Reduction In Fraction Research Articles

Dry inside: progressive unsaturation within leaves with increasing vapour pressure deficit affects estimation of key leaf gas exchange parameters.

Climate change not only leads to higher air temperatures but also increases the vapour pressure deficit (VPD) of the air. Understanding the direct effect of VPD on leaf gas exchange is crucial for precise modelling of stomatal functioning. We conducted combined leaf gas exchange and online isotope discrimination measurements on four common European tree species across a VPD range of 0.8-3.6 kPa, while maintaining constant temperatures without soil water limitation. In addition to applying the standard assumption of saturated vapour pressure inside leaves (ei), we inferred ei from oxygen isotope discrimination of CO2 and water vapour. ei desaturated progressively with increasing VPD, consistently across species, resulting in an intercellular relative humidity as low as 0.73 ± 0.11 at the highest tested VPD. Assuming saturation of ei overestimated the extent of reductions in stomatal conductance and CO2 mole fraction inside leaves in response to increasing VPD compared with calculations that accounted for unsaturation. In addition, a significant decrease in mesophyll conductance with increasing VPD only occurred when the unsaturation of ei was considered. We suggest that the possibility of unsaturated ei should not be overlooked in measurements related to leaf gas exchange and in stomatal models, especially at high VPD.

Efficacy and safety of Resmetirom, a selective thyroid hormone receptor-β agonist, in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD): a systematic review and meta-analysis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health problem owing to its high prevalence and associated morbidity and mortality secondary to progressive liver disease and cardiovascular events. Resmetirom, a selective thyroid hormone receptor-β agonist has been developed as a therapeutic modality for MASLD. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of resmetirom compared to a placebo in the treatment of MASLD. Eligible studies were systematically identified by screening PubMed, Scopus, Web of Science, Cochrane library, Embase, and ClinicalTrials.gov from 2014 to 2024. Only randomized controlled trials comparing the efficacy and safety of resmetirom in the treatment of MASLD against placebo were included in the analysis. Meta-analysis was performed using RevMan 5.4 software. Four studies with low risk of bias and involving a total of 2359 participants were identified. The metanalysis included only three clinical trials with 2234 participants. A significant reduction in MRI-proton density fat fraction (MRI-PDFF) with 80 mg Resmetirom compared to that with placebo [SMD − 27.74 (95% CI − 32.05 to − 32.42), p < 0.00001] at 36–52 weeks as well as at 12–16 weeks [SMD − 30.92 (95% CI − 36.44 to − 25.40), p < 0.00001]. With Resmetirom 100 mg dose at 36–52 weeks [SMD − 36.05 (95% CI − 40.67 to − 31.43), p < 0.00001] and 12–16 weeks [SMD − 36.89 (95% CI − 40.73 to − 33.05), p < 0.00001] were observed. Resmetirom treatment was associated with a significant reduction in LDL-c triglyceride, lipoproteins. and liver enzymes. There was significant reduction FT4 and increase in SHBG and sex steroids with Resmetirom compared to placebo. There was no major difference in the overall treatment emergent adverse events at 80 mg [OR 1.55 (95% CI 0.84 to 2.87), and 100 mg [OR 1.13 (95% CI 0.78 to 1.63), doses of Resmetirom compared to placebo. However, gastrointestinal adverse events diarrhoea and nausea occurred in ≥ 10% in the Resmetirom group compared to placebo at < 12 week. Resmetirom treatment showed modest efficacy in treating MASLD with reduction in MRI-PDFF, LDL-c, triglyceride, lipoproteins, liver enzymes and NASH biomarkers without significant safety concerns. Larger and long-term RCTs may further confirm this promising outcomes of Resmetirom use in MASLD.

MGDA-assisted plant washing agent for improving the removal of Cd and Cu from farmland soils

Utilizing plant extracts for soil washing is a promising and cost-efficient strategy to permanently remove toxic metals from farmland soils. However, the efficiency of current plant extracts in heavy metals removal is constrained by the need of excessively high liquid-solid ratios (>10:1), which limits their practical application in the farmland soils. To address this challenge, we developed a novel binary washing agent consisting of Fructus mume residue extract (RPM) and methylglycinediacetate acid (MGDA). Through optimization experiments, we determined an optimal composition of 50 g L−1 RPM and 0.34 g L−1 MGDA (RPMG3), which exhibited a remarkable synergistic effect on the removal of Cd and Cu from two polluted farmland soils. Compared to the single use of RPM or MGDA, RPMG3 increased metal removal efficiency by 44.6%–303.8% in the alkaline dryland soil and 55.8%–141.9% in the slightly acidic paddy soil, at an optimum liquid-solid ratio of 2:1. The contents of soil Cd and Cu can be reduced to below the risk screening values via acid activation, metal ion exchange, and complexation of functional groups. Moreover, the potential ecological risks associated with Cd in the soils were significantly mitigated due to the decrease in exchangeable and reducible Cd fractions following RPMG3 washing. Additionally, RPM and RPMG3 washing led to enhancements in soil organic carbon and nutrient concentrations, as well as increased activities of soil enzymes including catalase, urease, and β-glucosidase. Notably, RPMG3 washing exhibited the most pronounced promotion effect on wheat seed germination and growth. Taken together, the binary complex of RPMG3 demonstrates potential as an environmentally friendly green washing agent capable of in reducing heavy metals from farmland soil with great efficiency, even at low liquid-solid ratios.

Evaluating the role of sex-related structure-function differences on airway aerosol transport and deposition.

Several experimental studies have found that females have higher deposition of particles in the airways compared with males. This has implications for the delivery of aerosolized therapeutics and for understanding sex differences in respiratory system response to environmental exposures. This study evaluates several factors that potentially contribute to sex differences in particle deposition, using scale-specific structure-function models of 1D ventilation distribution, particle transport, and deposition. The impact of gravity, inhalation flow rate, and dead space are evaluated in 12 structure-based models (seven female; five male). Females were found to have significantly higher total, bronchial, and alveolar deposition than males across a particle size range from 0.01 to 10 . Results suggest that higher deposition fraction in females is due to higher alveolar deposition for smaller particle sizes, and higher bronchial deposition for larger particles. Females had higher alveolar deposition in the lower lobes, and slightly lower particle concentration in the left upper lobe. Males were found to be more sensitive to changes due to gravity, showing greater reduction in bronchial deposition fraction. Males were also more sensitive to change in inhalation flow rate, and to scaling of dead space due to the larger male baseline airway size. Predictions of sex differences in particle deposition - that are consistent with the literature - suggest that sex-based characteristics of lung and airway size interacting with particle size gives rise to differences in regional deposition.

Sedimentation and transformation of heavy metals during the transport from the Yellow River estuary to the sea: Evidence from surface sediments of the Yellow River subaqueous delta

Estuarine and coastal areas are one of the ultimate sinks for terrestrial heavy metals which play a vital role on the aquatic ecosystem. This study examined heavy metals contents and speciations in Yellow River subaqueous delta surface sediment, to characterize their sedimentation and transformation during transport from estuary to the sea. The results showed that higher concentrations were found in the seaward and the shear front affected areas. The surface sediments were generally not contaminated by heavy metals, except for Cd was highly enriched, while the post-standardization spatial distribution reflected the effect of estuarine processes as a “filter” that effectively intercepting heavy metals. The dominated phase was residual fraction for Cr, Cu, Zn, Cd, while reducible fraction for Ni and carbonate fraction for Pb. The transformation of heavy metal species was mainly influenced by the changes in the sediment components such as carbonate minerals, organic matter and FeMn oxides.

Effect of hold-type on cyclic life and microstructural evolution of an austenitic stainless steel

The present work investigates the effect of different type of hold on the change in microstructure and cyclic life. i.e., number of cycles to failure of the 304LN grade austenitic stainless steel at an elevated temperature. The strain-controlled low cycle fatigue and creep-fatigue interaction tests were carried out in air at 540 °C for constant total strain amplitude levels of ± 0.5 % and ± 0.7 %. The duration of hold-time was maintained at a constant level of 600 s at peak tensile, compressive and both peak tensile-compressive strain during different creep-fatigue interaction tests. Due to incorporation of creep damage, the cyclic life of the creep-fatigue interaction-tested samples has been found to be lower than that of the low cycle fatigue-tested samples. The tensile-hold appears to have maximum impact on reduction in cyclic life during creep-fatigue interaction tests followed by tension-compression hold and compressive hold. The scanning electron microscopy and electron back scattered diffraction analyses of creep-fatigue interaction-tested samples have revealed that the grain size coarsening, reduction in twin boundary fraction and increase in average Kernel Average Misorientation are the key factors in reduction of cyclic life.

Forecasting the solar modulation potential: Tests of time series models

This study analyzes the predictability of the solar modulation potential using time series models. Recently, new data sets for the modulation potential have become available, at daily, monthly, and annual resolutions. At lower frequencies, the data show the well-known 11-22-year cycle. Both the periodicity and amplitude vary over time. At higher resolutions, the probability distribution has heavy tails, while the data show the intermittent outliers characteristic of multifractal processes. Forecasting experiments are run using regressions in levels and differences, frequency domain methods, models with sinusoidal terms and neural networks. For the daily data, all the models achieve high degrees of accuracy at proximate horizons. As the horizon extends, accuracy falls away rapidly. At 27 days, corresponding to one solar rotation, a transfer function in differences achieves a more accurate forecast than either regressions or neural nets, since it is able to replicate the range of the data. At the annual resolution, both the regression and neural net predict well at horizons of 1 year. Again, forecast accuracy deteriorates sharply as the forecast horizon extends. At the monthly resolution, forecasting is problematic. The resolution is not low enough to bring out the low frequency cycles, but there is so much short-term dependence that the data are completely dominated by serial correlation. Any model incorporating proximate lags will generate inertial forecasts. Any model using lower frequency cyclical terms will be unable to pick up on near-term patterns. The forecasting skill of time series models appears limited to short horizons. The recommendation for forecasting over longer intervals is some combination of physics and statistical models.

Pressure Support Ventilation During Extracorporeal Membrane Oxygenation Support in Patients With Acute Respiratory Distress Syndrome.

In the initial phases of veno-venous extracorporeal membrane oxygenation (VV ECMO) support for severe acute respiratory distress syndrome (ARDS), ultraprotective controlled mechanical ventilation (CMV) is typically employed to limit the progression of lung injury. As patients recover, transitioning to assisted mechanical ventilation can be considered to reduce the need for prolonged sedation and paralysis. This study aimed to evaluate the feasibility of transitioning to pressure support ventilation (PSV) during VV ECMO and to explore variations in respiratory mechanics and oxygenation parameters following the transition to PSV. This retrospective monocentric study included 191 adult ARDS patients treated with VV ECMO between 2009 and 2022. Within this population, 131 (69%) patients were successfully switched to PSV during ECMO. Pressure support ventilation was associated with an increase in respiratory system compliance (p = 0.02) and a reduction in pulmonary shunt fraction (p < 0.001). Additionally, improvements in the cardiovascular Sequential Organ Failure Assessment score and a reduction in pulmonary arterial pressures (p < 0.05) were recorded. Ninety-four percent of patients who successfully transitioned to PSV were weaned from ECMO, and 118 (90%) were discharged alive from the intensive care unit (ICU). Of those who did not reach PSV, 74% died on ECMO, whereas the remaining patients were successfully weaned from extracorporeal support. In conclusion, PSV is feasible during VV ECMO and potentially correlates with improvements in respiratory function and hemodynamics.

Predicting recurrent glioblastoma clinical outcome to immune checkpoint inhibition and low-dose bevacizumab with tumor in situ fluid circulating tumor DNA analysis

ObjectiveMost recurrent glioblastoma (rGBM) patients do not benefit from immune checkpoint inhibition, emphasizing the necessity for response biomarkers. This study evaluates whether tumor in situ fluid (TISF) circulating tumor DNA (ctDNA) could serve as a biomarker for response to low-dose bevacizumab (Bev) plus anti-PD-1 therapy in rGBM patients, aiming to enhance systemic responses to immunotherapy.MethodsIn this phase II trial, 32 GBM patients with first recurrence after standard therapy were enrolled and then received tislelizumab plus low-dose Bev each cycle. TISF samples were analyzed for ctDNA using a 551-gene panel before each treatment.ResultsThe median progression-free survival (mPFS) and overall survival (mOS) were 8.2 months (95% CI, 5.2–11.1) and 14.3 months (95% CI, 6.5–22.1), respectively. The 12-month OS was 43.8%, and the objective response rate was 56.3%. Patients with more than 20% reduction in the mutant allele fraction and tumor mutational burden after treatment were significantly associated with better prognosis compared to baseline TISF-ctDNA. Among detectable gene mutations, patients with MUC16 mutation, EGFR mutation & amplification, SRSF2 amplification, and H3F3B amplification were significantly associated with worse prognosis.ConclusionsLow-dose Bev plus anti-PD-1 therapy significantly improves OS in rGBM patients, offering guiding significance for future individualized treatment strategies. TISF-ctDNA can monitor rGBM patients' response to combination therapy and guide treatment.Clinical trial registrationThis trial is registered with ClinicalTrials.gov, NCT05540275.

An altered cell-specific subcellular distribution of translesion synthesis DNA polymerase kappa (POLK) in aging neurons.

Genomic stability is critical for cellular function, however, in the central nervous system highly metabolically active differentiated neurons are challenged to maintain their genome over the organismal lifespan without replication. DNA damage in neurons increases with chronological age and accelerates in neurodegenerative disorders, resulting in cellular and systemic dysregulation. Distinct DNA damage response strategies have evolved with a host of polymerases. The Y-family translesion synthesis (TLS) polymerases are well known for bypassing and repairing damaged DNA in dividing cells. However, their expression, dynamics, and role if any, in enduring postmitotic differentiated neurons of the brain are completely unknown. We show through systematic longitudinal studies for the first time that DNA polymerase kappa (POLK), a member of the Y-family polymerases, is highly expressed in neurons. With chronological age, there is a progressive and significant reduction of nuclear POLK with a concomitant accumulation in the cytoplasm that is predictive of brain tissue age. The reduction of nuclear POLK in old brains is congruent with an increase in DNA damage markers. The nuclear POLK colocalizes with damaged sites and DNA repair proteins. The cytoplasmic POLK accumulates with stress granules and endo/lysosomal markers. Nuclear POLK expression is significantly higher in GABAergic interneurons compared to excitatory pyramidal neurons and lowest in non-neurons, possibly reflective of the inherent biological differences such as firing rates and neuronal activity. Interneurons associated with microglia have significantly higher levels of cytoplasmic POLK in old age. Finally, we show that neuronal activity itself can lead to an increase in nuclear POLK levels and a reduction of the cytoplasmic fraction. Our findings open a new avenue in understanding how different classes of postmitotic neurons deploy TLS polymerase(s) to maintain their genomic integrity over time, which will help design strategies for longevity, healthspan, and prevention of neurodegeneration.

Abstract Mo014: Cardioactive molecules identified by functional in vivo screening prevent anthracycline cardiotoxicity

Introduction: Promotion of cardiomyocyte survival upon insult is mandatory to allow maintenance of ventricular function and dam development of severe heart dysfunction. Recently, through an in vivo functional screening of the mouse secretome we identified potent mediators of cardiomyocyte survival among 1200 soluble factors expressed by AAV vectors. The cardiac overexpression of the most effective cytokines (Chrdl1, Fam3c and Fam3b) maintained cardiac function after myocardial infarction by blunting oxidative damage, decreasing cell death, promoting autophagy, and inhibiting myofibroblast activation (Ruozi, Bortolotti et al. 2022. Sci Transl Med 14, eabo0699) Aim: We investigated the effect of cardioactive proteins in a mouse anthracycline model of cardiotoxicity. Material and Methods: Mimicking clinical chronic therapeutic regimens, doxorubicin (24 mg/kg) was administered to C57/BL6 female mice one week after AAV9-driven cardiac overexpression of Chrdl1, Fam3b or Fam3c. Echocardiography was performed after 6 and 8 weeks and was followed by histology and molecular analysis. Apoptosis, autophagy and mitochondrial function was analysed in primary cardiomyocytes along with pathway investigation. Results: AAV9-mediated overexpression of Chrdl1, Fam3b and Fam3c markedly improved animal survival. Echocardiographic assessment revealed significant reduction of left ventricular ejection fraction and marked heart dilatation in control animals, while all treated animals maintained functional and anatomical parameters. Treated mice showed normal cardiac mass and cardiomyocyte cross-sectional area, reduced interstitial collagen deposition and decreased expression of profibrotic genes. In both rodents and human cardiomyocytes, Chrdl1, Fam3b and Fam3c factors decreased doxorubicin induced apoptosis, induced protective macroautophagy and preserved mitochondrial morphology. Chrdl1 prevented doxorubicin-mediated BMP upregulation and autophagy engulfment through the inhibition of a detrimental molecular pathway downstream the BMP receptor. Conclusions: The development of biotherapeutics that act as pro-survival factors for cardiomyocytes offers significant translational perspectives in cardio-oncology.

Abstract Mo002: Pharmacological Inhibition of p38 MAPK Attenuates Doxorubicin-induced Cardiotoxicity, Senescence, and Inflammation in C57BL/6 mice

Introduction: Doxorubicin (DOX)-induced cardiotoxicity has been associated with induction of senescence, inflammation, and activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Losmapimod (LOSM), an orally active p38 MAPK inhibitor, is an anti-inflammatory agent with cardioprotective effects. Nevertheless, the effect of LOSM against DOX-induced cardiotoxicity has not been reported. The objective of the current work is to determine the effects of LOSM on DOX-induced chronic cardiotoxicity in C57BL/6 mice with particular focus on senescence and inflammatory pathways. Methods: Five-week-old C57BL/6 mice were fed diet containing LOSM (estimated daily intake 12 mg/kg/day) or a control diet for four days. Thereafter, mice were randomized to receive six weekly intraperitoneal injections of either DOX (4 mg/kg/week for 6 weeks) or saline. Three days after the last injection, cardiac function was assessed by trans-thoracic echocardiography. Gene expressions of senescence and inflammatory markers were quantified using real-time PCR and serum inflammatory markers were assessed by Luminex. Results: LOSM ameliorated DOX-induced cardiac dysfunction as evidenced by mitigated DOX-induced reduction in left ventricular fraction and fractional shortening. Notably, LOSM attenuating DOX-induced upregulation of p21 Cip1 , a marker of senescence, in the heart and the liver. Additionally, LOSM demonstrated anti-inflammatory effects, with reduced cardiac interleukin-1α and interleuken-6 gene expression in DOX-treated mice suggesting a senomorphic effect of LOSM. Systemic inflammation, assessed by serum cytokine levels, showed decreased interleukin-6 concentration in both DOX-treated mice and LOSM-treated mice. Conclusion: This is the first study to determine the effect of pharmacological inhibition of p38 MAPK against DOX-induced cardiotoxicity in vivo. Our study underscores the potential therapeutic efficacy of p38 MAPK inhibition in ameliorating DOX-induced cardiotoxicity, offering insights into novel strategies for mitigating chemotherapy-related cardiac complications, and suggesting a possible senomorphic effects of losmapimod.

Abstract We064: Investigating the Cardioprotective Role of Neutrophil-Specific STING in Myocardial Ischemia/Reperfusion Injury

Introduction: Inflammation following myocardial ischemia/reperfusion injury (MI/R) plays a significant role in damaging cardiomyocytes and influencing infarct size, with neutrophils being the most rapid and numerous cells recruited to the myocardium post reperfusion. Single-cell RNA sequencing data identified neutrophils with upregulated type I interferon (IFN) signaling in the hearts of mice 24 hours post-MI/R. Aim: This study aims to address how the type I IFN neutrophil phenotype identified affects inflammation in MI/R. We hypothesize that neutrophils with upregulated type I IFN signaling are cardioprotective in MI/R. Methods: Male neutrophil-specific STING knockout (KO) mice underwent 60 minutes of ischemia followed by reperfusion for 24 hours. Immune cells were isolated from the left ventricle for flow cytometry. Subsequently, mice underwent 60 minutes of ischemia followed by reperfusion, and cardiac function was assessed two weeks-post reperfusion. Results: Flow cytometry revealed a significant decrease in the number of neutrophils in the myocardium of neutrophil-specific STING KO mice compared to wildtype mice after 24 hours of reperfusion (5.7x10 4 ± 1.0x10 4 ; 8.7x10 4 ± 1.9x10 4 , Two-way ANOVA, N=5-6, p=0.0006). Neutrophil-specific STING KO mice showed significant reduction in ejection fraction (29.2% ± 6.4) compared to wildtype mice (38.3% ± 6.7; Two-way ANOVA, N=4-5, p=0.036), and significantly increased left ventricular end systolic volume (4.39mm ± 0.48) compared to wildtype mice (3.59 ± 0.62; Two-way ANOVA, N=4-5, p=0.017), indicating impaired cardiac function in knockout mice. Conclusion: These data suggest that neutrophil STING plays a cardioprotective role in MI/R. These studies provide the foundation to further investigate the cardioprotective mechanisms behind neutrophil-specific STING. Identifying a novel cardioprotective mechanism could be a clinically feasible point of intervention to improve recovery after MI/R.

Abstract We144: Fto Deficiency Causes Cardiac Dysfunction by Altering Expression of Serca2a mRNA

Introduction and Research Question: The impact of post-transcriptional regulation of gene expression, including N6-methyladenosine (m6A) messenger RNA methylation, on cardiac function has not yet been fully understood. Our study found that the absence of the m6A eraser, Fat mass and obesity-associated protein (Fto), in cardiomyocytes of adult mice led to cardiac dysfunction and cardiac hypertrophy. Methods and Results: To evaluate Fto physiological functions, we generated a tamoxifen-inducible cardiac-specific Fto knockout mouse model (Fto cKO). This resulted in a substantial reduction of Fto at both mRNA and protein levels in the whole heart, leading to an almost complete absence of Fto within cardiomyocytes. Echocardiography analyses showed that Fto cKO mice exhibit impaired cardiac functions, indicated by a 30% reduction in ejection fraction and 40% decrease in fractional shortening after one month of deletion of cardiac Fto ( p&lt;0.01 ). We found a significant increase in heart weight to body weight ratios in Fto cKO animals ( p&lt;0.05 ). This result corresponded with an increased expression of hypertrophic markers including Nppb and Myh7 mRNA in the absence of Fto ( p&lt;0.01 ). We noted an increase in the length of Fto cKO cardiomyocytes ( p&lt;0.05 ) in isolated cardiomyocytes, a characteristic feature of eccentric pathologic hypertrophy. Electron microscopy analysis of intact hearts showed ultrastructure abnormalities in cardiomyocytes from Fto cKO mice including Z-line density loss and disarray in cristae alignment of mitochondria. Moreover, cardiomyocytes from Fto cKO mice demonstrated defects in sarcomeric shortening including a prolongation of time to 90% peak, time to 90% rest, and decay time constant of relaxation for sarcomere shortening ( p&lt;0.001 ), compared to control mice. Mechanistically, we found down-regulation of Serca2a and Ryr2 mRNA in cardiomyocytes lacking Fto. We further demonstrated that Fto binds Serca2a mRNA and controls its cytoplasmic-nuclear shuttling. Fto deficiency led to accumulation of Serca2a mRNA in the nucleus. Conclusion: These findings suggest that Fto plays a pivotal role as a crucial regulator for cardiac function. Consequently, our results unveil a significant and novel mechanism through which Fto-dependent regulation contributes to the preservation of cardiac homeostasis.

High-sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent anthracycline cardiotoxicity: the Cardiac CARE RCT

Background Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by rises in plasma cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. Methods In a multicentre prospective randomised open-label blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent plasma high-sensitivity cardiac troponin concentration monitoring and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Randomised controlled trial – patients at high risk of cardiotoxicity (plasma cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomised to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary end point was 6-month change in left ventricular ejection fraction. Prognostic cohort study – in low-risk non-randomised patients with plasma cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in left ventricular ejection fraction (± 2%). Results Between October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomised to cardioprotection (n = 29) or standard care (n = 28) had mean left ventricular ejection fractions of 65.7 ± 6.6% and 64.9 ± 5.9%, respectively, at 6 months. Twenty patients (68.9%) were adherent to cardioprotection therapy at 6 months. Adverse events were more commonly reported in the cardioprotection group, with 71.4% of patients having at least one adverse event compared with 12.7% non-randomised and 10.3% standard care patients. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean percentage-point difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was –0.4% (95% confidence interval –3.59 to 2.85%; p = 0.82). In low-risk non-randomised patients, baseline and 6-month left ventricular ejection fractions were 69.3 ± 5.7% and 66.4 ± 6.3%, respectively (estimated mean difference 2.9%, 95% confidence interval 1.45 to 4.28%; p = 0.92, not equivalent). The main secondary objective of demonstrating zero percentage-point change with equivalence of ± 2% was not met. Conclusions Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment plasma cardiac troponin I concentrations. Low-risk non-randomised patients had similar modest declines in left ventricular ejection fraction, suggesting that the clinical utility of routine cardiac troponin monitoring remains undefined. The modest short-term declines in left ventricular ejection fraction suggest that early cardioprotection therapy has a limited role in patients receiving anthracycline-based chemotherapy. Limitations Treatment effect might have been influenced by several patients stopping cardioprotection treatment within 2 months of randomisation. Across all groups, reduction in left ventricular ejection fraction was lower than expected and patients with high-risk cardiac troponin I concentrations did not exhibit a greater fall in left ventricular ejection fraction than low-risk patients. These factors, together with the trial being powered to detect a 5-percentage-point change in left ventricular ejection fraction, mean that a small treatment effect was not excluded. Future work Future work should aim to understand the transition from small changes in cardiac function, 6 months after completion of anthracycline chemotherapy, to the late development of heart failure in this population. Trial registration This trial is registered as ISRCTN24439460 and EudraCT 2017-000896-99. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/48/20) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.

Predicting factors for omitting beta-blockers in patients with tachycardia-induced cardiomyopathy after successful catheter ablation for atrial fibrillation.

Tachycardia induces a reduction in the left ventricular ejection fraction (LVEF), which is defined as tachycardia-induced cardiomyopathy (TIC). Conversion to and maintenance of sinus rhythm by catheter ablation can improve LVEF in patients with TIC due to atrial fibrillation (AF). Beta-blockers are mandatory for the treatment of heart failure with reduced LVEF(HFrEF), but the necessity of beta-blockers in TIC patients even after catheter ablation remains unclear. We examined the effect of beta-blockers on cardiac function in TIC patients after catheter ablation. We retrospectively analyzed 124 patients with a history of heart failure and an LVEF of ≤ 50% who underwent catheter ablation for AF. TIC was defined as a ≥ 10% improvement in the baseline LVEF and an improvement to an LVEF of ≥ 50% at 6months after ablation. Patients with other cardiomyopathy diagnosed before the ablation were excluded. LVEF was significantly increased with the reductions of the left ventricular and left atrial volumes at the 6-month follow-up in all 80 patients with TIC. No beta-blockers were prescribed during the post-ablation follow-up in 21 patients with TIC. The absolute values of and changes in the echocardiographic parameters between before and after ablation were not significantly different between patients with and without beta-blockers after the ablation. A simple score using the history of hospitalization for heart failure and use of beta-blockers or diuretics prior to ablation was useful in identifying TIC patients who did not need prescription of beta-blockers after catheter ablation. LVEF similarly improved in both patients with and without prescription of beta-blockers after the ablation. Beta-blockers may not need to be prescribed after successful catheter ablation for AF in LVEF of ≤ 50% patients without other cause of cardiomyopathy diagnosed before the ablation, a history of hospitalization for heart failure and prescription of beta-blockers and diuretics before the ablation.

Chemical fractionation of heavy metals and zinc isotope source identification in sediments of the Huangpu River, Shanghai, China

BackgroundThe Huangpu River serves as a vital water source for around 24 million individuals residing in the metropolitan area of Shanghai. Despite this, elevated levels of heavy metals persist in the sediments of the river, with their chemical fractionation and sources remaining inadequately understood.ResultsTo improve the management of heavy metal contamination, sequential extractions and zinc (Zn) isotopic compositions were utilized to evaluate pollution levels in the Huangpu River. The findings reveal that the majority of heavy metals in the river sediments are present in residual fractions, constituting an average of 67.5% for Cd, 57.6% for Cu, 60.6% for Ni, 56.2% for Pb, and 74.4% for Cr, with the exception of Zn (33.8%). Furthermore, a substantial portion of Zn, exceeding 66%, was found in acid-exchangeable, reducible, and oxidizable fractions, indicating a high potential for Zn release into aquatic ecosystems.ConclusionFurther analysis of Zn isotopes pinpointed traffic emissions, including exhaust fumes and tire wear particles (account for ~ 34.0%), along with anthropogenic emissions and fertilizer (~ 31.7%), as the major culprits behind this contamination. These findings highlight the critical need for stricter regulations to control heavy metal contamination from traffic and domestic sources within the Huangpu River basin.

Extremal functions for twisted sharp Sobolev inequalities with lower order remainder terms. The high-dimensional case

Abstract We prove existence of extremal functions and compactness of the set of extremal functions for twisted sharp 𝑛-dimensional Sobolev inequalities with lower order remainder terms when n ≥ 5 n\geq 5 .

Precipitate Dissolution and Grain Growth during Solution Treatment of Ce‐Containing 15Cr–22Ni–1Nb Austenitic Heat‐Resistant Steel

The precipitate dissolution and grain growth during the solution treatment of a newly developed Ce‐containing 15Cr–22Ni–1Nb steel are investigated. The dissolution of eutectic NbC is the result of the elements diffusion along the concentration gradients, and honeycomb (Fe,Cr,Ni,Si)2(Nb,Mo) Laves phase transforms into a more stable Mo2C‐type M2C carbide. As the cerium content is increased from 0 to 0.0630 mass%, the area fraction of eutectic precipitates in forged and solution‐treated 15Cr–22Ni steel is decreased first and then increased. For the steel with 0.0055 mass% cerium content, the substantial reduction in the area fraction of precipitates during hot forging and solution treatment is ascribed to the severe abnormal grain growth. In the case of 15Cr–22Ni steel with 0.0019 and 0.0630 mass% cerium content, the average size of austenite grains after solution treatment is reduced, the multipeak development of grain size distribution is restrained, the range of grain size distribution is narrowed, and the variation coefficient of grain growth, the critical size of abnormally grown grain, and the proportion of abnormally grown grain are all decreased. The variation coefficient of grain growth and the critical size of abnormally grown grain in the steel are increased as the solution time is extended, whereas the proportion of abnormally grown grain presents a general trend of reduction. The established mathematical model of grain growth in the paper can be well applied to predict and control the average size of austenite grains in 15Cr–22Ni steel after solution treatment.

Neoadjuvant inetetamab and pertuzumab with taxanes and carboplatin (TCbIP) In locally advanced HER2-positive breast cancer: a prospective cohort study with propensity-matched analysis

BackgroundInetetamab is the first domestically developed innovative anti-HER2 monoclonal antibody in China, proven effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remain to be validated.MethodsThis prospective cohort study aimed to evaluate the efficacy and safety of inetetamab combined with pertuzumab, taxanes, and carboplatin (TCbIP) in neoadjuvant therapy for HER2-positive LABC, comparing it to data from patients treated with the TCbHP regimen (trastuzumab combined with pertuzumab, taxanes, and carboplatin) using propensity score matching (PSM). The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints.ResultsForty-four patients with clinical stage IIA-IIIC HER2-positive LABC were prospectively enrolled and treated with the TCbIP regimen. The tpCR rate among 28 patients who completed surgery was 60.7%, comparable to and slightly higher than the TCbHP group in PSM (60.7% vs. 53.6%, P = 0.510). The ORR was 96.4%, and the DCR reached 100.0%. The most common ≥ grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs.ConclusionNeoadjuvant therapy with TCbIP showed good efficacy and safety in patients with HER2-positive LABC and might be another promising option for neoadjuvant treatment.Trial registrationNCT05749016 (registration date: Nov 01, 2021).