Invasive Assessment of Coronary Artery Disease in Clonal Hematopoiesis of Indeterminate Potential.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) occurs due to acquired mutations in bone marrow progenitor cells. CHIP confers a 2-fold risk of atherosclerotic cardiovascular disease. However, there are limited data regarding specific cardiovascular phenotypes. The purpose of this study was to define the coronary artery disease phenotype of the CHIP population-based on coronary angiography. METHODS: We recruited 1142 patients from the Vanderbilt University Medical Center cardiac catheterization laboratory and performed DNA sequencing to determine CHIP status. Multivariable logistic regression models and proportional odds models were used to assess the association between CHIP status and angiography phenotypes. RESULTS: We found that 18.4% of patients undergoing coronary angiography had a CHIP mutation. Those with CHIP had a higher risk of having obstructive left main (odds ratio, 2.44 [95% CI, 1.40-4.27]; P=0.0018) and left anterior descending (odds ratio, 1.59 [1.12-2.24]; P=0.0092) coronary artery disease compared with non-CHIP carriers. We additionally found that a specific CHIP mutation, ten eleven translocase 2 (TET2), has a larger effect size on left main stenosis compared with other CHIP mutations. CONCLUSIONS: This is the first invasive assessment of coronary artery disease in CHIP and offers a description of a specific atherosclerotic phenotype in CHIP wherein there is an increased risk of obstructive left main and left anterior descending artery stenosis, especially among TET2 mutation carriers. This serves as a basis for understanding enhanced morbidity and mortality in CHIP.

Costs and health benefits of the rural energy transition to carbon neutrality in China.

The rural energy transition is critical in China's efforts to achieve carbon neutrality and improve air quality. However, the costs and health benefits associated with the transition to carbon neutrality remain unclear. Here we explore the cost-effective transition pathways and air quality-related health impacts using an integrated energy-air quality-health modeling framework. We find that decarbonizing rural cooking and heating would triple contemporary energy consumption from 2014 to 2060, considerably reducing energy poverty nationwide. By 2060, electric cooking ranges and air-to-air heat pumps should be widely integrated, costing an additional 13 billion USD nationally in transformation costs, with ~40% concentrated in Shandong, Heilongjiang, Shanxi and Hebei provinces. Rural residential decarbonization would remarkably improve air quality in northern China, yielding substantial health co-benefits. Notably, monetized health benefits in most provinces are projected to offset transformation costs, except for certain relatively lower-development southwestern provinces, implying more financial support for rural residents in these areas will be needed.

Three-year hospital-wide pain management system implementation at a tertiary medical center: Pain prevalence analysis.

We developed a pain management system over a 3-year period. In this project, "Towards a pain-free hospital", we combined evidence-based medicine and medical expertise to develop a series of policies. The intervention mainly included the development of standard procedures for inpatient pain management, the implementation of hospital-wide pain medicine education and training, the establishment of a dashboard system to track pain status, and regular audits and feedback. This study aimed to gain an understanding of the changes in the prevalence of pain in inpatients under the care of the pain management system. The subjects of the survey are inpatients over 20 years old, and who had been hospitalized in the general ward for at least 3 days. The patients would be excluded if they were unable to respond to the questions. We randomly selected eligible patients in the general ward. Our trained interviewers visited inpatients to complete the questionnaires designed by our pain care specialists. A total of 3,094 inpatients completed the survey from 2018 to 2020. During the three-year period, the prevalence of pain was 69.5% (2018) (reference), 63.3% (2019) (OR:0.768, p<0.01), and 60.1% (2020) (OR:0.662, p <0.001). The prevalence rates of pain in patients undergoing surgery during the 3-year period were 81.4% (2018), 74.3% (2019), and 68.8% (2020), respectively. As for care-related causes of pain, injection, change in position/chest percussion, and rehabilitation showed a decreasing trend over the 3-year period of study. Our pain management system provided immediate professional pain management, and achieved a good result in the management of acute moderate to severe pain, especially perioperative pain. Studies on pain prevalence and Pain-Free Hospitals are scarce in Asia. With the aid of the policies based on evidence-based medicine and the dashboard information system, from 2018 to 2020, the prevalence of pain has decreased year by year.

Implications of wheat straw logistic systems for bioenergy sustainable development in China: Costs, energy consumption, and GHG emissions.

Wheat straw is a priority choice for bioenergy production, bioenergy as the essential low carbon emissions energy can be a good choice for alternating the petroleum-based fuels. In this study, face-to-face surveys were conducted to analyze the costs, energy consumption, and greenhouse gas emissions involved in wheat straw logistic systems in China. The result identified five logistic modes, including two short-distance transportation and three long-distance transportation modes. These five modes exhibited costs ranging from 17.34-31.95 $ t-1, energy consumption between 108.30 and 1060.45 MJ t-1, and greenhouse gas emissions ranging from 0.71-11.52 kg CO2-eq t-1. A sensitivity analysis showed that the most important parameters in the short-distance transport group were the harvest rate and the bale weight. In the long-distance transport group, the distance from the depot to the end user and the truck capacity. After an overall consideration of the costs, energy consumption, and greenhouse gas emissions, an optimal wheat straw logistic system was found in the short-distance transport group due to maximum harvest rate and bale weight by using better combines and balers. Whereas the distance from the depot to the end user should be reduced and higher capacity trucks should be used to have relatively optimal modes for the long-distance transport group. This study provides a valuable reference for bioenergy industries in feedstock collection.

Assessment of hyperbaric patients at risk of malnutrition using the Malnutrition Screening Tool - a pilot study.

BACKGROUND: Nutritional assessment and support is essential for wound management. The hyperbaric oxygen clinic is a unique outpatient service where chronically unwell patients present daily for hyperbaric oxygen treatment (HBOT) over several weeks, allowing time for effective nutritional intervention. This is the first study to examine the prevalence of those at risk of malnutrition in a cohort of hyperbaric medical patients. METHODS: A prospective study was undertaken over six months. Following consent, 39 enrolled patients had the Malnutrition Screening Tool and Baseline Characteristic Collection Form completed. Those at risk of malnutrition were given an option to be assessed by a dietitian to complete a Subjective Global Assessment (SGA). At the completion of treatment, the patients completed a questionnaire. RESULTS: Twelve of the 39 patients screened were at risk of malnutrition using our screening process. Of these, all the patients with available SGA results were diagnosed with moderate to severe malnutrition. Patients receiving HBOT for non-healing wounds and osteoradionecrosis were most at risk of malnutrition. CONCLUSION: The prevalence of patients being at risk of malnutrition in our hyperbaric medical service was about one in three. Malnutrition screening should be part of routine patient assessment in order to ensure patients receive timely nutritional intervention. This may improve wound healing.

Assessment of brain-derived neurotrophic factor and osteopontin in a healthy pediatric population.

Biomarkers are routinely used for noninvasive identification or monitoring of disease processes in clinical practice, as well as surrogate end points for drug development. There is a significant lack of data regarding biomarkers in children. An understanding of biomarker levels in a healthy pediatric cohort is essential as more studies begin to apply noninvasive biomarkers to pediatric populations. Brain-derived neurotrophic factor (BDNF) functions in neuronal survival and plasticity and is associated with exercise capacity and inflammatory disease processes. Osteopontin (OPN) plays a regulatory role in inflammation and may be a clinically useful biomarker of cardiovascular disease processes, ventricular remodeling, and skeletal muscle regeneration. This study describes our initial experience with a cohort of healthy pediatric patients and seeks to provide normal values of BDNF and OPN with correlation to age, gender, and cardiovascular and fitness measures. Serum BDNF and plasma OPN were measured using enzyme-linked immunosorbent assay in 33 healthy pediatric subjects. Subjects underwent complete cardiac evaluation, including echocardiography, exercise stress testing, and health risk assessment. The 5th-95th percentile was 5.63-37.86 ng/ml for serum BDNF and 4.9-164.9 ng/ml for plasma OPN. Plasma OPN correlated with number of days of exercise per week (r = 0.46, p = 0.008). No other correlations were significant. This study provides the initial data on serum BDNF and plasma OPN in children and begins to explore the relationships of BDNF and OPN to cardiovascular health and fitness in the pediatric population.

Multicellular dosimetric chain for molecular radiotherapy exemplified with dose simulations on 3D cell spheroids.

PURPOSE: Absorbed radiation dose-response relationships are not clear in molecular radiotherapy (MRT). Here, we propose a voxel-based dose calculation system for multicellular dosimetry in MRT. We applied confocal microscope images of a spherical cell aggregate i.e. a spheroid, to examine the computation of dose distribution within a tissue from the distribution of radiopharmaceuticals. METHODS: A confocal microscope Z-stack of a human hepatocellular carcinoma HepG2 spheroid was segmented using a support-vector machine algorithm and a watershed function. Heterogeneity in activity uptake was simulated by selecting a varying amount of the cell nuclei to contain 111In, 125I, or 177Lu. Absorbed dose simulations were carried out using vxlPen, a software application based on the Monte Carlo code PENELOPE. RESULTS: We developed a schema for radiopharmaceutical dosimetry. The schema utilizes a partially supervised segmentation method for cell-level image data together with a novel main program for voxel-based radiation dose simulations. We observed that for 177Lu, radiation cross-fire enabled full dose coverage even if the radiopharmaceutical had accumulated to only 60% of the spheroid cells. This effect was not found with 111In and 125I. Using these Auger/internal conversion electron emitters seemed to guarantee that only the cells with a high enough activity uptake will accumulate a lethal amount of dose, while neighboring cells are spared. CONCLUSIONS: We computed absorbed radiation dose distributions in a 3D-cultured cell spheroid with a novel multicellular dosimetric chain. Combined with pharmacological studies in different tissue models, our cell-level dosimetric calculation method can clarify dose-response relationships for radiopharmaceuticals used in MRT.

Laminin-511 and laminin-521-based matrices for efficient hepatic specification of human pluripotent stem cells.

Human pluripotent stem cells (hPSCs) have gained a solid foothold in basic research and drug industry as they can be used in vitro to study human development and have potential to offer limitless supply of various somatic cell types needed in drug development. Although the hepatic differentiation of hPSCs has been extensively studied, only a little attention has been paid to the role of the extracellular matrix. In this study we used laminin-511, laminin-521, and fibronectin, found in human liver progenitor cells, as culture matrices for hPSC-derived definitive endoderm cells. We observed that laminin-511 and laminin-521 either alone or in combination support the hepatic specification and that fibronectin is not a vital matrix protein for the hPSC-derived definitive endoderm cells. The expression of the laminin-511/521-specific integrins increased during the definitive endoderm induction and hepatic specification. The hepatic cells differentiated on laminin matrices showed the upregulation of liver-specific markers both at mRNA and protein levels, secreted human albumin, stored glycogen, and exhibited cytochrome P450 enzyme activity and inducibility. Altogether, we found that laminin-511 and laminin-521 can be used as stage-specific matrices to guide the hepatic specification of hPSC-derived definitive endoderm cells.

Hyperspectral Imaging Coupled with Random Frog and Calibration Models for Assessment of Total Soluble Solids in Mulberries.

Chemometrics methods coupled with hyperspectral imaging technology in visible and near infrared (Vis/NIR) region (380-1030 nm) were introduced to assess total soluble solids (TSS) in mulberries. Hyperspectral images of 310 mulberries were acquired by hyperspectral reflectance imaging system (512 bands) and their corresponding TSS contents were measured by a Brix meter. Random frog (RF) method was used to select important wavelengths from the full wavelengths. TSS values in mulberry fruits were predicted by partial least squares regression (PLSR) and least-square support vector machine (LS-SVM) models based on full wavelengths and the selected important wavelengths. The optimal PLSR model with 23 important wavelengths was employed to visualise the spatial distribution of TSS in tested samples, and TSS concentrations in mulberries were revealed through the TSS spatial distribution. The results declared that hyperspectral imaging is promising for determining the spatial distribution of TSS content in mulberry fruits, which provides a reference for detecting the internal quality of fruits.

A critical assessment of in vitro tissue models for ADME and drug delivery.

Cultured cells are widely used in the evaluation of new drugs and drug delivery systems. Cells can be grown at different levels of complexity ranging from simple reductionist models to complex organotypic models. The models are based on primary, secondary or stem cell derived cell cultures. Generation of tissue mimics with cultured cells is a difficult task, because the tissues have well-defined morphology, complex protein expression patterns and multiple inter-linked functions. Development of organotypic cell culture models requires proper biomaterial matrix and cell culture protocols that are able to guide the cells to the correct phenotype. This review illustrates the critical features of the cell culture models and, then, selected models are discussed in more detail (epidermal, corneal epithelial, retinal pigment epithelium, and hepatocyte models). The cell models are critically evaluated paying attention to the level of characterization and reliability of in vivo translation. Properties of the cell models must be characterized in detail using multiple biological assays and broad sets of model drugs. Robust in vivo predictions can be achieved with well-characterized cell models that are used in combination with computational methods that will bridge the gap between in vitro cell experiments and physiological situation in vivo in the body.

Shape modulation of octanuclear Cu(I) or Ag(I) dichalcogeno template clusters with respect to the nature of their encapsulated anions: a combined theoretical and experimental investigation.

M8L6 clusters (M = Cu(I), Ag(I); L = dichalcogeno ligand) are known for their ability to encapsulate various kinds of saturated atomic anions. Calculations on the models [M8(E2PH2)6](2+) (M = Cu(I), Ag(I); E = S, Se) and the ionic or neutral [M8(X)(E2PH2)6](q) (X = H, F, Cl, Br, O, S, Se, N, P, C) indicate that the cubic M8L6 cage adapts its shape for maximizing the host-guest bonding interaction. The interplay between size, covalent and ionic bonding favors either a cubic, tetracapped tetrahedral, or bicapped octahedral structure of the metal framework. Whereas the large third- and fourth-row main group anions maintain the cubic shape, a distortion toward a tetracapped tetrahedral arrangement of the metals occurs in the case of hydride, fluoride, and oxide. The distortion is strong in the case of hydride, weak in the case of fluoride, and intermediate in the case of oxide. Density functional theory (DFT) calculations predict a bicapped octahedral architecture in the case of nitride and carbide. These computational results are supported by X-ray structures, including those of new fluorine- and oxygen-containing compounds. It is suggested that other oxygen-containing as well as so far unknown nitride-containing clusters should be feasible. For the first time, the dynamical behavior of the encapsulated hydride has been investigated by metadynamics simulations. Our results clearly demonstrate that the interconversion mechanism between two identical tetracapped tetrahedral configurations occurs through a succession of M-H bonds breaking and forming which present very low activation energies and which involve a rather large number of intermediate structures. This mechanism is full in accordance with (109)Ag and (1)H state NMR measurements.

Black art posters, an incentive to increase study enrollment among Blacks in a large cohort study.

OBJECTIVE: Black art posters were offered to replace or augment the established $10 incentive for questionnaire completion in a longitudinal cohort study. METHOD: Eighty-one churches located in the US southern region were divided between two intervention groups, with a control group of 24 churches from the same region. Primary outcome measures were study enrollment rates and questionnaire return rates between December 2003 and July 2004 as a proportion of church goal. RESULTS: 9.3% of participants returning questionnaires selected a poster in preference to $10. Half of participants offered both monetary and art incentives indicated a poster selection. Crude questionnaire return rates were 57.4% for the pooled intervention churches and 38.2% for the control churches. Enrollment rates among those offered both incentives were significantly higher (p<0.01) than when monetary incentives alone were offered after adjustment for church size, promotional dates, and average income of church members. Survey return rates were also higher in the churches offered both incentives (p=0.04). CONCLUSION: These data suggest that the black art posters improved study enrollment and survey return rates. The relatively low rate of poster selection suggests that the art primarily influenced participation indirectly, by creating a more culturally inclusive image of the study.

Feasibility of running clinics to collect biological specimens in a nationwide cohort study--Adventist Health Study-2.

PURPOSE: Collecting biologic and questionnaire data allows analyses that can include both genetic/biomarker and behavioral factors. Therefore, the feasibility of collecting biological specimens from a nationally dispersed cohort (Adventist Health Study-2) was tested. METHODS: We selected 2130 subjects from California, Washington, Texas, and Louisiana to simulate a widely scattered cohort. Clinics were held at local church halls. Nonclinic attendees were invited to mail in their blood samples. The remaining nonparticipants were offered a home visit by a venipuncturist. RESULTS: Sixty-four percent of nonblack and 38.4% of black invitees attended the clinics. Another 11.3% of nonblack and 5.9% of black subjects from a subsample mailed in their blood samples. A venipuncturist visit collected samples from another 5.3% of nonblack subjects, but hurricanes disrupted this method among blacks. This experience suggests that we could collect biological samples from 81.2% and at least 44.3% of the nonblack and black subjects, respectively. CONCLUSIONS: We have demonstrated the feasibility of collecting biological specimens from black as well as nonblack subjects, with an efficient, cost-effective system, and limited personpower, overcoming many of the complexities imposed by scattered subjects, diversity of culture, as well as cumbersome and varied state legislation governing clinics and clinic personnel.