Distinct Disease States Research Articles

A clinician's perspective on the new organ mesentery and non-vascular mesenteropathies.

Mesentery was discovered as a new organ in 2017. It is a continuous membranous tissue from the duodenojejunal flexure to the anorectal junction. It has distinct anatomy, physiology, and disease states. Primary mesenteropathies include vascular and non-vascular diseases. Some of them are common, and some of them are rarely seen in clinical practice. Secondary mesenteropathies occur when infection or malignancy in another organ spreads to the mesentery. Each entity has specific diagnostic and treatment protocols. Increased awareness of different mesenteropathies and an understanding of their various presentations at different stages of life can help in early diagnosis and improved clinical outcomes.

Stage-dependent phosphoproteome remodeling of Parkinson's disease blood cells

The complexity and heterogeneity of PD necessitate advanced diagnostic and prognostic tools to elucidate its molecular mechanisms accurately. In this study, we addressed this challenge by conducting a pilot phospho-proteomic analysis of peripheral blood mononuclear cells (PBMCs) from idiopathic PD patients at varying disease stages to delineate the functional alterations occurring in these cells throughout the disease course and identify key molecules and pathways contributing to PD progression. By integrating clinical data with phospho-proteomic profiles across various PD stages, we identify potential stage-specific molecular signatures indicative of disease progression. This integrative approach allows for the discernment of distinct disease states and enhances our understanding of PD heterogeneity.

Resource-rational psychopathology.

Psychopathology is vast and diverse. Across distinct disease states, individuals exhibit symptoms that appear counter to the standard view of rationality (expected utility maximization). We argue that some aspects of psychopathology can be described as resource-rational, reflecting a rational trade-off between reward and cognitive resources. We review work on two theories of this kind: rational inattention, where a capacity limit applies to perceptual channels, and policy compression, where the capacity limit applies to action channels. We show how these theories can parsimoniously explain many forms of psychopathology, including affective, primary psychotic, and neurodevelopmental disorders, as well as many effects of psychoactive medications on these disorders. While there are important disorder-specific differences and the theories are by no means universal, we argue that resource rationality offers a useful new perspective on psychopathology. By emphasizing the role of cognitive resource constraints, this approach offers a more inclusive picture of rationality. Some aspects of psychopathology may reflect rational trade-offs rather than the breakdown of rationality. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A novel pilot study to evaluate the efficacy and safety of a wireless patch system in patients with chronic nausea and vomiting.

Gastric sensorimotor disorders (functional dyspepsia [FD] and gastroparesis [GP]) are prevalent and burdensome. Prolonged ambulatory recording using a wireless patch may provide novel information in these patients. Consecutive adult patients (age ≥ 18 years) referred for gastric emptying scintigraphy (GES) were eligible for study inclusion. Patients were excluded if they had prior foregut surgery; were taking opioids or other medications known to affect gastric emptying; had a HgbA1C > 10; or were recently hospitalized. Three wireless motility patches were applied to the skin prior to GES. Patients wore the patches for 6 days while recording meals, symptoms, and bowel movements using an iPhone app. Twenty-three consecutive adults (87% women; mean age = 43.9 years; mean BMI = 26.7 kg/m2) were enrolled. A gastric histogram revealed three levels of gastric myoelectric activity: weak, moderate, and strong. Patients with delayed gastric emptying at 4 h had weak gastric myoelectrical activity. Patients with nausea and vomiting had strong intestinal activity. Those with FD had weak gastric and intestinal myoelectric activity, and a weak meal response in the stomach, intestine, and colon compared to those with nausea alone or vomiting alone. Patients with FD, and those with delayed gastric emptying, had unique gastrointestinal myoelectrical activity patterns. Reduced postprandial pan-intestinal myoelectric activity may explain the symptoms of FD in some patients. Recording gastrointestinal activity over a prolonged period in the outpatient setting has the potential to identify unique pathophysiologic patterns and meal-related activity that distinguishes patients with distinct gastric sensorimotor disease states.

Abstract 2307: State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia (CML)

Abstract Chronic myeloid leukemia (CML) is initiated and initially maintained by BCR-ABL which is clinically targeted using tyrosine kinase inhibitors (TKIs). Although TKIs can induce long-term remission, they are frequently not curative. Thus, CML is an ideal system to test our hypothesis that transcriptome-based state-transition models accurately predict cancer evolution and treatment response. We collected time-sequential blood samples from tetracycline-off (Tet-Off) BCR-ABL-inducible transgenic mice that recapitulates human chronic phase CML and wild-type controls. From the transcriptome, we constructed a CML state-space and a three-well leukemogenic potential landscape that describes CML state-transition from health to disease. The potential’s stable critical points were used to define three distinct disease states. The Early state was characterized by anti-CML genes (n=35) that opposed leukemia progression, whereas an expanding number of pro-CML genes characterized the Transition state (n=357) and Late states (n=1,858). Gene modules that were co-regulated at the unstable points in the potential landscape were identified as the drivers of transition between stable disease states. To investigate CML therapies we used two treatments: silencing of BCR/ABL by readministering Tet (Tet-on, Tet-off [TOTO]) which represented a best-case scenario of disease being cured, and TKI (nilotinib) therapy which represents current clinical practice. TOTO returned the diseased mice transcriptomes to a near health state, without reaching it, suggesting partly irreversible transformation. TKI, however, only reverted the transcriptome to an intermediate disease state, without approaching health, and disease relapse occurred soon after treatment. Finally, using only the earliest time-point as initial conditions, our state-transition models accurately predicted both disease progression and treatment response to both therapies for each individual mouse. In conclusion, these results show state-transition analysis is a valuable approach to gain real time insights into CML development, progression and ongoing treatment response that can also be applied to other type of leukemia and cancers in general. We predicted disease evolution and treatment response in a murine model that recapitulates human disease, supporting this as a potentially valuable approach to time clinical intervention even before phenotypic changes become detectable. Citation Format: David E. Frankhouser, Russell C. Rockne, Dandan Zhao, Sergio Branciamore, Lisa Uechi, Denis O'Meally, Yu-Hsuan Fu, Ya-Huei Kuo, Bin Zhang, Guido Marcucci. State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia (CML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2307.

Using blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification.

Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. Bulk RNA-sequencing of blood cells was performed on AD patients of Chinese descent (n=214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n=208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co-expression network analysis (WGCNA) and deconvolution analysis identified AD-associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD-associated genes, gene modules, cell types, and established AD classification models. WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs]>0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell-type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. We comprehensively analyze the blood transcriptomes of a well-characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease. Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers. Immune-associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease.

Panoramic view of clinical features of lupus erythematosus: a cross-sectional multicentre study from China

ObjectiveLupus erythematosus (LE) is a complicated disease with highly heterogeneous clinical manifestations. Previous studies have rarely included all subgroups of patients with lupus and have overlooked the importance of the...

Chapter 1 - The definition of precision medicine in neurodegenerative disorders and the one disease-many diseases tension

Precision medicine is a patient-centered approach that aims to translate new knowledge to optimize the type and timing of interventions for the greatest benefit to individual patients. There is considerable interest in applying this approach to treatments designed to slow or halt the progression of neurodegenerative diseases. Indeed, effective disease-modifying treatment (DMT) remains the greatest unmet therapeutic need in this field. In contrast to the enormous progress in oncology, precision medicine in the field of neurodegeneration faces multiple challenges. These are related to major limitations in our understanding of many aspects of the diseases. A critical barrier to advances in this field is the question of whether the common sporadic neurodegenerative diseases (of the elderly) are single uniform disorders (particularly related to their pathogenesis) or whether they represent a collection of related but still very distinct disease states. In this chapter, we briefly touch on lessons from other fields of medicine that might be applied to the development of precision medicine for DMT in neurodegenerative diseases. We discuss why DMT trials may have failed to date, and particularly the importance of appreciating the multifaceted nature of disease heterogeneity and how this has and will impact on these efforts. We conclude with comments on how we can move from this complex disease heterogeneity to the successful application of precision medicine principles in DMT for neurodegenerative diseases.

A unique cytotoxic CD4+ T cell-signature defines critical COVID-19.

SARS-CoV-2 infection causes a spectrum of clinical disease presentation, ranging from asymptomatic to fatal. While neutralising antibody (NAb) responses correlate with protection against symptomatic and severe infection, the contribution of the T-cell response to disease resolution or progression is still unclear. As newly emerging variants of concern have the capacity to partially escape NAb responses, defining the contribution of individual T-cell subsets to disease outcome is imperative to inform the development of next-generation COVID-19 vaccines. Immunophenotyping of T-cell responses in unvaccinated individuals was performed, representing the full spectrum of COVID-19 clinical presentation. Computational and manual analyses were used to identify T-cell populations associated with distinct disease states. Critical SARS-CoV-2 infection was characterised by an increase in activated and cytotoxic CD4+ lymphocytes (CTL). These CD4+ CTLs were largely absent in asymptomatic to severe disease states. In contrast, non-critical COVID-19 was associated with high frequencies of naïve T cells and lack of activation marker expression. Highly activated and cytotoxic CD4+ T-cell responses may contribute to cell-mediated host tissue damage and progression of COVID-19. Induction of these potentially detrimental T-cell responses should be considered when developing and implementing effective COVID-19 control strategies.

Reduced affinity of calcium sensing-receptor heterodimers and reduced mutant homodimer trafficking combine to impair function in a model of familial hypocalciuric hypercalcemia type 1.

Heterozygous loss-of-function mutation of the calcium sensing-receptor (CaSR), causes familial hypocalciuric hypercalcemia type 1 (FHH1), a typically benign condition characterized by mild hypercalcemia. In contrast, homozygous mutation of this dimer-forming G-protein coupled receptor manifests as the lethal neonatal severe hyperparathyroidism (NSHPT). To investigate the mechanisms by which CaSR mutations lead to these distinct disease states, we engineered wild-type (WT) and an exon 5-deficient disease-causing mutation, and transfected expression constructs into human embryonic kidney (HEK) cells. WT protein was mainly membrane-expressed whereas the mutant CaSR protein (mCaSR) was confined to the cytoplasm. Co-expression of WT CaSR directed mCaSR to the cell membrane. In assays of CaSR function, increases in extracellular [Ca2+] ([Ca2+]o) increased intracellular [Ca2+] ([Ca2+]i) in cells expressing WT CaSR while the response was reduced in cells co-expressing mutant and WT receptor. Untransfected cells or those expressing mCaSR alone, showed minimal, equivalent responses to increased [Ca2+]o. Immunoprecipitation experiments confirmed an association between mutant and wild-type CaSR. The affinity of the WT CaSR for calcium was three times greater than that of the heterodimer. The maximal functional response to [Ca]o was dependent on localization of CaSR to the membrane level and independent of homo- or heterodimerizations. In summary, these results suggest that heterodimerization of WT and mCaSR receptors, rescues the trafficking defect of the mutant receptors and also reduces the affinity of the WT-mutant heterodimer for [Ca]o. In contrast, the homozygous mutants do not produce functional receptors on cell membrane. These data indicate how substantial differences between signaling of hetero- and homodimeric mutants may lead to profound differences in the severity of disease in heterozygous and homozygous carriers of these mutations.

The diagnostic value of calcium binding protein S100A8/A9 and S100A12 in acute pancreatitis

Background: S100A8/A9 and S100A12 which are the major calcium-binding proinflammatory proteins secreted by granulocytes, has been proposed to be related to distinct disease states of inflammatory origin. This study aims to explore the circulating levels of S100A8/A9 and S100A12 in acute pancreatitis (AP) and reveal their relationship with conventional inflammatory markers. Material and Method: Serum S100A8/A9 and S100A12 were determined in AP patients (male/female: 17/13) by using a specific enzyme-linked immunosorbent assay (ELISA) method at both onset and remission and in 30 healthy controls (male/female: 17/13). Results: Significantly higher S100A8/A9 and S100A12 levels were found in AP patients compared to healthy controls (p

Structure‐based Computational Modeling of Germline PTEN Mutations in Cancer and Autism Risk: Implications for Therapeutic Targeting

The Phosphatase and TENsin homolog deleted on chromosome ten (PTEN) is a dual‐specificity phosphatase encoded by a tumor suppressor gene frequently somatically mutated in human cancer. Individuals with germline PTEN mutations are diagnosed with PTEN hamartoma tumor syndrome (PHTS). Clinically, PHTS has a variable phenotype spectrum, including distinct subsets of patients with autism spectrum disorder (ASD) and/or cancer. It remains unclear why mutations in one gene can lead to seemingly disparate phenotypes. Our pilot studies identified structural stability and functional differences in germline PTEN variants that contribute to cancer or to autismsuggesting distinct conformational disease states and a potential basis for allosteric communication via the inter‐domain region of PTEN. Thus, we hypothesized that key inter‐domain sites will delineate novel structurally correlated areas for potential drug targeting. Moreover, PTEN is inactivated by phosphorylation of C‐tail cluster sites (Ser/Thr residues 380‐385) which is known to play a critical role in the function and stability of PTEN. However, very little is known about the mechanism underlying such inactivation. We therefore sought to further understand whether C‐tail phosphorylation sites represent a possible phosphodegron motif that influences distinct conformational ensembles and inter‐domain interface specific to PTEN‐ASD and PTEN‐cancer phenotypes. By integrating in silico modeling, molecular simulations, and allosteric communication analyses we reveal the role of C‐tail phosphorylation on conformational dynamics and allosteric regulation of PTEN‐ASD and PTEN‐cancer phenotypes that exhibited the most exaggerated disease‐specific effects in our pilot studies. We show that C‐tail phosphorylation in PTEN‐ASD induces fluctuations in degradation‐sensitive sites (K13 and K289) that render a closed conformation. Furthermore, allosteric analysis reveals inter‐domain effector residues that strengthen the structural communication pathway. In contrast, a higher intrinsic flexibility and less stable conformational state emerges in PTEN‐cancer. Importantly, this reveals a less dense inter‐domain structural communication pathway that lacks effector degradation‐sensitive residues. Our integrative approach offers new insight into structurally correlated areas for potential drug targeting and will serve as the basis for designing novel therapeutics to attenuate PHTS‐associated cancer and ASD phenotypes.

Global incidence and mortality of hepatitis B and hepatitis C acute infections, cirrhosis and hepatocellular carcinoma from 2010 to 2019.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) contribute to significant healthcare burden globally. We aim to provide an updated and comprehensive analysis of global trends in the incidence and mortality of HBV and HCV related acute infections, cirrhosis and hepatocellular carcinoma (HCC). Estimates of annual cause-specific disease incidence and mortality for HBV and HCV were analysed using the 2010-2019 Global Burden of Diseases, Injuries and Risk Factors Study database. Three distinct disease states were evaluated: acute infections, cirrhosis and HCC. Age-standardized disease incidence and mortality were presented per 100,000 population and stratified by age, sex, year and 21 world regions. From 2010 to 2019, overall incidence of acute HBV declined by 19.3% (95% CI 4.1-32.0, p<.05) and HBV cirrhosis declined by 15.0% (95% CI 9.8-20.7, p<.05). Incidence of HCV cirrhosis increased by 5.6% (95% CI 0.3-10.2, p<.05) and HCV HCC remained stable. Incidence of acute HCV declined until 2015, after which it began increasing. From 2010 to 2019, overall mortality for HBV cirrhosis and HCV cirrhosis declined, whereas mortality for acute infections and HCC remained stable. Major differences in HBV and HCV incidence and mortality trends were observed when stratified by world regions. In conclusion, while our analyses of global trends in HBV and HCV incidence and mortality demonstrate encouraging trends, disparities in disease epidemiology were observed across world regions. These observations will identify regions and populations where greater focus and resources are needed to continue progressing towards viral hepatitis elimination.

Dynamic risk profiling of HCC recurrence after curative intent liver resection.

Following liver resection (LR) for HCC, the likelihood of survival is dynamic, in that multiple recurrences and/or metastases are possible, each having variable impacts on outcomes. We sought to evaluate the natural progression, pattern, and timing of various disease states after LR for HCC using multistate modeling and to create a practical calculator to provide prognostic information for patients and clinicians. Adult patients undergoing LR for HCC between January 2000 and December 2018 were retrospectively identified at a single center. Multistate analysis modeled post-LR tumor progression by describing transitions between distinct disease states. In this model, the states included surgery, intrahepatic recurrence (first, second, third, fourth, fifth), distant metastasis with or without intrahepatic recurrence, and death. Of the 486 patients included, 169 (34.8%) remained recurrence-free, 205 (42.2%) developed intrahepatic recurrence, 80 (16.5%) developed distant metastasis, and 32 (7%) died. For an average patient having undergone LR, there was a 33.1% chance of remaining disease-free, a 31.0% chance of at least one intrahepatic recurrence, a 16.3% chance of distant metastasis, and a 19.8% chance of death within the first 60 months post-LR. The transition probability from surgery to first intrahepatic recurrence, without a subsequent state transition, increased from 3% (3 months) to 17.4% (30 months) and 17.2% (60 months). Factors that could modify these probabilities included tumor size, satellite lesions, and microvascular invasion. The online multistate model calculator can be found on https://multistatehcc.shinyapps.io/home/. In contrast to standard single time-to-event estimates, multistate modeling provides more realistic prognostication of outcomes after LR for HCC by taking into account many postoperative disease states and transitions between them. Our multistate modeling calculator can provide meaningful data to guide the management of patients undergoing postoperative surveillance and therapy.

An Invitation to Commentary on Using Telemedicine within Otolaryngology Practice during the Covid-19 Catastrophe

The COVID-19 epidemic had a significant impact on how otolaryngologists deliver care and treatment to their patients in the outpatient setting. Throughout this Public Health Emergency (PHE), maintaining a continuum of care with existing patients and establishing a relationship with potential patients is difficult. State and municipal governments have issued orders for the citizens to remain at homes and stay under shelters in several places to prevent the spread of COVID-19.Wide adaptability in providing services via remote communications technology has been allowed to avoid exposure concerns to healthcare professionals, patients, and the general public. The use of telehealth or online services will allow otolaryngologists to provide essential care to patients while reducing the pandemic's clinical and budgetary burden. It increases the continuum of care, lowers costs, and enhances patient self-management and overall results, according to studies, notably in the treatment of distinct disease states. [1]The considerable coding and billing challenges associated with deploying telehealth services are explained to encourage otolaryngologists to adopt this technology.

EFFECT OF MATERNAL ABO BLOOD TYPE ON BIRTH WEIGHT

Background: ABO blood group has been recognized as a risk factor for distinct disease states. The association between ABO blood group and adverse pregnancy outcomes has not been extensively studied, especially in relation to birth weight. The aim of the present study is to determine whether ABO blood group contributes to the adverse pregnancy outcomes like low birth weight. Methods: Medical data including ABO phenotypes were collected from hospital database and retrospectively reviewed. Adverse pregnancy outcome studied was low birth weight. Birth week was also noted for each subject. Results: 500 charts of mothers who had given birth in our hospital were studied. Overall 146 (29.2%) women had type O blood, 108 (21.6%) had type A blood, 194 (38.8%) had type B blood and 52 (10.4%) had type AB blood. Pregnant women with type B blood group had significantly lower birth weights compared with type O, A and AB. Birth weeks of all groups were found to be similar with no statistically significant difference Conclusions: Maternal ABO phenotype is associated with low birth weight, while no association was found between blood type and birth week. We postulate that maternal/fetal immune system genes which are directly associated with ABO blood groups could affect pregnant with a resulting birth weight alterations. KEYWORDS: ABO blood type, Birth weight, Pregnancy.

A narrative review of oligometastatic prostate cancer-an evolving paradigm.

There has been growing interest in oligometastatic prostate cancer (OMPC) with a mounting body of evidence to suggest that it is a distinct disease state, both biologically and prognostically, when compared to polymetastatic prostate cancer. Three subgroups have been recognised; de novo synchronous, metachronous/oligorecurrent and oligoprogressive disease. The belief that patients with OMPC can be treated more aggressively to improve survival is transforming patient care. Identifying these patients poses the first challenge, and we explore the imaging modalities currently utilised and those that are promising. For patients with de novo synchronous OMPC, both early systemic treatment in addition to androgen deprivation therapy (ADT) and radiotherapy to the prostate increase overall survival (OS), and both are increasingly being integrated into routine clinical practice. Metastasis-directed therapy (MDT) has predominantly been delivered using stereotactic body radiotherapy (SBRT) in prostate cancer and studies have shown SBRT is well-tolerated, provides excellent local control and can be used to delay ADT in the metachronous setting. We discuss the current management strategies in OMPC, review the evidence supporting the use of SBRT and outline ongoing trials.

An underrepresented majority: A systematic review utilizing allodynic criteria to examine the present scarcity of discrete animal models for episodic migraine.

Despite increasing evidence differentiating episodic and chronic migraine, little work has determined how currently utilized animal models of migraine best represent each distinct disease state. In this review, we seek to characterize accepted preclinical models of migraine-like headache by their ability to recapitulate the clinical allodynic features of either episodic or chronic migraine. From a search of the Pu bMed database for "animal models of migraine", "headache models" and "preclinical migraine", we identified approximately 80 recent (within the past 20 years) publications that utilized one of 10 different models for migraine research. Models reviewed fit into one of the following categories: Dural KCl application, direct electrical stimulation, nitroglycerin administration, inflammatory soup injection, CGRP injection, medication overuse, monogenic animals, post-traumatic headache, specific channel activation, and hormone manipulation. Recapitulation of clinical features including cephalic and extracephalic hypersensitivity were evaluated for each and compared. Episodic migraineurs comprise over half of the migraine population, yet the vast majority of current animal models of migraine appear to best represent chronic migraine states. While some of these models can be modified to reflect episodic migraine, there remains a need for non-invasive, validated models of episodic migraine to enhance the clinical translation of migraine research.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

The summary presented herein represents Part II of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients with castration-resistant disease. Please refer to Part I for discussion of the management of patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1[Figure: see text] and detailed herein. The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.

Chronobiological Influence Over Cardiovascular Function: The Good, the Bad, and the Ugly.

Essentially all biological processes fluctuate over the course of the day, observed at cellular (eg, transcription, translation, and signaling), organ (eg, contractility and metabolism), and whole-body (eg, physical activity and appetite) levels. It is, therefore, not surprising that both cardiovascular physiology (eg, heart rate and blood pressure) and pathophysiology (eg, onset of adverse cardiovascular events) oscillate during the 24-hour day. Chronobiological influence over biological processes involves a complex interaction of factors that are extrinsic (eg, neurohumoral factors) and intrinsic (eg, circadian clocks) to cells. Here, we focus on circadian governance of 6 fundamentally important processes: metabolism, signaling, electrophysiology, extracellular matrix, clotting, and inflammation. In each case, we discuss (1) the physiological significance for circadian regulation of these processes (ie, the good); (2) the pathological consequence of circadian governance impairment (ie, the bad); and (3) whether persistence/augmentation of circadian influences contribute to pathogenesis during distinct disease states (ie, the ugly). Finally, the translational impact of chronobiology on cardiovascular disease is highlighted.