Sex specific emergence of trisomic Dyrk1a-related skeletal phenotypes in the development of a Down syndrome mouse model.

Skeletal insufficiency affects all individuals with Down syndrome (DS) or Trisomy 21 (Ts21) and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits and Dyrk1a overexpression were transitory until postnatal day (P) 30 when there were persistent trabecular and cortical deficits and Dyrk1a was trending overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization of Dyrk1a improved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomic Dyrk1a are important to find temporally specific treatment periods for bone and other phenotypes associated with Ts21.

Genetic dissection of triplicated chromosome 21 orthologs yields varying skeletal traits in Down syndrome model mice.

Down syndrome (DS) phenotypes result from triplicated genes, but the effects of three copy genes are not well known. A mouse mapping panel genetically dissecting human chromosome 21 (Hsa21) syntenic regions was used to investigate the contributions and interactions of triplicated Hsa21 orthologous genes on mouse chromosome 16 (Mmu16) on skeletal phenotypes. Skeletal structure and mechanical properties were assessed in femurs of male and female Dp9Tyb, Dp2Tyb, Dp3Tyb, Dp4Tyb, Dp5Tyb, Dp6Tyb, Ts1Rhr and Dp1Tyb;Dyrk1a+/+/- mice. Dp1Tyb mice, with the entire Hsa21 homologous region of Mmu16 triplicated, display bone deficits similar to those of humans with DS and served as a baseline for other strains in the panel. Bone phenotypes varied based on triplicated gene content, sex and bone compartment. Three copies of Dyrk1a played a sex-specific, essential role in trabecular deficits and may interact with other genes to influence cortical deficits related to DS. Triplicated genes in Dp9Tyb and Dp2Tyb mice improved some skeletal parameters. As triplicated genes can both improve and worsen bone deficits, it is important to understand the interaction between and molecular mechanisms of skeletal alterations affected by these genes.

Novel methodology for the evaluation of symptoms reported by patients with newly diagnosed atrial fibrillation: Application of natural language processing to electronic medical records data.

INTRODUCTION: Understanding symptom patterns in atrial fibrillation (AF) can help in disease management. We report on the application of natural language processing (NLP) to electronic medical records (EMRs) to capture symptom reports in patients with newly diagnosed (incident) AF. METHODS AND RESULTS: This observational retrospective study included adult patients with an index diagnosis of incident AF during January 1, 2016 through June 30, 2018, in the Optum datasets. The baseline and follow-up periods were 1 year before/after the index date, respectively. The primary objective was identification of the following predefined symptom reports: dyspnea or shortness of breath; syncope, presyncope, lightheadedness, or dizziness; chest pain; fatigue; and palpitations. In an exploratory analysis, the incidence rates of symptom reports and cardiovascular hospitalization were assessed in propensity-matched patient cohorts with incident AF receiving first-line dronedarone or sotalol. Among 30 447 patients with an index AF diagnosis, the NLP algorithm identified at least 1 predefined symptom in 9734 (31.9%) patients. The incidence rate of symptom reports was highest at 0-3 months post-diagnosis and lower at >3-6 and >6-12 months (pre-defined timepoints). Across all time periods, the most common symptoms were dyspnea or shortness of breath, followed by syncope, presyncope, lightheadedness, or dizziness. Similar temporal patterns of symptom reports were observed among patients with prescriptions for dronedarone or sotalol as first-line treatment. CONCLUSION: This study illustrates that NLP can be applied to EMR data to characterize symptom reports in patients with incident AF, and the potential for these methods to inform comparative effectiveness.

Impact of anticoagulation therapy on the cognitive decline and dementia in patients with non-valvular atrial fibrillation (cognitive decline and dementia in patients with non-valvular atrial fibrillation [CAF] trial).

Background: Atrial fibrillation (AF) is associated with a risk for cognitive impairment and dementia, which is more pronounced in patients with a history of clinical stroke. Anticoagulation use and efficacy impact long-term risk of dementia in AF patients in observational trials. Methods: The cognitive decline and dementia in patients with non-valvular atrial fibrillation (CAF) Trial was a randomized, prospective, open-label vanguard clinical study with blinded endpoint assessment involving patients with moderate- to high-risk (CHADS2 or CHA2DS2-Vasc scores of ≥2) non-valvular AF assigned to dabigatran etexilate or warfarin. The primary endpoint was incident dementia or moderate cognitive decline at 24 months. Results: A total of 101 patients were enrolled [mean age:73.7 ± 6.0 years, male: 54(53.5%)]. Prior stroke and stroke risk factors were similar between groups. Average INR over the study was 2.41 ± 0.68 in the warfarin group. No patient experienced a stroke or developed dementia. Mini-Mental Status Evaluation, Hachinski Ischemic scale, cognitive subscale of the Alzheimer's Disease Assessment Scale, Disability Assessment for Dementia, Quality of Life Improvement as assessed by Minnesota Living with Heart Failure Scale and the Anti-Clot Treatment Scale Quality of Life Survey scores did not vary at baseline or change over 2 years. Biomarker analysis indicated a similar efficacy of anticoagulation strategies. Conclusion: Use of dabigatran and well-managed warfarin therapy were associated with similar risks of stroke, cognitive decline, and dementia at 2 years, suggestive that either strategy is acceptable. The results of this Vanguard study did not support the pursuit of a larger formally powered study.

Increased dosage and treatment time of Epigallocatechin-3-gallate (EGCG) negatively affects skeletal parameters in normal mice and Down syndrome mouse models.

Bone abnormalities affect all individuals with Down syndrome (DS) and are linked to abnormal expression of DYRK1A, a gene found in three copies in people with DS and Ts65Dn DS model mice. Previous work in Ts65Dn male mice demonstrated that both genetic normalization of Dyrk1a and treatment with ~9 mg/kg/day Epigallocatechin-3-gallate (EGCG), the main polyphenol found in green tea and putative DYRK1A inhibitor, improved some skeletal deficits. Because EGCG treatment improved mostly trabecular skeletal deficits, we hypothesized that increasing EGCG treatment dosage and length of administration would positively affect both trabecular and cortical bone in Ts65Dn mice. Treatment of individuals with DS with green tea extract (GTE) containing EGCG also showed some weight loss in individuals with DS, and we hypothesized that weights would be affected in Ts65Dn mice after EGCG treatment. Treatment with ~20 mg/kg/day EGCG for seven weeks showed no improvements in male Ts65Dn trabecular bone and only limited improvements in cortical measures. Comparing skeletal analyses after ~20mg/kg/day EGCG treatment with previously published treatments with ~9, 50, and 200 mg/kg/day EGCG showed that increased dosage and treatment time increased cortical structural deficits leading to weaker appendicular bones in male mice. Weight was not affected by treatment in mice, except for those given a high dose of EGCG by oral gavage. These data indicate that high doses of EGCG, similar to those reported in some treatment studies of DS and other disorders, may impair long bone structure and strength. Skeletal phenotypes should be monitored when high doses of EGCG are administered therapeutically.

The ENHANCE-AF clinical trial to evaluate an atrial fibrillation shared decision-making pathway: Rationale and study design.

INTRODUCTION: Shared decision making (SDM) may result in treatment plans that best reflect the goals and wishes of patients, increasing patient satisfaction with the decision-making process. There is a knowledge gap to support the use of decision aids in SDM for anticoagulation therapy in patients with atrial fibrillation (AF). We describe the development and testing of a new decision aid, including a multicenter, randomized, controlled, 2-arm, open-label ENHANCE-AF clinical trial (Engaging Patients to Help Achieve Increased Patient Choice and Engagement for AF Stroke Prevention) to evaluate its effectiveness in 1,200 participants. METHODS: Participants will be randomized to either usual care or to a SDM pathway incorporating a digital tool designed to simplify the complex concepts surrounding AF in conjunction with a clinician tool and a non-clinician navigator to guide the participants through each step of the tool. The participant-determined primary outcome for this study is the Decisional Conflict Scale, measured at 1 month after the index visit during which a decision was made regarding anticoagulation use. Secondary outcomes at both 1 and 6 months will include other decision making related scales as well as participant and clinician satisfaction, oral anticoagulation adherence, and a composite rate of major bleeding, death, stroke, or transient ischemic attack. The study will be conducted at four sites selected for their ability to enroll participants of varying racial and ethnic backgrounds, health literacy, and language skills. Participants will be followed in the study for 6 months. CONCLUSIONS: The results of the ENHANCE-AF trial will determine whether a decision aid facilitates high quality shared decision making in anticoagulation discussions for stroke reduction in AF. An improved shared decision-making experience may allow patients to make decisions better aligned with their personal values and preferences, while improving overall AF care.

Post-operative Urinary Dysfunction Following Shoulder Surgery: Rates and Risk Factors.

Background: Post-operative urinary retention (POUR) and dysfunction are recognized complications following orthopaedic surgery. Recent literature has focused on urinary retention and its associated complications following hip and knee reconstruction and lower extremity surgery. There is a paucity of literature focusing on POUR and shoulder surgery. The purpose of this study is to describe the rates of urinary dysfunction in patients undergoing shoulder surgery as well as the associated risk factors. Methods: This was a single institution, prospective cohort study. Eligibility criteria included patients older than 50 years of age undergoing open or arthroscopic shoulder surgery. The primary outcome was the American Urological Association (AUA) symptom score (7 questions total scored 0-5, total 35 points max) administered before and after surgery. Higher scores reflect worse urinary dysfunction. Intra-operative data such as type of surgery, type of anesthesia, use of anticholinergics, peripheral nerve block, length of case, and amount of intravenous fluids were collected. Results: Of 194 patients, the mean age was 61.4 years (Standard Deviation (S.D.) = 13.0)) and the average BMI was 29.2 (S.D. = 5.6). The sample was 35.6% female. Overall, 46.4% reported worse AUA scores post-operatively within the first 3 to 5 days, including 4.1% of which were clinically defined as "moderately worse" (>5 point worse) or "much worse" (>11 points worse). Worse preoperative AUA scores correlated with worse postop AUA score on linear regression analysis (r=0.883, P<0.0001). Males with a history of BPH showed a statistically significant positive association with worsening urinary dysfunction postoperatively (P=0.039). Four patients (2.1%) required postoperative catheterization. A significantly higher percentage of patients with preoperative AUA scores of ≥11 experienced worsening of urinary function post-operatively (P=0.04). Conclusion: Worsening of urinary function following shoulder surgery is common. The AUA score may be used to identify at-risk patients and to track changes in urinary function post-operatively. Men with a diagnosis of BPH are at particularly high risk. Further investigation is needed to elucidate the impact of urinary dysfunction on patient outcomes, satisfaction, and cost as well as the role of prophylactic medications.

Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts.

Trisomy 21 (Ts21) causes alterations in skeletal development resulting in decreased bone mass, shortened stature and weaker bones in individuals with Down syndrome (DS). There is a sexual dimorphism in bone mineral density (BMD) deficits associated with DS with males displaying earlier deficits than females. The relationships between causative trisomic genes, cellular mechanisms, and influence of sex in DS skeletal abnormalities remain unknown. One hypothesis is that the low bone turnover phenotype observed in DS results from attenuated osteoblast function, contributing to impaired trabecular architecture, altered cortical geometry, and decreased mineralization. DYRK1A, found in three copies in humans with DS, Ts65Dn, and Dp1Tyb DS model mice, has been implicated in the development of postnatal skeletal phenotypes associated with DS. Reduced copy number of Dyrk1a to euploid levels from conception in an otherwise trisomic Ts65Dn mice resulted in a rescue of appendicular bone deficits, suggesting DYRK1A contributes to skeletal development and homeostasis. We hypothesized that reduction of Dyrk1a copy number in trisomic osteoblasts would improve cellular function and resultant skeletal structural anomalies in trisomic mice. Female mice with a floxed Dyrk1a gene (Ts65Dn,Dyrk1afl/wt) were mated with male Osx-Cre+ (expressed in osteoblasts beginning around E13.5) mice, resulting in reduced Dyrk1a copy number in mature osteoblasts in Ts65Dn,Dyrk1a+/+/Osx-Cre P42 male and female trisomic and euploid mice, compared with littermate controls. Male and female Ts65Dn,Dyrk1a+/+/+ (3 copies of DYRK1A in osteoblasts) and Ts65Dn,Dyrk1a+/+/Osx-Cre (2 copies of Dyrk1a in osteoblasts) displayed similar defects in both trabecular architecture and cortical geometry, with no improvements with reduced Dyrk1a in osteoblasts. This suggests that trisomic DYRK1A does not affect osteoblast function in a cell-autonomous manner at or before P42. Although male Dp1Tyb and Ts65Dn mice exhibit similar skeletal deficits at P42 in both trabecular and cortical bone compartments between euploid and trisomic mice, female Ts65Dn mice exhibit significant cortical and trabecular deficits at P42, in contrast to an absence of genotype effect in female Dp1Tyb mice in trabecular bone. Taken together, these data suggest skeletal deficits in DS mouse models and are sex and age dependent, and influenced by strain effects, but are not solely caused by the overexpression of Dyrk1a in osteoblasts. Identifying molecular and cellular mechanisms, disrupted by gene dosage imbalance, that are involved in the development of skeletal phenotypes associated with DS could help to design therapies to rescue skeletal deficiencies seen in DS.

Current Analysis of Skeletal Phenotypes in Down Syndrome.

PURPOSE: Down syndrome (DS) is caused by trisomy 21 (Ts21) and results in skeletal deficits including shortened stature, low bone mineral density, and a predisposition to early onset osteoporosis. Ts21 causes significant alterations in skeletal development, morphology of the appendicular skeleton, bone homeostasis, age-related bone loss, and bone strength. However, the genetic or cellular origins of DS skeletal phenotypes remain unclear. RECENT FINDINGS: New studies reveal a sexual dimorphism in characteristics and onset of skeletal deficits that differ between DS and typically developing individuals. Age-related bone loss occurs earlier in the DS as compared to general population. Perturbations of DS skeletal quality arise from alterations in cellular and molecular pathways affected by the overexpression of trisomic genes. Sex-specific alterations occur in critical developmental pathways that disrupt bone accrual, remodeling, and homeostasis and are compounded by aging, resulting in increased risks for osteopenia, osteoporosis, and fracture in individuals with DS.

Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.

BACKGROUND: COVID-19 is caused by the severe acute respiratory syndrome virus SARS-CoV-2. It is widely recognized as a respiratory pathogen, but neurologic complications can be the presenting manifestation in a subset of infected patients. CASE PRESENTATION: We describe a 78-year old immunocompromised woman who presented with altered mental status after witnessed seizure-like activity at home. She was found to have SARS-CoV-2 infection and associated neuroinflammation. In this case, we undertake the first detailed analysis of cerebrospinal fluid (CSF) cytokines during COVID-19 infection and find a unique pattern of inflammation in CSF, but no evidence of viral neuroinvasion. CONCLUSION: Our findings suggest that neurologic symptoms such as encephalopathy and seizures may be the initial presentation of COVID-19. Central nervous system inflammation may associate with neurologic manifestations of disease.

Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.

BACKGROUND: COVID-19 is caused by the severe acute respiratory syndrome virus SARS-CoV-2. It is widely recognized as a respiratory pathogen, but neurologic complications can be the presenting manifestation in a subset of infected patients. CASE PRESENTATION: We describe a 78-year old immunocompromised woman who presented with altered mental status after witnessed seizure-like activity at home. She was found to have SARS-CoV-2 infection and associated neuroinflammation. In this case, we undertake the first detailed analysis of cerebrospinal fluid (CSF) cytokines during COVID-19 infection and find a unique pattern of inflammation in CSF, but no evidence of viral neuroinvasion. CONCLUSION: Our findings suggest that neurologic symptoms such as encephalopathy and seizures may be the initial presentation of COVID-19. Central nervous system inflammation may associate with neurologic manifestations of disease.

Interaction of sexual dimorphism and gene dosage imbalance in skeletal deficits associated with Down syndrome.

All individuals with Down syndrome (DS), which results from trisomy of human chromosome 21 (Ts21), present with skeletal abnormalities typified by craniofacial features, short stature and low bone mineral density (BMD). Differences in skeletal deficits between males and females with DS suggest a sexual dimorphism in how trisomy affects bone. Dp1Tyb mice contain three copies of all of the genes on mouse chromosome 16 that are homologous to human chromosome 21, males and females are fertile, and therefore are an excellent model to test the hypothesis that gene dosage influences the sexual dimorphism of bone abnormalities in DS. Dp1Tyb as compared to control littermate mice at time points associated with bone accrual (6 weeks) and skeletal maturity (16 weeks) showed deficits in BMD and trabecular architecture that occur largely through interactions between sex and genotype and resulted in lower percent bone volume in all female and Dp1Tyb male mice. Cortical bone in Dp1Tyb as compared to control mice exhibited different changes over time influenced by sex × genotype interactions including reduced cortical area in both male and female Dp1Tyb mice. Mechanical testing analyses suggested deficits in whole bone properties such as bone mass and geometry, but improved material properties in female and Dp1Tyb mice. Sexual dimorphisms and the influence of trisomic gene dosage differentially altered cellular properties of male and female Dp1Tyb bone. These data establish sex, gene dosage, skeletal site and age as important factors in skeletal development of DS model mice, paving the way for identification of the causal dosage-sensitive genes. Skeletal differences in developing male and female Dp1Tyb DS model mice replicated differences in less-studied adolescents with DS and established a foundation to understand the etiology of trisomic bone deficits.

Post-operative urinary retention after lower extremity arthroplasty and the peri-operative role of selective alpha-1 adrenergic blocking agents in adult male patients: a propensity-matched retrospective cohort study.

PURPOSE: The purpose of this study was to determine whether male patients taking pre-operative selective alpha-1 adrenergic blocking agents have a lower likelihood of developing post-operative urinary retention (POUR) and a shorter length of hospitalization following lower extremity arthroplasty. METHODS: A retrospective cohort study was conducted of patients who underwent primary or revision total hip or knee arthroplasty, or unicompartmental knee arthroplasty at an academic institution from January 2002 to May 2014. A cohort of male patients aged 35 and older who were taking a selective alpha-1 blocker prior to surgery (N = 229) were compared with a control group (N = 330) not taking one of these medications. Propensity score-matched logistic regression was performed to isolate the effect of taking a selective alpha-1 blocker on POUR. RESULTS: When evaluating for the outcome of POUR while controlling for age, hypertension, benign prostatic hyperplasia, urinary tract infections, type of anaesthesia, and procedure, those patients taking an alpha-1 blocker had a 12.1% decreased relative risk (95% CI 3.4 to 20.8%; p = 0.007) of developing POUR compared with patients not taking these medications. Mean length of stay was 3.8 days (95% CI 3.6 to 4.1) in the cohort taking selective alpha-1 blockers compared with 4.7 days (95% CI 4.4 to 4.9) for the control cohort. CONCLUSIONS: After controlling for known risk factors for the development of POUR, the use of selective alpha-1 blockers pre-operatively reduces the risk of developing urinary retention after lower extremity arthroplasty and is associated with a 1-day decreased length of stay.

Stroke-independent contribution of atrial fibrillation to dementia: a meta-analysis.

Background: Atrial fibrillation (AF) is associated with an increased risk of dementia. It is presently unknown to what extent AF contributes to dementia onset independently from prevalent and incident cerebrovascular accidents (CVAs)/transient ischaemic attacks (TIAs). Methods: MEDLINE/PubMed and Embase databases were searched for prospective observational results, which produced risk estimates for dementia in AF patients, adjusted for prevalent and incident CVAs/TIAs. Results: Five prospective observational studies were included, comprising 61 008 patients, having a median follow-up of 12.5 years. Meta-analysis of observational results indicates an increased risk of dementia in AF, adjusted for cerebrovascular clinical events (HR 1.28, 95% CI 1.17 to 1.41, I2=0%). Funnel plot analysis did not reveal a statistically significant asymmetry. Meta-regression analysis did not indicate statistically significant associations between baseline study-level covariates and risk estimates. Conclusion: AF confers a nearly 30% increased risk of dementia, independently from CVAs/TIAs. Screening for AF and subsequent optimised management to lower risk of cranial injury could help in preventing dementia, a condition characterised by high social and healthcare costs.

The AAHKS Clinical Research Award: Prophylactic Tamsulosin Does Not Reduce the Risk of Urinary Retention Following Lower Extremity Arthroplasty: A Double-Blinded Randomized Controlled Trial.

BACKGROUND: Postoperative urinary retention (POUR) is common. Selective alpha-1 adrenergic antagonists, such as tamsulosin, are effective for treating urinary retention. The purpose of this study is to determine whether perioperative prophylactic tamsulosin reduces the incidence of POUR following total hip and knee arthroplasty. METHODS: Male patients 35 years of age and older undergoing primary total hip or knee arthroplasty at a single center from 2015 to 2018 were eligible for inclusion. Patients were randomized to receive tamsulosin 0.4 mg or placebo daily for 5 days preoperatively, the morning of surgery, and the first postoperative day. The incidence of POUR was determined during the postoperative hospitalization. RESULTS: A total of 176 patients were enrolled in the study. Two patients were withdrawn prior to randomization. The remaining 174 were randomized to tamsulosin (n = 87) or placebo (n = 87). After an additional 43 patients were withdrawn prior to surgery, 131 patients completed the study (tamsulosin, n = 64; placebo, n = 67). A total of 42 patients (32.1%) developed POUR, with 18 cases (28.1%) in the tamsulosin group and 24 cases (35.8%) in the placebo group (P = .345), resulting in an odds ratio of 0.701 and a risk difference of 7.69%. CONCLUSION: Prophylactic tamsulosin did not reduce the incidence of POUR after hip and knee arthroplasty compared to placebo. The odds ratio indicates an approximately 30% decreased odds of developing POUR in the tamsulosin group, albeit not statistically significant. Tamsulosin does not appear to be effective as a prophylactic measure for reducing POUR in male hip and knee arthroplasty patients.

Intraobserver and Interobserver Reliability of Radiographic Analysis of Proximal Humerus Fractures in Adolescents.

BACKGROUND: Multiple studies have shown low intrarater and interrater agreement of radiographic classification systems for proximal humerus fractures (PHFs) in adults. There is no standardized method of measuring angulation of pediatric PHFs, nor is there consensus as to the amount of angulation and displacement that require operative fixation of adolescent PHFs. We propose a new standardized method to measure fracture angulation that is similar to the method used to measure the epiphyseal-shaft angle for slipped capital femoral epiphysis. The primary purpose of this study was to evaluate the intraobserver and interobserver reliability of our proposed method compared with a nonstandardized method. The secondary purpose was to evaluate the intrarater and interrater agreement of the Neer and Horowitz (NH), and Salter-Harris (SH) classification systems. METHODS: Seven raters evaluated 26 deidentified anteroposterior shoulder radiographs of patients 10 to 16 years of age with PHFs. Raters classified each fracture using the NH and SH systems, and used their own method to measure fracture angulation. This process was repeated 2 weeks later. During the second round, raters also measured fracture angulation using our proposed standardized method. Two weeks after the second round, raters reevaluated the radiographs using the standardized method. Intraclass correlation coefficients were calculated. RESULTS: Excellent intraobserver and interobserver agreement was achieved for the standardized method of measuring fracture angulation. All of the raters had an intrarater reliability classified as excellent (>0.80) using the standardized method. Good intrarater and excellent interrater agreement was achieved when raters used their own fracture angulation measurement method but wide confidence intervals suggested that the results were less precise. Fair to moderate intrarater and interrater reliability was seen for the NH and SH classifications. CONCLUSIONS: Our standardized method for measuring angulation in adolescent PHFs demonstrated excellent intrarater and interrater reliability. We propose that this technique may be a more precise method of measuring fracture angulation and this method should be used in future studies that evaluate indications for operative management of adolescent PHFs. LEVEL OF EVIDENCE: Level III-diagnostic.

Improving CHA2DS2-VASc stratification of non-fatal stroke and mortality risk using the Intermountain Mortality Risk Score among patients with atrial fibrillation.

Background: Oral anticoagulation (OAC) therapy guidelines recommend using CHA2DS2-VASc to determine OAC need in atrial fibrillation (AF). A usable tool, CHA2DS2-VASc is challenged by its predictive ability. Applying components of the complete blood count and basic metabolic profile, the Intermountain Mortality Risk Score (IMRS) has been extensively validated. This study evaluated whether use of IMRS with CHA2DS2-VASc in patients with AF improves prediction. Methods: Patients with AF undergoing cardiac catheterisation (N=10 077) were followed for non-fatal stroke and mortality (mean 5.8±4.1 years, maximum 19 years). CHA2DS2-VASc and IMRS were calculated at baseline. IMRS categories were defined based on previously defined criteria. Cox regression was adjusted for demographic, clinical and treatment variables not included in IMRS or CHA2DS2-VASc. Results: In women (n=4122, mean age 71±12 years), the composite of non-fatal stroke/mortality was stratified (all p-trend <0.001) by CHA2DS2-VASc (1: 12.6%, 2: 22.8%, >2: 48.1%) and IMRS (low: 17.8%, moderate: 40.9%, high risk: 64.5%), as it was for men (n=5955, mean age 68±12 years) by CHA2DS2-VASc (<2: 15.7%, 2: 30.3%, >2: 51.8%) and IMRS (low: 19.0%, moderate: 42.0%, high risk: 65.9%). IMRS stratified stroke/mortality (all p-trend <0.001) in each CHA2DS2-VASc category. Conclusions: Using IMRS jointly with CHA2DS2-VASc in patients with AF improved the prediction of stroke and mortality. For example, in patients at the OAC treatment threshold (CHA2DS2 -VASc = 2), IMRS provided ≈4-fold separation between low and high risk. IMRS provides an enhancing marker for risk in patients with AF that reflects the underlying systemic nature of this disease that may be considered in combination with the CHA2DS2-VASc score.

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes.

Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~10mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~20mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2-3mg per day (~40-60mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4mg/mL] or a water control, with treatments yielding average daily intakes of ~50mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)-which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking-and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone.

Return to Play After Osteochondral Autograft Transplantation of the Capitellum: A Systematic Review.

PURPOSE: To determine the rate of return to play and to identify lesion or osteochondral graft characteristics that may influence the return to competitive athletics after osteochondral autograft transplantation (OAT) for symptomatic osteochondritis dissecans (OCD) lesions. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A duplicate search of PubMed, Embase, Scopus, Web of Science, and CENTRAL databases was performed, beginning from the database inception dates through July 2016, for all articles evaluating the return to play after OAT for OCD lesions of the capitellum. A methodological quality assessment was completed for all included studies. Patient demographics, osteochondral lesion and graft characteristics, the number of patients, and timing of return to competitive activity were collected and evaluated. Association between graft size/number, the time to osseous healing, and return to sport was evaluated. RESULTS: Seven articles met the inclusion criteria. All included studies were case series of moderate quality with a mean Methodological Index for Non-Randomized Studies score of 12/16. Overall, 94% (119/126) of patients undergoing OAT for OCD lesions of the capitellum successfully returned to competitive sports. The mean reported time for unrestricted return to athletic competition after OAT was 5.6 months (range, 3-14 months). CONCLUSIONS: Current best evidence suggests that OAT is successful in treating advanced OCD lesions of the capitellum and returning athletes to high-level competition. Evidence supporting the association between the size and number of grafts used and the time to osseous healing and return to sport is currently limited. Our assessment of the time to return to athletic competition was limited because of variable surgical technique, postoperative rehabilitation protocols, and outcome assessment. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.