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Introduction: Adherence to imatinib in chronic myeloid leukemia (CML) patients is estimated to be as low as 70% despite its clinical benefit, and our understanding of the impact of nonadherence in this population is limited. This study presents a novel application of the Alternating Conditional Estimation (ACE) algorithm in newly diagnosed CML patients to map the full dose–response curve (DRC) and determine how the strength of this curve varies over time. Methods: We applied the ACE algorithm alongside a backward elimination procedure to detect the presence of time dependence and nonlinearity in the relationship between imatinib adherence and time-to-remission. An extended Cox model allowing for the flexible modeling of identified effects via unpenalized B-splines was subsequently fit and assessed. Results: The substantial improvement in model fit associated with the extended Cox approach suggests that traditional Cox proportional hazards model assumptions do not hold in this setting. Results indicate that the DRC for imatinib is non-linearly increasing, with an attenuated effect above a 74% adherence rate. The strength of this effect on remission varied over time and was strongest in the initial months of treatment, reaching a peak around 90 days post-initiation (log hazard ratio: 2.12, 95% confidence interval: 1.47 to 2.66). Conclusion: Most patients that achieved remission did so by 4 months (120 days) with consistently high adherence, suggesting that this could be a critical time and duration for realizing treatment benefit and patient monitoring. Findings regarding the relationship between adherence and remission can additionally help guide the design of future studies. [ABSTRACT FROM AUTHOR]

Fricke gel dosimeters are appropriate candidates for gamma dosimetry. Polyvinyl alcohol Fricke gel dosimeters are the most recent introduced gel dosimeters which have low ion diffusion. In this work, samples of ferrous-xylenol orange-polyvinyl alcohol gel dosimeters were prepared and characterized using optical spectroscopy. Using win XCOM program and the elemental composition of the gel, the mass attenuation coefficients for photons were evaluated. The results exhibited that the prepared gel is the nearly radiological blood-, soft tissue- and water-equivalent. The 60Co gamma cell unit was used to irradiate the gel samples. A dose range response was found linear from 10 to 30 Gy and suitable for blood irradiation dosimetry. Additionally, the gel response good repeatability was confirmed by the coefficient of variation calculations. Furthermore, chemical yield of the gel was estimated to be 34.6. The good characteristics of the prepared gel make it appropriate for dosimetry of blood irradiators. [ABSTRACT FROM AUTHOR]

Hormesis or hormetic effect is characterized by a biphasic response caused by a stressor or stressor agent. The first phase of hormesis is stimulation at low or sublethal doses, whereas the second phase occurs through inhibition or death at high or lethal doses of the stressor. Both phases are represented using mathematical models in the form of dose-response curves. In plants, hormesis has morphological, physiological, biochemical and molecular effects. These effects act as response mechanisms of adjustment or coupling to the stressor. Adjustment or coupling mechanisms can be exploited in plant tissue culture (PTC) to increase or promote plant length, number of leaves, number of roots, biomass and secondary metabolites, or to induce or enhance morphogenesis in vitro. This review compiles recent findings on hormesis using PTC techniques and the mechanisms of response to different stressors. Stressor agents that present a hormetic dose response (stimulation, inhibition) include silver nanoparticles (50, 100 mg/L), arsenic (1.15, 50.15 mg/kg), multi-walled carbon nanotubes (50, 200 mg/L), 60Co gamma rays (20, 60 Gy), microplastics (0.01, 0.1 mg/L), and a magnetic field (65, 172 mT), among others. In addition, topics such as general plant hormetic response to abiotic stressors, physiological and biochemical aspects of hormesis, hormetic response to metals and nanomaterials, and other curious examples of hormesis are included. Hormesis could be considered as a novel strategy to improve growth and differentiation in different PTC areas and applications. It is suggested to document new cases of hormesis and carry out future studies to elucidate and understand the hormetic effect response mechanisms to different stressors through in vitro biological models. [ABSTRACT FROM AUTHOR]

There has been substantial research interest in finding activities/agents that slow the onset and reduce the severity of numerous age-related diseases/conditions. This assessment indicates that the most studied agent intended to promote health in human population investigations for a broad spectrum of diseases are the statins, with large-scale epidemiological studies addressing numerous health endpoints. The key findings are that statin treatment consistently reduces the occurrence and attenuates the course of numerous non-communicable and contagious pathologies and numerous types of cancer with high mortality rates by about 20–50%. That one agent could affect such a broad based and consistently positive trends in epidemiological studies is unexpected and impressive, along with consistent cell and animal model research. Underlying mechanisms have been proposed that significantly contribute to the spectrum of salutary effects of statins, especially the capacity to activate Nrf2 showing hormetic dose responses in multiple organs and cell types, due to its bioavailability and broad tissue distribution. The widespread use of statins, which has the capacity to enhance human health span, should be considered for experimental exploration as a novel public health strategy that includes practical approaches for reduction of the most common adverse effects of this class of drugs including myalgia/myopathy and transaminitis. [ABSTRACT FROM AUTHOR]

Hormesis implies that the effects of various materials or conditions that organisms are exposed to, may not have linear dose-response characteristics but rather, can be biphasic. Thus the response to a low dose of a stressor may be the opposite to that occurring at higher doses. Such a dual response is postulated for many toxicants and physical conditions and may involve a beneficial adaptive response. Such a non-linear effect is undoubtedly present in many useful pharmacological and nutraceutical agents with can be toxic at high concentrations. This somewhat divisive topic is an area of study that should be objectively studied and not clouded by political and policy considerations. The objective of this review is to examine claims concerning those exposures where hormesis seems to exist and also those where there is no good supporting evidence. The breadth of this phenomenon and potential mechanisms underlying hormetic events are discussed together with their limitations.

Abstract Human induced pluripotent stem cell-derived sensory neuron (iPSC-dSN) models are a valuable resource for the study of neurotoxicity but are affected by poor replicability and reproducibility, often due to a lack of optimization. Here, we identify experimental factors related to culture conditions that substantially impact cellular drug response in vitro and determine optimal conditions for improved replicability and reproducibility. Treatment duration and cell seeding density were both found to be significant factors, while cell line differences also contributed to variation. A replicable dose–response in viability was demonstrated after 48-h exposure to docetaxel or paclitaxel. Additionally, a replicable dose-dependent reduction in neurite outgrowth was demonstrated, demonstrating the applicability of the model for the examination of additional phenotypes. Overall, we have established an optimized iPSC-dSN model for the study of taxane-induced neurotoxicity.

In this research, thermoluminescent pellets were prepared by adding Mg, Cu, Na and Si impurities to lithium fluoride (LiF) crystal powder via melting and quenching methods to study dosimetric characteristics. Here, its reproducibility, dose response, dosimeter sensitivity, thermal and optical fading were investigated and the obtained results were compared with the properties of LiF: Cu, Mg, P crystal nominated as GR-200.

Daridorexant is approved for the treatment of insomnia at two dose levels (25 and 50 mg). Dose-efficacy and -safety response relationships were evaluated using Phase 2 and 3 data. Data (N = 2153) from one Phase 2 (daridorexant 5, 10, 25, 50 mg, placebo once daily for 1 month) and two Phase 3 studies (daridorexant 10 and 25 or 25 and 50 mg, placebo once daily for 3 months) were pooled. Dose-response analyses at 1 month of double-blind treatment were performed using a linear regression and a two-stage meta-analysis approach. Efficacy endpoints were polysomnography-derived wake after sleep onset, latency to persistent sleep (LPS), self-reported total sleep time and the Insomnia Daytime Symptoms and Impacts Questionnaire total score (only Phase 3 data for the latter). Safety endpoints were the incidence of total adverse events (AEs) and AEs corresponding to somnolence/fatigue. Dose-responses for all efficacy endpoints were significant in the observed dose range (both statistical approaches, p < 0.01). All dose-response relationships were linear except for LPS (two-stage meta-analysis) which showed a change in slope above 10 mg without reaching a plateau. No significant dose-response was observed for any AE (both approaches, p > 0.05). The incidence of AEs corresponding to somnolence/fatigue was low at all doses and, without linear assumption (two-stage meta-analysis) there was no dose-dependency (p = 0.369). The data support the use of 50 mg as the preferred daridorexant dose in patients with insomnia disorder to provide the greatest opportunity for efficacy with no increased risk for AEs, including somnolence/fatigue, compared to lower doses. • Analysis of Phase 2/3 data to evaluate the dose-response relationship of daridorexant. • Daridorexant showed a dose-response relationship on sleep and daytime functioning. • No evidence of a dose-response for adverse events, including somnolence/fatigue. • Results indicate a positive benefit-risk balance for daridorexant 25 mg and 50 mg. • Results support 50 mg as the preferred dose for insomnia disorder. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell-derived sensory neuron (iPSC-dSN) models are a valuable resource for the study of neurotoxicity but are affected by poor replicability and reproducibility, often due to a lack of optimization. Here, we identify experimental factors related to culture conditions that substantially impact cellular drug response in vitro and determine optimal conditions for improved replicability and reproducibility. Treatment duration and cell seeding density were both found to be significant factors, while cell line differences also contributed to variation. A replicable dose–response in viability was demonstrated after 48-h exposure to docetaxel or paclitaxel. Additionally, a replicable dose-dependent reduction in neurite outgrowth was demonstrated, demonstrating the applicability of the model for the examination of additional phenotypes. Overall, we have established an optimized iPSC-dSN model for the study of taxane-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

The current radiation dose estimates used in medical imaging, radiation oncology or environmental assessments are not entirely accurate from a fundamental physics perspective, let alone for biological consequences. The "one cloth fits all" approach of radiation-matter interactions cannot assess the effects of interactions of the same species of radiation of different energies on the same isotope of an element. Preliminary steps to set the radiation dosimetry in the right direction are suggested. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the acute effect of low, moderate, or high doses of taurine on anaerobic and physiological performance in female rugby players. A total of 16 sub-elite female rugby athletes (21.3 ± 1.5 yr, 168.0 ± 4.9 cm, 62.1 ± 3.5 kg mean ± SD) participated in this research. Following familiarization, participants attended 4 successive tests separated by 72 h in a randomized, counter-balanced, crossover research design. Following an over night fast, participants completed a 5-min 60 Watt warm-up followed by a 30-s Wingate anaerobic test on a cycle ergometer after ingestion of either 2 g taurine (LOWTAU), 4 g (MODTAU), 6 g (HIGHTAU) or placebo (PLA) 1 h before the test. Peak (PP) and mean power (MP) along with heart rate (HR), rating of perceived exertion (RPE), capillary lactate and blood glucose were measured. LOWTAU did not affect PP, MP, HR, lactate and glucose compared to PLA (p > 0.05), while MODTAU improved MP and HIGHTAU improved PP and MP compared to PLA and LOWTAU (p < 0.05). MODTAU and HIGHTAU had little effect on HR, blood lactate and glucose (p > 0.05). A single dose of taurine (MODTAU or HIGHTAU) 1 h prior to competition or training would provide an ergogenic effect on subsequent power output. [ABSTRACT FROM AUTHOR]

The use of herbicides on crops often results in unintentional, low-dose exposure of non-target organisms, such as insects. While these exposures are increasingly known to alter the survival and physiology of insects, it remains unclear whether these effects can vary between populations and modify other fitness-related traits, such as behaviour and immunity. Here, we addressed these questions by testing the effects of sublethal exposure to a glyphosate-based herbicide (GBH) on the behaviour and immunity of European earwig males from six natural populations. We exposed each male to a dose of a common GBH (Roundup©) that was either recommended for crops, five times lower than that recommended for crops, or to a control solution. Twenty-four hours later, we measured the activity, boldness, and aggregation of each male. We then exposed them to an entomopathogenic fungus, monitored their survival for 6 weeks, and measured the immune response of the survivors. We found a condition-dependent effect of GBH exposure on male activity. Exposure to low doses induced a positive association between activity and weight, which was not observed in the high-dose and control groups. However, GBH had no effect on any of the other measured traits. All these results were consistent across the six populations tested, although we did find population-specific differences in almost all measurements on males. Further research is now needed to better understand the dose–response to GBH on male activity and its biological impact, as well as to evaluate the effectiveness of detoxification processes in this species. Overall, these results emphasise the importance of investigating the effects of herbicides on insects to expand our general understanding of the use and potential risks of plant protection products in integrated pest management programs. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type I (MPS I) is a rare metabolic disorder caused by deficiency of α-L-iduronidase (IDUA), resulting in glycosaminoglycan (GAG) accumulation and multisystemic disease. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy, but these do not address all manifestations of the disease. We infused MPS I mice with an adeno-associated virus 9 (AAV9)-IDUA vector (RGX-111) at doses from 107 to 1010 vector genomes (vg) via intrathecal (IT), intravenous (IV), and intrathecal+intravenous (IT+IV) routes of administration. In mice administered doses ≤109 vg IT or ≤108 vg IV, there was no therapeutic benefit, while in mice administered 109 vg IV, there was a variable increase in IDUA activity with inconclusive neurocognitive and cardiac assessments. However, at the 1010 vg dose, we observed substantial metabolic correction, with restored IDUA levels and normalized tissue GAGs for all treatment groups. Aortic insufficiency was mostly normalized, neurologic deficit was prevented, and microcomputed tomography (micro-CT) analysis showed normalization of skeletal parameters. Histologic analysis showed minimal GAG storage and lysosomal pathology. We thus report a minimal effective dose of 1010 vg (5 × 1011 per kg) RGX-111 for IV and IT routes of administration in MPS I mice, which prevented neurocognitive deficit, cardiac insufficiency, and skeletal manifestations, as a model for genetic therapy of human MPS I.

Statistically significant increases in ischemic heart disease (IHD) mortality with cumulative occupational external radiation dose were observed in the National Registry for Radiation Workers (NRRW) cohort. There were 174 541 subjects in the NRRW cohort. The start of follow up was 1955, and the end of the follow-up for each worker was chosen as the earliest date of death or emigration, their 85th birthday or 31 December 2011. The dose-response relationship showed a downward curvature at a higher dose level >0.4 Sv with the overall shape of the dose-response relationship best described by a linear-quadratic model. The smaller risk at dose >0.4 Sv appears to be primarily associated with workers who started employment at a younger age (<30 years old) and those who were employed for more than 30 years. We modelled the dose response by age-at-first exposure. For the age-at-first exposure of 30+ years old, a linear dose-response was the best fit. For age-at-first exposure <30 years old, there was no evidence of excess risk of IHD mortality for radiation doses below 0.1 Sv or above 0.4 Sv, excess risk was only observed for doses between 0.1–0.4 Sv. For this age-at-first exposure group, it was also found that the doses they received when they were less than 35 years old or greater than 50 years old did not contribute to any increased IHD risk. [ABSTRACT FROM AUTHOR]

Objective: Conventional randomized controlled trials (RCTs) have long served as the foundation of research in clinical psychology; however, most treatments for eating disorders show only modest effects on reduction of symptoms and maintenance of long‐term remission. New options for psychotherapy treatment development research, beyond continuing to pursue additive or subpopulation approaches, are needed. Methods: One option is to apply dose–response designs, which are commonplace in studies of pharmacology, toxicology, and medical research, and characterized by the evaluation of the amount of exposure (dose) to an intervention, and the resulting changes in body function or health (response). Results: Eating disorder interventions are particularly well‐suited for dose–response treatment designs. The deadly nature of eating disorders makes it imperative that patients are not turned away for not being "ready" to engage with treatment. By identifying optimal doses, research will likely yield a more parsimonious course of treatment, which will lend itself to reduced costs, greater uptake, and reduced drop‐out. Discussion: Limited use of within‐subject designs in trials for patients with eating disorders has produced fast‐track efficacy studies and omitted key elements in the treatment development pathway. To decrease reliance on RCT's, dose–response methods should be applied as an alternative study design. Public Significance: Eating disorders are associated with medical and psychiatric comorbidities, poor quality of life, and high mortality. Access to evidence‐based services for patients with eating disorders is limited, and identifying additional effective treatment options can be difficult because of challenges inherent to randomized‐controlled trials. This manuscript describes an alternative trial methodology to maximize the information that can be gathered prior to utilizing a standard large‐scale efficacy design. [ABSTRACT FROM AUTHOR]

Introduction Cannabinoids are being used by patients to help with chronic pain management and to address the 2 primary chronic pain comorbidities of anxiety and sleep disturbance. It is necessary to understand the biphasic effects of cannabinoids to improve treatment of this symptom triad. Methods A scoping review was conducted to identify whether biphasic effects of cannabinoids on pain severity, anxiolysis, and sleep disturbance have been reported. The search included the Embase, Biosis, and Medline databases of clinical literature published between 1970 and 2021. The inclusion criteria were (1) adults more than 18 years of age, (2) data or discussion of dose effects associated with U-shaped or linear dose responses, and (3) measurements of pain and/or anxiety and/or sleep disturbance. Data were extracted by 2 independent reviewers (with a third reviewer used as a tiebreaker) and subjected to a thematic analysis. Results After the database search and study eligibility assessment, 44 publications met the final criteria for review. Eighteen publications that specifically provided information on dose response were included in the final synthesis: 9 related to pain outcomes, 7 measuring anxiety, and 2 reporting sleep effects. Conclusions This scoping review reports on biphasic effects of cannabinoids related to pain, sleep, and anxiety. Dose–response relationships are present, but we found gaps in the current literature with regard to biphasic effects of cannabinoids in humans. There is a lack of prospective research in humans exploring this specific relationship. [ABSTRACT FROM AUTHOR]

To examine the distortion of the linear quadratic (LQ) model of in vitro cytogenetic dose response over an extended range of γ-ray doses by analyzing the available literature data, and to establish the dose ranges, in which the LQ dose response curve (DRC) can be most accurately fitted for biological dosimetry. Data on yields of dicentrics (Dic) or dicentrics plus centric rings (Dic + CR) induced in vitro in human lymphocytes by acute γ-rays were extracted from 108 open sources. The overall dose response dataset in the dose range up to 50 Gy was fitted to a fractional-rational (FR) model, which included a 'basic' LQ function in the numerator, and a reduction factor dependent on the square of the dose in the denominator. Cytogenetic dose response data obtained at Grigoriev Institute for Medical Radiology, Kharkiv, Ukraine (GIMRO) in the range 0.1 − 20.3 Gy acute γ-rays were fitted to the LQ model with the progressive changing minimum or maximum radiation dose. The overall dose response, as expected, followed the LQ function in the dose range ≤5 Gy, but in the extended dose range appeared to be S-shaped, with intensive saturation and a plateau at doses ≥22 Gy. Coefficients of the 'basic' LQ equation in FR model were very close to many published DRCs; calculated asymptote was 17. Fitting of the GIMRO dataset to the LQ model with the shift of the dose range showed the increase in linear coefficient with the increment of either minimum or maximum radiation dose, while the decline of the quadratic coefficient was regulated mostly by the increase of the highest dose. The best goodness of fit, assessed by lower χ2 values, occurred for dose ranges 0.1 − 1.0 Gy; 0.5 − 5.9 Gy; 1.0 − 7.8 Gy; 2.0 − 9.6 Gy, 3.9 − 16.4 Gy and 5.9 − 20.3 Gy. The 'see-saw' effect in changes of LQ coefficients was confirmed by re-fitting datasets published by other laboratories. The classical LQ model with fixed coefficients appears to have limited applicability for cytogenetic dosimetry at radiation doses >5 Gy due to the saturation of the dose response. Different response of the LQ coefficients to the changes of the dose range must be considered during the DRC construction. Proper selection of minimum and maximum dose in calibration experiments makes it possible to improve the goodness of fit of the LQ DRC. [ABSTRACT FROM AUTHOR]

Selecting a safe and clinically beneficial dose can be difficult in drug development. Dose justification often relies on dose-response modeling where parametric assumptions are made in advance which may not adequately fit the data. This is especially problematic in longitudinal dose-response models, where additional parametric assumptions must be made. This paper proposes a class of longitudinal dose-response models to be used in the Bayesian model averaging paradigm which improve trial operating characteristics while maintaining flexibility a priori. A new longitudinal model for non-monotonic longitudinal profiles is proposed. The benefits and trade-offs of the proposed approach are demonstrated through a case study and simulation. [ABSTRACT FROM AUTHOR]

Numerous therapeutic and diagnostic approaches used within a clinical setting depend on the administration of compounds via systemic delivery. Biomaterials at the nanometer scale, as dendrimers, act as delivery systems by improving cargo bioavailability, circulation time, and the targeting of specific tissues. Although evaluating the efficacy of pharmacological agents based on nanobiomaterials is crucial, conducting toxicological assessments of biomaterials is essential for advancing clinical translation. Here, a zebrafish larvae model was explored to assess the biocompatibility of poly(amido amine) (PAMAM), one of the most exploited dendrimers for drug delivery. We report the impact of a systemic injection of polyethylene glycol (PEG)-modified G4 PAMAM conjugated with rhodamine (Rho) as a mimetic drug (PEG–PAMAM–Rho) on survival, animal development, inflammation, and neurotoxicity. A concentration- and time-dependent effect was observed on mortality, developmental morphology, and innate immune system activation (macrophages). Significant effects in toxicological indicators were reported in the highest tested concentration (50 mg/mL PEG–PAMAM–Rho) as early as 48 h post-injection. Additionally, a lower concentration of PEG–PAMAM–Rho (5 mg/mL) was found to be safe and subsequently tested for neurotoxicity through behavioral assays. In accordance, no significative signs of toxicity were detected. In conclusion, the dose response of the animal was assessed, and the safe dosage for future use in theragnostics was defined. Additionally, new methodologies were established that can be adapted to further studies in toxicology using other nanosystems for systemic delivery. [ABSTRACT FROM AUTHOR]

Introduction: Asthma treatment guidelines classify inhaled corticosteroid (ICS) regimens as low, medium, or high dose. However, efficacy and safety are not independently assessed accordingly. Moreover, differences in ICS duration of action are not considered when a dose regimen is selected. We investigated the efficacy and safety implications of these limitations for available ICS molecules. Methods: Published pharmacodynamic and pharmacokinetic parameters were used, alongside physiological and pharmacological principles, to estimate the efficacy and safety of available ICS molecules. Extent and duration of glucocorticoid receptor (GR) occupancy in the lung (efficacy) and cortisol suppression (systemic exposure and safety) were estimated. Results: Some ICS regimens (e.g., fluticasone furoate, fluticasone propionate, and ciclesonide) rank high for efficacy but low for systemic exposure, contrary to how ICS dose equivalence is currently viewed. Differences in dose–response relationships for efficacy and systemic exposure were unique for each ICS regimen and reflected in their therapeutic indices. Notably, even low doses of most ICSs can generate high GR occupancy (≥ 90%) across the entire dose interval at steady state, which may explain previously reported difficulties in obtaining dose responses within the clinical dose range and observations that most clinical benefit typically occurs at low doses. The estimated post dose duration of lung GR occupancy for ICS molecules was categorized as 4–6 h (short), 14–16 h (medium), 25–40 h (long), or > 80 h (ultra-long), suggesting potentially large differences in anti-inflammatory duration of action. Conclusion: In a real-world clinical setting where there may be poor adherence to prescribed therapy, our findings suggest a significant therapeutic advantage for longer-acting ICS molecules in patients with asthma. Plain Language Summary: Patients with asthma often rely on inhaled corticosteroids to manage their symptoms by controlling lung inflammation. Inhaled corticosteroids can be used at low, medium, or high doses; however, the effectiveness, safety, and how long the effects last for a particular inhaled corticosteroid molecule are not considered when choosing them. This study investigated the safety and efficacy of different inhaled corticosteroid molecules. Leveraging published data on the mode of anti-inflammatory action and the rates these molecules are absorbed and eliminated from the body, we estimated their effectiveness and safety profiles, including duration of action in the lungs and systemic exposure levels. Some inhaled corticosteroid molecules such as fluticasone furoate, fluticasone propionate, and ciclesonide were found to exhibit high anti-inflammatory effectiveness in the lungs with minimal systemic exposure, contrasting the perceived similarities among currently used drug molecules. Anti-inflammatory duration of the unwanted systemic effect in the rest of the body was unique for each inhaled corticosteroid molecule. Notably, even the lowest doses of most inhaled corticosteroids were found to be effective in the lungs when taken as prescribed, supporting previous observations that clinical benefits are mostly realized at lower doses. Furthermore, estimated post dose durations of effectiveness for different inhaled corticosteroid molecules varied widely among different molecules, with some lasting a few hours and others lasting more than 80 h, suggesting significant differences in their duration of action. Overall, these findings demonstrate the potential advantage of using longer-acting inhaled corticosteroids, particularly for patients with asthma who may face challenges in adhering to prescribed regimens. [ABSTRACT FROM AUTHOR]

Objective. The aim of this work is to investigate the response of the Roos chamber (type 34001) irradiated by clinical proton beams in magnetic fields. Approach. At first, a Fano test was implemented in Monte Carlo software package GATE version 9.2 (based on Geant4 version 11.0.2) using a cylindrical slab geometry in a magnetic field up to 1 T. In accordance to an experimental setup (Fuchs et al), the magnetic field correction factors k Q B ⃗ of the Roos chamber were determined at different energies up to 252 MeV and magnetic field strengths up to 1 T, by separately simulating the ratios of chamber signals M Q / M Q B ⃗ , without and with magnetic field, and the dose-conversion factors D w , Q B ⃗ / D w , Q in a small cylinder of water, with and without magnetic field. Additionally, detailed simulations were carried out to understand the observed magnetic field dependence. Main results. The Fano test was passed with deviations smaller than 0.25% between 0 and 1 T. The ratios of the chamber signals show both energy and magnetic field dependence. The maximum deviation of the dose-conversion factors from unity of 0.22% was observed at the lowest investigated proton energy of 97.4 MeV and B ⃗ = 1 T. The resulting k Q B ⃗ factors increase initially with the applied magnetic field and decrease again after reaching a maximum at around 0.5 T; except for the lowest 97.4 MeV beam that show no observable magnetic field dependence. The deviation from unity of the factors is also larger for higher proton energies, where the maximum lies at 1.0035(5), 1.0054(7) and 1.0069(7) for initial energies of E 0 = 152, 223.4 and 252 MeV, respectively. Significance. Detailed Monte Carlo studies showed that the observed effect can be mainly attributed to the differences in the transport of electrons produced both outside and inside of the air cavity in the presence of a magnetic field. [ABSTRACT FROM AUTHOR]

Isometric exercise is a non-pharmacologic intervention to improve muscle hemodynamic responses and blood pressure in humans. However, the effects of intensity, duration, and muscle mass factors of isometric exercise on local muscle hemodynamic responses and systemic blood pressure regulation have not been studied. The purpose of this study was to assess whether various modes of isometric exercise could induce various levels of muscle hemodynamic responses that are related to the blood pressure changes. Near-infrared spectroscopy was used to assess muscle hemodynamic responses after 4 isometric exercise protocols in 20 healthy adults. One-way analysis of variance (ANOVA) with repeated measures was used to assess the effect of factors of isometric exercise on oxyhemoglobin, deoxy-hemoglobin, blood volume, and oxygenation. For oxygenation, the lowest mean was recorded for the unilateral isometric handgrip exercise at 30% of MVC for 2 min (−0.317 ± 0.379 μM) while the highest mean was observed for the isometric wall squat (1.496 ± 0.498 μM, P < 0.05). Additionally, both the bilateral isometric handgrip exercise at 30% MVC for 1 min (1.340 ± 0.711 μM, P < 0.05) and the unilateral isometric handgrip exercise at 20% MVC for 3 min (0.798 ± 0.324 μM, P < 0.05) are significantly higher than 30% of MVC for 2 min. Blood pressure showed an inverse trend with oxygenation changes of the forearm muscle. The study indicates that the duration and muscle mass of isometric exercise are more effective on oxygenation responses and systematic blood pressure regulation, and suggests that the local muscle oxygenation factor following isometric contractions may mediate systematic blood pressure regulation.

Background and purpose: Lung cancer is a leading cause of cancer-related mortality, and stereotactic body radiotherapy (SBRT) has become a standard treatment for early-stage lung cancer. However, the heterogeneous response to radiation at the tumor level poses challenges. Currently, standardized dosage regimens lack adaptation based on individual patient or tumor characteristics. Thus, we explore the potential of delta radiomics from on-treatment magnetic resonance (MR) imaging to track radiation dose response, inform personalized radiotherapy dosing, and predict outcomes. Materials and methods: A retrospective study of 47 MR-guided lung SBRT treatments for 39 patients was conducted. Radiomic features were extracted using Pyradiomics, and stability was evaluated temporally and spatially. Delta radiomics were correlated with radiation dose delivery and assessed for associations with tumor control and survival with Cox regressions. Results: Among 107 features, 49 demonstrated temporal stability, and 57 showed spatial stability. Fifteen stable and non-collinear features were analyzed. Median Skewness and surface to volume ratio decreased with radiation dose fraction delivery, while coarseness and 90th percentile values increased. Skewness had the largest relative median absolute changes (22 %–45 %) per fraction from baseline and was associated with locoregional failure (p = 0.012) by analysis of covariance. Skewness, Elongation, and Flatness were significantly associated with local recurrence-free survival, while tumor diameter and volume were not. Conclusions: Our study establishes the feasibility and stability of delta radiomics analysis for MR-guided lung SBRT. Findings suggest that MR delta radiomics can capture short-term radiographic manifestations of the intra-tumoral radiation effect.

Background: Dietary components can influence the incidence of colorectal cancer (CRC). Folate is one of the compounds that plays an essential role in the formation of DNA structures, which can lead to or prevent tumorigenesis. The present study is the first systematic review and dose–response meta-analysis of cohort studies evaluating the association between dietary folate intake and the risk of CRC. Methods: The PubMed/Medline, Scopus, and ISI Web of Science databases were systematically searched for cohort studies that assessed the association between folate intake and CRC up to January 2024. Summary relative risks (RRs) and 95 % confidence intervals (CIs) were calculated using a random effects model. Also, linear and nonlinear dose-response analyses were conducted for the dose-response associations between folate intake and risk of CRC. Results: Eighteen prospective cohort studies with 931,469 participants, 14,860 CRC patients, 3536 colon cancer (CC) patients, and 1075 rectal cancer (RC) patients were included in the analysis. The summary RR of CRC for each 100-μg increase in dietary folate intake was 0.97 (95 % CI: 0.95–0.99, I2: 0.0 %, P-heterogeneity: 0.616), which can be related to BMI (0.97 (95 % CI: 0.95–0.99)); a more protective effect was also observed in subjects who drank alcohol (0.97 (95 % CI: 0.95–0.99)) and those who smoked (0.97 (95 % CI: 0.95–0.99)). Additionally, it was positively related to a 7 % lower risk of CC (0.93 (95 % CI: 0.87–0.99, I2: 33.7 %, P-heterogeneity: 0.159)), and the null relation for RC was 0.98 (95 % CI: 0.90–1.08), I2: 16.6 %, P-heterogeneity: 0.309). There was evidence of nonlinearity in which up to 500 μg/day dietary folate intake was inversely associated with CC (P nonlinearity = 0.04). Conclusion: The findings showed an inverse association between dietary folate intake and the risk of CRC, especially in high-risk persons, those who have a higher BMI, alcohol drinkers, and smokers.

Background With the accelerated aging of the national population, the rapid increase of the elderly with dementia has become an increasingly prominent problem. Sleep is the basic need of the human body, and sleep problems have become an independent risk factor for the cognitive function of the elderly. Moderate sleep duration is essential for the removal of brain wastes, synaptic plasticity, and the maintenance of normal function of the nervous system. However, the current sleep problems of the elderly have not attracted widespread attention, and the sleep time of the elderly needs to be further studied. Objective To explore the dose-response relationship between sleep duration and risk of senile dementia. Methods CNKI, Wanfang Data, VIP, CBM, PubMed, Cochrane Library, Embase and Web of Science databases were searched for prospective cohort studies on the relationship between sleep duration and risk of senile dementia from inception to June 2023. Literature data were independently extracted by two researchers, and literature quality evaluation was performed. Dose-response Meta-analysis was performed by applying restricted cubic spline regression model in Stata 16.0 software. Results A total of 9 papers with 58 342 study subjects and 9 887 exposures were included. Meta-analysis showed that sleep duration was associated with the risk of senile dementia (RR=1.32, 95%CI=1.17-1.48, P

Abstract Background We evaluated the dose–response relationship between the level of attendance at the English National Health Service Diabetes Prevention Programme (DPP) and risk of progression to type 2 diabetes amongst individuals participating in the programme. Methods We linked data on DPP attendance for 51,803 individuals that were referred to the programme between 1st June 2016 and 31st March 2018 and attended at least one programme session, with primary care records of type 2 diabetes diagnoses from the National Diabetes Audit up to 31st March 2020. Weibull survival regressions were used to estimate the association between the number of programme sessions attended and risk of progression to type 2 diabetes. Results Risk of developing type 2 diabetes declined significantly for individuals attending seven of the 13 programme sessions and continued to decline further up to 12 sessions. Attending the full 13 sessions was associated with a 45.5% lower risk (HR: 0.545 95% CI: 0.455 to 0.652). Compared to individuals that only partially attended the programme, attendance at 60% or more of the sessions was associated with a 30.7% lower risk of type 2 diabetes (HR: 0.693 95% CI: 0.645 to 0.745). Conclusions Reducing the risk of progression to type 2 diabetes through diabetes prevention programmes requires a minimum attendance level at seven of the 13 programme sessions (54%). Retaining participants beyond this minimum level yields further benefits in diabetes risk reduction. Commissioners may wish to consider altering provider payment schedules to incentivise higher retention levels beyond 60% of programme sessions.

BACKGROUND: The local hemodynamic response after cupping therapy has been considered as a contributing factor for improving muscle tissue health; however, the effects of cupping pressure and duration on the spatial hemodynamic response have not been investigated. OBJECTIVE: The objective of this study was to investigate the hemodynamic response inside and outside the cupping cup under various pressures and durations of cupping therapy. METHODS: A 3-way factorial design with repeated measures was used to investigate the main and interaction effects of the location (areas inside and outside the cup), pressure (- 225 and - 300 mmHg) and duration (5 and 10 min) on the hemodynamic response of the biceps muscle. A functional near-infrared spectroscopy was used to assess hemodynamic changes in 18 participants. RESULTS: A significant three-way interaction of the location, pressure, and duration factors was observed in oxyhemoglobin (p = 0.023), deoxy-hemoglobin (p = 0.013), and blood volume (p = 0.013). A significant increase was observed in oxyhemoglobin, blood volume, and oxygenation compared to pre-cupping (p < 0.05) in the area outside the cup. CONCLUSION: Our findings indicate that an appropriate combination of cupping pressure and duration can effectively affect the spatial hemodynamic response of the biceps. [ABSTRACT FROM AUTHOR]

A model to estimate the time course of a phytochrome photostationary state (PSS) under an arbitrary light environment was developed. It is the solution of differential equations that use conversion rates between active and inactive forms of previously reported phytochromes. The model estimated that 90% of the PSS changes were completed using approximately 3.4 mmol m-2 of integrated end-of-day far-red light irradiation, and 99% of the changes were completed with approximately 6.9 mmol m-2 irradiation. Although these values were affected by the spectral photon flux density of the far-red light. They were consistent with previous results that examined dose requirements of far-red irradiation. The rate at which the PSS changes approached equilibrium was maximized under a red light, followed by far-red, green, and blue light. This estimation method could be used to control phytochrome responses for horticulture via artificial lighting. [ABSTRACT FROM AUTHOR]

The Pugwash Conferences have been a highly visible attempt to create profoundly important discussions on matters related to global safety and security at the highest levels, starting in 1957 at the height of the Cold War. This paper assesses, for the first time, the formal comments offered at this first Pugwash Conference by the Nobel Prize-winning radiation geneticist, Hermann J. Muller, on the effects of ionizing radiation on the human genome. This analysis shows that the presentation by Muller was highly biased and contained scientific errors and misrepresentations of the scientific record that resulted in seriously misleading the attendees. The presentation of Muller at Pugwash served to promote, on a very visible global scale, continued misrepresentations of the state of the science and had a significant impact on policies and practices internationally and both scientific and personal belief systems concerning the effects of low dose radiation on human health. These misrepresentations would come to affect the adoption and use of nuclear technologies and the science of radiological and chemical carcinogen health risk assessment, ultimately having a profound effect on global environmental health. [ABSTRACT FROM AUTHOR]

Background: Predicting biological responses to mixed radiation types is of considerable importance when combining radiation therapies that use multiple radiation types and delivery regimens. These may include the use of both low‐ and high‐linear energy transfer (LET) radiations. A number of theoretical models have been developed to address this issue. However, model predictions do not consistently match published experimental data for mixed radiation exposures. Furthermore, the models are often computationally intensive. Accordingly, there is a need for efficient analytical models that can predict responses to mixtures of low‐ and high‐LET radiations. Additionally, a general formalism to calculate equieffective dose (EQDX) for mixed radiations is needed. Purpose: To develop a computationally efficient analytical model that can predict responses to complex mixtures of low‐ and high‐LET radiations as a function of either absorbed dose or EQDX. Methods: The Zaider‐Rossi model (ZRM) was modified by replacing the geometric mean of the quadratic coefficients in the interaction term with the arithmetic mean. This modified ZRM model (mZRM) was then further generalized to any number of radiation types and its validity was tested against published experimental observations. Comparisons between the predictions of the ZRM and mZRM, and other models, were made using two and three radiation types. In addition, a generalized formalism for calculating EQDX for mixed radiations was developed within the context of mZRM and validated with published experimental results. Results: The predictions of biological responses to mixed‐LET radiations calculated with the mZRM are in better agreement with experimental observations than ZRM, especially when high‐ and low‐LET radiations are mixed. In these situations, the ZRM overestimated the surviving fraction. Furthermore, the EQDX calculated with mZRM are in better agreement with experimental observations. Conclusion: The mZRM is a computationally efficient model that can be used to predict biological response to mixed radiations that have low‐ and high‐LET characteristics. Importantly, interaction terms are retained in the calculation of EQDX for mixed radiation exposures within the mZRM framework. The mZRM has application in a wide range of radiation therapies, including radiopharmaceutical therapy. [ABSTRACT FROM AUTHOR]

We introduce a framework of dose-response modeling for the evaluation of drug combinations. We focus on adaptive techniques in dose-finding studies when several endpoints can be observed simultaneously on each subject. This framework may fit well for clinical trials and we discuss its algorithmization. The generalized bivariate probit model is discussed in particular. Necessary conditions for plausible behavior of drug combinations are given from the theoretical stochastic perspective. [ABSTRACT FROM AUTHOR]

This study was conducted to evaluate the response of PVA Fricke gel dosimeters by two different methods, optical spectroscopy and magnetic resonance imaging. At first, samples of PVA Fricke xylenol orange gel dosimeters were prepared in our laboratory. Then, the samples were irradiated up to 25 Gy by gamma rays. Finally, studies on the optical absorbance and magnetic resonance of the prepared Fricke gel dosimeters were carried out. Optical absorbance measurements of the samples were performed with a spectrophotometer. Magnetic resonance measurements of the gel dosimeters were carried out by means of a 1.5 T scanner. Radiation induced oxidation of ferrous ions with the yield proportional to absorbed dose was observed. The dosimeters were found to offer good linearity in the range of 0-15 Gy. MRI scans of the dosimeters also showed that the longitudinal relaxation time is dose dependent. The findings suggest PVA Fricke gel dosimeters as a dosimetric tool for medical applications like radiation therapy.

Purpose: To analyze the relationships between the evolution of training-load values and countermovement jump (CMJ) as an indicator of stress and fatigue in a high-level 800-m runner during a whole season, including indoor (ID) and outdoor season (OD). Methods: Over 42 weeks, daily training load was quantified as the result of the product of the intensity and volume, and it was termed load index (LI). CMJ was measured in every running session after warm-up and immediately after the last effort of the session. Other jump-related variables such as CMJ height loss, average weekly CMJ, initial CMJ of the next consecutive session, and initial CMJ of the following week were studied. Results: A significant negative relationship was observed between LI and weekly CMJ (ID: r = −.68, P <.001, common variance [CV] = 46%; OD: r = −.73, P <.001, CV = 53%), initial CMJ of the following week (OD: r = −.71, P <.01, CV = 50%), and CMJ height loss (ID: r = −.58, P <.01, CV = 34%; OD: r = −.52, P <.01, CV = 27%). A significant positive relationship was observed between LI and initial CMJ of the next consecutive session when LI values were <8 (OD: r =.72; P <.01, CV = 52%). However, from values ≥8, the relationship turned into a significant negative one (ID: r = −.74; P <.01, CV = 55%; OD: r = −64, P <.01, CV = 41%). Conclusions: CMJ may be a valid indicator of the degree of stress or fatigue generated by specific training sessions of a competitive athlete within a single session, a week, or even the following week. There could be an individual limit LI value from which the training volume does not allow a positive effect on high-speed actions such as a CMJ in the next consecutive session. [ABSTRACT FROM AUTHOR]

Alexandria TM Lee,1 Saihong Ignatius Ou1,2 1Department of Medicine, University of California Irvine School of Medicine, Orange, CA, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, USACorrespondence: Saihong Ignatius Ou, University of California Irvine School of Medicine, Department of Medicine, Division of Hematology-Oncology, Chao Family Comprehensive Cancer Center, 200 South Manchester, Suite 400, Orange, CA, 92868, USA, Tel +1 714-456-5153, Email siou@hs.uci.eduAbstract: Alectinib, a next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has demonstrated superior progression-free survival over crizotinib with both 300 mg twice daily (J-ALEX) or 600 mg twice daily (ALEX, ALESIA) dosing in three pivotal clinical trials. Given the similar median PFS achieved in the J-ALEX trial and the Asian subgroup of the ALEX trial, there remains debate about the optimal alectinib dose for Asians. The third pivotal alectinib trial, ALESIA, which was conducted exclusively in Asia to support the registration of alectinib in China, utilized 600 mg alectinib twice daily. The mature PFS was not reached at the initial publication of ALESIA. At ESMO Asia 2022, the 5-year update of ALESIA was presented with an impressive mature investigator-assessed PFS of 41.6 months (95% CI 33.1– 58.9), which is numerically longer than the mature PFS of 34.1 months achieved by alectinib at 300 mg twice daily in the J-ALEX trial. Based on these results, as well as retrospective pharmacokinetic and responses and PFS data, Alectinib at 600 mg twice daily is the optimal dose for Asians. This has been based on the ALESIA trial and on the retrospective pharmacokinetic and responses and PFS data and has set the benchmark for ALK TKI as the first-line treatment for advanced ALK+ NSCLC in Asia. Importantly, lorlatinib, another next generation ALK TKI, also achieved an impressive hazard ratio with a still immature PFS in all patients, including Asian patients, in a recent subgroup analysis after a median follow-up time of 36.7 months. We await the final mature PFS of lorlatinib overall and for Asian patients in the CROWN trial to see if lorlatinib will set a new standard.Keywords: ALESIA, CROWN, alectinib, lorlatinib, brigatinib, pharmacokinetics, dose response, ALK fusion, NSCLC

BackgroundEmpirical evidence has shown that light therapy (LT) can reduce depression symptoms by stimulating circadian rhythms. However, there is skepticism and inconclusive results, along with confusion regarding dosing. The purpose of this study is to quantify light as a stimulus for the circadian system and create a dose-response relationship that can help reduce maladies among adolescents and young adults (AYAs). This will provide a reference for light exposure and neural response, which are crucial in the neuropsychological mechanism of light intervention. The study also aims to provide guidance for clinical application.MethodsThe latest quantitative model of CLA (circadian light) and CSt,f (circadian stimulus) was adopted to quantify light dose for circadian phototransduction in youth depression-related light therapy. Articles published up to 2023 through Web of Science, Cochrane Library, Medline (OVID), CINAHL, APA PsycINFO, Embase, and Scholars were retrieved. A meta-analysis of 31 articles (1,031 subjects) was performed using Stata17.0, CMA3.0 (comprehensive meta-analysis version 3.0) software, and Python 3.9 platform for light therapy efficacy comparison and dose-response quantification.ResultsUnder various circadian stimulus conditions (0.1 < CSt,f < 0.7) of light therapy (LT), malady reductions among AYAs were observed (pooled SMD = −1.59, 95%CI = −1.86 to −1.32; z = −11.654, p = 0.000; I2 = 92.8%), with temporal pattern (p = 0.044) and co-medication (p = 0.000) suggested as main heterogeneity sources. For the efficacy advantage of LT with a higher circadian stimulus that is assumed to be influenced by visualization, co-medication, disease severity, and time pattern, sets of meta-analysis among random-controlled trials (RCTs) found evidence for significant efficacy of circadian-active bright light therapy (BLT) over circadian-inactive dim red light (SMD = −0.65, 95% CI = −0.96 to −0.34; z = −4.101, p = 0.000; I2 = 84.9%) or circadian-active dimmer white light (SMD = −0.37, 95% CI = −0.68 to −0.06; z = −2.318, p = 0.02; I2 = 33.8%), whereas green-blue, circadian-active BLT showed no significant superiority over circadian-inactive red/amber light controls (SMD = −0.21, 95% CI = −0.45 to 0.04; z = −2.318, p = 0.099; I2 = 0%). Overall, circadian-active BLT showed a greater likelihood of clinical response than dim light controls, with increased superiority observed with co-medication. For pre-to-post-treatment amelioration and corresponding dose-response relationship, cumulative duration was found more influential than other categorical (co-medication, severity, study design) or continuous (CSt,f) variables. Dose-response fitting indicated that the therapeutic effect would reach saturation among co-medicated patients at 32–42 days (900–1,000 min) and 58–59 days (1,100–1,500 min) among non-medicated AYAs. When exerting high circadian stimulus of light therapy (0.6 < CSt,f < 0.7), there was a significantly greater effect size in 1,000–1,500 min of accumulative duration than 1,500 min of duration, indicating a threshold for practical guidance.LimitationsThe results have been based on limited samples and influenced by a small sample effect. The placebo effect could not be ignored.ConclusionsAlthough the superiority of LT with higher circadian stimulus over dimmer light controls remains unproven, greater response potentials of circadian-active BLT have been noticed among AYAs, taking co-medication, disease severity, time pattern, and visual characteristics into consideration. The dose-response relationship with quantified circadian stimulus and temporal pattern had been elaborated under various conditions to support clinical depression treatment and LT device application in the post-pandemic era.

To address the challenge of limited throughput with traditional toxicity testing, a newly developed high-throughput transcriptomics (HTT) platform, together with a 5-day in vivo rat model, offers an alternative approach to estimate chemical exposures and provide reasonable estimates of toxicological endpoints. This study contains an HTT analysis of 18 environmental chemicals with known liver toxicity. They were evaluated using male Sprague Dawley rats exposed to various concentrations daily for five consecutive days via oral gavage, with data collected on the sixth day. Here, we further explored the 5-day rat model to identify potential gene signatures that can differentiate between toxic and non-toxic liver responses and provide us with a potential histopathological endpoint of chemical exposure. We identified a distinct gene expression pattern that differentiated non-hepatotoxic compounds from hepatotoxic compounds in a dose-dependent manner, and an analysis of the significantly altered common genes indicated that toxic chemicals predominantly upregulated most of the genes and several pathways in amino acid and lipid metabolism. Finally, our liver injury module analysis revealed that several liver-toxic compounds showed similarities in the key injury phenotypes of cellular inflammation and proliferation, indicating potential molecular initiating processes that may lead to a specific end-stage liver disease. [ABSTRACT FROM AUTHOR]

Ultra-processed foods (UPFs), according to the NOVA classification food system, are food products that are processed using advanced processing technology, which improves palatability and sensory quality. However, UPFs increase the daily intake of energy, sodium, sugar, and total fat (including saturated fat), and decrease the intake of fiber. This might trigger overweight and obesity, the initial stages of noncommunicable diseases (NCDs). However, the effect of UPF consumption on NCDs remains under debate. This study aimed to synthesize the effect size of UPF dose response on various NCDs by using a meta-analysis method. The main output was a hazard ratio (HR) and a 95% confidence interval (CI). Using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) selection guidelines, 18 research articles were chosen for further effect size synthesis. The results showed that UPF consumption significantly increased the daily intake of carbohydrates, added sugar, saturated fat, sodium, energy, cholesterol, and total fat; increases of 49.64, 40.78, 30.00, 27.76, 26.67, 25.69, and 15.77%, respectively, were observed. Moreover, with UPF consumption, the fiber intake was way below the daily dietary recommendation (DR), at −38.55%. Further, a 10% increment in UPF consumption significantly affects diabetes, cardiovascular diseases, obesity, and cancer (HR ± 95% CI: 1.115 ± 0.044, 1.096 ± 0.053, 1.068 ± 0.050, and 1.020 ± 0.020, respectively). Thus, limiting daily UPF consumption could help prevent obesity and various NCDs. [ABSTRACT FROM AUTHOR]

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This study aimed to evaluate the response of Toona ciliata seedlings to sublethal doses of glyphosate. The increasing use of glyphosate in agriculture concerns the scientific community, as the drift of this pollutant into aquatic systems or atmospheric currents can affect non-target species. Therefore, we need to understand how non-target species respond to small doses of this herbicide. T. ciliata seedlings (clone BV-1110) were exposed to sublethal doses of glyphosate (0, 9.6, 19.2, 38.4, 76.8 g ae ha−1). Anatomical, physiological, and photochemical analyses were performed 60 days after herbicide application, and growth assessments were carried out after 160 days of cultivation. We found that sublethal doses of glyphosate above 19.2 g ae ha−1 induced toxicity symptoms in Toona ciliata leaves. These symptoms were mild in some cases, such as chlorosis, but severe in other cases, such as tissue necrosis. We observed a positive relationship between increased plant height and photochemical yield with plant exposure to sub-doses 9.6 and 19.2 g ae ha−1. A sublethal dose of 38.4 g ae ha−1 improved the photosynthetic rate and carboxylation efficiency. Thus, we confirmed the hypothesis of a hormetic effect when T. ciliata was exposed to sub-doses of glyphosate equal to or lower than 38.4 g ae ha−1. However, the sublethal dose of 76.8 g ae ha−1 must be considered toxic, impacting photosynthetic activity and, consequently, the height of T. ciliata. The stem diameter of T. ciliata responded positively to increasing glyphosate doses. This occurs to compensate for the negative effect of glyphosate on water absorption. Further research will provide valuable information for harnessing the potential benefits of hormesis to improve the productivity of T. ciliata. [ABSTRACT FROM AUTHOR]

The evolution of azole resistance in fungal pathogens presents a major challenge in both crop production and human health. Apple orchards across the world are faced with the emergence of azole fungicide resistance in the apple scab pathogen Venturia inaequalis. Target site point mutations observed in this fungus to date cannot fully explain the reduction in sensitivity to azole fungicides. Here, polygenic resistance to tebuconazole was studied across a population of V. inaequalis. Genotyping by sequencing allowed Quantitative Trait Loci (QTLs) mapping to identify the genetic components controlling this fungicide resistance. Dose-dependent genetic resistance was identified, with distinct genetic components contributing to fungicide resistance at different exposure levels. A QTL within linkage group seven explained 65% of the variation in the effective dose required to reduce growth by 50% (ED50). This locus was also involved in resistance at lower fungicide doses (ED10). A second QTL in linkage group one was associated with dose-dependent resistance, explaining 34% of variation at low fungicide doses (ED10), but did not contribute to resistance at higher doses (ED50 and ED90). Within QTL regions, non-synonymous mutations were observed in several ATP-Binding Cassette and Major Facilitator SuperFamily transporter genes. These findings provide insight into the mechanisms of fungicide resistance that have evolved in horticultural pathogens. Identification of resistance gene candidates supports the development of molecular diagnostics to inform management practices. [ABSTRACT FROM AUTHOR]

Background. Eccentric exercise may trigger mechanical stress, resulting in muscle damage that may decrease athletic performance. L-citrulline potentially prevents skeletal muscle damage after acute eccentric exercise. This study aimed to assess the dose-response effect of L-citrulline as a preventive therapy for skeletal muscle damage in mice after acute eccentric exercise. Methods. This is a controlled laboratory in vivo study with a post-test-only design. Male mice (BALB/c, n=25) were randomized into the following groups: a normal control (C1) (n=5); a negative control (C2) with downhill running and placebo intervention (n=5); treatment groups: T1 (n=5), T2 (n=5), and T3 (n=5), were subjected to downhill running and 250, 500, and 1,000 mg/kg of L-citrulline, respectively, for seven days. Blood plasma was used to determine the levels of TNNI2 and gastrocnemius muscle tissue NOX2, IL-6, and caspase 3 using ELISA. NF-χB and HSP-70 expressions were determined by immunohistochemistry. Results. Skeletal muscle damage (plasma TNNI2 levels) in mice after eccentric exercise was lower after 250 and 500 mg/kg of L-citrulline. Further, changes in oxidative stress markers, NOX2, were reduced after a 1,000 mg/kg dose. However, a lower level of change has been observed in levels of cellular response markers (NF-κB, HSP-70, IL-6, and caspase 3) after administration of L-citrulline doses of 250, 500, and 1,000 mg/kg. Conclusion. L-citrulline may prevent skeletal muscle damage in mice after acute eccentric exercise through antioxidant effects as well as inflammatory and apoptotic pathways. In relation to dose-related effects, it was found that L-citrulline doses of 250, 500, and 1,000 mg/kg significantly influenced the expression of NF-κB and HSP-70, as well as the levels of IL-6 and caspase 3. Meanwhile, only doses of 250 and 500 mg/kg had an impact on TNNI2 levels, and the 1,000 mg/kg dose affected NOX2 levels. [ABSTRACT FROM AUTHOR]

Simple Summary: Proton pump inhibitors (PPIs) are commonly used for acid reduction in peptic ulcer diseases and esophageal reflux diseases. The effects of changing gut microbiota, and prolonged hypergastrinemia were reported. This study demonstrated that long-term PPI use in CRC patients was associated with an increased risk of death with dose–response effect but not for recurrence. PPIs may play a complex role in CRC patients. The dose–response effect of proton pump inhibitors on colorectal cancer prognosis is still under exploration. This population-based study in Taiwan was designed to examine the effect of proton pump inhibitors on overall death, colorectal cancer-specific death, and recurrence in colorectal cancer patients with different cumulative proton pump inhibitor dose levels. This cohort study was based on the Taiwan Cancer Registry and Taiwan National Health Insurance Research Database from 2005 to 2020. After frequency matching with a 1:1 ratio, a total of 20,889 users with proton pump inhibitors and 20,889 without proton pump inhibitors were analyzed. The cumulative defined daily dose level of proton pump inhibitor was stratified to explore the dose–response relationship. A proton pump inhibitor exposure cumulative defined daily dose > 60 after colorectal cancer diagnosis had higher risk of all-cause death than non-proton pump inhibitor users with adjusted hazard ratios of 1.10 (95% CIs: 1.04–1.18). For recurrence, a proton pump inhibitor exposure cumulative defined daily dose > 60 had reduced recurrence risk with an adjusted hazard ratio of 0.84 (95% CIs: 0.76–0.93). This study demonstrated that the long-term use of proton pump inhibitors in patients with colorectal cancer was associated with an increased risk of death that related to the proton pump inhibitor exposure cumulative defined daily dose > 60 and had different dose–response effect in various dose level. [ABSTRACT FROM AUTHOR]

This study focused on the thermoluminescence (TL) characteristics of YAl 3 (BO 3) 4 (YAB) phosphors modified with various contents of Sm3+ ions. The TL response of the YAB: Sm3+ phosphors exposed to beta irradiation was measured across the temperature range of 25–500 °C, exhibiting three TL maxima at 70, 235, and 408 °C. Preheating protocol was also carried out to remove the low temperature TL peak followed by further experiments with the two-remaining high-temperature peaks. In the TL measurements conducted with variable heating rates (HR) between 0.1 and 5 °Cs-1, an anomalous heating rate behaviour was observed. A semi-localized transition model was used to address this feature. There was a standard deviation of less than 5% in the reusability measurements. The results of the kinetic parameters obtained by initial rise (IR) and various heating rate (VHR) methods were compared with those obtained by glow curve deconvolution (GCD) method. T m - T stop analysis revealed a continuous distribution of trap levels with a trap depth ranging from 1.35 to 2.20 eV. Through the use of GCD, the glow curve was found to demonstrate general order kinetics and consist of seven superimposed traps. The values of the kinetic parameters obtained for the glow curve agreed with those obtained by other methods excluding the VHR method encountering an anomalous impact. The results obtained from these tests showed that the sample could be successfully used for TL dosimetry applications. [ABSTRACT FROM AUTHOR]

Introduction: Despite their inclination to induce tolerance, addictive states, and respiratory depression, synthetic opioids are among the most effective clinically administered drugs to treat severe acute/chronic pain and induce surgical anesthesia. Current medical interventions for opioid-induced respiratory depression (OIRD), wooden chest syndrome, and opioid use disorder (OUD) show limited efficacy and are marked by low success in the face of highly potent synthetic opioids such as fentanyl. D-Cysteine ethylester (D-CYSee) prevents OIRD and post-treatment withdrawal inmale/ female rats and mice with minimal effect on analgesic status. However, the potential aversive or rewarding effects of D-CYSee have yet to be fully characterized and its efficacy could be compromised by interactions with opioid-reward pathology. Methods: Using a model of fentanyl-induced conditioned place preference (CPP), this study evaluated 1) the dose and sex dependent effects of fentanyl to induce rewarding states, and 2) the extent to which D-CYSee alters affective state and the acquisition of fentanyl-induced seeking behaviors. Results: Fentanyl reward-related effects were found to be dose and sex dependent. Male rats exhibited a range-bound dose response centered at 5 µg/kg. Female rats exhibited a CPP only at 50 µg/kg. This dose was effective in 25% of females with the remaining 75% showing no significant CPP at any dose. Pretreatment with 100 mg/kg, but not 10 mg/kg, D-CYSee prevented acquisition of fentanyl seeking in males while both doses were effective at preventing acquisition in females. Discussion: These findings suggest that D-CYSee is an effective co-treatment with prescribed opioids to reduce the development of OUD. [ABSTRACT FROM AUTHOR]