The field of pharmacometrics has been responsible for countless advancements within the drug development space. In recent years, we have witnessed the implementation of both new and revived analytical methods to increase clinical trial success and even supplement the need for clinical trials all together. Throughout this article we will explore the path of pharmacometrics from its inception to present day. At this point in time, the target of drug development has been the average patient, and population approaches have primarily been utilized to support just that. The challenge we are now facing involves the translation from treating the typical patient to treating the real-world patient. For this reason, it is our opinion that future development efforts should account more for the individual. With advanced pharmacometric methods and growing technological infrastructure, precision medicine can become a development priority rather than a clinician's burden.

Biosafe wearable healthcare monitor has attracted significant attention owing to their applicability to wearable electronics. However, the narrow sensing range and poor response limit the application of flexible devices for comprehensive monitoring of human health-related physiological signals (i.e. pulse diagnosis). Critical challenges remain in the development of biocompatible materials and the design of flexible bio-integrated platforms for these purposes, targeting performance approaching those of conventional wafer-based technologies and long-term operational stability. In this context, this work presents a robust and flexible MXene/polydopamine (PDA)-composite-film-based pressure sensor in a portable/wearable fashion, which establishes a unique intercalated spherical-like PDA molecules structure, thereby resulting in excellent sensing performance. The MXene/PDA-based pressure sensor has sensitivity of up to 138.8 kPa-1 in the pressure range of 0.18-6.20 kPa with fast response and recovery speed (t1<100 ms; t2<50 ms). Associated embodiment involves real-time precise measurements of a variety of health-related physiological signals, ranging from wrist pulse, to finger motions, to vocalization and to facial expressions, with high sensitivity and accuracy. Studies on human subjects establish the clinical significance of these devices for future opportunities of health monitoring and intelligent control to predict and diagnose diseases.

An important objective of evolutionary biology has always been to grasp the evolutionary and genetic processes that contribute to speciation. The present work provides the first detailed account of the genetic and physiological adaptation to changing environmental temperatures as well as the reasons causing intraspecific divergence in the Eothenomys miletus from the Hengduan mountain (HM) region, one of the biodiversity hotspots. 161 E. miletus individuals from five populations in the HM region had their genomes simplified sequenced, and one additional individual from each community had their genomes resequenced. We then characterized the genetic diversity and population structure of each population and compared the phenotypic divergence in traits using neutral molecular markers. We detected significant phenotypic and genetic alterations in E. miletus from the HM region that were related to naturally occurring diverse habitats by combining morphometrics and genomic techniques. The E. miletus existed asymmetric gene flow patterns, indicating that five E. miletus populations exhibit a isolation-by-island model, and this was supported by the correlation between FST and geographic distance. Finally, PST estimated by phenotypic measures of most wild traits were higher than differentiation at neutral molecular markers, indicating directional natural selection favouring different phenotypes in different populations must have been involved to achieve this much differentiation. Our findings give information on the demographic history of E. miletus, new insights into their evolution and adaptability, and literature for studies of a similar nature on other wild small mammals from the HM region.

Recent declines in eastern wild turkeys (Meleagris gallopavo silvestris) has prompted increased interest in management and research of this important game species. However, the mechanisms underlying these declines are unclear, leaving uncertainty in how best to manage this species. Foundational to effective management of wildlife species is understanding the biotic and abiotic factors that influence demographic parameters and the contribution of vital rates to population growth. Our objectives for this study were to: 1) conduct a literature review to collect all published vital rates for eastern wild turkey over the last 50 years, 2) perform a scoping review of the biotic and abiotic factors that have been studied relative to wild turkey vital rates and highlight areas that require additional research, and 3) use the published vital rates to populate a life-stage simulation analysis (LSA) and identify the vital rates that make the greatest contribution to population growth. Based on published vital rates for eastern wild turkey, we estimated a mean asymptotic population growth rate (λ) of 0.91 (95% CI = 0.71, 1.12). Vital rates associated with after second year (ASY) females were most influential in determining population growth. Survival of ASY females had the greatest elasticity (0.53), while reproduction of ASY females had lower elasticity (0.21), but high process variance, causing it to explain a greater proportion of variance in λ. Our scoping review found that most research has focused on the effects of habitat characteristics at nest sites and the direct effects of harvest on adult survival, while research on topics such as disease, weather, predators, or anthropogenic activity on vital rates have received less attention. We recommend that future research take a more mechanistic approach to understanding variation in wild turkey vital rates as this will assist managers in determining the most appropriate management approach.

The future of deprescribing research: seizing opportunities and learning from the past Michael A. Steinman, MDUniversity of California, San Francisco and the San Francisco VA Medical CenterWord count: 1549References: 10Funding: This work was supported by the National Institute on Aging (grants R24AG064025 and K24AG049057)Disclosures: Dr. Steinman receives royalties from UpToDate and honoraria from the American Geriatrics Society. This manuscript is based on a lecture given at the First International Conference on Deprescribing (ICOD), Kolding, Denmark, September 2022.

Objective: Combining different drugs increases the potential for drug-drug interactions en-hancing the risk of adverse drug reactions. We aimed to unravel potential pharma-cokinetic interactions between aripiprazole and duloxetine. Methods: Plasma concentrations of aripiprazole of two groups of 78 patients each, receiving aripiprazole as a monotherapy, or combined with duloxetine, were compared. A po-tential impact of duloxetine on the metabolism of aripiprazole was expected in high-er plasma concentrations of aripiprazole and higher dose-adjusted plasma concen-trations. Results: Patients co-medicated with duloxetine showed significantly higher plasma concen-trations of aripiprazole (p=0.019) by 54.2%. Dose-adjusted plasma concentrations were 45.6% higher (p=0.001). 65.4 % of these patients exhibited aripiprazole plasma concentrations above the upper limit of the therapeutic reference range, in the con-trol group this was only the case for 43.6% of the patients (p=0.006). A positive rela-tionship was found between the daily dose of duloxetine and dose-adjusted plasma concentrations of aripiprazole (p=0.034). Conclusions: Combining duloxetine and aripiprazole leads to significantly higher drug concentra-tions of aripiprazole, most likely via an inhibition of cytochrome P450 CYP2D6 and to a lesser extent of CYP3A4 by duloxetine. Clinicians have to consider increasing aripiprazole concentrations when adding duloxetine to a treatment regimen with ari-piprazole.

Understanding landscape connectivity has become a global priority for mitigating the impact of landscape fragmentation on biodiversity. Link-based methods traditionally rely on relating pairwise genetic distance between individuals or demes to their landscape distance (e.g., geographic distance, cost distance). In this study, we present an alternative to conventional statistical approaches to refine cost surfaces by adapting the Gradient Forest (GF) approach to produce a resistance surface. Used in community ecology, GF is an extension of random forest (RF), and has been implemented in genomic studies to model species genetic offset under future climatic scenarios. By design, this adapted method, resGF, has the ability to handle multiple environmental predicators and is not subjected to traditional assumptions of linear models such as independence, normality and linearity. Using genetic simulations, resGF performance was compared to other published methods. In univariate scenarios, resGF was able to distinguish the true surface contributing to genetic diversity among competing surfaces better than the compared methods. In multivariate scenarios, the GF approach performed similarly to the other RF-based approach using least-cost transect analysis (LCTA). Additionally, two worked examples are provided using two previously published datasets. This machine learning algorithm has the potential to improve our understanding of landscape connectivity and can inform long-term biodiversity conservation strategies.

Bioretention is widely used in urban sustainable stormwater management. However, limited numerical research has been conducted on its performance in cold regions, particularly for winter snowmelt, spring runoff and summer large storms (> 50 mm) for urban flood mitigation. In this study, HYDRUS 1D was used to explore these knowledge gaps. The model was comprehensively calibrated and validated against 2-year hydrologic and water quality data of four bioretention columns with different designs under lab-simulated cold region conditions. The Morris method was used to measure the sensitivity and interaction of the calibrated hydraulic parameters. The model revealed that the effective hydraulic conductivity ( KS) values of the soil media were similar for winter snowmelt and spring runoff when the soil temperature was around -0.5 °C. Preferential flow is likely to occur in soil media during winter or spring of cold regions. The summer modeling showed that the bioretention could substantially reduce peak flow, ponding depth and duration for large storm events (even for 1:100 local storm with 83.4 mm in 4 hours). The water quality modeling confirmed experimental results that the bioretention effectively removed phosphate and ammonium but had leaching issues for chloride and nitrate. Finally, optimization and recommendations of bioretention columns were provided.

Context – The negative effects of socioeconomic, environmental and ethnic inequalities on childhood respiratory diseases are known in the development of persistent asthma and can result in adverse outcomes. However, little is known about the effects of these disparities on pediatric intensive care unit (PICU) outcomes in respiratory diseases. Objective – The purpose of this systematic review is to evaluate the literature on disparities in socioeconomic, environmental and ethnic determinants on PICU outcomes. We hypothesize that these disparities negatively influence the outcomes of children’s respiratory diseases at the PICU. Methods – A literature search (in PubMed, Embase.com and Web of Science Core Collection) was performed up to September 30, 2022. Two authors extracted the data and independently evaluated the risk of bias with appropriate assessment methods. Articles were included if the patients were below 18 years of age (excluding neonatal intensive care unit admissions), they concerned respiratory diseases and incorporated socioeconomic, ethnic or environmental disparities. Results – Of 8746 references reviewed, 15 articles were included; seven articles on the effect of socioeconomic status, five articles on ethnicity, one on the effect of sex and lastly two on environmental factors. All articles but one showed an unfavorable outcome at the PICU. Conclusion – Disparities in socioeconomic (such as a low-income household, public health insurance), ethnic and environmental factors (such as exposure to tobacco smoke and diet) have been assessed as risk factors for the severity of children’s respiratory diseases and can negatively influence the outcomes of these children at the PICU.

Carnivores participate in forest disturbance recovery by dispersing the seeds that pass through their digestive systems. The objective of this study was to evaluate the capacity of mammals for Juniperus deppeana seed dispersal with an experimental evaluation of endozoochory and diploendozoochory, through indices of recovery, viability, changes in testas, and retention of seeds in the digestive tract. Juniperus deppeana fruits were collected in the Sierra Fría Natural Protected Area, Aguascalientes, Mexico, and were administered in the diet of gray fox (Urocyon cinereoargenteus), coati (Nasua narica) and domestic rabbits (Oryctolagus cuniculus) these three mammals represented the endozoochory. For the diploendozoochory, seeds excreted by rabbits were incorporated into the diets of bobcat (Lynx rufus) and cougar (Puma concolor) in a local zoo. The seeds present in the scats were collected, and recovery rates and retention times were estimated; viability was estimated by X-ray optical densitometry, and testa thicknesses and surfaces were checked by scanning electron microscopy. The results showed a recovery of seeds greater than 70% in all the animals; the retention time was < 24 h in the endozoochory, but the time was longer (24-96 h) in the diploendozoochory (P < 0.05). Seed viability (x ̵̅ ± SD) was decreased in rabbits (74.0 ± 11.5 %) compared to fruits obtained directly from the canopy (89.7 ± 2.0 %), while gray fox, coati, bobcat and puma did not affect viability (P < 0.05). An increase in the thickness of the testas was also observed in seeds excreted from all mammals (P < 0.05). Through evaluation, our results suggest that mammalian endozoochory and diploendozoochory contribute to dispersal of J. deppeana by maintaining viable seeds with adaptive characteristics in the testa to promote resilience and forest restoration. In particular, felines (predators) can provide an ecosystem service through scarification and seed dispersal.

Symphysis-Fundus Measurement; the Human Factor

In this paper, we study the optimal control of a discrete-time stochastic differential equation (SDE) of mean-field type, where the coefficients can depend on both a function of the law and the state of the process. We establish a new version of the maximum principle for discrete-time mean-field type stochastic optimal control problems. Moreover, the cost functional is also of the mean-field type. This maximum principle differs from the classical principle one since we introduce new discrete-time mean-field backward (matrix) stochastic equations. Based on the discrete-time mean-field backward stochastic equations where the adjoint equations turn out to be discrete backward SDEs with mean field, we obtain necessary first-order and sufficient optimality conditions for the stochastic discrete mean-field optimal control problem. To verify, we apply the result to production and consumption choice optimization problem.

Parkinson’s Disease (PD) and vitamin D share a unique link as Vitamin D deficiency (VDD) prevails in PD. Thus, an in-depth understanding of Vitamin D biology in PD might be crucial for therapeutic strategies emphasizing Vitamin D. Specifically, explicating the effect of VDD and genetic polymorphisms of vitamin D-associated genes in PD, like VDR (Vitamin D Receptor) or GC (Vitamin D Binding Protein), may aid the process along with polymorphisms of Vitamin D metabolizing genes (e.g., CYP2R1, CYP27A1) in PD. Literature review of single nucleotide polymorphisms (SNPs) related to Vitamin D levels [GC (GC1-rs7041, GC2-rs4588), CYP2R1, CYP24A1, CYP27B1] and Vitamin D function [VDR (FokI - rs2228570, ApaI - rs7976091, BsmI-rs1544410, TaqI-rs731236)] was conducted to explore their relationship with PD severity globally. Furthermore, the DisGeNET database was utilized to explore the gene-disease associations in PD, and STRING alongside Cytoscape was utilized to identify critical genes associated with PD. VDR-FokI polymorphism was reported to be significantly associated with PD in Hungarian, Chinese, and Japanese populations, whereas VDR-ApaI polymorphism was found to affect PD in the Iranian population. However, VDR-TaqI and BsmI polymorphisms had no significant association with PD severity. Conversely, GC1 polymorphisms reportedly affected Vitamin D levels without influencing the disease severity. CYP2R1 (excluding rs1993116) was also reportedly linked to clinical manifestations of PD. Genetic polymorphisms might cause VDD despite enough sunlight exposure and vitamin D-rich food intake, enhancing inflammation, and thereby influencing PD pathophysiology. Knowledge of the polymorphisms associated with vitamin D appears promising for developing new therapeutic strategies against PD.

Oxygen and extracellular matrix (ECM)-derived biopolymers play vital roles in regulating many cellular functions in both the healthy and diseased liver. This study reveals the importance of synergistically tuning the internal microenvironment to enhance oxygen availability alongside phenotypic ECM ligand presentation to promote native metabolic functions of human liver three-dimensional (3D) cell aggregates. First, fluorinated (PFC) chitosan microparticles (MPs) were generated with a microfluidic chip, then their oxygen transport properties were studied using a custom ruthenium-based oxygen sensing approach. Next, to allow for integrin engagements the surfaces of these MPs were functionalized using liver ECM proteins including fibronectin, laminin-111, laminin-511, and laminin-521. These MPs were used to assemble heterogeneous composite spheroids composed of human hepatocytes and human hepatic stellate cells. After in vitro culture, liver-specific functions and cell adhesion patterns were compared between groups and cells showed enhanced liver phenotypic responses in response to laminin-511 and 521 as evidenced via enhanced E-cadherin and vinculin expression as well as albumin and urea secretion. Furthermore, hepatocytes and stellate cells arranged in more phenotypic arrangements when cocultured with laminin-511 and 521 modified MPs providing clear evidence that specific ECM proteins have distinctive roles in the phenotypic regulation of liver cells in engineering 3D spheroids. This study advances efforts to create more physiologically relevant organ models allowing for well-defined conditions and phenotypic cell signaling which together improve the relevance of 3D spheroid and organoid models.

A document by Tasneem Naqvi. Click on the document to view its contents.

Rationale: The fundamental understanding of Grignard-type organolanthanides(III) is still in its infancy. Decarboxylation of metal carboxylate ions is a powerful method to obtain organometallic ions which are well suited for gas-phase investigation by using ESI-MS in combination with DFT calculations. Methods： (RCO2)LnCl3- (R = CH3, Ln = La-Lu except Pm; Ln = La, R = CH3CH2, CH2CH, CHC, C6H5 and C6H11) ions were produced via ESI of LnCl3 and RCO2H/RCO2Na in methanol. Collision-induced dissociation (CID) was employed to examine whether RLnCl3- can be obtained via decarboxylation of (RCO2)LnCl3-. With the aid of DFT calculations, the influences of Ln and R on the formation of RLnCl3- can be uncovered. Results: When R was fixed as methyl, CID of (CH3CO2)LnCl3- (Ln = La-Lu except Pm) all gave (CH3)LnCl3- and LnCl3·- with a variation in the relative intensity ratio of (CH3)LnCl3-/LnCl3·-. The trend is following as (CH3)EuCl3-/EuCl3·- < (CH3)YbCl3-/YbCl3·- ≈ (CH3)SmCl3-/SmCl3·- < other (CH3)LnCl3-/LnCl3·-, which generally complies with the trend of Ln(III)/Ln(II) reduction potentials. When Ln was fixed as La and R groups were varied as CH3CH2, CH2CH, CHC, C6H5 and C6H11, the fragmentation behaviors of these (RCO2)LaCl3- are diverse. Except for (C6H11CO2)LaCl3-, the rest four (RCO2)LaCl3- ions all underwent decarboxylation to give RLaCl3-. The relative intensities of RLaCl3- compared to (RCO2)LaCl3- decrease as follow: CHC > CH2CH > C6H5 > CH3 > CH3CH2 >> C6H11 (not visible). Conclusion： A series of Grignard-type organolanthanide(III) ions RLnCl3- (R = CH3, Ln = La-Lu except Pm; Ln = La, R = CH3CH2, CH2CH, CHC and C6H5) were generated from (RCO2)LnCl3- via CO2 loss while (C6H5)LaCl3- not. The experimental and theoretical results suggest that the reduction potentials of Ln(III)/Ln(II) couples as well as the bulkiness and hybridization of hydrocarbyl groups play crucial roles in promoting or limiting the formation of RLnCl3- via decarboxylation.

BACKGROUND: Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end of induction (EOI) Curie Scores (CS) was previously described in patients undergoing a single autologous hematopoietic cell transplant (AHCT) as consolidation therapy. OBJECTIVE: We now examine the prognostic significance of CS in patients randomized to tandem AHCT on the Children’s Oncology Group (COG) trial ANBL0532. STUDY DESIGN: A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 was performed. Evaluable patients had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received a tandem AHCT (n=80). Optimal CS cut points maximized the outcome difference (≤ vs >CS cut-off) according to the Youden index. RESULTS: For recipients of tandem AHCT, the optimal cut point at diagnosis was CS=12, with superior EFS from study enrollment for patients with CS<12 (3-year EFS 74.2±7.9%) vs CS>12 (59.2±7.1%) (p=0.002). At EOI, the optimal cut point was CS=0, with superior end-induction EFS for patients with CS=0 (72.9±6.4%) vs CS>0 (46.5±9.1%) (p=0.002). CONCLUSION: In the setting of tandem transplantation for children with high-risk neuroblastoma, Curie scores at diagnosis and end-induction may identify a more favorable patient group. Patients treated with tandem AHCT who exhibited a CS<12 at diagnosis or CS=0 at EOI had superior EFS compared to those with CS above these cut points.

Camera traps have become in-situ sensors for collecting information on animal abundance and occupancy estimates. When deployed over a large landscape, camera traps have become ideal for measuring the health of ecosystems, particularly in unstable habitats where it can be dangerous or even impossible to observe using conventional methods. However, manual processing of imagery is extremely time and labor intensive. Because of the associated expense, many studies have started to employ machine learning tools, such as convolutional neural networks (CNNs). One drawback is that for the majority of networks a large number of images (millions) are needed to devise an effective identification or classification model. This study examines specific factors pertinent to camera trap placement in the field that may influence the accuracy metrics of a deep learning model that has been trained with a small set of images. False negatives and false positives may occur due to a variety of environmental factors that make it difficult for even a human observer to classify, including local weather patterns and daylight. We transfer-trained a CNN to detect 16 different object classes (14 animal species, humans, and fires) across 9,576 images taken from camera traps placed in the Chernobyl Exclusion Zone. After analyzing wind speed, cloud cover, temperature, and image contrast, there was a significant positive association between CNN success and temperature. Furthermore, we found that the model was more successful when images were taken during the day as well as when precipitation was not present. We show that external variables at camera trap locations have a noticeable effect on CNN accuracy. Qualitative site-specific factors can confuse quantitative classification algorithms such as CNNs. This study suggests that further exploration into the causes of error in classification modeling is necessary given the unique challenges posed by the analysis of camera trap imagery.