Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation.

Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division. PLK1 activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate PLK1 in mitosis remain poorly understood. Here, we identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome missegregation, and cytokinetic defects. Moreover, Chk2 deficiency increases sensitivity to PLK1 inhibitors, suggesting that Chk2 status may be an informative biomarker for PLK1 inhibitor efficacy. This work demonstrates that Chk2 sustains mitotic PLK1 activity and protects genome stability through discrete functions in interphase DNA damage repair and mitotic chromosome segregation.

ATR promotes clearance of damaged DNA and damaged cells by rupturing micronuclei.

The human ataxia telangiectasia mutated and Rad3-related (ATR) kinase functions in the nucleus to protect genomic integrity. Micronuclei (MN) arise from genomic and chromosomal instability and cause aneuploidy and chromothripsis, but how MN are removed is poorly understood. Here, we show that ATR is active in MN and promotes their rupture in S phase by phosphorylating Lamin A/C at Ser395, which primes Ser392 for CDK1 phosphorylation and destabilizes the MN envelope. In cells harboring MN, ATR or CDK1 inhibition reduces MN rupture. Consequently, ATR inhibitor (ATRi) diminishes activation of the cytoplasmic DNA sensor cGAS and compromises cGAS-dependent autophagosome accumulation in MN and clearance of micronuclear DNA. Furthermore, ATRi reduces cGAS-mediated senescence and killing of MN-bearing cancer cells by natural killer cells. Thus, in addition to the canonical ATR signaling pathway, an ATR-CDK1-Lamin A/C axis promotes MN rupture to clear damaged DNA and cells, protecting the genome in cell populations through unexpected cell-autonomous and cell-non-autonomous mechanisms.

Identifying barriers and utility of obtaining ambulatory blood pressure monitoring in a pediatric chronic kidney disease population.

BACKGROUND: Hypertension is a prevalent complication of Chronic Kidney Disease (CKD) and Ambulatory Blood Pressure Monitoring (ABPM) is the gold standard for diagnosis. The aim of our study was to assess the usefulness of obtaining ABPM and to identify barriers to ABPM in this pediatric patient population. METHOD: In this retrospective analysis of patients with CKD stage 3-5 who were seen in one academic medical center's outpatient Pediatric Nephrology clinics between 2018 and 2021, we performed logistic regression to evaluate for associations between demographic factors and odds of having an ABPM. RESULT: Among 96 patients included in the study, 48 patients carried a diagnosis of hypertension. 31 patients had ABPM performed with usable data. In those who had ABPM done, 21 had normotension and 10 had undertreated hypertension. Our study also showed 1 had masked hypertension and 5 had white coat hypertension or effect. We did not find a statistically significant difference in those who did or did not undergo ABPM evaluation based on gender, previous diagnosis of hypertension, distance from clinic, language preference, or racial or ethnic identity. CONCLUSION: ABPM is a useful tool in our CKD population for the diagnosis and management of hypertension. We did not identify specific barriers to ABPM in our CKD population, and there were no differences in patients who obtained ABPM when looking at specific demographic and disease characteristics. Given these findings, we recommend focusing on areas of future improvement in spheres of patient and provider education as well as better quantification using surveys to further illuminate barriers.

ATR protects centromere identity by promoting DAXX association with PML nuclear bodies.

Centromere protein A (CENP-A) defines centromere identity and nucleates kinetochore formation for mitotic chromosome segregation. Here, we show that ataxia telangiectasia and Rad3-related (ATR) kinase, a master regulator of the DNA damage response, protects CENP-A occupancy at interphase centromeres in a DNA damage-independent manner. In unperturbed cells, ATR localizes to promyelocytic leukemia nuclear bodies (PML NBs), which house the histone H3.3 chaperone DAXX (death domain-associated protein 6). We find that ATR inhibition reduces DAXX association with PML NBs, resulting in the DAXX-dependent loss of CENP-A and an aberrant increase in H3.3 at interphase centromeres. Additionally, we show that ATR-dependent phosphorylation within the C terminus of DAXX regulates CENP-A occupancy at centromeres and DAXX localization. Lastly, we demonstrate that acute ATR inhibition during interphase leads to kinetochore formation defects and an increased rate of lagging chromosomes. These findings highlight a mechanism by which ATR protects centromere identity and genome stability.

Retrospective study assessing outcomes in cardiac surgery after implementation of Quantra.

BACKGROUND: The Quantra QPlus System is a cartridge-based device with a unique ultrasound technology that can measure the viscoelastic properties of whole blood during coagulation. These viscoelastic properties correlate directly with hemostatic function. The primary objective of this study was to assess blood product utilization in cardiac surgery patients before and after the implementation of the Quantra QPlus System. METHODS: Yavapai Regional Medical Center implemented the Quantra QPlus System to aid in their efforts to reduce the transfusion of allogenic blood products and improve outcomes in patients undergoing cardiac surgery. A total of 64 patients were enrolled prior to the utilization of the Quantra (pre-Quantra cohort), and 64 patients were enrolled after (post-Quantra cohort). The pre-Quantra cohort had been managed via standard laboratory assays along with physician discretion for transfusion decisions. The utilization of blood products and frequency of transfusions were compared and analyzed between the two cohorts. (using the Student's t-test) RESULTS: The implementation of the Quantra resulted in a change in the pattern of blood product utilization leading to a demonstrated decrease in the amount of blood products transfused and the associated costs. The amount of FFP transfused was significantly decreased by 97% (P = 0.0004), whereas cryoprecipitate decreased by 67% (P = 0.3134), platelets decreased by 26% (P = 0.4879), and packed red blood cells decreased by 10% (P = 0.8027) however these trends did not reach statistical significance. The acquisition cost of blood products decreased by 41% for total savings of roughly $40,682. CONCLUSIONS: Use of the Quantra QPlus System has the potential to improve patient blood management and decrease costs. STUDY REGISTERED AT CLINICALTRIALS.GOV: NCT05501730.

Keeping RelApse in Chk: molecular mechanisms of Chk1 inhibitor resistance in lymphoma.

Chk1 is a member of the DNA damage response pathway, whose loss leads to replication stress and genome instability. Because of its protective role against lethal levels of DNA replication stress, Chk1 has been studied as a valuable and intriguing target for cancer therapy. However, one of the most prominent challenges with this strategy is development of resistance to Chk1 inhibitors, rendering the treatment ineffective. In their recent papers, Hunter and colleagues demonstrate multiple mechanisms by which Chk1 inhibitor resistance can arise in lymphomas. Specifically, this series of papers identify the relationship between dysfunction in NF-κB and the development of Chk1 inhibitor resistance through a loss of Chk1 activity in mouse models of lymphoma. They identify that cells lacking Chk1 activity can compensate for this loss through up-regulation of alternative pathways, such as PI3K/AKT. Finally, this work also identifies a novel role for Claspin, an important Chk1 activator, in female fertility and cancer development, furthering our understanding of how dysfunction in the Claspin/Chk1 signaling pathway affects disease states. These findings improve our understanding of drug resistance in cancer therapy, which has important implications for clinical use of Chk1 inhibitors.

Discordances between pediatric and adult thresholds in the diagnosis of hypertension in adolescents with CKD.

BACKGROUND: Adolescents with chronic kidney disease (CKD) are a unique population with a high prevalence of hypertension. Management of hypertension during the transition from adolescence to adulthood can be challenging given differences in normative blood pressure values in adolescents compared with adults. METHODS: In this retrospective analysis of the Chronic Kidney Disease in Children Cohort Study, we compared pediatric versus adult definitions of ambulatory- and clinic-diagnosed hypertension in their ability to discriminate risk for left ventricular hypertrophy (LVH) and kidney failure using logistic and Cox models, respectively. RESULTS: Overall, among 363 adolescents included for study, the prevalence of systolic hypertension was 27%, 44%, 12%, and 9% based on pediatric ambulatory, adult ambulatory, pediatric clinic, and adult clinic definitions, respectively. All definitions of hypertension were statistically significantly associated with LVH except for the adult ambulatory definition. Presence of ambulatory hypertension was associated with 2.6 times higher odds of LVH using pediatric definitions (95% CI 1.4-5.1) compared to 1.4 times higher odds using adult definitions (95% CI 0.8-3.0). The c-statistics for discrimination of LVH was statistically significantly higher for the pediatric definition of ambulatory hypertension (c=0.61) compared to the adult ambulatory definition (c=0.54), and the Akaike Information Criterion was lower for the pediatric definition. All definitions were associated with progression to kidney failure. CONCLUSION: Overall, there was not a substantial difference in pediatric versus adult definitions of hypertension in predicting kidney outcomes, but there was slightly better risk discrimination of the risk of LVH with the pediatric definition of ambulatory hypertension.

Urinary Cannabis Metabolite Concentrations in Cannabis Hyperemesis Syndrome.

OBJECTIVE: Cannabis Hyperemesis Syndrome (CHS) is characterized by recurrent episodes of intractable emesis associated with heavy use of cannabis. Recognition of CHS can be problematic due to the lack of specific biomarkers, which can point the clinician to the diagnosis. We present, retrospectively, a series of adolescent/young adult patients who presented to a pediatric gastroenterology (GI) service with acute on chronic nausea and vomiting, subsequently found to have CHS with associated elevated urinary cannabis metabolite concentrations. METHODS: We describe 15 patients referred to our pediatric GI division for intractable emesis with spot urinary cannabis metabolite carboxy-THC (THC-COOH) concentrations from January 1, 2018 through April 20, 2019. Urinary testing was performed using gas chromatography mass-spectrometry (GC-MS) in a manner consistent with Clinical Laboratory Improvement Amendments (CLIA) requirements at Mayo Clinic laboratory (Rochester, MN). The laboratory cutoffs were 3.0 ng/mL. Data was extracted via chart review and analyzed via online statistical application. RESULTS: Fifteen patients (seven females, eight males) were studied with an average age of 17.7 years. All patients reported frequent cannabis use for at least 1 month and exhibited intractable, non-bilious emesis for at least 2 weeks. Twelve patients also reported weight loss. Two patients had underlying gastrointestinal disease (one with Crohn disease and one with irritable bowel syndrome). All patients had essentially normal GI workup including laboratory tests, imaging studies and endoscopies.Fourteen of 15 patients had urinary THC-COOH concentrations >100 ng/mL, with seven individuals exhibiting levels >500 ng/mL. One patient had a urinary TCH-COOH concentration level under 100 ng/mL had not used cannabis for 2 weeks. Most other patients had used cannabis within 2 days of providing a urine sample. The Binomial test for CHS patients with urinary THC-COOH levels over 100 ng/mL was significant with a P-value of <0.0005 (one tail test). CONCLUSION: CHS is associated with an elevated urinary THC-COOH level usually exceeding 100 ng/mL, which is indicative of significant chronic cannabis exposure. In patients with a history consistent with CHS, urine THC-COOH testing may help guide the diagnostic evaluation of these patients and decrease the need for further workup.

Sympathomimetic-Induced Hyperthermia and Hyponatremia: A Simulation Case for Emergency Medicine Residents.

Introduction: MDMA (3,4-methylenedioxymethamphetamine) is a popular drug of abuse associated with a variety of clinical manifestations. There are a number of life-threatening sequelae, including, but not limited to, agitated delirium, cardiac dysrhythmias, and hyperthermia. Similar to other substances that cause sympathomimetic toxidromes, MDMA also induces a syndrome of inappropriate antidiuretic hormone secretion-like state resulting in hyponatremia. The management of hyperthermia is of particular importance, as time to correction, particularly at temperatures greater than 106 °F, is directly associated with increased risk of morbidity and mortality. Methods: We created a simulation-based intervention to address and improve clinical skills relating to the management of MDMA intoxication. The scenario used a simulated patient to teach emergency medicine residents how to properly diagnose sympathomimetic toxicity and manage resultant hyperthermia and hyponatremia with cooling measures and appropriate fluid administration. Learners participated in a debrief session and were given an anonymous survey to assess their perceived knowledge. The case was performed as part of monthly emergency medicine resident didactics. Results: Eighteen learners took part in the case, with a 100% response rate. All participants agreed that the scenario increased their knowledge of cooling methods in severe hyperthermia, particularly whole-body packing. Eighty-nine percent (n = 16) reported that the scenario changed their practice patterns. Discussion: This simulated scenario requires minimal resources and can be instituted with emergency medicine residents from all levels of training. The scenario achieved its primary goal of improving residents' perceived knowledge of cooling measures in severe hyperthermia.

Trends in Living Donation by Race and Ethnicity Among Children With End-stage Renal Disease in the United States, 1995-2015.

BACKGROUND: Living donor kidney transplants have declined among adults with end-stage renal disease (ESRD), with increases in racial/ethnic disparities over time. Secular trends in racial/ethnic disparities in living donor kidney transplantation have not been well studied in children. METHODS: Using multivariable Cox modeling, we examined changes in living donor kidney transplant rates over time and probability of receiving living donor kidney transplantation within 2 years of incident ESRD by race/ethnicity among 19 772 children in the US Renal Data System, 1995-2015. We also examined racial/ethnic concordance between donors and recipients. RESULTS: Overall, living donor kidney transplant rates declined by 3% annually since 1995 for all racial/ethnic groups except Asians for whom living donor kidney transplant rates remained stable; however, disparities persist. Compared with non-Hispanic white children, Hispanics were 42% less likely (adjusted hazard ratio: 0.58; 95% confidence interval: 0.49-0.67), Asians 39% less likely (0.61; 0.47-0.79), and blacks 66% less likely (0.34; 0.28-0.42) to receive living kidney donor transplantation within 2 years, even when accounting for deceased donor transplantation as a competing risk. Additionally, while 95% of non-Hispanic white children had non-Hispanic white donors, only 56% of Asian recipients had Asian donors (P < 0.001). Asian recipients were more likely to have nonrelated donors (P < 0.001). CONCLUSIONS: There are ongoing declines in living donation for children with ESRD for uncertain reasons, and minority populations experience significantly reduced access to timely living donor transplant, even when accounting for changes in deceased donation and donor-recipient relationships.

Metabolic reduction after long-duration flight is not related to fat-free mass loss or flight duration in a migratory passerine.

Migratory birds catabolize large quantities of protein during long flights, resulting in dramatic reductions in organ and muscle mass. One of the many hypotheses to explain this phenomenon is that decrease in lean mass is associated with reduced resting metabolism, saving energy after flight during refueling. However, the relationship between lean body mass and resting metabolic rate remains unclear. Furthermore, the coupling of lean mass with resting metabolic rate and with peak metabolic rate before and after long-duration flight have not previously been explored. We flew migratory yellow-rumped warblers (Setophaga coronata) in a wind tunnel under one of two humidity regimes to manipulate the rate of lean mass loss in flight, decoupling flight duration from total lean mass loss. Before and after long-duration flights, we measured resting and peak metabolism, and also measured fat mass and lean body mass using quantitative magnetic resonance. Flight duration ranged from 28 min to 600 min, and birds flying under dehydrating conditions lost more fat-free mass than those flying under humid conditions. After flight, there was a 14% reduction in resting metabolism but no change in peak metabolism. Interestingly, the reduction in resting metabolism was unrelated to flight duration or to change in fat-free body mass, indicating that protein metabolism in flight is unlikely to have evolved as an energy-saving measure to aid stopover refueling, but metabolic reduction itself is likely to be beneficial to migratory birds arriving in novel habitats.

Test of a clinical model of poor physical health and suicide: The role of depression, psychosocial stress, interpersonal conflict, and panic.

BACKGROUND: This study employed a structural equation model to examine the relationships between poor physical health, suicide, depression, psychosocial stress, interpersonal conflict, and panic. METHODS: The sample consisted of a large, archived set of mental health treatment-seeking adults who completed a behavioral outcome questionnaire prior to beginning treatment. RESULTS: Results supported the extant literature indicating that poor physical health, depression, psychosocial stress, interpersonal conflict, and panic impose increased risk for suicidal ideation, with depression demonstrating the highest risk for increased suicidal ideation. The results also supported the hypotheses that depression, psychosocial stress, interpersonal conflict, and panic would mediate the association between poor physical health and suicidal ideation. Although no a priori hypotheses were made regarding relationships among the 15 physical illnesses examined, results indicated that HIV/AIDS had the strongest correlation with depression and the weakest correlation with interpersonal conflict. LIMITATIONS: Firstly, the study sample was primarily Caucasian, limiting its generalizability. Secondly, causal inferences should be interpreted with caution, due to the quasi-experimental design. Thirdly, these data were self-reported, which create response biases since suicidal ideation is stigmatized. CONCLUSIONS: These findings highlight the importance of considering interpersonal factors as potential mediators in the relationship between poor physical health, mental illness, and suicide. Clinically, the impact of an active major depressive episode on an individual who is struggling with a serious physical illness may be strongly predictive of suicidal ideation.

Repetitive Fragile Sites: Centromere Satellite DNA As a Source of Genome Instability in Human Diseases.

Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which are often sites of aberrant rearrangements that may lead to chromosome fusions and genetic abnormalities. While the centromere has an essential role in chromosome segregation during mitosis, the long and repetitive nature of the highly identical repeats has greatly hindered in-depth genetic studies, and complete annotation of all human centromeres is still lacking. Here, we review our current understanding of human centromere genetics and epigenetics as well as recent investigations into the role of centromere DNA in disease, with a special focus on cancer, aging, and human immunodeficiency⁻centromeric instability⁻facial anomalies (ICF) syndrome. We also highlight the causes and consequences of genomic instability at these large repetitive arrays and describe the possible sources of centromere fragility. The novel connection between alpha-satellite DNA instability and human pathological conditions emphasizes the importance of obtaining a truly complete human genome assembly and accelerating our understanding of centromere repeats' role in physiology and beyond.

Provisional Tic Disorder: What to tell parents when their child first starts ticcing.

The child with recent onset of tics is a common patient in a pediatrics or child neurology practice. If the child's first tic was less than a year in the past, the diagnosis is usually Provisional Tic Disorder (PTD). Published reviews by experts reveal substantial consensus on prognosis in this situation: the tics will almost always disappear in a few months, having remained mild while they lasted. Surprisingly, however, the sparse existing data may not support these opinions. PTD may have just as much importance for science as for clinical care. It provides an opportunity to prospectively observe the spontaneous remission of tics. Such prospective studies may aid identification of genes or biomarkers specifically associated with remission rather than onset of tics. A better understanding of tic remission may also suggest novel treatment strategies for Tourette syndrome, or may lead to secondary prevention of tic disorders. This review summarizes the limited existing data on the epidemiology, phenomenology, and outcome of PTD, highlights areas in which prospective study is sorely needed, and proposes that tic disorders may completely remit much less often than is generally believed.

Emotion-focused treatments for anorexia nervosa: a systematic review of the literature.

PURPOSE: The present review explores emotion-focused treatments for anorexia nervosa (AN). METHODS: We conducted a systematic literature search across key databases (PsychINFO, PubMed/Medline, and Web of Science) prior to September 2015. Twenty studies were selected for systematic review. RESULTS: The present review found initial evidence supporting the acceptability and feasibility of emotion-focused treatments for AN. Although preliminary results are promising, further controlled studies are necessary to establish the efficacy of emotion-focused treatments for AN. CONCLUSIONS: Future controlled trials should compare emotion-focused treatments against each other and against other AN treatments. Future studies should also examine the mechanisms of action for the emotion-focused treatments and treatment moderators.

Phosphorylation at serine 331 is required for Aurora B activation.

Aurora B kinase activity is required for successful cell division. In this paper, we show that Aurora B is phosphorylated at serine 331 (Ser331) during mitosis and that phosphorylated Aurora B localizes to kinetochores in prometaphase cells. Chk1 kinase is essential for Ser331 phosphorylation during unperturbed prometaphase or during spindle disruption by taxol but not nocodazole. Phosphorylation at Ser331 is required for optimal phosphorylation of INCENP at TSS residues, for Survivin association with the chromosomal passenger complex, and for complete Aurora B activation, but it is dispensable for Aurora B localization to centromeres, for autophosphorylation at threonine 232, and for association with INCENP. Overexpression of Aurora B(S331A), in which Ser331 is mutated to alanine, results in spontaneous chromosome missegregation, cell multinucleation, unstable binding of BubR1 to kinetochores, and impaired mitotic delay in the presence of taxol. We propose that Chk1 phosphorylates Aurora B at Ser331 to fully induce Aurora B kinase activity. These results indicate that phosphorylation at Ser331 is an essential mechanism for Aurora B activation.

Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2.

Using chemical genetics to reversibly inhibit Cdk1, we find that cells arrested in late G2 are unable to delay mitotic entry after irradiation. Late G2 cells detect DNA damage lesions and form gamma-H2AX foci but fail to activate Chk1. This reflects a lack of DNA double-strand break processing because late G2 cells fail to recruit RPA (replication protein A), ATR (ataxia telangiectasia and Rad3 related), Rad51, or CtIP (C-terminal interacting protein) to sites of radiation-induced damage, events essential for both checkpoint activation and initiation of DNA repair by homologous recombination. Remarkably, inhibition of Akt/PKB (protein kinase B) restores DNA damage processing and Chk1 activation after irradiation in late G2. These data demonstrate a previously unrecognized role for Akt in cell cycle regulation of DNA repair and checkpoint activation. Because Akt/PKB is frequently activated in many tumor types, these findings have important implications for the evolution and therapy of such cancers.

Vertebrate cells genetically deficient for Cdc14A or Cdc14B retain DNA damage checkpoint proficiency but are impaired in DNA repair.

A recent study suggested that human Cdc14B phosphatase has a central function in the G2 DNA damage checkpoint. In this study, we show that chicken DT40, human HCT116, and human telomerase reverse transcription-immortalized retinal pigment epithelial cells deleted for the Cdc14A or Cdc14B gene are DNA damage checkpoint proficient and arrest efficiently in G2 in response to irradiation. Cdc14A knockout (KO) or Cdc14B-KO cells also maintain normal levels of Chk1 and Chk2 activation after irradiation. Surprisingly, however, irradiation-induced gamma-H2A.X foci and DNA double-strand breaks persist longer in Cdc14A-KO or Cdc14B-KO cells than controls, suggesting that Cdc14 phosphatases are required for efficient DNA repair.

Adipose tissue distribution after weight restoration and weight maintenance in women with anorexia nervosa.

BACKGROUND: Body image distortions are a core feature of anorexia nervosa (AN). We, and others, previously reported abnormalities in adipose tissue distribution after acute weight restoration in adult women with AN compared with body mass index-matched healthy control women. Whether these abnormalities persist over time remains unknown. OBJECTIVES: We aimed to 1) replicate previous findings that showed preferential central accumulation of adipose tissue in recently weight-restored AN women compared with control subjects, 2) describe the change within patients with longer-term (1-y) weight maintenance, and 3) compare adipose tissue distribution after 1-y maintenance with that of control subjects. DESIGN: Body composition and adipose tissue distribution were assessed by whole-body magnetic resonance imaging in women with AN shortly after weight normalization (n = 30) and again 1 y after hospital discharge (n = 16) and in 8 female control subjects at 2 time points. RESULTS: With acute weight restoration, AN patients had significantly greater visceral and intermuscular adipose tissue compared with control women [visceral: 0.75 +/- 0.26 compared with 0.51 +/- 0.26 kg in AN patients and controls, respectively (P = 0.02); intermuscular: 0.46 +/- 0.17 compared with 0.29 +/- 0.13 kg in AN patients and controls, respectively (P = 0.01)]. With maintenance of normal weight for approximately 1 y, visceral adipose tissue distribution in AN patients was not different from that in healthy control subjects. CONCLUSIONS: In adult women with AN, normalization of weight in the short term is associated with a distribution of adipose tissue that is consistent with a central adiposity phenotype. This abnormal distribution appears to normalize within a 1-y period of weight maintenance. This research was registered at clinicaltrials.gov as NCT 00271921 and NCT 00368667.

From guidelines to careflows: modelling and supporting complex clinical processes.

Research on computer interpretable clinical guidelines has largely focused on individual points of care rather than processes of care. Whether we consider simple aids like clinical alerts and reminders or more sophisticated data interpretation and decision-making, guideline developers tend to focus on specific tasks rather than processes like care plans and pathways which are extended in time. In contrast, research on business process modelling has demonstrated notations and tools which deal directly with process modelling, but has not been concerned with problems like data interpretation and decision making. In this chapter we describe these two traditions, and compare some of their strengths and weaknesses. We also briefly discuss the distinct theoretical frameworks which have grown up around them, notably Petri nets for workflow modelling and mathematical logics for guidelines. We conclude that these offer complementary views of clinical processes and that a key research challenge is find a way of unifying them.