Citations

Accurate prediction of progression in subjects at risk of Alzheimer's disease is crucial for enrolling the right subjects in clinical trials. However, a prospective comparison of state-of-the-art algorithms for predicting disease onset and progression is currently lacking. We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of a 5-year future time period, of three key outcomes: clinical diagnosis, Alzheimer's Disease Assessment Scale Cognitive Subdomain (ADAS-Cog13), and total volume of the ventricles. The methods used by challenge participants included multivariate linear regression, machine learning methods such as support vector machines and deep neural networks, as well as disease progression models. No single submission was best at predicting all three outcomes. For clinical diagnosis and ventricle volume prediction, the best algorithms strongly outperform simple baselines in predictive ability. However, for ADAS-Cog13 no single submitted prediction method was significantly better than random guesswork. Two ensemble methods based on taking the mean and median over all predictions, obtained top scores on almost all tasks. Better than average performance at diagnosis prediction was generally associated with the additional inclusion of features from cerebrospinal fluid (CSF) samples and diffusion tensor imaging (DTI). On the other hand, better performance at ventricle volume prediction was associated with inclusion of summary statistics, such as the slope or maxima/minima of patient-specific biomarkers. On a limited, cross-sectional subset of the data emulating clinical trials, performance of the best algorithms at predicting clinical diagnosis decreased only slightly (2 percentage points) compared to the full longitudinal dataset. The submission system remains open via the website https://tadpole.grand-challenge.org, while TADPOLE SHARE (https://tadpole-share.github.io/) collates code for submissions. TADPOLE's unique results suggest that current prediction algorithms provide sufficient accuracy to exploit biomarkers related to clinical diagnosis and ventricle volume, for cohort refinement in clinical trials for Alzheimer's disease. However, results call into question the usage of cognitive test scores for patient selection and as a primary endpoint in clinical trials.

The objective of this study was to examine the effect of pulling angle on time-zero mechanical properties of intact infraspinatus tendon or infraspinatus tendon repaired with the modified Mason-Allen technique in a canine model in vitro. Thirty-six canine shoulder samples were used. Twenty intact samples were randomly allocated into functional pull (135°) and anatomic pull (70°) groups (n = 10 per group). The remaining sixteen infraspinatus tendons were transected from the insertion and repaired using the modified Mason-Allen technique before being randomly allocated into functional pull or anatomic pull groups (n = 8 per group). Load to failure testing was performed on all specimens. The ultimate failure load and ultimate stress of the functional pulled intact tendons were significantly lower compared with anatomic pulled tendons (1310.2 ± 167.6 N vs. 1687.4 ± 228.2 N, p = 0.0005: 55.6 ± 8.4 MPa vs. 67.1 ± 13.3 MPa, p = 0.0334). For the tendons repaired with the modified Mason-Allen technique, no significant differences were observed in ultimate failure load, ultimate stress or stiffness between functional pull and anatomic pull groups. The variance of pulling angle had a significant influence on the biomechanical properties of the rotator cuff tendon in a canine shoulder model in vitro. Load to failure of the intact infraspinatus tendon was lower at the functional pulling position compared to the anatomic pulling position. This result indicates that uneven load distribution across tendon fibers under functional pull may predispose the tendon to tear. However, this mechanical character is not presented after rotator cuff repair using the modified Mason-Allen technique.

Objectives:Patients with Trisomy 21 (T21) commonly have gastrointestinal symptoms and diseases that prompt evaluation with esophagogastroduodenoscopy (EGD). Our objective is to characterize duodenal histological abnormalities in these patients when undergoing EGD. A secondary aim is to explore associations of histologic findings with different therapies.Methods:Patients 30 years old or younger with T21 who underwent EGD from 2000 to 2020 at 6 hospitals were included in this retrospective cohort study. Duodenal biopsies were categorized based on reported histopathology findings as normal or abnormal. Abnormal pathology reports were reviewed and categorized into villous atrophy (VA) and duodenitis without VA. The VA group was further categorized based on the presence or absence of celiac disease (CD).Results:We identified 836 patients with T21 who underwent EGD, 419 (50.1%) of whom had duodenal histologic abnormalities. At the time of the first (index) abnormal duodenal biopsy, 290 of 419 had VA and of those, 172 of 290 met CD diagnostic criteria, while 118 of 290 did not meet CD criteria (nonspecific VA). Among the patients with an abnormal biopsy, acid suppression at the time of the index biopsy was less common in patients with VA‐CD compared to patients without VA or patients with nonspecific VA (12.2% vs 45.7% vs 44.9%).Conclusions:Half of the T21 patients in this cohort had abnormal duodenal biopsies including a subgroup with nonspecific VA. In this cohort, acid suppression use was more prevalent in patients with abnormalities other than CD.

Abstract Cancer is a significant burden worldwide that adversely impacts life expectancy, quality of life, health care costs, and workforce productivity. Although currently recommended screening tests for individual cancers reduce mortality, they detect only a minority of all cancers and sacrifice specificity for high sensitivity, resulting in a high cumulative rate of false positives. Blood-based multicancer early detection tests (MCED) based on next-generation sequencing (NGS) and other technologies hold promise for broadening the number of cancer types detected in screened populations and hope for reducing cancer mortality. The promise of this new technology to improve cancer detection rates and make screening more efficient at the population level demands the development of novel trial designs that accelerate clinical adoption. Carefully designed clinical trials are needed to address these issues.

Objective To describe differences between North America and Europe in the perioperative management of patients undergoing surgical aortic valve replacement (SAVR). Methods Patients with moderate or greater aortic stenosis or regurgitation requiring SAVR were enrolled in a prospective observational cohort evaluating the safety and efficacy of a new stented bioprosthesis at 25 centres in North America (Canada and the USA) and 13 centres in Europe (Germany, the Netherlands, France, the UK, Switzerland and Italy). While all patients underwent implantation with the same bioprosthetic model, perioperative management was left to the discretion of participating centres. Perioperative care was described in detail including outcomes up to 1-year follow-up. Results Among 1118 patients, 643 (58%) were implanted in North America, and 475 (42%) were implanted in Europe. Patients in Europe were older, had a lower body mass index, less bicuspid disease and worse degree of aortic stenosis at baseline. In Europe, anticoagulant therapy at discharge was more aggressive, whereas length of stay was longer, and discharges directly to home were less common. Rehospitalisation risk was lower in Europe at 30 days (8.5% vs 15.9%) but converged at 1-year follow-up (26.5% vs 28.1%). Within continents, there were major differences between individual countries concerning perioperative management. Conclusion Contemporary perioperative management of SAVR patients varies between North America and Europe in patient selection, procedural techniques, antithrombotic regimen and discharge management. Furthermore, rehospitalisation differed largely between continents and countries. Hence, geographical setting must be considered during design and interpretation of trials on SAVR. Trial registration number NCT02088554.

AbstractBackgroundGoal directed point of care ultrasound (POCUS) is a bedside tool to assist with clinical diagnosis. We examined the impact of POCUS performed by consulting cardiologist (CC) during initial cardiology consult on clinical management and downstream testing.MethodsSixty‐nine study patients (pts) seen in a general cardiology outpatient clinic of a tertiary center by an expert imaging CC were compared to a control group of 65 pts seen by three different CCs without POCUS during the same time‐period, in whom the first standard echo (SE) was performed after the initial visit.ResultsBaseline characteristics were similar between the two groups for age, cardiac risk factors, and referral diagnoses. Echo findings on POCUS and by SE (mean delay of 17.2 days after visit) in the control group were comparable for RV size and function and for valvular heart disease. More patients with lower LVEF, higher LV filling pressures, new regional wall motion abnormalities, and increased aortic root size were present among POCUS group resulting in greater yield of echo abnormalities. There were more cardiovascular medication changes at the first visit (15.3% vs. 5.7%, p < .01), less referral for noninvasive stress testing (10% vs. 29%, p < .01), more advanced cardiac testing and subspecialty referrals (29% vs. 18% pts, p = .06), in the study compared to the control group after cardiology visit.ConclusionPOCUS at time of consultation detects more abnormal echo findings, results in more medication adjustments, less referral for noninvasive stress testing, earlier referral for advanced cardiac diagnostic imaging, and subspecialty cardiac referrals.

Abstract Background Carbapenemase-producing (CP) Escherichia coli (CP-Ec) are a global public health threat. We aimed to describe the clinical and molecular epidemiology and outcomes of patients from several countries with CP-Ec isolates obtained from a prospective cohort. Methods Patients with CP-Ec were enrolled from 26 hospitals in 6 countries. Clinical data were collected, and isolates underwent whole-genome sequencing. Clinical and molecular features and outcomes associated with isolates with or without metallo-β-lactamases (MBLs) were compared. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after the index culture. Results Of the 114 CP-Ec isolates in Consortium on resistance against carbapenems in Klebsiella and other Enterobacterales-2 (CRACKLE-2), 49 harbored an MBL, most commonly blaNDM-5 (38/49, 78%). Strong regional variations were noted with MBL-Ec predominantly found among patients in China (23/49). Clinically, MBL-Ec were more often from urine sources (49% vs 29%), less often met criteria for infection (39% vs 58%, P = .04), and had lower acuity of illness when compared with non–MBL-Ec. Among patients with infection, the probability of a better DOOR outcome for a randomly selected patient with MBL-Ec as compared with non–MBL-Ec was 62% (95% CI: 48.2–74.3%). Among infected patients, non–MBL-Ec had increased 30-day (26% vs 0%; P = .02) and 90-day (39% vs 0%; P = .001) mortality compared with MBL-Ec. Conclusions Emergence of CP-Ec was observed with important geographic variations. Bacterial characteristics, clinical presentations, and outcomes differed between MBL-Ec and non–MBL-Ec. Mortality was higher among non-MBL isolates, which were more frequently isolated from blood, but these findings may be confounded by regional variations.

Abstract Health-related quality of life (HRQoL) and vulnerability are variably affected in patients with myelodysplastic syndromes (MDS) and other cytopenic states; however, the heterogeneity of these diseases has limited our understanding of these domains. The National Heart, Lung, and Blood Institute-sponsored MDS Natural History Study is a prospective cohort enrolling patients undergoing workup for suspected MDS in the setting of cytopenias. Untreated patients undergo bone marrow assessment with central histopathology review for assignment as MDS, MDS/myeloproliferative neoplasm (MPN), idiopathic cytopenia of undetermined significance (ICUS), acute myeloid leukemia (AML) with &lt;30% blasts, or “At-Risk.” HRQoL data are collected at enrollment, including the MDS-specific Quality of Life in Myelodysplasia Scale (QUALMS). Vulnerability is assessed with the Vulnerable Elders Survey. Baseline HRQoL scores from 449 patients with MDS, MDS/MPN, AML &lt;30%, ICUS or At-Risk were similar among diagnoses. In MDS, HRQoL was worse for vulnerable participants (eg, mean Patent-Reported Outcomes Management Information Systems [PROMIS] Fatigue of 56.0 vs 49.5; P &lt; .001) and those with worse prognosis (eg, mean Euroqol-5 Dimension-5 Level [EQ-5D-5L] of 73.4, 72.7, and 64.1 for low, intermediate, and high-risk disease; P = .005). Among vulnerable MDS participants, most had difficulty with prolonged physical activity (88%), such as walking a quarter mile (74%). These data suggest that cytopenias leading to MDS evaluation are associated with similar HRQoL, regardless of eventual diagnosis, but with worse HRQoL among the vulnerable. Among those with MDS, lower-risk disease was associated with better HRQoL, but the relationship was lost among the vulnerable, showing for the first time that vulnerability trumps disease risk in affecting HRQoL. This study is registered at www.clinicaltrials.gov as NCT02775383.

AbstractIntroductionMost patients undergoing a left atrial appendage occlusion (LAAO) procedure are admitted for overnight observation. A same‐day discharge strategy offers the opportunity to improve resource utilization without compromising patient safety. We compared the patient safety outcomes and post‐discharge complications between same‐day discharge versus hospital admission (HA) (>1 day) in patients undergoing LAAO procedure.MethodsA systematic search of MEDLINE and Embase was conducted. Outcomes of interest included peri‐procedural complications, re‐admissions, discharge complications including major bleeding and vascular complications, ischemic stroke, all‐cause mortality, and peri‐device leak >5 mm. Mantel–Haenszel risk ratios (RRs) with 95% CIs were calculated.ResultsA total of seven observational studies met the inclusion criteria. There was no statistically significant difference between same‐day discharge versus HA regarding readmission (RR: 0.61; 95% confidence interval [CI]: [0.29–1.31]; p = .21), ischemic stroke after discharge (RR: 1.16; 95% CI: [0.49–2.73]), peri‐device leak >5 mm (RR: 1.27; 95% CI: [0.42–3.85], and all‐cause mortality (RR: 0.60; 95% CI: [0.36–1.02]). The same‐day discharge study group had significantly lower major bleeding or vascular complications (RR: 0.71; 95% CI: [0.54–0.94]).ConclusionsThis meta‐analysis of seven observational studies showed no significant difference in patient safety outcomes and post‐discharge complications between same‐day discharge versus HA. These findings provide a solid basis to perform a randomized control trial to eliminate any potential confounders.