé pour évaluer la disponibilité des équipements et des ressources humaines en traumatologie en contexte préhospitalier et aux services d'urgence. Le sondage a été distribué 2 fois par année à 50 hôpitaux entre janvier 2017 et septembre 2018. Des tests t appariés ayant une hypothèse non nulle ont été utilisés pour évaluer les changements dans les réponses au sondage; les résultats ayant une valeur p < 0,05 étaient considérés comme statistiquement significatifs. Résultats: Le taux de participation au sondage était de 100 %. À la fin de la période étudiée, il y avait une amélioration significative du nombre de fournisseurs (p = 0,04), de personnel infirmier (p = 0,01) et d'espaces de réanimation réservés à la traumatologie (p = 0,04) dans les services d'urgence. Il y avait aussi une augmentation significative de la disponibilité de l'équipement, notamment des outils de prise en charge avancée des voies respiratoires (p = 0,02), des appareils de perfusion rapide (p = 0,02) et d'armoires chauffantes (p = 0,04). Les équipements de radiographie (p = 0,03) et de tomographie par ordinateur (p = 0,04) ainsi que les équipements facilitant la télémédecine et les téléconférences (p = 0,04) sont devenus plus accessibles pendant la période étudiée. Les réserves de produits sanguins et l'accès à ces produits a aussi augmenté de manière significative (p = 0,02). Conclusion: Notre étude montre que les ressources en traumatologie dans les établissements de santé en région rurale peuvent être évaluées de manière standardisée, et les résultats indiquent qu'il y a des occasions de combler les lacunes en équipement et en personnel. Notres méthodes peuvent être reproduites dans tout réseau de traumatologie couvrant un grand territoire où les établissements de santé sont dispersés, pour fournir des données critiques sur l'organisation des ressources de traumatologie en région rurale.

You "Cantu": Multidisciplinary Collaboration Resulting in Successful Orthognathic Surgery.

Cantú syndrome (CS) is a rare autosomal dominant disorder caused by a heterozygous pathogenic variant in the ABCC9 or KCNJ8 gene. The disorder is characterized by congenital generalized hypertrichosis, coarse acromegaloid facial features (broad nasal bridge, epicanthal folds, wide mouth, macroglossia), skeletal abnormalities (calvarial thickening, metaphyseal flares, coxa valga, scoliosis), tortuous vasculature (meningeal arteriovenous malformations), and cardiac abnormalities (patent ductus arteriosus, pericardial effusion). Despite the constellation of craniofacial features, there are currently no documented cases of a patient with CS having orthognathic surgery. The purpose of this report is to highlight the multidisciplinary collaboration, including establishment of a genetic diagnosis, cardiac management, and orthodontic therapy, in performing successful orthognathic surgery in a patient with CS.

Feasibility and impact of Fit & Strong! Program in Portuguese older adults with osteoarthritis: A pilot randomized controlled trial.

This pilot study used a small randomized trial to examine the feasibility and the impact of an 8-week multicomponent program among Portuguese older adults with osteoarthritis. Participants were identified from the electronic registers from three primary healthcare centers. Thirty-one older adults (50+ years) with osteoarthritis were randomly assigned to experimental (n= 23) and control conditions (n= 8). Acceptance, attendance and retention rates were measured. The effect of the program on physical performance, osteoarthritis symptomatology (pain and stiffness), functionality, physical activity, depression, anxiety and fear of movement were assessed at baseline, posttest, and 4-months. The acceptance rate was 34%, and 90.4% attended all sessions of the program. The posttest retention rate in experimental group was 69.6% and 100% in control group. Findings demonstrated benefits of the Program on physical performance, function, anxiety, and fear of movement among participants. In the future, it will be important to improve the acceptance rate, however, the high attendance rate and observed effects indicate that the program is an attractive and effective intervention for Portuguese older adults with osteoarthritis.

The Rare Association of Cleft Lip and/or Palate and Wilms Tumor.

There is currently no recognized connection between the occurrence of cleft lip and/or palate (CL/P) and Wilms tumor (WT). A retrospective review of cleft team records (2001-2015) revealed 3 cases of children, all male, with concomitant diagnoses of CL/P and WT treated at our institution. These patients presented as infants for care of their CL/P, all with additional congenital anomalies, developmental delays, and growth delays. Between the ages of 1 and 4 years, each was diagnosed with WT, which was treated with chemotherapy and partial nephrectomy, +/- radiation, leading to full remission in all cases.

Challenge and Yield of Enrolling Racially and Ethnically Diverse Patient Populations in Low Event Rate Clinical Trials.

BACKGROUND AND PURPOSE: We report patient enrollment and retention by race and ethnicity in the CREST (Carotid Revascularization Endarterectomy Versus Stent Trial) and assess potential effect modification by race/ethnicity. In addition, we discuss the challenge of detecting differences in study outcomes when subgroups are small and the event rate is low. METHODS: We compared 2502 patients by race, ethnicity, baseline characteristics, and primary outcome (any periprocedural stroke, death, or myocardial infarction and subsequent ipsilateral stroke up to 10 years). RESULTS: Two hundred forty (9.7%) patients were minority by race (6.1%) or ethnicity (3.6%); 109 patients (4.4%) were black, 32 (1.3%) Asian, 2332 (93.4%) white, 11 (0.4%) other, and 18 (0.7%) unknown. Ninety (3.6%) were Hispanic, 2377 (95%) non-Hispanic, and 35 (1.4%) unknown. The rate of the primary end point for all patients was 10.9%±0.9% at 10 years and did not differ by race or ethnicity (Pinter>0.24). CONCLUSIONS: The proportion of minorities recruited to CREST was below their representation in the general population, and retention of minority patients was lower than for whites. Primary outcomes did not differ by race or ethnicity. However, in CREST (like other studies), the lack of evidence of a racial/ethnic difference in the treatment effect should be interpreted with caution because of low statistical power to detect such a difference. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732.