Best anticoagulation strategy with and without appendage occlusion for stroke-prophylaxis in postablation atrial fibrillation patients with cardiac amyloidosis.

INTRODUCTION: Both atrial fibrillation (AF) and amyloidosis increase stroke risk. We evaluated the best anticoagulation strategy in AF patients with coexistent amyloidosis. METHODS: Consecutive AF patients with concomitant amyloidosis were divided into two groups based on the postablation stroke-prophylaxis approach; group 1: left atrial appendage occlusion (LAAO) in eligible patients and group 2: oral anticoagulation (OAC). Group 1 patients were further divided into Gr. 1A: LAAO + half-does NOAC (HD-NOAC) for 6 months followed by aspirin 81 mg/day and Gr. 1B: LAAO + HD-NOAC. In group 1 patients, with complete occlusion at the 45-day transesophageal echocardiogram, patients were switched to aspirin, 81 mg/day at 6 months. In case of leak, or dense "smoke" in the left atrium (LA) or enlarged LA, they were placed on long-term half-dose (HD) NOAC. Group 2 patients remained on full-dose NOAC during the whole study period. RESULTS: A total of 92 patients were included in the analysis; group 1: 56 and group 2: 36. After the 45-day TEE, 31 patients from group 1 remained on baby-aspirin and 25 on HD NOAC. At 1-year follow-up, four stroke, one TIA and six device-thrombus were reported in group 1A, compared to none in patients in group 1B (5/31 vs. 0/25, p = .03). No bleeding events were reported in group 1, whereas group 2 had five bleeding events (one subdural hematoma, one retinal hemorrhage, and four GI bleedings). Additionally, one stroke was reported in group 2 that happened during brief discontinuation of OAC. CONCLUSION: In patients with coexistent AF and amyloidosis, half-dose NOAC following LAAO was observed to be the safest stroke-prophylaxis strategy.

Long-term measurement and characterization of boundary layer optical turbulence.

The United States Naval Academy long-term scintillation measurement campaign was a multi-year effort to characterize optical turbulence in the near-maritime atmospheric boundary layer (ABL). At its core, the field experiment consists of in situ measurements of bulk atmospheric and oceanographic parameters, as well as path-averaged measurements of the refractive index structure parameter, C n2, collected using a large-aperture scintillometer. The field experiment ran from January 1st, 2020, through September 26th, 2023, representing the most comprehensive collection of optical turbulence measurements in the near-maritime ABL to date. Long-term measurements enable researchers to evaluate existing theory and develop new models applicable to this environment. The present study characterizes some of the physical relationships that affect optical turbulence. This characterization focuses on the relationship between local optical turbulence and select atmospheric and oceanographic parameters. The impact of temperature gradients on the extent of optical turbulence was analyzed, along with its interactions with relative humidity and wind speed. The diurnal and seasonal variations in measured C n2 were examined, with comparisons drawn against other environments. Further information and the full dataset are publicly available through the optical turbulence benchmark repository [Jellen et al., GitHub, 2023].

Catheter ablation approach and outcome in HIV+ patients with recurrent atrial fibrillation.

INTRODUCTION: Earlier studies have shown a clear association between severity of human immunodeficiency virus (HIV) infection and incident atrial fibrillation (AF). We present the long-term outcome of catheter ablation (CA) and electrophysiological characteristics in HIV+ AF patients. METHODS: This study evaluated 1438 consecutive AF patients [31 (2.15%) with HIV and 1407 (97.8%) without HIV diagnosis] undergoing their first CA at our center. A total of 31 HIV patients and 31 controls were generated by propensity matching, based on calculated risk factor scores, using a logistic model. During first procedure, all received isolation of pulmonary vein (PV) + posterior wall and superior vena cava. Non-PV triggers, defined as ectopic triggers originating from sites other than PVs, were identified at the redo ablation with high-dose isoproterenol challenge. RESULTS: Clinical characteristics were not different between the groups. When compared to the control, by the end of 5 years after the first procedure, recurrence was significantly greater in HIV group [100% vs. 54%, p < .001]. Among patients that underwent redo ablation non-PV triggers were higher in HIV group [93.5% vs. 54%, p < .001], and most frequently originated from the coronary sinus [67.7% vs. 45.2%, p < .001] and left atrial appendage [41.9% vs. 25.8%, p < .001]. After focal ablation of non-PV trigger, no difference in arrhythmia recurrence between two groups [80.6% vs. 87.1%, p = .753] at 1-year follow up was found. CONCLUSION: Our findings suggest that non-PV triggers are highly prevalent in HIV+ AF patients resulting in higher rate of the mid- and long-term arrhythmia recurrence.

Prevalence of atrial fibrillation and procedural outcome in patients undergoing catheter ablation for premature ventricular complexes.

INTRODUCTION: Atrial fibrillation (AF) and premature ventricular complexes (PVC) are common arrhythmias. We aimed to investigate AF prevalence in patients with PVC and its impact on PVC ablation outcomes. METHODS: Consecutive patients undergoing PVC ablation at a single institution between 2016 and 2019 were included and prospectively followed for 2 years. Patients with severe valvular heart disease, hyperthyroidism, malignancy, alcohol use disorder and advanced renal/hepatic diseases were excluded. Twelve-lead electrocardiograms were used to diagnose AF and assess PVC morphology. All PVCs were targeted for ablation using 4-mm irrigated-tip catheters at standardized radiofrequency power guided by 3-D mapping and intracardiac echocardiography. Patients were followed with remote monitoring, device interrogations and office visits every 6 months for 2 years. Detection of any PVCs in follow-up was considered as recurrence. RESULTS: A total of 394 patients underwent PVC ablation and 96 (24%) had concurrent AF. Patients with PVC and AF were significantly older (68.2 ± 10.8 vs. 58.3 ± 15.8 years, p < .001), had lower LV ejection fraction (43.3 ± 13.3% vs. 49.6 ± 12.4%, p < .001), higher CHA2 DS2 -VASc (2.8 ± 1.3 vs. 2.0 ± 1.3, p < .001) than those without. PVCs with ≥2 morphologies were detected in 60.4% and 13.7% patients with vs without AF (p < .001). At 2-year follow-up, PVC recurrence rate was significantly higher in patients with vs without AF (17.7% vs. 9.4%, p = .02). CONCLUSION: AF was documented in 1/4 of patients undergoing PVC ablation and was associated with lower procedural success at long-term follow-up. This was likely attributed to older age, worse LV function and higher prevalence of multiple PVC morphologies in patients with concurrent AF.

Best ablation strategy in patients with premature ventricular contractions with multiple morphology: a single-centre experience.

AIMS: This study aimed to examine the clinical benefits of targeted ablation of all Premature ventricular complex (PVC) morphologies vs. predominant PVC only. METHODS AND RESULTS: A total of 171 consecutive patients with reduced left ventricular ejection fraction (LVEF) and ≥2 PVC morphology with high burden (>10%/day) undergoing their first ablation procedure were included in the analysis. At the initial procedure, prevalent PVC alone was ablated in the majority. However, at the redo, all PVC morphologies were targeted for ablation. : At the first procedure, 152 (89%) patients received ablation of the dominant PVC only. In the remaining 19 (11%) patients, all PVC morphologies were ablated. At two years, high PVC burden was detected in 89 (52%) patients. Repeat procedure was performed in 78 of 89, where all PVC morphologies were ablated. At 5 years after the repeat procedure, 71 (91%) had PVC burden of <5% [3.8 ± 1.1% vs. 15.4 ± 4.3% in successful vs. failed subjects (P < 0.001)]. In patients with low PVC burden after the initial procedure, LVEF improved from 37.5% to 41.6% [mean difference (MD): 3.39 ± 2.9%, P < 0.001], whereas a reduction in LVEF from 39.8% to 34.5% (MD: 6.45 ± 4.7%, P < 0.001) was recorded in patients with high PVC burden. One year after the repeat procedure, LVEF improved from 36.2% to 41.7% (MD: 5.5 ± 4.3%, P < 0.001) in patients with successful ablation. CONCLUSION: In this observational series, ablation of all PVC morphologies was associated with significantly lower PVC burden and improvement of LVEF at long-term follow-up, compared with ablation of the dominant morphology only.

Hybrid optical turbulence models using machine-learning and local measurements.

Accurate prediction of atmospheric optical turbulence in localized environments is essential for estimating the performance of free-space optical systems. Macro-meteorological models developed to predict turbulent effects in one environment may fail when applied in new environments. However, existing macro-meteorological models are expected to offer some predictive power. Building a new model from locally measured macro-meteorology and scintillometer readings can require significant time and resources, as well as a large number of observations. These challenges motivate the development of a machine-learning informed hybrid model framework. By combining a baseline macro-meteorological model with local observations, hybrid models were trained to improve upon the predictive power of each baseline model. Comparisons between the performance of the hybrid models, selected baseline macro-meteorological models, and machine-learning models trained only on local observations, highlight potential use cases for the hybrid model framework when local data are expensive to collect. Both the hybrid and data-only models were trained using the gradient boosted decision tree architecture with a variable number of in situ meteorological observations. The hybrid and data-only models were found to outperform three baseline macro-meteorological models, even for low numbers of observations, in some cases as little as one day. For the first baseline macro-meteorological model investigated, the hybrid model achieves an estimated 29% reduction in the mean absolute error using only one day-equivalent of observation, growing to 41% after only two days, and 68% after 180 days-equivalent training data. The data-only model generally showed similar, but slightly lower performance, as compared to the hybrid model. Notably, the hybrid model's performance advantage over the data-only model dropped below 2% near the 24 days-equivalent observation mark and trended towards 0% thereafter. The number of days-equivalent training data required by both the hybrid model and the data-only model is potentially indicative of the seasonal variation in the local microclimate and its propagation environment.

Association of a longitudinal, preclinical ultrasound curriculum with medical student performance.

INTRODUCTION: Point-of-care ultrasound (US) is used in clinical practice across many specialties. Ultrasound (US) curricula for medical students are increasingly common. Optimal timing, structure, and effect of ultrasound education during medical school remains poorly understood. This study aims to retrospectively determine the association between participation in a preclinical, longitudinal US curriculum and medical student academic performance. METHODS: All first-year medical students at a medical school in the Midwest region of the United States were offered a voluntary longitudinal US curriculum. Participants were selected by random lottery. The curriculum consisted of five three-hour hands on-sessions with matching asynchronous content covering anatomy and pathologic findings. Content was paired with organ system blocks in the standard first year curriculum at our medical school. Exam scores between the participating and non-participating students were compared to evaluate the objective impact of US education on performance in an existing curriculum. We hypothesized that there would be an association between participation in the curriculum and improved medical student performance. Secondary outcomes included shelf exam scores for the surgery, internal medicine, neurology clerkships and USMLE Step 1. A multivariable linear regression model was used to evaluate the association of US curriculum participation with student performance. Scores were adjusted for age, gender, MCAT percentile, and science or engineering degree. RESULTS: 76 of 178 students applied to participate in the curriculum, of which 51 were accepted. US curriculum students were compared to non-participating students (n = 127) from the same class. The US curriculum students performed better in cardiovascular anatomy (mean score 92.1 vs. 88.7, p = 0.048 after adjustment for multiple comparisons). There were no significant differences in cumulative cardiovascular exam scores, or in anatomy and cumulative exam scores for the gastroenterology and neurology blocks. The effect of US curriculum participation on cardiovascular anatomy scores was estimated to be an improvement of 3.48 points (95% CI 0.78-6.18). No significant differences were observed for USMLE Step 1 or clerkship shelf exams. There were no significant differences in either preclinical, clerkship or Step 1 score for the 25 students who applied and were not accepted and the 102 who did not apply. CONCLUSIONS: Participation in a preclinical longitudinal US curriculum was associated with improved exam performance in cardiovascular anatomy but not examination of other cardiovascular system concepts. Neither anatomy or comprehensive exam scores for neurology and gastrointestinal organ system blocks were improved.

Targeting non-pulmonary vein triggers in persistent atrial fibrillation: results from a prospective, multicentre, observational registry.

AIMS: We evaluated the efficacy of an ablation strategy empirically targeting pulmonary veins (PVs) and posterior wall (PW) and the prevalence and clinical impact of extrapulmonary trigger inducibility and ablation in a large cohort of patients with persistent atrial fibrillation (PerAF). METHODS AND RESULTS: A total of 1803 PerAF patients were prospectively enrolled. All patients underwent pulmonary vein antrum isolation (PVAI) extended to the entire PW. A standardized protocol was performed to confirm persistent PVAI and elicit any triggers originating from non-PV sites. All non-PV triggers initiating sustained atrial tachyarrhythmias were ablated. Ablation of non-PV sites triggering non-sustained runs (<30 s) of atrial tachyarrhythmias or promoting frequent premature atrial complexes (≥10/min) was left to operator's discretion. Overall, 1319 (73.2%) patients had documented triggers from non-PV areas. After 17.4 ± 8.5 months of follow-up, the cumulative freedom from atrial tachyarrhythmias among patients without inducible non-PV triggers (n = 484) was 70.2%. Patients with ablation of induced non-PV triggers had a significantly higher arrhythmia control than those whose triggers were not ablated (67.9% vs. 39.4%, respectively; P < 0.001). After adjusting for clinically relevant variables, patients in whom non-PV triggers were documented but not ablated had an increased risk of arrhythmia relapse (hazard ratio: 2.39; 95% confidence interval: 2.01-2.83; P < 0.001). CONCLUSION: Pulmonary vein antrum isolation extended to the entire PW might provide acceptable long-term arrhythmia-free survival in PerAF patients without inducible non-PV triggers. In our population of PerAF patients, non-PV triggers could be elicited in ∼70% of PerAF patients and their elimination significantly improved outcomes.

Arrhythmia profile and ablation-outcome in elderly women with atrial fibrillation undergoing first catheter ablation.

BACKGROUND: This study evaluated the arrhythmia profile and ablation outcome in women with atrial fibrillation (AF) aged ≥75 years. METHODS: A total of 573 consecutive female patients undergoing first AF ablation were classified into group 1: ≥75 years (n = 221) and group 2: < 75 years (n = 352). Isolation of PVs, posterior wall and superior vena cava was performed in all. Non-PV triggers from other areas were ablated based on operator's discretion. RESULTS: Group 1 had higher prevalence of hypertension (154 (69.7%) vs. 188 (53.4%), p < .001) and non-paroxysmal AF (136 (61.5%) vs. 126 (35.8%), p < .001). Non-PV triggers were detected in 194 (87.8%) patients from group 1 and 143 (40.6%) from group 2 (p < .001) and were ablated in 152 (68.8%) and 114 (32.4%) from group 1 and 2 respectively. Remaining patients (group 1: 69/221 and group 2: 238/352) received no additional ablation. At 4 years, 109 (49.3%) and 185 (52.6%) from group 1 and 2, respectively, were arrhythmia-free, p = .69. When stratified by ablation-strategy, success-rate was similar across groups in patients receiving non-PV trigger ablation (96 (63.2%) in group 1 and 76 (66.7%) in group 2, p = .61), whereas it was significantly lower in group 1 patients not receiving additional ablation compared to those from group 2 (13 (18.8%) vs. 109 (45.8%), p < .001). CONCLUSION: Non-paroxysmal AF was more common in women aged ≥75 years. Furthermore, significantly higher number of non-PV triggers were detected in elderly women and ablation of those provided similar ablation success as that in women aged < 75 years.

Machine-learning informed macro-meteorological models for the near-maritime environment.

Macro-meteorological models predict optical turbulence as a function of weather data. Existing models often struggle to accurately predict the rapid fluctuations in Cn2 in near-maritime environments. Seven months of Cn2 field measurements were collected along an 890 m scintillometer link over the Severn River in Annapolis, Maryland. This time series was augmented with local meteorological measurements to capture bulk-atmospheric weather measurements. The prediction accuracy of existing macro-meteorological models was analyzed in a range of conditions. Next, machine-learning techniques were applied to train new macro-meteorological models using the measured Cn2 and measured environmental parameters. Finally, the Cn2 predictions generated by the existing macro-meteorological models and new machine-learning informed models were compared for four representative days from the data set. These new models, under most conditions, demonstrated a higher overall Cn2 prediction accuracy, and were better able to track optical turbulence. Further tuning and machine-learning architectural changes could further improve model performance.

The use of emerging safety biomarkers in nonclinical and clinical safety assessment - The current and future state: An IQ DruSafe industry survey.

Pharmaceutical and biotechnology companies rarely disclose their use of translational emerging safety biomarkers (ESBs) during drug development, and the impact of ESB use on the speed of drug development remains unclear. A cross-industry survey of 20 companies of varying size was conducted to understand current trends in ESB use and future use prospects. The objectives were to: (1) determine current ESB use in nonclinical and clinical drug development and impact on asset advancement; (2) identify opportunities, gaps, and challenges to greater ESB implementation; and (3) benchmark perspectives on regulatory acceptance. Although ESBs were employed in only 5-50% of studies/programs, most companies used ESBs to some extent, with larger companies demonstrating greater nonclinical use. Inclusion of ESBs in investigational new drug applications (INDs) was similar across all companies; however, differences in clinical trial usage could vary among the prevailing health authority (HA). Broader implementation of ESBs requires resource support, cross-industry partnerships, and collaboration with HAs. This includes generating sufficient foundational data, demonstrating nonclinical to clinical translatability and practical utility, and clearly written criteria by HAs to enable qualification. If achieved, ESBs will play a critical role in the development of next-generation, translationally-tailored standard laboratory tests for drug development.

Machine learning informed predictor importance measures of environmental parameters in maritime optical turbulence.

Prediction of the index of refraction structure constant Cn2 in the low-altitude maritime environment is challenging. To improve predictive models, deeper understanding of the relationships between environmental parameters and optical turbulence is required. To that end, a robust data set of Cn2 as well as numerous meteorological parameters were collected over a period of approximately 15 months along the Chesapeake Bay adjacent to the Severn River in Annapolis, Maryland. The goal was to derive new insights into the physical relationships affecting optical turbulence in the near-maritime environment. Using data-driven machine learning feature selection approaches, the relative importance of 12 distinct, measurable environmental parameters was analyzed and evaluated. Random forest nodal purity analysis was the primary machine learning approach to relative importance determination. The relative feature importance results indicated that air temperature and pressure were important parameters in predicting Cn2 in the maritime environment. In addition, the relative importance findings suggest that the air-water temperature difference, temporal hour weight, and time of year, as measured through seasonality, have strong associations with Cn2 and could be included to improve model prediction accuracy.

Association between prolonged P wave duration and left atrial scarring in patients with paroxysmal atrial fibrillation.

BACKGROUND: We evaluated the association of P wave duration (PWD) with left atrial scar (LAS) in patients with paroxysmal atrial fibrillation (PAF). METHODS: Consecutive patients with PAF undergoing their first catheter ablation were screened and only those in sinus rhythm at baseline were included in the analysis. A standard 12-lead electrocardiogram (ECG) was performed in all and three-dimensional voltage mapping of the left atrium was generated for identification of low-voltage areas (≤0.2 mV) before the procedure. RESULTS: In total, 411 patients with PAF were included in this study of which 181 had LASs (scar group), while 230 had no scar (nonscar group). In the scar group, patients were older (65.5 ± 8.8 vs 59.7 ± 11.7 years; P < .001), the proportion of female was higher (47.5% vs 37.4%; P = .04) and left atrial (LA) diameter (4.1 ± 0.6 vs 3.9 ± 0.6 cm; P < .001) was larger compared with the nonscar group. There was no significant difference in terms of hypertension, sleep apnea, and diabetes between the two groups. When comparing ECG characteristics between the two groups, PWD was significantly longer in the scar group (122.9 ± 18.5 and 116.9 ± 28.0 ms; P = .01). A multivariate analysis was performed, after adjustment of age, sex, LA diameter, PWD ≥ 120 ms was found to be an independent predictor of LA scarring (OR: 1.69, p-value: 0.02). CONCLUSION: In the current series, prolonged PWD was found to be independently associated with LA scarring in PAF, even after adjustment for age, sex, and LA diameter.

Diversity in Emergency Medicine: Are We Supporting a Career Interest in Emergency Medicine for Everyone?

STUDY OBJECTIVE: Women and students underrepresented in medicine are less likely to apply for residency in emergency medicine. The latter are from racial or ethnic populations that are underrepresented as physicians relative to the general population. The factors that result in lower application rates from women and groups underrepresented in medicine are inadequately described in the literature. This study's objective was to test whether female students and those underrepresented in medicine have lower interest in emergency medicine even after controlling for academic ability, student indebtedness, and common career values consistent with emergency medicine career interest. METHODS: Secondary data analyses were conducted on a cross section of all residency applicants from 2005 to 2010. Data sources included American Medical College Application Service, the Electronic Residency Application Service, and the Graduating Questionnaire. Data linkage was by the Association of American Medical Colleges and provided deidentified to the authors. A binary logistic regression model was fitted with the outcome variable planned career into emergency medicine versus another specialty on the Graduating Questionnaire. The binary logistic regression model independent variables included demographics, student attitudes, debt, grade point average, standardized tests, and medical school experiences. RESULTS: The binary logistic regression model included 17,067 individuals. Being a woman (odds ratio 0.75) and from a background underrepresented in medicine (odds ratio 0.68) independently correlated with lower emergency medicine interest. Age, medical debt, importance of work-life balance, confidence in specialty choice, and plan to care for underserved populations were positively associated with emergency medicine interest. Importance of specialty competitiveness and importance of mentorship advice were correlated with lower emergency medicine interest. CONCLUSION: Female medical students and those underrepresented in medicine were less likely to plan for a career in emergency medicine. This correlation remained significant even when other previously identified factors that have predicted a career in emergency medicine were controlled for.

Creation of a Flight Nurse Critical Care Ultrasound Program.

OBJECTIVE: Our objectives were 2-fold: to describe the creation of a flight nurse (FN) ultrasound (US) program and to evaluate whether critical care US performed by nonphysician providers in the prehospital setting can clarify patient assessment. METHODS: Twenty FNs completed a didactic and hands-on US curriculum focusing on critical care modalities. FNs displayed competency by successful completion of an objective-structured clinical examination. Portable US devices were used during patient transports when deemed clinically indicated by the FN. If US was subsequently performed, the FN was asked if US use prompted a change in assessment. Associations were evaluated with chi-square and bivariate logistic regression analyses. RESULTS: FNs reported US use during 102 (12.3%) patient transports, of which intensive care unit (ICU) to ICU (58.8%) constituted the majority of cases followed by emergency department (ED) to ED (28.4%), ED to ICU (4.9%), and scene to ED (2.9%). FNs agreed or strongly agreed that US use clarified the cause of patient symptoms in 67.4% of transports. CONCLUSION: FNs were more likely to perform US when they expressed lower confidence in their initial patient assessment. FNs reported that US helped to clarify patient assessments.

Impact of rotor ablation in non-paroxysmal AF patients: Findings from the per-protocol population of the OASIS trial at long-term follow-up.

The objective of this study was to evaluate the long-term efficacy of FIRM ablation with PVAI vs PVAI plus posterior wall isolation (PWI) and non-PV trigger ablation in persistent (PeAF) and long-standing persistent AF (LSPAF) patients. The procedure time was recorded to be 180.6 ±â€¯35.9 and 124.03 ±â€¯45.4 minutes in the FIRM+PVI and PVI + PWI + non-PV trigger ablation group respectively. At 24-month follow-up, 24% (95% CI 8.7%-37.8%) in the FIRM-ablation group and 48% (95% CI 27.6-63.3%) in the non-PV trigger ablation group remained arrhythmia-free off-antiarrhythmic drugs after a single procedure. Clinical Trial Registration:ClinicalTrials.gov (Identifier: NCT02533843).

Is Science the Only Driver in Species Selection? An Internal Study to Evaluate Compound Requirements in the Minipig Compared to the Dog in Preclinical Studies.

Dogs have been often chosen as a nonrodent species for preclinical development of small molecule drugs mainly due to availability and relative ease of handling. Recently, focus has increased on the minipig as a potential alternative to the dog, based on either scientific rationale or public opinion concerns. There are, however, other factors influencing nonrodent choices, in particular drug amount and synthesis time, which differ between species and therefore may impact the milestones of a drug development program. To assess the magnitude of compound need, a retrospective internal survey was conducted on drug amounts used in dog studies which were translated into the requirements for minipigs. Compound need approximately doubles if minipigs are used. Costs of compound are accordingly higher, and synthesis times are slightly increased. In our company, the differences were not considered significant enough to preclude the use of minipigs if the later preclinical program might benefit from improved human risk prediction.

Scientific and Regulatory Policy Committee: Recommended ("Best") Practices for Determining, Communicating, and Using Adverse Effect Data from Nonclinical Studies.

Recommendations (best practices) are provided by the Society of Toxicologic Pathology's Adversity Working Group for making consistent interpretations of test article-related effects as "adverse" and assigning a "no observed adverse effect level" (NOAEL) in nonclinical toxicity studies. Adverse is a term indicating "harm" to the test animal, while nonadverse indicates lack of harm. Adverse findings in the study reports should be defined in relation to effects on the test species used and within the context of the given study. Test article-related effects should be described on their own merits, and decisions to consider them as adverse or nonadverse should be justified. Related effects may be discussed together; in particular, markers of toxicity that are not in and of themselves adverse ideally should be discussed in conjunction with the causal toxicity to determine adversity. Adverse findings should be identified in subreports (clinical data, pathology data, etc.) if sufficient information is available, and/or in the final study report as individual or grouped findings, but study NOAELs should be established at the level of the overall study report. Interpretations such as "not biologically relevant" or "not toxicologically important" should be avoided unless defined and supported by scientific rationale. Decisions defining adverse findings and the NOAEL in final study reports should combine the expertise of all contributing scientific disciplines. Where possible, use of NOAELs in data tables should be linked to explanatory text that places them in context. Ideally, in nonclinical summary documents, NOAELs from multiple studies are considered together in defining the most important adverse responses in the most sensitive species. These responses are then considered along with an understanding of their likely mechanisms, as well as other information such as variability in species sensitivity, comparative pathology, reversibility and progression, kinetics, and metabolism of the test substance to help assess human risk.

Characterizing "Adversity" of Pathology Findings in Nonclinical Toxicity Studies: Results from the 4th ESTP International Expert Workshop.

The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports, to serve as a valuable prerequisite for future organ- or lesion-specific workshops planned by the ESTP.

Competency-based education: programme design and challenges to implementation.

CONTEXT: Competency-based education (CBE) has been widely cited as an educational framework for medical students and residents, and provides a framework for designing educational programmes that reflect four critical features: a focus on outcomes, an emphasis on abilities, a reduction of emphasis on time-based training, and promotion of learner centredness. Each of these features has implications and potential challenges for implementing CBE. METHODS: As an experiment in CBE programme design and implementation, the University of Michigan Master of Health Professions Education (UM-MHPE) degree programme was examined for lessons to be learned when putting CBE into practice. The UM-MHPE identifies 12 educational competencies and 20 educational entrustable professional activities (EPAs) that serve as the vehicle for both learning and assessment. The programme also defines distinct roles of faculty members as assessors, mentors and subject-matter experts focused on highly individualised learning plans adapted to each learner. CONCLUSIONS: Early experience with implementing the UM-MHPE indicates that EPAs and competencies can provide a viable alternative to traditional courses and a vehicle for rigorous assessment. A high level of individualisation is feasible but carries with it significant costs and makes intentional community building essential. Most significantly, abandoning a time-based framework is a difficult innovation to implement in a university structure that is predicated on time-based education.