Individual Tolerance Research Articles

Pedicle screw path planning for multi-level vertebral fixation.

For the spinal internal fixation procedures, connecting rods to the pedicle screws are commonly used in all spinal segments from the cervical to sacral spine. So far, we have only seen single vertebral screw trajectory planning methods in literatures. Joint screw placements in multi-level vertebrae with the constraint of an ipsilateral connecting rod are not considered. In this paper, a screw trajectory planning method that considers screw-rod joint system with both multi-level vertebral constraints and individual vertebral safety tolerance areproposed. The proposed method addresses three challenging constraints jointly for multi-level vertebral fixation with pedicle screws. First, a cylindrical screw safe passage model is suggested instead of a unique mathematical optimal trajectory for a single pedicle. Second, the flexible screw cap accessibility model is also included. Third, the connecting rod is modeled to accommodate the spine contour and support the needed gripping capacity. The retrospective clinical data of relative normal shape spines from Beijing Jishuitan hospital were used in the testing. The screw trajectories from the existing methods based on single vertebra and the proposed method based on multi-level vertebrae optimization are calculated andcompared. The results showed that the calculated screw placements by the proposed method can achieve 88% success rate without breaking the pedicle cortex and 100% in clinical class A quality (allow less than 2mm out of the pedicle cortex) compared to 86.1% and 99.1%, respectively, with the existing methods. Expert evaluation showed that the screw path trajectories and the connecting rod calculated by the new method satisfied the clinical implantationrequirements. The new screw planning approach that seeks an overall optimization for multi-level vertebral fixation is feasible and more advantageous for clinical use than the single vertebral approaches.

The utility of heart rate and heart rate variability to identify limits of tolerance to moderate-intensity work in the heat: a secondary analysis.

We investigated the utility of heart rate (HR) and heart rate variability (HRV) for identifying individuals who may terminate work early due to excessive heat strain. Forty-eight men and women (median=36 years; Q1=20 years; Q3=54 years) attempted 180 min of moderate-intensity work at a fixed metabolic rate (∼200W/m2; ∼3.5 METs) in a hot environment (wet-bulb globe temperature: 32 °C). Receiver operating characteristics (ROC) curves were used to identify the ability of indices of HR (absolute HR, percentage of maximum HR, percentage of HR reserve) and HRV (root-mean-square of successive differences (RMSSD), high-frequency power, and detrended fluctuation analysis component alpha 1 (DFA α1)) to discriminate between participants who completed the 180 min work bout or terminated prematurely. Participants who terminated work prematurely (n=26) exhibited higher HR and percentage of HR measures, as well as reduced RMSSD and DFA α1 after the first hour of work compared to participants who completed the bout. The discriminative utility of HR and HRV indices was strongest within the first hour of work, with percentage of HR reserve demonstrating excellent discriminative power (ROC area under curve (AUC) of 0.8). Stratifying participants by age and sex improved ROC AUC point estimates for most indices, particularly in female participants. The study provides preliminary evidence supporting the use of noninvasive cardiac monitoring for predicting work tolerance in healthy individuals exposed to occupational heat stress. HR and percentage of HR reserve were suggested to discriminate work termination most effectively. Further investigations are warranted to explore the influence of individual factors and refine the discriminative thresholds for early identification of excessive occupational heat strain.

Склонность к риску при решении социальной дилеммы в условиях коллективного взаимодействия

An important role in decision-making is taking a risk, which can direct a person towards one of a number of alternatives. Research involving the study of risk-taking in the context of social dilemmas considers cooperation or non-cooperation as possible decision-making options. A classic example of this choice is the decision-making process in the context of the "Prisoner's Dilemma". The choice between cooperating or not cooperating is characterized by risk, since such decisions have uncertain consequences. Despite the widespread popularity of the "Prisoner's Dilemma," the influence of the factor of collective interaction on an individual's behavior in this context has not been sufficiently studied. The aim of this research is to investigate attitudes towards risk taking in solving social dilemmas, taking into account the process of social interaction. The research methods used were the "Iterated prisoner's dilemma", including a stage of socialization through the formation of small social groups, and economic games to identify emotional and cognitive indicators of attitudes of risks in conditions of uncertainty. The analyzed sample consisted of 124 individuals aged 18 to 36 years (M = 20.39, SD = 2.80), of whom, 100 were female (80.65%), and 24 were male (19.35%). The results of the study did not demonstrate a connection between risk-taking and decisionmaking in solving social dilemmas in collective action. However, there was a slight increase in risk tolerance in individuals who chose defection in most rounds prior to socialization. This indicates the need for anticipating the future decisions of others in order to maximize rewards. An additional analysis was also conducted on a female sample, which confirmed the existence of gender-specificity in solving a social dilemma under conditions of collective interaction.

Mutual Fund Investment Strategies for Retail Investors: An Empirical Study in the Light of Market Movements

Mutual fund investment strategies provide retail investors with diversified and professionally managed portfolios, making them an attractive option for wealth accumulation. One popular approach is index investing, where funds track a market index, aiming to replicate its returns. This strategy offers low costs and broad exposure. On the other hand, active management involves fund managers making investment decisions to outperform the market. While potentially yielding higher returns, it comes with higher fees. Asset allocation is another key strategy, where investors diversify their holdings across various asset classes like stocks, bonds, and commodities. This helps manage risk and optimize returns based on individual risk tolerance and financial goals. For those seeking stability, income funds focus on generating regular dividends, suited for conservative investors. In contrast, growth funds target capital appreciation by investing in companies with high growth potential. Careful consideration of these strategies, aligned with one's financial objectives and risk appetite, is essential for retail investors to make informed mutual fund choices.

ЭФФЕКТИВНОСТЬ ПРИМЕНЕНИЯ МЕТОДОВ КОЛЛАПСОТЕРАПИИ В КОМПЛЕКСНОМ ЛЕЧЕНИИ БОЛЬНЫХ ТУБЕРКУЛЕЗОМ ЛЕГКИХ С ЛЕКАРСТВЕННОЙ УСТОЙЧИВОСТЬЮ ВОЗБУДИТЕЛЯ

Objective: to evaluate effectiveness of collapse therapies – artificial pneumoperitoneum (APP) and valve bronchial blockage (VBB) – in the complex treatment of pulmonary TB patients with drug resistance. Materials and methods. We carried out a retrospective analysis of case records of pulmonary TB patients admitted to hospital in 2014–2023. The patients were divided into two groups: group 1 included 181 patients with destructive pulmonary TB and multiple/ extensive drug resistance (MDR/XDR), they received chemotherapy complemented by APP and VBB; group 2 included 84 patients with destructive pulmonary TB and MDR/XDR, they received chemotherapy alone due to different impartial reasons. Chemotherapy regimens for MDR/XDR TB considered individual drug tolerance during the whole observation period. Results. After two months of treatment sputum conversion confirmed by microscopy and cultural studies was observed in 72.9% of group 1 and 57.1% of group 2 (p = 0,01), cavity closure confirmed by X-ray examinations was observed more frequently in group 1 than group 2 (65.7 vs 39.3% respectively, p < 0.001). Additional applications of VBB enabled to increase the incidence of cavity closure in group 1 vs group 2 (71.3 and 54.8%, respectively, p = 0.01). Conclusion. The results demonstrated that applications of collapse therapies in the complex treatment of pulmonary TB patients with MDR/XDR improved treatment effectiveness as confirmed by sputum conversion and cavity closure vs chemotherapy alone.

Discrimination of polysorbate 20 by high-performance liquid chromatography-charged aerosol detection and characterization for components by expanding compound database and library

Analyzing polysorbate 20 (PS20) composition and the impact of each component on stability and safety is crucial due to formulation variations and individual tolerance. The similar structures and polarities of PS20 components make accurate separation, identification, and quantification challenging. In this work, a high-resolution quantitative method was developed using single-dimensional high-performance liquid chromatography (HPLC) with charged aerosol detection (CAD) to separate 18 key components with multiple esters. The separated components were characterized by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) with an identical gradient as the HPLC-CAD analysis. The polysorbate compound database and library were expanded over 7-time compared to the commercial database. The method investigated differences in PS20 samples from various origins and grades for different dosage forms to evaluate the composition-process relationship. UHPLC-Q-TOF-MS identified 1329 to 1511 compounds in 4 batches of PS20 from different sources. The method observed the impact of 4 degradation conditions on peak components, identifying stable components and their tendencies to change. HPLC-CAD and UHPLC-Q-TOF-MS results provided insights into fingerprint differences, distinguishing quasi products.

NLRs and inflammasome signaling in opioid-induced hyperalgesia and tolerance.

We investigated the role that innate immunological signaling pathways, principally nod-like receptors (NLRs) and inflammasomes, in the manifestation of the contradictory outcomes associated with opioids, namely hyperalgesia, and tolerance. The utilization of opioids for pain management is prevalent; nonetheless, it frequently leads to an increased sensitivity to pain (hyperalgesia) and reduced efficacy of the medication (tolerance) over an extended period. This, therefore, represents a major challenge in the area of chronic pain treatment. Recent studies indicate that the aforementioned negative consequences are partially influenced by the stimulation of NLRs, specifically the NLRP3 inflammasome, and thesubsequent assembly of the inflammasome. This process ultimately results in the generation of inflammatory cytokines and the occurrence of neuroinflammation and the pathogenesis of hyperalgesia. We also explored the putative downstream signaling cascades activated by NOD-like receptors (NLRs) and inflammasomes in response to opioid stimuli. Furthermore, we probed potential therapeutic targets for modifying opioid-induced hyperalgesia, with explicit emphasis on the activation of the NLRP3 inflammasome. Ultimately, our findings underscore the significance of conducting additional research in this area that includes an examination of the involvement of various NLRs, immune cells, and genetic variables in the development of opioid-induced hyperalgesia and tolerance. The present review provides substantial insight into the possible pathways contributing to the occurrence of hyperalgesia and tolerance in individuals taking opioids.

Research on the Pension Investment and Asset Management

The study explored how to develop a pension investment portfolio and analyzed solutions for special cases. We first reviewed the global context of pension investment and emphasized the crucial role of pension in financial planning. Subsequently, we specifically analyzed the "firefighter case" and decided whether to choose "one-time payment" or "fixed benefits". Finally, specific results were provided and some suggestions were given. In addition, we emphasize the importance of individual risk tolerance and investment goals in formulating investment strategies to ensure that investment portfolios match individual needs. Through the guidance of this study, investors can learn how to manage their pension investments and achieve long-term financial security and robust retirement plans. The diversity and effective management of pension investment portfolios are crucial for the success of pensions, and this is worthy of careful consideration and action by every investor.

STABILOMETRIC ANALYSIS OF MOTOR DISORDERS IN PATIENTS WITH ISCHEMIC STROKE IN THE CAROTID ARTERY IN THE EARLY REHABILITATION PERIOD

The purpose of the study is to analyze stabilometric parameters for motor disorders in patients with an ischemic stroke in the carotid artery in the early rehabilitation period and to monitor their dynamics under rehabilitation therapy with biofeedback (BFB) stabilization training.
 Materials and Methods. The study involved 24 patients aged 44–75. We chose the patients with mild and moderate motor impairments who were at the second stage of medical rehabilitation at Bryansk City Hospital No. 1. The patients suffered stroke 1–6 months ago. The stabilographic study was carried out on a BFB stabiloanalyzer “Stabilan-01-2” (RITM, Taganrog). The stabilometric training consisted of 7–10 sessions and included various computer games taking into account the type of paresis, the severity of coordination disorders and individual load tolerance. At the beginning of therapy, training lasted 5–10 minutes but gradually it increased up to 15–20 minutes. MS EXCEL and IBM Statistica 12.0 were used for statistical analysis of the obtained data. The Wilcoxon test was used to assess the dynamics. All obtained differences were significant (p≤0.05).
 Results. During the study, a change in stabilometric parameters was noted towards a decrease in the main parameters of the stabilographic test (“Frontal spread” (p=0.049), “Mean spread” (p=0.045)) and the Romberg test (“Mean spread” with eyes closed (p=0.046) and “Time rate of statokinesigram area” with eyes closed (p=0.043)), which indicated an improvement in the patients’ motor skills during rehabilitation therapy.
 Conclusions. The results of the analysis allow us to consider stabilization training with biofeedback an effective treatment modality in the early rehabilitation period for patients with ischemic stroke in the carotid artery.

Predictors of treatment switching in the Big Multiple Sclerosis Data Network.

Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods. The objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry. In this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect. Every one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio [aHR] 1.08; 95% CI 1.07-1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08-1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48-2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79-8.41; reference = 1996-2006). Switching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices.

The combined effects of acidification and acute warming on the embryos of Pacific herring (Clupea pallasii)

Anthropogenic climate change is projected to affect marine ecosystems by challenging the environmental tolerance of individuals. Marine fishes may be particularly vulnerable to emergent climate stressors during early life stages. Here we focus on embryos of Pacific herring (Clupea pallasii), an important forage fish species widely distributed across the North Pacific. Embryos were reared under a range of temperatures (10-16°C) crossed with two pCO2 levels (600 and 2000 μatm) to investigate effects on metabolism and survival. We further tested how elevated pCO2 affects critical thermal tolerance (CTmax) by challenging embryos to short-term temperature fluctuations. Experiments were repeated on embryos collected from winter and spring spawning populations to determine if spawning phenology corresponds with different limits of environmental tolerance in offspring. We found that embryos could withstand acute exposure to 20°C regardless of spawning population or incubation treatment, but that survival was greatly reduced after 2-3 hours at 25°C. We found that pCO2 had limited effects on CTmax. The survival of embryos reared under chronically warm conditions (12°, 14°, or 16°C) was significantly lower relative to 10°C treatments in both populations. Oxygen consumption rates (MO2) were also higher at elevated temperatures and pCO2 levels. However, heart contraction measurements made 48 hours after CTmax exposure revealed a greater increase in heart rate in embryos reared at 10°C compared to 16°C, suggesting acclimation at higher incubation temperatures. Our results indicate that Pacific herring are generally tolerant of pCO2 but are vulnerable to acute temperature stress. Importantly, spring-spawning embryos did not clearly exhibit a higher tolerance to heat stress compared to winter offspring.

How Demographics and General Economic Mood Affect Investor Risk Tolerance?

Investment decisions made ​​by investors are strongly influenced by their risk tolerance. Individual risk tolerance will influence their asset allocation decision. This paper used primary data to examine the factors influencing investor risk tolerance. Two factors considered in this study are demographics and general economic mood. Demographic characteristics include gender, occupation, age, marital status, income, and education. General economic mood is people's perceptions about the prospects for a country's economy at present and in the future. Using convenience sampling, we distributed questionnaires to investors in the Indonesia Stock Exchange and senior students. The total number of data used in this research is 200 respondents. This research found that the general economic mood, gender, and occupation positively impact investor risk tolerance. In contrast, our research found the negative impact of education and average monthly income on investors' risk tolerance. Further, age and marital status do not affect the investor's risk tolerance. This finding is important for financial planners to advise on personal investment decisions.

Genomic predictions and GWAS for heat tolerance in pigs based on reaction norm models with performance records and data from public weather stations considering alternative temperature thresholds.

Genetic improvement of livestock productivity has resulted in greater production of metabolic heat and potentially greater susceptibility to heat stress. Various studies have demonstrated that there is genetic variability for heat tolerance and genetic selection for more heat tolerant individuals is possible. The rate of genetic progress tends to be greater when genomic information is incorporated into the analyses as more accurate breeding values can be obtained for young individuals. Therefore, this study aimed (1) to evaluate the predictive ability of genomic breeding values for heat tolerance based on routinely recorded traits, and (2) to investigate the genetic background of heat tolerance based on single-step genome-wide association studies for economically important traits related to body composition, growth and reproduction in Large White pigs. Pedigree information was available for 265,943 animals and genotypes for 8686 animals. The studied traits included ultrasound backfat thickness (BFT), ultrasound muscle depth (MDP), piglet weaning weight (WW), off-test weight (OTW), interval between farrowing (IBF), total number of piglets born (TNB), number of piglets born alive (NBA), number of piglets born dead (NBD), number of piglets weaned (WN) and weaning-to-estrus interval (IWE). The number of phenotypic records ranged from 6059 (WN) to 172,984 (TNB). Single-step genomic reaction norm predictions were used to calculate the genomic estimated breeding values for each individual. Predictions of breeding values for the validation population individuals were compared between datasets containing phenotypic records measured in the whole range of temperatures (WR) and datasets containing only phenotypic records measured when the weather station temperature was above 10°C (10C) or 15°C (15C), to evaluate the usefulness of these datasets that may better reflect the within-barn temperature. The use of homogeneous or heterogeneous residual variance was found to be trait-dependent, where homogeneous variance presented the best fit for MDP, BFT, OTW, TNB, NBA, WN and IBF, while the other traits (WW and IWE) had better fit with heterogeneous variance. The average prediction accuracy, dispersion and bias values considering all traits for WR were 0.36 ± 0.05, -0.07 ± 0.13 and 0.76 ± 0.10, respectively; for 10C were 0.39 ± 0.02, -0.05 ± 0.07 and 0.81 ± 0.05, respectively; and for 15C were 0.32 ± 0.05, -0.05 ± 0.11 and 0.84 ± 0.10, respectively. Based on the studied traits, using phenotypic records collected when the outside temperature (from public weather stations) was above 10°C provided better predictions for most of the traits. Forty-three and 62 candidate genomic regions were associated with the intercept (overall performance level) and slope term (specific biological mechanisms related to environmental sensitivity), respectively. Our results contribute to improve genomic predictions using existing datasets and better understand the genetic background of heat tolerance in pigs. Furthermore, the genomic regions and candidate genes identified will contribute to future genomic studies and breeding applications.

Natural Protein Intake in Children with Phenylketonuria: Prescription vs. Actual Intakes

In phenylketonuria (PKU), an important component of the UK dietary management system is a 50 mg phenylalanine (Phe)/1 g protein exchange system used to allocate the Phe/natural protein intakes according to individual patient tolerance. Any foods containing protein ≤ 0.5 g/100 g or fruits/vegetables containing Phe ≤ 75 mg/100 g are allowed without measurement or limit. In children with PKU, we aimed to assess the difference between the prescribed natural protein intake and their actual consumed intake, and to calculate the natural protein/Phe intake from foods given without measurement or restriction. Over a 6-month duration, three one-day diet diaries were collected every month by caregivers of children with PKU at the beginning of a follow-up study. Dietary intakes of Phe, as well as natural and total protein intakes, were calculated using Nutritics® (v5.09). Weekly blood Phe spots were collected by caregivers. The target blood Phe level was ≤360 μmol/L for ages up to 12 years and ≤600 μmol/L for ages ≥12 years. Sixteen early treated children (69% females) with PKU were recruited. The median age was 11 years (range: 9–13), and most had classical PKU (n = 14/16). A median of 18 (range 12–18) one-day diaries and 22 blood spots were analysed for each subject over 6 months. The median prescribed natural protein was 6 g/day (range: 3–27), but when calculated, the actual median intake from all foods consumed was 10 g/day (range: 4–37). The median prescribed Phe was 300 mg/day (range: 150–1350), but the actual median intake was 500 mg/day (range: 200–1850). The median difference between the prescribed and actual natural protein daily intakes was +4 g/day (range: −2.5 to +11.5), with a median percentage increase of 40% for natural protein/Phe intake (p < 0.001). The median blood Phe level was 250 μmol/L (range 20–750), with 91% of blood Phe levels within the target range. Only one patient (11 years) had less than 75% of their blood Phe levels within the target range. The UK Phe exchange system provides flexibility in the dietary management of PKU. With this method, the actual natural protein intake was 167% higher than the prescribed amount. Although this led to a variable daily protein intake, the majority of children (n = 15/16) experienced no deterioration in their metabolic control.

Recent progress in understanding the cellular and genetic basis of plant responses to low oxygen holds promise for developing flood-resilient crops.

With recent progress in active research on flooding and hypoxia/anoxia tolerance in native and agricultural crop plants, vast knowledge has been gained on both individual tolerance mechanisms and the general mechanisms of flooding tolerance in plants. Research on carbohydrate consumption, ethanolic and lactic acid fermentation, and their regulation under stress conditions has been accompanied by investigations on aerenchyma development and the emergence of the radial oxygen loss barrier in some plant species under flooded conditions. The discovery of the oxygen-sensing mechanism in plants and unravelling the intricacies of this mechanism have boosted this very international research effort. Recent studies have highlighted the importance of oxygen availability as a signalling component during plant development. The latest developments in determining actual oxygen concentrations using minute probes and molecular sensors in tissues and even within cells have provided new insights into the intracellular effects of flooding. The information amassed during recent years has been used in the breeding of new flood-tolerant crop cultivars. With the wealth of metabolic, anatomical, and genetic information, novel holistic approaches can be used to enhance crop species and their productivity under increasing stress conditions due to climate change and the subsequent changes in the environment.

Which measures predict risk taking in a multi-stage controlled investment decision process?

We assess the ability of different risk profiling measures to predict risk taking along a multistage process that reflects individuals’ discovery of their willingness to take risks. We find that the individual willingness to take risks varies along the process, but its level is always related to a composite measure of the individual risk tolerance. Assessment of the risk tolerance cannot be substituted by a simulated experience, although the latter can improve the perception of the risk and reward potential of the investment and motivate higher risk taking. The risk tolerance measure addresses different notions of risk, but we found that the individual loss aversion is the most powerful predictor of risk taking at all stages of the discovery process. By contrast, we found that neither the self-assessed risk tolerance measures nor the investment experience are suitable for consistently predicting risk taking at different stages of the process.

Risk and Investment Value Analysis in the U.S. Airline Sector of the Stock Market

Amid the evolving global economic landscape, the U.S. airline industry has undergone significant transformations, thus raising the need for comprehensive analyses of its investment value and inherent risks. Financial health, risk management strategies, and investment potential of key players in the U.S. airline sector were assessed, namely, Southwest Airlines, American Airlines, and Singapore Airlines. The research methodology involves a thorough evaluation of the financial ratios of these airlines, their strategic initiatives such as hedging, as well as their environmental, social, and governance (ESG) risk ratings. Key metrics such as Return on Invested Capital (ROIC), the Piotroski F-Score, Altman Z-Score, and debt ratios among others form the foundation of the analysis, providing insights into their operational efficiency, financial strength, and risk profiles. The study concludes that each airline exhibits a distinct financial profile with varying levels of investment potential. The choice between investing in these airlines hinges on individual investor preferences, risk tolerance, and investment horizons. The results reveal that Southwest Airlines and Singapore Airlines present lower risk profiles, potentially appealing to conservative investors, while American Airlines could appeal to more aggressive investors due to its high potential returns, albeit at a higher risk. Meanwhile, Singapore Airlines offers a balanced profile attractive to growth-focused investors. The importance of aligning investment decisions with personal investment objectives and risk tolerance was underscored, thereby providing valuable insights for potential investors in the U.S. airline sector.

Impact of sacubitril valsartan initiation in patients with HFrEF and severe mitral regurgitation referred for percutaneous mitral repair

Abstract Background In patients with heart failure with reduced ejection fraction (HFrEF), the severity of functional mitral regurgitation (MR) is a major predictor of worsened symptoms and poor outcomes. Percutaneous MR repair has been shown to improve outcomes in HFrEF with MR. However, because MR is related to abnormal myocardial function and adverse remodeling, the optimization of guideline-directed medical therapy (GDMT) could improve loading conditions, reversal remodelling and left ventricle function and also may reduce MR severity. We sought to evaluated whether the left ventricle reverse remodeling induced by the addition of sacubitril/valsartan may reduce MR severity sufficiently to avoid need for percutaneous MR repair approach. Methods We performed a single-center, prospective assessor-blinded study to determine the reverse remodeling response of sacubitril/valsartan therapy in HFrEF patients (NYHA class II-IV) with MR evaluated for percutaneous MR repair. Echocardiographic images were assessed offline by 2 investigators blinded to both the clinical data and timing of echocardiograms. Doses of sacubitril/valsartan were optimized to individual tolerance. A clinical and echocardiographic 1 year follow-up was performed. Results Thirty-nine HFrEF patients with MR grade 3-4 were included (mean age 63 years old, 69,2% male). Optimal dose of sacubitril/valsartan was reached in 63,2% of patients. After 1-year follow-up, only 1 patient died and, as we show in Table 1, a significant improvement on NYHA functional class and NT-ProBNP values were present. Left ventricle ejection fraction improved (29.7 ± 6.7% vs 41.3 ± 13.2%; P < 0.001) and left ventricular end-diastolic and end-systolic volume indexed to body surface area decreased (123.4 ± 35.7 mL/m2 vs 98.4 ± 39.7 mL/m2; P < 0.001 and 87.7 ± 30.0 mL/m2 vs 61.9 ± 35.3 mL/m2; P < 0.001, respectively). Volumetric remodeling was associated with a reduction in the degree of mitral regurgitation (64.1% grade 3 and 35.9% grade 4 at the beginning to 28.9% grade 1, 36.8% grade 2, 21.5% grade 3 and 13.2% grade 4 after one year of follow-up; [scale from 0-4]). Conclusion The optimization of GDMT with sacubitril/valsartan induced an improvement on functional class and a beneficial reverse cardiac remodelling, with enhancement of left ventricle function and reducing MR severity, enough in 24 patients to avoid need for percutaneous MR repair. In HFrEF patients with grade 3-4 mitral regurgitation, our results reinforce importance of ensuring optimal GDMT before a percutaneous mitral valve repair approach.Table 1.Changes during follow-up.

High-Dose Targeted Radiation with 131I-Apamistamab Prior to HCT Demonstrated a Dose-Response for Durable Complete Remission in Patients with R/R AML

Background: Most older patients (pts) with relapsed or refractory (R/R) AML cannot tolerate intensive treatment and are not eligible for curative allogeneic hematopoietic cell transplant (alloHCT). 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. 131I-apamistamab led induction and conditioning can provide these pts with access to alloHCT. Methods: SIERRA (NCT02665065) was a multi-center, randomized, controlled phase 3 study comparing the efficacy of 131I-apamistamab led induction and conditioning versus physician's choice of conventional care (CC) in pts ≥55 years of age with active, R/R AML. Pts were randomized (1:1, n=153) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. Primary endpoint was durable complete remission (dCR), defined as CR ≥6 mos with or without platelet recovery (CRp). Pts not achieving CR in CC could crossover (CO) to receive 131I-apamistamab. Treatment with 131I-apamistamab was prescribed as an individualized dose for each pt following a dosimetric infusion and biodistribution analysis, with the prescribed activity of 131I set to deliver a maximum estimated radiation dose to the liver as the dose limiting organ of 24 Gy (determined as the maximum tolerable dose (MTD)) in earlier studies), thereby providing the highest dose to the diseased bone marrow and circulating leukemic cells without exceeding individual organ radiation dose tolerances. Here, we performed an analysis to determine whether a radiation dose-response relationship could be established based on either 1) administered radiation dose to liver and the rate of achieving the primary endpoint of dCR (with 95% binomial confidence intervals) or 2) dCR rate and the ratio of bone marrow/liver absorbed radiation dose as an indicator of favorable biodistribution between target/risk organ. Results: All pts receiving the therapeutic dose of 131I-apamistamab (n=66) were able to receive an alloHCT, and the primary endpoint (dCR) was achieved in 13 pts receiving 131I-apamistamab vs 0 pts in CC (p<0.0001). The median absorbed liver dose was 21.6 Gy (IQR: 21.0 - 22.8 Gy), median absorbed dose to bone marrow was 16.0 Gy (IQR: 11.5 - 22.3 Gy), and median ratio between marrow/liver dose was 0.79 (IQR: 0.52 - 1.02). Table 1 shows the distribution and rate of dCR for pts who received above or below 22 Gy administered dose to liver (24 Gy to liver was the established MTD from earlier studies, in which doses were escalated in 2 Gy increment and thus, 22 Gy represented MTD-1), and for pts stratified by marrow/liver dose ratio (higher ratio representing more favorable biodistribution). Pts with ≤22 Gy liver dose had a dCR rate of 13.5% vs. 27.6% for pts with >22 Gy liver dose, and pts with <median dose to bone marrow had a dCR rate of 12.1% vs. 27.3% for pts with ≥median estimated marrow dose. Importantly, pts with increasingly favorable biodistribution had nominally higher dCR rates of 10.0%, 20.0% and 26.9% for a marrow/liver ratio <0.6, 0.6-0.9 and >0.9, respectively, as illustrated in Figure 1. Taken together this demonstrates a radiation dose-response for the primary endpoint in this study. Overall, safety was similar across doses to the liver. Conclusion: 131I-apamistamab led induction and conditioning followed by alloHCT resulted in statistically significant improvement in dCR at 6 mos vs conventional care. A dose-response was demonstrated for pts receiving 131I-apamistamab with those receiving a liver dose closer to the MTD of 24 Gy having about twice the dCR rate compared to pts 22 Gy (MTD-1) or less. We also found pts with higher marrow/liver ratio experienced considerably higher rates of dCR which highlights the importance of maximizing the dose to target tissues, within the limits of established risk organ dose tolerances.

ОЦЕНКА ТОЛЕРАНТНОСТИ К ФИЗИЧЕСКОЙ НАГРУЗКЕ НА СТАЦИОНАРНОМ ЭТАПЕ РЕАБИЛИТАЦИИ У ЛИЦ, ПЕРЕНЕСШИХ ОСТРЫЙ КОРОНАРНЫЙ СИНДРОМ

Abstract. Introduction. It is proven that integrated cardiac rehabilitation helps reduce mortality and hospital readmission rates and improves the quality of life of patients with acute coronary syndrome experience. Key aspect of integrated cardiac rehabilitation is aerobic training contributing to higher exercise tolerance. Aim. This research aims at assessing the changes in exercise tolerance in acute coronary syndrome patients at the second stage of medical rehabilitation. Materials and Methods. The research involved 162 patients of the Department of Medical Rehabilitation of Adult Patients with Somatic Diseases, who have experienced acute coronary syndrome. To assess the patients’ exercise tolerance, we used the six-minute walk test under electrocardiography control with the Accordix system (Neurosoft, Russia) upon their admission and immediately before their discharge from the hospital. Along with drug therapy, the personalized medical rehabilitation plans included electrocardiography-controlled aerobic training, laser therapy, psychological intervention, and occupational therapy classes. Rehabilitation efficiency was assessed by six-minute walk test (m) and Functional Independence Measurement (FIM) scale (score). The findings were analyzed statistically using nonparametric criteria. Results and Discussion. There were reduced exercise tolerance and limited daily activities in a significant part of cardiological patients before admission to the hospital. Upon completion of the medical rehabilitation course, the patients’ exercise tolerance increased significantly, resulting in better individual exercise tolerances, longer distances covered within the six-minute walk test, and the larger total amount of daily activities the patients can perform. Conclusions. Electrocardiography-controlled physical training based on the patient’s initial stamina level promotes increasing their exercise tolerance, their tolerance to daily activities, their mobility, independence, and, accordingly, their life quality.