Implementation of Multiple Marker Screening for Preterm Preeclampsia in a Single Tertiary Obstetric Centre.

OBJECTIVES: Early assessment of pregnant individuals for risk of preterm preeclampsia (PE) is possible at the 11-14 week ultrasound visit using a validated multiple marker algorithm, allowing timely use of preventative low-dose acetylsalicylic acid (LDA) in high-risk patients. With no established early screening program for preterm PE in Canada, our objectives were to assess the acceptability and operational impact of routine screening for preterm PE during the 11-14 week ultrasound visit, evaluate uptake and adherence to LDA when recommended, and assess screening performance. METHODS: A prospective implementation study of preterm PE screening among pregnant patients at the ultrasound unit of a tertiary obstetric centre in Toronto, Canada. RESULTS: A total of 1057 patients were screened, with an acceptance rate of 87.1%. First-trimester ultrasound appointment time increased by a median time of 7 minutes (Interquartile range 6-9). By 16 weeks gestation, 88.7% of high-risk patients had started LDA, with adherence of 88.7%‒94.6% from 16‒36 weeks. Satisfaction with counselling was ≥7/10 in more than 95% of patients. There were 7 cases of preterm PE (0.73%), 3 in the low-risk group (0.35%), and 4 in the high-risk group (4.1%). When accounting for LDA use, the treatment-adjusted detection rate was 78.6%. CONCLUSIONS: We demonstrate successful implementation of a validated, effective screening and prevention program for preterm PE as a first step in the implementation of a broader program adaptable for cultural, access/equity considerations, and marker availability.

Midodrine for the Prevention of Vasovagal Syncope : A Randomized Clinical Trial.

BACKGROUND: Recurrent vasovagal syncope is common, responds poorly to treatment, and causes physical trauma and poor quality of life. Midodrine prevents hypotension and syncope during tilt tests in patients with vasovagal syncope. OBJECTIVE: To determine whether midodrine can prevent vasovagal syncope in usual clinical conditions. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT01456481). SETTING: 25 university hospitals in Canada, the United States, Mexico, and the United Kingdom. PATIENTS: Patients with recurrent vasovagal syncope and no serious comorbid conditions. INTERVENTION: Patients were randomly assigned 1:1 to placebo or midodrine and followed for 12 months. MEASUREMENTS: The primary outcome measure was the proportion of patients with at least 1 syncope episode during follow-up. RESULTS: The study included 133 patients who had had a median of 6 syncope episodes in the prior year (median age, 32 years; 73% female). Compared with patients receiving placebo, fewer patients receiving midodrine had at least 1 syncope episode (28 of 66 [42%] vs. 41 of 67 [61%]). The relative risk was 0.69 (95% CI, 0.49 to 0.97; P = 0.035). The absolute risk reduction was 19 percentage points (CI, 2 to 36 percentage points), and the number needed to treat to prevent 1 patient from having syncope was 5.3 (CI, 2.8 to 47.6). The time to first syncope was longer with midodrine (hazard ratio, 0.59 [CI, 0.37 to 0.96]; P = 0.035; log-rank P = 0.031). Adverse effects were similar in both groups. LIMITATION: Small study size, young and healthy patients, relatively short observation period, and high proportion of patients from 1 center. CONCLUSION: Midodrine can reduce the recurrence of syncope in healthy, younger patients with a high syncope burden. PRIMARY FUNDING SOURCE: The Canadian Institutes of Health Research.

Comparing Entrustment and Competence: An Exploratory Look at Performance-Relevant Information in the Final Year of a Veterinary Program.

Workplace-based assessments and entrustment scales have two primary goals: providing formative information to assist students with future learning; and, determining if and when learners are ready for safe, independent practice. To date, there has not been an evaluation of the relationship between these performance-relevant information pieces in veterinary medicine. This study collected quantitative and qualitative data from a single cohort of final-year students (n = 27) across in-training evaluation reports (ITERs) and entrustment scales in a distributed veterinary hospital environment. Here we compare progression in scoring and performance within and across student, within and across method of assessment, over time. Narrative comments were quantified using the Completed Clinical Evaluation Report Rating (CCERR) instrument to assess quality of written comments. Preliminary evidence suggests that we may be capturing different aspects of performance using these two different methods. Specifically, entrustment scale scores significantly increased over time, while ITER scores did not. Typically, comments on entrustment scale scores were more learner specific, longer, and used more of a coaching voice. Longitudinal evaluation of learner performance is important for learning and demonstration of competence; however, the method of data collection could influence how feedback is structured and how performance is ultimately judged.

Frequency of injuries associated with syncope in the prevention of syncope trials.

AIMS: Syncope can lead to injuries. We determined the frequency, severity, and predictors of injuries due to syncope in cohorts of syncope patients. METHODS AND RESULTS: Participants were enrolled in the POST2 (fludrocortisone) and POST4 (midodrine) vasovagal syncope (VVS) randomized trials, and POST3 enrolled patients with bifascicular block and syncope. Injury was defined as minor (bruising, abrasions), moderate (lacerations), and severe (fractures, burns, joint pain), and recorded up to 1 year after enrolment. A total of 459 patients (median 39 years) were analysed. There were 710 faints occurred in 186 patients during a 1-year follow-up. Fully 56/186 (30%) of patients were injured with syncope (12% of overall group). There were 102 injuries associated with the 710 faints (14%), of which 19% were moderate or severe injuries. Neither patient age, sex, nor the presence of prodromal symptoms associated with injury-free survival. Patients with bifascicular block were more prone to injury (relative risk 1.98, P = 0.018). Patients with ≥4 faints in the prior year had more injuries than those with fewer faints (relative risk 2.97, P < 0.0001), but this was due to more frequent syncope, and not more injuries per faint. In VVS patients, pharmacological therapy significantly reduced the likelihood of an injury due to a syncopal spell (relative risk 0.64, P = 0.015). Injury severity did not associate with age, sex, or prior-year syncope frequency. CONCLUSION: Injuries are frequent in syncope patients, but only 4% of injuries were severe. None of age, sex, and prodromal symptoms associate with injury.

A proof of principle study of atomoxetine for the prevention of vasovagal syncope: the Prevention of Syncope Trial VI.

AIMS: There are few effective therapies for vasovagal syncope (VVS). Pharmacological norepinephrine transporter (NET) inhibition increases sympathetic tone and decreases tilt-induced syncope in healthy subjects. Atomoxetine is a potent and highly selective NET inhibitor. We tested the hypothesis that atomoxetine prevents tilt-induced syncope. METHODS AND RESULTS: Vasovagal syncope patients were given two doses of study drug [randomized to atomoxetine 40 mg (n = 27) or matched placebo (n = 29)] 12 h apart, followed by a 60-min drug-free head-up tilt table test. Beat-to-beat heart rate (HR), blood pressure (BP), and cardiac haemodynamics were recorded using non-invasive techniques and stroke volume modelling. Patients were 35 ± 14 years (73% female) with medians of 12 lifetime and 3 prior year faints. Fewer subjects fainted with atomoxetine than with placebo [10/29 vs. 19/27; P = 0.003; risk ratio 0.49 (confidence interval 0.28-0.86)], but equal numbers of patients developed presyncope or syncope (23/29 vs. 21/27). Of patients who developed only presyncope, 87% (13/15) had received atomoxetine. Patients with syncope had lower nadir mean arterial pressure than subjects with only presyncope (39 ± 18 vs. 69 ± 18 mmHg, P < 0.0001), and this was due to lower trough HRs in subjects with syncope (67 ± 30 vs. 103 ± 32 b.p.m., P = 0.006) and insignificantly lower cardiac index (2.20 ± 1.36 vs. 2.84 ± 1.05 L/min/m2, P = 0.075). There were no significant differences in stroke volume index (32 ± 6 vs. 35 ± 5 mL/m2, P = 0.29) or systemic vascular resistance index (2156 ± 602 vs. 1790 ± 793 dynes*s/cm5*m2, P = 0.72). CONCLUSION: Norepinephrine transporter inhibition significantly decreased the risk of tilt-induced syncope in VVS subjects, mainly by blunting reflex bradycardia, thereby preventing final falls in cardiac index and BP.

First-trimester preeclampsia screening and prevention: impact on patient satisfaction and anxiety.

BACKGROUND: Preeclampsia affects between 2% and 5% of pregnant people in North America. First-trimester preeclampsia screening based on the Fetal Medicine Foundation risk calculation algorithm combined with treatment of high-risk patients with aspirin effectively reduces the incidence of preterm preeclampsia more than the currently used risk factor-based screening. However, the impact of such screening on patient satisfaction and maternal anxiety is unknown. OBJECTIVE: This study aimed to assess the impact of first-trimester prediction and prevention of preterm preeclampsia on patient satisfaction and anxiety. STUDY DESIGN: Consenting pregnant patients participating in a local first-trimester (11-13+6 weeks) preterm preeclampsia screening and prevention implementation study1 were contacted 6 weeks postpartum to complete an online patient satisfaction survey, designed to assess their satisfaction with the screening program and their levels of trait anxiety (using an abbreviated version of the State-Trait Anxiety Inventory [STAIT-5]). In addition to assessing overall patient satisfaction, the level of patient satisfaction was stratified and compared according to levels of patient risk for preterm preeclampsia. RESULTS: Between June 2021 and December 2021, surveys were emailed to 765 participants. The response rate was 47.80% (358/765). Overall, 93% of participants reported high levels of satisfaction with preterm preeclampsia screening (70%-100%), and 98% stated that they would recommend the screening to all pregnant patients. With respect to levels of satisfaction with the program's support in reducing feelings of worry and anxiety, 87.9% of the total sample reported high satisfaction (70%-100%). The level of clinically significant symptoms of anxiety did not differ significantly between low- and high-risk groups (8% vs 10.8%, respectively). CONCLUSION: Overall, first-trimester preeclampsia screening was associated with high patient satisfaction and did not lead to differences in patient anxiety between those with high- and low-risk screen results.

Impact of bundle branch block morphology on outcomes of patients with syncope and bifascicular block: A SPRITELY (POST 3) substudy.

BACKGROUND: Permanent pacing is often considered for patients with syncope and bifascicular block. OBJECTIVE: The purpose of this study was to determine whether QRS morphology or other electrocardiographic characteristics can identify patients who may benefit from permanent pacing. METHODS: The Syncope: Pacing or Recording in the Later Years (SPRITELY) trial was a multicenter trial that randomized patients with bifascicular block and syncope (n = 115) to empiric pacemaker implantation vs implantable loop recorder (ILR) monitoring. In this SPRITELY subanalysis, baseline 12-lead electrocardiograms were evaluated for bundle branch block (BBB) morphology, QRS width, and PR and QT intervals and their impact on clinical outcomes was assessed. RESULTS: There were 41 patients with left BBB (36%), 69 patients with right bundle branch block (RBBB) and left anterior fascicular block (60%), and 5 patients with RBBB and left posterior fascicular block (4%). Pacemaker implant compared with ILR was associated with a significant reduction of major study-related events (MSREs) in both patients with left BBB (23.8% vs 78.9%; P = .001) and those with RBBB (27% vs 72.9%; P < .0001). Similarly, a reduction of MSREs was observed in both patients with trifascicular block (23% vs 84.6%; P < .0001) and those with bifascicular block (26.6% vs 68.9%; P = .002). In the group randomized to ILR monitoring, the type of BBB was not a predictor of recurrent syncope (P = .30), bradycardia requiring pacemaker (P = .15), or MSREs (P = .42). The presence of PR interval prolongation or QRS width in this group did not predict MSREs (P = .22 and P = .96, respectively). CONCLUSION: In patients with syncope and bifascicular block, pacemaker implantation reduces adverse events as compared with ILR monitoring, irrespective of the type of BBB or the presence of PR interval prolongation.

The Implementation of Preeclampsia Screening and Prevention (IMPRESS) Study.

BACKGROUND: Preeclampsia affects between 2% and 5% of pregnancies and is one of the leading causes of perinatal morbidity and mortality worldwide. Despite strong evidence that the combination of systematic preeclampsia screening based on the Fetal Medicine Foundation preeclampsia risk calculation algorithm with treatment of high-risk patients with low-dose aspirin reduces the incidence of preterm preeclampsia more than currently used risk-factor-based screening, real-world implementation studies have not yet been done in Canada. OBJECTIVE: This study aimed to assess the operational feasibility of implementing first-trimester screening and prevention of preterm preeclampsia (<37 weeks) alongside a publicly funded first-trimester combined screening program for aneuploidies. STUDY DESIGN: This was a prospective implementation study. Consecutive pregnant patients referred for first-trimester combined screening (11-13+6 weeks) were offered screening for preeclampsia based on the Fetal Medicine Foundation algorithm concomitantly with their aneuploidy screen. Consenting participants were screened using maternal risk factors, mean arterial pressure, uterine artery Doppler pulsatility index, pregnancy-associated plasma protein-A, and placental growth factor. Risk for preterm preeclampsia (<37 weeks) was calculated using the Fetal Medicine Foundation algorithm, and individuals with a risk score ≥1 per 100 were recommended to use aspirin (162 mg once daily at bedtime, <16-36 weeks). Implementation metrics assessed included: acceptability, operational impact, proportion of aspirin initiation, quality and safety measures, and screen performance. RESULTS: Between December 1, 2020 and April 23, 2021, 1124 patients consented to preeclampsia screening (98.3% uptake), and 92 (8.2%) screened positive. Appointments for patients receiving first-trimester combined screening aneuploidy and preeclampsia screening averaged 6 minutes longer than first-trimester combined screening alone, and adding uterine artery Doppler pulsatility index averaged 2 minutes. Of the 92 patients who screened as high-risk for preeclampsia, 72 (78.3%) were successfully contacted before 16 weeks' gestation. Of these, 62 (86.1%) initiated aspirin, and 10 (13.9%) did not. Performance audit identified a consistent negative bias with mean arterial pressure measurements (median multiple of the median <1 in 10%); other variables were satisfactory. There were 7 cases of preterm preeclampsia (0.69%): 5 and 2 in the high- and low-risk groups, respectively. Screening detected 5 of 7 (71.4 %) preterm preeclampsia cases, with improved performance after adjustment for aspirin treatment effect. CONCLUSION: This study confirms the operational feasibility of implementing an evidence-based preeclampsia screening and prevention program in a publicly funded Canadian setting. This will facilitate implementation into clinical service and the scaling up of this program at a regional and provincial level.

Longitudinal assessment of competency development at The Ohio State University using the competency-based veterinary education (CBVE) model.

With the development of the American Association of Veterinary Medical Colleges' Competency-Based Veterinary Education (CBVE) model, veterinary schools are reorganizing curricula and assessment guidelines, especially within the clinical rotation training elements. Specifically, programs are utilizing both competencies and entrustable professional activities (EPAs) as opportunities for gathering information about student development within and across clinical rotations. However, what evidence exists that use of the central tenets of the CBVE model (competency framework, milestones and EPAs) improves our assessment practices and captures reliable and valid data to track competency development of students as they progress through their clinical year? Here, we report on validity evidence to support the use of scores from in-training evaluation report forms (ITERs) and workplace-based assessments of EPAs to evaluate competency progression within and across domains described in the CBVE, during the final year clinical training period of The Ohio State University's College of Veterinary Medicine (OSU-CVM) program. The ITER, used at the conclusion of each rotation, was modified to include the CBVE competencies that were assessed by identifying the stage of student development on a series of descriptive milestones (from pre-novice to competent). Workplace based assessments containing entrustment scales were used to assess EPAs from the CBVE model within each clinical rotation. Competency progression and entrustment scores were evaluated on each of the 31 rotations offered and high-stakes decisions regarding student performance were determined by a collective review of all the ITERs and EPAs recorded for each learner across each semester and the entire year. Results from the class of 2021, collected on approximately 190 students from 31 rotations, are reported with more than 55 299 total competency assessments combined with milestone placement and 2799 complete EPAs. Approximately 10% of the class was identified for remediation and received additional coaching support. Data collected longitudinally through the ITER on milestones provides initial validity evidence to support using the scores in higher stakes contexts such as identifying students for remediation and for determining whether students have met the necessary requirements to successfully complete the program. Data collected on entrustment scores did not, however, support such decision making. Implications are discussed.

A Cost-Utility Analysis of the Syncope: Pacing or Recording in The Later Years (SPRITELY) Trial.

Background: The Syncope: Pacing or Recording in the Later Years (SPRITELY) trial reported that a strategy of empiric permanent pacing in patients with syncope and bifascicular block reduces major adverse events more effectively than acting on the results of an implantable cardiac monitor (ICM). Our objective was to determine the cost-effectiveness of using the ICM, compared with a pacemaker (PM), in the management of older adults (age > 50 years) with bifascicular block and syncope enrolled in the SPRITELY trial. Methods: SPRITELY was a pragmatic, open-label randomized controlled trial with a median follow-up of 33 months. The primary outcome of this analysis is the cost per additional quality-adjusted life-year (QALY). Resource utilization and utility data were collected prospectively, and outcomes at 2 years were compared between the 2 arms. A decision analytic model simulated a 3-year time horizon. Results: The mean cost incurred by participants randomized to the PM arm was $9918, compared to $15,416 (both in Canadian dollars) for participants randomized to the ICM arm. The ICM strategy resulted in 0.167 QALYs fewer than the PM strategy. Cost and QALY outcomes are sensitive to the proportion of participants randomized to the ICM arm who subsequently required PM insertion. In 40,000 iterations of probabilistic sensitivity analysis, the PM strategy resulted in cost-savings in 99.7% of iterations, compared with the ICM strategy. Conclusions: The PM strategy was dominant-that is, less costly and estimated to result in a greater number of QALYs. For patients with unexplained syncope, bifascicular block, and age > 50 years, a PM is more likely to be cost-effective than an ICM.

Contexte: L'essai SPRITELY ( S yncope: P acing or R ecording i n t h e L ater Y ears) a été mené auprès de patients ayant subi une syncope et un bloc bifasciculaire. Elle a montré qu'une méthode de stimulation électrique permanente et empirique du cœur permet de réduire les événements indésirables majeurs plus efficacement qu'une méthode reposant sur les résultats d'un moniteur cardiaque implantable. Notre objectif était de déterminer le rapport coût-efficacité de l'utilisation du moniteur cardiaque implantable par rapport à un stimulateur cardiaque dans la prise en charge de personnes âgées de plus de 50 ans présentant un bloc bifasciculaire et une syncope, inscrits à l'essai SPRITELY. Méthodologie: SPRITELY était un essai contrôlé ouvert et pragmatique à répartition aléatoire, dont le suivi médian était de 33 mois. Le paramètre d'évaluation principal de cette analyse était le coût supplémentaire par année de vie ajustée en fonction de la qualité (AVAQ). Les données sur l'utilisation des ressources et l'utilité ont été recueillies de manière prospective, et les résultats à deux ans ont été comparés entre les deux groupes. Un modèle décisionnel analytique a été utilisé pour simuler un horizon temporel de trois ans. Résultats: Le coût moyen pour les participants répartis aléatoirement dans le groupe utilisant un stimulateur cardiaque était de 9 918 $ CAN comparativement à 15 416 $ CAN pour ceux utilisant un moniteur cardiaque implantable. La stratégie du moniteur cardiaque implantable s'est traduite par une réduction de 0,167 du nombre d'AVAQ par rapport à la stratégie reposant sur le stimulateur cardiaque. Les résultats relatifs aux coûts et aux AVAQ sont sensibles à la proportion de participants répartis aléatoirement dans le groupe du moniteur cardiaque implantable qui ont par la suite dû recevoir un stimulateur cardiaque. Sur 40 000 itérations de l'analyse de sensibilité probabiliste, la stratégie du stimulateur cardiaque a occasionné des économies dans 99,7 % des itérations comparativement à la stratégie du moniteur cardiaque implantable. Conclusions: La stratégie du stimulateur cardiaque était dominante, autrement dit moins coûteuse et, selon les estimations, entraînerait un plus grand nombre d'AVAQ. Pour les patients de plus de 50 ans présentant une syncope idiopathique et un bloc bifasciculaire, un stimulateur cardiaque est plus susceptible d'être moins coûteux qu'un moniteur cardiaque implantable.

Randomized Pragmatic Trial of Pacemaker Versus Implantable Cardiac Monitor in Syncope and Bifascicular Block.

OBJECTIVES: In this study, the authors tested whether a strategy of empiric permanent pacing reduces major composite events more effectively than acting on the results of an implantable cardiac monitor (ICM). BACKGROUND: Syncope may be caused by intermittent complete heart block in patients with bifascicular heart block, but competing diagnoses coexist. Whether empiric permanent pacing or acting on investigative results provides best care is unknown. METHODS: This was a multinational, randomized, pragmatic clinical trial of patients ≥50 years of age with bifascicular block, preserved left ventricular function, and ≥1 syncope in the preceding year. The primary composite outcome measure comprised cardiovascular death, syncope, bradycardia resulting in pacemaker insertion, and device complications. RESULTS: There were 57 and 58 subjects randomized to receive a pacemaker or ICM. A total of 41 patients had left bundle branch block and 74 had right bundle branch block and a left fascicular block. Patients were followed for a median 33 months. There were fewer composite primary outcomes in patients randomized to pacemaker compared with ICM, respectively (20 [35%] vs 44 [76%]; chi square P < 0.0001), with lower actuarial probabilities of a primary outcome (0.45 and 1.00; P < 0.001). Syncope was as likely in the groups randomized to receive a pacemaker or ICM (29% vs 26%, chi-square P = 0.95). CONCLUSIONS: Empiric permanent pacing compared with ICM reduced major adverse events but not syncope in older patients with bifascicular block and recent syncope. There remains a substantial likelihood of syncope recurrence in patients who receive a permanent pacemaker likely caused by vasodepressor syncope. (Syncope: Pacing or Recording in the Later Years [SPRITELY]; NCT01423994).

Sex Differences in Vasovagal Syncope: A Post Hoc Analysis of the Prevention of Syncope Trials (POST) I and II.

BACKGROUND: Vasovagal syncope (VVS) occurs in > 40% of individuals at least once in their lifetime. Sex-dependent differences in presentation and outcomes are not understood. We sought to determine differences in clinical presentation, treatment modalities, and outcomes of VVS between men and women. METHODS: Data were collected as part of the Prevention of Syncope Trials (POST) I and II, 2 multicenter, placebo-controlled, randomized trials testing the effectiveness of metoprolol and fludrocortisone, respectively. Data regarding clinical presentation, outcomes, and time to first syncope event after randomization were compared. RESULTS: Of the 418 patients (280 women and 138 men), women were younger at the time of first syncope event (21 vs 26 years P = 0.002) and had a lower baseline systolic blood pressure (117 vs 124 mm Hg, P < 0.001). Response to heat as a trigger for syncope was more common in women (68% vs 48%, P = 0.011). Clinical presentation in women consisted more commonly of feeling warm, having seizures, and experiencing more postsyncope fatigue (68% vs 54%, P = 0.048; 10% vs 2.7%, P = 0.045; 75% vs 59%, P = 0.017, respectively). Women were more likely to experience recurrent syncope after adjustment for prerandomization syncope burden and randomization assignment (hazard ratio, 1.56; 95% confidence interval, 1.10-2.22; P = 0.012). CONCLUSION: Clinical presentation and provocative factors of VVS differ between men and women, as do recurrent events. Recognition of these differences may help target therapy specifically in men and women.

Quality of life improves in vasovagal syncope patients after clinical trial enrollment regardless of fainting in follow-up.

BACKGROUND: Frequent syncope is linked to poorer health-related quality of life (HRQoL). Recurrent syncope has been observed to reduce in all groups after seeing a syncope expert and enrolling in a clinical trial. It is unknown if HRQoL improves with this reduction in syncope recurrence. OBJECTIVES: We examined the change in HRQoL over time in vasovagal syncope (VVS) patients seen by a syncope expert and enrolled in a trial. We also explored whether change differed with treatment or the frequency of fainting during follow up. METHODS: The Short Form Health Survey (SF36) was completed at baseline (BL), 6 m, and 12 m post-enrollment by VVS patients in the 1st and 2nd Prevention of Syncope Trials, which were multi-centered, randomized, placebo-controlled trials of metoprolol (POST) and fludrocortisone (POST2). Differences in HRQoL at BL, 6 m, and 12 m were analyzed and compared by faints in follow-up and randomization group. RESULTS: Complete study data were available for 143 VVS patients (40 ±â€¯17 years, 62% F). Over 12 months, patients reported improvement in all SF36 dimensions except for bodily pain. Post hoc analyses indicated that differences first occurred between BL and 6 m for all but general health. Fainting in follow-up or drug randomization group did not diminish the improvements. The baseline syncope burden was not different whether patients' HRQoL improved or not. CONCLUSION: HRQoL of VVS patients improves over time after enrolling in a clinical trial, even with recurrent faints or randomization to placebo. Improvements may result from alternative factors, such as interaction with experts or patient adjustment.

Genetic Association Study in Multigenerational Kindreds With Vasovagal Syncope: Evidence for Involvement of Sex-Specific Serotonin Signaling.

BACKGROUND: Several studies suggest that vasovagal syncope has a genetic origin, but this is unclear. We assessed whether plausible gene variants associate with vasovagal syncope. METHODS: We studied 160 subjects in 9 kindreds comprising 82 fainters and 78 controls. The diagnosis was ascertained with the Calgary Syncope Score. Common genetic variants were genotyped for 12 genes for vascular signaling, potassium channels, the HTR1A(serotonin 5-HT1A receptor), SLC6A4(serotonin reuptake transporter), and COMT(catecholamine O-methyltransferase). Sex-specific associations between genotypes and phenotypes were tested. RESULTS: In 9 out of 12 variants, there was no significant association between genotype and phenotype. However, the HTR1A(-1019) G alleles associated with syncope in males, but not in females ( P=0.005). CC and GG males had 9% versus 77% likelihoods of syncope. The SLC6A4 promoter L alleles associated with decreased syncope in males but increased in females ( P=0.059). The LL and SS males had 25% and 47% syncope likelihoods, whereas females had 75% and 50% syncope likelihoods. The COMT c.472 A alleles associated with decreased syncope in males but increased in females ( P=0.017). The GG and AA males had 50% and 15% syncope likelihoods, whereas females had 52% and 73% syncope likelihoods. CONCLUSIONS: There is a sex-dependent effect of alleles of serotonin signaling and vasovagal syncope, supporting the serotonin hypothesis of the physiology of vasovagal syncope.

A functional cell-based bioassay for assessing adrenergic autoantibody activity in postural tachycardia syndrome.

BACKGROUND: Activating autoantibodies (AAb) to adrenergic receptors (AR) have previously been reported in patients with postural tachycardia syndrome (POTS). These AAb may contribute to a final common pathway for overlapping disease processes, reflecting a possible autoimmune contribution to POTS pathophysiology. In prior studies, measurement of AAb activity was inferred from costly, low-throughput, and laborious physiological assays. In the present study, we developed and validated an alternative cell-based bioassay for measuring AAb activity in serum by means of pre-treatment with monoamine oxidase (MAO). METHODS: A total of 37 POTS patients and 61 sex-matched healthy control participants were included. Serum was pre-treated with MAO to remove endogenous catecholamines that could falsely inflate AR activation by AAb. A receptor-transfected cell-based bioassay was used to detect presence of α1AR-AAb and ß1AR-AAb in serum. RESULTS: MAO effectively degraded catecholamines as demonstrated by suppression of norepinephrine-induced α1AR activation in POTS (6.4 â€‹± â€‹0.7 vs. 5.5 â€‹± â€‹0.9; P â€‹= â€‹0.044) and in controls (4.1 â€‹± â€‹0.5 vs. 3.9 â€‹± â€‹0.6; P â€‹= â€‹0.001). Mean activity values were greater in the POTS vs. Controls for α1AR-AAb (6.2 â€‹± â€‹1.2 vs. 5.3 â€‹± â€‹1.0; P â€‹< â€‹0.001) and ß1AR-AAb (5.7 â€‹± â€‹1.8 vs. 4.1 â€‹± â€‹0.9; P â€‹< â€‹0.001). Compared to controls, more POTS patients were positive for α1AR-AAb activity (22% vs 4%; P â€‹= â€‹0.007) and ß1AR-AAb activity (52% vs. 2%; P â€‹< â€‹0.001). CONCLUSIONS: The co-presence of norepinephrine in serum samples can artifactually elevate α1AR and ß1AR activity, which can be avoided by serum pre-treatment with MAO. Using this novel bioassay, we show that POTS patients have increased α1AR-AAb and ß1AR-AAb activity compared to healthy controls in the largest POTS cohort reported to-date.

Validity evidence for programmatic assessment in competency-based education.

INTRODUCTION: Competency-based education (CBE) is now pervasive in health professions education. A foundational principle of CBE is to assess and identify the progression of competency development in students over time. It has been argued that a programmatic approach to assessment in CBE maximizes student learning. The aim of this study is to investigate if programmatic assessment, i. e., a system of assessment, can be used within a CBE framework to track progression of student learning within and across competencies over time. METHODS: Three workplace-based assessment methods were used to measure the same seven competency domains. We performed a retrospective quantitative analysis of 327,974 assessment data points from 16,575 completed assessment forms from 962 students over 124 weeks using both descriptive (visualization) and modelling (inferential) analyses. This included multilevel random coefficient modelling and generalizability theory. RESULTS: Random coefficient modelling indicated that variance due to differences in inter-student performance was highest (40%). The reliability coefficients of scores from assessment methods ranged from 0.86 to 0.90. Method and competency variance components were in the small-to-moderate range. DISCUSSION: The current validation evidence provides cause for optimism regarding the explicit development and implementation of a program of assessment within CBE. The majority of the variance in scores appears to be student-related and reliable, supporting the psychometric properties as well as both formative and summative score applications.

Clusters, Gaps, and Randomness: Vasovagal Syncope Recurrence Patterns.

OBJECTIVES: This study elucidated the temporal recurrence patterns of syncope in patients with frequent vasovagal syncope (VVS). BACKGROUND: Understanding the temporal distribution of fainting spells in syncope patients may illuminate biological processes and inform decision making. METHODS: Patients from the POST 2 (Prevention of Syncope Trial 2) were included; all had VVS and fainted ≥4 times in the study year, providing ≥3 interevent intervals (IEIs). Only fainting spells separated by ≥1 day were included. IEI distributions were analyzed using Poisson modeling and cumulative sum distributions. RESULTS: Twenty-four patients (5 males, 19 females; mean 33 years of age) had a total of 286 syncopal events and 262 IEIs, with a median 6 IEI. They resembled excluded subjects in age and sex but fainted more often in their lives (median: 57 vs. 13 fainting spells, respectively; p < 0.0001) and in the previous year (median: 23 vs. 3 fainting spells, respectively; p < 0.0001). Subjects had a median IEI duration of 8 (interquartile range: 4 to 19) days. The IEI distributions were fit well by Poisson models with a median r2 of 0.94 (95% confidence interval: 0.91 to 0.97). The patients' Poisson rate constant frequencies were 7 to 263 fainting spells/year with a median rate of 19 fainting spells/year. The modal syncope frequency was 10 to 15 fainting spells per year. Seven patients had biexponential distributions, and many patients fainted in clusters. CONCLUSIONS: Patients with frequent VVS have fainting spells that occur randomly in time. Clusters of syncope occur, and in this population, there is a central tendency to 10 to 15 fainting spells per year. This provides a quantitative measure of frequency and predictability that may afford individualized treatment goals.

Prospective Assessment of the Risk of Vasovagal Syncope During Driving.

OBJECTIVES: This study sought to estimate the likelihood of a motor vehicle accident causing serious risk or harm in patients with frequent vasovagal syncope, and compare this with international accident data. BACKGROUND: Recurrent vasovagal syncope poses a risk because of fainting while driving, but prospective, benchmarked estimates of this risk have not been reported. METHODS: Data were from the POST (Prevention of Syncope Trial)-1 and -2, which were multicenter randomized studies of patients with ≥3 lifetime vasovagal syncope spells. POST-1 patients (reported in 2005) received metoprolol or placebo for ≤1 year between 1998 and 2004; POST 2 patients received fludrocortisone or placebo for ≤1 year between 2006 and 2011. Accident data were recovered from Internet reports from the United States, United Kingdom, and Canada. RESULTS: A total of 418 patients (age 38 ± 17 years) had a median of 10 lifetime faints and a median of 3 faints in the previous year. Total follow-up time was 323 years, or 0.77 years per person. A total of 174 subjects fainted, having a total of 615 faints. Two patients fainted while driving, without fatality or injury, with a likelihood of 0.62% per person-year. The risk of serious harm or death was <0.0035% per person-year, and 0.0018% per faint. In the general U.S., U.K., and Canadian driving populations, the risk of serious harm or death was 0.067% per driver-year, and the risk of death was 0.009%. CONCLUSIONS: The estimated risk of serious harm or death was <0.0035% per person-year in highly symptomatic patients, less than the risk of serious harm or death in the general population. (A Randomized Clinical Trial of Fludrocortisone for Vasovagal Syncope: The Second Prevention of Syncope Trial [POST II]; NCT00118482).