Key Time Points Research Articles

Patient-reported outcomes in patients with relapsed or refractory follicular lymphoma treated with zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy: results from the ROSEWOOD trial

Objective We report patient-reported outcomes (PROs) measuring health-related quality of life (HRQoL) from the ROSEWOOD trial (NCT03332017), which demonstrated superior efficacy and a manageable safety profile with zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) in patients with heavily pretreated relapsed/refractory follicular lymphoma (R/R FL). Methods PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30) and EQ-5D-5L questionnaires at baseline and subsequently every 12 weeks. All QLQ-C30 domains and EQ-5D-5L visual analog scale (VAS) scores were analyzed descriptively. At the key clinical timepoints (weeks 12 and 24), a mixed model for repeated measures (MMRM) analysis was used to evaluate the key PRO endpoints, including global health status, physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting. Clinically meaningful change was defined as a ≥ 5-point mean difference from baseline and between the ZO and O arms. Results Patients were randomized to ZO (n = 145) or O (n = 72). By week 48, descriptive analysis results indicated that patients in the ZO arm demonstrated improved outcomes in role functioning and fatigue and nausea/vomiting symptoms, compared with those in the O arm. Both groups experienced improvements in pain symptoms. EQ-5D-5L VAS scores showed no observable differences between treatment arms through week 48. MMRM analysis revealed that the global health status/quality of life of patients treated with ZO improved, as did fatigue, at week 12. At week 24, patients in the ZO arm experienced a clinically meaningful improvement in role functioning, pain, and fatigue. Conclusions In patients with R/R FL, ZO was associated with improved PROs compared with O. These findings suggest that zanubrutinib contributed clinically meaningful benefits to patient HRQoL when added to obinutuzumab. Trial registration The ROSEWOOD trial is registered on ClinicalTrials.gov (BGB-3111-212; ClinicalTrials.gov identifier: NCT03332017).

Examining the evolution trajectory of construction and demolition waste in China: An empirical analysis based on spatial metrology and the environmental Kuznets curve

Curbing the increasing construction and demolition waste (C&DW) is critical for achieving China's goals of cleaner production and environmental sustainability. This paper based on the Environmental Kuznets Curve (EKC) and combining spatial econometrics with the GM (1,1) model, predicts key time points that will change the growth trend of C&DW and explores measures to reduce production. The results indicate that: (1)As of 2022, more than 87% of China's regional C&DW is unevenly distributed and agglomeration exists. More than 50% of the regions exhibit “high-high” agglomeration, which can lead to an inevitable inter-regional transfer of C&DW, but the central region has formed a “segregation zone”. (2) The evolution trajectory of C&DW shows a “growth-decline-regrowth” pattern, with points of change for regrowth occurring when GDP per capita reaches 142,914.24. Construction enterprises and consumption levels contribute significantly to C&DW, while the opposite is true for education, market competition, and transportation. (3) More than 95% of regions will experience C&DW regrowth during 2036–2040. Economic development is no longer considered to play a leading role in C&DW reduction measures. Even if the economic growth rate is increased by 10%, 30%, or even 50%, C&DW will enter the era of full-scale regrowth only three years earlier on average. This paper aims to shift the current focus of C&DW forecasting from solely on model innovation to accurately calculating the timing of future C&DW regrowth by verifying the EKC hypothesis application. This approach fills the gap in the quantitative analysis of long-term C&DW forecasting and provides new empirical cases for the theory of environmental economics. Furthermore, it addresses potential obstacles for decision-makers in achieving “zero waste cities”, thereby promoting global cleaner production and environmental sustainability.

The Impact of Remote Ischemic Preconditioning on Inflammation Markers in Patients Undergoing Coronary Artery Bypass Grafting.

This study aimed to investigate if remote ischemic preconditioning reduces the inflammatory process on patients undergoing coronary artery bypass grafting (CABG). We conducted a case-control study involving 80 patients, half of whom underwent ischemic preconditioning for severe coronary artery disease (CAD) and subsequently underwent CABG. We assessed interleukin (IL)-1 and IL-6 levels using the enzyme-linked immunosorbent assay (ELISA) method, high-sensitivity troponin I (hsTnI) using chemiluminescent immunoassay (CLIA), and C-reactive protein (CRP) using the turbidimetric method at three key time points: before surgery (visit 1 or V1), immediately postoperatively (visit 2 or V2), and 1 week postoperatively (visit 3 or V3) in all subjects. Ischemic preconditioned patients showed a significant decrease in proinflammatory markers (IL-1, IL-6) but not in CRP or hsTnI. This study demonstrated that remote ischemic preconditioning significantly reduced the levels of specific proinflammatory markers (IL-1 and IL-6), which may suggest general systemic protection. However, it did not demonstrate cardioprotection per se, as evidenced by the absence of a statistically significant decrease in hsTnI level.

Iron supplementation post-blood donation in Vietnam: Impact on hemoglobin, red cell indices, and iron reserves

Background. Regular blood donation plays a pivotal role in mitigating the formation of free radicals by regulating iron accumulation. However, frequent blood donation can lead to chronic iron deficiency. In this study, we aimed to evaluate the effectiveness of daily iron supplementation as an intervention to expedite hemoglobin (Hb) recovery among frequent blood donors at a hospital in Vietnam. Methodology. Conducted longitudinally within the Hematology Department of a Hanoi hospital from February to July 2023, our study involved 104 eligible participants. They received a daily iron supplement comprising 100 mg of elemental iron, 0.75 mg of folic acid, and 5 mg of zinc sulfate for a minimum of 8 weeks. Blood samples were collected at three key time points: before blood donation during recruitment, immediately after donation, and at least 8 weeks post-donation. Results. Our findings revealed moderate, statistically significant positive correlations between elemental iron administration and changes in platelet count (PLT), hematocrit (HCT), and mean corpuscular hemoglobin (MCH) (r = 0.753, p <0.001; r = 0.887, p <0.001; and r = 0.703, p <0.001, respectively). Additionally, weak but significant correlations were observed between elemental iron administration and red blood cell count (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width coefficient of variation (RDWC), and red cell distribution width standard deviation (RDWS) (r = 0.260, p = 0.002; r = 0.302, p = 0.005; r = 0.160, p = 0.010; r = 0.120, p = 0.020; and r = 0.400, p <0.001, respectively). Conclusion. Over an eight-week duration, the regimen of daily iron supplementation yielded significant improvements in both red cell variables, red cell indices, and iron study variables, demonstrating its potential clinical impact.

Impact of the orofacial muscular rehabilitation exercise on facial expression recovery post-orthognathic surgery

ObjectiveThis study aimed to evaluate the impact of myofunctional rehabilitation of the orofacial muscles through specific exercises on the recovery of facial expression in patients following orthognathic surgery. Material and MethodsThe study included 62 patients who underwent Le Fort I and sagittal split ramus osteotomy (SSRO). Patients were divided into two groups: the first group started immediate post-operative myofunctional rehabilitation of the orofacial muscles through specific exercises. In contrast, patients in Group II did not undergo any myofunctional rehabilitation post-operative exercises. The recovery of facial expressions postoperatively was evaluated in both calm and smiling states by comparing the differences between 3D facial scanning data of chosen facial anatomical structures collected at five key time points: pre-surgery (D0), 2 days (D2), 14 days (D14), 1 month (D30), and 3 months (D90) postoperatively. ResultsThe analysis revealed that characteristic angles and lengths experienced significant changes post-surgery, with ∠chRnchL and ∠chRsnchL decreasing at D2 and normalizing by D30 in the experimental group, while the control group showed a slower recovery, normalizing by D90. The ChL-R length decreased at D2, returning to normal by D30 in the experimental group and D90 in the control group. The height Li-Ls increased at D2 and normalized by D30 in calm and smiling expressions across single and double jaw surgery patients. These findings underscore the more rapid recovery in the experimental group compared to the control group (P < 0.05; P < 0.005; P < 0.0001). ConclusionInitiating myofunctional rehabilitation immediately following orthognathic surgery enhances facial muscle function recovery, improves patient confidence, and expedites social reintegration. This approach is crucial for functional and psychological benefits.

Assessment of Thoracic Radiographic Alterations in Dogs with Heartworm and Their Correlation with Pulmonary Hypertension, Pre- and Post-Adulticide Treatment.

Pulmonary hypertension (PH) is a prevalent and severe complication in dogs infected with Dirofilaria immitis. This study aimed to elucidate the progression of PH by analyzing radiographic parameters and the Right Pulmonary Artery Distensibility (RPAD) Index at three key time points: diagnosis (day 0), discharge (day 90), and six months post-discharge (day 270). Fifty-two heartworm-infected dogs were divided into two groups: non-hypertensive and hypertensive. Radiographic measurements, including Vertebral Heart Size (VHS), CrPA/R4 ratio, and CdPA/R9 ratio, along with the RPAD Index, were assessed on Days 0, 90, and 270. Results indicated that, in Group A, the RPAD Index improved significantly from 42% on Day 0 to 43.16% on Day 90, with no significant change by Day 270 (42%). In contrast, hypertensive dogs exhibited a persistently low RPAD Index, averaging 17% throughout this study (p < 0.001). Radiographic parameters in hypertensive dogs showed continuous elevation compared to non-hypertensive dogs, with significant increases in VHS, CrPA/R4, and CdPA/R9 ratios on day 270 compared to day 0 (p < 0.05). The results confirmed that PH persisted in dogs with D. immitis after adulticide treatment, highlighting the importance of regular radiographic monitoring for assessing and managing long-term outcomes in dogs with PH during and after adulticide treatment. Continuous surveillance is thus essential for the effective post-treatment management of PH in dogs.

Nursing of forearm hematoma after transradial coronary intervention.

Complications such as forearm hematoma after coronary intervention through the radial artery are a common complication. By observing, describing, and analyzing the pictures taken during clinical diagnosis and consultation, we summarize the prevention, treatment, and nursing of forearm hematoma after percutaneous coronary intervention, to provide reference for the nursing of patients with forearm hematoma. We have innovatively summarized the risk classification of forearm hematoma and the three key time points for preventing hematoma. Complications such as forearm hematoma after coronary intervention through the radial artery are a common complication. We have innovatively summarized the risk classification of forearm hematoma and the three key time points for preventing hematoma, providing reference for the prevention and management of forearm hematoma in clinical practice. For patients undergoing transradial coronary intervention, the three key time points for preventing hematoma and symptomatic management based the risk classification of forearm hematoma are crucial.

The impact of admission modes on the treatment outcome and in-hospital mortality rate of STEMI patients undergoing PPCI

The current research on ST elevation myocardial infarction (STEMI) patients has been mostly limited to Door-to-Balloon (D-to-B) time. This study aimed to compare the effects of different hospital admission modes to on the time metrics of patients undergoing primary percutaneous coronary intervention (PPCI). It also examined the effects of these modes on in-hospital mortality and other influencing factors. The goal was to prompt healthcare facilities at all levels, including chest hospitals, the Centers for Disease Control and Prevention (CDC), and communities to take measures to enhance the treatment outcomes for patients with STEMI. A total of 1053 cases of STEMI patients admitted to Tianjin Chest Hospital from December 2016 to December 2023 and successfully underwent PPCI were selected for this study. They were divided into three groups based on the admission modes: the ambulances group (363 cases), the self-presentation group (305 cases), and the transferred group (385 cases). Multivariate logistic regression was used to explore the impact of different modes of hospital admission on the standard-reaching rate of key treatment time metrics. The results showed that the S-to-FMC time of transferred patients (OR = 0.434, 95% CI 0.316–0.596, P < 0.001) and self-presentation patients (OR = 0.489, 95% CI 0.363–0.659, P < 0.001) were more likely to exceed the standard than that of ambulance patients; The cath lab pre-activation time of self-presented patients was also less likely to meet the standard than that of ambulance patients (OR = 0.695, 95% CI 0.499–0.967, P = 0.031); D-to-W time of self-presentation patients was less likely to reach the standard than that of ambulance patients (OR = 0.323, 95% CI 0.234–0.446, P < 0.001);However, the FMC-to-ECG time of self-presentation patients was more likely to reach the standard than that of ambulance patients (OR = 2.601, 95% CI 1.326–5.100, P = 0.005). The Cox proportional hazards model analysis revealed that for ambulance patients, the time spent at each key treatment time point is shorter, leading to lower in-hospital mortality rate (HR0.512, 95% CI 0.302–0.868, P = 0.013) compared to patients admitted by other means. We found that direct arrival of STEMI patients to the PCI hospital via ambulance at the onset of the disease significantly reduces the S-to-FMC time, FMC-to-ECG time, D-to-W time, and catheterization room activation time compared to patients who self-present. This admission mode enhances the likelihood of meeting the benchmark standards for each time metric, consequently enhancing patient outcomes.

Identifying key circulating tumor DNA parameters for predicting clinical outcomes in metastatic non-squamous non-small cell lung cancer after first-line chemoimmunotherapy

Circulating tumor DNA (ctDNA) provides valuable tumor-related information without invasive biopsies, yet consensus is lacking on optimal parameters for predicting clinical outcomes. Utilizing longitudinal ctDNA data from the large phase 3 IMpower150 study (NCT02366143) of atezolizumab in combination with chemotherapy with or without bevacizumab in patients with stage IV non-squamous Non-Small Cell Lung Cancer (NSCLC), here we report that post-treatment ctDNA response correlates significantly with radiographic response. However, only modest concordance is identified, revealing that ctDNA response is likely not a surrogate for radiographic response; both provide distinct information. Various ctDNA metrics, especially early ctDNA nadirs, emerge as primary predictors for progression-free survival and overall survival, potentially better assessing long-term benefits for chemoimmunotherapy in NSCLC. Integrating radiographic and ctDNA assessments enhances prediction of survival outcomes. We also identify optimal cutoff values for risk stratification and key assessment timepoints, notably Weeks 6–9, for insights into clinical outcomes. Overall, our identified optimal ctDNA parameters can enhance the prediction of clinical outcomes, refine trial designs, and inform therapeutic decisions for first-line NSCLC patients.

Circular RNAs regulate neuron size and migration of midbrain dopamine neurons during development

Midbrain dopamine (mDA) neurons play an essential role in cognitive and motor behaviours and are linked to different brain disorders. However, the molecular mechanisms underlying their development, and in particular the role of non-coding RNAs (ncRNAs), remain incompletely understood. Here, we establish the transcriptomic landscape and alternative splicing patterns of circular RNAs (circRNAs) at key developmental timepoints in mouse mDA neurons in vivo using fluorescence-activated cell sorting followed by short- and long-read RNA sequencing. In situ hybridisation shows expression of several circRNAs during early mDA neuron development and post-transcriptional silencing unveils roles for different circRNAs in regulating mDA neuron morphology. Finally, in utero electroporation and time-lapse imaging implicate circRmst, a circRNA with widespread morphological effects, in the migration of developing mDA neurons in vivo. Together, these data for the first time suggest a functional role for circRNAs in developing mDA neurons and characterise poorly defined aspects of mDA neuron development.

A Machine Learning Model for Risk Stratification of Postdiagnosis Diabetic Ketoacidosis Hospitalization in Pediatric Type 1 Diabetes: Retrospective Study.

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in pediatric type 1 diabetes (T1D), occurring in approximately 20% of patients, with an economic cost of $5.1 billion/year in the United States. Despite multiple risk factors for postdiagnosis DKA, there is still a need for explainable, clinic-ready models that accurately predict DKA hospitalization in established patients with pediatric T1D. We aimed to develop an interpretable machine learning model to predict the risk of postdiagnosis DKA hospitalization in children with T1D using routinely collected time-series of electronic health record (EHR) data. We conducted a retrospective case-control study using EHR data from 1787 patients from among 3794 patients with T1D treated at a large tertiary care US pediatric health system from January 2010 to June 2018. We trained a state-of-the-art; explainable, gradient-boosted ensemble (XGBoost) of decision trees with 44 regularly collected EHR features to predict postdiagnosis DKA. We measured the model's predictive performance using the area under the receiver operating characteristic curve-weighted F1-score, weighted precision, and recall, in a 5-fold cross-validation setting. We analyzed Shapley values to interpret the learned model and gain insight into its predictions. Our model distinguished the cohort that develops DKA postdiagnosis from the one that does not (P<.001). It predicted postdiagnosis DKA risk with an area under the receiver operating characteristic curve of 0.80 (SD 0.04), a weighted F1-score of 0.78 (SD 0.04), and a weighted precision and recall of 0.83 (SD 0.03) and 0.76 (SD 0.05) respectively, using a relatively short history of data from routine clinic follow-ups post diagnosis. On analyzing Shapley values of the model output, we identified key risk factors predicting postdiagnosis DKA both at the cohort and individual levels. We observed sharp changes in postdiagnosis DKA risk with respect to 2 key features (diabetes age and glycated hemoglobin at 12 months), yielding time intervals and glycated hemoglobin cutoffs for potential intervention. By clustering model-generated Shapley values, we automatically stratified the cohort into 3 groups with 5%, 20%, and 48% risk of postdiagnosis DKA. We have built an explainable, predictive, machine learning model with potential for integration into clinical workflow. The model risk-stratifies patients with pediatric T1D and identifies patients with the highest postdiagnosis DKA risk using limited follow-up data starting from the time of diagnosis. The model identifies key time points and risk factors to direct clinical interventions at both the individual and cohort levels. Further research with data from multiple hospital systems can help us assess how well our model generalizes to other populations. The clinical importance of our work is that the model can predict patients most at risk for postdiagnosis DKA and identify preventive interventions based on mitigation of individualized risk factors.

A Comprehensive Study on Aberrant CD20-Positive Mycosis Fungoides: Clinical and Prognostic Insights.

As the majority of T-cell lymphomas lack CD20 expression, cases of mycosis fungoides (MF) exhibiting aberrant CD20 expression are exceedingly uncommon. We aim to comprehensively evaluate the clinical, histopathological, and prognostic features of 7 patients diagnosed with CD20-positive MF. This retrospective study examines seven cases of MF with aberrant CD20 expression. The study provides details of demographics, clinical features, histopathology and treatment outcomes. Key time points include initial diagnosis of MF, detection of CD20 expression and follow-up, with a mean follow-up of 46 months. Aberrant CD20-positive MF was diagnosed at an average age of 58.6 years, approximately 5.6 years after first MF diagnosis. Following CD20 detection, patients presented with advanced disease stages, requiring treatments such as chemotherapy, brentuximab vedotin, and allogeneic hematopoietic stem cell transplantation. Four patients died from lymphoma, with an average survival time of 52 months. Aberrant CD20 expression in MF is rare but indicates a progressive course associated with poor prognosis. This often requires systemic chemotherapy and, in certain instances, allogeneic hematopoietic stem cell transplantation. This study provides important insights into the clinical attributes, disease progression, and treatment options for MF patients with aberrant CD20 expression. Further research is necessary to validate the effectiveness of emerging therapies and enhance our understanding of the underlying mechanisms and prognostic determinants specific to this unique MF subgroup.

Optimization of emergency evacuation in complex rail transit station

Post-earthquake fires in populated stations pose a significant threat to passenger safety, necessitating the implementation of efficient emergency evacuation procedures to adequately safeguard lives and property. Utilizing Building Information Modeling (BIM) and Pathfinder, this study innovatively delves into the emergency evacuation optimization measures under a post-earthquake fire. Three pivotal research questions are explored: a comparative analysis of the Required Safe Egress Time (RSET) versus the Available Safe Egress Time (ASET) to evaluate the safety of evacuation procedures; a focused examination of critical time points and influential factors during evacuation process; and the formulation of optimization measures to enhance evacuation efficiency. The Beijing Xiyuan rail transit station was chosen as a case study, with four post-earthquake fire scenarios simulated. Additionally, the impact of obstacles and injured personnel resulting from the earthquake was considered. The results show that: (1) During evacuations, critical issues arise at specific time points. The entrances of escalators/stairs, turnstiles, and exits are key sites, where congestion becomes critical issues. (2) Evacuating rescue personnel through public non-paid areas saves 9.1 % of the evacuation time compares to crossing turnstiles. (3) The most impactful measures for optimizing evacuation is that trains arrive in only one direction, followed by the deployment of evacuation guidance. Thus, key control time points and optimization measures for the evacuation process of complex urban rail transit stations can be obtained. The findings provide insights and guidance for optimizing emergency evacuation in rail transit stations to mitigate post-earthquake fire risks and ensure public safety.

Application of a welfare assessment protocol for Australian lot-fed cattle: The effect of time and frequency of assessment

Farm animal welfare assessment protocols enable the capture and reporting of information to address any concerns raised by the industry or the public alike. To underpin commercial protocols, research to address validity, repeatability, and practicality, including studies to determine appropriate sampling methodology, is needed. For protocols that adopt an animal outcome-based approach, including the proposed protocol for Australian lot-fed cattle, appropriate sampling is required to ensure validity of observations. The aim of this study was to determine optimal timing and frequency of pen-side assessments. The proposed welfare assessment protocol was applied at four time points for 208 sample pens at four feedlots during a seven-month period. To determine the effect of time of day, the number of behavioural measures were reduced using Principal Component (PC) analysis, and then a Generalized Linear Mixed Model applied to consider relevant resource and environmental factors. Three primary components of cattle behaviour and demeanour were identified. PC 1 (17.61 % of total variation in the observed cattle behaviour) related to activity and rest, with cattle most active at 08:00 h and 17:00 h, and least active at 14:00 h. PC 2 (10.15 % variation) related to engagement with environment and feeding. At 17:00 h more cattle were observed to express positive welfare outcomes, such as engagement and feeding behaviours. PC 3 (7.07 % variation) captured behaviour and demeanour that reflected cattle mental state, but minimal variation was identified related to time of day. PC 1–3 varied by feedlot and visit number, and PC 1 scores also differed by cattle feeding program. Results indicate that to capture variation in cattle activity and rest, repeated assessments at two key time points; early-morning and early afternoon, are required for accurate pen-side welfare assessments of lot-fed cattle. These findings suggest further refinement of the welfare assessment protocol for lot-fed cattle is recommended to facilitate commercial adoption.

Comparison of Immune Indicators Related to Phagocytosis of Five Species of Sea Urchins under Artificial Infection with the Pathogenic Bacterium of Black Mouth Disease.

To screen for immune indicators closely related to disease resistance, two species of sea urchin susceptible to black mouth disease (Strongylocentrotus intermedius, S. intermedius ♀ × Heliocidaris crassispina ♂) and three species of sea urchin resistant to black mouth disease (H. crassispina, H. crassispina ♀ × S. intermedius ♂ and Mesocentrotus nudus) were artificially infected with the black mouth pathogen Vibrio echinoideorum. The phagocytosis-related immune indices of the five sea urchin species were compared at different time points post-infection. The results demonstrated that the parameters such as apoptotic rate of phagocytes, mean contribution value (MCV) of single effective phagocyte on Acid Phosphatase (ACP), Reactive Oxygen Species (ROS), and Total Antioxidant Capacity (T-AOC) of the five sea urchin species first increased and then decreased after infection. The key time points were 3 h to 6 h and 48 h post-infection when the black mouth disease-resistant and susceptible sea urchins demonstrated differences. At 3 h or 6 h post-infection, the up-regulation folds in MCV of ACP, ROS and T-AOC of black mouth disease-resistant sea urchins were considerably higher than that of the susceptible sea urchins. At 6 h post-infection, the apoptosis rate and the phagocytic index (PI) of the black mouth disease-resistant sea urchins were significantly higher than those of the susceptible sea urchins (p < 0.05). At 48 h post-infection, the necrosis rate of phagocytes, MCV of ACP and MCV of ROS of the black mouth disease-resistant sea urchins were significantly lower than those of the susceptible sea urchins (p < 0.05). The apoptosis and necrosis rate of phagocytes, PI, and MCV on ACP, ROS may be used as indicators of disease resistance in sea urchins. Disease resistance standards in immune indices can be summarized as phagocytosis increases greatly in the early infection stage and decreases timely to a normal level after killing the pathogen in a short period.

P-261 A comparative analysis of artificial intelligence models for blastulation in In vitro fertilization: single-frame vs. full-frame approach

Abstract Study question How does the performance of an blastulation prediction model using full-frame data over 3 days compare to a single-frame model using day 3 data? Summary answer The single-frame model, based on a day 3 embryo image, demonstrated comparable predictive performance to the full-frame model What is known already Pregnancy rates following blastocyst transfer have been reported to be higher than those after cleavage transfer. However, not all cleavage embryos reach the blastocyst stage, leading to the exploration of predictive models using embryo images and artificial intelligence. Clinical practice often involves the decision to culture embryos to the blastocyst stage on day 3 based on embryo quality assessments. Recently, there has been interest in using morphokinetics data for predicting blastulation and pregnancy outcomes. While the importance of morphokinetics in IVF outcomes is acknowledged, the specific time frames and features contributing significantly to accurate predictions remain unclear. Study design, size, duration This retrospective study analyzed a dataset of 15,615 timelapse images from 906 patients at a single IVF center. The Single-Frame Model used a single image collected at 66.7 hours post-ICSI, and the Full-Frame Model used 145 frames collected from fertilization to 66.7 hours post-ICSI. Blastulation criteria included reaching a blastocyst on day 5, deemed suitable for transfer or freezing by an experienced embryologist. Participants/materials, setting, methods We trained the data using ResNet for the one-frame model and 3D CNN for the full-frame model. The ResNet model used pre-trained weights, while the 3D CNN model was built from scratch with no pre-trained weights. The models were evaluated using the AUROC, accuracy, and F1 score metrics. The statistical significance of the AUC performance differences was assessed using DeLong’s test. Main results and the role of chance Our study revealed similar AUC performance between the Single-Frame and Full-Frame Models for day 3 embryos. The Single-Frame Model exhibited an AUROC of 0.76, accuracy of 0.71, and an F1 score of 0.75, while the Full-Frame Model demonstrated comparable performance with an AUROC of 0.75, accuracy of 0.70, and an F1 score of 0.72. DeLong’s test was employed to assess the statistical significance of the difference in AUROC, yielding a non-significant p-value of 0.4884. This study underscores that the Single-Frame Model provides similar predictive performance for blastulation compared to the Full-Frame Model. Limitations, reasons for caution Our analysis was limited to images taken at 66.7 hours post-ICSI to mirror clinical practice. Further investigations at different time points are necessary to determine the optimal time for blastulation prediction. Additional analysis of the Day 1 and Day 2 single frames may offer further insights. Wider implications of the findings Accurate prediction of blastulation on day 3 is pivotal for embryo survival and IVF success. Our study challenges the assumption that more data improves AI models, highlighting the importance of day 3 observations. Further research is warranted to identify key time points and features for better predictive accuracy. Trial registration number not applicable

Tibial cortex transverse transport surgery improves wound healing in patients with severe type 2 DFUs by activating a systemic immune response: a cross-sectional study.

Tibial cortex transverse transport (TTT) surgery has become an ideal treatment for patients with type 2 severe diabetic foot ulcerations (DFUs) while conventional treatments are ineffective. Based on our clinical practice experience, the protective immune response from TTT surgery may play a role against infections to promote wound healing in patients with DFUs. Therefore, this research aimed to systematically study the specific clinical efficacy and the mechanism of TTT surgery. Between June 2022 and September 2023, 68 patients with type 2 severe DFUs were enrolled and therapized by TTT surgery in this cross-sectional and experimental study. Major clinical outcomes including limb salvage rate and antibiotics usage rate were investigated. Ten clinical characteristics and laboratory features of glucose metabolism and kidney function were statistically analyzed. Blood samples from 6 key time points of TTT surgery were collected for label-free proteomics and clinical immune biomarker analysis. Besides, tissue samples from 3 key time points were for spatially resolved metabolomics and transcriptomics analysis, as well as applied to validate the key TTT-regulated molecules by RT-qPCR. Notably, 64.7% of patients did not use antibiotics during the entire TTT surgery. TTT surgery can achieve a high limb salvage rate of 92.6% in patients with unilateral or bilateral DFUs. Pathway analysis of a total of 252 differentially expressed proteins (DEPs) from the proteomic revealed that the immune response induced by TTT surgery at different stages was first comprehensively verified through multi-omics combined with immune biomarker analysis. The function of upward transport was activating the systemic immune response, and wound healing occurs with downward transport. The spatial metabolic characteristics of skin tissue from patients with DFUs indicated downregulated levels of stearoylcarnitine and the glycerophospholipid metabolism pathway in skin tissue from patients with severe DFUs. Finally, the expressions of PRNP (prion protein) to activate the immune response, PLCB3 (PLCB3, phospholipase C beta 3) and VE-cadherin to play roles in neovascularization, and PPDPF (pancreatic progenitor cell differentiation and proliferation factor), LAMC2 (laminin subunit gamma 2) and SPRR2G (small proline rich protein 2G) to facilitate the developmental process mainly keratinocyte differentiation were statistically significant in skin tissues through transcriptomic and RT-qPCR analysis. Tibial cortex transverse transport (TTT) surgery demonstrates favorable outcomes for patients with severe type 2 DFUs by activating a systemic immune response, contributing to anti-infection, ulcer recurrence, and the limb salvage rate for unilateral or bilateral DFUs. The specific clinical immune responses, candidate proteins, genes, and metabolic characteristics provide directions for in-depth mechanistic research on TTT surgery. Further research and public awareness are needed to optimize TTT surgery in patients with severe type 2 DFUs.

Empleo y salarios de los graduados universitarios: evaluación del impacto de un programa de ayuda financiera mediante propensity score matching

Introduction / Objective: Educational funding in Venezuela is limited, especially in private higher education institutions, due to existing budget constraints. Despite these limitations, some grant programmes manage to serve a significant proportion of students. The purpose of this research was to evaluate the impact of a financial aid programme at a Latin American university by analysing the probability of employment and remuneration at three key points in time: during the degree programme, upon graduation, and three years after graduation. Methodology: A sample of graduates from various programmes was used, and information about their career paths was collected by means of a follow-up survey. The analysis was conducted using propensity score matching through the Average Treatment Effect on the Treated (ATT) estimator, employing both parametric and non-parametric methods. Results: The results indicate an inverse relationship between the financial aid received and the salary earned during the evaluation periods, alongside a positive relationship with the probability of being employed. However, none of the estimated coefficients were significant, whether for the nearest neighbour, the 5 or 10 nearest neighbours, the Kernel estimation, or the local linear estimation, taking into account the common support and the 20% trimming. Conclusions: It cannot be concluded that the grant received during the degree programme significantly improves employment and remuneration outcomes. This suggests the need for a comprehensive programme that includes support in job placement processes in order to enhance these outcomes.

Two transcriptionally and functionally distinct waves of neutrophils during mouse acute liver injury.

Neutrophils are key mediators of inflammation during acute liver injury (ALI). Emerging evidence suggests that they also contribute to injury resolution and tissue repair. However, the different neutrophil subsets involved in these processes and their kinetics are undefined. Herein, we characterized neutrophil kinetics and heterogeneity during ALI. We used the carbon tetrachloride model of ALI and employed flow cytometry, tissue imaging, and quantitative RT-PCR to characterize intrahepatic neutrophils during the necroinflammatory early and late repair phases of the wound healing response to ALI. We FACS sorted intrahepatic neutrophils at key time points and examined their transcriptional profiles using RNA-sequencing. Finally, we evaluated neutrophil protein translation, mitochondrial function and metabolism, reactive oxygen species content, and neutrophil extracellular traps generation. We detected 2 temporarily distinct waves of neutrophils during (1) necroinflammation (at 24 hours after injury) and (2) late repair (at 72 hours). Early neutrophils were proinflammatory, characterized by: (1) upregulation of inflammatory cytokines, (2) activation of the noncanonical NF-κB pathway, (3) reduction of protein translation, (4) decreased oxidative phosphorylation, and (5) higher propensity to generate reactive oxygen species and neutrophil extracellular traps. In contrast, late neutrophils were prorepair and enriched in genes and pathways associated with tissue repair and angiogenesis. Finally, early proinflammatory neutrophils were characterized by the expression of a short isoform of C-X-C chemokine receptor 5, while the late prorepair neutrophils were characterized by the expression of C-X-C chemokine receptor 4. This study underscores the phenotypic and functional heterogeneity of neutrophils and their dual role in inflammation and tissue repair during ALI.

Synchronously in vivo real-time monitoring bacterial load and temperature with evaluating immune response to decipher bacterial infection.

Determining the precise course of bacterial infection requires abundant in vivo real-time data. Synchronous monitoring of the bacterial load, temperature, and immune response can satisfy the shortage of real-time in vivo data. Here, we conducted a study in the joint-infected mouse model to synchronously monitor the bacterial load, temperature, and immune response using the second near-infrared (NIR-II) fluorescence imaging, infrared thermography, and immune response analysis for 2 weeks. Staphylococcus aureus (S. aureus) was proved successfully labeled with glucose-conjugated quantum dots in vitro and in subcutaneous-infected model. The bacterial load indicated by NIR-II fluorescence imaging underwent a sharp drop at 1 day postinfection. At the same time, the temperature gap detected through infrared thermography synchronously brought by infection reached lowest value. Meanwhile, the flow cytometry analysis demonstrated that immune response including macrophage, neutrophil, B lymphocyte, and T lymphocyte increased to the peak at 1 day postinfection. Moreover, both M1 macrophage and M2 macrophage in the blood have an obvious change at ~1 day postinfection, and the change was opposite. In summary, this study not only obtained real-time and long-time in vivo data on the bacterial load, temperature gap, and immune response in the mice model of S. aureus infection, but also found that 1 day postinfection was the key time point during immune response against S. aureus infection. Our study will contribute to synchronously and precisely studying the complicated complex dynamic relationship after bacterial infection at the animal level.