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Circadian rhythms control organismal physiology throughout the day. At the cellular level, clock regulation is established by a self-sustained Bmal1-dependent transcriptional oscillator network. However, it is still unclear how different tissues achieve a synchronized rhythmic physiology. That is, do they respond independently to environmental signals, or require interactions with each other to do so? We show that unexpectedly, light synchronizes the Bmal1-dependent circadian machinery in single tissues in the absence of Bmal1 in all other tissues. Strikingly, light-driven tissue autonomous clocks occur without rhythmic feeding behavior and are lost in constant darkness. Importantly, tissue-autonomous Bmal1 partially sustains homeostasis in otherwise arrhythmic and prematurely aging animals. Our results therefore support a two-branched model for the daily synchronization of tissues: an autonomous response branch, whereby light entrains circadian clocks without any commitment of other Bmal1-dependent clocks, and a memory branch using other Bmal1-dependent clocks to "remember" time in the absence of external cues.
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Factores de Transcripción ARNTL/fisiología , Relojes Circadianos/genética , Factores de Transcripción ARNTL/metabolismo , Animales , Proteínas CLOCK/metabolismo , Relojes Circadianos/fisiología , Ritmo Circadiano/genética , Conducta Alimentaria/fisiología , Femenino , Homeostasis , Luz , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Especificidad de Órganos/fisiología , Fotoperiodo , Núcleo Supraquiasmático/metabolismoRESUMEN
Mammals rely on a network of circadian clocks to control daily systemic metabolism and physiology. The central pacemaker in the suprachiasmatic nucleus (SCN) is considered hierarchically dominant over peripheral clocks, whose degree of independence, or tissue-level autonomy, has never been ascertained in vivo. Using arrhythmic Bmal1-null mice, we generated animals with reconstituted circadian expression of BMAL1 exclusively in the liver (Liver-RE). High-throughput transcriptomics and metabolomics show that the liver has independent circadian functions specific for metabolic processes such as the NAD+ salvage pathway and glycogen turnover. However, although BMAL1 occupies chromatin at most genomic targets in Liver-RE mice, circadian expression is restricted to â¼10% of normally rhythmic transcripts. Finally, rhythmic clock gene expression is lost in Liver-RE mice under constant darkness. Hence, full circadian function in the liver depends on signals emanating from other clocks, and light contributes to tissue-autonomous clock function.
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Factores de Transcripción ARNTL/fisiología , Relojes Circadianos/genética , Hígado/metabolismo , Factores de Transcripción ARNTL/metabolismo , Animales , Proteínas CLOCK/metabolismo , Relojes Circadianos/fisiología , Ritmo Circadiano/genética , Femenino , Regulación de la Expresión Génica , Homeostasis , Luz , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Especificidad de Órganos/fisiología , Fotoperiodo , Núcleo Supraquiasmático/metabolismoRESUMEN
Adverse cardiac outcomes in COVID-19 patients, particularly those with preexisting cardiac disease, motivate the development of human cell-based organ-on-a-chip models to recapitulate cardiac injury and dysfunction and for screening of cardioprotective therapeutics. Here, we developed a heart-on-a-chip model to study the pathogenesis of SARS-CoV-2 in healthy myocardium established from human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and a cardiac dysfunction model, mimicking aspects of preexisting hypertensive disease induced by angiotensin II (Ang II). We recapitulated cytopathic features of SARS-CoV-2-induced cardiac damage, including progressively impaired contractile function and calcium handling, apoptosis, and sarcomere disarray. SARS-CoV-2 presence in Ang II-treated hearts-on-a-chip decreased contractile force with earlier onset of contractile dysfunction and profoundly enhanced inflammatory cytokines compared to SARS-CoV-2 alone. Toward the development of potential therapeutics, we evaluated the cardioprotective effects of extracellular vesicles (EVs) from human iPSC which alleviated the impairment of contractile force, decreased apoptosis, reduced the disruption of sarcomeric proteins, and enhanced beta-oxidation gene expression. Viral load was not affected by either Ang II or EV treatment. We identified MicroRNAs miR-20a-5p and miR-19a-3p as potential mediators of cardioprotective effects of these EVs.
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Angiotensina II , COVID-19 , Células Madre Pluripotentes Inducidas , Dispositivos Laboratorio en un Chip , Miocitos Cardíacos , Humanos , Angiotensina II/farmacología , Apoptosis/efectos de los fármacos , COVID-19/virología , COVID-19/metabolismo , Citocinas/metabolismo , Vesículas Extracelulares/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/virología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , SARS-CoV-2/fisiologíaRESUMEN
The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine1. Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules1. Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington's disease2, was recently approved by the United States' Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial1,3,4. The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound5, improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug6,7, these processes are often unselective and the stereoisotopic purity can be difficult to measure7,8. Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.
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Benceno/química , Técnicas de Química Sintética , Ciclohexenos/química , Ciclohexenos/síntesis química , Deuterio/química , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/síntesis química , Bases de Datos de Compuestos Químicos , Cinética , Estructura Molecular , Estereoisomerismo , Tetrabenazina/análogos & derivados , Tetrabenazina/síntesis química , Tetrabenazina/química , Tungsteno/químicaRESUMEN
SARS-CoV-2 (CoV2) infected, asymptomatic individuals are an important contributor to COVID transmission. CoV2-specific immunoglobulin (Ig)-as generated by the immune system following infection or vaccination-has helped limit CoV2 transmission from asymptomatic individuals to susceptible populations (e.g. elderly). Here, we describe the relationships between COVID incidence and CoV2 lineage, viral load, saliva Ig levels (CoV2-specific IgM, IgA and IgG), and ACE2 binding inhibition capacity in asymptomatic individuals between January 2021 and May 2022. These data were generated as part of a large university COVID monitoring program in Ohio, United States of America, and demonstrate that COVID incidence among asymptomatic individuals occurred in waves which mirrored those in surrounding regions, with saliva CoV2 viral loads becoming progressively higher in our community until vaccine mandates were established. Among the unvaccinated, infection with each CoV2 lineage (pre-Omicron) resulted in saliva Spike-specific IgM, IgA, and IgG responses, the latter increasing significantly post-infection and being more pronounced than N-specific IgG responses. Vaccination resulted in significantly higher Spike-specific IgG levels compared to unvaccinated infected individuals, and uninfected vaccinees' saliva was more capable of inhibiting Spike function. Vaccinees with breakthrough Delta infections had Spike-specific IgG levels comparable to those of uninfected vaccinees; however, their ability to inhibit Spike binding was diminished. These data are consistent with COVID vaccines having achieved hoped-for effects in our community, including the generation of mucosal antibodies that inhibit Spike and lower community viral loads, and suggest breakthrough Delta infections were not due to an absence of vaccine-elicited Ig, but instead limited Spike binding activity in the face of high community viral loads.
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Formación de Anticuerpos , COVID-19 , Anciano , Humanos , COVID-19/epidemiología , SARS-CoV-2 , Saliva , Universidades , Infección Irruptiva , Inmunoglobulina A , Inmunoglobulina G , Inmunoglobulina MRESUMEN
Molecular clocks and daily feeding cycles support metabolism in peripheral tissues. Although the roles of local clocks and feeding are well defined at the transcriptional level, their impact on governing protein abundance in peripheral tissues is unclear. Here, we determine the relative contributions of local molecular clocks and daily feeding cycles on liver and muscle proteomes during the active phase in mice. LC-MS/MS was performed on liver and gastrocnemius muscle harvested 4 h into the dark phase from WT, Bmal1 KO, and dual liver- and muscle-Bmal1-rescued mice under either ad libitum feeding or time-restricted feeding during the dark phase. Feeding-fasting cycles had only minimal effects on levels of liver proteins and few, if any, on the muscle proteome. In contrast, Bmal1 KO altered the abundance of 674 proteins in liver and 80 proteins in muscle. Local rescue of liver and muscle Bmal1 restored â¼50% of proteins in liver and â¼25% in muscle. These included proteins involved in fatty acid oxidation in liver and carbohydrate metabolism in muscle. For liver, proteins involved in de novo lipogenesis were largely dependent on Bmal1 function in other tissues (i.e., the wider clock system). Proteins regulated by BMAL1 in liver and muscle were enriched for secreted proteins. We found that the abundance of fibroblast growth factor 1, a liver secreted protein, requires BMAL1 and that autocrine fibroblast growth factor 1 signaling modulates mitochondrial respiration in hepatocytes. In liver and muscle, BMAL1 is a more potent regulator of dark phase proteomes than daily feeding cycles, highlighting the need to assess protein levels in addition to mRNA when investigating clock mechanisms. The proteome is more extensively regulated by BMAL1 in liver than in muscle, and many metabolic pathways in peripheral tissues are reliant on the function of the clock system as a whole.
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Relojes Circadianos , Ritmo Circadiano , Animales , Ratones , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Cromatografía Liquida , Relojes Circadianos/genética , Ritmo Circadiano/genética , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Hígado/metabolismo , Músculos/metabolismo , Proteoma/metabolismo , Espectrometría de Masas en TándemRESUMEN
Due to the large multi-elemental space desired for property screening and optimization, high-entropy alloys (HEAs) hold greater potential over conventional alloys for a range of applications, such as structural materials, energy conversion, and catalysis. However, the relationship between the HEA composition and its local structural/elemental configuration is not well understood, particularly in noble-metal-based HEA nanomaterials, hindering the design and development of nano-HEAs in energy conversion and catalysis applications. Herein, we determined precise atomic-level structural and elemental arrangements in model HEAs composed of RhPtPdFeCo and RuPtPdFeCo to unveil their local characteristics. Notably, by changing just one constituent element in the HEA (Rh to Ru), we found dramatic changes in the elemental arrangement from complete random mixing to a local single elemental ordering feature. Additionally, we demonstrate that the local ordering in RuPtPdFeCo can be further controlled by varying the Ru concentration, allowing us to toggle between local Ru clustering and distinct heterostructures in multicomponent systems. Overall, our study presents a practical approach for manipulating local atomic structures and elemental arrangements in noble-metal-based HEA systems, which could provide in-depth knowledge to mechanistically understand the functionality of noble-metal-based HEA nanomaterials in practical applications.
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Platinum exhibits desirable catalytic properties, but it is scarce and expensive. Optimizing its use in key applications such as emission control catalysis is important to reduce our reliance on such a rare element. Supported Pt nanoparticles (NPs) used in emission control systems deactivate over time because of particle growth in sintering processes. In this work, we shed light on the stability against sintering of Pt NPs supported on and encapsulated in Al2O3 using a combination of nanocrystal catalysts and atomic layer deposition (ALD) techniques. We find that small amounts of alumina overlayers created by ALD on preformed Pt NPs can stabilize supported Pt catalysts, significantly reducing deactivation caused by sintering, as previously observed by others. Combining theoretical and experimental insights, we correlate this behavior to the decreased propensity of oxidized Pt species to undergo Ostwald ripening phenomena because of the physical barrier imposed by the alumina overlayers. Furthermore, we find that highly stable catalysts can present an abundance of under-coordinated Pt sites after restructuring of both Pt particles and alumina overlayers at a high temperature (800 °C) in C3H6 oxidation conditions. The enhanced stability significantly improves the Pt utilization efficiency after accelerated aging treatments, with encapsulated Pt catalysts reaching reaction rates more than two times greater than those of a control supported Pt catalyst.
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OBJECTIVE: To identify factors associated with overtreatment of presumed urinary tract infection (UTI) among children with spina bifida using such criteria. STUDY DESIGN: A retrospective review of children with spina bifida (age <21 years) evaluated in the Emergency Department (ED) at a single institution was performed. Patients with a urinalysis (UA) performed who were reliant on assisted bladder emptying were included. The primary outcome was overtreatment, defined as receiving antibiotics for presumed UTI but ultimately not meeting spina bifida UTI criteria (≥2 urologic symptoms plus pyuria and urine culture growing >100k CFU/mL). The primary exposure was whether the components of the criteria available at the time of the ED visit (≥2 urologic symptoms plus pyuria) were met when antibiotics were initiated. RESULTS: Among 236 ED encounters, overtreatment occurred in 80% of cases in which antibiotics were initiated (47% of the entire cohort). Pyuria with <2 urologic symptoms was the most important factor associated with overtreatment (OR 9.6). Non-Hispanic White race was associated with decreased odds of overtreatment (OR 0.3). CONCLUSIONS: Overtreatment of presumed UTI among patients with spina bifida was common. Pyuria, which is not specific to UTI in this population, was the main driver of overtreatment. Symptoms are a cornerstone of UTI diagnosis among children with spina bifida, should be collected in a standardized manner, and considered in a decision to treat.
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Mechanical load is one of the main determinants of cardiac structure and function. Mechanical load is studied in vitro using cardiac preparations together with loading protocols (e.g., auxotonic, isometric). However, such studies are often limited by reductionist models and poorly simulated mechanical load profiles. This hinders the physiological relevance of findings. Living myocardial slices have been used to study load in vitro. Living myocardial slices (LMS) are 300-µm-thick intact organotypic preparations obtained from explanted animal or human hearts. They have preserved cellular populations and the functional, structural, metabolic and molecular profile of the tissue from which they are prepared. Using a three-element Windkessel (3EWK) model we previously showed that LMSs can be cultured while performing cardiac work loops with different preload and afterload. Under such conditions, LMSs remodel as a function of the mechanical load applied to them (physiological load, pressure or volume overload). These studies were conducted in commercially available length actuators that had to be extensively modified for culture experiments. In this paper, we demonstrate the design, development and validation of a novel device, MyoLoop. MyoLoop is a bioreactor that can pace, thermoregulate, acquire and process data, and chronically load LMSs and other cardiac tissues in vitro. In MyoLoop, load is parametrised using a 3EWK model, which can be used to recreate physiological and pathological work loops and the remodelling response to these. We believe MyoLoop is the next frontier in basic cardiovascular research enabling reductionist but physiologically relevant in vitro mechanical studies.
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Reactores Biológicos , Corazón , Animales , Humanos , Miocardio , Proyectos de InvestigaciónRESUMEN
Trace palladium in synthetic materials can be rapidly and inexpensively semiquantified by a catalysis-based fluorometric method that converts resorufin allyl ether to resorufin. However, whether sulfur compounds would interfere with this method has not been systematically studied. Herein, we show that although thiourea in solution interferes with quantification, sulfide, thiol, and thiocarbamate do not. The fluorometric method can also detect palladium bound to sulfur-based scavenger resin and outperform inductively coupled plasma mass spectrometry for detecting trace palladium in ibuprofen.
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Fluorometría , Ibuprofeno , Paladio , Paladio/química , Ibuprofeno/química , Ibuprofeno/análisis , Catálisis , Fluorometría/métodos , Estructura Molecular , Compuestos de Azufre/química , Compuestos de Azufre/análisisRESUMEN
The catalytic performance of atomically dispersed catalysts (ADCs) is greatly influenced by their atomic configurations, such as atom-atom distances, clustering of atoms into dimers and trimers, and their distributions. Scanning transmission electron microscopy (STEM) is a powerful technique for imaging ADCs at the atomic scale; however, most STEM analyses of ADCs thus far have relied on human labeling, making it difficult to analyze large data sets. Here, we introduce a convolutional neural network (CNN)-based algorithm capable of quantifying the spatial arrangement of different adatom configurations. The algorithm was tested on different ADCs with varying support crystallinity and homogeneity. Results show that our algorithm can accurately identify atom positions and effectively analyze large data sets. This work provides a robust method to overcome a major bottleneck in STEM analysis for ADC catalyst research. We highlight the potential of this method to serve as an on-the-fly analysis tool for catalysts in future in situ microscopy experiments.
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PURPOSE: To quantify trends in ophthalmology practice consolidation in the United States. DESIGN: A retrospective cross-sectional study. PARTICIPANTS: Providers in the Centers for Medicare and Medicaid Services (CMS) National Downloadable File with a primary specialty designation of ophthalmology. METHODS: We used the CMS database to determine national practice consolidation trends in ophthalmology on individual physician and group practice levels and analyzed by region, sex, and years spent in practice. We used the Cochran-Armitage test to determine the statistical significance of practice size differences between 2015 and 2022. MAIN OUTCOME MEASURES: Temporal practice size trends for physicians and practices in ophthalmology and regional, sex-specific, and age-related trends. RESULTS: Between 2015 and 2022, the number of ophthalmologists decreased from 17 656 to 17 615 (-0.2%), whereas the number of practices decreased from 7149 to 5890 (-18%). The percentage of ophthalmologists in practices of 1 to 2 members decreased from 35% to 28%, whereas those in groups of 50 or more increased from 7% to 11%. The percentage of practices with 1 to 2 members decreased from 75% to 71%, and those with 50 or more increased from 0.2% to 0.4%. Consolidation trends were significant on individual ophthalmologist (P < 0.001) and group practice (P < 0.001) levels. All regions, sexes, and subgroups of years spent in practice demonstrated consolidation (P < 0.001). The Northeast showed the greatest increase in groups of 50 or more physicians (+7%) between 2015 and 2022. Proportionally fewer female than male ophthalmologists were associated with practice sizes of 1 to 2 members in 2015 (29% and 36%, respectively) and 2022 (23% and 30%, respectively). Proportionally fewer ophthalmologists with 0 to 10 years of experience in practice were associated with practice sizes of 1 to 2 members than those with more than 30 years in practice in 2015 (18% and 48%, respectively) and 2022 (14% and 40%, respectively). CONCLUSIONS: Ophthalmology has undergone practice consolidation from 2015 to 2022. A decrease in the proportion of physicians affiliated with smaller practice sizes seems to have occurred. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Oftalmólogos , Oftalmología , Anciano , Humanos , Masculino , Femenino , Estados Unidos , Estudios Retrospectivos , Estudios Transversales , MedicareRESUMEN
BACKGROUND: Mucosal biopsies in eosinophilic esophagitis (EoE) can exhibit lamina propria (LP) fibrosis, which may portend stenotic complications; however, the histologic diagnosis of LP fibrosis is subjective. We sought to assess and improve the consistency of LP fibrosis diagnosis among our pathologist group. METHODS: At a large pediatric hospital, 25 esophageal biopsy slides from 19 patients (16 with EoE) exhibiting a wide spectrum of LP area, artifacts, and fibrosis severity were scanned into whole-slide images. Staff pediatric pathologists (n = 8) separate from the authors classified each biopsy by LP adequacy and fibrosis severity 1 month before and after completion of an educational tutorial. Consensus was defined as >70% agreement. RESULTS: At baseline, 16/25 (64%) cases reached consensus for no fibrosis (n = 3), fibrosis (n = 7), or inadequate LP (n = 6); agreement was fair (α = 0.34). Post-tutorial, 13/25 (52%) cases reached consensus for no fibrosis (n = 2), fibrosis (n = 7), or inadequate LP (n = 4); agreement was again fair (α = 0.33). There was moderate agreement in grading of fibrosis severity (α = 0.54). CONCLUSION: We document only fair-to-moderate agreement in the diagnosis of esophageal LP fibrosis and adequacy in a large pediatric pathologist group despite targeted education, highlighting a challenge in incorporating this feature into EoE research and clinical decision-making.
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Esofagitis Eosinofílica , Humanos , Niño , Biopsia/métodos , Esofagitis Eosinofílica/diagnóstico , Esofagitis Eosinofílica/patología , Membrana Mucosa/patología , Mucosa Esofágica/patología , FibrosisRESUMEN
BACKGROUND: This study examines whether symptoms of depression, anxiety, or comorbid depression and anxiety are associated with future use of nicotine or THC in e-cigarettes. METHODS: Data were from an online survey of youth and young adults in urban areas of Texas with complete data (n = 2,307) in spring 2019 (baseline) and spring 2020 (12-month follow-up). Multivariable logistic regression models examined associations between self-reported symptoms of depression, anxiety, or comorbid depression and anxiety at baseline and past 30-day e-cigarette use with nicotine or THC at 12-month follow-up. Analyses adjusted for baseline demographics and baseline past 30-day e-cigarette, combustible tobacco, marijuana, and alcohol use and stratified by race/ethnicity, gender, grade level, and SES. RESULTS: Participants were 16-23 years old, 58.1% female and 37.9% Hispanic. At baseline, 14.7% reported symptoms of comorbid depression and anxiety, 7.9% depression, and 4.7% anxiety. Prevalence of past 30-day e-cigarette use at 12-month follow-up was 10.4% with nicotine and 10.3% with THC. Symptoms of depression and comorbid depression and anxiety at baseline were significantly associated with both nicotine and THC use in e-cigarettes 12 months later. Symptoms of anxiety were associated with nicotine use in e-cigarettes 12 months later. CONCLUSIONS: Symptoms of anxiety and depression may be important indicators of future nicotine and THC vaping among young people. Clinicians should be aware of groups most at risk who may benefit from substance use counseling and intervention.
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Sistemas Electrónicos de Liberación de Nicotina , Productos de Tabaco , Adolescente , Adulto Joven , Humanos , Femenino , Adulto , Masculino , Nicotina , Depresión/epidemiología , Encuestas y Cuestionarios , Ansiedad/epidemiologíaRESUMEN
BACKGROUND: Facial Hemangiomas are often recommended to be removed exclusively in the operating room under general anesthesia, especially for children under the age of 4. Assumed parental and patient anxiety and possible blood loss pushes surgeons away from attempting excision under local anesthesia. METHODS: A review was conducted to assess the outcomes of children who underwent excision of facial hemangiomas under local anesthesia alone by 1 plastic surgeon with a minimum of 3 months follow-up. Complications and hemangioma recurrence were recorded. A survey was given 3 to 6 months after treatment to assess parental satisfaction, anxiety, and thought process about anesthesia. RESULTS: Eighteen children (9 males and 9 females) underwent in-office excision between 2020 and 2021. The mean age of this cohort was 12 months ( ranging 2-52 m). The average facial hemangioma size was 2.088 cm (ranging 1.0-3.2 cm). Ten patients experienced complete resolution (56%) at 12-month follow-up. There were no hospitalizations or cases of significant (>10 mL) blood loss, infection, dehiscence, hematoma, or scar hypertrophy. The average level of parental anxiety before the procedure was 3.3/10, and 1.6/10 after the procedure. Total 13/14 parents gave 4/4 ratings for satisfaction with the quality of care, team responsiveness, pain management, and management of expectations. CONCLUSIONS: Facial hemangioma removal under local anesthesia alone is a safe and feasible alternative treatment method for patients younger than 4 years of age.
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Anestesia Dental , Hemangioma , Masculino , Femenino , Humanos , Niño , Preescolar , Lactante , Anestesia Local , Hemangioma/cirugía , Anestesia General , Quirófanos , Estudios RetrospectivosRESUMEN
For many biological systems, a variety of simulation models exist. A new simulation model is rarely developed from scratch, but rather revises and extends an existing one. A key challenge, however, is to decide which model might be an appropriate starting point for a particular problem and why. To answer this question, we need to identify entities and activities that contributed to the development of a simulation model. Therefore, we exploit the provenance data model, PROV-DM, of the World Wide Web Consortium and, building on previous work, continue developing a PROV ontology for simulation studies. Based on a case study of 19 Wnt/ß-catenin signaling models, we identify crucial entities and activities as well as useful metadata to both capture the provenance information from individual simulation studies and relate these forming a family of models. The approach is implemented in WebProv, a web application for inserting and querying provenance information. Our specialization of PROV-DM contains the entities Research Question, Assumption, Requirement, Qualitative Model, Simulation Model, Simulation Experiment, Simulation Data, and Wet-lab Data as well as activities referring to building, calibrating, validating, and analyzing a simulation model. We show that most Wnt simulation models are connected to other Wnt models by using (parts of) these models. However, the overlap, especially regarding the Wet-lab Data used for calibration or validation of the models is small. Making these aspects of developing a model explicit and queryable is an important step for assessing and reusing simulation models more effectively. Exposing this information helps to integrate a new simulation model within a family of existing ones and may lead to the development of more robust and valid simulation models. We hope that our approach becomes part of a standardization effort and that modelers adopt the benefits of provenance when considering or creating simulation models.
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Modelos Biológicos , Vía de Señalización Wnt , Animales , Fenómenos Bioquímicos , Biología Computacional , Gráficos por Computador , Simulación por Computador , Humanos , Programas Informáticos , Biología de SistemasRESUMEN
AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
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Cardiomiopatía Hipertrófica , Proteínas Musculares/genética , Proteínas Quinasas/genética , Cardiomiopatía Hipertrófica/genética , Heterocigoto , Humanos , Mutación , SarcómerosRESUMEN
BACKGROUND: There is a paucity of information regarding financial trends in orthopedic upper extremity surgery. If progress is to be made in advancing agreeable reimbursement models, a more comprehensive understanding of these trends is needed. The purpose of this study was to assess national and geographic trends in Medicare reimbursement rates for shoulder and elbow surgical procedures over the past 2 decades. METHODS: The 10 most billed Common Procedural Terminology (CPT) codes for both orthopedic shoulder surgery and elbow/upper arm surgery were determined. Medicare reimbursement data for these CPT codes were compiled between 2000 and 2020 and adjusted for inflation. The percentage change for each procedure and the average change in reimbursement each year were analyzed. Data from 2000, 2010, and 2020 were organized by state. The total percent change in physician fee and the percent change per year were tabulated for each CPT code using inflation-adjusted data and averaged by state. RESULTS: From 2000 to 2020, when corrected for inflation, shoulder and elbow procedures decreased on average by 29.3% and 24.5%, respectively. Shoulder procedures experienced a greater numerical yet statistically insignificant decline in mean reimbursement percent decrease (P = .16), average percent decrease per year (P = .11), a more negative compound annual growth rate (P = .14), and a greater R-squared value as compared with elbow and upper arm procedures. For shoulder procedures, the average percent difference in inflation-adjusted Medicare reimbursement rates from 2000 to 2020 varied from -22.6% in Alaska to -34.1% in Michigan; division data varied from -27.8% in the Mountain Division to -31.2% in the East North Central Division; and region data varied from -28.3% in the West to -30.5% in the Northeast. For elbow and upper arm procedures, the average percent difference in inflation-adjusted Medicare reimbursement rates from 2000 to 2020 varied from -17.6% in Alaska to -29.8% in Michigan; division data varied from -23.0% in the Mountain Division to -26.7% in the East North Central Division; and region data varied from -23.5% in the West to -25.7% in the Northeast. DISCUSSION: Inflation-adjusted Medicare reimbursement in upper extremity surgery has decreased markedly between 2000 and 2020. The degree of decrease varies geographically. If access to quality and sustainable surgical orthopedic care is to persist in the United States, increased awareness of these trends is important. The trends identified in this study can serve to customize regional health care policymaking.