Bias in team decision-making for advanced heart failure therapies: model application.

Bias in advanced heart failure therapy allocation results in inequitable outcomes for minoritized populations. The purpose of this study was to examine how bias is introduced during group decision-making with an interprofessional team using Breathett's Model of Heart Failure Decision-Making. This was a secondary qualitative descriptive analysis from a study focused on bias in advanced heart failure therapy allocation. Team meetings were recorded and transcribed from four heart failure centers. Breathett's Model was applied both deductively and inductively to transcripts (n = 12). Bias was identified during discussions about patient characteristics, clinical fragility, and prior clinical decision-making. Some patients were labeled as "good citizens" or as adherent/non-adherent while others benefited from strong advocacy from interprofessional team members. Social determinants of health also impacted therapy allocation. Interprofessional collaboration with advanced heart failure therapy allocation may be enhanced with the inclusion of patient advocates and limit of clinical decision-making using subjective data.

A retrospective analysis of anticoagulant safety among heart transplant recipients undergoing endomyocardial biopsy.

BACKGROUND: Transvenous endomyocardial biopsy is an invasive procedure which is used to diagnose rejection following an orthotopic heart transplant. Endomyocardial biopsy is widely regarded as low risk with all-cause complication rates below 5% in most safety studies. Following transplant, some patients require therapeutic anticoagulation. It is unknown whether anticoagulation increases endomyocardial biopsy bleeding risk. METHODS: Records from 2061 endomyocardial biopsies performed for post-transplant rejection surveillance at our institution between November 2016 and August 2022 were reviewed. Bleeding complications were defined as vascular access-related hematoma or bleeding, procedure-related red blood cell transfusion, and new pericardial effusion. Relative risk and small sample-adjusted 95% confidence interval was calculated to investigate the association between bleeding complications and anticoagulation. RESULTS AND CONCLUSIONS: The overall risk of bleeding was 1.2% (25/2061 cases). There was a statistically significant increase in bleeding among patients on intravenous (RR 4.46, CI 1.09-18.32) but not oral anticoagulants (RR .62, CI .15-2.63) compared to patients without anticoagulant exposure. There was a trend toward increased bleeding among patients taking warfarin with INR ≥ 1.8 (RR 3.74, CI .90-15.43). Importantly, no bleeding events occurred in patients taking direct oral anticoagulants such as apixaban. Based on these results, intravenous rather than oral anticoagulation was associated with a significantly higher risk of bleeding complications following endomyocardial biopsy.

A novel approach for assessing bias during team-based clinical decision-making.

Many clinical processes include multidisciplinary group decision-making, yet few methods exist to evaluate the presence of implicit bias during this collective process. Implicit bias negatively impacts the equitable delivery of evidence-based interventions and ultimately patient outcomes. Since implicit bias can be difficult to assess, novel approaches are required to detect and analyze this elusive phenomenon. In this paper, we describe how the de Groot Critically Reflective Diagnoses Protocol (DCRDP) can be used as a data analysis tool to evaluate group dynamics as an essential foundation for exploring how interactions can bias collective clinical decision-making. The DCRDP includes 6 distinct criteria: challenging groupthink, critical opinion sharing, research utilization, openness to mistakes, asking and giving feedback, and experimentation. Based on the strength and frequency of codes in the form of exemplar quotes, each criterion was given a numerical score of 1-4 with 1 representing teams that are interactive, reflective, higher functioning, and more equitable. When applied as a coding scheme to transcripts of recorded decision-making meetings, the DCRDP was revealed as a practical tool for examining group decision-making bias. It can be adapted to a variety of clinical, educational, and other professional settings as an impetus for recognizing the presence of team-based bias, engaging in reflexivity, informing the design and testing of implementation strategies, and monitoring long-term outcomes to promote more equitable decision-making processes in healthcare.

Group Dynamics and Allocation of Advanced Heart Failure Therapies-Heart Transplants and Ventricular Assist Devices-By Gender, Racial, and Ethnic Group.

Background US regulatory framework for advanced heart failure therapies (AHFT), ventricular assist devices, and heart transplants, delegate eligibility decisions to multidisciplinary groups at the center level. The subjective nature of decision-making is at risk for racial, ethnic, and gender bias. We sought to determine how group dynamics impact allocation decision-making by patient gender, racial, and ethnic group. Methods and Results We performed a mixed-methods study among 4 AHFT centers. For ≈ 1 month, AHFT meetings were audio recorded. Meeting transcripts were evaluated for group function scores using de Groot Critically Reflective Diagnoses protocol (metrics: challenging groupthink, critical opinion sharing, openness to mistakes, asking/giving feedback, and experimentation; scoring: 1 to 4 [high to low quality]). The relationship between summed group function scores and AHFT allocation was assessed via hierarchical logistic regression with patients nested within meetings nested within centers, and interaction effects of group function score with gender and race, adjusting for patient age and comorbidities. Among 87 patients (24% women, 66% White race) evaluated for AHFT, 57% of women, 38% of men, 44% of White race, and 40% of patients of color were allocated to AHFT. The interaction between group function score and allocation by patient gender was statistically significant (P=0.035); as group function scores improved, the probability of AHFT allocation increased for women and decreased for men, a pattern that was similar irrespective of racial and ethnic groups. Conclusions Women evaluated for AHFT were more likely to receive AHFT when group decision-making processes were of higher quality. Further investigation is needed to promote routine high-quality group decision-making and reduce known disparities in AHFT allocation.

Impact of Temporary Preoperative Mechanical Support on Heart Transplant Outcomes.

We sought to assess the impact of temporary preoperative mechanical circulatory support (TPMCS) on heart transplantation outcomes. A total of 4,060 adult heart transplants from June 1, 2006, to December 31, 2019, were identified in the Scientific Registry of Transplant Recipients database as having TPMCS. Recipients were divided into groups based on their type of TPMCS: intra-aortic balloon pump (IABP), temporary ventricular assist device (VAD), biventricular assist device (BIVAD), and extracorporeal membrane oxygenation (ECMO). Perioperative outcomes and survival were compared among groups. Recipients with IABP were associated with older age, a smoking history, and a significantly shorter wait list time ( p < 0.01). Recipients with ECMO had a significantly increased in-hospital mortality as well as an increased incidence of dialysis ( p < 0.01). Kaplan-Meier analysis revealed worse 1 and 5 year survival for recipients with ECMO. Cox model demonstrated a significantly increased risk of mortality with BIVAD (hazard ratio [HR], 1.33; 95% CI, 1.12-1.57; p < 0.01) and ECMO (HR, 1.64; 95% CI, 1.33-2.03; p < 0.01). While patients with IABP have a survival comparable to patients without TPMCS or durable left VAD, outcomes for BIVADs and ECMO are not as favorable. Transplantation centers must continue to make careful choices about the type of TPMCS utilized before heart transplant.

Allocation changes in heart transplantation: What has really changed?

OBJECTIVE: In 2018, the heart allocation system changed status classifications and broadened geographic distribution. We examined this change at a national level based on the immediate pre- and postchange periods. METHODS: Using the Scientific Registry of Transplant Recipients database, we identified all adult primary, isolated heart transplants from October 18, 2017, to October 17, 2019. Two time periods were compared: (1) October 18, 2017, to October 17, 2018 (pre); and (2) October 18, 2018, to October 17, 2019 (post). Comparisons were made between groups, and a multivariable logistic regression model was created to identify factors associated with pretransplant temporary mechanical circulatory support. Volume analysis at the regional, state, and center level was also conducted as the primary focus. RESULTS: A total of 5381 independent heart transplants were identified within the time frame. On unadjusted analysis, there was a significant increase in temporary mechanical circulatory support (pre, 11.1%; post, 36.2%, P < .01) and decrease in waitlist days (pre, 93 days; post, 41 days; P < .01). Distance traveled (nautical miles) (pre, 83; post, 225; P < .01) and ischemic time (hours) (pre, 3.0; post, 3.4; P < .01) were significantly increased. On multivariable analysis, the postallocation time period was independently associated with temporary MCS (odds ratio, 4.463; 95% confidence interval, 3.844-5.183; P < .001). Transplant volumes did not significantly change after the allocation change at a regional, state, and center level. CONCLUSIONS: Since the planned alteration to the allocation system, there have been changes in the use of temporary mechanical circulatory support as well as distance and ischemic time associated with transplant, but no significant volume changes were observed. Continued observation of outcomes and volume under the new allocation system will be necessary in the upcoming years.

Interfacing Machine Learning and Microbial Omics: A Promising Means to Address Environmental Challenges.

Microbial communities are ubiquitous and carry an exceptionally broad metabolic capability. Upon environmental perturbation, microbes are also amongst the first natural responsive elements with perturbation-specific cues and markers. These communities are thereby uniquely positioned to inform on the status of environmental conditions. The advent of microbial omics has led to an unprecedented volume of complex microbiological data sets. Importantly, these data sets are rich in biological information with potential for predictive environmental classification and forecasting. However, the patterns in this information are often hidden amongst the inherent complexity of the data. There has been a continued rise in the development and adoption of machine learning (ML) and deep learning architectures for solving research challenges of this sort. Indeed, the interface between molecular microbial ecology and artificial intelligence (AI) appears to show considerable potential for significantly advancing environmental monitoring and management practices through their application. Here, we provide a primer for ML, highlight the notion of retaining biological sample information for supervised ML, discuss workflow considerations, and review the state of the art of the exciting, yet nascent, interdisciplinary field of ML-driven microbial ecology. Current limitations in this sphere of research are also addressed to frame a forward-looking perspective toward the realization of what we anticipate will become a pivotal toolkit for addressing environmental monitoring and management challenges in the years ahead.

Safety of direct oral anticoagulants in solid organ transplant recipients: A meta-analysis.

There is limited evidence comparing direct oral anticoagulants (DOACs) and warfarin in solid organ transplant (SOT) recipients. We performed a pooled analysis to study the safety and efficacy of DOACs in this patient population. We searched PubMed, Embase, and Scopus databases using the search terms "heart transplant" or "lung transplant" or "liver transplant" or "kidney transplant" or "pancreas transplant" and "direct oral anticoagulant" for literature search. Random effects model with Mantel-Haenszel method was used to pool the outcomes. Pooled analysis included 489 patients, of which 259 patients received DOACs and 230 patients received warfarin. When compared to warfarin, the use of DOACs was associated with decreased risk of composite bleed (RR .49, 95% CI .32-.76, p = .002). There were no differences in rates of major bleeding (RR .55, 95% CI .20-1.49, p = .24) or venous thromboembolism (RR .65, 95% CI .25-1.70, p = .38) between the two groups. Evidence from pooled analysis suggests that DOACs are comparable to warfarin in terms of safety in SOT recipients. Further research is warranted to conclusively determine whether DOACs are safe alternatives to warfarin for anticoagulation in SOT recipients.

Transcatheter Mitral Valve Repair in Patients with Heart Failure: A Meta-Analysis.

BACKGROUND: Severe secondary mitral regurgitation (MR) is associated with poor prognosis in heart failure patients with left ventricular systolic dysfunction. Few observational and randomized controlled studies demonstrated the efficacy of transcatheter mitral valve repair in heart failure patients with significant MR. A meta-analysis of published studies was performed to evaluate the role of transcatheter mitral valve repair using the MitraClip device in heart failure patients with significant secondary MR. METHODS: A literature search was performed using PubMed, Cochran CENTRAL, and Embase databases using the search terms "percutaneous mitral valve repair" or "transcatheter mitral valve repair" and "heart failure." Studies that compared medical therapy plus transcatheter mitral valve repair using MitraClip to medical therapy alone in heart failure patients with significant secondary MR were included for pooled analysis. A random-effects model with the Mantel-Haenszel method was used to analyze the data. RESULTS: Four studies, 2 randomized controlled and 2 nonrandomized studies met the criteria for analysis. Pooled analysis included a total of 1,421 patients, of which 746 patients underwent transcatheter mitral valve repair and 675 patients received medical therapy alone. When compared to medical therapy, transcatheter mitral valve repair significantly decreased all-cause mortality (OR 0.58, 95% CI 0.37-0.91; p = 0.02). A trend toward significant reduction in rehospitalizations (OR 0.35, 95% CI 0.12-1.00; p = 0.05) was also observed. Periprocedural complications ranged from 7.5 to 12.6%. CONCLUSION: Evidence from pooled analysis suggests that transcatheter mitral valve repair using MitraClip on top of medical therapy, in appropriately selected symptomatic heart failure patients with significant secondary MR, provides survival benefit and may decrease hospitalizations when compared with guideline-directed medical therapy alone.

Management of COVID-19 in a durable left ventricular assist device recipient: A continuity of care perspective.

COVID-19 is impacting the cardiovascular community both here in the United States and globally. The rapidly emerging cardiac complications have heightened implications for those with underlying cardiovascular disease. We describe an early case of COVID-19 in a left ventricular assist device recipient in the United States. We discuss our clinical management during the initial admission, outpatient management, and a unique complication of this disease over a 40-day disease course.

Continuous-Flow Left Ventricular Assist Devices and the Aortic Valve: Interactions, Issues, and Surgical Therapy.

PURPOSE OF REVIEW: Concomitant valve disease is common in patients undergoing continuous-flow left ventricular assist device (CF-LVAD) implantation. In this review, we characterize the epidemiology and management of aortic valve disease following CF-LVAD. RECENT FINDINGS: Studies suggest that 20-40% of patients have mild or greater aortic insufficiency (AI) at baseline and that AI progresses following CF-LVAD implantation. AI, either pre-existing or de novo, can have deleterious effects on LVAD efficacy and clinical outcomes. Surgical methods to correct AI in patients supported with CF-LVAD include central oversewing of the aortic valve, complete closure of the aortic valve, patch closure of the ventriculo-aortic junction, or aortic valve replacement with a bioprosthesis. Transcatheter options have recently emerged as feasible modalities to address AI. CF-LVADs contribute to the progression of aortic insufficiency (AI) and its development de novo. Prompt recognition, assessment, and treatment are important. Aortic valve repairs and replacements, now including TAVR, are the primary surgical methods to correct AI.

The epitranscriptome landscape of small noncoding RNAs in stem cells.

Stem cells (SCs) are unique cells that have an inherent ability to self-renew or differentiate. Both fate decisions are strongly regulated at the molecular level via intricate signaling pathways. The regulation of signaling networks promoting self-renewal or differentiation was thought to be largely governed by the action of transcription factors. However, small noncoding RNAs (ncRNAs), such as vault RNAs, and their post-transcriptional modifications (the epitranscriptome) have emerged as additional regulatory layers with essential roles in SC fate decisions. RNA post-transcriptional modifications often modulate RNA stability, splicing, processing, recognition, and translation. Furthermore, modifications on small ncRNAs allow for dual regulation of RNA activity, at both the level of biogenesis and RNA-mediated actions. RNA post-transcriptional modifications act through structural alterations and specialized RNA-binding proteins (RBPs) called writers, readers, and erasers. It is through SC-context RBPs that the epitranscriptome coordinates specific functional roles. Small ncRNA post-transcriptional modifications are today exploited by different mechanisms to facilitate SC translational studies. One mechanism readily being studied is identifying how SC-specific RBPs of small ncRNAs regulate fate decisions. Another common practice of using the epitranscriptome for regenerative applications is using naturally occurring post-transcriptional modifications on synthetic RNA to generate induced pluripotent SCs. Here, we review exciting insights into how small ncRNA post-transcriptional modifications control SC fate decisions in development and disease. We hope, by illustrating how essential the epitranscriptome and their associated proteome are in SCs, they would be considered as novel tools to propagate SCs for regenerative medicine.

Electrostatically coupled SiO2 nanoparticles/poly (L-DOPA) antifouling coating on a nanofiltration membrane.

In this work, the fouling resistance of TFC (thin film composite) nanofiltration membranes have been enhanced using an electrostatically coupled SiO2 (silica dioxide) nanoparticles/poly(L-DOPA) (3-(3,4-dihydroxyphenyl)-l-alanine) antifouling coating. SiO2 nanoparticles were synthesized in different size ranges and combined with L-DOPA; and then coated as an anti-fouling layer on the membrane surface by recirculated deposition. Membranes were coated with S-NP (silica nanoparticles) in small (19.8 nm), medium (31.6 nm) and large (110.1 nm) sizes. The zwitterionic compound L-DOPA in the form of self-polymerized poly(L-DOPA) (PDOPA) helped with the attachment of the S-NP to the membrane surface. It was confirmed by AFM (atomic force microscopy) measurement that coating of membranes led to an increase in hydrophilicity and reduction in surface roughness, which in turn led to a 60% reduction in the adhesion force of the foulant on the membrane as compared to the neat membrane. The modified membranes experienced almost no flux decline during the filtration experimental period, whereas the unmodified membrane showed a sharp flux decline. The best coating conditions of silica nanoparticles resulting in enhanced anti-fouling properties were identified. The biofouling film formation on the membranes was evaluated quantitatively using the flow cytometry method. The results indicated that the modified membranes had 50% lower microbial population growth in terms of total event count compared to the neat membrane. Overall, the experimental results have confirmed that the coating of electrostatically coupled SiO2 nanoparticles and PDOPA (S-NP/PDOPA) on TFC-NF (nanofiltration) membrane surfaces is effective in improving the fouling resistance of the membranes. This result has positive implications for reducing membrane fouling in desalination and industrial wastewater treatment applications.

Heart Transplantation in Women.

Over the past 5 decades, heart transplantation has become an established therapy with greater quality of life and survival than expected from end-stage heart failure. Nonetheless, challenges still exist, especially for women undergoing heart transplantation. Women have greater post-transplant survival than their male counterparts but worse quality of life. Pregnancy may occur, especially because more women are reaching child-bearing age after transplantation. Successful outcomes have been reported but require a systematic multidisciplinary approach. Women are more likely to be sensitized, with preformed anti-human leukocyte antigens antibodies related to prior pregnancies, posing challenges for their pretransplant and post-transplant management.

Impact of Change in Body Mass Index on Outcomes After Left Ventricular Assist Device Implantation in Obese Patients.

Obesity could be a risk factor portending a poor prognosis after left ventricular assist device (LVAD) implantation. We sought to determine the impact of change in body mass index (BMI) on outcomes in obese patients supported by LVAD. Fifty-nine patients, who received LVAD between January 2010 and June 2015, with BMI ≥30 kg/m at the time of LVAD implantation, were retrospectively analyzed. Patients were divided into two groups based upon whether BMI after 6 months of device support decreased when compared with before. Thirty-eight patients who experienced decrease in BMI (group D) were compared with 21 patients whose BMI increased (group I). Baseline characteristics were similar between the groups except for body weight and BMI, which were significantly higher in group D (BMI: 35.9 ± 4.0 kg/m vs. 33.4 ± 3.5 kg/m; p = 0.018). During mean follow-up of 560 ± 178 days, group I had significantly higher incidence of infection [events per patient-years (eppy): nondevice related: 0.18 vs. 0.35, p = 0.01; device related: 0.1 vs. 0.32, p < 0.01; sepsis: 0.1 vs. 0.32, p < 0.01], heart failure (eppy: 0.1 vs. 0.25, p < 0.01), and renal failure (eppy: 0.03 vs. 0.14, p < 0.01). Survival at 2 years was significantly lower in group I (84.8% vs. 57.1%, p = 0.025). Increase in BMI in obese patients on LVAD is associated with worse survival with a higher incidence of infection, heart failure, and renal failure. Weight control may be a modifiable factor to improve prognosis.

Identification and Management of Cranial Anomalies in Perinatology.

Neonatal skull and head shape anomalies are rare. The most common cranial malformations encountered include craniosynostosis, deformational plagiocephaly, cutis aplasia, and encephalocele. Improved prenatal imaging can diagnose morphologic changes as early as the second trimester. Prenatal identification also provides perinatologists and neonatologists with valuable information that helps to optimize care during and after delivery. Cranial anomalies require a multidisciplinary team approach and occasionally a lifetime of care. Today, care begins with the perinatologist as many cranial anomalies can be identified in utero with recent advances in prenatal testing.

Pilot Randomized Controlled Trial to Reduce Readmission for Heart Failure Using Novel Tablet and Nurse Practitioner Education.

BACKGROUND: Heart failure education programs are not standardized. The best form of education is unclear. We evaluated whether addition of a novel tablet application to nurse practitioner (NP) education was superior to NP education alone in reducing 30-day readmission after heart failure hospitalization. METHODS: From February 2015-March 2016, patients admitted to a quaternary academic center with primary diagnosis of heart failure were randomized to 1) treatment - NP education plus tablet application (interactive conditional logic program that flags patient questions to medical staff), or 2) control - NP education. The primary outcome was reduction in 30-day readmission rate. Secondary outcomes included satisfaction and education assessed via survey. RESULTS: Randomization included 60 patients to treatment and 66 to control. A total of 13 patients withdrew prior to intervention (treatment n = 4, control n = 1) or were lost to follow-up (treatment n = 3, control n = 5). The 30-day readmission rate trended lower for treatment compared with control, but results were not statistically significant (13.2% [7/53], 26.7% [16/60], respectively, P = .08). Similarly, satisfaction trended higher with treatment than control (P = .08). Treatment patients rated explanations from their physicians higher than control (Always: 83.7%, 55.8%, respectively, P = .01). CONCLUSIONS: NP education plus tablet use was not associated with significantly lower 30-day readmission rates in comparison with NP alone, but a positive trend was seen. Patient satisfaction trended higher and heart failure explanations were better with NP education plus tablet. A larger study is needed to determine if NP education plus tablet reduces readmission rates following heart failure admission.

Institutional Cost Comparison Between Heart Transplants and Left Ventricular Assist Device Implantations.

OBJECTIVES: Increased numbers of end-stage heart failure patients and improved technology have led to increased use of left ventricular assist devices as a viable alternative to heart transplants. Given the current economic climate, we compared costs of heart transplant versus device placement. MATERIALS AND METHODS: Medical records of patients who received heart transplants or left ventricular assist devices were cross-referenced with institutional financial data. The device cohort was limited to those receiving durable (not temporary) devices. Index admission, 1-year readmission, and overall 1-year charges were compared using standard statistical methods. RESULTS: Of 184 identified patients with end-stage heart failure surgical therapy, 121 received left ventricular assist devices, 43 had heart transplants, and 20 received left ventricular assist devices as bridge to heart transplant; these latter patients were excluded from our analyses. At index admission, mean charges were $863 433 ± $398 427 for device patients and $725 877 ± $488 685 for transplant patients (P = .05). One-year mean readmission rates were similar (4.65/transplant patient and 4.53/device patient; P = .94), with corresponding 1-year survival rates of 87.8% and 78.0% (P = .04). Total readmission charges during year 1 were $169 732 ± $242 366 for device patients and $201 682 ± $297 565 for transplant patients (P = .08), with corresponding overall charges at 1 year of $1 029 732 ± $450 498 and $927 559 ± $562 404 (P = .49). CONCLUSIONS: During the first year, heart transplant and left ventricular assist device placement have similar costs. Initial index admission costs seem to favor heart transplant, with device pump costs accounting for some of the difference. From a 1-year survival perspective, heart transplant may be more effective; however, with lack of suitable donors, left ventricular assist devices are valuable in the armamentarium of advanced heart failure surgical options.

Successful heart transplantation using a donor heart afflicted by takotsubo cardiomyopathy.

Takotsubo cardiomyopathy, also known as apical ballooning syndrome, stress cardiomyopathy, or broken heart syndrome, is a disease characterized by transient ventricular dysfunction in the absence of obstructive coronary artery disease. Herein, we present a case in which a heart with mild takotsubo cardiomyopathy was utilized as the donor organ for an orthotopic heart transplant.

Role of Ccr4-Not complex in heterochromatin formation at meiotic genes and subtelomeres in fission yeast.

BACKGROUND: Heterochromatin is essential for chromosome segregation, gene silencing and genome integrity. The fission yeast Schizosaccharomyces pombe contains heterochromatin at centromeres, subtelomeres, and mating type genes, as well as at small islands of meiotic genes dispersed across the genome. This heterochromatin is generated by partially redundant mechanisms, including the production of small interfering RNAs (siRNAs) that are incorporated into the RITS protein complex (RNAi-Induced Transcriptional Silencing). The assembly of heterochromatin islands requires the function of the RNA-binding protein Mmi1, which recruits RITS to its mRNA targets and to heterochromatin islands. In addition, Mmi1 directs its targets to an exosome-dependent RNA elimination pathway. RESULTS: Ccr4-Not is a conserved multiprotein complex that regulates gene expression at multiple levels, including RNA degradation and translation. We show here that Ccr4-Not is recruited by Mmi1 to its RNA targets. Surprisingly, Ccr4 and Caf1 (the mRNA deadenylase catalytic subunits of the Ccr4-Not complex) are not necessary for the degradation or translation of Mmi1 RNA targets, but are essential for heterochromatin integrity at Mmi1-dependent islands and, independently of Mmi1, at subtelomeric regions. Both roles require the deadenylase activity of Ccr4 and the Mot2/Not4 protein, a ubiquitin ligase that is also part of the complex. Genetic evidence shows that Ccr4-mediated silencing is essential for normal cell growth, indicating that this novel regulation is physiologically relevant. Moreover, Ccr4 interacts with components of the RITS complex in a Mmi1-independent manner. CONCLUSIONS: Taken together, our results demonstrate that the Ccr4-Not complex is required for heterochromatin integrity in both Mmi1-dependent and Mmi1-independent pathways.