Vitamin D deficiency (VDD) is common in women with and without polycystic ovary syndrome (PCOS) and may be associated with metabolic and endocrine disorders in PCOS. The aim of this meta-analysis is ...to assess the associations of serum vitamin D levels with metabolic and endocrine dysregulations in women with PCOS, and to determine effects of vitamin D supplementation on metabolic and hormonal functions in PCOS patients. The literature search was undertaken through five databases until 16 January 2015 for both observational and experimental studies concerning relationships between vitamin D and PCOS. A total of 366 citations were identified, of which 30 were selected (n = 3182). We found that lower serum vitamin D levels were related to metabolic and hormonal disorders in women with PCOS. Specifically, PCOS patients with VDD were more likely to have dysglycemia (e.g., increased levels of fasting glucose and homeostatic model assessment-insulin resistance index (HOMA-IR)) compared to those without VDD. This meta-analysis found no evidence that vitamin D supplementation reduced or mitigated metabolic and hormonal dysregulations in PCOS. VDD may be a comorbid manifestation of PCOS or a minor pathway in PCOS associated metabolic and hormonal dysregulation. Future prospective observational studies and randomized controlled trials with repeated VDD assessment and better characterization of PCOS disease severity at enrollment are needed to clarify whether VDD is a co-determinant of hormonal and metabolic dysregulations in PCOS, represents a consequence of hormonal and metabolic dysregulations in PCOS or both.
Purpose
Shift work, short sleep duration, employment as a flight attendant, and exposure to light at night, all potential causes of circadian disruption, have been inconsistently associated with ...breast cancer (BrCA) risk. The aim of this meta-analysis is to quantitatively evaluate the combined and independent effects of exposure to different sources of circadian disruption on BrCA risk in women.
Methods
Relevant studies published through January 2014 were identified by searching the PubMed database. The pooled relative risks (RRs) and corresponding 95 % confidence intervals (CIs) were estimated using fixed- or random effects models as indicated by heterogeneity tests. Generalized least squares trend test was used to assess dose–response relationships.
Results
A total of 28 studies, 15 on shift work, 7 on short sleep duration, 3 on flight attendants, and 6 on light at night were included in the analysis. The combined analysis suggested a significantly positive association between circadian disruption and BrCA risk (RR = 1.14; 95 % CI 1.08–1.21). Separate analyses showed that the RR for BrCA was 1.19 (95 % CI 1.08–1.32) for shift work, 1.120 (95 % CI 1.119–1.121) for exposure to light at night, 1.56 (95 % CI 1.10–2.21) for employment as a flight attendant, and 0.96 (95 % CI 0.86–1.06) for short sleep duration. A dose–response analysis showed that each 10-year increment of shift work was associated with 16 % higher risk of BrCA (95 % CI 1.06–1.27) based on selected case–control studies. No significant dose–response effects of exposure to light at night and sleep deficiency were found on BrCA risk.
Conclusions
Our meta-analysis demonstrates that circadian disruption is associated with an increased BrCA risk in women. This association varied by specific sources of circadian disrupting exposures, and a dose–response relationship remains uncertain. Therefore, future rigorous prospective studies are needed to confirm these relationships.
dental extractions (DEs) in persons with hemophilia A or B (PWH-A or PWH-B) are often associated with bleeding and needing hemostatic therapies (HTs).
to analyze the American Thrombosis and ...Hemostasis Network (ATHN) dataset (ATHNdataset) to assess trends, uses and impacts of HT on bleeding outcomes following DEs.
PWH seen at ATHN affiliates who underwent DEs and opted to share their data with the ATHNdataset between 2013-2019 were identified. The type of DEs, use of HT and bleeding outcomes were assessed.
Among 19,048 PWH ≥2 years of age, 1157 underwent 1301 episodes of DE. Those on prophylaxis experienced a nonsignificant reduction in dental bleeding episodes. Standard half-life factor concentrates were used more often than extended half-life products. PWHA were more likely to undergo DE in the first 30 years of life. Those with severe hemophilia were less likely to undergo DE than those with a mild disease (OR: 0.83; 95% CI: 0.72-0.95). PWH with inhibitors had statistically significantly increased odds of dental bleeding (OR: 2.09, 95% CI; 1.21-3.63).
our study showed that persons with mild hemophilia and younger age were more likely to undergo DE; the presence of inhibitors increased the likelihood of bleeding, while those with prophylaxis and receiving HT experienced a non-statistically significant reduction in bleeding.
Hemophilia A is characterized by unpredictable spontaneous bleeds and chronic comorbidities. However, limited data exists at the national level into detailed management patterns related to patient ...clinical characteristics, representative real‐world dosing and treatment frequency, and costs. To assess and characterize the US severe hemophilia A (SHA) population, including subgroups of patients, in terms of clinical and demographic characteristics, healthcare resource utilization received at hemophilia treatment centers (HTCs), and projected annual costs of treatment utilizing data from the ATHNdataset of the American Thrombosis and Hemostasis Network (ATHN). Adult male people with SHA (PwSHA) (FVIII < 1%) were identified in the ATHNdataset between January 2013 and September 2019. This retrospective cohort study described patients’ demographic and clinical characteristics, clinical history, as well as the HTC‐related health resource utilization (HRU), treatment utilization, and projected annual treatment costs of US PwSHA received over the most recent year. Results are reported for the overall population and for three mutually exclusive subpopulations of patients: PwSHA with a history of and/or current inhibitors, PwSHA without a history of inhibitors but with (or a history of) one or more transfusion‐transmitted infections (hepatitis B virus HBV, hepatitis C virus HCV, or human immunodeficiency virus HIV), and PwSHA without a history of inhibitors or of transfusion‐transmitted infections (HBV, HCV, or HIV). Of the overall PwSHA cohort (N = 3677), there was a high prevalence of HCV (24.1%) and HIV (13.7%), while the prevalence of HBV (4.9%) was lower. Note that 20.5% of PwSHA overall currently or ever had FVIII inhibitors. On average, PwSHA had 2.8 total HTC visits per year, including 0.9 comprehensive care visits, 1.1 telephone contact visits, 0.5 office visits, and 0.1 surgeries or other procedures. However, 23.3% of PwSHA were not seen at an HTC, and 33.8% of PwSHA did not have a comprehensive care visit during their most recent year of data. HTC‐related HRU was similar between the overall cohort and across the patient subpopulations, although PwSHA and inhibitors had more frequent HTC visits (a mean of 3.6 visits annually vs. 2.5–2.8 in the other groups). Using reported treatment frequency and dosing, estimated mean annual hemophilia treatment costs varied by treatment and across the three subpopulations: extended half‐life factor product ($893,609–934,301 by subpopulation), standard half‐life factor product ($798,700–930,812), plasma‐derived factor product ($613,220–801,061), and non‐factor product treatment ($765,289—833,240). This study summarized recent sociodemographic and clinical characteristics, HTC‐related HRU, and HA treatments and projected costs among adult PwSHA, including among key subpopulations of PwSHA. PwSHA experience substantial clinical and resource burden on a chronic basis, despite the care coordination efforts of ATHN‐affiliated HTCs. These findings motivate further exploration of the drivers of resource utilization, observed differences across subpopulations and other disparities, and ongoing monitoring of clinical and treatment burden in the face of an evolving care landscape.
Introduction
Up to 30% of individuals with hemophilia A develop inhibitors to replacement factor VIII (FVIII), rendering the treatment ineffective. The underlying mechanism of inhibitor development ...remains poorly understood. The My Life, Our Future Research Repository (MLOF RR) has gathered
F8
and
F9
mutational information, phenotypic data, and biological material from over 11,000 participants with hemophilia A (HA) and B as well as carriers enrolled across US hemophilia treatment centers, including over 5,000 whole-genome sequences. Identifying genes associated with inhibitors may contribute to our understanding of why certain patients develop those neutralizing antibodies.
Aim and Methods
Here, we performed a genome-wide association study and gene-based analyses to identify genes associated with inhibitors in participants with HA from the MLOF RR.
Results
We identify a genome-wide significant association within the human leukocyte antigen (HLA) locus in participants with HA with
F8
intronic inversions. HLA typing revealed independent associations with the HLA alleles major histocompatibility complex, class II, DR beta 1 (HLA DRB1*15:01) and major histocompatibility complex, class II, DQ beta 1 (DQB1*03:03). Variant aggregation tests further identified low-frequency variants within
GRID2IP
(glutamate receptor, ionotropic, delta 2
GRID2
interacting protein 1) significantly associated with inhibitors.
Conclusion
Overall, our study confirms the association of DRB1*15:01 with FVIII inhibitors and identifies a novel association of DQB1*03:03 in individuals with HA carrying intronic inversions of
F8
. In addition, our results implicate
GRID2IP
, encoding
GRID2
-interacting protein, with the development of inhibitors, and suggest an unrecognized role of this gene in autoimmunity.
Abstract Self-report data suggests a large proportion of total physical activity (PA) occurs at work. However, adults with higher levels of occupational PA may compensate by engaging in less ...non-occupational PA. The study aims were to 1) estimate the intensity, volume, and duration of PA in American adults that occurs at work, and 2) determine if those more active at work are less active outside of work. A cross-sectional sample of full-time employed adults ( N = 510) was recruited from Georgia city and county governments in 2013–2015. Participants wore an Actigraph GT3X + accelerometer for two weeks. In 2016, for 442 participants with complete data including work schedules and self-reported job titles, accelerometer wear minutes were classified as either occupational or non-occupational, and as sedentary, LPA (light-intensity PA), or MVPA (moderate-to-vigorous intensity PA). The proportion of daily PA that occurred during work was 41.2% for total PA, 41.0% for LPA, and 39.5% for MVPA. Higher levels of occupational LPA were associated with lower levels of non-occupational LPA ( r = − 0.38, P < 0.0001). However, higher levels of occupational MVPA were associated with higher levels of non-occupational MVPA ( r = 0.17, P < 0.0001). These associations remained significant in a MANOVA adjusting for labor sector and other covariates. On average, employed adults get more LPA and MVPA outside of work. Adults who do more occupational MVPA do not compensate by doing less non-occupational MVPA. In contrast, adults who do more occupational LPA do compensate by doing less non-occupational LPA. Evaluations of interventions to reduce sedentary behavior should be designed to detect compensation effects.
Numerous studies have engineered nanoparticles with different physicochemical properties to enhance the delivery efficiency to solid tumors, yet the mean and median delivery efficiencies are only ...1.48% and 0.70% of the injected dose (%ID), respectively, according to a study using a nonphysiologically based modeling approach based on published data from 2005 to 2015. In this study, we used physiologically based pharmacokinetic (PBPK) models to analyze 376 data sets covering a wide range of nanomedicines published from 2005 to 2018 and found mean and median delivery efficiencies at the last sampling time point of 2.23% and 0.76%ID, respectively. Also, the mean and median delivery efficiencies were 2.24% and 0.76%ID at 24 h and were decreased to 1.23% and 0.35%ID at 168 h, respectively, after intravenous administration. While these delivery efficiencies appear to be higher than previous findings, they are still quite low and represent a critical barrier in the clinical translation of nanomedicines. We explored the potential causes of this poor delivery efficiency using the more mechanistic PBPK perspective applied to a subset of gold nanoparticles and found that low delivery efficiency was associated with low distribution and permeability coefficients at the tumor site (
< 0.01). We also demonstrate how PBPK modeling and simulation can be used as an effective tool to investigate tumor delivery efficiency of nanomedicines.
The critical barrier for clinical translation of cancer nanomedicine stems from the inefficient delivery of nanoparticles (NPs) to target solid tumors. Rapid growth of computational power, new ...machine learning and artificial intelligence (AI) approaches provide new tools to address this challenge. In this study, we established an AI-assisted physiologically based pharmacokinetic (PBPK) model by integrating an AI-based quantitative structure-activity relationship (QSAR) model with a PBPK model to simulate tumor-targeted delivery efficiency (DE) and biodistribution of various NPs. The AI-based QSAR model was developed using machine learning and deep neural network algorithms that were trained with datasets from a published “Nano-Tumor Database” to predict critical input parameters of the PBPK model. The PBPK model with optimized NP cellular uptake kinetic parameters was used to predict the maximum delivery efficiency (DEmax) and DE at 24 (DE24) and 168 h (DE168) of different NPs in the tumor after intravenous injection and achieved a determination coefficient of R2 = 0.83 root mean squared error (RMSE) = 3.01 for DE24, R2 = 0.56 (RMSE = 2.27) for DE168, and R2 = 0.82 (RMSE = 3.51) for DEmax. The AI-PBPK model predictions correlated well with available experimentally-measured pharmacokinetic profiles of different NPs in tumors after intravenous injection (R2 ≥ 0.70 for 133 out of 288 datasets). This AI-based PBPK model provides an efficient screening tool to rapidly predict delivery efficiency of a NP based on its physicochemical properties without relying on an animal training dataset.
The graphic abstract has been uploaded as an individual high-resolution TIFF file separately. Display omitted
•An AI-based PBPK model for nanoparticles in tumor-bearing mice is built.•An AI-based QSAR model is built to predict PBPK parameters related to tumor.•The AI-PBPK model can predict biodistribution based on physicochemical properties.•This AI-PBPK model represents a new research paradigm for cancer nanomedicines.
Low tumor delivery efficiency is a critical barrier in cancer nanomedicine. This study reports an updated version of "Nano-Tumor Database", which increases the number of time-dependent concentration ...data sets for different nanoparticles (NPs) in tumors from the previous version of 376 data sets with 1732 data points from 200 studies to the current version of 534 data sets with 2345 data points from 297 studies published from 2005 to 2021. Additionally, the current database includes 1972 data sets for five major organs (i.e., liver, spleen, lung, heart, and kidney) with a total of 8461 concentration data points. Tumor delivery and organ distribution are calculated using three pharmacokinetic parameters, including delivery efficiency, maximum concentration, and distribution coefficient. The median tumor delivery efficiency is 0.67% injected dose (ID), which is low but is consistent with previous studies. Employing the best regression model for tumor delivery efficiency, we generate hypothetical scenarios with different combinations of NP factors that may lead to a higher delivery efficiency of >3%ID, which requires further experimentation to confirm. In healthy organs, the highest NP accumulation is in the liver (10.69%ID/g), followed by the spleen 6.93%ID/g and the kidney 3.22%ID/g. Our perspective on how to facilitate NP design and clinical translation is presented. This study reports a substantially expanded "Nano-Tumor Database" and several statistical models that may help nanomedicine design in the future.
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