搜索结果：Transactions of the American Clinical and Climatological Association

In 2005, Elias Zerhouni, Director of the National Institutes of Health, posited that: “It is the responsibility of those of us involved in today's biomedical research enterprise to translate the remarkable scientific innovations we are witnessing into health gains for the nation.”1 To attain this goal, he announced the launch of the Clinical and Translational Science Awards. The CTSAs would provide academic institutions the resources with which to bridge traditional bench and clinical research, develop methodologies for bringing bench discoveries into medical practice more expeditiously, create innovative models for training both undergraduates and graduates in the clinical and translational sciences, and apply advances in medical informatics and community-based research to improve patient care. More importantly, the CTSAs introduced the moniker “clinical and translational science” into the lexicon of American medicine and science. Recognizing that this new area of science would need a forum for sharing news, ideas and research results, a group began discussions in 2005 about the creation of a journal focused on translational medicine. Those discussions were formalized in a meeting at the Union League of Philadelphia in 2006 and led to the publication of the first issue of CTS—Clinical and Translational Science in May of 2008. The members of the group that met at the Union League are represented today in the list of associate editors on the masthead of CTS. Blackwell Publishing, a family-owned Oxford, United Kingdom, publishing house that published its first book in 1897, was the initial publisher of CTS thanks to the efforts of Steven Korn and Laura Colantoni. However, prior to the first issue, and with the support of Danette Somers, Wiley became the publisher of CTS following its purchase of Blackwell. In 2008, Dr. Barry Coller, Physician in Chief, Vice President for Medical Affairs and Director of the CTSA at the Rockefeller Institute and a group of colleagues from various CTSAs from across the country founded the Society of Clinical and Translational Science. CTS soon became “an” official journal of the Society as well as “an” official journal of the Association of Patient-Oriented Research. In 2012, the Society for Clinical and Translational Science (SCTS), the Association for Clinical Research Training and the Association for Patient-Oriented Research (APOR) merged to form the Association of Clinical and Translational Science (ACTS).2 CTS became “the” official journal of the new Association in the same year in order to support its missions: to promote research, education, advocacy, and mentoring to improve human health. The CTS journal has not been immune to the exigencies of the world of publishing. Several years ago, Wiley discontinued the print edition of CTS providing only the online journal to readers and access to the online edition was limited to libraries with an institutional subscription to the journal or to the relatively few individual members of ACTS. Authors could elect to have their full articles accessible to anyone through PubMed or other search engines if they were willing to pay an “open-access” fee. The journal has continued to publish the abstracts of the yearly Joint Association Scientific Meeting, an In the News section that provides up-to-date information about new funding opportunities and other news of interest to translational scientists, commentaries from individual CTSA's and an editorial from the President of the Association. While we continued to publish manuscripts reflecting the large spectrum of the clinical and translational sciences, we found that we were the home for a group of translational sciences, CTS also became a primary home for manuscripts that did not fit with the focus of any competing journal: articles related to community engagement, mentoring, education and newly developed fields such as population health, comparative health informatics and research ethics. Indeed, despite a blossoming number of “translational science” journals, CTS has maintained a healthy backlog of accepted manuscripts. In late 2015, the ACTS was informed that John Wiley & Sons, Inc., consistent with the contractual relationship between the journal and the publisher, would terminate its relationship with the Association in 90 days and that the ownership of the journal had transferred from Wiley to the American Society for Clinical Pharmacology and Therapeutics (ASCPT). At the same time, I was informed that my contract, set to end December 30, 2015, would not be renewed by the ASCPT and that going forward, the ASCPT would select both its own editor and its own editorial board for CTS. ASCPT has a subscription journal, the Journal of the American Society for Clinical Pharmacology and Therapeutics and our understanding is that CTS will serve as an “open-access” journal to complement their subscription journal. The creation of open-access journals “downstream” of subscription journals is becoming an increasingly frequent paradigm in the publishing industry. One need only look at the American Heart Association family of journals (Journal of the American Heart Association—JAHA), the Journal of the American Medical Association (JAMA-medicine, JAMA-opthalmology), and the Journal of the American College of Cardiology (JACC Heart Failure) to see the evolution of this paradigm. Indeed, even the Journal of Clinical Investigation is reported to be considering creation of an open-access journal to enable them to publish articles “downstream” of their subscription journal. Over the past four months we have worked assiduously to create a smooth transition from Wiley/ACTS to ASCPT and I am happy to say that every manuscript submitted to CTS prior to October 2015 will be published prior to the end of 2015 under the original rubric and therefore, without publication costs to the authors. In 1884, William Osler and a group of colleagues formed the first medical and research society in America, the American Clinical and Climatologic Association, with the goal of improving medical research, education and clinical care. Its members espoused the belief that the best treatment for tuberculosis was to place patients in an ideal climate. (http://www.accasociety.org) In 1886, senior leaders of American medicine formed the Association of American Physicians (AAP) in an effort to provide an opportunity for America's growing cadre of clinical scientists to communicate and to interact socially and with a focus on pathology-based research including postmortem findings. In 1909, a group of young scientists formed the American Society for the Advancement of Clinical Investigation with a focus on understanding the biologic basis of disease (later changed to the American Society of Clinical Investigation—ASCI) and in their first meeting in Washington DC, the group listened to a lecture from a guest speaker and several scientific presentations. These three societies set the bar for future associations of physicians and scientists in that they have met yearly since their founding and have communicated with each other through society journals. The society journal that emanated from the ACCA in 1892 (The Transactions of the American Clinical and Climatologic Association) and from the AAP/ASCI (The Journal of Clinical Investigation) in the late 1940's, continue to publish today. An unofficial “publications committee” of the ACTS has been meeting over the past 6 months to find a way forward for ACTS and hopefully news of a phoenix rising will be forthcoming in the near future because history has taught us that a successful society needs a successful journal to advance its interest in science, research and advocacy. I would like to take this opportunity to thank the large number of individuals who were critical to the success of the journal from the recognition in 2005 of the need for a journal focused on translational science to the completion of this last issue under my tenure as Editor-in-Chief. Shawn Morton of Wiley has been a supportive publisher who has kept us on track over the past 5 years and facilitated the transition to the ASCPT. Dr. Steven Reis served as Editor for the CTSA Profile Section of CTS and has continuously commissioned enlightening articles documenting innovative programs or novel structures that have facilitated discovery and or training amongst the growing number of clinical and translational science awardees. Each of the Society/Association's presidents have fully supported the journal and contributed to its growth: Drs. Barry Coller, Anantha Shekhar, Michael Lichtenstein, and Rebecca Jackson. The Associate Editors and the members of the Editorial Board have not only contributed to the journal but have also reviewed manuscripts and provided important insights and comments and our Deputy Editor, Scott Waldman, has been an excellent sounding board when controversial manuscripts or commentaries have crossed my desk. We hope that CTS has served the community of translational scientists well and has helped to push our discipline towards the goals set by Dr. Zerhouni ten years ago.

Varicella-zoster virus (VZV) is the etiologic agent of varicella (chicken pox), a childhood exanthematic disease that develops as a result of primary infection, and zoster (shingles), caused by reactivation of the virus persisting in a latent form in the dorsal sensory ganglia. Although varicella is generally a mild self-limiting illness, in immunocompromised subjects and adults it can have a serious clinical course that can lead to permanent damage of the central nervous system. In these and in most zoster cases, treatment with anti-herpetic drugs and/or immunotherapy is necessary. Because it is highly contagious, varicella is one of the most common exanthematic diseases. It is preventable by vaccination with an attenuated vaccine administered around the first year of age, and with a boost vaccination in school age. This article briefly describes the natural history and pathophysiology of VZV infection and its current epidemiology and provides an overview of current and future vaccine options to protect against varicella and/or zoster.

Erectile function is a haemodynamic phenomenon depending on the integrity of neurological, vascular, endocrinological, tissue (corpora cavernosa), psychological and relational factors; changes in any one of these components may lead to erectile dysfunction (ED). ED and its comorbid conditions share common risk factors such as endothelial dysfunction, atherosclerosis and metabolic and hormonal abnormalities. Furthermore, although cross-sectional studies have shown a clear age-dependent association between ED, diabetes mellitus, hypertension, metabolic syndrome (MetS) and cardiovascular diseases, longitudinal evidence has recently emphasized that ED could be an early marker of these conditions. Recently, the European Association of Urology and American Urology Association provided consensus guidelines for the management of ED patients. However, the metabolic aspect of ED is rather neglected or not sufficiently treated. In this study, more emphasis will be placed on the presence of ED comorbid metabolic factors. The primary and secondary goals of therapy, according to current guidelines and to prevent their clinical evolution, will also be provided. We review the concepts of metabolic diseases related to ED and their treatment. Criteria for the diagnosis and treatment of hypogonadism, metabolic and vascular disease related to ED were analysed. ED can mark the starting point for the evaluation and prevention of significant severe diseases (such as diabetes, MetS, dyslipidaemia, arteriosclerosis, hypertension, ischaemic cardiopathy, neuropathy, etc.) hitherto unknown by the patients. Most widely used criteria for the diagnosis and treatment of these diseases were reported. We suggest a clinical approach which allows the identification of metabolic and others systemic pathologies contributing to the development of ED. This approach may constitute an improvement in disease prognosis and either induce a spontaneous reduction of ED or facilitate its specific therapy.

The competency of any intelligent agent is bounded by its formal account of the world in which it operates. Clinical AI lacks such an account. Existing frameworks address evaluation, regulation, or system design in isolation, without a shared model of the clinical world to connect them. We introduce the Clinical World Model, a framework that formalizes care as a tripartite interaction among Patient, Provider, and Ecosystem. To formalize how any agent, whether human or artificial, transforms information into clinical action, we develop parallel decision-making architectures for providers, patients, and AI agents, grounded in validated principles of clinical cognition. The Clinical AI Skill-Mix operationalizes competency through eight dimensions. Five define the clinical competency space (condition, phase, care setting, provider role, and task) and three specify how AI engages human reasoning (assigned authority, agent facing, and anchoring layer). The combinatorial product of these dimensions yields a space of billions of distinct competency coordinates. A central structural implication is that validation within one coordinate provides minimal evidence for performance in another, re

A growing awareness of the mechanisms by which phytochemicals can influence upstream endogenous cellular defence processes has led to intensified research into their potential relevance in the prevention and treatment of disease. Pharmaceutical medicine has historically looked to plants as sources of the starting materials for drug development; however, the focus of nutraceutical medicine is to retain the plant bioactive in as close to its native state as possible. As a consequence, the potency of a nutraceutical concentrate or an extract may be lower than required for significant gene expression. The molecular structure of bioactive phytochemicals to a large extent determines the molecule's bioavailability. Polyphenols are abundant in dietary phytochemicals, and extensive in vitro research has established many of the signalling mechanisms involved in favourably modulating human biochemical pathways. Such pathways are associated with core processes such as redox modulation and immune modulation for infection control and for downregulating the synthesis of inflammatory cytokines. Although the relationship between oxidative stress and chronic disease continues to be affirmed, direct-acting antioxidants such as vitamins A, C, and E, beta-carotene, and others have not yielded the expected preventive or therapeutic responses, even though several large meta-analyses have sought to evaluate the potential benefit of such supplements. Because polyphenols exhibit poor bioavailability, few of their impressive in vitro findings have been replicated in vivo. SFN, an aliphatic isothiocyanate, emerges as a phytochemical with comparatively high bioavailability. A number of clinical trials have demonstrated its ability to produce favourable outcomes in conditions for which there are few satisfactory pharmaceutical solutions, foreshadowing the potential for SFN as a clinically relevant nutraceutical. Although myrosinase-inert broccoli sprout extracts are widely available, there now exist myrosinase-active broccoli sprout supplements that yield sufficient SFN to match the doses used in clinical trials.

In this work, we expand the idea of Samuelson[3] and Shepp[2,5,6] for stock optimization using the Bachelier model [4] as our models for the stock price at the money (X[stock price]= K[strike price]) for the American call and put options [1]. At the money (X= K) for American options, the expected payoff of both the call and put options is zero. Shepp investigated several stochastic optimization problems using martingale and stopping time theories [2,5,6]. One of the problems he investigated was how to optimize the stock price using both the Black-Scholes (multiplicative) and the Bachelier (additive) models [7,6] for the American option above the strike price K (exercise price) to a stopping point. In order to explore the non-relativistic quantum effect on the expected payoff for both the call and put options at the money, we assumed the stock price to undergo a stochastic process governed by the Bachelier (additive) model [4]. Further, using Ito calculus and martingale theory, we obtained a differential equation for the expected payoff for both the call and put options in terms of delta and gamma. We also obtained the solution to the non-relativistic Schroedinger equation as the ex

Binomial tree methods (BTM) and explicit difference schemes (EDS) for the variational inequality model of American options with time dependent coefficients are studied. When volatility is time dependent, it is not reasonable to assume that the dynamics of the underlying asset's price forms a binomial tree if a partition of time interval with equal parts is used. A time interval partition method that allows binomial tree dynamics of the underlying asset's price is provided. Conditions under which the prices of American option by BTM and EDS have the monotonic property on time variable are found. Using convergence of EDS for variational inequality model of American options to viscosity solution the decreasing property of the price of American put options and increasing property of the optimal exercise boundary on time variable are proved. First, put options are considered. Then the linear homogeneity and call-put symmetry of the price functions in the BTM and the EDS for the variational inequality model of American options with time dependent coefficients are studied and using them call options are studied.

The role of the weather as a trigger of sickle cell acute painful episodes has long been debated. To more accurately describe the role of the weather as a trigger of painful events, we conducted a case-crossover study of the association between local weather conditions and the occurrence of painful episodes. From the Cooperative Study of Sickle Cell Disease, we identified 813 patients with sickle cell anaemia who had 3570 acute painful episodes. We found an association between wind speed and the onset of pain, specifically wind speed during the 24-h period preceding the onset of pain. Analysing wind speed as a categorical trait, showed a 13% increase (95% confidence interval: 3%, 24%) in odds of pain, when comparing the high wind speed to lower wind speed (P = 0.007). In addition, the association between wind speed and painful episodes was found to be stronger among men, particularly those in the warmer climate regions of the United States. These results are in agreement with another study that found an association between wind speed and hospital visits for pain in the United Kingdom, and lends support to physiological and clinical studies that have suggested that skin cooling is associated with sickle vasoocclusion and perhaps pain.

OBJECTIVES: To study climatological and public health events which might have affected the 2007 two-wave dengue outbreak in Taiwan, an island with both tropical and subtropical regions, where the 2007 dengue incidence exceeded the combined total of the previous four years. METHODS: A multi-phase Richards model was fitted to weekly cumulative dengue data to pinpoint the turning points of the outbreak. We obtained the 'initial' reproduction numbers for the two waves of the outbreak. By means of correlation analysis we explored the possible impact of climatological events on the occurrence of turning points. RESULTS: Three turning points occurred around early August, late August/early September, and late October/early November. The 'initial' reproduction number for the first wave was R(i) = 4.67 (95% CI: 0*-10.92), where 0* = max{0, lower bound}, and R(i) = 3.93 (95% CI: 1.74-6.13) for the second wave. The highest correlation was between dengue incidence and two climatological variables: maximum temperature at a lag of 5 weeks (r = 0.66 and 0.71) and total precipitation at a lag of seven weeks (r = 0.53). Conclusions The first two turning points were partially attributable to two typhoons around early to mid-August that brought a sharp drop in temperature and substantial rainfall. The drop in temperature first drove the dengue incidence down, then the rainfall drove it up at the beginning of fall. In recent years, Taiwan has witnessed increasingly frequent large summer dengue outbreaks that persisted into early winter, perhaps due to warmer autumns. This highlights the possible impact of global warming on the spread of infectious diseases.

Ethereum is one of the most popular platforms for the development of blockchain-powered applications. These applications are known as Dapps. When engineering Dapps, developers need to translate requests captured in the front-end of their application into one or more smart contract transactions. Developers need to pay for these transactions and, the more they pay (i.e., the higher the gas price), the faster the transaction is likely to be processed. Therefore developers need to optimize the balance between cost (transaction fees) and user experience (transaction processing times). Online services have been developed to provide transaction issuers (e.g., Dapp developers) with an estimate of how long transactions will take to be processed given a certain gas price. These estimation services are crucial in the Ethereum domain and several popular wallets such as Metamask rely on them. However, their accuracy has not been empirically investigated so far. In this paper, we quantify the transaction processing times in Ethereum, investigate the relationship between processing times and gas prices, and determine the accuracy of state-of-the-practice estimation services. We find that transact

Abstract Tropical forests are recognized for their role in providing diverse ecosystem services (ESs), with carbon uptake the best recognized. The capacity of tropical forests to provide ESs is strongly linked to their enormous biodiversity. However, causal relationships between biodiversity and ESs are poorly understood. This may be because biodiversity is often translated into species richness. Here, we argue that focusing on multiple attributes of biodiversity—structure, composition, and function—will make relationships between biodiversity and ESs clearer. In this review, we discuss the ecological processes behind ESs from tropical humid and subhumid forests of South America. Our main goal is to understand the links between the ESs and those three biodiversity attributes. While supporting and regulating services relate more closely to forest structure and function, provisioning services relate more closely to forest composition and function, and cultural services are more related to structure and composition attributes. In this sense, ESs from subhumid forests (savannas) differ from those provided by the Amazon Forest, although both ecosystems are recognized as harboring tremendous biodiversity. Given this, if anthropogenic drivers of change promote a shift in the Amazon Forest toward savanna—the savannization hypothesis—the types of services provided will change, especially climate regulating services. This review emphasizes the importance of deeply understanding ecosystem structure, composition, and function to better understand the services ecosystems provide. Understanding that anthropogenic impacts on biodiversity occur through these three main attributes, it becomes easier to anticipate how humans will impact ESs.

Since most of the traded options on individual stocks is of American type it is of interest to generalize the results obtained in semi-static trading to the case when one is allowed to statically trade American options. However, this problem has proved to be elusive so far because of the asymmetric nature of the positions of holding versus shorting such options. Here we provide a unified framework and generalize the fundamental theorem of asset pricing (FTAP) and hedging dualities in arXiv:1502.06681 (to appear in Annals of Applied Probability) to the case where the investor can also short American options. Following arXiv:1502.06681, we assume that the longed American options are divisible. As for the shorted American options, we show that the divisibility plays no role regarding arbitrage property and hedging prices. Then using the method of enlarging probability spaces proposed in arXiv:1604.05517, we convert the shorted American options to European options, and establish the FTAP and sub- and super-hedging dualities in the enlarged space both with and without model uncertainty.

BACKGROUND: During the last decades, dengue viruses have spread throughout the Americas region, with an increase in the number of severe forms of dengue. The surveillance system in Guadeloupe (French West Indies) is currently operational for the detection of early outbreaks of dengue. The goal of the study was to improve this surveillance system by assessing a modelling tool to predict the occurrence of dengue epidemics few months ahead and thus to help an efficient dengue control. METHODS: The Box-Jenkins approach allowed us to fit a Seasonal Autoregressive Integrated Moving Average (SARIMA) model of dengue incidence from 2000 to 2006 using clinical suspected cases. Then, this model was used for calculating dengue incidence for the year 2007 compared with observed data, using three different approaches: 1 year-ahead, 3 months-ahead and 1 month-ahead. Finally, we assessed the impact of meteorological variables (rainfall, temperature and relative humidity) on the prediction of dengue incidence and outbreaks, incorporating them in the model fitting the best. RESULTS: The 3 months-ahead approach was the most appropriate for an effective and operational public health response, and the most accurate (Root Mean Square Error, RMSE = 0.85). Relative humidity at lag-7 weeks, minimum temperature at lag-5 weeks and average temperature at lag-11 weeks were variables the most positively correlated to dengue incidence in Guadeloupe, meanwhile rainfall was not. The predictive power of SARIMA models was enhanced by the inclusion of climatic variables as external regressors to forecast the year 2007. Temperature significantly affected the model for better dengue incidence forecasting (p-value = 0.03 for minimum temperature lag-5, p-value = 0.02 for average temperature lag-11) but not humidity. Minimum temperature at lag-5 weeks was the best climatic variable for predicting dengue outbreaks (RMSE = 0.72). CONCLUSION: Temperature improves dengue outbreaks forecasts better than humidity and rainfall. SARIMA models using climatic data as independent variables could be easily incorporated into an early (3 months-ahead) and reliably monitoring system of dengue outbreaks. This approach which is practicable for a surveillance system has public health implications in helping the prediction of dengue epidemic and therefore the timely appropriate and efficient implementation of prevention activities.

We consider a financial market where stocks are available for dynamic trading, and European and American options are available for static trading (semi-static trading strategies). We assume that the American options are infinitely divisible, and can only be bought but not sold. In the first part of the paper, we work within the framework without model ambiguity. We first get the fundamental theorem of asset pricing (FTAP). Using the FTAP, we get the dualities for the hedging prices of European and American options. Based on the hedging dualities, we also get the duality for the utility maximization. In the second part of the paper, we consider the market which admits non-dominated model uncertainty. We first establish the hedging result, and then using the hedging duality we further get the FTAP. Due to the technical difficulty stemming from the non-dominancy of the probability measure set, we use a discretization technique and apply the minimax theorem.

This paper is dedicated to the design and evaluation of the first AMR parser tailored for clinical notes. Our objective was to facilitate the precise transformation of the clinical notes into structured AMR expressions, thereby enhancing the interpretability and usability of clinical text data at scale. Leveraging the colon cancer dataset from the Temporal Histories of Your Medical Events (THYME) corpus, we adapted a state-of-the-art AMR parser utilizing continuous training. Our approach incorporates data augmentation techniques to enhance the accuracy of AMR structure predictions. Notably, through this learning strategy, our parser achieved an impressive F1 score of 88% on the THYME corpus's colon cancer dataset. Moreover, our research delved into the efficacy of data required for domain adaptation within the realm of clinical notes, presenting domain adaptation data requirements for AMR parsing. This exploration not only underscores the parser's robust performance but also highlights its potential in facilitating a deeper understanding of clinical narratives through structured semantic representations.

Objective: Integrating EHR data with other resources is essential in rare disease research due to low disease prevalence. Such integration is dependent on the alignment of ontologies used for data annotation. The International Classification of Diseases (ICD) is used to annotate clinical diagnoses; the Human Phenotype Ontology (HPO) to annotate phenotypes. Although these ontologies overlap in biomedical entities described, the extent to which they are interoperable is unknown. We investigate how well aligned these ontologies are and whether such alignments facilitate EHR data integration. Materials and Methods: We conducted an empirical analysis of the coverage of mappings between ICD and HPO. We interpret this mapping coverage as a proxy for how easily clinical data can be integrated with research ontologies such as HPO. We quantify how exhaustively ICD codes are mapped to HPO by analyzing mappings in the UMLS Metathesaurus. We analyze the proportion of ICD codes mapped to HPO within a real-world EHR dataset. Results and Discussion: Our analysis revealed that only 2.2% of ICD codes have direct mappings to HPO in UMLS. Within our EHR dataset, less than 50% of ICD codes have mapping

We present the results of processing the effects of the powerful Gamma Ray Burst GRB221009A captured by the charged particle detectors (electrostatic analyzers and solid-state detectors) onboard spacecraft at different points in the heliosphere on October 9, 2022. To follow the GRB221009A propagation through the heliosphere we used the electron and proton flux measurements from solar missions Solar Orbiter and STEREO-A; Earth magnetosphere and the solar wind missions THEMIS and Wind; meteorological satellites POES15, POES19, MetOp3; and MAVEN - a NASA mission orbiting Mars. GRB221009A had a structure of four bursts: less intense Pulse 1 - the triggering impulse - was detected by gamma-ray observatories at 131659 UT (near the Earth); the most intense Pulses 2 and 3 were detected on board all the spacecraft from the list, and Pulse 4 detected in more than 500 s after Pulse 1. Due to their different scientific objectives, the spacecraft, which data was used in this study, were separated by more than 1 AU (Solar Orbiter and MAVEN). This enabled tracking GRB221009A as it was propagating across the heliosphere. STEREO-A was the first to register Pulse 2 and 3 of the GRB, almost 100 secon

American options are studied in a general discrete market in the presence of proportional transaction costs, modelled as bid-ask spreads. Pricing algorithms and constructions of hedging strategies, stopping times and martingale representations are presented for short (seller's) and long (buyer's) positions in an American option with an arbitrary payoff. This general approach extends the special cases considered in the literature concerned primarily with computing the prices of American puts under transaction costs by relaxing any restrictions on the form of the payoff, the magnitude of the transaction costs or the discrete market model itself. The largely unexplored case of pricing, hedging and stopping for the American option buyer under transaction costs is also covered. The pricing algorithms are computationally efficient, growing only polynomially with the number of time steps in a recombinant tree model. The stopping times realising the ask (seller's) and bid (buyer's) option prices can differ from one another. The former is generally a so-called mixed (randomised) stopping time, whereas the latter is always a pure (ordinary) stopping time.