Citations

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.

Abstract The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post‐mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. Highlights Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance

AbstractBackgroundThe Cavernous Hemangioma Exclusively Endonasal Resection (CHEER) staging system has become the gold standard for outcomes reporting in endoscopic orbital surgery for orbital cavernous hemangiomas (OCHs). A recent systematic review demonstrated similar outcomes between OCHs and other primary benign orbital tumors (PBOTs). Therefore, we hypothesized that a simplified and more comprehensive classification system could be developed to predict surgical outcomes of other PBOTs.MethodsPatient and tumor characteristics as well as surgical outcomes from 11 international centers were recorded. All tumors were retrospectively assigned an Orbital Resection by Intranasal Technique (ORBIT) class and stratified based on surgical approach as either exclusively endoscopic or combined (endoscopic and open). Outcomes based on approach were compared using chi‐squared or Fisher's exact tests. The Cochrane‐Armitage test for trend was used to analyze outcomes by class.ResultsFindings from 110 PBOTs from 110 patients (age 49.0 ± 15.0 years, 51.9% female) were included in the analysis. Higher ORBIT class was associated with a lower likelihood of gross total resection (GTR). GTR was more likely to be achieved when an exclusively endoscopic approach was utilized (p < 0.05). Tumors resected using a combined approach tended to be larger, to present with diplopia, and to have an immediate postoperative cranial nerve palsy (p < 0.05).ConclusionEndoscopic treatment of PBOTs is an effective approach, with favorable short‐term and long‐term postoperative outcomes as well as low rate of adverse events. The ORBIT classification system is an anatomic‐based framework that effectively facilitates high‐quality outcomes reporting for all PBOTs.

Abstract Purpose: The determinants of response or resistance to radioiodine (RAI) are unknown. We aimed to identify genomic and transcriptomic factors associated with structural responses to RAI treatment of metastatic thyroid cancer, which occur infrequently, and to test whether high MAPK pathway output was associated with RAI refractoriness. Experimental Design: Exceptional response to RAI was defined as reduction of tumor volume based on RECIST v1.1. We performed a retrospective case–control study of genomic and transcriptomic characteristics of exceptional responders (ER; n = 8) versus nonresponders (NR; n = 16) matched by histologic type and stage at presentation on a 1:2 ratio. Results: ER are enriched for mutations that activate MAPK through RAF dimerization (RAS, class 2 BRAF, RTK fusions), whereas NR are associated with BRAFV600E, which signals as a monomer and is unresponsive to negative feedback. ER have a lower MAPK transcriptional output and a higher thyroid differentiation score (TDS) than NR (P &lt; 0.05). NR are enriched for 1q-gain (P &lt; 0.05) and mutations of genes regulating mRNA splicing and the PI3K pathway. BRAFV600E tumors with 1q-gain have a lower TDS than BRAFV600E/1q-quiet tumors and transcriptomic signatures associated with metastatic propensity. Conclusions: ER tumors have a lower MAPK output and higher TDS than NR, whereas NR have a high frequency of BRAFV600E and 1q-gain. Molecular profiling of thyroid cancers and further functional validation of the key findings discriminating ER from NR may help predict response to RAI therapy.

Background: Many health care organizations offer pediatric infusions in outpatient infusion centers or, as in our organization, in a hospital-based outpatient Pediatric Infusion Therapy Center (PITC). When restrictions related to the COVID-19 pandemic decreased our PITC appointment capacity by 40%, other patient and family satisfaction issues were exacerbated. We implemented a new approach to pediatric infusions with the aim of improving patient and family satisfaction and reducing the amount of time in an appointment itinerary without negatively affecting patient safety. Methods: Our team used a phased approach to pilot the administration of short chemotherapy infusions in the same outpatient clinic examination rooms where consultation and routine office visits were conducted. Patients saw their specialist for an examination and, if clinically indicated, their infusion was administered in the same room. Appointment itineraries were then completed. The team tracked efficiency, satisfaction, and safety metrics related to the new process. Results: All efficiency metrics improved. No harm came to the 49 unique patients who received a total of 184 infusions. Patient appointment itineraries were shortened by an average of 1.03 hr. Satisfaction survey responses indicated a clear preference (93%) for the new process. Discussion: The novel approach of offering short infusions in outpatient clinic examination rooms provides an opportunity to ease capacity constraints and further increase patient and family satisfaction. This method may be especially helpful for health care organizations when external influences (e.g., lack of physical space, challenging patient volumes, and pandemics) necessitate a change.

Congenital myopathies are a vast group of genetic muscle diseases. Among the causes are mutations in the MYH2 gene resulting in truncated type IIa myosin heavy chains (MyHCs). The precise cellular and molecular mechanisms by which these mutations induce skeletal muscle symptoms remain obscure. Hence, in the present study, we aimed to explore whether such genetic defects would alter the presence as well as the post-translational modifications of MyHCs and the functionality of myosin molecules. For this, we dissected muscle fibers from four myopathic patients with MYH2 truncating mutations and from five human healthy controls. We then assessed 1) MyHCs presence/post-translational modifications using LC/MS; 2) relaxed myosin conformation and concomitant ATP consumption with a loaded Mant-ATP chase setup; 3) myosin activation with an unloaded in vitro motility assay; and 4) cellular force production with a myofiber mechanical setup. Interestingly, the type IIa MyHC with one additional acetylated lysine (Lys35-Ac) was present in the patients. This was accompanied by 1) a higher ATP demand of myosin heads in the disordered-relaxed conformation; 2) faster actomyosin kinetics; and 3) reduced muscle fiber force. Overall, our findings indicate that MYH2 truncating mutations impact myosin presence/functionality in human adult mature myofibers by disrupting the ATPase activity and actomyosin complex. These are likely important molecular pathological disturbances leading to the myopathic phenotype in patients.

Background: The aim of this study is to compare clinical and radiographic outcomes of open reduction and internal fixation versus closed reduction and percutaneous pinning of metacarpal fractures in relation to anatomic and surgical variables. Methods: Electronic medical records at two institutions were reviewed for patients who underwent surgical intervention for metacarpal fractures. Data were collected from those who underwent reduction and internal fixation with either plates or Kirschner wires (K-wires). Inclusion criteria included minimum postoperative follow-up of 60 days and age 18 years or older. Exclusion criteria included insufficient radiographic data, previously attempted closed reduction with immobilization, pathologic fracture mechanism, history of previous trauma or surgery to the affected bone, and fixation technique other than plate or K-wire. Results: We reviewed data for patients treated over a 22-year time period. Ultimately, 81 metacarpal shaft and neck fractures in 60 patients met inclusion criteria. Among all metacarpal fractures, complications were present in 39 (48.1%) cases. There were no significant associations between complication prevalence and hardware type. Revision surgery was required in 11 (13.6%) patients; there were no significant associations between revision procedures and hardware type. Postoperatively, all patients with imaging data had radiograph follow-up to assess union status. There was no significant association between time to union and hardware type. Conclusions: Outcomes showed no significant difference between plate and pin fixation for metacarpal shaft and neck fractures. These findings suggest that surgeons may have flexibility to decide on the type of operative intervention while considering patient-specific factors, such as the need for early mobilization.

Purpose: The advent of new imaging agents offers enhanced sensitivity and specificity in the detection and staging of prostate cancer. A growing array of treatment options and ongoing advancements in imaging technologies allow earlier and more extensive detection of metastatic disease and shifting the boundaries between disease states previously defined by conventional imaging. This review seeks to synthesize existing data and expert opinion to better guide patient management in the new era of targeted precision imaging (TPI). Materials and Methods: The Radiographic Assessments for Detection of Advanced Recurrence VI Group gathered to develop pathways/recommendations regarding how TPI could best be deployed, given approvals of key radiotracers including 18F-fluciclovine, 68Ga-PSMA, and 18F-DCFPyL positron emission tomography/CT. Results: Radiographic Assessments for Detection of Advanced Recurrence VI Group members developed consensus pathways/suggestions based on the best available evidence for use of TPI in prostate cancer. Conclusions: Patients with prostate cancer have the potential to benefit from judicious use of TPI. However, additional research is needed to ensure that TPI is used appropriately and provides actionable findings that inform treatment decisions for these patients.

The variances in operating room (OR) cancellation rates between different service lines and operators within these service lines were assessed by reviewing the electronic medical record (EMR) covering 34,561 cases performed by 199 OR operators in 2018. We assumed that cancellations would differ between different service lines, but the between-operators variance was minimal within the service line. We hypothesized that most variability would be secondary to patient-specific (weekdays, time of year, and national holidays), seasonal and administrative issues. Of 4165 case cancellations, the majority (73.1%) occurred before the patient arrived at the hospital. A total of 60% of all cancellations were within gastroenterology, interventional cardiology, and orthopedics. Cancellation rate variability between surgeons operating within the same service line greatly varied between services from very homogenous to very diverse across providers. The top reasons for cancellation were: date change, canceled by a patient, or “no show”. The highest cancellation rates occurred on Mondays and Tuesdays, in January and September, and during weeks associated with national holidays. In summary, cancellation variability must be analyzed at the level of individual specialties, operators, and time variability.