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.

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.

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.

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.

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.

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.

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.

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.

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.

Chk1 is required for spindle checkpoint function.

The spindle checkpoint delays anaphase onset in cells with mitotic spindle defects. Here, we show that Chk1, a component of the DNA damage and replication checkpoints, protects vertebrate cells against spontaneous chromosome missegregation and is required to sustain anaphase delay when spindle function is disrupted by taxol, but not when microtubules are completely depolymerized by nocodazole. Spindle checkpoint failure in Chk1-deficient cells correlates with decreased Aurora-B kinase activity and impaired phosphorylation and kinetochore localization of BubR1. Furthermore, Chk1 phosphorylates Aurora-B and enhances its catalytic activity in vitro. We propose that Chk1 augments spindle checkpoint signaling and is required for optimal regulation of Aurora-B and BubR1 when kinetochores produce a weakened signal. In addition, Chk1-deficient cells exhibit increased resistance to taxol. These results suggest a mechanism through which Chk1 could protect against tumorigenesis through its role in spindle checkpoint signaling.

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.

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.

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.

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.

c-Jun-deficient cells undergo premature senescence as a result of spontaneous DNA damage accumulation.

Mouse embryo fibroblasts deficient for the c-Jun proto-oncogene (c-Jun-/- MEF) undergo p53-dependent premature senescence in conventional culture. This phenotype becomes evident only after several cell divisions, suggesting that senescence may result from exposure to unknown environmental factors. Here, we show that c-Jun-/- MEF can proliferate successfully in low oxygen (3% O2), indicating that premature senescence under conventional culture conditions is a consequence of hyperoxic stress. c-Jun-/- MEF exhibit higher basal levels of DNA damage compared to normal fibroblasts in high but not low oxygen, implying that senescence results from chronic accumulation of spontaneous DNA damage. This accumulation may be attributable, at least in part, to inefficient repair, since DNA damage induced by gamma ionizing radiation and H2O2 persists for longer in c-Jun-/- MEF than in wild-type MEF. Unexpectedly, p53 expression, phosphorylation, and transcriptional activity are largely unaffected by oxygen exposure, indicating that the accumulation of spontaneous DNA damage does not result in chronic activation of p53 as judged by conventional criteria. Finally, we find that c-Jun associates with nuclear foci containing gammaH2AX and ATM following irradiation, suggesting a potential role for c-Jun in DNA repair processes per se.

The impact of a genetics education program on physicians' knowledge and genetic counseling referral patterns.

BACKGROUND: Gaps in the knowledge of general practitioners (GPs) in medical genetics prevent the effective utilization of genetic services and increase the risk of liability. Educators recommend that genetics should be integrated into existing teaching programs but the effectiveness of these types of programs is unknown. AIM: The objective of this study was to provide a 2-year educational program for GPs untrained in genetics and to document its impact on genetic knowledge and referrals to a genetic counselor (GC). METHODS: Eight genetic lectures series were given at quarterly intervals. Family practice residents received additional training in a genetics clinic, and participated in monthly seminars and bi-annual journal clubs. A pretest-post-test study design (n = 143) was used to evaluate the genetic knowledge of GPs. Post-test scores [mean (%) +/- SD; 76.1 +/- 16.8] showed significant improvement compared to pretest scores (61.9 +/- 19.1). The majority of participants (81%) indicated that the program would have an impact on their clinical practice. The number of referrals to a GC from GPs untrained in genetics did not change over the 2-year period of the program. CONCLUSION: The results suggest that an integrated educational program in genetics can enhance physicians' knowledge but may not alter referral patterns to a GC.

An ontological approach to modelling tasks and goals.

Current approaches to modelling plans and processes in AI are limited by current understanding of "goals" and "intentions". We discuss this question in a medical context, viewing goals as clinical objectives and plans and processes as collections of tasks to achieve those objectives. The specific context for this discussion is the CREDO project, which aims to develop a comprehensive approach to supporting complex treatment plans and care pathways and provides an opportunity to carry out an extensive investigation of the key problem of formalising goals in medical informatics and AI generally. A review of 222 clinical services required in the management of breast cancer has yielded a systematic classification of tasks involved in breast cancer care and a similar classification of the clinical goals associated with these tasks. A six-component model of goal structure is proposed based on these ontological analyses. Although the model has been derived from a corpus of examples from medicine many of the issues encountered, and the solution proposed, appear to be relevant to other domains.

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.