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OBJECTIVE: To create a scalable and feasible retrospective consecutive knee osteoarthritis (OA) radiographic database with limited human labor using commercial and custom-built artificial intelligence (AI) tools. METHODS: We applied four AI tools, two commercially available and two custom-built tools, to analyze 6 years of clinical consecutive knee radiographs from patients aged 35-79 at the University of Copenhagen Hospital, Bispebjerg-Frederiksberg Hospital, Denmark. The tools provided Kellgren-Lawrence (KL) grades, joint space widths, patella osteophyte detection, radiographic view detection, knee joint implant detection, and radiographic marker detection. RESULTS: In total, 25,778 knee radiographs from 8575 patients were included in the database after excluding inapplicable radiographs, and 92.5% of the knees had a complete OA dataset. Using the four AI tools, we saved about 800 hours of radiologist reading time and only manually reviewed 16.0% of the images in the database. CONCLUSIONS: This study shows that clinical knee OA databases can be built using AI with limited human reading time for uniform grading and measurements. The concept is scalable temporally and across geographic regions and could help diversify further OA research by efficiently including radiographic knee OA data from different populations globally. We can prevent data dredging and overfitting OA theories on existing trite cohorts by including various gene pools and continuous expansion of new clinical cohorts. Furthermore, the suggested tools and applied approaches provide an ability to retest previous hypotheses and test new hypotheses on real-life clinical data with current disease prevalence and trends.
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Osteoartritis de la Rodilla , Humanos , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/epidemiología , Articulación de la Rodilla/diagnóstico por imagen , Estudios Retrospectivos , Inteligencia Artificial , RodillaRESUMEN
In October 2022, the World Health Organization (WHO) convened an expert panel in Lisbon, Portugal in which the 2005 WHO TEFs for chlorinated dioxin-like compounds were reevaluated. In contrast to earlier panels that employed expert judgement and consensus-based assignment of TEF values, the present effort employed an update to the 2006 REP database, a consensus-based weighting scheme, a Bayesian dose response modeling and meta-analysis to derive "Best-Estimate" TEFs. The updated database contains almost double the number of datasets from the earlier version and includes metadata that informs the weighting scheme. The Bayesian analysis of this dataset results in an unbiased quantitative assessment of the congener-specific potencies with uncertainty estimates. The "Best-Estimate" TEF derived from the model was used to assign 2022 WHO-TEFs for almost all congeners and these values were not rounded to half-logs as was done previously. The exception was for the mono-ortho PCBs, for which the panel agreed to retain their 2005 WHO-TEFs due to limited and heterogenous data available for these compounds. Applying these new TEFs to a limited set of dioxin-like chemical concentrations measured in human milk and seafood indicates that the total toxic equivalents will tend to be lower than when using the 2005 TEFs.
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Dioxinas , Bifenilos Policlorados , Dibenzodioxinas Policloradas , Animales , Humanos , Teorema de Bayes , Dibenzofuranos/toxicidad , Dibenzofuranos Policlorados/toxicidad , Dioxinas/toxicidad , Mamíferos , Bifenilos Policlorados/toxicidad , Dibenzodioxinas Policloradas/toxicidad , Organización Mundial de la SaludRESUMEN
INTRODUCTION: The objective of this study was to study associations of a wide range of halogenated biphenyls, dibenzo-p-dioxins, dibenzofurans and diphenylethers with body mass index (BMI) and evaluate changes in their concentration following bariatric surgery. METHODS: Subcutaneous fat, visceral fat and liver tissue samples were collected from 106 patients undergoing Roux-en-Y gastric bypass surgery for weight loss or patients who were undergoing abdominal surgery for nonbariatric reasons. We measured concentrations of an extensive panel of chlorinated and brominated biphenyls, dioxins, and furans, and brominated diphenylethers in the samples. We conducted linear regression to examine associations with BMI, adjusting for age and gender. Changes in concentration for indicator chemicals were evaluated in samples collected following bariatric surgery in a small subpopulation. RESULTS: After adjustments for age and gender and correction for multiple testing, seven ortho-chlorinated biphenyls, one nonortho-chlorinated biphenyl, four PCDD/Fs and one ortho-brominated biphenyl were associated with BMI. The strongest associations between BMI and lipid-adjusted concentrations were seen with PCB-105 in subcutaneous fat (beta = 16.838 P-val = 1.45E-06) PCB-126 in visceral fat (beta = 15.067 P-val = 7.72E-06) and PCB-118 (beta = 14.101 P-val = 2.66E-05) in liver. The concentrations of sum PCBs, chlorinated toxic equivalent quantity (TEQ's) and brominated compounds increased significantly with weight loss in subcutaneous fat in a group of ten individuals resampled up to five years after bariatric surgery and substantial weight loss. CONCLUSION: We show that selected polychlorinated biphenyls PCBs and structurally related polychlorinated dibenzo-p-dioxins dibenzofurans (PCDD/Fs) were associated with BMI. Concentrations of these lipophilic compounds in subcutaneous fat increased following bariatric surgery.
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Cirugía Bariátrica , Benzofuranos , Dibenzodioxinas Policloradas , Índice de Masa Corporal , Dibenzofuranos , Humanos , Pérdida de PesoRESUMEN
The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting.
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Anticoagulantes/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Accidente Cerebrovascular/prevención & control , Administración Oral , Anticoagulantes/farmacocinética , Fibrilación Atrial/complicaciones , Fibrilación Atrial/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Accidente Cerebrovascular/metabolismoRESUMEN
Over the past decade, personalized medicine has received considerable attention from researchers, drug developers, and regulatory agencies. Personalized medicine includes identifying patients most likely to benefit and those most likely to experience adverse reactions in response to a drug, and tailoring therapy based on pharmacokinetics or pharmacodynamic response, as well. Perhaps most exciting is finding ways to identify likely responders through genetic, proteomic, or other tests, so that only likely responders will be treated. However, less precise methods such as identifying historical, demographic, or other indicators of increased or reduced responsiveness are also important aspects of personalized medicine. The cardiovascular field has not used many genetic or proteomic markers, but has regularly used prognostic variables to identify likely responders. The development of biomarker-based approaches to personalized medicine in cardiovascular disease has been challenging, in part, because most cardiovascular therapies treat acquired syndromes, such as acute coronary syndrome and heart failure, which develop over many decades and represent the end result of several pathophysiological mechanisms. More precise disease classification and greater understanding of individual variations in disease pathology could drive the development of targeted therapeutics. Success in designing clinical trials for personalized medicine will require the selection of patient populations with attributes that can be targeted or that predict outcome, and the use of appropriate enrichment strategies once such attributes are identified. Here, we describe examples of personalized medicine in cardiovascular disease, discuss its impact on clinical trial design, and provide insight into the future of personalized cardiovascular medicine from a regulatory perspective.
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Medicina de Precisión/tendencias , United States Food and Drug Administration , Biomarcadores , Biotransformación/genética , Cardiología/legislación & jurisprudencia , Cardiología/tendencias , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/farmacología , Ensayos Clínicos como Asunto , Interacciones Farmacológicas , Etiquetado de Medicamentos , Predicción , Humanos , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Selección de Paciente , Proyectos de Investigación , Estados UnidosRESUMEN
There is no doubt that chloronaphthalenes (PCNs) and their brominated counterparts (PBNs) are dioxin-like compounds, but there is less evidence for mixed bromo/chloronaphthalenes (PXNs). In this article we review information relating to the dioxin-like potency of PCNs and PBNs obtained in vivo, in vitro, and in silico. The aim was to help and improve the quality of data when assessing the contribution of these compounds in the risk analysis of dioxin-like contaminants in foods and other sample types. In vivo and in vitro studies have demonstrated that PCN/PBN congeners are inducers of aryl hydrocarbon hydroxylase, ethoxyresorufin O-deethylase, and luciferase enzymes that are features specifically indicative of planar diaromatic halogenated hydrocarbons such as dioxin and dioxin-like compounds. PCNs in the environment are of multisource origin. The limited data on PBNs in the environment suggest that these also appear to originate from different sources. The toxicological data on these compounds is even scarcer, most of it directed toward explaining the exposure risk from accidental contamination of feed with the commercial PBN containing product, Firemaster BP-6. The occurrence of PBNs and PXNs is possible as ultra-trace environmental and food-chain contaminants produced at least from combustion processes at unknown concentrations. Available toxicological and environmental data enable a focus on PCNs as dioxin analogues to an extent that specific local or regional environmental influences could result in a risk to human health. There is the possibility that they may act synergistically with the better-known classic dioxin and other dioxin-like compounds. PBNs and PXNs are much less studied than the dioxins, but are known to be products of anthropogenic processes that contaminate the environment. A continuously increasing use of bromine for manufacture of brominated flame retardants over the past three decades is anticipated as a stream of "brominated" wastes, that when degraded (combusted), will release PBNs and PXNs. This calls for advanced analytical methods and greater interest toxicologically to understand and control pollution and exposure by PBNs and PXNs. Particular congeners of bromonaphthalene in single studies were found to be much more toxic than their chlorinated counterparts. In addition, brominated/chlorinated naphthalenes also seem to be more potent toxicants than PCNs. About 20% of PCN congeners exhibit a dioxin-like toxicity with relative potencies varying between around 0.003 and 0.000001, but additional and more rigorous data are needed to confirm these figures. Recent food surveys have estimated a small but relevant human exposure to these compounds in foods, giving an additional source of dioxin-like toxicity to those compounds already covered by the World Health Organization-Toxic Equivalency Factors (TEFs) scheme. Given the additivity of response postulated for other dioxin-like compounds, it would seem unwise to ignore this additional contribution. Few data available showed that PBN congeners also exhibit a dioxin-like toxicity and are even more potent than PCN congeners, but the relative potency values were not derived for them until now. There are no toxicological data available for PXNs.
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Halógenos/química , Naftalenos/toxicidad , Receptores de Hidrocarburo de Aril/efectos de los fármacos , Animales , Carga Corporal (Radioterapia) , Cromatografía de Gases y Espectrometría de Masas , Masculino , Naftalenos/química , Naftalenos/farmacocinética , Ratas , Ratas WistarRESUMEN
PURPOSE: Results of two randomized trials (ROADMAP and ORIENT) suggest that high-dose (40 mg/day) olmesartan (Olm) is associated with increased cardiovascular mortality compared to placebo in diabetic patients. We evaluated the risks of acute myocardial infarction (AMI) and death in patients initiating Olm compared with an active comparator group, other angiotensin receptor blockers (ARBs), with a focus on high-dose and diabetic subgroups. METHODS: We conducted a cohort study with patients who initiated Olm or another ARB between 2003 and 2011, using the UK Clinical Practice Research Datalink GOLD. We included patients who had no prior ARB or angiotensin converting enzyme inhibitor exposure during the preceding 6 months. Hazard ratios (HRs) were estimated using Cox regression models with both multivariable adjustment and propensity score matching. RESULTS: There were 3964 Olm and 54 653 other-ARB initiators, respectively. Adjusted HRs comparing Olm and other-ARBs were 1.04 (95% CI: 0.75-1.42) for AMI and 1.16 (0.95-1.42) for death, using multivariable adjustment. Comparing patients initiated with a high-dose Olm and a high-dose other-ARB, HRs were 3.09 (0.94-10.13) for AMI and 2.03 (0.74-5.61) for death, using multivariable adjustment; and 4.38 (0.97-19.66) and 1.99 (0.63-6.32) for AMI and death, using propensity score matching. CONCLUSIONS: Overall, no differences in risk were observed in the main cohort analyses comparing Olm initiators with patients initiating therapy with other ARBs; however, HRs were marginally increased for all study endpoints which compared high-dose subgroups, suggesting potential increased risk may be associated with high-dose Olm. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
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Antagonistas de Receptores de Angiotensina/administración & dosificación , Imidazoles/administración & dosificación , Infarto del Miocardio/epidemiología , Accidente Cerebrovascular/epidemiología , Tetrazoles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antagonistas de Receptores de Angiotensina/efectos adversos , Estudios de Cohortes , Bases de Datos Factuales , Diabetes Mellitus/epidemiología , Diabetes Mellitus/fisiopatología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Modelos de Riesgos Proporcionales , Análisis de Regresión , Riesgo , Accidente Cerebrovascular/etiología , Tetrazoles/efectos adversosRESUMEN
The European Commission asked EFSA to update its 2011 risk assessment on tetrabromobisphenol A (TBBPA) and five derivatives in food. Neurotoxicity and carcinogenicity were considered as the critical effects of TBBPA in rodent studies. The available evidence indicates that the carcinogenicity of TBBPA occurs via non-genotoxic mechanisms. Taking into account the new data, the CONTAM Panel considered it appropriate to set a tolerable daily intake (TDI). Based on decreased interest in social interaction in male mice, a lowest observed adverse effect level (LOAEL) of 0.2 mg/kg body weight (bw) per day was identified and selected as the reference point for the risk characterisation. Applying the default uncertainty factor of 100 for inter- and intraspecies variability, and a factor of 3 to extrapolate from the LOAEL to NOAEL, a TDI for TBBPA of 0.7 µg/kg bw per day was established. Around 2100 analytical results for TBBPA in food were used to estimate dietary exposure for the European population. The most important contributors to the chronic dietary LB exposure to TBBPA were fish and seafood, meat and meat products and milk and dairy products. The exposure estimates to TBBPA were all below the TDI, including those estimated for breastfed and formula-fed infants. Accounting for the uncertainties affecting the assessment, the CONTAM Panel concluded with 90%-95% certainty that the current dietary exposure to TBBPA does not raise a health concern for any of the population groups considered. There were insufficient data on the toxicity of any of the TBBPA derivatives to derive reference points, or to allow a comparison with TBBPA that would support assignment to an assessment group for the purposes of combined risk assessment.
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EFSA was asked for a scientific opinion on the risks for animal and human health related to the presence of polychlorinated naphthalenes (PCNs) in feed and food. The assessment focused on hexaCNs due to very limited data on other PCN congeners. For hexaCNs in feed, 217 analytical results were used to estimate dietary exposures for food-producing and non-food-producing animals; however, a risk characterisation could not be performed because none of the toxicological studies allowed identification of reference points. The oral repeated dose toxicity studies performed in rats with a hexaCN mixture containing all 10 hexaCNs indicated that the critical target was the haematological system. A BMDL20 of 0.05 mg/kg body weight (bw) per day was identified for a considerable decrease in the platelet count. For hexaCNs in food, 2317 analytical results were used to estimate dietary exposures across dietary surveys and age groups. The highest exposure ranged from 0.91 to 29.8 pg/kg bw per day in general population and from 220 to 559 pg/kg bw per day for breast-fed infants with the highest consumption of breast milk. Applying a margin of exposure (MOE) approach, the estimated MOEs for the high dietary exposures ranged from 1,700,000 to 55,000,000 for the general population and from 90,000 to 230,000 for breast-fed infants with the highest consumption of breast milk. These MOEs are far above the minimum MOE of 2000 that does not raise a health concern. Taking account of the uncertainties affecting the assessment, the Panel concluded with at least 99% certainty that dietary exposure to hexaCNs does not raise a health concern for any of the population groups considered. Due to major limitations in the available data, no assessment was possible for genotoxic effects or for health risks of PCNs other than hexaCNs.
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This statement provides scientific guidance on the information needed to support the risk assessment of the detoxification processes applied to products intended for animal feed in line with the acceptability criteria of the Commission Regulation (EU) 2015/786.
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The European Commission asked EFSA to update its 2011 risk assessment on polybrominated diphenyl ethers (PBDEs) in food, focusing on 10 congeners: BDE-28, -47, -49, -99, -100, -138, -153, -154, -183 and 209. The CONTAM Panel concluded that the neurodevelopmental effects on behaviour and reproductive/developmental effects are the critical effects in rodent studies. For four congeners (BDE-47, -99, -153, -209) the Panel derived Reference Points, i.e. benchmark doses and corresponding lower 95% confidence limits (BMDLs), for endpoint-specific benchmark responses. Since repeated exposure to PBDEs results in accumulation of these chemicals in the body, the Panel estimated the body burden at the BMDL in rodents, and the chronic intake that would lead to the same body burden in humans. For the remaining six congeners no studies were available to identify Reference Points. The Panel concluded that there is scientific basis for inclusion of all 10 congeners in a common assessment group and performed a combined risk assessment. The Panel concluded that the combined margin of exposure (MOET) approach was the most appropriate risk metric and applied a tiered approach to the risk characterisation. Over 84,000 analytical results for the 10 congeners in food were used to estimate the exposure across dietary surveys and age groups of the European population. The most important contributors to the chronic dietary Lower Bound exposure to PBDEs were meat and meat products and fish and seafood. Taking into account the uncertainties affecting the assessment, the Panel concluded that it is likely that current dietary exposure to PBDEs in the European population raises a health concern.
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OBJECTIVES: ICU admission is associated with decreased physical function for years after discharge. The underlying mechanisms responsible for this muscle function impairment are undescribed. The aim of this study was to describe the biomechanical properties of the quadriceps muscle in ICU survivors 12 months after ICU discharge. DESIGN: Case-control study with consecutive inclusion of ICU survivors and age- and sex-matched controls. SETTING: Patients were treated at a mixed 18-bed ICU at a tertiary care university hospital and tested at a biomechanical university laboratory. PATIENTS: We included 16 male ICU patients (Acute Physiology and Chronic Health Evaluation II score 20 ± 7, mean ± SD), who had stayed in the ICU >72 hrs and survived to 12 months and 15 age- and sex-matched controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An extensive battery of biomechanical tests, including maximum, fast, and endurance contractions, was administered during isometric knee extensions while simultaneously recording surface electromyography (quadriceps and hamstrings). Compared to controls, ICU survivors had reduced maximal voluntary torque (22%, 179 ± 64 Nm vs. 230 ± 57 Nm, p = 0.03), absolute rate of force development (50%, 868 ± 372 Nm/sec vs. 1739 ± 470 Nm/sec, p < 0.001) and relative rate of force development (32%, 512 ± 260% maximum voluntary contraction/sec vs. 754 ± 189% maximum voluntary contraction/sec, p < 0.01), and endurance time (40%, 136 ± 84 sec vs. 226 ± 111 sec, p < 0.02). Rate of force development, but not maximal voluntary torque, was significantly reduced after adjusting for muscle mass. Electromyography data indicated no impairment of motor activation strategy or central motor drive. Also, no difference in reaction time was found between patients and controls. CONCLUSIONS: ICU survivors had reduced rate of force development and muscular endurance 1 yr after ICU discharge. Our data indicate that the functional deficits experienced by ICU survivors originate in muscle tissue rather than the nervous system. Also, increased attention to velocity-orientated exercise during rehabilitation of ICU patients may have the potential to better physical outcome after critical illness.
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Actividades Cotidianas , Enfermedad Crítica/rehabilitación , Contracción Muscular , Fuerza Muscular , Enfermedades Musculares/prevención & control , Anciano , Fenómenos Biomecánicos , Estudios de Casos y Controles , Enfermedad Crítica/epidemiología , Dinamarca/epidemiología , Electromiografía , Humanos , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Enfermedades Musculares/epidemiología , Enfermedades Musculares/etiología , Resistencia Física , Músculo Cuádriceps , Factores de RiesgoRESUMEN
OBJECTIVE: To evaluate the effect of body weight-supported progressive high-intensity locomotor training in Parkinson's disease (PD) on (1) clinical status; (2) quality of life; and (3) gait capacity. DESIGN: Open-label, fixed sequence crossover study. SETTING: University motor control laboratory. PARTICIPANTS: Patients (N=13) with idiopathic PD (Hoehn and Yahr stage 2 or 3) and stable medication use. INTERVENTIONS: Patients completed an 8-week (3 × 1h/wk) training program on a lower-body positive-pressure treadmill. Body weight support was used to facilitate increased intensity and motor challenges during treadmill training. The training program contained combinations of (1) running and walking intervals, (2) the use of sudden changes (eg, in body weight support and speed), (3) different types of locomotion (eg, chassé, skipping, and jumps), and (4) sprints at 50 percent body weight. MAIN OUTCOME MEASURES: The Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Questionnaire-39 items (PDQ-39), and the six-minute walk test were conducted 8 weeks before and pre- and posttraining. RESULTS: At the end of training, statistically significant improvements were found in all outcome measures compared with the control period. Total MDS-UPDRS score changed from (mean ± 1SD) 58±18 to 47±18, MDS-UPDRS motor part score changed from 35±10 to 29±12, PDQ-39 summary index score changed from 22±13 to 13±12, and the six-minute walking distance changed from 576±93 to 637±90m. CONCLUSIONS: Body weight-supported progressive high-intensity locomotor training is feasible and well tolerated by patients with PD. The training improved clinical status, quality of life, and gait capacity significantly.
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Terapia por Ejercicio , Tolerancia al Ejercicio/fisiología , Estado de Salud , Enfermedad de Parkinson/rehabilitación , Calidad de Vida , Caminata/fisiología , Anciano , Estudios de Cohortes , Estudios Cruzados , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Resultado del Tratamiento , Soporte de Peso/fisiologíaRESUMEN
The 'entourage effect' term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the 'entourage effect' is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the 'entourage effect' from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the 'entourage effect' is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement).
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Recycled bioresources (biosolids, compost-like-output, meat and bonemeal ash, poultry litter ash, paper sludge ash) were added to the feed of dairy cattle to simulate incidental ingestion from agricultural utilisation, to investigate the transfer of organic contaminants from the ingested materials to milk. The bioresources were blended with a loamy sand soil at agronomic rates to simulate a single application to land, which was added to the diet at 5 % of the total intake on a dry matter (DM) basis. Biosolids, and control treatments consisting of unamended soil, were also added directly to the feed at 5 % DM. The cattle were fed the bioresource amended diets for a target period of three to four weeks, depending on material, and monitoring continued for four weeks after treatment withdrawal. Milk samples were taken weekly with chemical analysis of selected samples for a range of organic contaminants including: polychlorinated, polybrominated and mixed-halogenated dioxins, furans and biphenyls, polychlorinated naphthalenes and alkanes (often called chlorinated paraffins), polycyclic aromatic hydrocarbons and chlorobenzenes. No statistically significant additional transfer of organic contaminants to the milk was detected due to the relatively low levels of contaminants present when the bioresources were incorporated with soil at agronomic rates. However, direct biosolids ingestion by cattle significantly increased the transfer of contaminants to milk in comparison to control animals. Although present in larger concentrations in biosolids than their chlorinated counterparts, the carry over rates and bioconcentration factors of brominated dioxins and furans were considerably smaller. Direct ingestion of biosolids resulted in most contaminants approaching, but not always completely reaching, steady state concentrations within the treatment feeding period, however, concentrations generally declined to control values within four-weeks after withdrawing the biosolids-amended diet.
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Dioxinas , Bifenilos Policlorados , Hidrocarburos Policíclicos Aromáticos , Animales , Bovinos , Leche , Naftalenos , Clorobencenos , Furanos , Alcanos , Biosólidos , Suelo , Ingestión de AlimentosRESUMEN
The first patient was misclassified in the diagnostic conclusion according to a local clinical expert opinion in a new clinical implementation of a knee osteoarthritis artificial intelligence (AI) algorithm at Bispebjerg-Frederiksberg University Hospital, Copenhagen, Denmark. In preparation for the evaluation of the AI algorithm, the implementation team collaborated with internal and external partners to plan workflows, and the algorithm was externally validated. After the misclassification, the team was left wondering: what is an acceptable error rate for a low-risk AI diagnostic algorithm? A survey among employees at the Department of Radiology showed significantly lower acceptable error rates for AI (6.8 %) than humans (11.3 %). A general mistrust of AI could cause the discrepancy in acceptable errors. AI may have the disadvantage of limited social capital and likeability compared to human co-workers, and therefore, less potential for forgiveness. Future AI development and implementation require further investigation of the fear of AI's unknown errors to enhance the trustworthiness of perceiving AI as a co-worker. Benchmark tools, transparency, and explainability are also needed to evaluate AI algorithms in clinical implementations to ensure acceptable performance.
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Some types of poultry bedding made from recycled materials have been reported to contain environmental contaminants such as polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs, dioxins), polychlorinated biphenyls (PCBs) brominated flame retardants (BFRs) polychlorinated naphthalenes (PCNs), polybrominated dioxins (PBDD/Fs), perfluoroalkyl substances (PFAS), etc. In one of the first studies of its kind, the uptake of these contaminants by chicken muscle tissue, liver, and eggs from three types of recycled, commercially available bedding material was simultaneously investigated using conventional husbandry to raise day old chickens to maturity. A weight of evidence analysis showed that PCBs, polybrominated diphenylethers (PBDEs), PCDD/Fs, PCNs and PFAS displayed the highest potential for uptake which varied depending on the type of bedding material used. During the first three to four months of laying, an increasing trend was observed in the concentrations of ΣTEQ (summed toxic equivalence of PCDD/Fs, PCBs, PBDD/Fs, PCNs and polybrominated biphenyls), NDL-PCBs and PBDEs in the eggs of chickens raised on shredded cardboard. Further analysis using bio-transfer factors (BTFs) when egg production reached a steady state, revealed that some PCB congeners (PCBs 28, 81, 138, 153 and 180) irrespective of molecular configuration or chlorine number, showed the highest tendency for uptake. Conversely, BTFs for PBDEs showed good correlation with bromine number, increasing to a maximum value for BDE-209. This relationship was reversed for PCDFs (and to some extent for PCDDs) with tetra- and penta- chlorinated congeners showing a greater tendency for selective uptake. The overall patterns were consistent, although some variability in BTF values was observed between tested materials which may relate to differences in bioavailability. The results indicate a potentially overlooked source of food chain contamination as other livestock products (cow's milk, lamb, beef, duck, etc.) could be similarly impacted.
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Dioxinas , Fluorocarburos , Bifenilos Policlorados , Dibenzodioxinas Policloradas , Femenino , Bovinos , Animales , Ovinos , Dioxinas/análisis , Bifenilos Policlorados/análisis , Pollos , Dibenzodioxinas Policloradas/análisis , Dibenzofuranos/análisis , Éteres Difenilos Halogenados/análisis , Fluorocarburos/análisis , Dibenzofuranos Policlorados/análisis , Monitoreo del AmbienteRESUMEN
Polycyclic aromatic hydrocarbons (PAH) are known carcinogens and are abundant in the environment and foodstuffs. Currently the majority of PAH research focuses on benzo[a]pyrene (BaP), although a much greater range of PAH are known to have detrimental effects to human health. Monitoring a large number of PAH is expensive, time consuming and analytically demanding, yet there is currently no clear basis for determining which PAH should be monitored to give an indication of overall exposure. A thorough statistical examination of the relationships between different PAH in different foodstuffs has not previously been carried out. Using a test dataset of homogenised edible flesh from shellfish samples as a case study a modelling process using principal components analysis regression is proposed to determine which PAH subset (from a total of 27 monitored PAH) should be assessed as indicators for general PAH exposure. Multivariate ordination and clustering show that PAH concentrations of compounds of similar chemical structure can be highly correlated in the samples, e.g. the five ringed isomers PAHs benzo[b]fluoranthene, benzo[j]fluoranthene and benzo[k]fluoranthene. The model selection process determined which subsets of PAH can be used to predict the presence and abundance of other PAHs in shellfish samples. Models were more accurate in predicating PAHs concentrations of PAH where concentrations were measured above the limit of detection (LoD). PAH with values below the LoD were harder to predict accurately. The current analysis highlights that laboratories should focus on the following PAHs BaP, benzo[a]anthracene, benzo[g,h,i]perylene, phenanthrene, benzo[g,h,i]fluoranthene, chrysene, benzo[k]fluoranthene, benzo[b]fluoranthene and fluoranthene when analysing shellfish samples. Focussing monitoring on this group of PAH may give a better indication of overall PAH content of samples that the summed PAH indicator methods currently adopted.
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Carcinógenos Ambientales/análisis , Exposición a Riesgos Ambientales/estadística & datos numéricos , Monitoreo del Ambiente/métodos , Contaminación de Alimentos/análisis , Hidrocarburos Policíclicos Aromáticos/análisis , Mariscos/análisis , Animales , Inocuidad de los Alimentos , Humanos , Modelos BiológicosRESUMEN
The analgesic potential of Cannabis sativa L.-based medicinal cannabis products for treatment of cancer associated chronic pains has gained increased interest in recent years. To ensure a controlled distribution of these products and investigate their therapeutic potential, several countries have established so-called pilot trials. Many doctors, however, are hesitant to prescribe medicinal cannabis primarily due to lack of research evidence regarding the products' efficacy, safety and thus questionable dosing guidelines. This review aims to elucidate clinical research supporting administration of medicinal cannabis in cancer patients for analgesic purposes. The cannabinoids' effects on the endocannabinoid system (ECS) and its implication in pain regulation is included to illustrate the complexity related to this research field. Published clinical studies on medicinal cannabis primarily consist of observational studies and only one pilot randomized controlled trial (RCT), where more RCTs exist on the cannabis-based product, Sativex® (GW Pharma Ltd., Cambridge, UK). The studies indicate analgesic potential, however non-significantly, for most patients and with acceptable safety profile. Summarizing, high-quality RCTs are scarce in this research field, and the limitations of the observational studies complicates interpretation of clinical outcomes. Despite discrepancy among the studies, they do show indications for administration and dosing regimens providing analgesic effects for some cancer patients.
RESUMEN
Sacubitril/valsartan was approved by the Food and Drug Administration in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure (HHF) in patients with chronic heart failure with reduced ejection fraction defined as left ventricular ejection fraction (LVEF) ≤ 40%. This approval was based on PARADIGM-HF trial. Subsequently, PARAGON-HF was conducted to support a claim for sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF), defined as LVEF ≥ 45%. PARAGON-HF failed to meet the pre-defined threshold for statistical significance for the primary composite endpoint. However, analysis of the primary endpoint by LVEF as a continuous variable demonstrated that sacubitril/valsartan was efficacious in patients with mildly abnormal LVEF similar to patients with LVEF ≤ 40% evaluated in PARADIGM-HF. This led to a broader indication for sacubitril/valsartan-"to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. LVEF is a variable measure, so use clinical judgment in deciding whom to treat." This article describes the rationale for a revised indication for sacubitril/valsartan, emphasizes the need to go beyond a dichotomous classification of HF based on a traditional LVEF cut-off and clarifies that the product label for sacubitril/valsartan does not refer to HFpEF.