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General and Comparative Endocrinology Aug 2024Estrogen receptors (ERs) are thought to be the ancestor of all steroid receptors and are present in most lophotrochozoans studied to date, including molluscs, annelids,... (Review)
Review
Estrogen receptors (ERs) are thought to be the ancestor of all steroid receptors and are present in most lophotrochozoans studied to date, including molluscs, annelids, and rotifers. A number of studies have investigated the functional role of estrogen receptors in invertebrate species, although most are in molluscs, where the receptor is constitutively active. In vitro experiments provided evidence for ligand-activated estrogen receptors in annelids, raising important questions about the role of estrogen signalling in lophotrochozoan lineages. Here, we review the concordant and discordant evidence of estradiol receptor signalling in lophotrochozoans, with a focus on annelids and rotifers. We explore the de novo synthesis of estrogens, the evolution and expression of estrogen receptors, and physiological responses to activation of estrogen receptors in the lophotrochozoan phyla Annelida and Rotifera. Key data are missing to determine if de novo biosynthesis of estradiol in non-molluscan lophotrochozoans is likely. For example, an ortholog for the CYP11 gene is present, but confirmation of substrate conversion and measured tissue products is lacking. Orthologs CYP17 and CYP19 are lacking, yet intermediates or products (e.g. estradiol) in tissues have been measured. Estrogen receptors are present in multiple species, and for a limited number, in vitro data show agonist binding of estradiol and/or transcriptional activation. The expression patterns of the lophotrochozoan ERs suggest developmental, reproductive, and digestive roles but are highly species dependent. E exposures suggest that lophotrochozoan ERs may play a role in reproduction, but no strong dose-response relationship has been established. Therefore, we expect most lophotrochozoan species, outside of perhaps platyhelminths, to have an ER but their physiological role remains elusive. Mining genomes for orthologs gene families responsible for steroidogenesis, coupled with in vitro and in vivo studies of the steroid pathway are needed to better assess whether lophotrochozoans are capable of estradiol biosynthesis. One major challenge is that much of the data are divided across a diversity of species. We propose that the polychaetes Capitella teleta or Platyneris dumerilii, and rotifer Brachionus manjavacas may be strong species choices for studies of estrogen receptor signalling, because of available genomic data, established laboratory culture techniques, and gene knockout potential.
Topics: Animals; Signal Transduction; Receptors, Estradiol; Annelida; Receptors, Estrogen; Rotifera; Estradiol
PubMed: 38677339
DOI: 10.1016/j.ygcen.2024.114519 -
Regulatory Toxicology and Pharmacology... Aug 2023In this study we evaluated the outcomes of non-clinical toxicity studies of various SARS-CoV-2 vaccines produced with different manufacturing technologies, with focus on...
In this study we evaluated the outcomes of non-clinical toxicity studies of various SARS-CoV-2 vaccines produced with different manufacturing technologies, with focus on Repeated Dose Toxicity (RDT) and Developmental and Reproductive Toxicity (DART) studies. We found that RDT and DART studies at doses relevant for human treatment showed no adverse effects while remaining observations were expected findings including local reactogenicity, immune response and macroscopic findings at the injection site. We have also reviewed the European Medicines Agency (EMA) nonclinical assessment reports for market authorization. Regardless of utilized vaccine manufacturing technology EMA assessment of the non-clinical studies consisted most frequently of comments related to study design, species selection and missing data. Sponsors have often submitted platform studies (vaccine studies with the same technology/construct but using other antigens) as supplementary data. Animal model-based toxicity testing has shown rather small effects, which have been never serious adverse effects. The translational value to support clinical development is mainly to inflammatory effects, indicative of the primary action of the vaccines. From a 3R perspective supportive platform technology data consisting of previously executed RDT and DART studies from the same platform technology are encouraged to be implemented in the vaccine assessment process.
Topics: Animals; Humans; COVID-19; COVID-19 Vaccines; SARS-CoV-2; Toxicity Tests; Vaccines
PubMed: 37356612
DOI: 10.1016/j.yrtph.2023.105438 -
Computers in Biology and Medicine Jan 2024Cone-beam computed tomography (CBCT) is generally reconstructed with hundreds of two-dimensional X-Ray projections through the FDK algorithm, and its excessive ionizing...
Cone-beam computed tomography (CBCT) is generally reconstructed with hundreds of two-dimensional X-Ray projections through the FDK algorithm, and its excessive ionizing radiation of X-Ray may impair patients' health. Two common dose-reduction strategies are to either lower the intensity of X-Ray, i.e., low-intensity CBCT, or reduce the number of projections, i.e., sparse-view CBCT. Existing efforts improve the low-dose CBCT images only under a single dose-reduction strategy. In this paper, we argue that applying the two strategies simultaneously can reduce dose in a gentle manner and avoid the extreme degradation of the projection data in a single dose-reduction strategy, especially under ultra-low-dose situations. Therefore, we develop a Joint Denoising and Interpolating Network (JDINet) in projection domain to improve the CBCT quality with the hybrid low-intensity and sparse-view projections. Specifically, JDINet mainly includes two important components, i.e., denoising module and interpolating module, to respectively suppress the noise caused by the low-intensity strategy and interpolate the missing projections caused by the sparse-view strategy. Because FDK actually utilizes the projection information after ramp-filtering, we develop a filtered structural similarity constraint to help JDINet focus on the reconstruction-required information. Afterward, we employ a Postprocessing Network (PostNet) in the reconstruction domain to refine the CBCT images that are reconstructed with denoised and interpolated projections. In general, a complete CBCT reconstruction framework is built with JDINet, FDK, and PostNet. Experiments demonstrate that our framework decreases RMSE by approximately 8 %, 15 %, and 17 %, respectively, on the 1/8, 1/16, and 1/32 dose data, compared to the latest methods. In conclusion, our learning-based framework can be deeply imbedded into the CBCT systems to promote the development of CBCT. Source code is available at https://github.com/LianyingChao/FusionLowDoseCBCT.
Topics: Humans; Image Processing, Computer-Assisted; Phantoms, Imaging; Cone-Beam Computed Tomography; Algorithms; X-Rays
PubMed: 38086140
DOI: 10.1016/j.compbiomed.2023.107830 -
Journal of Affective Disorders Feb 2024CYP2C19 is a key factor influencing escitalopram (SCIT) exposure. However, different studies reported various results. This study aims to develop a population...
BACKGROUND AND PURPOSE
CYP2C19 is a key factor influencing escitalopram (SCIT) exposure. However, different studies reported various results. This study aims to develop a population pharmacokinetic (popPK) model characterizes the disposition of SCIT in the Chinese population. Based on the popPK model, the study simulates non-adherence scenarios and proposes remedial strategies to facilitate SCIT personalized therapy.
METHODS
Nonlinear mixed-effects modeling using data from two Chinese bioequivalence studies was employed. Monte-Carlo simulation was used to explore non-adherence scenarios and propose remedial strategies based on the proportion of time within the therapeutic window.
RESULTS
Results showed that a one-compartment model with transit absorption and linear elimination described the data well, CYP2C19 phenotypes and weight were identified as significant covariates impacting SCIT exposure. Patients were recommended to take the entire delayed dose immediately if the delay time was no >12 h, followed by the regular regimen at the next scheduled time. When there is one or two doses missed, taking a double dose immediately was recommended to the CYP2C19 intermediate and extensive population, and a 1.5-fold dose was recommended to the CYP2C19 poor metabolizers with the consideration of adverse effects.
LIMITATION
All samples were derived from the homogenized Chinese healthy population for model building, which may pose certain constraints on the ability to identify significant covariates, such as age.
CONCLUSION
The study highlights the importance of considering patient characteristics for personalized medication and offers a unique perspective on utilizing the popPK repository in precision dosing.
Topics: Humans; Escitalopram; Cytochrome P-450 CYP2C19; Phenotype; Computer Simulation
PubMed: 37949237
DOI: 10.1016/j.jad.2023.11.016 -
Journal of Clinical Medicine Mar 2024Acute coronary syndromes (ACS), encompassing conditions like ST-elevation myocardial infarction (STEMI) and non-ST-elevation acute coronary syndromes (NSTE-ACS),... (Review)
Review
The Evolving Field of Acute Coronary Syndrome Management: A Critical Appraisal of the 2023 European Society of Cardiology Guidelines for the Management of Acute Coronary Syndrome.
Acute coronary syndromes (ACS), encompassing conditions like ST-elevation myocardial infarction (STEMI) and non-ST-elevation acute coronary syndromes (NSTE-ACS), represent a significant challenge in cardiovascular care due to their complex pathophysiology and substantial impact on morbidity and mortality. The 2023 European Society of Cardiology (ESC) guidelines for ACS management introduce several updates in key areas such as invasive treatment timing in NSTE-ACS, pre-treatment strategies, approaches to multivessel disease, and the use of imaging modalities including computed tomography (CT) coronary angiography, magnetic resonance imaging (MRI), and intracoronary imaging techniques, such as optical coherence tomography (OCT) and intravascular ultrasound (IVUS). They also address a modulation of antiplatelet therapy, taking into consideration different patient risk profiles, and introduce new recommendations for low-dose colchicine. These guidelines provide important evidence-based updates in practice, reflecting an evolution in the understanding and management of ACS, yet some potentially missed opportunities for more personalized care and technology adoption are discussed.
PubMed: 38610650
DOI: 10.3390/jcm13071885 -
Diabetes Technology & Therapeutics Jan 2024Connected insulin pens are creating opportunities for the millions of individuals with diabetes using multiple daily injections (MDI) therapy across the globe....
Connected insulin pens are creating opportunities for the millions of individuals with diabetes using multiple daily injections (MDI) therapy across the globe. Continuous glucose monitoring (CGM) data from connected insulin pens are revealing gaps and opportunities to significantly improve care for this population. In this article, we report real-world findings of the InPen™ smart insulin pen paired with CGM (InPen system), used by persons with type 1 diabetes (T1D) and type 2 diabetes (T2D). A retrospective cohort analysis was conducted with the real-world data collected from the InPen system of individuals ( = 3793 with T1D, = 552 with T2D, and = 808 unidentified) who used the system from January 01, 2020, to December 31, 2021. Diabetes management (e.g., missed and mistimed insulin dosing, mismatched food intake, and correction dose delivery) and glycemic outcomes were assessed. In the overall and T1D populations, a dosing frequency of ≥3 doses per day and a missed dose frequency of <20% was associated with improved glycemia. In adults with T2D, missing <20% of doses was the significant factor determining improved glycemia. This analysis, integrating data from a smart insulin pen and CGM, provides insights into the impact of dosing behavior on glycemic outcomes and informs counseling strategies for the diabetes care team, through technologically advanced insulin management for those using MDI therapy.
Topics: Adult; Humans; Insulin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Blood Glucose Self-Monitoring; Retrospective Studies; Blood Glucose; Insulin, Regular, Human
PubMed: 37855818
DOI: 10.1089/dia.2023.0365 -
Vaccines Jul 2023As the world continues to urbanize, particularly in low- and middle-income countries, understanding the barriers and effective interventions to improve urban... (Review)
Review
INTRODUCTION
As the world continues to urbanize, particularly in low- and middle-income countries, understanding the barriers and effective interventions to improve urban immunization equity is critical to achieving both Immunization Agenda 2030 targets and the Sustainable Development Goals. Approximately 25 million children missed one or more doses of the diphtheria, tetanus and pertussis (DTP3) vaccine in 2021 and it is estimated that close to 30% of the world's children missing the first dose of DTP, known as zero-dose, live in urban and peri-urban settings.
METHODS
The aim of this research is to improve understanding of urban immunization equity through a qualitative review of mixed method studies, urban immunization strategies and funding proposals across more than 70 urban areas developed between 2016 and 2020, supported by Gavi, the Vaccine Alliance. These research studies and strategies created a body of evidence regarding the barriers to vaccination in urban settings and potential interventions relevant to low- and middle-income countries (LMICs) with a focus on the vaccination of urban poor, populations of concern and residents of informal settlements. Through the document review we identified common challenges to achieving equitable coverage in urban areas and mapped proposed interventions.
RESULTS
We identified 70 documents as part of the review and categorized results across (1) social determinants of health, (2) immunization service-delivery barriers and (3) quality of services. Barriers and solutions identified in the documents were categorized in these thematic areas, drawing information from results in more than 21 countries.
CONCLUSION
Populations of concern such as migrants, refugees, residents of informal settlements and the urban poor face barriers to accessing care which include poor availability and quality of service. Example solutions proposed to these challenges include tailored delivery strategies, improved use of digital data collection and child-friendly services. More research is required on the efficacy of the proposed interventions identified and on gender-specific dynamics in urban poor areas affecting equitable immunization coverage.
PubMed: 37515016
DOI: 10.3390/vaccines11071200 -
Journal of Pharmacy Practice Dec 2023To determine the impact of a business intelligence dashboard tool to optimize automated dispensing cabinets (ADCs). A pre-post implementation design was used to...
To determine the impact of a business intelligence dashboard tool to optimize automated dispensing cabinets (ADCs). A pre-post implementation design was used to evaluate key performance indicators (KPI) before and after the implementation of a dashboard tool to optimize ADCs. Eleven ADCs were optimized in 2 phases according to dashboard recommendations: (1) removal of unused medications over 90 days, (2) adjusting periodic automatic replenishment (PAR) levels, and (3) addition of commonly dispensed medications. The KPI measures that were assessed included inventory cost, no. of stocked medications, stockout percentage, vend to refill ratio, and missing dose messages from nursing. An interrupted-time-series regression was used to quantify the impact of ADCs on the means of measured KPIs. Differences in mean distribution of all KPIs, except missing dose, between the pre- and post-ADC periods during the Phase 1 period were statistically significant: inventory cost (54.2 vs 56), stockout percentage (1.55 vs 1.12), vend to refill ratio (6.83 vs 6.14), and missing dose messages (221 vs 229). Only the mean ADC utilization (57.3 vs 64) and missing dose (228 vs 179) were statistically different between the pre- and post-ADC periods in Phase 2. The interrupted-time-series analysis showed that Phase 1 optimization significantly reduced the cost of inventory (β = -$1.238.00, < .01), no. Stocked medications (β = -8.2, < .01), percent stockout (β = -.49%, < .01), vend-to-refill ratio (β = -1.29%, P<.01) and ADC utilization (β = -.2, < .01). Automated dispensing cabinets optimization, through the use of a dashboard tool, had a positive impact on almost all measured KPIs.
Topics: Humans; Medication Systems, Hospital; Medication Errors; Pharmacy Service, Hospital; Commerce
PubMed: 35953085
DOI: 10.1177/08971900221118159 -
Infectious Diseases and Therapy Nov 2023Pertussis, caused by Bordetella pertussis, remains one of the most widespread, contagious, and vaccine-preventable diseases. It results in notable morbidity and... (Review)
Review
Pertussis, caused by Bordetella pertussis, remains one of the most widespread, contagious, and vaccine-preventable diseases. It results in notable morbidity and mortality as well as severe medical, social, and economic burden. Despite high global vaccine coverage, pertussis continues to be a significant epidemiologic problem, with outbreak episodes every few years just as in the pre-vaccination era. In Türkiye, there is a lack of comprehensive data on the current burden of pertussis in different age and risk groups, leading to underdiagnosis and underreporting of the disease, especially in adults who are often not considered at risk. Available data from Türkiye also reveal inadequate levels of protective antibodies in preterm newborns, emphasizing the need for additional preventive measures. Authors stated that improving physician awareness of pertussis symptoms in patients with prolonged cough, increasing access to routine pertussis tests, and conducting surveillance studies would aid in accurate diagnosis and reporting in Türkiye. As the Turkish Ministry of Health Antenatal Care Management Guide suggests routine second and third pregnancy check-up visits at weeks 18-24 and 28-32 correspondingly, this period can be considered the ideal vaccination time for Türkiye. Introducing a booster dose of Tdap at around 10 years of age or during national military service would reduce transmission and protect susceptible individuals. Identifying individuals at high risk of severe pertussis and prioritizing them for a booster dose is also crucial in Türkiye. Enhancing surveillance systems, increasing healthcare professionals' awareness through training, and organizing catch-up visits for missed vaccinations during the COVID-19 pandemic are mentioned as additional strategies to improve pertussis prevention in Türkiye. This review focuses on the global and regional burden of pertussis and obstacles to effective prevention and evaluates existing strategies to achieve lifelong pertussis prevention. Literature and current strategies were also discussed from a Turkish national standpoint.
PubMed: 37815753
DOI: 10.1007/s40121-023-00876-0 -
The Annals of Thoracic Surgery Oct 2023The objective of this study was to evaluate patterns, predictors, and long-term outcomes of recurrent disease after complete resection for early-stage non-small cell...
BACKGROUND
The objective of this study was to evaluate patterns, predictors, and long-term outcomes of recurrent disease after complete resection for early-stage non-small cell lung cancer (NSCLC) using the National Lung Screening Trial (NLST).
METHODS
The frequency of recurrence in patients with pathologic stage I-II NSCLC who underwent complete resection (lobectomy or bilobectomy) in the NLST was evaluated. Predictors of increased risk of recurrence were assessed by Fine-Gray competing risks regression.
RESULTS
Of the 497 patients meeting study inclusion criteria, 94 experienced a recurrence-a rate of 4.9 (95% CI, 4.0-6.0) per 100 person-years. The 5-year cumulative incidence of recurrence was 20.1% (95% CI, 16.5%-23.9%). Most patients experienced recurrences at distant sites alone (n = 47 [50.0%]) or at both locoregional and distant sites (n = 30 [31.9%]). The median time from resection to recurrence was 18.8 (10.6-30.7) months. The incidence rate of recurrence was significantly lower among patients with lung cancer detected by low-dose computed tomography screening during one of the three screening rounds of the NLST when compared with patients with lung cancer detected by chest radiography screening and patients with lung cancer not detected by any form of screening (ie, those diagnosed after a negative or missed screening exam and those diagnosed during follow-up after the three screening rounds of the NLST were completed) (P < .001). Median survival (from the date of recurrence) of patients with pathologic stage I and stage II disease who had recurrences at locoregional, distant, or both sites was 63.0, 23.1, and 9.8 months and 28.9, 8.7, and 10.2 months, respectively.
CONCLUSIONS
In this analysis of NLST participants with completely resected stage I-II NSCLC, the 5-year cumulative incidence of recurrence was 20%. Nearly 82% of recurrences were at distant sites and associated with poor survival.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Early Detection of Cancer; Lung; Recurrence; Neoplasm Recurrence, Local; Neoplasm Staging; Retrospective Studies
PubMed: 37356517
DOI: 10.1016/j.athoracsur.2023.06.004