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Neurological long Covid (NLC) is a major post-acute sequela of SARS-CoV-2 infection, affecting up to 10% of infected patients. The clinical presentation of patients with NLC is varied, but general NLC symptoms have been noted to closely mimic symptoms of cerebral venous outflow disorders (CVD). Here we review key literature and discuss evidence supporting this comparison. We also aimed to describe the similarity between CVD symptomatology and neuro-NLC symptoms from two perspectives: a Twitter-distributed survey for long covid sufferers to estimate nature and frequency of neurological symptoms, and through a small cohort of patients with long covid who underwent CVD work up per our standard workflow. Over 700 patients responded, and we argue that there is a close symptom overlap with those of CVD. CVD workup in a series of 6 patients with neurological long COVID symptoms showed jugular vein stenosis by CT venography and varying degrees of increased intracranial pressure. Finally, we discuss the potential pathogenic association between vascular inflammation, associated with COVID-19 infection, venous outflow congestion, and its potential involvement in NLC.

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Stable isotope data have made pivotal contributions to nearly every discipline of the physical and natural sciences. As the generation and application of stable isotope data continues to grow exponentially, so does the need for a unifying data repository to improve accessibility and promote collaborative engagement. This paper provides an overview of the design, development, and implementation of IsoBank (www.isobank.org), a community-driven initiative to create an open-access repository for stable isotope data implemented online in 2021. A central goal of IsoBank is to provide a web-accessible database supporting interdisciplinary stable isotope research and educational opportunities. To achieve this goal, we convened a multi-disciplinary group of over 40 analytical experts, stable isotope researchers, database managers, and web developers to collaboratively design the database. This paper outlines the main features of IsoBank and provides a focused description of the core metadata structure. We present plans for future database and tool development and engagement across the scientific community. These efforts will help facilitate interdisciplinary collaboration among the many users of stable isotopic data while also offering useful data resources and standardization of metadata reporting across eco-geoinformatics landscapes.

Asunto(s)

Bases de Datos Factuales , Metadatos , Isótopos , Internet

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Cognitive abilities of primates, including humans, continue to improve through adolescence 1,2. While a range of changes in brain structure and connectivity have been documented 3,4, how they affect neuronal activity that ultimately determines performance of cognitive functions remains unknown. Here, we conducted a multilevel longitudinal study of monkey adolescent neurocognitive development. The developmental trajectory of neural activity in the prefrontal cortex accounted remarkably well for working memory improvements. While complex aspects of activity changed progressively during adolescence, such as the rotation of stimulus representation in multidimensional neuronal space, which has been implicated in cognitive flexibility, even simpler attributes, such as the baseline firing rate in the period preceding a stimulus appearance had predictive power over behavior. Unexpectedly, decreases in brain volume and thickness, which are widely thought to underlie cognitive changes in humans 5 did not predict well the trajectory of neural activity or cognitive performance changes. Whole brain cortical volume in particular, exhibited an increase and reached a local maximum in late adolescence, at a time of rapid behavioral improvement. Maturation of long-distance white matter tracts linking the frontal lobe with areas of the association cortex and subcortical regions best predicted changes in neuronal activity and behavior. Our results provide evidence that optimization of neural activity depending on widely distributed circuitry effects cognitive development in adolescence.

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Strenuous physical training increases total blood volume (BV) through expansion of plasma (PV) and red cell volumes (RCV). In contrast, exogenous erythropoietin (EPO) treatment increases RCV but decreases PV, rendering BV stable or slightly decreased. This study aimed to determine the combined effects of strenuous training and EPO treatment on BV and markers of systemic and muscle iron homeostasis. In this longitudinal study, 8 healthy non-anemic males were treated with EPO (50 IU/kg body mass, 3x/week, subcutaneously) across 28 days of strenuous training (4d/week, exercise energy expenditures of 1334±24 kcal/d) while consuming a controlled, energy-balanced diet providing 39±4 mg/d iron. Before (PRE) and after (POST) intervention, BV compartments were measured using carbon monoxide rebreathing, and markers of iron homeostasis were assessed in blood and skeletal muscle (vastus lateralis). Training + EPO increased (p<0.01) RCV (13±6%) and BV (5±4%), whereas PV remained unchanged (p=0.86). The expansion of RCV was accompanied by a large decrease in whole-body iron stores, as indicated by decreased (p<0.01) ferritin (-77±10%) and hepcidin (-49±23%) concentrations in plasma. Training + EPO decreased (p<0.01) muscle protein abundance of ferritin (-25±20%) and increased (p<0.05) transferrin receptor (47±56%). These novel findings illustrate that strenuous training combined with EPO results in both increased total oxygen carrying capacity and hypervolemia in young healthy males. The decrease in plasma and muscle ferritin suggests that the marked upregulation of erythropoiesis alters systemic and tissue iron homeostasis, resulting in a decline in whole-body and skeletal muscle iron stores.

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Acute mountain sickness (AMS) is a well-studied illness defined by clinical features (e.g., headache and nausea), as assessed by the Lake Louise score (LLS). Although obvious in its severe form, early stages of AMS are poorly defined and easily confused with common travel-related conditions. Measurement of hypoxaemia, the cause of AMS, should be helpful, yet to date its utility for identifying AMS susceptibility remains unclear. This study quantified altitude-induced hypoxaemia in individuals during an ascent to 4800 m to determine the utility of nocturnal pulse oximetry measurements for prediction of AMS. Eighteen individuals (36 ± 16 years of age) ascended to 4800 m over 12 days. Symptomology of AMS was assessed each morning via LLS criteria, with participants categorized as either AMS-positive (LLS ≥ 3 with headache) or AMS-negative. Overnight peripheral oxygen saturations (ov- S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_2}}}$ ) were recorded continuously (1 Hz) using portable oximeters. Derivatives of these recordings were compared between AMS-positive and -negative subjects (Mann-Whitney U-test). Exploratory analyses (Pearson's) were conducted to investigate relationships between overnight parameters and AMS severity. Overnight derivatives, including ov- S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_2}}}$ , heart rate/ov- S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_2}}}$ , variance, oxygen desaturation index, hypoxic burden and total sleep time at <80% S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_2}}}$ , all differed significantly between AMS-positive and -negative subjects (all P < 0.01), with cumulative/relative frequency plots highlighting these differences visually. Exploratory analysis revealed that ov- S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_2}}}$ from 3850 m was correlated with peak LLS at 4800 m (r = 0.58-0.61). The findings highlight the potential for overnight oximetry to predict AMS susceptibility during ascent to high altitude. Further investigation is required to develop, evaluate and optimize predictive models to improve AMS management and prevention.

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Astringency, commonly described as a drying, roughening, and/or puckering sensation associated with polyphenol-rich foods affects their palatability. While the compounds eliciting astringency are known, its mechanism of action is debated. This study investigated the role of transient receptor potential (TRP) channels A1 and V1 in astringency perception. If TRP A1 or V1 have a functional role in astringency perception, then desensitizing these receptors should decrease perceived astringency. Thirty-seven panelists underwent unilateral lingual desensitization of TRP A1 and V1 channels using mustard oil and capsaicin, respectively. Panelists then evaluated four astringent stimuli: epicatechin (EC), epigallocatechin gallate (EGCG), tannic acid (TA), and potassium alum (Alum), via 2-AFC and intensity ratings. When TRPA1 receptors were desensitized on one half of the tongue via mustard oil, no significant differences were observed between the treated and untreated sides for both 2-AFC and intensity ratings. Similarly, when TRPV1 receptors were desensitized on one half of the tongue via capsaicin, no significant differences were observed between the treated and untreated sides for both 2-AFC and intensity ratings. These findings challenge the notion that TRP channels play a pivotal role in astringency perception.

Asunto(s)

Capsaicina , Planta de la Mostaza , Aceites de Plantas , Canal Catiónico TRPA1 , Canales Catiónicos TRPV , Taninos , Humanos , Canales Catiónicos TRPV/metabolismo , Canal Catiónico TRPA1/metabolismo , Masculino , Adulto , Femenino , Capsaicina/farmacología , Planta de la Mostaza/química , Aceites de Plantas/farmacología , Aceites de Plantas/química , Taninos/farmacología , Taninos/química , Canales de Potencial de Receptor Transitorio/metabolismo , Adulto Joven , Percepción del Gusto/efectos de los fármacos , Percepción del Gusto/fisiología , Catequina/análogos & derivados , Catequina/farmacología , Catequina/química , Persona de Mediana Edad , Compuestos de Alumbre/farmacología , Gusto/efectos de los fármacos , Gusto/fisiología , Astringentes/farmacología , Lengua/efectos de los fármacos , Lengua/metabolismo

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This study evaluates the use of poly(vinyl alcohol), collagen, and chitosan blends for developing a microneedle patch for the delivery of meloxicam (MEL). Results confirm successful MEL encapsulation, structural integrity, and chemical stability even after ethylene oxide sterilization. Mechanical testing indicates the patch has the required properties for effective skin penetration and drug delivery, as demonstrated by load-displacement curves showing successful penetration of pig ear surfaces at 3N of normal load. In vitro imaging confirms the microneedle patch penetrates the pig's ear cadaver skin effectively and uniformly, with histological evaluation revealing the sustained presence and gradual degradation of microneedles within the skin. Additionally, in vitro drug diffusion experiments utilizing ballistic gel suggest that microneedles commence dissolution almost immediately upon insertion into the gel, steadily releasing the drug over 24 h. Furthermore, the microneedle patch demonstrates ideal drug release capabilities, achieving nearly 100% release of meloxicam content from a single patch within 18 h. Finally, in vivo studies using pigs demonstrate the successful dissolution and transdermal drug delivery efficacy of biodegradable microneedle patches delivering meloxicam in a porcine model, with over 70% of microneedles undergoing dissolution after 3 days. While low detectable meloxicam concentrations were observed in the bloodstream, high levels were detected in the ear tissue, confirming the release and diffusion of the drug from microneedles. This work highlights the potential of microneedle patches for controlled drug release in veterinary applications.

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Sistemas de Liberación de Medicamentos , Meloxicam , Agujas , Tiazinas , Meloxicam/administración & dosificación , Meloxicam/farmacocinética , Animales , Porcinos , Sistemas de Liberación de Medicamentos/instrumentación , Tiazinas/administración & dosificación , Tiazinas/farmacocinética , Tiazinas/química , Tiazoles/administración & dosificación , Tiazoles/farmacocinética , Tiazoles/química , Administración Cutánea , Piel/metabolismo , Liberación de Fármacos

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Proximity labeling (PL) has given researchers the tools to explore protein-protein interactions (PPIs) in living systems; however, most PL studies are performed on intracellular targets. We have adapted the original PL method to investigate PPIs within the extracellular compartment, which we term extracellular PL (ePL). To demonstrate the utility of this modified technique, we investigated the interactome of the matrisome protein TIMP2. TIMPs are a family of multifunctional proteins that were initially defined by their ability to inhibit metalloproteinases, the major mediators of extracellular matrix (ECM) turnover. TIMP2 exhibits broad expression and is often abundant in both normal and diseased tissues. Understanding the functional transformation of matrisome regulators, such as TIMP2, during disease progression is essential for the development of ECM-targeted therapeutics. Using dual orientation fusion proteins of TIMP2 with BioID2/TurboID, we describe the TIMP2 proximal interactome (MassIVE MSV000095637). We also illustrate how the TIMP2 interactome changes in the presence of different stimuli, in different cell types, in unique culture conditions (2D vs 3D), and with different reaction kinetics, demonstrating the power of this technique versus classical PPI methods. We propose that screening of matrisome targets in disease models using ePL will reveal new therapeutic targets for further comprehensive studies.

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Generative artificial intelligence (AI) and large language-models (LLMs) are increasingly being recognized as tools that can potentially transform many industries, including health care. The implementation and use of these tools among radiologists is likely variable, driven by radiology practice and institutional factors. Radiologists from various practices were asked about their perspectives on generative AI and LLMs in radiology.

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The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age at which to initiate screening in average-risk individuals and those with increased risk based on personal history of childhood, adolescent, and young adult cancer.

Asunto(s)

Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/normas , Detección Precoz del Cáncer/métodos , Tamizaje Masivo/métodos , Tamizaje Masivo/normas

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Objective: We examined the effect of frailty on in-hospital mortality, readmission rates, and hospitalization costs after transcatheter and surgical aortic valve replacement in a population-level cohort. Methods: The Nationwide Readmissions Database was queried for patients who underwent transcatheter or surgical aortic valve replacement during 2016-2018. Multivariate logistic regression was used to discern independent effects of frailty on outcomes. Kaplan-Meier time-to-event analysis was used to evaluate the effect of frailty on freedom from readmission. Results: A total of 243,619 patients underwent aortic valve replacement: 142,786 (58.6%) transcatheter aortic valve replacements and 100,833 (41.4%) surgical aortic valve replacements. Frail patients constituted 16,388 (11.5%) and 7251 (7.2%) in the transcatheter aortic valve replacement and surgical aortic valve replacement cohorts, respectively. Compared with nonfrail patients, frail patients had greater in-hospital mortality (transcatheter aortic valve replacement: 3.2% vs 1.1%; surgical aortic valve replacement: 6.1% vs 2.0%; both P < .001), longer length of stay (transcatheter aortic valve replacement: 4 vs 2 days; surgical aortic valve replacement: 13 vs 6 days; P < .001), and greater cost (transcatheter aortic valve replacement: $51,654 vs $44,401; surgical aortic valve replacement: $60,782 vs $40,544; P < .001). Time-to-event analysis showed that frail patients had higher rates of readmission over the calendar year in both transcatheter aortic valve replacement (P < .001) and surgical aortic valve replacement (P < .001) cohorts. This association persisted on adjusted multivariate regression for mortality (transcatheter aortic valve replacement odds ratio [95% CI] 1.98 [1.65-2.37], surgical aortic valve replacement 1.96 [1.60-2.41]), 30-day readmission (transcatheter aortic valve replacement 1.38 [1.27-1.49], surgical aortic valve replacement 1.47 [1.30-1.65]), and 90-day readmission (transcatheter aortic valve replacement 1.41 [1.31-1.52], surgical aortic valve replacement 1.60 [1.43-1.79]) (P < .001 for all). Conclusions: For patients undergoing transcatheter or surgical aortic valve replacement, frailty is associated with in-hospital mortality, readmission, and higher costs. Further efforts to optimize outcomes for frail patients are warranted.

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Neonatal dilated cardiomyopathy (DCM) is a poorly understood muscular disease of the heart. Several homozygous biallelic variants in LMOD2, the gene encoding the actin-binding protein Leiomodin 2, have been identified to result in severe DCM. Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting in neonatal death. Thus, it is evident that Lmod2 is essential to normal human cardiac muscle function. This study aimed to understand the underlying pathophysiology and signaling pathways related to the first reported LMOD2 variant (c.1193 G > A, p.Trp398*). Using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model harboring the homologous mutation to the patient, we discovered dysregulated actin-thin filament lengths, altered contractility and calcium handling properties, as well as alterations in the serum response factor (SRF)-dependent signaling pathway. These findings reveal that LMOD2 may be regulating SRF activity in an actin-dependent manner and provide a potential new strategy for the development of biologically active molecules to target LMOD2-related cardiomyopathies.

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The past decade has seen impressive advances in neuroimaging, moving from qualitative to quantitative outputs. Available techniques now allow for the inference of microscopic changes occurring in white and gray matter, along with alterations in physiology and function. These existing and emerging techniques hold the potential of providing unprecedented capabilities in achieving a diagnosis and predicting outcomes for traumatic brain injury (TBI) and a variety of other neurological diseases. To see this promise move from the research lab into clinical care, an understanding is needed of what normal data look like for all age ranges, sex, and other demographic and socioeconomic categories. Clinicians can only use the results of imaging scans to support their decision-making if they know how the results for their patient compare with a normative standard. This potential for utilizing magnetic resonance imaging (MRI) in TBI diagnosis motivated the American College of Radiology and Cohen Veterans Bioscience to create a reference database of healthy individuals with neuroimaging, demographic data, and characterization of psychological functioning and neurocognitive data that will serve as a normative resource for clinicians and researchers for development of diagnostics and therapeutics for TBI and other brain disorders. The goal of this article is to introduce the large, well-curated Normative Neuroimaging Library (NNL) to the research community. NNL consists of data collected from ∼1900 healthy participants. The highlights of NNL are (1) data are collected across a diverse population, including civilians, veterans, and active-duty service members with an age range (18-64 years) not well represented in existing datasets; (2) comprehensive structural and functional neuroimaging acquisition with state-of-the-art sequences (including structural, diffusion, and functional MRI; raw scanner data are preserved, allowing higher quality data to be derived in the future; standardized imaging acquisition protocols across sites reflect sequences and parameters often recommended for use with various neurological and psychiatric conditions, including TBI, post-traumatic stress disorder, stroke, neurodegenerative disorders, and neoplastic disease); and (3) the collection of comprehensive demographic details, medical history, and a broad structured clinical assessment, including cognition and psychological scales, relevant to multiple neurological conditions with functional sequelae. Thus, NNL provides a demographically diverse population of healthy individuals who can serve as a comparison group for brain injury study and clinical samples, providing a strong foundation for precision medicine. Use cases include the creation of imaging-derived phenotypes (IDPs), derivation of reference ranges of imaging measures, and use of IDPs as training samples for artificial intelligence-based biomarker development and for normative modeling to help identify injury-induced changes as outliers for precision diagnosis and targeted therapeutic development. On its release, NNL is poised to support the use of advanced imaging in clinician decision support tools, the validation of imaging biomarkers, and the investigation of brain-behavior anomalies, moving the field toward precision medicine.

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PURPOSE: Energy deficiency decreases muscle protein synthesis (MPS), possibly due to greater whole-body essential amino acid (EAA) requirements and reliance on energy stores. Whether energy deficit-induced anabolic resistance is overcome with non-nitrogenous supplemental energy or if increased energy as EAA is needed is unclear. We tested the effects of energy as EAA or carbohydrate, combined with an EAA-enriched whey protein, on post-exercise MPS (%/h) and whole-body protein turnover (g protein/240 min). METHODS: 17 adults (mean ± SD; age: 26 ± 6 y, BMI: 25 ± 3 kg/m 2 ) completed a randomized, parallel study including two 5-d energy conditions (BAL, energy balance; DEF, -30 ± 3% energy requirements) separated by ≥7 d. Volunteers consumed EAA-enriched whey with added EAA (+EAA; 304 kcal, 56 g protein, 48 g EAA, 17 g carbohydrate, 2 g fat; n = 8) or added carbohydrate (+CHO; 311 kcal, 34 g protein, 24 g EAA, 40 g carbohydrate, 2 g fat; n = 9) following exercise. MPS and whole-body protein synthesis (PS), breakdown (PB), and net balance (NET; PS-PB) were estimated postexercise with isotope kinetics. RESULTS: MPS rates were greater in +EAA (0.083 ± 0.02) than +CHO (0.059 ± 0.01; P = 0.015) during DEF, but similar during BAL ( P = 0.45) and across energy conditions within treatments ( P = 0.056). PS rates were greater for +EAA (BAL, 117.9 ± 16.5; DEF, 110.3 ± 14.8) than +CHO (BAL, 81.6 ± 8.0; DEF, 83.8 ± 5.9 g protein/240 min; both P < 0.001), and greater during BAL than DEF in +EAA ( P = 0.045). PB rates were less in +EAA (8.0 ± 16.5) than +CHO (37.8 ± 7.6 g protein/240 min; P < 0.001), and NET was greater in +EAA (106.1 ± 6.3) than +CHO (44.8 ± 8.5 g protein/240 min; P < 0.001). CONCLUSIONS: These data suggest that supplementing EAA-enriched whey protein with more energy as EAA, not carbohydrate, maintains postexercise MPS during energy deficit at rates comparable to those observed during energy balance.

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BACKGROUND: This study compared perioperative outcomes as well as encounter and 90-day costs between patients undergoing traditional vs robotic total knee arthroplasty (rTKA). MATERIALS AND METHODS: A total of 430 TKAs (215 rTKAs, 215 traditional) were retrospectively reviewed. All rTKAs were performed with an imageless, second-generation robotic system. Cohorts were propensity score matched by age, sex, body mass index, and American Society of Anesthesiologists score. Perioperative data and 90-day complications were subsequently compared. Cox regression analyses evaluated survival to all-cause revisions. Univariable analyses compared total cost of care for the initial encounter and 90-day postoperative period. Multivariable regression analyses were then performed to evaluate associations with increased encounter and 90-day costs. RESULTS: Patients undergoing rTKA had a higher incidence of discharge home (86.5% vs 60.0%; P<.001). The rTKA cohort trended toward a lower incidence of 90-day emergency department visits, and there was a significantly lower percentage of 90-day readmissions (4.2% vs 13.5%; P=.001). Cox hazard ratio demonstrated no difference in survival to all-cause revisions (hazard ratio, 1.3; 95% CI, 0.5-3.7; P=.64). The cost of surgery was significantly higher in the rTKA cohort ($9292 vs $8392; P<.001); however, there was no difference in cost of encounter ($10,356.86 vs $10,396.44; P=.110) or at 90 days postoperatively ($11,103.89 vs $11,040.13; P=.739). rTKA did not have a significant association with increased cost at 90 days postoperatively (odds ratio, 0.96; 95% CI, 0.90-1.02; P=.180). CONCLUSION: rTKA had a higher intraoperative cost compared with traditional TKA. However, with increased home discharges and fewer 90-day readmissions, rTKA was not associated with increased cost at 90 days. [Orthopedics. 202x;4x(x):xx-xx.].

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Research suggests that placebos administered without deception (i.e. non-deceptive placebos) may provide an effective and low-effort intervention to manage stress and improve mental health. However, whether non-deceptive placebos administered remotely online can manage distress for people at risk for developing high levels of affective symptoms remains unclear. Volunteers experiencing prolonged stress from the COVID-19 pandemic were recruited into a randomized controlled trial to examine the efficacy of a non-deceptive placebo intervention administered remotely online on affective outcomes. COVID-related stress, overall stress, anxiety, and depression were assessed at baseline, midpoint, and endpoint. Compared with the control group, participants in the non-deceptive placebo group reported significant reductions from baseline in all primary affective outcomes after 2 weeks. Additionally, participants in the non-deceptive placebo group found the intervention feasible, acceptable, and appropriate for the context. Non-deceptive placebos, even when administered remotely online, offer an alternative and effective way to help people manage prolonged stress. Future large-scale studies are needed to determine if non-deceptive placebos can be effective across different prolonged stress situations and for clinical populations.

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The use of acute carbon monoxide inhalation (COi) and hot water immersion (HWI) are of growing interest as interventions to stimulate erythropoietin (EPO) production. However, whether EPO production is further augmented when combining these stressors and whether there are sex differences in this response are poorly understood. Therefore, we measured circulating EPO concentration in response to acute COi and HWI independently and in combination and determined whether the responses were altered by sex. Participants completed three study visits-COi, HWI, and combined COi and HWI-separated by 1 week in a randomized, balanced, crossover design. Renal blood velocity was measured during all interventions, and carboxyhaemoglobin was measured during and after COi. Serum samples were analysed every hour for 6 h post-intervention for EPO concentration. HWI decreased renal blood velocity (46.2 cm/s to 36.2 cm/s) (P < 0.0001), and COi increased carboxyhaemoglobin (1.5%-12.8%) (P < 0.0001) without changing renal blood velocity (46.4-45.2 cm/s) (P = 0.4456). All three interventions increased peak EPO concentration from baseline (COi: 6.02-9.74 mIU/mL; HWI: 6.80-11.10 mIU/mL; COi + HWI: 6.71-10.91 mIU/mL) (P = 0.0048) and to the same extent (P = 0.3505). On average, females increased EPO while males did not in response to COi (females: 6.17 mIU/mL; males: 1.27 mIU/mL) (P = 0.0010), HWI (females: 6.47 mIU/mL; males: 2.14 mIU/mL) (P = 0.0104), and COi and HWI (females: 6.65 mIU/mL; males: 1.76 mIU/mL) (P = 0.0256). These data emphasize that combining these interventions does not augment EPO secretion and that these interventions may work better in females.

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Standard nonlinear regression is commonly used when modeling indifference points due to its ability to closely follow observed data, resulting in a good model fit. However, standard nonlinear regression currently lacks a reasonable distribution-based framework for indifference points, which limits its ability to adequately describe the inherent variability in the data. Software commonly assumes data follow a normal distribution with constant variance. However, typical indifference points do not follow a normal distribution or exhibit constant variance. To address these limitations, this paper introduces a class of nonlinear beta regression models that offers excellent fit to discounting data and enhances simulation-based approaches. This beta regression model can accommodate popular discounting functions. This work proposes three specific advances. First, our model automatically captures non-constant variance as a function of delay. Second, our model improves simulation-based approaches since it obeys the natural boundaries of observable data, unlike the ordinary assumption of normal residuals and constant variance. Finally, we introduce a scale-location-truncation trick that allows beta regression to accommodate observed values of 0 and 1. A comparison between beta regression and standard nonlinear regression reveals close agreement in the estimated discounting rate k obtained from both methods.