Dose-response Curves Research Articles

Causal Inference for Continuous Multiple Time Point Interventions.

There are limited options to estimate the treatment effects of variables which are continuous and measured at multiple time points, particularly if the true dose-response curve should be estimated as closely as possible. However, these situations may be of relevance: in pharmacology, one may be interested in how outcomes of people living with-and treated for-HIV, such as viral failure, would vary for time-varying interventions such as different drug concentration trajectories. A challenge for doing causal inference with continuous interventions is that the positivity assumption is typically violated. To address positivity violations, we develop projection functions, which reweigh and redefine the estimand of interest based on functions of the conditional support for the respective interventions. With these functions, we obtain the desired dose-response curve in areas of enough support, and otherwise a meaningful estimand that does not require the positivity assumption. We develop -computation type plug-in estimators for this case. Those are contrasted with g-computation estimators which are applied to continuous interventions without specifically addressing positivity violations, which we propose to be presented with diagnostics. The ideas are illustrated with longitudinal data from HIV positive children treated with an efavirenz-based regimen as part of the CHAPAS-3 trial, which enrolled children years in Zambia/Uganda. Simulations show in which situations a standard g-computation approach is appropriate, and in which it leads to bias and how the proposed weighted estimation approach then recovers the alternative estimand of interest.

Effect of Ultrahigh Dose Rate on Biomolecular Radiation Damage.

Dose rate is one of the important parameters in radiation-induced biomolecular damage. The effects of dose rate have been known to modify radiation toxicity in biological systems. The rate and extent of sublethal DNA damage (e.g., base damage and single-strand breaks) repair and those of cell proliferation have been manifested by dose rate. However, the recent preclinical application of ultrahigh dose rate [(UHDR) ca. 40 Gy/s and higher] radiation modalities have been shown to lower the type and extent of radiation damage to biological systems. At these UHDR, radiation-induced physicochemical and chemical processes are expected to differ from those observed after irradiation at conventional dose rates (CONV). It is unclear whether these UHDR conditions can affect the quality (type) and quantity (extent) of biomolecular damage such as DNA lesions. Here, we comparatively study the influence of indirect effects of CONV and UHDR on the formation of DNA strand breaks and clustered damage including densely accumulated lesions in an aerated and an anoxic dilute aqueous solution of a plasmid DNA model under low and high hydroxyl radical (•OH) scavenging conditions. Aqueous solutions of purified supercoiled plasmid DNA (pUC19) were prepared in either air- or nitrogen-saturated conditions, with Tris buffer added as the radiation-produced •OH scavenger at low and high scavenging capacities. These DNA samples were irradiated using kV X-ray systems at CONV (0.1 Gy/s) and high dose rate (HDR, 25 Gy/s) as well as UHDR (55 and 125 Gy/s) under different scavenging and environmental conditions. DNA lesions including strand breaks and clustered damage including densely accumulated lesions were quantified by gel electrophoresis and the yields of these lesions were calculated from the dose-response curve. Non-DSB clustered damage including densely accumulated lesions were evaluated by treating DNAs using bacterial endonuclease enzymes (Fpg and Nth) prior to gel electrophoresis. UHDR of 55 and 125 Gy/s induced lower amounts of both isolated strand breaks and clustered DNA damage including densely accumulated lesions at doses >40 Gy in the presence of oxygen, compared to the abundance of these lesions induced by 0.1 and 25 Gy/s irradiation under the same dose conditions. Overall, the strand break and clustered damage including densely accumulated lesions yields decreased by factors of 1.3-3.5 after UHDR. We did not observe these differences either via •OH scavenging or by removing oxygen from the solution. In addition, our results point out that the inter-track recombination reactions did not contribute to the observed dose-rate effects on DNA damage. The effects of dose rate on DNA damage are highly dependent on the total dose, as expected, but also on the •OH scavenging capacity that is employed in the aqueous DNA solutions. These important variables may be relevant in biological systems as well. On a practical level, our in vitro plasmid DNA model, which permits to precisely vary the scavenging capacity and gassing conditions (air saturated vs. N2 saturated) can help to differentiate dose-rate effects on biomolecular damage. Our results indicate that the radical-radical reactions are important in understanding the dose-rate effect on DNA damage.

Novel Effects of Chlorhexidine Gluconate on Gram-Positive vs Gram-Negative Microorganisms

Abstract Introduction/Objective Chlorhexidine Gluconate (CHG) is a widely used antiseptic for the skin, oral areas, and cleansing oneself for surgery. Uses of CHG throughout healthcare centers have proven to reduce potential pathogens and lessen risks of central venous catheter blood infections. Gram-positive and gram-negative microorganisms can lead to major diseases such as prostatitis, candidiasis, endocarditis, and more. It is crucial to understand the effects that CHG has on these organisms so we can accurately apply it to treat these various illnesses. It also allows us to better understand the source of surgical site infections (SSIs) and prevent them. Methods/Case Report A minimum bactericidal concentration (MBC) was employed to see how various CHG concentrations (0% (control), 1%, 3%, 5%, 7%, and 9%) would affect the gram-positive (C. albicans and S. aureus) and gram-negative (P. aeruginosa and E. coli) microorganisms. First, a 1.0 McFarland suspension was created for each organism. Then, the various CHG concentration wells for each microorganism would be created within 96 well plates. In each well, there was always 300 μL of solution (containing the McFarland suspension and CHG liquid formula (HibiClensTM). After 4 minutes of CHG exposure in each well, an inoculating loop was used to streak a petri dish. One trial was completed after all concentrations were done for each microoganism. Each trial was incubated for 24 hours and there were a total of 6 trials. Results (if a Case Study enter NA) The substantial results challenged the previously assumed hypothesis that gram- negative microorganisms are more resistant to CHG. The separation between the two types of microorganisms became evident at even the 1% CHG concentration. C. albicans and S. aureus are thriving with averages of approximately 74,333 CFU/mL and 70,333.3 CFU/mL respectively for 1% CHG in comparison to the 1% CHG concentration for P. aeruginosa (2,500 CFU/mL) and E. coli (22,334.3 CFU/mL). Additionally. P. aeruginosa and E. coli had no colonies in any of the trials at 7% and 9% CHG, while C. albicans and S. aureus were present in numerous amounts. Conclusion Through numerous trials using an MBC as a new method, dose response curves for E. coli, P. aeruginosa, S. aureus, and C. albicans were deduced. The curves displayed how gram-positive microorganisms are more resistant to CHG than gram-negative microorganisms, defying what was previously assumed. In regards to various diseases and infections caused by these various bacteria, CHG may now be assesed for potential forms of treatment.

Efficacy of pharmacological interventions for ADHD: protocol for an updated systematic review and dose–response network meta-analysis

BackgroundAttention-deficit/hyperactivity disorder (ADHD) affects approximately 5% of children globally, with symptoms often persisting into adulthood. While pharmacological interventions are commonly employed for management, understanding the optimal dosing for efficacy and tolerability remains crucial. This study aims to conduct a dose–response network meta-analysis to estimate the efficacy of pharmacological treatments across different doses, aiming to inform clinical decision-making and improve treatment outcomes.MethodsThis updated systematic review will include randomized controlled trials evaluating ADHD medication efficacy in children, adolescents, and adults. An updated search from a 2018 NMA will be conducted across multiple electronic databases with no language restrictions, using specific eligibility criteria focused on randomized controlled trials. The primary outcome will assess the severity of ADHD core symptoms, while secondary outcomes will consider treatment tolerability. A dose–response Bayesian hierarchical model will be used to estimate dose–response curves for each medication, identifying optimal dosing strategies.DiscussionWith this dose–response network meta-analysis, we aim to better understand the dose–response relationship of pharmacological treatment in ADHD, which could help clinician to the identification of optimal doses.Systematic review registrationOSF https://doi.org/10.17605/OSF.IO/3MY4A.

A novel 3D polymer gel dosimeter based on polymethyl methacrylate gel (PMMAG) for radiotherapy: Ultrasonic evaluation

This study investigates the characteristics of a novel polymer gel dosimeter (PMMAG) for radiotherapy applications, focusing on its radiation absorption and sensitivity properties. The PMMAG dosimeters were evaluated using both UV–vis spectrophotometry and ultrasonic techniques. The results of the study, UV–vis analysis revealed a significant increase in dose response with the introduction of a cross-linker, peaking at a monomer-to-cross-linker ratio of 5:3. Sensitivity analysis indicated optimal sensitivity at this ratio, with values reaching 0.021 a.u./Gy. Ultrasound evaluation showed that the speed of sound and attenuation coefficient demonstrated a linear relationship and a strong positive correlation with an increase in the applied radiation dose, with the highest sensitivity observed at 8 Gy. The optimal sample exhibited the highest dose-response values at both 4 Gy and 8 Gy doses. Sensitivity values ranged from 2.1 to 2.75. The ultrasonic measurements demonstrated a significantly larger dynamic range in dose response curves compared to UV–vis dose-response data. It is concluded that ultrasound shows great potential as a technique for the evaluation of polymer gel dosimeters. The PMMAG can be introduced as a novel dosimeter for ionizing radiation dosimetry, validated through both optical and ultrasound assessment methods. The consistent and reliable performance of the PMMAG dosimeters makes them suitable for various applications in radiation therapy.

Dy3+ doped Zn0.66Mg0.3Al2O4 nanophosphor for high dose radiation thermoluminescence dosimetric applications

Zinc Magnesium Aluminate doped with Dysprosium (Zn (1-x-y) Mg(y)Al2O4:x Dy (x=0.04 and y=0.3 mol%)) was prepared using the solution combustion synthesis method. The prepared phosphor was characterized using energy-dispersive X-ray spectroscopy, scanning electron microscopy, X-ray diffraction, transmission electron microscopy, and Fourier transform infrared, respectively, to study crystal structure, surface morphology, and vibrational properties. The thermoluminescence peak temperatures were 250°C, 248°C, and 246°C at irradiating doses of 600–1000 Gy, respectively. Through the computation of the activation energy (E), order of kinetics (b), and frequency factor (s−1), the kinetic parameters were assessed using the TL glow curve. It is observed from the TL dose-response curve that the intensity rises nearly linearly for all doses between 600 and 1000 Gy. Nanophosphor Zn0.66Mg0.3Al2O4:0.04Dy shows almost linear dose-response for a dose range of 600–1000 Gy and an optimum activation energy (E) of 0.93–0.97 eV, which makes it suitable for high-dose radiation thermoluminescence dosimetric applications.

T-cell engagers: model interrogation as a tool to quantify the interplay of relative affinity and target expression on trimer formation.

T-cell engagers (TCEs) represent a promising therapeutic strategy for various cancers and autoimmune disorders. These bispecific antibodies act as bridges, connecting T-cell receptors (TCRs) to target cells (either malignant or autoreactive) via interactions with specific tumour-associated antigens (TAAs) or autoantigens to form trimeric synapses, or trimers, that co-localise T-cells with target cells and stimulate their cytotoxic function. Bispecific TCEs are expected to exhibit a bell-shaped dose-response curve, with a defined optimal TCE exposure for maximizing trimer formation. The shape of the dose-response is determined by a non-trivial interplay of binding affinities, exposure and antigens expression levels. Furthermore, excessively low binding to the TCR may reduce efficacy, but mitigate risk of over-stimulating cytokine secretion or induce effector cell exhaustion. These inevitable trade-off highlights the importance of quantitatively understanding the relationship between TCE concentration, target expression, binding affinities, and trimer formation. We utilized a mechanistic target engagement model to show that, if the TCE design parameters are close to the recommended ranges found in the literature, relative affinities for TCR, TAA and target expression levels have qualitatively different, but predictable, effects on the resulting dose-response curve: higher expression levels shift the curve upwards, higher antigen affinity shifts the curve to the left, and higher TCR affinity shifts the curve upwards and to the left.

Identifying effects of volatile organic compounds exposure on kidney stone prevalence in U.S. adults: a cross-sectional analysis of NHANES 2007-2020.

Our aim was to comprehensively investigate the relationship between blood volatile organic compounds (VOCs) and kidney stone prevalence for U.S. adults. In this cross-sectional study, 10,052 participants from the 2007-2020 National Health and Nutrition Examination Survey (NHANES) were included. Multivariate logistic regression model was employed to investigate the association between 9 blood VOCs and kidney stones. We explored the dose-response relationship between blood VOCs and kidney stones using restricted cubic spline (RCS) analysis. Additionally, weighted quantile sum (WQS) regression model was performed to assess the overall association of 9 blood VOCs with kidney stones. Finally, subgroup analyses were conducted to identify the findings in different populations at high prevalence. Logistic regression analysis and dose-response risk curves revealed that blood benzene (aOR = 1.308, 95% CI: 1.118-1.530, P = 0.001), blood ethylbenzene (aOR = 1.280, 95% CI: 1.054-1.554, P = 0.013), blood m-/p-xylene (aOR = 1.187, 95% CI: 1.008-1.398, P = 0.040), blood 2,5-dimethylfuran (aOR = 1.319, 95% CI: 1.135-1.533, P < 0.001) and blood furan (aOR = 1.698, 95% CI: 1.305-2.209, P < 0.001) were positively associated with the prevalence of kidney stones. WQS regression analysis revealed that exposure to mixed blood VOCs was positively correlated with kidney stone prevalence (OR = 1.34, 95% CI: 1.14-1.57), with furans carrying the greatest weight. Subgroup analyses suggested that kidney stones were more susceptible to the effects of blood VOCs in young and middle-aged, female, overweight and obese, non-hypertensive, and non-diabetic populations. In this study, the results indicated that high VOC exposure was positively and independently associated with kidney stones in U.S. adults. This finding highlighted the need for public health strategies to reduce VOC exposure and its role in kidney stone prevention and treatment.

Transpulmonary Pressure as a Predictor of Successful Lung Recruitment: Reanalysis of a Multicenter International Randomized Clinical Trial.

Recruitment maneuvers are used in patients with ARDS to enhance oxygenation and lung mechanics. Heterogeneous lung and chest-wall mechanics lead to unpredictable transpulmonary pressures and could impact recruitment maneuver success. Tailoring care based on individualized transpulmonary pressure might optimize recruitment, preventing overdistention. This study aimed to identify the optimal transpulmonary pressure for effective recruitment and to explore its association with baseline characteristics. We performed post hoc analysis on the Esophageal Pressure Guided Ventilation (EpVent2) trial. We estimated the dose-response relationship between end-recruitment end-inspiratory transpulmonary pressure and the change in lung elastance after a recruitment maneuver by using logistic regression weighted by a generalized propensity score. A positive change in lung elastance was indicative of overdistention. We examined how patient characteristics, disease severity markers, and respiratory parameters predict transpulmonary pressure by using multivariate linear regression models and dominance analyses. Of 121 subjects, 43.8% had a positive change in lung elastance. Subjects with a positive change in lung elastance had a mean ± SD transpulmonary pressure of 15.1 ± 4.9 cm H2O, compared with 13.9 ± 3.9 cm H2O in those with a negative change in lung elastance. Higher transpulmonary pressure was associated with increased probability of a positive change in lung elastance (adjusted odds ratio 1.35 per 1 cm H2O of transpulmonary pressure, 95% CI 1.13-1.61; P = .001), which indicated an S-shaped dose-response curve, with overdistention probability > 50% at transpulmonary pressure values > 18.3 cm H2O. The volume of recruitment was transpulmonary pressure-dependent (P < .001; R2 = 0.49) and inversely related to a change in lung elastance after adjusting for baseline lung elastance (P < .001; R2= 0.43). Negative correlations were observed between transpulmonary pressure and body mass index, PEEP, Sequential Organ Failure Assessment score, and PaO2 /FIO2 , whereas baseline lung elastance showed a positive correlation. The body mass index emerged as the dominant negative predictor of transpulmonary pressure (ranking 1; contribution to R2 = 0.08), whereas pre-recruitment elastance was the sole positive predictor (contribution to R2 = 0.06). Higher end-recruitment transpulmonary pressure increases the volume of recruitment but raises the risk of overdistention, providing the rationale for transpulmonary pressure to be used as a clinical target. Predictors, for example, body mass index, could guide recruitment maneuver individualization to balance adequate volume gain with overdistention.

8801 Towards Safe and Efficacious Medical Therapy for Patients with Clinically Non-Functioning Pituitary Tumors

Abstract Disclosure: D. Zhang: None. M. Bergsneider: None. W. Kim: None. M.B. Wang: None. H. Vinters: None. A.P. Heaney: None. Clinically non-functioning pituitary tumors (CNFTs) account for one-third of all pituitary adenomas. They do not cause clinical and/or biochemical evidence of tumor-related hormone hypersecretion, grow insidiously and typically present with mass effect symptoms such as headache and visual field deficits. Surgical resection is the current standard of care for CNFTs but complete resection is infrequently achieved due to their size and invariable invasion of locally adjacent structures. CNFT remnant tumor regrowth rates approach 50% and these patients may need repeat surgery and/or radiotherapy (RT). The latter is quite effective in achieving tumor control, but carries a risk of hypopituitarism of ∼ 40% at 10 years. Although dopamine agonists and somatostatin receptor ligands have been explored as medical therapy, there are currently no consistently effective medical treatments for CNFTs. There is a clear unmet need for novel safe and effective medical therapies for these comparatively common tumors. In a highly innovative approach we have used patient-derived ex vivo 3D tumoroid human CNFTs in an automated high throughput compound screen (HTS) to identify novel tumoricidal and growth inhibitory compounds for CNFTs. To date, we have screened ∼4,000 compounds and have identified 13 potential hits that inhibited tumor cell proliferation (a reduction of 76±15%) and induced apoptosis (induction rate of 8.2 ± 6.6) in the CNFT tumoroids respectively. The hit compounds to date fall into 3 categories based on their targets, namely Na+/K+-ATPase inhibitors (n=6), reactive oxygen species (ROS) regulators (n=4), and cell cycle inhibitors (n=3). Representative “hit” compounds from each group identified in our primary screen were rescreened in triplicate in 20 concentrations from 25µM to 50pM at 2-fold dilutions. Dose-response curves characterized compound doses that inhibited cell viability by 50% (IC50) and ranged from 13nM to 103nM. Two of these 3 compounds also induced 2-3-fold apoptosis at 0.1uM with the final compound displaying a potent 5-10-fold pro-apoptotic effect at 0.15uM concentration. In parallel, we used single cell RNA sequencing to validate targets that emerged from our HTS and to characterize the mechanism of action (MOA) of these hit compounds. As proof of concept, several of the known drug targets were noted to be amongst the highest differentially expressed genes in the CNFT tumor cell population. This approach validating a candidate target in conjunction with demonstrable activity of a drug for that same target in CNFTs may simultaneously provide us with a back-bone molecule to further develop with structural activity relationship analysis and/or allow us to individualize drug choice in patients based on immunocytochemical tumor target expression. Presentation: 6/1/2024

ROMI: a randomized two-stage basket trial design to optimize doses for multiple indications.

Optimizing doses for multiple indications is challenging. The pooled approach of finding a single optimal biological dose (OBD) for all indications ignores that dose-response or dose-toxicity curves may differ between indications, resulting in varying OBDs. Conversely, indication-specific dose optimization often requires a large sample size. To address this challenge, we propose a Randomized two-stage basket trial design that Optimizes doses in Multiple Indications (ROMI). In stage 1, for each indication, response and toxicity are evaluated for a high dose, which may be a previously obtained maximum tolerated dose, with a rule that stops accrual to indications where the high dose is unsafe or ineffective. Indications not terminated proceed to stage 2, where patients are randomized between the high dose and a specified lower dose. A latent-cluster Bayesian hierarchical model is employed to borrow information between indications, while considering the potential heterogeneity of OBD across indications. Indication-specific utilities are used to quantify response-toxicity trade-offs. At the end of stage 2, for each indication with at least one acceptable dose, the dose with highest posterior mean utility is selected as optimal. Two versions of ROMI are presented, one using only stage 2 data for dose optimization and the other optimizing doses using data from both stages. Simulations show that both versions have desirable operating characteristics compared to designs that either ignore indications or optimize dose independently for each indication.

Strength of activation and temporal dynamics of bioluminescent-optogenetics in response to systemic injections of the luciferin

BioLuminescent OptoGenetics (“BL-OG”) is a chemogenetic method that can evoke optogenetic reactions in the brain non-invasively. In BL-OG, an enzyme that catalyzes a light producing reaction (i.e., a luciferase) is tethered to an optogenetic element that is activated in response to bioluminescent light. Bioluminescence is generated by injecting a chemical substrate (luciferin, e.g., h-Coelenterazine; h-CTZ) that is catalyzed by the luciferase. By directly injecting the luciferin into the brain, we show that bioluminescent light is proportional to spiking activity, and this relationship scales as a function of luciferin dosage. Here, we build on these previous observations by characterizing the temporal dynamics and dose response curves of bioluminescence generated by luminopsins (LMOs), a proxy of BL-OG effects, to intravenous (IV) injections of the luciferin. We imaged bioluminescence through a thinned skull of mice running on a wheel, while delivering h-CTZ via the tail vein with different dosage concentrations and injection rates. The data reveal a systematic relationship between strength of bioluminescence and h-CTZ dosage, with higher concentration generating stronger bioluminescence. We also found that bioluminescent activity occurs rapidly (< 60 s after IV injection) regardless of concentration dosage. However, as expected, the onset time of bioluminescence is delayed as the injection rate decreases. Notably, the strength and time decay of bioluminescence is invariant to the injection rate of h-CTZ. Taken together, these data show that BL-OG effects are highly consistent across injection parameters of h-CTZ, highlighting the reliability of BL-OG as a minimally invasive neuromodulation method.

Bugs on Drugs: Paracetamol Exposure Reveals Genotype-Specific Generational Effects on Life History Traits in Drosophila melanogaster.

Few investigations have been made to determine whether pharmaceutical drugs cause any generational effects. These effects can be divided into intergenerational and transgenerational effects. In insects, the F1 offspring of exposed individuals are considered to show intergenerational effects (as they have been exposed as germ cells or early embryos), while the F2 generation is fully non-exposed and considered to show transgenerational effects. Here, the common over-the-counter (OTC) drug, paracetamol, is investigated for genotype-specific responses and effects across generations on three life-history traits: fecundity, longevity, and spontaneous locomotor activity levels in the model species Drosophila melanogaster. Seven isofemale D. melanogaster lines were exposed to a high and intermediate dose of paracetamol determined by a dose-response curve. NMR investigations verified the long-term presence of paracetamol in the food substrate. Phenotypic effects of paracetamol ingestion were investigated on flies exposed to the drug and in their offspring and grand-offspring. The dose-response curve indicated genotype-specific responses to paracetamol. In the following experiment, all traits investigated displayed significant effects of paracetamol ingestion for at least one of the seven isofemale lines, and we detected strong genotype-specific responses to paracetamol. Fecundity tended to increase in individuals directly exposed to the drug whereas fecundity in the F2 generation was reduced (transgenerational). Longevity generally decreased in directly exposed individuals but tended to increase in F1 offspring (intergenerational). Paracetamol effects on spontaneous locomotor activity were primarily detected as transgenerational effects and were rarely seen in directly exposed individuals. However, across lines, no clear overall trend could be determined for any trait. The generational effects and marked genotype-specific response to paracetamol warrants further investigation of both genotype-specific responses and generational effects in general.

Associations of dietary total, heme, non-heme iron intake with diabetes, CVD, and all-cause mortality in men and women with diabetes

BackgroundIron metabolism disorders significantly increase the risk of diabetes and its related complications by inducing oxidative stress, inflammation, insulin resistance, and disturbances in glucose and lipid metabolism. However, whether dietary iron intake can influence progression of diabetes remains unclear. The present study aims to investigate the relationship between total iron, heme iron, and non-heme iron intake and diabetes, CVD, and all-cause mortality among men and women with diabetes in the U.S. population. MethodsA total of 4416 adults with diabetes(2415 men and 2001 women) from the NHANES 2003–2014 were enrolled. Dietary information was collected by 24-h dietary recall during two nonconsecutive days. Dietary total iron intake was measured based on the dietary survey. Dietary heme iron intake was calculated based on its proportion in dietary total iron intake from each food. non-heme iron is the difference between total iron and heme iron. Diabetes, CVD, and all-cause mortality status were identified as main outcomes. Cox models and RCS analysis were performed to estimate the hazard ratios and 95%CIs. ResultsFor men, the participants with a higher dietary heme iron intake were associated with higher risks of CVD (HRheme iron = 1.61,95%CI:1.03–2.51) and all-cause mortality (HRheme iron = 1.42,95%CI:1.10–1.83). For women, participants in the highest quartile of dietary total/heme/non-heme iron intake had a higher diabetes mortality risk ((HRtotal iron = 2.33,95%CI:1.24–4.38; HRheme iron = 1.87,95%CI:1.00–3.49; HRnon-heme iron = 2.28,95%CI:1.19–4.39), compared to those in the lowest quartile. Additionally, the dose–response curve for the relationship between dietary non-heme iron intake and CVD mortality followed a reverse J-shape in women with diabetes. ConclusionsHigher dietary heme iron intake was associated with an increased CVD mortality risk in both men and women with diabetes. Additionally, higher dietary total, heme, and non-heme iron intake was linked to an increased risk of diabetes mortality among women with diabetes. Therefore, women with diabetes should pay more attention on the overconsumption of any type of dietary iron.

Antipsychotic Drugs: A Concise Review of History, Classification, Indications, Mechanism, Efficacy, Side Effects, Dosing, and Clinical Application.

The introduction of the first antipsychotic drug, chlorpromazine, was a milestone for psychiatry. The authors review the history, classification, indications, mechanism, efficacy, side effects, dosing, drug initiation, switching, and other practical issues and questions related to antipsychotics. Classifications such as first-generation/typical versus second-generation/atypical antipsychotics are neither valid nor useful; these agents should be described according to the Neuroscience-based Nomenclature (NbN). Antipsychotic drugs are not specific for treating schizophrenia. They reduce psychosis regardless of the underlying diagnosis, and they go beyond nonspecific sedation. All currently available antipsychotic drugs are dopamine blockers or dopamine partial agonists. In schizophrenia, effect sizes for relapse prevention are larger than for acute treatment. A major unresolved problem is the implausible increase in placebo response in antipsychotic drug trials over the decades. Differences in side effects, which can be objectively measured, such as weight gain, are less equivocal than differences in rating-scale-measured (subjective) efficacy. The criteria for choosing among antipsychotics are mainly pragmatic and include factors such as available formulations, metabolism, half-life, efficacy, and side effects in previous illness episodes. Plasma levels help to detect nonadherence, and once-daily dosing at night (which is possible with many antipsychotics) and long-acting injectable formulations are useful when adherence is a problem. Dose-response curves for both acute treatment and relapse prevention follow a hyperbolic pattern, with maximally efficacious average dosages for schizophrenia of around 5 mg/day risperidone equivalents. Computer apps facilitating the choice between drugs are available. Future drug development should include pharmacogenetics and focus on drugs for specific aspects of psychosis.

Establishment of human pluripotent stem cell-derived cortical neurosphere model to study pathomechanisms and chemical toxicity in Kleefstra syndrome

In the present study, we aimed to establish and characterize a mature cortical spheroid model system for Kleefstra syndrome (KS) using patient-derived iPSC. We identified key differences in the growth behavior of KS spheroids determined by reduced proliferation marked by low Ki67 and high E-cadherin expression. Conversely, in the spheroid-based neurite outgrowth assay KS outperformed the control neurite outgrowth due to higher BDNF expression. KS spheroids were highly enriched in VGLUT1/2-expressing glutamatergic and ChAT-expressing cholinergic neurons, while TH-positive catecholamine neurons were significantly underrepresented. Furthermore, high NMDAR1 expression was also detected in the KS spheroid, similarly to other patients-derived neuronal cultures, denoting high NMDAR1 expression as a general, KS-specific marker. Control and KS neuronal progenitors and neurospheres were exposed to different toxicants (paraquat, rotenone, bardoxolone, and doxorubicin), and dose-response curves were assessed after acute exposure. Differentiation stage and compound-specific differences were detected with KS neurospheres being the most sensitive to paraquat. Altogether this study describes a robust 3D model system expressing the disease-specific markers and recapitulating the characteristic pathophysiological traits. This platform is suitable for testing developing brain-adverse environmental effects interactions, drug development, and screening towards individual therapeutic strategies.

On the dose-response association of fine and ultrafine particles in an urban atmosphere: toxicological outcomes on bronchial cells at realistic doses of exposure at the Air Liquid Interface

Air pollution and particulate matter (PM) are the leading environmental cause of death worldwide. Exposure limits have lowered to increase the protection of human health; accordingly, it becomes increasingly important to understand the toxicological mechanisms on cellular models at low airborne PM concentrations which are relevant for actual human exposure. The use of air liquid interface (ALI) models, which mimic the interaction between airborne pollutants and lung epithelia, is also gaining importance in inhalation toxicological studies. This study reports the effects of ALI direct exposure of bronchial epithelial cells BEAS-2B to ambient PM1 (i.e. particles with aerodynamic diameter lower than 1 μm). Gene expression (HMOX, Cxcl-8, ATM, Gadd45-a and NQO1), interleukin (IL)-8 release, and DNA damage (Comet assay) were evaluated after 24 h of exposure. We report the dose-response curves of the selected toxicological outcomes, together with the concentration-response association and we show that the two curves differ for specific responses highlighting that concentration-response association may be not relevant for understanding toxicological outcomes. Noteworthy, we show that pro-oxidant effects may be driven by the deposition of freshly emitted particles, regardless of the airborne PM1 mass concentration. Furthermore, we show that reference airborne PM1 metrics, namely airborne mass concentration, may not always reflect the toxicological process triggered by the aerosol.These findings underscore the importance of considering different aerosol metrics to assess the toxicological potency of fine and ultrafine particles. To better protect human health additional metrics should be defined, than account for the properties of the entire aerosol mixture including specific as particle size (i.e. particles with aerodynamic diameter lower than 20 nm), the relevant aerosol sources (e.g., traffic combustion, secondary organic aerosol …) as well as their atmospheric processing (freshly emitted vs aged ones).

Multiple Herbicide Resistance in Annual Ryegrass (Lolium rigidum Gaudin) in the Southeastern Cropping Region of Australia

Annual ryegrass (Lolium rigidum) is a problematic weed in winter crops and fallows in the southeastern cropping region (SCR) of Australia. This weed has evolved resistance to multiple herbicide groups, globally. In Australia, L. rigidum is more prevalent in the western and southern regions than in SCR. To assess the herbicide resistance status of L. rigidum, the response of five L. rigidum populations (collected from the SCR) to glyphosate, glufosinate, paraquat, haloxyfop-P-ethyl, and clethodim is determined using dose–response curves. Three parametric logistic models are used to determine the herbicide dose required to achieve 50% survival (LD50) and 50% growth reduction (GR50). The LD50 values for 50% survival at 28 days after treatment range from 1702 g a.e. ha−1 to 8225 g a.e. ha−1 for glyphosate, 1637 g a.i. ha−1 to 1828 g a.i. ha−1 for glufosinate, 141 g a.i. ha−1 to 307 g a.i. ha−1 for paraquat, 11 g a.i. ha−1 to 107 g a.i. ha−1 for haloxyfop-P-ethyl, and 17 g a.i. ha−1 to 48 g a.i. ha−1 for clethodim. The resistance factor, based on GR50 value, is highest in the S7 population (2.2 times) for glyphosate, the S11 population (2.3 times) for glufosinate, the S11 population (2.0 time) for paraquat, the S7 population (3.9 times) for haloxyfop-P-ethyl, and the S3 population (3.1 times) for clethodim, compared with the susceptible or less tolerant population. The S11 population is found to be resistant to five tested herbicides, based on resistance factors. Similarly, the S3 population is highly resistant to glyphosate, haloxyfop-P-ethyl, and clethodim compared with the W4 population. These results suggest that L. rigidum populations in the SCR exhibit resistance to multiple herbicide groups at labelled field rates. The findings highlight the necessity of adopting an integrated management approach, including the use of residual herbicides, tank mixing herbicides with different modes of action, and rotating herbicides in conjunction with cultural and mechanical control methods.

Association between vitamin B2 intake and cognitive performance among older adults: a cross-sectional study from NHANES

The impact of vitamin B2 (riboflavin) intake on cognitive performance among older adults in the United States (US) remains inadequately understood. This study aimed to explore the association between vitamin B2 intake and cognitive performance among non-institutionalized elderly people in the US. Weighted logistic regression was used to evaluate the association between vitamin B2 intake and cognitive performance. Vitamin B2 intake was determined from the mean of two 24-hour dietary recall interviews. Three cognitive ability assessment tests, namely the Immediate Recall Test (IRT), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST), were performed. Participants included all older adults over 60 who underwent cognitive scoring, with cut-offs defined based on the lowest quartile (25th percentile) for each test (the cut-offs for the three scores were 15.625, 12, and 33, respectively). Sensitivity analysis, including dose-response curves, subgroup analyses, interaction effects, per 1 standard deviation (SD), recommended dietary allowance (RDA), and residual energy model analysis, were performed to solidify the solid association between vitamin B2 and cognitive performance. A total of 2893 individuals aged over 60 were included, with a mean age of 69 (7) years, and 46% were men. There was a significant association between vitamin B2 intake and all three cognitive scores (IRT, Odds Ratio = 0.77, 95% confidence interval: [0.65,0.92]; AFT, 0.75, [0.64,0.88]; DSST, 0.72, [0.59,0.88]). Moreover, vitamin B2 intake above the RDA reduced the risk of low cognitive performance (IRT, 0.66, [0.46,0.93]; AFT, 0.83, [0.62,1.11]; DSST, 0.65, [0.45,0.92]) compared to intake below the RDA. Dose-response curves indicated that higher vitamin B2 intake was negatively associated with the risk of low cognitive performance. Physical activity may modify the association between vitamin B2 and cognitive performance. Vitamin B2 intake was positively associated with cognitive performance among older adults. Adequate vitamin B2 intake could help protect cognitive function.

Electrochemical Impedance Spectroscopy-Based Microfluidic Biosensor Using Cell-Imprinted Polymers for Bacteria Detection.

The rapid and sensitive detection of bacterial contaminants using low-cost and portable point-of-need (PoN) biosensors has gained significant interest in water quality monitoring. Cell-imprinted polymers (CIPs) are emerging as effective and inexpensive materials for bacterial detection as they provide specific binding sites designed to capture whole bacterial cells, especially when integrated into PoN microfluidic devices. However, improving the sensitivity and detection limits of these sensors remains challenging. In this study, we integrated CIP-functionalized stainless steel microwires (CIP-MWs) into a microfluidic device for the impedimetric detection of E. coli bacteria. The sensor featured two parallel microchannels with three-electrode configurations that allowed simultaneous control and electrochemical impedance spectroscopy (EIS) measurements. A CIP-MW and a non-imprinted polymer (NIP)-MW suspended perpendicular to the microchannels served as the working electrodes in the test and control channels, respectively. Electrochemical spectra were fitted with equivalent electrical circuits, and the charge transfer resistances of both cells were measured before and after incubation with target bacteria. The charge transfer resistance of the CIP-MWs after 30 min of incubation with bacteria was increased. By normalizing the change in charge transfer resistance and analyzing the dose-response curve for bacterial concentrations ranging from 0 to 107 CFU/mL, we determined the limits of detection and quantification as 2 × 102 CFU/mL and 1.4 × 104 CFU/mL, respectively. The sensor demonstrated a dynamic range of 102 to 107 CFU/mL, where bacterial counts were statistically distinguishable. The proposed sensor offers a sensitive, cost-effective, durable, and rapid solution for on-site identification of waterborne pathogens.