Clinical Outcomes and Predictors of Advanced Therapy for the Management of Right Heart Thrombus.

BACKGROUND: The role of advanced therapies (systemic thrombolysis, catheter-based treatment, and surgical thrombectomy) for the management of right heart thrombus is poorly defined. In this study, we assessed the clinical predictors and outcomes of advanced therapy compared with anticoagulation alone for the acute management of right heart thrombus. METHODS: In this observational cohort study, we analyzed consecutive patients who were treated for right heart thrombus. The primary end point was 90-day all-cause mortality. Clinical predictors of utilizing advanced therapy were assessed with multivariable logistic regression. Propensity score matching was utilized to compare adjusted outcomes between patients receiving advanced therapies versus anticoagulation alone. RESULTS: A total of 345 patients were included in the study. Advanced therapy was utilized in 13.6% (N=47) of patients, of which 25.5% (N=12/47) was systemic thrombolysis, 23.4% (N=11/47) was endovascular thrombectomy, and 53.2% (N=25/47) was surgical thrombectomy. Younger age (odds ratio, 0.98 [95% CI, 0.96-0.99]) and concurrent pulmonary embolism (odds ratio, 5.36 [95% CI, 2.48-12.1]) predicted utilization of advanced therapy. In propensity score-matched analysis, there was no difference in 90-day mortality (hazard ratio, 0.46 [95% CI, 0.17-1.22]), in-hospital mortality (odds ratio, 0.64 [95% CI, 0.17-2.19]), or length of stay (ß, -4.39 [95% CI, -14.0 to 5.22]) between advanced therapy and anticoagulation. CONCLUSIONS: Among a diverse cohort of patients with right heart thrombus, outcomes did not differ between those who underwent advanced therapy and anticoagulation alone. Important predictors for utilizing advanced treatment included younger age and the presence of a concurrent pulmonary embolism. Future studies assessing advanced therapy in larger and broader patient populations are necessary.

Trends in Discharge Rates for Acute Pulmonary Embolism in U.S. Emergency Departments.

BACKGROUND: Outpatient management of select patients with low-risk acute pulmonary embolism (PE) has been proven to be safe and effective, yet recent evidence suggests that patients are still managed with hospitalization. Few studies have assessed contemporary real-world trends in discharge rates from U.S. emergency departments (EDs) for acute PE. OBJECTIVE: To evaluate whether the proportion of discharges from EDs for acute PE changed between 2012 and 2020 and which baseline characteristics are associated with ED discharge. DESIGN: Serial cross-sectional analysis. SETTING: U.S. EDs participating in the National Hospital Ambulatory Medical Care Survey. PATIENTS: Patients with ED visits for acute PE between 2012 and 2020. MEASUREMENTS: National trends in the proportion of discharges for acute PE and factors associated with ED discharge. RESULTS: Between 2012 and 2020, there were approximately 1 635 300 visits for acute PE. Overall, ED discharge rates remained constant over time, with rates of 38.2% (95% CI, 17.9% to 64.0%) between 2012 and 2014 and 33.4% (CI, 21.0% to 49.0%) between 2018 and 2020 (adjusted risk ratio, 1.01 per year [CI, 0.89 to 1.14]). No baseline characteristics, including established risk stratification scores, were predictive of an increased likelihood of ED discharge; however, patients at teaching hospitals and those with private insurance were more likely to receive oral anticoagulation at discharge. Only 35.9% (CI, 23.9% to 50.0%) of patients who were considered low-risk according to their Pulmonary Embolism Severity Index (PESI) class, 33.1% (CI, 21.6% to 47.0%) according to simplified PESI score, and 34.8% (CI, 23.3% to 48.0%) according to hemodynamic stability were discharged from the ED setting. LIMITATIONS: Cross-sectional survey design and inability to adjudicate diagnoses. CONCLUSION: In a representative nationwide sample, rates of discharge from the ED for acute PE appear to have remained constant between 2012 and 2020. Only one third of low-risk patients were discharged for outpatient management, and rates seem to have stabilized. Outpatient management of low-risk acute PE may still be largely underutilized in the United States. PRIMARY FUNDING SOURCE: None.

Endovascular Interventions for Peripheral Artery Disease: A Contemporary Review.

PURPOSE OF REVIEW: Peripheral artery disease (PAD) is an increasingly prevalent but frequently underdiagnosed condition that can be associated with high rates of morbidity and mortality. While an initial noninvasive approach is the cornerstone of management, revascularization is often pursued for patients with treatment-refractory claudication or chronic limb-threatening ischemia (CLTI). In this review, we discuss the current state of endovascular interventions for PAD and explore the many new emerging technologies. RECENT FINDINGS: The last decade has resulted in numerous advances in PAD interventions including the ongoing evolution of drug-coated devices, novel approaches to complex lesions, and contemporary evidence from large clinical trials for CLTI. Advances in endovascular management have allowed for increasingly complex lesions to be tackled percutaneously. Future directions for the field include the continued evolution in device technology, continued development of state-of-the-art techniques to revascularization of complex lesions, and increased collaboration between a largely multidisciplinary field.

Clinical Significance of Right Heart Thrombus With and Without an Associated Pulmonary Embolism.

BACKGROUND: Right heart thrombus is a rare but serious form of venous thromboembolic disease that may be associated with pulmonary embolism. The prognosis of patients with right heart thrombus presenting without a concomitant pulmonary embolism remains ill-defined. METHODS: We conducted a multi-center observational cohort study to compare patients presenting with right heart thrombus with and without a concurrent pulmonary embolism. The primary endpoint was 90-day all-cause mortality. Multivariable regression was utilized to assess primary and secondary outcomes. RESULTS: Of 231 patients with right heart thrombus, 104 (45.0%) had a pulmonary embolism at admission. The median age of the cohort was 59.4 years (interquartile range 44.9-71.3). Pulmonary embolism in the setting of a right heart thrombus was associated with an increased adjusted hazard of 90-day mortality (hazard ratio 3.68; 95% confidence interval [CI], 1.51-8.97). Additionally, these patients had a higher adjusted risk of in-hospital mortality (odds ratio [OR] 2.55; 95% CI, 1.15-5.94) and admission to the intensive care unit (OR 2.45; 95% CI, 1.23-4.94). Thrombus mobility (OR 2.99; 95% CI, 1.35-6.78) and larger thrombus sizes (OR 1.04; 95% CI, 1.00-1.07) were associated with development of concurrent pulmonary embolism. CONCLUSIONS: Patients with right heart thrombus and pulmonary embolism had a more severe clinical presentation, required more advanced therapies, and had reduced survival compared with those without a concomitant pulmonary embolism. Important variables associated with development of concomitant pulmonary embolism include thrombus mobility and size. Right heart thrombus in the setting of acute pulmonary embolism represents a unique clinical entity that is associated with worse prognosis compared with right heart thrombus only.

Structures of Cancer Antigen Mesothelin and Its Complexes with Therapeutic Antibodies.

The tumor-associated antigen mesothelin is expressed at high levels on the cell surface of many human cancers, while its expression in normal tissues is limited. The binding of mesothelin to the tumor-associated cancer antigen 125 (CA-125) can lead to heterotypic cell adhesion and tumor metastasis within the pleural and peritoneal cavities. Immunotherapeutic strategies targeting mesothelin are being intensively investigated. Here, we report the crystal structures of mesothelin that reveal a compact, right-handed solenoid consisting of 24 short helices and connecting loops. These helices form a nine-layered spiral coil that resembles ARM/HEAT family proteins. Glycan attachments have been identified in the structure for all three predicted N-glycosylation sites and confirmed with samples from cell culture and patient ascites. The structures of full-length mesothelin and its complex with the Fab of MORAb-009 reveal the interaction of the antibody with the complete epitope, which has not been reported previously. The N-terminal half of mesothelin is conformationally rigid, suitable for eliciting specific antibodies, whereas its C-terminal portion is more flexible. The structure of the C-terminal shedding-resistant fragment of mesothelin complexed with a mAb 15B6 displays an extended linear epitope and helps explain the protection afforded by the antibody for the shedding sites. Significance: The structures of full-length mesothelin and its complexes with antibodies reported here are the first to be determined experimentally, providing atomic models for structural organization of this protein and its interactions with antibodies. It offers insights into the function of mesothelin and guidance for further development of therapeutic antibodies.

Cyclin-dependent kinase 4/6 inhibitor-associated thromboembolism: a critical evaluation of the current evidence.

Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors are an essential treatment modality for hormone receptor-positive breast cancer. As the rates of breast cancer continue to rise globally and the indications for CDK 4/6 inhibitors now extend beyond metastatic disease, more patients than ever are receiving these agents. Thrombosis is an emerging clinical concern with this class of agents, particularly venous thromboembolism. Although venous thromboembolism initially emerged as an adverse effect of interest in early trials, more recent studies have demonstrated even higher incidences of thrombosis in real-world clinical practice. In this review, we summarize the evidence to date that has informed the thrombosis risk for these agents both in clinical trials and real-world studies. We review data describing the venous and arterial thromboembolic risks in clinical trials of CDK 4/6 inhibitors as well as the now rather extensive real-world evidence available, including a comparison of risk for each of the 3 agents approved for use in breast cancer: palcociclib, ribociclib, and abemaciclib. As the role of prophylactic anticoagulation continues to remain unknown in women receiving CDK 4/6 inhibitors, future efforts directed at carefully investigating the risks and benefits of thromboprophylaxis may lead to improved outcomes in these patients.

Ototoxicity Review: A Growing Number of Non-Platinum-Based Chemo- and Immunotherapies.

OBJECTIVE: To raise awareness of the growing list of non-platinum-based chemo- and immunotherapeutic agents that have been associated with ototoxicity and to introduce the possible mechanism of ototoxicity of these agents. DATA SOURCES: PubMed, Embase, and Web of Science. REVIEW METHODS: A systematic review was performed following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-analyses). PubMed, Embase, and Web of Science databases were searched for published reports of ototoxicity from non-platinum-based chemo- and immunotherapeutic agents in adult and pediatric patients. Therapies that utilized any platinum-based agent were excluded. CONCLUSIONS: Ototoxicity from non-platinum-based chemo- and immunotherapies is an evolving problem. There were 54 reports-39 case reports and 15 cohort studies-documenting ototoxicity from 7 agents/combination therapies. Of these reports, 37 (69%) were published within the last 15 years (after 2005). No recovery of hearing was documented in 21 of 56 cases (38%). Pretreatment audiograms were uncommon (19/54 studies, 35%), despite documented ototoxic associations. IMPLICATIONS FOR PRACTICE: There is a growing number of novel, ototoxic, non-platinum-based chemo- and immunotherapeutic agents with various potential mechanisms of action. Otolaryngologists will need to prioritize awareness of these agents. This growing list of agents, many of which have reversible effects, suggest a need for standardized ototoxicity monitor protocols so that appropriate and timely management options can be implemented.

Is There an Optimal Repetitive Transcranial Magnetic Stimulation Target to Treat Chronic Tinnitus?

OBJECTIVE: Chronic tinnitus is a clinical symptom that affects 10% to 15% of the adult population. Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment, but significant heterogeneity exists in the treatment outcomes and stimulation parameters. In this study, we perform a qualitative systematic review to determine if there is an optimal rTMS site to treat tinnitus. DATA SOURCES: A literature search was performed by searching the MEDLINE, Embase, Web of Science, and Cochrane databases. REVIEW METHODS: Sham-controlled studies in adults were included that contained >10 patients with tinnitus for >3 months and utilized 10 to 20 electroencephalography coordinates. Study outcomes were considered positive if the treatment arm reported a significant reduction in the primary tinnitus score relative to sham. RESULTS: There were 1211 studies screened. Nineteen studies met the inclusion criteria, and 8 unique stimulation sites were reported. Studies had 53.7 ± 46.0 patients (mean ± SD). The mean duration of follow-up was 10.3 ± 9.6 weeks. Positive outcomes regarding tinnitus suppression were reported in 5 of 5 (100%) studies stimulating the temporoparietal junction midway between T3 and P3 or between T4 and P4. Tinnitus suppression at all other sites was less frequent with a combined success rate of only 8 of 14 (57.1%). CONCLUSION: Significant heterogeneity exists in the literature in regard to the optimal transcranial magnetic stimulation target. These preliminary findings suggest that the temporoparietal junction midway between T3 and P3 or T4 and P4 is a promising nonauditory rTMS target in the setting of chronic tinnitus. Future research should elucidate the effectiveness of this site for tinnitus suppression.

Venous and arterial thrombosis associated with abemaciclib therapy for metastatic breast cancer.

BACKGROUND: The CDK4/6 inhibitor abemaciclib is a mainstay of treatment for hormone receptor-positive breast cancer. However, increased venous thromboembolism (VTE) rates in multiple clinical trials resulted in a black-box warning for this agent. Thrombosis rates in unselected real-world populations receiving abemaciclib remain ill defined. METHODS: A multicenter observational cohort study was conducted of patients with metastatic breast cancer receiving abemaciclib. The primary end point was thrombosis during treatment or within 30 days of discontinuation. Multivariable logistic models assessed predictors of VTE, and a multivariable Cox proportional hazards model assessed mortality. RESULTS: A total of 364 patients were included, with a median treatment duration of 5.5 months. Twenty-six patients developed 27 (7.4%) thrombotic events (17 VTE, nine arterial thrombosis, and one with both events). No baseline characteristics were associated with increased VTE risk in multivariable modeling. Patients developing VTE during therapy had a higher risk of death than those who did not (hazard ratio, 2.09; 95% CI, 1.07-4.13). Median survival in patients who developed VTE compared with those who did not was 9.6 vs 25.8 months, respectively. The rate of VTE and any thrombosis during abemaciclib therapy was 9.1 and 13.7 events per 100 person-years, respectively, which is notably higher than rates observed in clinical trials. CONCLUSIONS: In a real-world setting, abemaciclib was associated with a VTE rate approximately two-fold greater than the already elevated rates reported in the MONARCH trials. Patients developing thrombosis on abemaciclib had a significantly higher risk of death. Given these findings, studies evaluating the role of thromboprophylaxis in patients receiving abemaciclib are needed.

Highly active CAR T cells that bind to a juxtamembrane region of mesothelin and are not blocked by shed mesothelin.

SignificanceMesothelin (MSLN) is a cell-surface protein that is a popular target for antibody-based therapies. We have identified shed MSLN as a major obstacle to successful antibody therapies and prepared a monoclonal antibody that inhibits shedding and makes very active CAR T cells whose activity is not blocked by shed MSLN and merits further preclinical development.

Eptacog beta, a novel recombinant factor VIIa, for the treatment of hemophilia.

Hemophilia A and B are X-linked hereditary bleeding disorders due to factor VIII (FVIII) or factor IX (FIX) deficiency, respectively. Major advancements have been made in the care of patients with hemophilia, yet the development of inhibitors to infused FVIII or FIX continues to be a formidable challenge. The current first-line therapy for acute bleeding episodes in patients diagnosed with inhibitors are bypassing agents including activated prothrombin complex concentrates (aPCCs) and recombinant factor VIIa (rFVIIa). Eptacog beta (SevenFact; LFB Biotechnologies, Hema Biologics) is a new rFVIIa product produced via expression in the milk of transgenic rabbits. This emerging platform has demonstrated numerous cost advantages to traditional cell culture systems including a better ability to scale up production and better protein yields. Eptacog beta is currently approved by the U.S. Food and Drug Administration (FDA) for the on-demand control of bleeding episodes in patients with hemophilia aged 12 to 75 with inhibitors. A potential future expansion of its current label could occur given the recent completion of two major phase III clinical trials evaluating its efficacy in children as well as its use for perioperative management. In this paper, we describe the preclinical and clinical literature documenting the development of eptacog beta and discuss its current and future application for the management of patients with hemophilia and inhibitors.

Design and System Considerations for Construction-Scale Concrete Additive Manufacturing in Remote Environments via Robotic Arm Deposition.

This work explores additive manufacturing (AM) of concrete by using a six-axis robotic arm and its use in large-scale, autonomous concrete construction. Concrete AM uses an extrusion method to deposit concrete beads in layers to create a three-dimensional (3D) shape. This method has been found to have many uses and advantages in construction applications. The lack of formwork and autonomous nature of this manufacturing method allows for new geometries and materials to be printed in unsafe or challenging environments. Autonomous construction has been suggested as a method of creating habitats in rapid-response scenarios. This article discusses research toward one such system that could be used to rapidly construct necessary habitats in response to low-resource and emergency situations. This required addressing certain limitations of a six-axis robotic arm platform along with overcoming system challenges to achieve deliverables for NASA's "3D Printed Habitat Challenge." This included system design to increase the build volume, integrate embedding, print non-coplanar sections, and minimize travel moves to address the challenges associated with continuous extrusion of cementitious material. The system was demonstrated by printing a one-third scale habitat, which represents the first 3d-printed fully enclosed structure at an architectural scale without the use of support.

Thrombotic and bleeding risk of angiogenesis inhibitors in patients with and without malignancy.

Over the past two decades, therapies targeting angiogenesis have developed into a major class of cancer therapeutics. The vascular endothelial growth factor (VEGF) family of signaling proteins, a group of potent angiogenic growth factors, and their receptors represent the main targets of this therapeutic class. To date, 16 antiangiogenic agents have been approved in the United States for the treatment of cancer and several more are in development. An important consideration with antiangiogenic therapy is toxicity, in particular thrombotic and bleeding risks. These complications have emerged as a major clinical concern that may affect the use of these agents in patients both with and without cancer who may already have an elevated risk of thrombosis and bleeding. Although these agents are frequently considered together as a class when contemplating their bleeding and thrombotic risks, in fact the risks for venous thromboembolism, arterial thrombosis, and bleeding vary significantly between different classes of antiangiogenic agents and even among different agents within a class. In this narrative review, we describe the literature investigating the venous and arterial thrombotic and bleeding risks associated with the currently available antiangiogenic drugs. In addition, we discuss these specific complications in the context of both cancer therapy as well as the management of nonmalignant disorders now managed with antiangiogenic agents, including hereditary hemorrhagic telangiectasia and neovascular age-related macular degeneration.

A tale of two tinnituses: Does hearing status influence central tinnitus localization?

Tinnitus is a complex symptom that manifests as the perception of sound in the absence of external stimuli. There are various patient-related factors and co-morbidities associated with tinnitus, however, the impact of hearing status on tinnitus is poorly understood. Various works suggest that tinnitus may originate in the central nervous system (CNS). Reports of tinnitus resolution following central insult provide further support for this concept. Based on these reports of tinnitus resolution, a line of research evaluating deep brain stimulation (DBS) of the caudate as a therapy for tinnitus has emerged. The emerging data show early promise and independent evaluation of this work suggests that hearing status may influence localization of tinnitus within the caudate. We closely review the available reports of tinnitus resolution following central insult and tinnitus outcomes in DBS to hypothesize that the CNS origins of tinnitus may vary based on hearing status. Our interpretation of the available literature suggests that the anterior aspect of the caudate may be a location for tinnitus intervention in patients with normal hearing or mild hearing loss (HL) and more posterior locations in the caudate may be a region of intervention in patients with moderate/ severe HL. Ultimately, this concept may shift the paradigm of thought on tinnitus to offer clinically and anatomically relevant information with targeted therapeutic options.

Aerosol jet printing of biological inks by ultrasonic delivery.

Printing is a promising method to reduce the cost of fabricating biomedical devices. While there have been significant advancements in direct-write printing techniques, non-contact printing of biological reagents has been almost exclusively limited to inkjet printing. Motivated by this lacuna, this work investigated aerosol jet printing (AJP) of biological reagents onto a nonfouling polymer brush to fabricate in vitro diagnostic (IVD) assays. The ultrasonication ink delivery process, which had previously been reported to damage DNA molecules, caused no degradation of printed proteins, allowing printing of a streptavidin-biotin binding assay with sub-nanogram ml-1 analytical sensitivity. Furthermore, a carcinoembryogenic antigen IVD was printed and found to have sensitivities in the clinically relevant range (limit of detection of approximately 0.5 ng ml-1 and a dynamic range of approximately three orders of magnitude). Finally, the multi-material printing capabilities of the aerosol jet printer were demonstrated by printing silver nanowires and streptavidin as interconnected patterns in the same print job without removal of the substrate from the printer, which will facilitate the fabrication of mixed-material devices. As cost, versatility, and ink usage become more prominent factors in the development of IVDs, this work has shown that AJP should become a more widely considered technique for fabrication.

An Extended Computational Study of Criegee Intermediate-Alcohol Reactions.

High-level ab initio calculations (DF-LCCSD(T)-F12a//B3LYP/aug-cc-pVTZ) are performed on a range of stabilized Criegee intermediate (sCI)-alcohol reactions, computing reaction coordinate energies, leading to the formation of α-alkoxyalkyl hydroperoxides (AAAHs). These potential energy surfaces are used to model bimolecular reaction kinetics over a range of temperatures. The calculations performed in this work reproduce the complicated temperature-dependent reaction rates of CH2OO and (CH3)2COO with methanol, which have previously been experimentally determined. This methodology is then extended to compute reaction rates of 22 different Criegee intermediates with methanol, including several intermediates derived from isoprene ozonolysis. In some cases, sCI-alcohol reaction rates approach those of sCI-(H2O)2. This suggests that in regions with elevated alcohol concentrations, such as urban Brazil, these reactions may generate significant quantities of AAAHs and may begin to compete with sCI reactions with other trace tropospheric pollutants such as SO2. This work also demonstrates the ability of alcohols to catalyze the 1,4-H transfer unimolecular decomposition of α-methyl substituted sCIs.

Chronic inflammation - inflammaging - in the ageing cochlea: A novel target for future presbycusis therapy.

Chronic, low-grade inflammation, or inflammaging, is a crucial contributor to various age-related pathologies and natural processes in aging tissue, including the nervous system. Over the past two decades, much effort has been done to understand the mechanisms of inflammaging in disease models such as type II diabetes, cardiovascular disease, Alzheimer's disease, Parkinson's disease, and others. However, despite being the most prevalent neurodegenerative disorder, the number one communication disorder, and one of the top three chronic medical conditions of our aged population; little research has been conducted on the potential role of inflammation in age-related hearing loss (ARHL). Recently, it has been suggested that there is an inflammatory presence in the cochlea, perhaps involving diffusion processes of the blood-brain barrier as it relates to the inner ear. Recent research has found correlations between hearing loss and markers such as C-reactive protein, IL-6, and TNF-α indicating inflammatory status in human case-cohort studies. However, there have been very few reports of in vivo research investigating the role of chronic inflammation's in hearing loss in the aging cochlea. Future research directed at better understanding the mechanisms of inflammation in the cochlea as well as the natural changes acquired with aging may provide a better understanding of how this process can accelerate presbycusis. Animal model experimentation and pre-clinical studies designed to recognize and characterize cochlear inflammatory mechanisms may suggest novel treatment strategies for preventing or treating ARHL. In this review, we seek to summarize key research in chronic inflammation, discuss its implications for possible roles in ARHL, and finally suggest directions for future investigations.

Inhibitor of DNA binding 4 (ID4) regulation of adipocyte differentiation and adipose tissue formation in mice.

Inhibitor of DNA binding 4 (ID4) is a helix-loop-helix protein that heterodimerizes with basic helix-loop-helix transcription factors inhibiting their function. ID4 expression is important for adipogenic differentiation of the 3T3-L1 cell line, and inhibition of ID4 is associated with a concomitant decrease in CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma mRNA and protein expression. Mice with a homozygous deletion of Id4 (Id4(-/-)) have reduced body fat and gain much less weight compared with wild-type littermates when placed on diets with high fat content. Mouse embryonic fibroblasts (MEFs) isolated from Id4(-/-) mice have reduced adipogenic potential when compared with wild-type MEFs. In agreement with changes in morphological differentiation, the levels of CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma were also reduced in MEFs from Id4(-/-) mice. Our results demonstrate the importance of ID4 in adipocyte differentiation and the implications of this regulation for adipose tissue formation.

ID2 (inhibitor of DNA binding 2) is a rhythmically expressed transcriptional repressor required for circadian clock output in mouse liver.

Id2 is a helix-loop-helix transcription factor gene expressed in a circadian manner in multiple tissues with a phase-locked relationship with canonical clock genes. Our previous studies have identified circadian phenotypes in Id2 null mice, including enhanced photo-entrainment and disruption of activity rhythms, and have demonstrated a potent inhibitory effect of ID proteins upon CLOCK-BMAL1 transactivation of clock gene and clock-controlled gene activity. We have now begun to explore the potential role that ID2 may play in specifically regulating clock output. Here we show that ID2 protein is rhythmically expressed in mouse liver. Time-of-day-specific liver gene expression in Id2(+/+) and Id2(-/-) mice under circadian conditions was studied using DNA microarray analysis, identifying 651 differentially expressed genes, including a subset of 318 genes deemed rhythmically expressed in other studies. Examination of individual time courses reveals that these genes are dysregulated in a highly time-specific manner. A cohort of different functional groups were identified, including genes associated with glucose and lipid metabolism, e.g. serum protein Igfbp1 and lipoprotein lipase. We also reveal that the Id2(-/-) mice show a reduction in lipid storage in the liver and white adipose tissue, suggesting that disruption of normal circadian activity of components of lipid metabolism can result in overt physiological alterations. These data reveal a role for the transcriptional repressor ID2 as a circadian output regulator in the periphery.