Cell growth and nutrient availability control the mitotic exit signaling network in budding yeast.

Cell growth is required for cell cycle progression. The amount of growth required for cell cycle progression is reduced in poor nutrients, which leads to a reduction in cell size. In budding yeast, nutrients can influence cell size by modulating the extent of bud growth, which occurs predominantly in mitosis. However, the mechanisms are unknown. Here, we used mass spectrometry to identify proteins that modulate bud growth in response to nutrient availability. This led to the discovery that nutrients regulate numerous components of the mitotic exit network (MEN), which controls exit from mitosis. A key component of the MEN undergoes gradual multisite phosphorylation during bud growth that is dependent upon bud growth and correlated with the extent of growth. Furthermore, activation of the MEN is sufficient to override a growth requirement for mitotic exit. The data suggest a model in which the MEN ensures that mitotic exit occurs only when an appropriate amount of bud growth has occurred.

Zero-Contrast Left Atrial Appendage Occlusion Using a Hybrid Echocardiography-Fluoroscopy Technique Without Iodinated Contrast.

Contrast exposure during left atrial appendage occlusion may be harmful in those with chronic kidney disease or allergy. This single-center registry (n = 31) demonstrates the feasibility and safety of zero-contrast percutaneous left atrial appendage occlusion using echocardiography, fluoroscopy, and fusion imaging, with 100% procedural success and no device complications at 45 days.

Congenital Pulmonic Valve Dysfunction Treated With SAPIEN 3 Transcatheter Heart Valve (from the COMPASSION S3 Trial).

Significant pulmonary regurgitation (PR) and pulmonary stenosis are common after surgical repair of some congenital heart defects. This prospective, single-arm, multicenter trial enrolled patients who underwent transcatheter heart valve (THV) implantation with a SAPIEN 3 valve to treat dysfunctional right ventricular outflow tract (RVOT) conduits or pulmonic surgical valves (≥ moderate PR and/or mean RVOT gradient ≥35 mm Hg). The primary end point was a nonhierarchical composite of THV dysfunction at 1 year comprising RVOT reintervention, ≥ moderate total PR, and mean RVOT gradient >40 mm Hg. A performance goal of <25% of upper confidence interval (CI) was prespecified for the primary end point, using a 95% exact binomial CI. Patients (n = 58) were enrolled between July 5, 2016 and July 17, 2018, with mean age of 32 years. Prestenting was performed in 53.4%. At discharge, the device success was 98.1% (single valve without explant, < moderate PR, gradient <35 mm Hg). At 30 days, there were no major adjudicated adverse clinical events. At 1 year, the primary end point composite was 4.3% (95% CI 0.5 to 14.5). The composite components were 0% (0 of 56) RVOT reintervention, 2.1% (1 of 47) ≥ moderate PR, and 2.1% (1 of 48) mean RVOT gradient >40 mm Hg. No mortality, endocarditis, thrombosis, or stent fracture were reported at 1 year. In conclusion, the SAPIEN 3 THV was safe and effective in patients with dysfunctional RVOT conduits or previously implanted valves in the pulmonic position to 1 year. Clinical trial registration: NCT02744677; https://clinicaltrials.gov/ct2/show/NCT02744677.

Incidence and time course of atrial fibrillation following patent foramen ovale closure.

OBJECTIVES: Determine the true incidence and time course of atrial fibrillation (AF) after patent foramen ovale closure (PFOc) using implantable loop recorders (ILR) placed during cryptogenic stroke evaluation. BACKGROUND: Published trials report a 2%-6.6% incidence of postimplant atrial fibrillation (PIAF) after PFOc, which is probably a gross underestimation, as only patients presenting in AF were captured. Episodes of paroxysmal and silent AF would have been missed. METHODS: Of 761 patients who underwent PFOc at a single center between January 2016 and December 2020, 35 patients had an ILR implanted before PFOc, without documentation of AF, and had ≥1 month of monitoring post-PFOc. The incidence, onset, and conclusion of AF episodes were determined from a review of patient records. RESULTS: The mean duration of ILR monitoring was 54.6 ± 39.4 weeks after PFOc. AF occurred in 13/35 (37%) patients. PFOc patients who developed PIAF were older than those who did not (62 ± 11 vs. 52 ± 14 years, p = 0.03). In 12/13, the initial PIAF event occurred within 4 weeks of PFOc, with the greatest frequency around 2 weeks and conclusion by 12 weeks in all. No recurrent strokes occurred during ILR monitoring. CONCLUSION: The actual incidence of PIAF was far greater than previously reported and was significantly associated with older age at PFOc. The timing of PIAF onset and termination were consistent with a postimplant inflammatory mechanism. The higher actual PIAF incidence underscores its low stroke potential in this population. A larger prospective trial is required to validate these preliminary results.

Prognostic communication about lung cancer in the precision oncology era: A multiple-perspective qualitative study.

BACKGROUND: Although most patients with cancer prefer to know their prognosis, prognostic communication between oncologists and patients is often insufficient. Targeted therapies for lung cancer improve survival yet are not curative and produce variable responses. This study sought to describe how oncologists communicate about prognosis with patients receiving targeted therapies for lung cancer. METHODS: This qualitative study included 39 patients with advanced lung cancer with targetable mutations, 14 caregivers, and 10 oncologists. Semistructured interviews with patients and caregivers and focus groups or interviews with oncologists were conducted to explore their experiences with prognostic communication. One oncology follow-up visit was audio-recorded per patient. A framework approach was used to analyze interview transcripts, and a content analysis of patient-oncologist dialogue was conducted. Themes were identified within each source and then integrated across sources to create a multidimensional description of prognostic communication. RESULTS: Six themes in prognostic communication were identified: Patients with targetable mutations develop a distinct identity in the lung cancer community that affects their information-seeking and self-advocacy; oncologists set high expectations for targeted therapy; the uncertain availability of new therapies complicates prognostic discussions; patients and caregivers have variable information preferences; patients raise questions about progression by asking about physical symptoms or scan results; and patients' expectations of targeted therapy influence their medical decision-making. CONCLUSIONS: Optimistic patient-oncologist communication shapes the expectations of patients receiving targeted therapy for lung cancer and affects their decision-making. Further research and clinical guidance are needed to help oncologists to communicate uncertain outcomes effectively.

An Unusual Cause of Shortness of Breath: Pulmonary Vein Stenosis After Surgical Mitral Valve Replacement.

A 79-year-old man with prior bioprosthetic mitral valve replacement presented with progressive shortness of breath and was found to have right upper pulmonary vein stenosis and paravalvular leak diagnosed with the use of multimodal imaging. The patient underwent balloon angioplasty, stenting of the pulmonary vein, and paravalvular leak closure with ultimate resolution of symptoms. (Level of Difficulty: Intermediate.).

Patient Perspectives on Serious Illness Conversations in Primary Care.

Background: The Serious Illness Care Program has been shown to improve quality and feasibility of value-based end-of-life conversations in primary care. Objectives: To elicit patients' perspectives on serious illness conversations conducted by primary care clinicians. Subjects and Methods: Telephone interviews were conducted with patients at an academic center in the United States, who had a recent serious illness conversation with their primary care clinician. Interviews were audio-recorded and qualitatively analyzed using thematic analysis. Results: A total of eleven patients were enrolled. We identified three major themes: (1) positive emotional experiences are facilitated by established patient-clinician relationships and/or clinicians' skills in navigating emotional challenges, (2) patients appreciate a personalized conversation, and (3) clinicians should orchestrate the experience of the conversation, from preparation through follow-up. Conclusion: Patients appreciate having serious illness conversations in the primary care setting. Future efforts can be focused on improving clinicians' skills in navigating emotional challenges during conversations and implementing system changes to optimize orchestration.

FEops HEARTguide Patient-Specific Computational Simulations for WATCHMAN FLX Left Atrial Appendage Closure: A Retrospective Study.

Background: Three-dimensional transesophageal echocardiography (3D-TEE) is the primary imaging tool for left atrial appendage closure planning. The utility of cardiac computed tomography angiography (CCTA) and patient-specific computational models is unknown. Objectives: The purpose of this study was to evaluate the accuracy of the FEops HEARTguide patient-specific computational modeling in predicting appropriate device size, location, and compression of the WATCHMAN FLX compared to intraprocedural 3D-TEE. Methods: Patients with both preprocedural and postprocedural CCTA and 3D-TEE imaging of the LAA who received a WATCHMAN FLX left atrial appendage closure device were studied (n = 22). The FEops HEARTguide platform used baseline CCTA imaging to generate a prediction of device size(s), device position(s), and device dimensions. Blinded (without knowledge of implanted device size/position) and unblinded (implant device size/position disclosed) simulations were evaluated. Results: In 16 (72.7%) patients, the blind simulation predicted the final implanted device size. In these patients, the 3D-TEE measurements were not significantly different and had excellent correlation (Pearson correlation coefficient (r) ≥ 0.90). No patients had peridevice leak after device implant. In the 6 patients for whom the model did not predict the implanted device size, a larger device size was ultimately implanted as per operator preference. The model measurements of the unblinded patients demonstrated excellent correlation with 3D-TEE. Conclusions: This is the first study to demonstrate that the FEops HEARTguide model accurately predicts WATCHMAN FLX device implantation characteristics. Future studies are needed to evaluate if computational modeling can improve confidence in sizing, positioning, and compression of the device without compromising technical success.

Conformal Left Atrial Appendage Seal Device for Left Atrial Appendage Closure: First Clinical Use.

OBJECTIVES: The authors report the first clinical experience with the Conformal Left Atrial Appendage Seal (CLAAS) device. BACKGROUND: The CLAAS device was designed to address the limitations of first-generation left atrial appendage closure (LAAC) devices by providing an implant that is minimally traumatic, can be deployed in a noncoaxial fashion, and does not require postprocedural oral anticoagulation. METHODS: Patients with atrial fibrillation at high stroke risk (CHA2DS2-VASc score ≥2) were recruited using standard selection criteria. The LAAC procedure was guided by transesophageal echocardiography with patients under general anesthesia. The CLAAS device is composed of a foam cup, with a Nitinol endoskeleton with an expanded polytetrafluoroethylene cover, delivered with a standard delivery system using a tether for full recapture. All patients received dual-antiplatelet therapy for 6 months, followed by aspirin alone. Transesophageal echocardiographic follow-up was scheduled for 45 days and 1 year. RESULTS: Twenty-two patients (63.7% with CHA2DS2-VASc scores ≥3, 76.2% with HAS-BLED scores ≥3) were enrolled. The device was successfully implanted in 18 patients and unsuccessfully in 4 patients. There were no serious procedural complications. On transesophageal echocardiography performed at 45 days, 1 significant leak (≥5 mm) was seen, which was due to a large posterior lobe not appreciated at the time of implantation, and 1 device-related thrombus was noted, which resolved on oral anticoagulation. There were no periprocedural strokes, major pericardial effusions, or systemic or device embolization. CONCLUSIONS: This first-in-human study demonstrates the clinical feasibility of the CLAAS device for LAAC.

Growth-dependent signals drive an increase in early G1 cyclin concentration to link cell cycle entry with cell growth.

Entry into the cell cycle occurs only when sufficient growth has occurred. In budding yeast, the cyclin Cln3 is thought to initiate cell cycle entry by inactivating a transcriptional repressor called Whi5. Growth-dependent changes in the concentrations of Cln3 or Whi5 have been proposed to link cell cycle entry to cell growth. However, there are conflicting reports regarding the behavior and roles of Cln3 and Whi5. Here, we found no evidence that changes in the concentration of Whi5 play a major role in controlling cell cycle entry. Rather, the data suggest that cell growth triggers cell cycle entry by driving an increase in the concentration of Cln3. We further found that accumulation of Cln3 is dependent upon homologs of mammalian SGK kinases that control cell growth and size. Together, the data are consistent with models in which Cln3 is a crucial link between cell growth and the cell cycle.

Preclinical Assessment of a Novel Conformable Foam-Based Left Atrial Appendage Closure Device.

BACKGROUND: Left atrial appendage (LAA) occlusion has been established as an alternative to systemic anticoagulation for stroke prevention in patients with atrial fibrillation; however, limitations of current devices have slowed adoption. We present preclinical evaluations of a novel device, the Conformal Left Atrial Appendage Seal (CLAAS). METHODS: An in vitro assessment of conformability was conducted to evaluate the two CLAAS devices (regular 27 mm and large 35 mm) and a Watchman 2.5 (27 mm). Devices were placed within silicone tubes and compressed in a vise submerged in a water bath at 37°C. Changes in device diameter and visual seal were noted. Acute (n = 1) and chronic 60-day (n = 6) canine studies with gross and histologic assessment were performed. RESULTS: Conformability bench tests demonstrated that the regular CLAAS implant was able to seal oval orifices from 20 × 30 mm to 15 × 33 mm and the large from 30 × 35 mm to 20 × 40 mm. As the CLAAS implant was compressed in the minor diameter, it increased in the major diameter, thereby filling the oval space, whereas the Watchman 2.5 showed gaps and maintained its round configuration when compressed in one direction. Seven devices were successfully implanted in the canine model with complete seal without thrombus. Histologic examination showed complete neointima covering with minimal inflammation at 60 days. CONCLUSIONS: Preclinical testing demonstrated the conformability of the CLAAS implant and its ability to seal the LAA. Clinical studies are ongoing to characterize the utility of the CLAAS implant in the treatment of patients with atrial fibrillation.

Courage, Justice, and Practical Wisdom as Key Virtues in the Era of COVID-19.

Fowers et al. (2017) recently made a general argument for virtues as the characteristics necessary for individuals to flourish, given inherent human limitations. For example, people can flourish by developing the virtue of friendship as they navigate the inherent (healthy) human dependency on others. This general argument also illuminates a pathway to flourishing during the COVID-19 pandemic, the risks of which have induced powerful fears, exacerbated injustices, and rendered life and death decisions far more common. Contexts of risk and fear call for the virtue of courage. Courage has emerged more powerfully as a central virtue among medical personnel, first responders, and essential workers. Longstanding inequalities have been highlighted during the pandemic, calling for the virtue of justice. When important personal and public health decisions must be made, the central virtue of practical wisdom comes to the fore. Wise decisions and actions incorporate the recognition of relevant moral concerns and aims, as well as responding in fitting and practical ways to the specifics of the situation. Practicing courage, justice, and practical wisdom illuminates a path to flourishing, even in a pandemic.

Experience and supportive care needs of metastatic lung cancer survivors living with uncertainty: a brief qualitative report.

PURPOSE: Molecularly targeted therapies have revolutionized non-small cell lung cancer (NSCLC) treatment. Many patients with metastatic NSCLC receiving targeted therapy may live several years with incurable cancer. We sought to describe how these metastatic cancer survivors and their caregivers experience uncertainty about the future and identify their unmet supportive care needs. METHODS: We conducted semi-structured interviews with patients with metastatic NSCLC receiving targeted therapy (n = 39) and their caregivers (n = 16). We used a framework approach to code and analyze the qualitative data. RESULTS: Metastatic lung cancer survivors described awareness of their mortality and the possibility that their cancer could progress at any time. Though some found ways to cope, many felt inadequately supported to manage their distress, especially since they were "doing fine medically." Survivors struggled with decisions about working and managing their finances given their uncertain life expectancy and sought trustworthy lung cancer information in plain language. They wished to compare experiences with other patients with their molecular subtype of NSCLC. Participants desired comprehensive cancer care that includes psychosocial support, preparation for the future, and ways to promote their own health, such as through lifestyle changes. CONCLUSIONS: Patients with metastatic NSCLC receiving targeted therapy and their caregivers experience distress related to living with uncertainty and desire more coping support, connection with peers, information, and healthy lifestyle guidance. IMPLICATIONS FOR CANCER SURVIVORS: Patients living with treatable yet incurable cancer and their caregivers are a growing population of cancer survivors. Recognition of their unmet needs may inform the development of tailored support services to help them live well with cancer.

Impact of Coronavirus Disease 2019 (COVID-19) on Patients With Congenital Heart Disease Across the Lifespan: The Experience of an Academic Congenital Heart Disease Center in New York City.

Background We sought to assess the impact and predictors of coronavirus disease 2019 (COVID-19) infection and severity in a cohort of patients with congenital heart disease (CHD) at a large CHD center in New York City. Methods and Results We performed a retrospective review of all individuals with CHD followed at Columbia University Irving Medical Center who were diagnosed with COVID-19 between March 1, 2020 and July 1, 2020. The primary end point was moderate/severe response to COVID-19 infection defined as (1) death during COVID-19 infection; or (2) need for hospitalization and/or respiratory support secondary to COVID-19 infection. Among 53 COVID-19-positive patients with CHD, 10 (19%) were <18 years of age (median age 34 years of age). Thirty-one (58%) had complex congenital anatomy including 10 (19%) with a Fontan repair. Eight (15%) had a genetic syndrome, 6 (11%) had pulmonary hypertension, and 9 (17%) were obese. Among adults, 18 (41%) were physiologic class C or D. For the entire cohort, 9 (17%) had a moderate/severe infection, including 3 deaths (6%). After correcting for multiple comparisons, the presence of a genetic syndrome (odds ratio [OR], 35.82; P=0.0002), and in adults, physiological Stage C or D (OR, 19.38; P=0.002) were significantly associated with moderate/severe infection. Conclusions At our CHD center, the number of symptomatic patients with COVID-19 was relatively low. Patients with CHD with a genetic syndrome and adults at advanced physiological stage were at highest risk for moderate/severe infection.