Cumulative Change Research Articles

Human culture is uniquely open-ended rather than uniquely cumulative.

Theories of how humans came to be so ecologically dominant increasingly centre on the adaptive abilities of human culture and its capacity for cumulative change and high-fidelity transmission. Here we revisit this hypothesis by comparing human culture with animal cultures and cases of epigenetic inheritance and parental effects. We first conclude that cumulative change and high transmission fidelity are not unique to human culture as previously thought, and so they are unlikely to explain its adaptive qualities. We then evaluate the evidence for seven alternative explanations: the inheritance of acquired characters, the pathways of inheritance, the non-random generation of variation, the scope of heritable variation, effects on organismal fitness, effects on genetic fitness and effects on evolutionary dynamics. From these, we identify the open-ended scope of human cultural variation as a key, but generally neglected, phenomenon. We end by articulating a hypothesis for the cognitive basis of this open-endedness.

Study on Failure Characteristics and Acoustic Emission Laws of Rock-like Specimens under Uniaxial Compression

Complex underground conditions make it challenging to conduct extensive coring, and it is difficult for laboratories to carry out a large number of rock mechanics experiments due to the limited number of cores. Rock-like specimens are commonly used in the laboratory to replace coal-rock specimens. In this paper, rock-like specimens with different proportions are produced to study the mechanical properties, failure characteristics, and acoustic emission laws of rock-like specimens under uniaxial compression. The results show that when the rock-like specimen does not contain gypsum, the stress of the specimen decreases rapidly after reaching the peak stress, which is similar to the mechanical properties of hard brittle rock. When the rock-like specimen contains gypsum, the stress of the specimen decreases slowly after reaching the compressive limit, and the failure of the specimen is gentle, which is similar to the mechanical properties of soft rock. When the specimen lacks gypsum, the strength of the rock-like specimen is larger, and the strength of the specimen is positively correlated with the proportion of cement. When the specimen contains gypsum, the strength of the rock-like specimen decreases sharply, and the strength of the rock-like specimen is negatively correlated with the proportion of gypsum. The maximum acoustic emission ringing count increases with higher cement content but decreases with increased gypsum content. The cumulative count change of acoustic emissions approximately underwent four stages, aligning well with the four stages of uniaxial compression failure observed in typical rock. The research results have important reference value for the selection of rock-like materials to replace the original rock materials for laboratory research.

Urinary Metal Levels and Coronary Artery Calcification: Longitudinal Evidence in the Multi-Ethnic Study of Atherosclerosis

BackgroundExposure to metals, a newly recognized risk factor for cardiovascular disease (CVD), could be related to atherosclerosis progression. ObjectivesThe authors hypothesized that higher urinary levels of nonessential (cadmium, tungsten, uranium) and essential (cobalt, copper, zinc) metals previously associated with CVD would be associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of CVD in MESA (Multi-Ethnic Study of Atherosclerosis). MethodsWe analyzed data from 6,418 MESA participants with spot urinary metal levels at baseline (2000-2002) and 1 to 4 repeated, continuous measures of CAC over a 10-year period. We used linear mixed-effect models to assess the association of baseline urinary metal levels with baseline CAC and cumulative change in CAC over a 10-year period. Urinary metals (μg/g creatinine) and CAC were log transformed. Models were adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors. ResultsAt baseline, the median CAC was 6.3 (Q1-Q3: 0.7-58.2). Comparing the highest to lowest quartile of urinary cadmium, CAC levels were 51% (95% CI: 32%, 74%) higher at baseline and 75% (95% CI: 47%, 107%) higher over the 10-year period. For urinary tungsten, uranium, and cobalt, the corresponding CAC levels over the 10-year period were 45% (95% CI: 23%, 71%), 39% (95% CI: 17%, 64%), and 47% (95% CI: 25%, 74%) higher, respectively, with no difference for models with and without adjustment for clinical factors. For copper and zinc, the corresponding estimates dropped from 55% to 33% and from 85% to 57%, respectively, after adjustment for clinical factors. The associations of metals with CAC were comparable in magnitude to those for classical CVD risk factors. ConclusionsExposure to metals was generally associated with extent of coronary calcification at baseline and follow-up. These findings support that metals are associated with the progression of atherosclerosis, potentially providing a novel strategy for the prevention and treatment of atherosclerosis progression.

Improvement and application of back random response detection: Based on cumulative sum and change point analysis.

In educational and psychological assessments, benefiting from back random response (BRR) is a major type of rapid guessing in misfitting item score patterns. Person-fit statistics (PFS) based on cumulative sum (CUSUM) and change point analysis (CPA) from statistical process control (SPC) are better than other PFS for detecting aberrant response. In this study, we developed new person-fit statistics based on three algorithms from CPA procedure and CUSUM method for detection of person misfit with dichotomous or polytomous items. By means of simulated data, the effectiveness of the new statistics to detect test-takers with BRR was investigated.

Evolution Pattern of Land Subsidence Using InSAR Time-Series Analysis in Bangkapi, Bangkok, Thailand

Subsidence in Bangkok has occurred continuously for a long time. This research applied radar satellite imagery (Sentinel-1 101 images, 2017–2022) to track land subsidence using the time series INSAR technique. The study area was in the Bang Kapi area in Bangkok, which has a high level of cumulative subsidence. The pattern of cumulative subsidence change was analyzed using the standard deviation ellipse (SDE) technique. The results showed that the Bang Kapi area had the highest cumulative subsidence in 2019 (-125.31 mm). The movement of the subsidence center changed every year in different directions with three patterns identifiable. The first pattern showed the evolution of subsidence in a northeast-southwest direction, the second pattern showed subsidence evolution in a northwest-southeast direction, and the third pattern presented evolution that did not appear to be in any specific direction. The size of the subsidence area in 2017 and 2022 increased, whereas between 2018 and 2021, the subsidence area decreased compared to other years during the research period.

Prioritizing social vulnerability in urban heat mitigation.

We utilized city-scale simulations to quantitatively compare the diverse urban overheating mitigation strategies, specifically tied to social vulnerability and their cooling efficacies during heatwaves. We enhanced the Weather Research and Forecasting model to encompass the urban tree effect and calculate the Universal Thermal Climate Index for assessing thermal comfort. Taking Houston, Texas, and United States as an example, the study reveals that equitably mitigating urban overheat is achievable by considering the city's demographic composition and physical structure. The study results show that while urban trees may yield less cooling impact (0.27 K of Universal Thermal Climate Index in daytime) relative to cool roofs (0.30 K), the urban trees strategy can emerge as an effective approach for enhancing community resilience in heat stress-related outcomes. Social vulnerability-based heat mitigation was reviewed as vulnerability-weighted daily cumulative heat stress change. The results underscore: (i) importance of considering the community resilience when evaluating heat mitigation impact and (ii) the need to assess planting spaces for urban trees, rooftop areas, and neighborhood vulnerability when designing community-oriented urban overheating mitigation strategies.

Efficacy of weekly dose of 1% atropine for myopia control in Chinese children

PurposeTo assess the effect of weekly 1% atropine use on children’s myopia progression and whether the effect is sustainable.MethodsMedical records of myopic children aged 3–15 years receiving weekly 1% atropine...

Spatio-temporal analysis of land use and land cover changes in a wetland ecosystem of Bangladesh using a machine-learning approach

This study investigates quantifiable and explicable changes in Land Use and Land Cover (LULC) within the context of a freshwater wetland, Hakaluki Haor, in Bangladesh. The haor is a vital RAMSAR site and Ecologically Critical Area (ECA), which needs to be monitored to investigate LULC change patterns for future management interventions. Leveraging Landsat satellite data, the Google Earth Engine Database, CART algorithm, ArcGIS 10.8 and the R programming language, this study analyses LULC dynamics from 2000 to 2023. It focuses explicitly on seasonal transitions between the rainy and dry seasons, unveiling substantial transformations in cumulative LULC change patterns over the study period. Noteworthy changes include an overall reduction (~51%) in Water Bodies. Concurrently, there is a significant increase (~353%) in Settlement areas. Moreover, vegetation substantially declines (71%), while Crop Land demonstrates varying coverage. These identified changes underscore the dynamic nature of LULC alterations and their potential implications for the environmental, hydrological, and agricultural aspects within the Hakaluki Haor region. The outcomes of this study aim to provide valuable insights to policymakers for formulating appropriate land-use strategies in the area.

Probabilistic assessment of rockburst risk in TBM-excavated tunnels with multi-source data fusion

In recent years, tunnel boring machines (TBMs) have become extensively utilized in underground engineering projects. However, as a prevalent type of dynamic geological hazard, rockburst poses a serious threat to the safety of personnel, equipment, and property. To ensure the safe advancement of TBMs, we integrate the data of microseismic monitoring, TBM excavation, and surrounding rock and establish multiple probabilistic assessment models of rockburst risk using probabilistic ensemble learning and quantum particle swarm optimization. In order to identify the most optimal model for geological engineers, a comprehensive evaluation system is devised based on metrics like accuracy, Cohen’s kappa, and F1-score. This system provides a thorough assessment of the models’ global and local generalization performance. The results indicate that the classification and regression tree-extremely randomized trees (CART-ERT) hybrid model achieves the highest score, demonstrating superior generalization performance with an accuracy of 93.06% and a Cohen’s kappa of 0.9074. Moreover, the F1-scores for no rockburst, low rockburst, moderate rockburst, and strong rockburst are 0.9412, 0.9444, 0.9189, and 0.9189, respectively. Based on the operational framework of the CART-ERT hybrid model, a user-friendly graphical user interface (GUI) system is developed. This significantly enhances the practicality and deployability of the model. Through application in a TBM diversion tunnel project in Xinjiang, the on-site early-warning accuracy of rockburst with the GUI system reaches 90%. Notably, the GUI system maintains high early-warning sensitivity and reliability for high-intensity rockburst such as moderate and strong ones. Lastly, to enhance the model’s interpretability, a variable importance measure (VIM) analysis on 14 features extracted from three types of heterogeneous data is conducted to assess their contributions to the early warning of rockburst. We discover that the cumulative energy change rate of microseismic events exhibits the highest importance score, indicating its crucial role in rockburst early warning.

Evaluation and Comparison of Fracture Strength and Fluoride Releasing Properties of New Alkasite Materials with Conventional Restorative Material, Bulk Fill Composite and Glass Ionomer Cement: An In-Vitro Study.

This study aimed to evaluate and compare fluoride ion release by Cention-N (self-cure and light-cure) and conventional glass-ionomer cement (GIC) at different pH levels and time intervals. For fluoride release assessment, 240 samples (10 mm diameter, 2 mm height) of Cention-N and conventional glass-ionomer cement were created using rubber rings. Samples were stored in deionized water, and the cumulative fluoride ion release and change in pH were assessed using a spectrophotometer and pH meter, respectively, at the end of 7 days, 14 days, and 21 days. The obtained data were subjected to statistical analysis. All three samples exhibited very high fluoride release in an acidic medium compared to the neutral medium. Although GIC demonstrated superior fluoride release, Cention-N displayed adequate fluoride release over a longer duration. Within the limitations of this study, it can be concluded that both Glass ionomer cement and Cention-N showed an initial fluoride burst.

A temporal difference matrix for historical cumulative change detection in time series PolSAR data

To detect historical cumulative changes in land cover, this study introduces a novel time series PolSAR change detection method. The objective is to address the inefficiency of traditional detection methods that use multiple pairwise comparisons, as well as to alleviate false positives and false negatives caused by the insufficient utilization of polarization and spatial context information in previous methods. The proposed method initially constructs a temporal difference matrix for time series PolSAR images and computes the difference image (DI) using the maximum eigenvalue of this matrix to depict the cumulative changes over time. Subsequently, the DI is segmented using an MRF-based image segmentation method with a limited amount of supervised information, yielding the cumulative change binary map. The efficacy of the proposed method is validated using three time series datasets covering different scenes acquired by different sensors, namely GaoFen3, Radarsat2 and Sentinel-1. The experimental results demonstrate that the method effectively characterizes cumulative changes in the time series while simultaneously considering disparities in radar backscatter intensity and polarization correlation. As a result, it significantly reduces erroneous and missed change detections and surpasses the existing methods by achieving the highest Recall, F1-score, IOU, Kappa, and overall accuracy. Furthermore, the DI calculation method serves as a versatile change descriptor applicable not only for capturing cumulative changes in time series but also for describing changes between dual temporal images.

Enhanced perturbation measurement range chirped pulse ϕ-OTDR for distributed static measurements using feedback frequency-shift compensation technology

Chirped-pulse phase-sensitive optical time-domain reflectometry (CP-ϕOTDR) is a newly developed distributed optical fiber sensing (DOFS) technology that can measure physical quantities across the length of optical fiber. The measurement of perturbations as strain or temperature changes is performed by comparing the time domain trace of Rayleigh backscattered (RBS) light with a reference trace. However, large strain or temperature fluctuations or laser frequency noises necessitate frequent updates of the reference, and short-term change measurements must be integrated to obtain absolute strain or temperature, which introduces a 1/f noise component due to the combination of noise with each cumulative change. In this study, we propose a novel CP-ϕOTDR system based on frequency-shift compensation (FSC) technology. This system utilizes real-time feedback control of the central frequency of the incident laser to compensate for time domain trace distortion caused by large perturbations. It overcomes the limitations associated with the total chirp bandwidth and eliminates the 1/f noise component by obviating the need for frequent updates of the reference trace. The measuring range for perturbations is only limited to the wavelength range supported by the integrated optical devices, typically on the order of nanometers, corresponding to at least tens of Kelvin in temperature fluctuations or hundreds of micro-strains. To validate the effectiveness, we conducted a temperature measurement experiment involving a 1 K variation, which is about 90 times the maximum measurable perturbation that the original CP-ϕOTDR system can demodulate with the reference unchanged. The results demonstrate that the FSC method significantly expands the perturbation measurement range of the CP-ϕOTDR system.

Serum ARGS-aggrecan in a phase 2 clinical trial targeting osteoarthritis

OBJECTIVETo monitor serum concentrations of the aggrecan ARGS neoepitope in a clinical trial of ADAMTS-5 inhibition as disease-modifying therapy of knee osteoarthritis, and to investigate relationships between reduction in ARGS and change in cartilage thickness, knee related pain and function. DESIGNROCCELLA trial participants received once-daily oral S201086 75, 150 or 300 mg, or placebo, for 52 weeks. Serum was collected at baseline, 4, 12, 28 and 52 weeks, and 2 weeks post treatment with ARGS measured by an in-house immunoassay. Change from baseline to week 52 in central medial femorotibial compartment cartilage thickness was measured by MRI, function and pain by WOMAC subscores. Associations between cumulative change in ARGS and change in cartilage thickness or WOMAC subscores were evaluated by linear regression. RESULTSS201086 reduced serum levels of ARGS in a dose-dependent manner throughout the treatment period. Maximal reduction was at 4 weeks with a 58.5% [95% CI 60.8%, 56.2%] reduction of ARGS compared to baseline for 300 mg S201086. Two weeks post treatment, ARGS concentrations rebounded with a dose-dependent overshoot compared to baseline levels. Cumulative change of ARGS concentration from baseline to week 52 had no effect on change in cartilage thickness (slope -0.8x10-6 [-2.9x10-6, 1.3x10-6]) or change in WOMAC pain and function (slopes -30x10-6 [-64x10-6, 5.2x10-6] and -97x10-6 [-214x10-6, 20x10-6], respectively) at week 52. CONCLUSIONSystemic inhibition of ADAMTS-5 resulted in markedly reduced serum ARGS, but change in serum ARGS concentrations showed no association with the progression of cartilage thinning, or patient reported pain and function. ClinicalTrials.govNCT03595618.

A Numerical Model for Analyzing Mechanical Slippage Effect on Crosswell Distributed Fiber-Optic Strain Measurements During Fracturing

Summary Distributed fiber-optic (FO) strain measurements have become a widely used method for monitoring and diagnosing far-field strain induced during hydraulic fracturing (HF). However, field observations have revealed that the mechanical decoupling between the fiber and the rock often happens. Despite this phenomenon, much of the current research assumes that the fiber cable remains mechanically coupled to the rock formation. To improve the accuracy and reliability of field data interpretation, it is essential to better understand the effect of fiber decoupling on strain responses. The objective of this study is to simulate strain responses while taking into account the impact of fiber slippage. In this study, we developed a numerical model that allows for accurate prediction and analysis of strain responses of crosswell distributed FO experiencing mechanical decoupling. Our model first uses the 3D displacement discontinuity method to calculate displacement fields induced by hydraulic fractures. The model then accounts for the occurrence of slippage and calculates the fiber displacement distribution with slippage effect. Additionally, the model can predict fiber strain distribution in cases where the stick-slip behavior is present. To better understand the impact of friction on strain and strain-rate signals, we conduct a sensitivity analysis. This allows us to explore the effects of different friction levels on the signals, which can be critical in achieving more accurate and reliable results. Our model results reveal several key observations. First, when fiber slippage is detected, we typically observe a broadening of the extension zone near the fracture on the strain/strain rate waterfall plots, which cannot provide a well-defined fracture domain corridor. The simulated strain rate pattern matches the field observation. Additionally, the size of the decoupling zone increases as the friction between the fiber and formation decreases. Also, the decoupling generates negative cumulative strain change after a certain period of closure. Furthermore, when the dynamic friction is smaller than the static friction, sudden strain releases appearing as sticking portions were visible in the strain/strain-rate waterfall plots, indicating the occurrence of stick-slip behavior in the fiber. We also observed that the sudden strain releases in the strain rate waterfall plot occur more frequently when the maximum fiber strain gradient is smaller. Moreover, the longer sticking portion was observed when the dynamic/static friction ratio was smaller. The key innovation of this study is the development of a forward numerical model that simulates strain responses while taking into account the coupling effect between fiber and formation. To the best of our knowledge, this is the first time that such a model has been presented. Overall, our study provides an important contribution to the field of HF monitoring by enabling a more accurate and reliable interpretation of strain signals, which can ultimately improve the safety and effectiveness of HF operations.

Abstract PO2-22-08: Nipple areolar complex changes after breast-conserving surgical therapy and periareolar mastopexy: a three-dimensional Surface Analysis

Abstract Objectives: The position and configuration of the nipple-areolar complex (NAC) have a high impact on satisfaction (objective and subjective) after breast-conserving therapy (BCT). The aim of this study is to objectively measure the changes in the NAC after breast conservation surgery by the use of the 3D whole body scanner and compare its results with the outcome reported by the patients. This will support further patients and help physicians to tailor their technique prior to breast-conserving surgery. Methods: In a unicentric pilot project 6 months after BET with periareolar mastopexy and adjuvant radiation between 2019 and 2022, 38 women were studied. The mean age was 56.3 ±11.6 and BMI was 24.6 ± 4.5 kg/m². Objective 3D parameters were collected using the Vectra Whole Body Surface Imaging System (WB360) based on breast and NAC dimensions. In addition, the patients received the BCT module and the mastopexy module items about satisfaction with the NAC from the BREAST Q questionnaire. Results: In a group of 38 women, BCT with periareolar mastopexy and irradiation showed a small but significant change in NAC position and shape (see Table 1). This small change is matched by the high satisfaction with the nipple and areola surveyed in the BREAST-Q questionnaire. More than 66% of the women were rather satisfied or very satisfied. The BREAST-Q results from the Items about satisfaction with the nipple and areola are shown in Table 2. However, 34% of participants reported being somewhat dissatisfied to very dissatisfied with the symmetry of placement. This could be due to a significant cumulative small change in nipple-sternal notch distance and nipple-midline distance. No significant difference was found when measuring the nipple-inframammary fold distance (p=0.649). The absolute difference was of 0.13 ± 1.22 mm. The change in breast diameter was of 0.55 ± 1.54 mm (relative 2,75 ± 7.95%). There was also no significance (p=0.042). This indicates that after BCT, the nipple-inframammary fold distance and breast diameter did not change significantly. Breast volume decreases insignificantly by 49.2 ± 136.1 cc (relative 12,96 ± 33.51) on the operated side (p=0.009). In particular, a difference in vertical diameter of the NAC of -4,79 mm (14,27%) was observed between the non-operated and the operated breast (p=0.005 by Wilcoxon-test). The BREAST-Q BCT Module consists of 8 domains. The higher the score, the higher the satisfaction with the questioned item. In our sample of 38 women, satisfaction with the surgeon(s) was highest (BREAST-Q score of 83,97 ± 19,12). The mean Q score for satisfaction with "psychosocial well-being" is 67,47 ± 22,03. For the item "sexual well-being", only 35 women answered sufficient questions and the mean Q score was 54,42 ± 16,43. “Satisfaction with breast” had a Q-score of 61,03 ± 19,36. The questions about "physical well-being" had a mean of 70,11 ± 16,69. The Q-score for “satisfaction with medical team”, “with office staff”, and “with information” can be seen in Table 3. Conclusions: In a nutshell, the conclusion of this study is that the Vectra XT 3D-Imaging is a useful tool to assess the cosmetic outcome in terms of NAC position and shape. Hence, it is a helpful tool to support the planning of the surgery and may have a positive impact on the outcome. Postoperatively, there was only a slight change in the NAC dimension and position compared with intraoperative planning. The 3D Surface Analysis is most useful in assessing the quality of reconstruction after BCT and additionally the NAC is therefore an important factor for patient satisfaction. Results of a multicenter study are pending. Table 1: Descriptive statistic and Wilcoxon-test Results from the measures from the Breast and from NAC Dimension and Position (n=38) The 3D Measures from the Breast and from NAC Dimension and Position Table 2: Results from the BREAST-Q mastopexy modul about satisfaction with the nipples (n=38) Satisfaction with the nipples Table 3: Results from the BREAST-Q BCT Modul after BCT and periareolar mastopexy und adjuvant radiation (n=38) BREAST-Q Scores Citation Format: Therese Peter, Konstantin Koban, Denis Ehrl, Pamina Geiger, Nadia Harbeck, Steffen Kahlert, Carolin Luczak, Johannes Schmid, Rachel Wuerstlein, Friederike Hagemann. Nipple areolar complex changes after breast-conserving surgical therapy and periareolar mastopexy: a three-dimensional Surface Analysis [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 PO2-22-08.

Motivations, changes and challenges of participating in food-related social innovations and their transformative potential: three cases from Berlin (Germany)

AbstractDominant agri-food systems are increasingly seen as unsustainable in terms of environmental degradation, mass production or high food waste. In an attempt to counteract these developments and foster sustainability transitions in agri-food systems, a variety of actors are engaging in socially innovative models of food production and consumption. Using a multiple case study approach, our study examines three contrasting alternative economic models in the city of Berlin: community gardens, the app Too Good To Go (TGTG), and a cooperative supermarket. Based on 15 qualitative interviews, we provide insights into their transformative potential by exploring participants' underlying motivations, the changes they have experienced, and the challenges and potential for future development of these models. We find that participation in community gardens and the cooperative supermarket is similarly motivated by social aspects and dissatisfaction with existing food access options, while TGTG users are more motivated by financial reasons. Our study shows that change is experienced mainly at the individual level, e.g. by building new relationships, changing cognitive framings, and learning (new) practices, especially in community-oriented settings. The individualization of change shows that these models have a rather low potential to lead to more systemic accounts of changes. Yet, they can prefigure regime change, describe resistance, and foster cumulative incremental change that may spill over into society. We conclude that in order to sustain this role and drive transitions, it is important to up- and outscale these models; and we provide recommendations on how these models can mutually support their development, establishment, and protection.

Uncertain process-based data integration and residual lifetime evaluation of PCB in airborne equipment with ADT and field data

Accurately evaluating the lifespan of the Printed Circuit Board (PCB) in airborne equipment is an essential issue for aircraft design and operation in the marine atmospheric environment. This paper presents a novel evaluation method by fusing Accelerated Degradation Testing (ADT) data, degradation data, and life data of small samples based on the uncertainty degradation process. An uncertain life model of PCB in airborne equipment is constructed by employing the uncertain distribution that considers the accelerated factor of multiple environmental conditions such as temperature, humidity, and salinity. In addition, a degradation process model of PCB in airborne equipment is constructed by employing the uncertain process of fusing ADT data and field data, in which the performance characteristics of dynamic cumulative change are included. Based on minimizing the pth sample moments, an integrated method for parameter estimation of the PCB in airborne equipment is proposed by fusing the multi-source data of life, degradation, and ADT. An engineering case illustrates the effectiveness and advantage of the proposed method.

Efficacy and Safety of Dapagliflozin in Patients With Acute Heart Failure

BackgroundThe primary goals during acute heart failure (AHF) hospitalization are decongestion and guideline-directed medical therapy (GDMT) optimization. Unlike diuretics or other GDMT, early dapagliflozin initiation could achieve both AHF goals. ObjectivesThe authors aimed to assess the diuretic efficacy and safety of early dapagliflozin initiation in AHF. MethodsIn a multicenter, open-label study, 240 patients were randomized within 24 hours of hospital presentation for hypervolemic AHF to dapagliflozin 10 mg once daily or structured usual care with protocolized diuretic titration until day 5 or hospital discharge. The primary outcome, diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose, was compared across treatment assignment using a proportional odds model adjusted for baseline weight. Secondary and safety outcomes were adjudicated by a blinded committee. ResultsFor diuretic efficiency, there was no difference between dapagliflozin and usual care (OR: 0.65; 95% CI: 0.41-1.02; P = 0.06). Dapagliflozin was associated with reduced loop diuretic doses (560 mg [Q1-Q3: 260-1,150 mg] vs 800 mg [Q1-Q3: 380-1,715 mg]; P = 0.006) and fewer intravenous diuretic up-titrations (P ≤ 0.05) to achieve equivalent weight loss as usual care. Early dapagliflozin initiation did not increase diabetic, renal, or cardiovascular safety events. Dapagliflozin was associated with improved median 24-hour natriuresis (P = 0.03) and urine output (P = 0.005), expediting hospital discharge over the study period. ConclusionsEarly dapagliflozin during AHF hospitalization is safe and fulfills a component of GDMT optimization. Dapagliflozin was not associated with a statistically significant reduction in weight-based diuretic efficiency but was associated with evidence for enhanced diuresis among patients with AHF. (Efficacy and Safety of Dapagliflozin in Acute Heart Failure [DICTATE-AHF]; NCT04298229)

Early Use of Erenumab vs Nonspecific Oral Migraine Preventives

Patients with migraine often cycle through multiple nonspecific preventive medications due to poor tolerability and/or inadequate efficacy leading to low adherence and increased disease burden. To compare the efficacy, tolerability, patient adherence, and patient satisfaction between erenumab and nonspecific oral migraine preventive medications (OMPMs) in patients with episodic migraine (EM) who had previously failed 1 or 2 preventive treatments. The 12-month prospective, interventional, global, multicenter, active-controlled, randomized clinical trial comparing sustained benefit of 2 treatment paradigms (erenumab qm vs oral prophylactics) in adult episodic migraine patients (APPRAISE) trial was a 12-month open-label, multicenter, active-controlled, phase 4 randomized clinical trial conducted from May 15, 2019, to October 1, 2021. This pragmatic trial was conducted at 84 centers across 17 countries. Overall, participants 18 years or older with a 12-month or longer history of migraine, and 4 or more but fewer than 15 monthly migraine days (MMDs) were included. Patients were randomized (2:1) to receive erenumab or OMPMs. Dose adjustment was permitted (label dependent). The primary end point was the proportion of patients completing 1 year of the initially assigned treatment and achieving a reduction of 50% or greater from baseline in MMDs at month 12. Secondary end points included the cumulative mean change from baseline in MMDs during the treatment period and the proportion of responders according to the Patients' Global Impression of Change (PGIC) scale at month 12 for patients taking the initially assigned treatment. A total of 866 patients were screened, of whom 245 failed the screening and 621 completed the screening and baseline period. Of the 621 randomized patients (mean [SD] age, 41.3 [11.2] years; 545 female [87.8%]; 413 [66.5%] in the erenumab group; 208 [33.5%] in the OMPM group), 523 (84.2%) completed the treatment phase, and 98 (15.8%) discontinued the study. At month 12, significantly more patients assigned to erenumab vs OMPM achieved the primary end point (232 of 413 [56.2%] vs 35 of 208 [16.8%]; odds ratio [OR], 6.48; 95% CI, 4.28-9.82; P <.001). Compared with OMPMs, treatment with erenumab showed higher responder rate (314 of 413 [76.0%] vs 39 of 208 [18.8%]; OR, 13.75; 95% CI, 9.08-20.83; P <.001) on the PGIC scale (≥5 at month 12). Significant reduction in cumulative average MMDs was reported with erenumab treatment vs OMPM treatment (-4.32 vs -2.65; treatment difference [SE]: -1.67 [0.35] days; P < .001). Substantially fewer patients in the erenumab arm compared with the OMPM arm switched medication (9 of 413 [2.2%] vs 72 of 208 [34.6%]) and discontinued treatment due to adverse events (12 of 408 [2.9%] vs 48 of 206 [23.3%]). No new safety signals were identified. Results of this randomized clinical trial demonstrated that earlier use of erenumab in patients with EM who failed 1 or 2 previous preventive treatments provided greater and sustained efficacy, safety, and adherence than continuous OMPM. ClinicalTrials.gov Identifier: NCT03927144.

Effects of paternal arachidonic acid supplementation on offspring behavior and hypothalamus inflammation markers in the mouse.

Arachidonic acid (AA) is involved in inflammation and plays a role in growth and brain development in infants. We previously showed that exposure of mouse sires to AA for three consecutive generations induces a cumulative change in fatty acid (FA) involved in inflammation and an increase in body and liver weight in the offspring. Here, we tested the hypothesis that paternal AA exposure changes the progeny's behavioral response to a proinflammatory insult, and asked whether tissue-specific FA are associated with that response. Male BALB/c mice were supplemented daily with three doses of AA for 10 days and crossed to non-supplemented females (n = 3/dose). Two-month-old unsupplemented male and female offspring (n = 6/paternal AA dose) were exposed to Gram-negative bacteria-derived lipopolysaccharides (LPS) or saline control two hours prior to open field test (OFT) behavioral analysis and subsequent sacrifice. We probed for significant effects of paternal AA exposure on: OFT behaviors; individual FA content of blood, hypothalamus and hypothalamus-free brain; hypothalamic expression profile of genes related to inflammation (Tnfa, Il1b, Cox1, Cox2) and FA synthesis (Scd1, Elovl6). All parameters were affected by paternal AA supplementation in a sex-specific manner. Paternal AA primed the progeny for behavior associated with increased anxiety, with a marked sex dimorphism: high AA doses acted as surrogate of LPS in males, realigning a number of OFT behaviors that in females were differential between saline and LPS groups. Progeny hypothalamic Scd1, a FA metabolism enzyme with documented pro-inflammatory activity, showed a similar pattern of differential expression between saline and LPS groups at high paternal AA dose in females, that was blunted in males. Progeny FA generally were not affected by LPS, but displayed non-linear associations with paternal AA doses. In conclusion, we document that paternal exposure to AA exerts long-term behavioral and biochemical effects in the progeny in a sex-specific manner.