Citations

Abstract Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p < 0.0001). These data demonstrate differences in hippocampal p-tau burden and regional distribution in CTE compared to PART that might be helpful in differential diagnosis and reveal insights into disease pathogenesis.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P < .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P < .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P < .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

Abstract Aims Cardiovascular disease and cancer share common pathogenesis and risk factors. Coronary microvascular dysfunction (CMD), reflecting impaired coronary microvascular dilation in response to stress, is related to a higher risk of major cardiovascular events; however, its association with cancer has not been explored. Methods and results A retrospective study on 1042 patients with non-obstructive coronary artery diseases (NOCADs) was performed. Data regarding demographic, clinical history, diagnostic coronary reactivity test, and cancer occurrence were collected. Coronary microvascular dysfunction was defined as coronary flow reserve (the ratio of hyperaemic blood flow to resting blood flow) ≤2.5. Thirty-four per cent had CMD (67.4% female and the average age was 52.4 ± 12.2 years). Of 917 patients with no history of cancer, 15.5% developed cancer during follow-up [median of 9 (4, 16) years]. Kaplan–Meier analysis showed that CMD patients had lower cancer-free survival compared with those without CMD (log-rank P = 0.005). Cox proportional hazard analyses showed that after adjusting for age, sex, hypertension, diabetes, smoking, and glomerular filtration rate, CMD is independently associated with cancer [hazard ratio, 1.4; 95% confidence interval (CI), 1.09–2.04; P = 0.04]. The rate of major adverse cardiovascular events (MACE) was significantly higher in CMD patients compared with that in non-CMD patients who had a previous history of cancer [odds ratio (OR), 2.5; 95% CI, 1–6.2; P = 0.04] and those with no history of cancer (OR, 1.4; 95% CI, 1.01–1.9; P = 0.044). Conclusion Coronary microvascular dysfunction is associated with cancer incidence in patients presenting with NOCADs. This study emphasizes follow-up in patients with CMD to evaluate the risk of MACE as well as potential malignant diseases.

Context.— Neoadjuvant systemic therapy refers to the use of systemic agent(s) for malignancy prior to surgical treatment and has recently emerged as an option for most breast cancer patients eligible for adjuvant systemic therapy. Consequently, treated breast carcinomas have become routine specimens in pathology practices. A standard protocol has not yet been universally adopted for the evaluation and reporting of these specimens. The American Joint Committee on Cancer staging system recognizes the challenges in staging breast carcinomas after neoadjuvant treatment and provides important data points but does not currently provide detailed guidance in estimating the residual tumor burden in the breast and lymph nodes. The Residual Cancer Burden system is the only Web-based system that quantifies treatment response as a continuous variable using residual tumor burden in the breast and the lymph nodes. Objective.— To provide clarifications and guidance for evaluation and reporting of postneoadjuvant breast specimens, discuss issues with the current staging and reporting systems, and provide specific suggestions for future modifications to the American Joint Committee on Cancer system and the Residual Cancer Burden calculator. Data Sources.— English-language literature on the subject and the data from the I-SPY 2, a multicenter, adaptive randomization phase 2 neoadjuvant platform trial for early-stage, high-risk breast cancer patients. Conclusions.— This article highlights challenges in the pathologic evaluation and reporting of treated breast carcinomas and provides recommendations and clarifications for pathologists and clinicians. It also provides specific recommendations for staging and discusses future directions.

AbstractPurposeThis study sought to develop and internally validate a machine learning model to identify risk factors and quantify overall risk of secondary meniscus injury in a longitudinal cohort after primary ACL reconstruction (ACLR).MethodsPatients with new ACL injury between 1990 and 2016 with minimum 2‐year follow‐up were identified. Records were extensively reviewed to extract demographic, treatment, and diagnosis of new meniscus injury following ACLR. Four candidate machine learning algorithms were evaluated to predict secondary meniscus tears. Performance was assessed through discrimination using area under the receiver operating characteristics curve (AUROC), calibration, and decision curve analysis; interpretability was enhanced utilizing global variable importance plots and partial dependence curves.ResultsA total of 1187 patients underwent ACLR; 139 (11.7%) experienced a secondary meniscus tear at a mean time of 65 months post‐op. The best performing model for predicting secondary meniscus tear was the random forest (AUROC = 0.790, 95% CI: 0.785–0.795; calibration intercept = 0.006, 95% CI: 0.005–0.007, calibration slope = 0.961 95% CI: 0.956–0.965, Brier’s score = 0.10 95% CI: 0.09–0.12), and all four machine learning algorithms outperformed traditional logistic regression. The following risk factors were identified: shorter time to return to sport (RTS), lower VAS at injury, increased time from injury to surgery, older age at injury, and proximal ACL tear.ConclusionMachine learning models outperformed traditional prediction models and identified multiple risk factors for secondary meniscus tears after ACLR. Following careful external validation, these models can be deployed to provide real‐time quantifiable risk for counseling and timely intervention to help guide patient expectations and possibly improve clinical outcomes.Level of evidenceIII.

Abstract Monoclonal B-cell lymphocytosis (MBL) is a common hematological premalignant condition that is understudied in screening cohorts. MBL can be classified into low-count (LC) and high-count (HC) types based on the size of the B-cell clone. Using the Mayo Clinic Biobank, we screened for MBL and evaluated its association with future hematologic malignancy and overall survival (OS). We had a two-stage study design including discovery and validation cohorts. We screened for MBL using an eight-color flow-cytometry assay. Medical records were abstracted for hematological cancers and death. We used Cox regression to evaluate associations and estimate hazard ratios and 95% confidence intervals (CIs), adjusting for age and sex. We identified 1712 (17%) individuals with MBL (95% LC-MBL), and the median follow-up time for OS was 34.4 months with 621 individuals who died. We did not observe an association with OS among individuals with LC-MBL (P = .78) but did among HC-MBL (hazard ratio, 1.8; 95% CI, 1.1-3.1; P = .03). Among the discovery cohort with a median of 10.0 years follow-up, 31 individuals developed hematological cancers with two-thirds being lymphoid malignancies. MBL was associated with 3.6-fold risk of hematological cancer compared to controls (95% CI, 1.7-7.7; P < .001) and 7.7-fold increased risk for lymphoid malignancies (95% CI:3.1-19.2; P < .001). LC-MBL was associated with 4.3-fold risk of lymphoid malignancies (95% CI, 1.4-12.7; P = .009); HC-MBL had a 74-fold increased risk (95% CI, 22-246; P < .001). In this large screening cohort, we observed similar survival among individuals with and without LC-MBL, yet individuals with LC-MBL have a fourfold increased risk of lymphoid malignancies. Accumulating evidence indicates that there are clinical consequences to LC-MBL, a condition that affects 8 to 10 million adults in the United States.

The precision health era is likely to reduce and respond to antimicrobial resistance (AMR). Our stewardship and precision efforts share terminology, seeking to deliver the “right drug, at the right dose, at the right time.” Already, rapid diagnostic testing, phylogenetic surveillance, and real-time outbreak response provide just a few examples of molecular advances we dub “precision stewardship.” However, the AMR causal factors range from the molecular to that of global health policy. Mirroring the cross-sectoral nature of AMR science, the research addressing the ethical, legal and social implications (ELSI) of AMR ranges across academic scholarship. As the rise of AMR is accompanied by an escalating sense of its moral and social significance, what is needed is a parallel field of study. In this paper, we offer a gap analysis of this terrain, or an agenda for “the ELSI of precision stewardship.” In the first section, we discuss the accomplishments of a multi-decade U.S. national investment in ELSI research attending to the advances in human genetics. In the next section, we provide an overview of distinct ELSI topics pertinent to AMR. The distinctiveness of an ELSI agenda for precision stewardship suggests new opportunities for collaboration to build the stewardship teams of the future.

Background: 5-aminolevulinic acid (5-ALA; GleolanTM, NX Development Corps., Lexington, USA) is approved for fluorescence-guided resections of suspected malignant gliomas. Experience has demonstrated that meningiomas also show fluorescence, which may be a useful surgical adjunct. We present an innovative design for a multi-center, prospective study to determine the clinical safety and potential benefit of fluorescence-guided resection of meningiomas with utmost bias reduction. Methods: All patients with suspected meningioma (all grades) receive GleolanTM 20 mg/kg 2–4 h prior to surgery supported by fluorescence excitation from a blue light source (Blue400, Zeiss Meditech, Oberkochen, Germany; FL400, Leica Microsystems, Heerbrugg, Switzerland). Surgeons are asked whether a residual tumor can be observed to fluoresce under blue light (BL) after the tumor is no longer recognizable using conventional illumination at the end of surgery. In addition, when faced with tissues of uncertain tissue type (so-called “indeterminate” tissue), this study records how often surgeons make a correct decision based on fluorescence and how this influences surgical strategy. The primary endpoint is the percentage of patients in whom one of these two benefits are observed. Other endpoints include the diagnostic accuracy of fluorescence compared to white light (WL) versus correlative histology. For bias reduction, pertinent data are derived from surgical videos reviewed by independent reviewers blinded to surgeons’ assessments of tissue type and fluorescence status. Data will be included from approximately 100 study participants completing the study at approximately 15 centers in the United States, Germany, and Austria. Results: As of May 2022, 88 patients have completed the study. No adverse safety signal has been detected. Conclusions: Preliminary data confirm the feasibility of our study design. Accrual is targeted for completion in the third quarter of 2022.

AbstractBackgroundImproved function is associated with reduced morbidity and mortality in patients with cancer. Cancer rehabilitation medicine (CRM) is a subspecialty of physical medicine and rehabilitation (PM&R) that focuses on improving function in patients with cancer. One of the barriers to patients accessing CRM services is the lack of referrals from oncology providers. Understanding the knowledge, attitudes and beliefs of oncology trainees regarding the importance of function and the role of CRM is essential to reducing educational gaps and improving patients' access to essential rehabilitation services.ObjectiveTo determine oncology trainees' knowledge, attitude and beliefs about the importance of function and the role of CRM in the care of patients with cancer.SettingThe study was conducted at a comprehensive cancer center in the United States.InterventionDescriptive survey study was administered to postgraduate oncology trainees who spent at least 1 day a week providing patient care.Main outcomeParticipants' report of their knowledge, attitudes, and beliefs on the importance of function and CRM in the care of patients with cancer.ResultsThe survey was sent to 197 oncology trainees with a response rate of 67% (n = 132) and 126 were ultimately included. All participants believed that function is important in the care of patients with cancer. The majority believed that better function improves treatment tolerance (94%) and survival (84%). Most reported that having CRM physicians (80%) and an inpatient rehabilitation unit (88%) in the oncological setting is important; however, most participants reported that they refer fewer than 25% of their patients to CRM services. Participants with prior exposure to PM&R were significantly more likely to consult PM&R compared to those without exposure (p = .005). Most oncology trainees (81%) believed that education in CRM should be part of their oncology training.ConclusionThis study demonstrates that oncology trainees believe that function is important. They also believe that access to CRM would improve treatment tolerance and survival, but most report that they rarely refer patients to CRM services. Most trainees desire increased exposure to CRM during oncology training.