Citations

Abstract Accurate biomarkers for predicting COVID‐19 severity have remained an unmet need due to an incomplete understanding of virus pathogenesis and heterogeneity among patients. Cellular senescence and its pro‐inflammatory phenotype are suggested to be a consequence of SARS‐CoV‐2 infection and potentially drive infection‐dependent pathological sequelae. Senescence‐associated markers in infected individuals have been identified primarily in the lower respiratory tract, while little is known about their presence in more easily accessible bio‐specimens. Here, we measured the abundance of senescence‐associated signatures in whole blood, plasma and peripheral blood mononuclear cells (PBMCs) of COVID‐19 patients and patients without an infection. Bulk transcriptomic and targeted proteomic assays revealed that the level of senescence‐associated markers, including the senescence‐associated secretory phenotype (SASP), is predictive of SARS‐CoV‐2 infection. Single‐cell RNA‐sequencing data demonstrated that a senescence signature is particularly enriched in monocytes of COVID‐19 patients, partially correlating with disease severity. Our findings suggest that monocytes are prematurely induced to senescence by SARS‐CoV‐2 infection, might contribute to exacerbating a SASP‐like inflammatory response and can serve as markers and predictors for COVID‐19 and its sequelae.

Aortic valve stenosis (AS) is increasing in prevalence due to the aging population, and severe AS is associated with significant morbidity and mortality. Echocardiography remains the mainstay for the initial detection and diagnosis of AS, as well as for grading of severity. However, there are important subgroups of patients, for example, patients with low-flow low-gradient or paradoxical low-gradient AS, where quantification of severity of AS is challenging by echocardiography and underestimation of severity may delay appropriate management and impart a worse prognosis. Aortic valve calcium score by computed tomography has emerged as a useful clinical diagnostic test that is complimentary to echocardiography, particularly in cases where there may be conflicting data or clinical uncertainty about the degree of AS. In these situations, aortic valve calcium scoring may help re-stratify grading of severity and, therefore, further direct clinical management. This review presents the evolution of aortic valve calcium score by computed tomography, its diagnostic and prognostic value, as well as its utility in clinical care.

Abstract Background In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug–drug interactions, but also a potential cardioprotective effect of these drugs. Aim In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease. Method A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus. Outcomes Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors. Results An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug–drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non–PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non–PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed. Clinical Implications Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease. Strengths and Limitations Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting. Conclusion The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors.

Objective: We tested the feasibility and effectiveness of a percutaneous atrial transseptal extracorporeal membrane oxygenation (ECMO) cannulation strategy in a right ventricular failure (RVF) model. Methods: We performed 4 nonsurvival porcine experiments. Percutaneous transseptal access was achieved using a steerable introducer. For guidance, we used fluoroscopy, transesophageal echocardiogram (TEE), and intracardiac echocardiography (ICE). A ProtekDuo rapid deployment cannula (LivaNova, London, UK) was advanced across the septum into the left atrium by 2 to 3 cm. Pulmonary hypertension (PH) was induced by partially clamping the pulmonary artery. ECMO flow was cycled from high (2 to 3 L/min) to low (0.2 to 0.3 L/min) over 2 to 3 hours. Results: Transseptal access using TEE and fluoroscopy was successful in 1 animal and unsuccessful in 1 animal. ICE provided optimal visualization for the remaining 2 animals. Mean arterial pressure (MAP) was associated immediately and consistently with high versus low ECMO flow rate (mean difference: 29 ± 3.1 mm Hg, P = 0.004) but was not restored to baseline values. RV pressure values were dynamic. Given time to equilibrate, mean RV pressure was restored to a baseline level. Conclusions: Percutaneous right atrium to left atrium transseptal cannulation relieved PH-RVF. MAP was restored to a viable level, and mean RV pressure was restored to a baseline level. Transseptal ECMO shows promise as a cannulation strategy to bridge patients with PH-RVF to lung transplant.

Abstract Background Approximately 15%–20% of patients with ulcerative colitis (UC) will require surgery during their lifetime. Ileal pouch–anal anastomosis (IPAA) is the preferred surgical option, which typically requires access to a specialist experienced in surgery for inflammatory bowel diseases (IBD). Methods The aims of this study are the assessment of the comparative use of IPAA for UC among different racial/ethnic groups and observe trends over the past decade in the United States as well as the comparative assessment of their respective postoperative outcomes. This was an observational retrospective study using the National Inpatient Sample (NIS) 2009–2018 dataset. All patients with ICD-9/10CM codes for UC were included. The primary outcome was comparative trends in IPAA construction across races/ethnicities in the past decade, which was compared to White patients as reference. Multivariate regression analyses were used to adjust for age, gender, Charlson comorbidity index, income in patient zip code, insurance status, hospital region, location, size, and teaching status. Results The number of patients discharged from US hospitals with an associated diagnosis of UC increased between 2009 and 2018, but the number of patients undergoing an IPAA decreased during that time period. Of 1 153 363 admissions related to UC, 60 688 required surgery for UC, of whom 16 601 underwent IPAA in the study period. Of all the patients undergoing surgery for UC, 2862 (4.7%) were Black, while 44 351 were White. This analysis indicated that Black patients were less likely to undergo IPAA both in 2009 and in 2018 compared to Whites. Hispanic patients were significantly less likely to receive IPAA in 2009 but were no longer less likely to receive IPAA in 2018 when compared to Whites. Conclusions The use of IPAA among Black patients requiring surgery for UC remains less common than amongst their White counterparts. Further research is needed to determine if racial disparity is a factor in decreased access to specialized care.

PURPOSE Axillary soft tissue (AXT) involvement with tumor cells extending beyond the positive lymph node (LN+) and extracapsular extension (ECE) has been overlooked in breast pathology specimen analysis. MATERIALS AND METHODS We analyzed 2,162 LN+ patients, dividing them into four groups on the basis of axillary pathology: (1) LN+ only, (2) LN+ and ECE only, (3) LN+ and AXT without ECE, and (4) LN+ with both AXT and ECE. The primary end points were 10-year locoregional failure (LRF), the 10-year axillary failure, and 10-year distant metastasis rates. Multivariable Cox models, accounting for clinical factors, were fitted using the entire cohort, and subgroups analyses were conducted. RESULTS The median follow-up was 9.4 years. The 10-year distant metastasis incidence was 42% for LN + AXT + ECE, 23% for both LN + AXT and LN + ECE only, and 13% for LN+ only. The 10-year axillary failure rates were 4.5% for LN + AXT + ECE, 4.6% for LN + AXT, 0.8% for LN + ECE only, and 1.6% for LN+ only. The 10-year LRF rates were 14% for LN + AXT + ECE, 10% for LN + AXT, 5.7% for LN + ECE only, and 6.2% for LN+ only. Multivariable analysis revealed that AXT was significantly associated with distant metastasis (hazard ratio [HR], 1.6; P < .001), locoregional failure (HR, 2.3; P < .001), and axillary failure (HR, 3.3; P = .003). Subgroup analyses showed that regional LN radiation (RLNR) improved locoregional tumor outcomes with AXT, ECE, or both (HR, 0.5; P = .03). Delivering ≤50 Gy to the axilla in the presence of AXT/ECE increased axillary failure (HR, 3.0; P = .04). Moreover, when delivering RLNR, axillary LN dissection could be de-escalated to sentinel node biopsy even in the presence of features such as AXT or ECE without significantly increasing any failure outcome: (HR, 1.0; P = .92) for LRF, (HR, 1.1; P = .94) axillary failure, and (HR, 0.4; P = .01) distant metastasis. CONCLUSION Routine reporting of axillary tissue involvement, beyond LNs and ECE, is crucial in predicting breast cancer outcomes. Ruling out the presence of AXT is imperative before any form of axillary de-escalation, especially RLNR omission.

Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8 + T cells. We have termed the rebound of cytotoxic CD8 + T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1 + CD8 + T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8 + T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency.

AbstractIntroduction/AimsUltrasound shear wave elastography (SWE) of the thenar muscles has the potential to provide a simple and noninvasive assessment of the severity of carpal tunnel syndrome (CTS), but its reliability is unknown. The purpose of this study was to assess the intra‐ and inter‐rater reliability of SWE measurements of the elastic modulus of individual thenar muscles, to assess their suitability for clinical application.MethodsFourteen healthy volunteers, seven male and seven female, participated in this study. The elastic modulus of the thenar muscles was measured with SWE, with two independent examiners to assess inter‐rater reliability. The first examiner also performed a second measurement after an interval of least 1 day to assess intra‐rater reliability. Reliability was evaluated using an intraclass correlation coefficient (ICC) and 95% confidence interval (CI).ResultsFor the abductor pollicis brevis (APB) and opponens pollicis (OPP), the CI of ICC in intra‐rater reliability was 0.47–0.85 and 0.56–0.88, respectively. The CI of ICC in inter‐rater reliability was 0.27–0.78 for the APB and 0.22–0.76 for the OPP. The ICCs of intra‐ and/or inter‐rater reliability of other thenar muscles were less than 0.5.DiscussionIn this study, SWE evaluations of thenar muscles were quite variable in terms of their reliability. A larger study will be needed to determine the source of this variability, improve reliability, and assess the value of SWE in the evaluation of the severity of CTS.