Cumulative Area Research Articles

Busulfan Exposure Target Attainment in Adults Undergoing Allogeneic Hematopoietic Cell Transplantation: A Single Day Versus a Multiple Day Therapeutic Drug Monitoring Regimen

Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. In this observational study, we included all adults who received an allogeneic HCT with intravenous once daily busulfan over 4 days as part of the conditioning regimen at the University Medical Centre Utrecht or between July 31, 2014 and November 12, 2021. The primary outcome was attainment of the therapeutic busulfan target (cumulative area under the curve [AUCcum] 80-100 mg*h/L). Dose adjustment was based on the estimated AUC of the preceding dosing day(s). Additional TDM was performed in the event of large dose adjustments (≥25%). The choice of TDM regimen was solely based on the first day the busulfan dose was administered (regimen d1 + 2 occurred when conditioning started on a Saturday). In all patients, blood sampling was performed on day 4 for evaluation. The AUCcum was estimated using a validated population pharmacokinetic model. Busulfan target exposure was compared between both TDM regimen groups using a propensity score adjusted logistic regression model. The variance in the AUCcum between the TDM regimens was compared using the F-test. Patients were stratified for age (categorical). In regimen d1, 87.6% (n = 113/129) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 97.4% was found (n = 74/76, adjusted odds ratio for non-therapeutic AUC = 0.19, 95% confidence interval [95% CI]: 0.04-0.89). Variance of busulfan exposure in the regimen d1 group (SD = 6.8 mg*h/L) differed significantly from the variance in the regimen d1 + 2 group (SD = 3.6 mg*h/L, F-test, P < .001). Performing busulfan TDM on both day 1 and day 2, rather than only on day 1, improves busulfan target exposure attainment in adults undergoing HCT, provided that subsequent TDM is carried out if required.

Normalized lactate load as an independent prognostic indicator in patients with cardiogenic shock

BackgroundEarly prognosis evaluation is crucial for decision-making in cardiogenic shock (CS) patients. Dynamic lactate assessment, for example, normalized lactate load, has been a better prognosis predictor than single lactate value in septic shock. Our objective was to investigate the correlation between normalized lactate load and in-hospital mortality in patients with CS.MethodsData were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The calculation of lactate load involved the determination of the cumulative area under the lactate curve, while normalized lactate load was computed by dividing the lactate load by the corresponding period. Receiver Operating Characteristic (ROC) curves were constructed, and the evaluation of areas under the curves (AUC) for various parameters was performed using the DeLong test.ResultsOur study involved a cohort of 1932 CS patients, with 687 individuals (36.1%) experiencing mortality during their hospitalization. The AUC for normalized lactate load demonstrated significant superiority compared to the first lactate (0.675 vs. 0.646, P < 0.001), maximum lactate (0.675 vs. 0.651, P < 0.001), and mean lactate (0.675 vs. 0.669, P = 0.003). Notably, the AUC for normalized lactate load showed comparability to that of the Sequential Organ Failure Assessment (SOFA) score (0.675 vs. 0.695, P = 0.175).ConclusionThe normalized lactate load was an independently associated with the in-hospital mortality among CS patients.

The search for optimal nocturnal diurnal heart rate Index targets in ICU patients: a retrospective observational study from large ICU database.

Circadian rhythms play a crucial role in cardiovascular health, with the nocturnal diurnal heart rate index (NDHRI) reflecting significant circadian variations. However, the optimal NDHRI target in Intensive Care Unit (ICU) patients remains undefined. This study aims to establish an evidence-based NDHRI target range and assess its association with mortality. Data from the eICU Collaborative Research Database (n = 32,412) were analyzed. NDHRI was calculated by dividing cumulative nighttime heart rate area by daytime area. Generalized additive models (GAMs) explored the non-linear relationship between mean NDHRI and mortality, adjusting for confounders. Subgroup analyses were conducted based on ethnicity, ICU type, and comorbidities. A U-shaped association was observed between hospital mortality and mean NDHRI (P < 0.001). The optimal NDHRI range (40.0%-45.0%) demonstrated the lowest mortality rates. The duration spent within this range correlated inversely with mortality (P < 0.001). Subgroup analyses consistently supported these findings across diverse patient profiles. Our findings suggest an association between maintaining NDHRI within the 40.0%-45.0% range and lower mortality rates in critically ill patients, highlighting the potential utility of monitoring circadian heart rate variations in the ICU. Further research and future randomized controlled trials are essential to confirm causality and should consider this NDHRI range as a pivotal reference target.

A Critical Review of the Status of Current Greenhouse Technology in China and Development Prospects

China’s greenhouse industry has undergone thousands of years of development history, although the development of modern greenhouses arrived late. After decades of development in China, its greenhouse industry is at the global forefront. China’s greenhouse industry is experiencing rapid development, transformation, and upgrading. China ranks first in the world in terms of the greenhouse industry. These greenhouses are mainly used for vegetable cultivation, playing an important role in the utilization of agricultural resources and food production. In 2023, the cumulative area of greenhouses nationwide was 1835.87 million ha. In this paper, we present the latest developments in the greenhouse sector. More specifically, we present an overview of the development of the greenhouse market, greenhouse production, the greenhouse industry, and technology development. Current problems are underpinned, development opportunities and prospects are analyzed, and measures and specific proposals are detailed for the technological development of the greenhouse sector, both for increasing product quantity and quality.

Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059.

Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.

Increasing risk of glacial lake outburst flood in Sikkim, Eastern Himalaya under climate warming

The increasing risk of Glacial Lake Outburst Floods (GLOFs) in the Eastern Himalaya is exacerbated by climate change-driven glacial ice mass loss, slowdown, and increasing infrastructure projects in the high-altitude regions. To quantify the current risk of potential future disasters we update the inventory of glacial lakes in Sikkim Himalaya, identify the most potentially dangerous glacial lakes (PDGL) and model their peak discharge in different scenarios. The updated glacial lake inventory includes 232 glacial lakes (of >0.01 km2) covering a cumulative area of 22.23 ± 0.10 km2. Our GLOF susceptibility mapping of all moraine-dammed glacial lakes using an Analytic Hierarchy Process (AHP) reveals one lake as very high risk, eight as high risk, 22 as medium risk, 56 as low risk, and 18 as very low risk. Further, we apply dam break flood simulations for the seven most dangerous lakes. Results reveal highest peak discharges of 9504 m3 s−1 and 8421 m3 s−1 in extreme case scenarios from the Khanchung and South Lhonak lakes, respectively. The lowest peak discharge of 622 m3 s−1 is estimated in a normal outburst event for Yongdi lake, with every scenario at least 447 m3 s−1 discharge is reaching to Chungthang town. We find that more than 10,000 people face direct threat of GLOF with potential large-scale infrastructure damage (∼1900 settlement, 5 bridges and 2 hydropower plants). The updated glacial lake dataset, GLOF susceptibility mapping, and modeling results demonstrate the urgent need to install an early warning system and control breaching of highly dangerous lakes.

Forest disturbance thresholds on summer low flows in the interior of British Columbia, Canada

Summer low flows are critically important for community water supply and various aquatic functions in the interior of British Columbia (BC), Canada. There is a critical need to determine forest disturbance thresholds on summer low flows, particularly in the context of climate change and increasing forest disturbance. The forest disturbance threshold is defined as the disturbance level above which significant changes in flow variables are detected. In this study, we developed a seasonal hydrological response curve to determine forest disturbance thresholds for significant hydrological impacts on summer low flows in 20 forested watersheds in the BC interior. Based on the proposed method, the results suggest that forest disturbance thresholds varied from 8 to 52 % of CECA (cumulative equivalent clear-cut area) with an average of 18 %, which were not significantly different from thresholds on annual streamflow. Watersheds characterized by more distinct dry summers, lower annual energy availability, higher snow contributions, larger sizes, and greater topographic gradients (represented by greater slope, elevation difference, and downslope distance gradient, and lower water retention index) had lower disturbance thresholds on summer low flows. Both positive (increasing) and negative (decreasing) impacts of forest disturbance on summer low flows were detected. These results can greatly support practical watershed management for sustaining water supply in the local communities. Our methodology can potentially be applied in any individual watershed to assess forest disturbance thresholds on summer low flows where long-term data on forest disturbance, climate, and hydrology are available.

Accumulation mechanism of multi-type unconventional oil and gas reservoirs in Northern China: Taking Hari Sag of the Yin’e Basin as an example

Abstract Many multi-types of unconventional oil and gas reservoirs have been found in some faulted basins in northern China, showing good exploration potential. However, the hydrocarbon accumulation mechanism in these areas is still unclear, which limits the understanding of the distribution of oil and gas. In this study, we took Hari Sag in Yin’e Basin as an example, conducted a systematic analysis on various types unconventional oil and gas reservoirs, and revealed its characteristics and accumulation mechanisms. The study showed that there were many types of unconventional oil and gas reservoirs in Hari Sag, such as biogas reservoirs, shale gas reservoirs, shale oil reservoirs, tight sandstone oil reservoirs, tight sandstone gas reservoirs, and volcanic gas reservoirs. These reservoirs generally had characteristics of “near/within source rocks accumulation,” “coexistence of oil reservoirs and gas reservoirs,” “shallow oil and deep gas,” and so on. Research on the mechanism of hydrocarbon accumulation showed that: the lack of effective hydrocarbon migration pathway was the main reason for “near/within source rocks accumulation” of oil and gas reservoirs; the differences in the thermal evolution degree of the main source rocks at different structural positions in the sag made the distribution characteristics of hydrocarbon as “coexistence of oil reservoirs and gas reservoirs” and “shallow oil and deep gas”; and the joint development of multi-type effective unconventional reservoirs created the situation of “coexistence of multi-type unconventional oil and gas reservoirs.” It is predicted that six types of unconventional oil and gas reservoirs have a cumulative area of 381 km2, indicating that the Hari Sag has great potential for unconventional oil and gas exploration. The research results can not only guide the unconventional oil and gas exploration in Hari Sag but also provide a theoretical basis for exploration research in similar blocks.

Quantifying the runoff reduction benefits of the ‘Grain for Green’ Programme using the VIC model

ABSTRACT Variable infiltration capacity model is used to quantitatively analyse the runoff reduction benefits of three basins on the Loess Plateau since the implementation of the ‘Grain for Green’ programme. The programme played an important role, contributing to >60% of the runoff variation in the different basins. Furthermore, for every 1000 km2 increase in cumulative forest area in basins, the rate of runoff coefficient reduction changed by −30%, −37.3% and 169% in the late stage of the programme compared to the early stage, respectively (‘-’ represents a decrease in reduction rate). This was closely related to the restoration of vegetation.

Determinants of radiation exposure during mobile cone-beam CT-guided robotic-assisted bronchoscopy.

Robotic-assisted bronchoscopy (RAB) is an emerging modality to sample pulmonary lesions. Cone-beam computed tomography (CBCT) can be incorporated into RAB. We investigated the magnitude and predictors of patient and staff radiation exposure during mobile CBCT-guided shape-sensing RAB. Patient radiation dose was estimated by cumulative dose area product (cDAP) and cumulative reference air kerma (cRAK). Staff equivalent dose was calculated based on isokerma maps and a phantom simulation. Patient, lesion and procedure-related factors associated with higher radiation doses were identified by logistic regression models. A total of 198 RAB cases were included in the analysis. The median patient cDAP and cRAK were 10.86 Gy cm2 (IQR: 4.62-20.84) and 76.20 mGy (IQR: 38.96-148.38), respectively. Among staff members, the bronchoscopist was exposed to the highest median equivalent dose of 1.48 μSv (IQR: 0.85-2.69). Both patient and staff radiation doses increased with the number of CBCT spins and targeted lesions (p < 0.001 for all comparisons). Patient obesity, negative bronchus sign, lesion size <2.0 cm and inadequate sampling by on-site evaluation were associated with a higher patient dose, while patient obesity and inadequate sampling by on-site evaluation were associated with a higher bronchoscopist equivalent dose. The magnitude of patient and staff radiation exposure during CBCT-RAB is aligned with safety thresholds recommended by regulatory authorities. Factors associated with a higher radiation exposure during CBCT-RAB can be identified pre-operatively and solicit procedural optimization by reinforcing radiation protective measures. Future studies are needed to confirm these findings across multiple institutions and practices.

Ablation of persistent atrial fibrillation based on atrial electrogram duration map: methodology and clinical outcomes from the AEDUM pilot study

Abstract Background Catheter ablation of persistent atrial fibrillation (PsAF) represents a challenge for the electrophysiologist and there are still divergences regarding the best ablative approach to adopt. Objectives Create a new map of the duration of atrial bipolar electrograms (Atrial Electrogram DUration Map, AEDUM) to recognize a functional substrate during sinus rhythm and guide a patient-tailored ablative strategy for PsAF. Methods 40 PsAF subjects were assigned in a 1:1 ratio to either for PVI alone (Group B1) or PVI+AEDUM areas ablation (Group B2). A cohort of 15 patients without AF history undergoing left-sided accessory pathway ablation was used as a control group (Group A). In all patients, voltage and AEDUM maps were created during sinus rhythm. The minimum follow-up was 12-months, with rhythm monitoring via 48-h ECG Holter or by implantable cardiac device. Results Electrogram (EGM) duration was higher in Group B than in Group A (49±16.2ms vs 34.2±3.8ms; p-value&amp;lt;0.001). In Group B the mean cumulative AEDUM area was 21.8±8.2cm2; no difference between the two subgroups was observed (22.3±9.1cm2 vs 21.2±7.2cm2; p-value=0.45). The overall bipolar voltage recorded inside the AEDUM areas was lower than in the remaining atrial areas [median:1.30mV (IQR:0.71–2.38mV) vs 1.54mV (IQR:0.79–2.97mV); p-value:&amp;lt;0.001)]. Low voltage areas (&amp;lt;0.5mV) were recorded in three (7.5%) patients in Group B. During the follow-up [median 511 days(376-845days)] patients who underwent PVI-only experienced more AF recurrence than those receiving a tailored approach (65% vs 35%; p-value=0.04). Conclusions All PsAF patients exhibited AEDUM areas. An ablation approach targeting these areas resulted in a more effective strategy compared with PVI only.AEDUM mapAEDUM map and lesion set

Evaluating the economic efficiency of open, laparoscopic, and robotic distal pancreatectomy: an updated systematic review and network meta-analysis.

This study compared the cost-effectiveness of open (ODP), laparoscopic (LDP), and robotic (RDP) distal pancreatectomy (DP). Studies reporting the costs of DP were included in a literature search until August 2023. Bayesian network meta-analysis was conducted, and surface under cumulative ranking area (SUCRA) values, mean difference (MD), odds ratio (OR), and 95% credible intervals (CrIs) were calculated for outcomes of interest. Cluster analysis was performed to examine the similarity and classification of DP approaches into homogeneous clusters. A decision model-based cost-utility analysis was conducted for the cost-effectiveness analysis of DP strategies. Twenty-six studies with 29,164 patients were included in the analysis. Among the three groups, LDP had the lowest overall costs, while ODP had the highest overall costs (LDP vs. ODP: MD - 3521.36, 95% CrI - 6172.91 to - 1228.59). RDP had the highest procedural costs (ODP vs. RDP: MD - 4311.15, 95% CrI - 6005.40 to - 2599.16; LDP vs. RDP: MD - 3772.25, 95% CrI - 4989.50 to - 2535.16), but incurred the lowest hospitalization costs. Both LDP (MD - 3663.82, 95% CrI - 6906.52 to - 747.69) and RDP (MD - 6678.42, 95% CrI - 11,434.30 to - 2972.89) had significantly reduced hospitalization costs compared to ODP. LDP and RDP demonstrated a superior profile regarding costs-morbidity, costs-mortality, costs-efficacy, and costs-utility compared to ODP. Compared to ODP, LDP and RDP cost $3110 and $817 less per patient, resulting in 0.03 and 0.05 additional quality-adjusted life years (QALYs), respectively, with positive incremental net monetary benefit (NMB). RDP costs $2293 more than LDP with a negative incremental NMB but generates 0.02 additional QALYs with improved postoperative morbidity and spleen preservation. Probabilistic sensitivity analysis suggests that LDP and RDP are more cost-effective options compared to ODP at various willingness-to-pay thresholds. LDP and RDP are more cost-effective than ODP, with LDP exhibiting better cost savings and RDP demonstrating superior surgical outcomes and improved QALYs.

Mapping global lake aquatic vegetation dynamics using 10-m resolution satellite observations

Aquatic vegetation is crucial for improving water quality, supporting fisheries and preserving biodiversity in lakes. Monitoring the spatiotemporal dynamics of aquatic vegetation is indispensable for the assessment and protection of lake ecosystems. Nevertheless, a comprehensive global assessment of lacustrine aquatic vegetation is lacking. This study introduces an automatic identification algorithm (with a total accuracy of 94.4%) for Sentinel-2 MSI, enabling the first-ever global mapping of aquatic vegetation distribution in 1.4 million lakes using 14.8 million images from 2019 to 2022. Results show that aquatic vegetation occurred in 81,116 lakes across six continents over the past four years, covering a cumulative maximum aquatic vegetation area (MVA) of 16,111.8 km2. The global median aquatic vegetation occurrence (VO, in %) is 3.0%, with notable higher values observed in South America (7.4%) and Africa (4.1%) compared with Asia (2.7%) and North America (2.4%). High VO is also observed in lakes near major rivers such as the Yangtze, Ob, and Paraná Rivers. Integrating historical data with our calculated MVA, the aquatic vegetation changes in 170 lakes worldwide were analyzed. It shows that 72.4% (123/170) of lakes experienced a decline in aquatic vegetation from the early 1980s to 2022, encompassing both submerged and overall aquatic vegetation. The most substantial decrease is observed in Asia and Africa. Our findings suggest that, beyond lake algal blooms and temperature, the physical characteristics of the lakes and their surrounding environments could also influence aquatic vegetation distribution. Our research provides valuable information for the conservation and restoration of lacustrine aquatic vegetation.

Assessment of CD8+ T-cell mediated immunity in an influenza A(H3N2) human challenge model in Belgium: a single centre, randomised, double-blind phase 2 study

Protection afforded by inactivated influenza vaccines can theoretically be improved by inducing T-cell responses to conserved internal influenza A antigens. We assessed whether, in an influenza controlled human infection challenge, susceptible individuals receiving a vaccine boosting T-cell responses would exhibit lower viral load and decreased symptoms compared with placebo recipients. In this single centre, randomised, double-blind phase 2 study, healthy adult (aged 18-55 years) volunteers with microneutralisation titres of less than 20 to the influenza A(H3N2) challenge strain were enrolled at an SGS quarantine facility in Antwerp, Belgium. Participants were randomly assigned double-blind using a permuted-block list with a 3:2 allocation ratio to receive 0·5 mL intramuscular injections of modified vaccinia Ankara (MVA) expressing H3N2 nucleoprotein (NP) and matrix protein 1 (M1) at 1·5 × 108 plaque forming units (4·3 × 108 50% tissue culture infectious dose [TCID50]; MVA-NP+M1 group) or saline placebo (placebo group). At least 6 weeks later, participants were challenged intranasally with 0·5 mL of a 1 × 106 TCID50/mL dose of influenza A/Belgium/4217/2015 (H3N2). Nasal swabs were collected twice daily from day 2 until day 11 for viral PCR, and symptoms of influenza were recorded from day 2 until day 11. The primary outcome was to determine the efficacy of MVA-NP+M1 vaccine to reduce the degree of nasopharyngeal viral shedding as measured by the cumulative viral area under the curve using a log-transformed quantitative PCR. This study is registered with ClinicalTrials.gov, NCT03883113. Between May 2 and Oct 24, 2019, 145 volunteers were enrolled and randomly assigned to the MVA-NP+M1 group (n=87) or the placebo group (n=58). Of these, 118 volunteers entered the challenge period (71 in the MVA-NP+M1 group and 47 in the placebo group) and 117 participants completed the study (71 in the MVA-NP+M1 group and 46 in the placebo group). 78 (54%) of the 145 volunteers were female and 67 (46%) were male. The primary outcome, overall viral load as determined by quantitative PCR, did not show a statistically significant difference between the MVA-NP+M1 (mean 649·7 [95% CI 552·7-746·7) and placebo groups (mean 726·1 [604·0-848·2]; p=0·17). All reported treatment emergent adverse events (TEAEs; 11 in the vaccination phase and 51 in the challenge phase) were grade 1 and 2, except for two grade 3 TEAEs in the placebo group in the challenge phase. Agrade 4 second trimester fetal death, considered possibly related to the MVA-NP+M1 vaccination, and an acute psychosis reported in a placebo participant during the challenge phase were reported. The use of an MVA vaccine to expand CD4+ or CD8+ T cells to conserved influenza A antigens in peripheral blood did not affect nasopharyngeal viral load in an influenza H3N2 challenge model in seronegative, healthy adults. Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority; and Barinthus Biotherapeutics.

Performance of risk scores in predicting major bleeding in left ventricular assist device recipients: a comparative external validation

BackgroundImplantation of a left ventricular assist device (LVAD) is a crucial therapeutic option for selected end-stage heart failure patients. However, major bleeding (MB) complications postimplantation are a significant concern. ObjectivesWe evaluated current risk scores’ predictive accuracy for MB in LVAD recipients. MethodsWe conducted an observational, single-center study of LVAD recipients (HeartWare or HeartMate-3, November 2010-December 2022) in the Netherlands. The primary outcome was the first post-LVAD MB (according to the International Society on Thrombosis and Haemostasis [ISTH] and Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS], and INTERMACS combined with intracranial bleeding [INTERMACS+] criteria). Mortality prior to MB was considered a competing event. Discrimination (C-statistic) and calibration were evaluated for the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score, Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke score, Anticoagulation and Risk Factors in Atrial Fibrillation score, Outpatient Bleeding Risk Index, venous thromboembolism score, atrial fibrillation score, and Utah Bleeding Risk Score (UBRS). ResultsOne hundred four patients were included (median age, 64 years; female, 20.2%; HeartWare, 90.4%; HeartMate-3, 9.6%). The cumulative MB incidence was 75.7% (95% CI 65.5%-85.9%) by ISTH and INTERMACS+ criteria and 67.0% (95% CI 56.0%-78.0%) per INTERMACS criteria over a median event-free follow-up time of 1916 days (range, 59-4521). All scores had poor discriminative ability on their intended prediction timeframe. Cumulative area under the receiving operator characteristic curve ranged from 0.49 (95% CI 0.35-0.63, venous thromboembolism-BLEED) to 0.56 (95% CI 0.47-0.65, UBRS) according to ISTH and INTERMACS+ criteria and from 0.48 (95% CI 0.40-0.56, Anticoagulation and Risk Factors in Atrial Fibrillation) to 0.56 (95% CI 0.47-0.65, UBRS) per INTERMACS criteria. All models showed poor calibration, largely underestimating MB risk. ConclusionCurrent bleeding risk scores exhibit inadequate predictive accuracy for LVAD recipients. There is a need for an accurate risk score to identify LVAD patients at high risk of MB who may benefit from patient-tailored antithrombotic therapy.

Abstract PO5-14-11: Leveraging a pharmacokinetic/pharmacodynamic (PK/PD) model to guide dose optimization of palbociclib (palbo) in combination with vepdegestrant

Abstract Background: Vepdegestrant is a potent, selective, orally bioavailable PROteolysis TArgeting Chimeric (PROTAC) estrogen receptor (ER) degrader. A phase 3 study will evaluate the combination of vepdegestrant and palbo in participants with ER+, human epidermal growth factor receptor negative (HER2[-]) advanced/metastatic breast cancer (NCT05909397). The recommended starting dose of palbo is 125 mg once daily for 3 weeks followed by 1 week off treatment for each 28-day cycle in combination with aromatase inhibitors or fulvestrant.1 Neutropenia is the most frequently reported adverse event for patients receiving palbo in clinical trials.1 When co-administered with vepdegestrant in a phase 1b cohort of the first-in-human phase 1/2 study (NCT04072952), higher rates of medically manageable neutropenia and increased palbo concentrations were observed compared with historical studies of palbo administered with letrozole or fulvestrant.1 Reduced starting doses of palbo (100 mg, 75 mg) are planned to mitigate increased rates of Grade 4 neutropenia while maintaining similar palbo exposure when combined with vepdegestrant. The analysis objective was to leverage a PK/PD model to simulate palbo exposure and neutropenia taking into consideration the dose modification and management for hematologic toxicities provided in the palbo prescribing information.1 Methods: A Monte-Carlo simulation platform2 was utilized to monitor absolute neutrophil count (ANC) in 1000 patients with weekly monitoring over 4 cycles (112 days) of palbo administration. Simulated ANC was determined using a semi-mechanistic model of chemotherapy-induced myelosuppression as previously described.3 Palbo dose modification methods included both dose hold and reduction based on an individual’s ANC and thresholds for Grade 3 (&amp;lt; 1000 mm3) or Grade 4 (&amp;lt; 500 mm3) neutropenia. Simulated neutropenia and exposures from palbo starting doses of 100 mg and 75 mg in the presence of a 25%, 49%, and 67% increase in typical exposure were compared to a palbo starting dose of 125 mg in the absence of increased exposure (historical reference). Average concentration is calculated as the cumulative area under the curve divided by the simulation duration. Results: After a 4-cycle simulation, the 100 mg starting dose of palbo simulated across varying levels of increased exposure resulted in similar Grade 4 neutropenia incidence and average concentration compared to the reference simulation (&amp;lt; 12% difference). The 75 mg starting dose of palbo simulated across varying levels of increased exposure resulted in lower Grade 4 neutropenia incidence as well as lower average concentration compared to the reference simulation (Table 1). Conclusion: The PK/PD model simulation allows for relative comparison of Grade 4 neutropenia incidence and average palbo concentration between the planned reduced starting doses of palbo in the context of increased exposure relative to standard palbo dosing, i.e., without vepdegestrant. This simulation indicates a reduced dose of palbo (100 mg) in combination with vepdegestrant produces similar incidence of Grade 4 neutropenia and comparable average palbo concentration compared to historical reference providing additional support for the study lead-in of NCT05909397. Citations: 1. IBRANCE® (Palbociclib) [Package Insert]. New York, US: Pfizer, Inc. 2. Jermain et al. ACOP13 2023. 3. Friberg et al. J Clin Oncol 2002. Table 1. 4-cycle simulation results comparing reduced starting doses of palbociclib in the presence of increased typical exposure to a reference standard palbociclib dosing in the absence of increased exposure Citation Format: Brian Jermain, Derek Yang, Weiwei Tan, Julia Perkins-Smith, Justin Hoffman, Jason Williams. Leveraging a pharmacokinetic/pharmacodynamic (PK/PD) model to guide dose optimization of palbociclib (palbo) in combination with vepdegestrant [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-14-11.

Impact of Hindlimb Disuse on Sepsis-Induced Myopathy in Older Adult Mice

BACKGROUND: Sepsis, a life-threatening condition due to an overactive immune response, adversely affects multiple organ systems. Despite its significance of accounting for 40% of total body mass, the skeletal muscle system is considered the forgotten organ system affected by sepsis. In addition to the inflammatory aspects of sepsis, patients in the intensive care unit (ICU) frequently experience prolonged periods of bed rest, which can lead to muscle disuse-induced myopathy characterized by muscle atrophy, weakness, and impaired regenerative capacity. Despite the higher incidence of sepsis in bedridden older adults, most research on sepsis-induced myopathy primarily focuses on younger adults under conditions that do not mimic bed rest. In this study, we simulated the clinical conditions of older adult ICU patients by combining sepsis with hindlimb disuse. Our hypotheses were that the combination of sepsis, disuse, and aging would exacerbate muscle atrophy and weakness, while also reducing the number of regenerative stem cells in muscle tissue. Methods: To investigate the functional and morphological responses of skeletal muscle to sepsis, we conducted experiments on 78-week-old male wild-type C57Bl6 mice. They underwent either cecal ligation and puncture (CLP, n = 17) or Sham (n = 14) surgeries. Four days post-surgery, the animals were allocated to hindlimb suspension (HLS — CLP, n=9; Sham, n=10) or normal ambulation (NA — CLP, n=8; Sham, n=4) for seven days. Terminal experiments were conducted after hindlimb suspension or normal ambulation treatments. We assessed peak force production ex vivo in solei muscles, examined the cross-sectional area (CSA) of relevant hindlimb muscles using immunohistochemistry, and quantified the abundance of stem cells through immunohistochemistry (e.g., PAX7+ cells) in muscle sections. Additionally, we evaluated markers of senescence by measuring the protein abundance of p16 and p53 in hindlimb muscle homogenates. Results: CLP surgery resulted in 50% mortality rate (p&lt;0.05). Percentage body mass loss was as follows: 5.3 ± 4.2 for Sham/NA group, 13.3 ± 5.2 for Sham/HLS group, 7.3 ± 4.4 for CLP/NA group, and 17.7 ± 5.5 for CLP/HLS group. Peak absolute force was significantly lower in Sham/HLS and CLP/HLS compared to Sham/NA (Sham/NA = 277±2.4, Sham/HLS = 189±28.4, CLP/NA = 264±23.0, CLP/HLS = 180±48.9 mN, p&lt;0.05). Mice exposed to CLP/HLS displayed a higher cumulative fiber area at smaller fiber sizes (800 to 1000 μm2) (p&lt;0.05), indicating muscle atrophy. CLP/NA caused a 9.8% reduction in solei muscle mass (p &lt; 0.05), while CLP/HLS led to an additional 30% loss in solei mass (p&lt;0.05). Furthermore, CLP/HLS significantly decreased the number of PAX7+ stem cells by 75% (p&lt;0.05). Notably, p16 was significantly increased in response to CLP/HLS (p&lt;0.05), while no changes were observed in p53 abundance. CONCLUSION: This study demonstrates the role of muscle disuse in exacerbating skeletal muscle functional and morphological abnormalities in older adult septic mice, emphasizing the critical contribution of disuse to the pathophysiology of sepsis-induced myopathy. NIH R21AG072011 to OL. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

TREASUREHUNT: Transients and Variability Discovered with HST in the JWST North Ecliptic Pole Time-domain Field

The James Webb Space Telescope (JWST) North Ecliptic Pole (NEP) Time-domain Field (TDF) is a >14′ diameter field optimized for multiwavelength time-domain science with JWST. It has been observed across the electromagnetic spectrum both from the ground and from space, including with the Hubble Space Telescope (HST). As part of HST observations over three cycles (the “TREASUREHUNT” program), deep images were obtained with the Wide Field Camera on the Advanced Camera for Surveys in F435W and F606W that cover almost the entire JWST NEP TDF. Many of the individual pointings of these programs partially overlap, allowing an initial assessment of the potential of this field for time-domain science with HST and JWST. The cumulative area of overlapping pointings is ∼88 arcmin2, with time intervals between individual epochs that range between 1 day and 4+ yr. To a depth of m AB ≃ 29.5 mag (F606W), we present the discovery of 12 transients and 190 variable candidates. For the variable candidates, we demonstrate that Gaussian statistics are applicable and estimate that ∼80 are false positives. The majority of the transients will be supernovae, although at least two are likely quasars. Most variable candidates are active galactic nuclei (AGNs), where we find 0.42% of the general z ≲ 6 field galaxy population to vary at the ∼3σ level. Based on a 5 yr time frame, this translates into a random supernova areal density of up to ∼0.07 transients arcmin−2 (∼245 deg−2) per epoch and a variable AGN areal density of ∼1.25 variables arcmin−2 (∼4500 deg−2) to these depths.

Implications of Temperature for the Modification of High-Overmature Shale Reservoirs: Experimental and Numerical Analysis

Summary High-temperature pore reconstruction technology is a reservoir reconstruction measure that has emerged in recent years. It is of great significance to study the variation in pore structure characteristics of shale under high temperature for reservoir reconstruction. To study the effect of high temperature on shale pores, scanning electron microscopy (SEM) experiments and fluid injection experiments were used to analyze the variation of pore structure characteristics under high temperature. Studies have shown that temperature has a great influence on the morphology and distribution characteristics of shale pores. In particular, there is a temperature between 300°C and 400°C that is suitable for modifying pores. The distribution characteristics, surface area, and volume of pores vary dramatically under this temperature threshold. The pore morphology and distribution characteristics changed from small and sparse to large and dense. The Brunauer-Emmett-Teller (BET) surface area increased by 95%. The cumulative surface area of Barrett-Joyner-Halenda (BJH) adsorption and desorption increased by 71.7% and 72%, respectively. The pore volume of the 2-nm to 20-nm pore size increased by 63.2%. The pore volume of pore sizes greater than 20 nm increased by 191.6%. The pore variation characteristics were in line with the typing law, and the fitting result R2 ranged from 0.92201 to 0.99882.

Comparison of the efficacy among different interventions for radiodermatitis: A Bayesian network meta‑analysis of randomized controlled trials.

Radiation dermatitis (RD) is a prevalent and difficult-to-manage consequence of radiation therapy (RT). A variety of interventions have been proven effective in preventing and treating RD. However, the optimal approach remains unclear. This network meta-analysis (NMA) conducted a comparison and ranking of the effectiveness and patient-reported outcomes (PROs) of the interventions currently utilized in RD. PubMed, Web of Science, Embase, and Cochrane Library were searched to identify pertinent randomized controlled trials (RCTs) focused on the prevention and treatment of RD. The primary outcome measures included the incidence of grade≥2 RD (i.e., percentage of moist desquamation) and RD score. The secondary outcome measures encompassed patients' subjective assessment scores of pains, itching and burning sensations. Our meta-analysis encompassed 42 studies and 4884 participants. Regarding the primary outcomes, photobiomodulation treatment (PBMT) ranked first in surface under curve cumulative ranking area (SUCRA:0.92) for reducing the incidence of grade≥2 RD. It demonstrated a significant difference when compared to Trolamine (OR 0.18,95%CrI 0.09-0.33) and Xonrid® (OR 0.28,95%CrI 0.12-0.66). Mepitelfilm (SUCRA: 0.98) achieved the highest rank in reducing the RD score, demonstrating superiority over StrataXRT® (MD -0.89, 95% CrI -1.49, -0.29). Henna (SUCRA: 0.89) demonstrated the highest effectiveness in providing pain relief, with a significant difference compared to Hydrofilm (MD -0.44, 95% CrI -0.84, -0.04) and Mepitelfilm (MD -0.55, 95% CrI -0.91, -0.19). Hydrofilm (SUCRA: 0.84) exhibited the fewest itching sensations, demonstrating superiority over Mepitelfilm (MD -0.50, 95% CrI -0.84, -0.17). No statistically significant difference was observed among various interventions in the assessment of burning sensations. PBMT and Mepitelfilm demonstrated better efficacy in reducing the incidence of grade≥2 RD and RD score, respectively. In terms of PROs, Henna and Hydrofilm had fewer complaints in pain and itching sensations, respectively. However, studies with larger sample size on different interventions are warranted in the future. PROSPERO registration number CRD42023428598.