Evaluation of Fasting Glucose-Insulin-C-Peptide-Derived Metabolic Indices for Identifying Metabolic Syndrome in Young, Healthy Adults.

Metabolic syndrome (MetS) is a condition defined by a cluster of symptoms, including excessive adipose tissue, impaired glucose homeostasis, dyslipidemia, and high blood pressure (BP). We aimed to evaluate the correlation between the MetS criteria (IDF) and fasting glucose-insulin-C-peptide-derived indices in a cohort of 128 healthy young adults who were 20-35 years old at the time of this study. We measured fasting serum glucose, insulin, C-peptide (CP), HDL-cholesterol, triglycerides, and hsCRP; HOMA-IR INS, HOMA-IR CP1, HOMA-IR CP2, HOMA-BETA, HOMA-BETA CP, QUICKI, disposition index (DI), CP index (CPI), and 20/C-peptide*glucose. Significant correlations were found between BMI and all HOMA indices, QUICKI, and CPI; waist circumferences and HOMA-IR INS, HOMA-BETA, and QUICKI (for both sexes); glucose and HOMA-IR INS/CP1/CP2, HOMA-BETA CP, DI, and QUICKI; HDL-cholesterol and HOMA-IR INS, HOMA-BETA, and QUICKI for males and females only with QUICKI; triglycerides and HOMA-IR INS, HOMA-BETA, and QUICKI; systolic BP and HOMA-IR INS, HOMA-BETA; diastolic BP and DI. The cut-off values for HOMA-IR INS, HOMA-BETA, and QUICKI in the combined group (females + males) were 1.855, 82.250, 0.355; 2.115, 106.370, 0.345 for males; 1.805, 71.305, 0.355 for females. A stronger correlation was found between males' indices and hsCRP. In conclusion, CP-derived indices do not add significant information, and the male sex is more predisposed to MetS.

Impact of solvent dry down, phase change, vehicle pH and slowly reversible keratin binding on skin penetration of cosmetic relevant compounds: II. Solids.

We extended a mechanistic, physics-based framework of the dry down process, previously developed for liquids and electrolytes, to solids and coded it into the latest UB/UC/P&G skin permeation model, herein renamed DigiSkin. The framework accounts for the phase change of the permeant from dissolved in a solvent (liquid) to precipitated on the skin surface (solid). The evaporation rate for the solid is reduced due to lower vapor pressure for the solid state versus subcooled liquid. These vapor pressures may differ by two orders of magnitude. The solid may gradually redissolve and penetrate the skin. The framework was tested by simulating the in vitro human skin permeation of the 38 cosmetically relevant solid compounds reported by Hewitt et al., J. Appl. Toxicol. 2019, 1-13. The more detailed handling of the evaporation process greatly improved DigiSkin evaporation predictions (r2 = 0.89). Further, we developed a model reliability prediction score classification using diverse protein reactivity data and identified that 15 of 38 compounds are out of model scope. Dermal delivery predictions for the remaining chemicals have excellent agreement with experimental data. The analysis highlighted the sensitivity of water solubility and equilibrium vapor pressure values on the DigiSkin predictions outcomes influencing agreement with the experimental observations.

Drug disposition in neonatal Göttingen Minipigs: Exploring Effects of Perinatal Asphyxia and Therapeutic Hypothermia.

Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. Since both perinatal asphyxia (PA) and TH influence physiology, altered pharmacokinetics (PK) and pharmacodynamics (PD) are expected. Given that TH is the standard of care for PA with moderate to severe hypoxic-ischemic encephalopathy (HIE), disentangling the effect of PA versus TH on PK/PD is not possible in clinical settings. However, animal models can provide insights into this matter. The (neonatal) Göttingen Minipig, the recommended strain for nonclinical drug development, was selected as translational model. Four drugs - midazolam (MDZ), fentanyl (FNT), phenobarbital (PHB), and topiramate (TPM), were intravenously administered under four conditions: control (C), therapeutic hypothermia (TH), hypoxia (H), hypoxia + TH (H+TH). Each group included six healthy male neonatal Göttingen Minipigs anesthetized for 24 hours. Blood samples were drawn at 0 (pre-dose), and 0.5, 2, 2.5, 3, 4, 4.5, 6, 8, 12, 24 hours post-drug administration. Drug plasma concentrations were determined using validated bioanalytical assays. The PK parameters were estimated through compartmental and non-compartmental PK analysis (NCA). The study showed a statistically significant decrease in FNT clearance (CL, 66% decrease) with approximately 3-fold longer half-life (t1/2) in the TH group. The H+TH group showed a 17% reduction in FNT CL with a 62% longer t1/2 compared to the C group, however non-statistically significant. Trends towards lower CL and longer t1/2 were observed in the TH and H+TH groups for MDZ and PHB. Additionally, TPM demonstrated a 28% decrease in CL in the H group compared to controls. Significance Statement The overarching goal of this study using the neonatal Göttingen Minipig model was to disentangle the effects of systemic hypoxia and TH on PK, using four model drugs. Such insights can subsequently be used to inform and develop a physiologically-based pharmacokinetic (PBPK) model, which is useful for drug exposure prediction in human neonates.

Can internship programs affect nursing students' critical thinking disposition, caring behaviors, and professional commitment?

BACKGROUND: Nursing students are given opportunities to develop critical thinking disposition, caring behaviors, and professional commitment through clinical training. Therefore, nurse educators should move away from traditional methods toward new ones, such as internship programs in clinical training. This study assessed the effect of nursing internship programs on senior undergraduate nursing students' critical thinking disposition, caring behaviors, and professional commitment. METHODS: This quasi-experimental study was conducted using a pretest-posttest design but with no control group. The study sample included 46 senior students enrolled in nursing internship programs. A demographic questionnaire, the Critical Thinking Disposition Inventory (CTDI), the Caring Assessment Report Evaluation (Care-Q), and the Nursing Professional Commitment Scale (NPCS) were used to collect data before and five months after the nursing internship programs were implemented. RESULTS: The study findings revealed that the senior nursing students' caring behaviors improved, but the total scores of critical thinking disposition and professional commitment did not change significantly after the nursing internship programs (p > 0.05). CONCLUSION: According to the results, nurse educators are recommended to adopt strategies to improve the effectiveness of internship programs on critical thinking disposition and professional commitment among senior undergraduate nursing students.

Emotion processes in social and political contexts: the case of affective polarisation.

Democratic societies have to face the challenge of increasing affective polarisation - a strong, emotionally fuelled, opposition between adherents of different political parties, or conflicting views and attitudes in different social groups. Social and psychological sciences can contribute to a better understanding of this phenomenon and the special role of emotion theory and research in this respect. In their invited contribution, Bakker and Lelkes note the lack of conceptual precision of the term affective and invite emotion scientists to fill this notion with a theoretical structure that encourages systematic research across different problem areas and cultures. Two invited comments on this article support this initiative but favour an approach that privileges discrete emotions. In his comment, Von Scheve argues that intentionality and the associated action tendencies are essential to understand the emotional basis of polarisation. Halperin et al., based on a conceptual analysis and their own empirical research, they highlight the multi-faceted emotion of disappointment, covering both negative and positive aspects, as the most promising candidate. Finally, I consider the potential role of mixed or blended emotions as well as the potential contributions of appraisal theory, especially with respect to appraisal bias and ensuing emotion dispositions and action tendencies.

Association between emergency department disposition and mortality in patients with COVID-19 acute respiratory distress syndrome.

Objectives: Patients hospitalized for COVID-19 frequently develop hypoxemia and acute respiratory distress syndrome (ARDS) after admission. In non-COVID-19 ARDS studies, admission to hospital wards with subsequent transfer to intensive care unit (ICU) is associated with worse outcomes. We hypothesized that initial admission to the ward may affect outcomes in patient with COVID-19 ARDS. Methods: This was a retrospective study of consecutive adults admitted for COVID-19 ARDS between March 2020 and March 2021 at Stanford Health Care. Mortality scores at hospital admission (Coronavirus Clinical Characterization Consortium Mortality Score [4C score]) and ICU admission (Simplified Acute Physiology Score III [SAPS-III]) were calculated, as well as ROX index for patients on high flow nasal oxygen. Patients were classified by emergency department (ED) disposition (ward-first vs. ICU-direct), and 28- and 60-day mortality and highest level of respiratory support within 1 day of ICU admission were compared. A second cohort (April 2021‒July 2022, n = 129) was phenotyped to validate mortality outcome. Results: A total of 157 patients were included, 48% of whom were first admitted to the ward (n = 75). Ward-first patients had more comorbidities, including lung disease. Ward-first patients had lower 4C and similar SAPS-III score, yet increased mortality at 28 days (32% vs. 17%, hazard ratio [HR] 2.0, 95% confidence interval [95% CI] 1.0‒3.7, p = 0.039) and 60 days (39% vs. 23%, HR 1.83, 95% CI 1.04‒3.22, p = 0.037) compared to ICU-direct patients. More ward-first patients escalated to mechanical ventilation on day 1 of ICU admission (36% vs. 14%, p = 0.002) despite similar ROX index. Ward-first patients who upgraded to ICU within 48 h of ED presentation had the highest mortality. Mortality findings were replicated in a sensitivity analysis. Conclusion: Despite similar baseline risk scores, ward-first patients with COVID-19 ARDS had increased mortality and escalation to mechanical ventilation compared to ICU-direct patients. Ward-first patients requiring ICU upgrade within 48 h were at highest risk, highlighting a need for improved identification of this group at ED admission.

Circadian time-dependent effects of experimental colitis on theophylline disposition and toxicity.

BACKGROUND AND PURPOSE: Drug disposition undergoes significant alteration in patients with inflammatory bowel disease (IBD), yet circadian time-dependency of these changes remains largely unexplored. In this study, we aimed to determine the temporal effects of experimental colitis on drug disposition and toxicity. EXPERIMENTAL APPROACH: RNA-sequencing was used to screen genes relevant to colitis induced by dextran sodium sulfate in mice. Liver microsomes and pharmacokinetic analysis were used to analyze the activity of key enzymes. Dual luciferase assays and chromatin immunoprecipitation (ChIP) were employed to elucidate regulatory mechanisms. KEY RESULTS: RNA sequencing analysis revealed that colitis markedly influenced expression of cytochrome P450 (CYP) enzymes. Specifically, a substantial down-regulation of CYP1A2 and CYP2E1 was observed in livers of mice with colitis at Zeitgeber Time 8 (ZT8), with no significant changes detected at ZT20. At ZT8, the altered expression corresponded to diminished metabolism and enhanced incidence of hepato-cardiac toxicity of theophylline, a substrate specifically metabolized by these enzymes. A combination of assays, integrating liver-specific Bmal1 knockout and targeted activation of BMAL1 showed that dysregulation in CYP1A2 and CYP2E1 during colitis was attributable to perturbed BMAL1 functionality. Luciferase reporter and ChIP assays collectively substantiated the role of BMAL1 in regulating Cyp1a2 and Cyp2e1 transcription through its binding affinity to E-box-like sites. CONCLUSION AND IMPLICATION: Our findings establish a strong link between colitis and chronopharmacology, shedding light on how IBD affects drug disposition and toxicity over time. This research provides a theoretical foundation for optimizing drug dosage in patients with IBD.

The Intoxication Equivalency of 11-Hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) Relative to Δ9-tetrahydrocannabinol (THC).

Δ9-tetrahydrocannabinol (THC) is a psychoactive phytocannabinoid found in the Cannabis sativa plant. THC is primarily metabolized into 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), that may themselves be psychoactive. There is very little research-based evidence concerning the pharmacokinetics and pharmacodynamics of 11-OH-THC as an individual compound. Male C57BL/6 mice were treated with THC or 11-OH-THC via i.p injection, tail vein i.v injection, or oral gavage (p.o), and whole blood compound levels were measured to determine pharmacokinetic parameters (Cmax, Tmax, t1/2, AUC, Vd, ClS, k and F) while also monitoring changes in catalepsy, body temperature, and nociception. 11-OH-THC achieved Tmax at 30 min for all routes of administration. The maximum concentration at 30 min was not different between i.v. and i.p. routes, but the p.o. Cmax was significantly lower. THC had a 10 min time to the maximum concentration - which was the first blood collection time point - for i.v. and i.p., and 60 min for p.o. with a lower Cmax for i.p. and p o. compared to i.v When accounting for circulating compound levels and ED50 responses, these data suggest that 11-OH-THC was 153% as active as THC in the tail-flick test of nociception, and 78% as active as THC for catalepsy. Therefore, 11-OH-THC displayed equal or greater activity than the parent compound THC, even when accounting for PK differences. Thus, the THC metabolite 11-OH-THC likely plays a critical role in the bioactivity of cannabis; understanding its activity when administered directly will aid in the interpretation of future animal and human studies. Significance Statement In this study we establish that the primary metabolite of THC - 11-OH-THC - displays equal or greater activity than THC in a mouse model of cannabinoid activity when directly administered and even when accounting for route of administration, sex, pharmacokinetic, and pharmacodynamic differences. These data provide critical insight into the bioactivity of THC metabolites that will inform the interpretation of future cannabinoid research and represent a model for how THC consumption and metabolism may affect cannabis use in humans.

Discharge to Skilled Nursing Facility Is a Risk Factor for Readmission: A Nationwide Propensity-Matched Study.

INTRODUCTION: General surgery procedures place stress on geriatric patients, and postdischarge care options should be evaluated. We compared the association of discharge to a skilled nursing facility (SNF) versus home on patient readmission. METHODS: We retrospectively reviewed the Nationwide Readmission Database (2016-2019) and included patients ≥65 y who underwent a general surgery procedure between January and September. Our primary outcome was 30-d readmissions. Our secondary outcome was predictors of readmission after discharge to an SNF. We performed a 1:1 propensity-matched analysis adjusting for patient demographics and hospital course to compare patients discharged to an SNF with patients discharged home. We performed a sensitivity analysis on patients undergoing emergency procedures and a stepwise regression to identify predictors of readmission. RESULTS: Among 140,056 included patients, 33,916 (24.2%) were discharged to an SNF. In the matched population of 19,763 pairs, 30-d readmission was higher in patients discharged to an SNF. The most common diagnosis at readmission was sepsis, and a greater proportion of patients discharged to an SNF were readmitted for sepsis. In the sensitivity analysis, emergency surgery patients discharged to an SNF had higher 30-d readmission. Higher illness severity during the index admission and living in a small or fringe county of a large metropolitan area were among the predictors of readmission in patients discharged to an SNF, while high household income was protective. CONCLUSIONS: Discharge to an SNF compared to patients discharged home was associated with a higher readmission. Future studies need to identify the patient and facility factors responsible for this disparity.

Drug disposition in cholestasis: An important concern.

Cholestasis, a chronic liver condition, disrupts bile acid homeostasis and complicates drug disposition, posing significant challenges in medicating cholestatic patients. Drug metabolism enzymes and transporters (DMETs) are pivotal in drug clearance. Research indicates that cholestasis leads to alterations in both hepatic and extrahepatic DMETs, with changes in expression and function documented in rodents and humans. This review synthesizes the modifications in key drug disposition components within cholestasis, focusing on cytochrome P450 (CYP450), drug transporters, and their substrates. Additionally, we briefly discuss certain drugs that have demonstrated efficacy in restoring DMET expression in cholestatic conditions. Ultimately, these insights necessitate a reevaluation of drug selection and dosing guidelines for patients with cholestasis.

One size does not fit all: the personal nature of completed embryo donation.

PURPOSE: To assess factors associated with embryo donation among individuals interested in donation in the United States. METHODS: An invitation to complete the 123-item survey was emailed from June to September 2022 to patients at a private practice fertility clinic with interest in donation at the time of IVF. Survey questions included disposition decision, attitudes about embryo status and genetic relatedness, donation disclosure, ideal donation arrangement, and decision satisfaction. RESULTS: Three hundred thirty-seven completed the survey. Two hundred thirty donated to another person(s), 75 discarded embryos, 25 remained undecided, and disposition was unknown for 7 respondents. There were no demographic differences between groups based on final disposition or use of donor gametes. Few gamete recipients were interested in donation due to biological attachment to embryos. Final embryo disposition was associated with religious factors, not wanting to waste embryos, and storage fee concerns. Final disposition was also significantly associated with concern about donor-conceived children's (DCP) welfare, being denied the ability to complete donation, personal IVF outcomes, financial or legal issues, future contact with DCP, cognitive appraisal of disposition, beliefs about embryos, someone else raising their genetic child, anonymity, and beliefs about DCP not knowing genetic relationships (p < .001). Donation to others was associated with less regret and greater satisfaction with the emotional/medical aspects of donation and counseling compared to those who discarded embryos (p < .001). CONCLUSION: The decision to donate embryos to another person(s) is complex. Counseling that considers individual circumstances, values, and evolving dynamics may facilitate informed decision-making for those navigating infertility treatment, family building, and embryo disposition.

Mass Balance, Metabolic Pathways, Absolute Bioavailability, And Pharmacokinetics of Giredestrant In Healthy Subjects.

Giredestrant is a potent and selective small molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination and metabolite profile of [14C]giredestrant. In Part 1 (mass balance), a single 30.8 mg oral dose of [14C]giredestrant (105 µCi) was administered to women of non-childbearing potential (WNCBP, n = 6). The mean recovery of total radioactivity (TR) in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In Part 2 (absolute bioavailability, aBA), WNCBP (n = 10) received an oral (30 mg capsule) or intravenous (30 mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant. Significance Statement This study provides definitive insight into the absorption, distribution, metabolism, and excretion of giredestrant in humans. The results show that giredestrant exhibits low clearance, high volume of distribution, and moderate oral bioavailability in humans. In addition, the data show that oxidative metabolism followed by excretion in feces is the primary elimination route of giredestrant in humans. These results will be used to further inform the clinical development of giredestrant.

Translational PK/PD and the first-in-human dose selection of a PD1/IL15: an engineered recombinant targeted cytokine for cancer immunotherapy.

Introduction: Interleukin 15 (IL-15) is a potential anticancer agent and numerous engineered IL-15 agonists are currently under clinical investigation. Selective targeting of IL-15 to specific lymphocytes may enhance therapeutic effects while helping to minimize toxicities. Methods: We designed and built a heterodimeric targeted cytokine (TaCk) that consists of an anti-programmed cell death 1 receptor antibody (anti-PD-1) and an engineered IL-15. This "PD1/IL15" selectively delivers IL-15 signaling to lymphocytes expressing PD-1. We then investigated the pharmacokinetic (PK) and pharmacodynamic (PD) effects of PD1/IL15 TaCk on immune cell subsets in cynomolgus monkeys after single and repeat intravenous dose administrations. We used these results to determine the first-in-human (FIH) dose and dosing frequency for early clinical trials. Results: The PD1/IL15 TaCk exhibited a nonlinear multiphasic PK profile, while the untargeted isotype control TaCk, containing an anti-respiratory syncytial virus antibody (RSV/IL15), showed linear and dose proportional PK. The PD1/IL15 TaCk also displayed a considerably prolonged PK (half-life range ∼1.0-4.1 days) compared to wild-type IL-15 (half-life ∼1.1 h), which led to an enhanced cell expansion PD response. The PD was dose-dependent, durable, and selective for PD-1+ lymphocytes. Notably, the dose- and time-dependent PK was attributed to dynamic TMDD resulting from test article-induced lymphocyte expansion upon repeat administration. The recommended first-in-human (FIH) dose of PD1/IL15 TaCk is 0.003 mg/kg, determined based on a minimum anticipated biological effect level (MABEL) approach utilizing a combination of in vitro and preclinical in vivo data. Conclusion: This work provides insight into the complex PK/PD relationship of PD1/IL15 TaCk in monkeys and informs the recommended starting dose and dosing frequency selection to support clinical evaluation of this novel targeted cytokine.

The longitudinal dispositions of people diagnosed with adjustment or severe stress disorders.

BACKGROUND: Adjustment and stress-related disorders are prevalent among psychiatric service users. Despite their prevalence, little is known about their prognosis. To reduce that gap, the present article documents the service use and diagnostic outcomes of people with adjustment or stress-related disorders presenting at Singapore's largest psychiatric emergency department. METHODS: Administrative data from 2014 to 2021 was retrieved to follow a group of 683 service users whose first-ever psychiatric presentation in 2014 warranted a diagnosis of adjustment or stress-related disorder. People were grouped a priori depending on whether different diagnoses were recorded within 7 days, 9 months, after 9 months or not at all. Survival curves characterized conversion to other diagnoses and engagement with healthcare services. Service use outcomes include the number of hospitalizations, outpatient appointments, emergency department visits, and prescriptions. RESULTS: Sixty-one percent (n = 417) never received another diagnosis over the 8-year period. This group used emergency services most and received the most pharmacotherapy shortly after their first visit. Of those who received another diagnosis, depression, personality disorders, and psychotic disorders were the most common. Those who received another diagnosis within 7 days (n = 70, 10%) received it on their first day of hospitalization (IQR 1-1), making the most use of inpatient services. The group who received another diagnosis within 9 months (n = 105, 15%) did so after 42 days (IQR 26-84) and had the highest relative number of deaths. Those who received another diagnosis after 9 months (n = 91, 13%) did so after 1,134 days (IQR 613-1,823) and had the longest period of engagement but made the least use of any psychiatric service, potentially suggesting a group whose early index diagnosis heralded vulnerability to future disorders. CONCLUSIONS: A large group of service users with acute stress or adjustment disorders will likely never be given another psychiatric diagnosis and appear to disengage following an initial period of high-intensity service use. The group that received a different diagnosis after the 9-month mark had prolonged contact with services but low intensity of service use and may represent a target for preventative intervention to help them improve their stress-managing skills and avoid developing other disorders.

Robust PWM control scheme for switched-capacitor MLI with leakage current suppression in grid-connected renewable energy application.

Typically, parasitic capacitances exist between the ground and the solar panel terminals in grid-connected PV systems. These parasitic capacitances provide a path for a leakage current, which leads to significant safety concerns, observable and seriously hazardous harmonic orders aligned with the injected grid current, and significant safety difficulties. In this research, a robust PWM controlling method that used competently in reducing the level of the leakage current and improving the power quality of a switched-capacitor Multilevel Inverter. This technique creates developed reference signals from the main signal to generate the switching scheme for the converter circuit. Additionally, the suggested control strategy only works with a small number of carrier signals, resulting in a quick system response and a simpler controller algorithm. Likewise, this controlling approach offers a stable way to maintain a constant output voltage in the suggested converter by adjusting the switching capacitors' voltages, which is not possible with traditional control techniques. MATLAB/Simulink is used to simulate the outcomes for both the suggested control approach and the traditional Phase Disposition (PD) PWM control method whereas the leakage current component reduces to 25 % compared to the captured component with the PDPWM. The simulation and the practical results based on the dSPACE-1103 hardware are quite similar.

Factors Affecting Leadership in Pharmacy Students: A Nationwide Survey.

Purpose: Leadership is increasingly becoming a priority in the forms of higher education associated with the Fourth Industrial Revolution; however, few studies have examined it in the context of pharmacy education. This study investigated the levels of communication competence, critical thinking disposition, problem-solving ability, and leadership of pharmacy students, and identified factors related to leadership. Methods: This study was conducted using a nationwide cross-sectional online survey with a self-administered questionnaire. A total of 416 third-to-sixth-year pharmacy students from all 35 pharmacy schools in South Korea, completed the survey from September 1 to 15, 2019. Data were analyzed using descriptive statistics, t-tests, Pearson's correlations, and multiple regression analysis. We verified construct validity by performing an exploratory factor analysis. Results: The pharmacy students revealed a moderate level of communication skills, critical thinking disposition, problem-solving ability, and leadership. Significant positive correlations were found among communication competence (r=0.724, p<0.001), critical thinking disposition (r=0.615, p<0.001), problem-solving ability (r=0.599, p<0.001), and leadership. After adjustment for control variables, communication competence (ß=0.319, p<0.001) was found to be the most significant predictor of leadership (F=104.12, p<0.001, R2=0.756). Conclusion: This study showed that the students' leadership was influenced by their competence in communicating effectively, thinking critically, and solving problems. Pharmacy educators should acknowledge and implement innovative curriculum and assessment approaches in preparing pharmacy students for their professional paths.

Validation of a Discharge Risk Calculator for Rural Patients Following Total Joint Arthroplasty.

INTRODUCTION: As the volume of total joint arthroplasty (TJA) in the US continues to grow, new challenges surrounding appropriate discharge surface. Arthroplasty literature has demonstrated discharge disposition to post-acute care facilities carries major risks regarding the need for revision surgery, patient co-morbidities, and financial burden. To quantify, categorize, and mitigaterisks, a decision tool that uses preoperative patient variables has previously been published and validated using an urban patient population. The aim of our investigation was to validate the same predictive model using patients in a rural setting undergoing total knee arthroplasty (TKA) and total hip arthroplasty (THA). METHODS: All TKA and THA procedures that were performed between January 2012 and September 2022 at our institution were collected. A total of 9,477 cases (39.6% TKA, 60.4% THA) were included for the validation analysis. There were nine preoperative variables that were extracted in an automated fashion from the electronic medical record. Included patients were then run through the predictive model, generating a risk score representing that patient's differential risk of discharge to a skilled nursing facility (SNF) versus home. Overall accuracy, sensitivity and specificity were calculated after obtaining risk scores. RESULTS: Score cutoff equally maximizing sensitivity and specificity was 0.23, and the proportion of correct classifications by the predictive tool in this study population was found to be 0.723, with an area under the curve (AUC) of 0.788-both higher than previously published accuracy levels. With the threshold of 0.23, sensitivity and specificity were found to be 0.720 and 0.723, respectively. CONCLUSION: The risk calculator showed very good accuracy, sensitivity, and specificity in predicting discharge location for rural patients undergoing TKA and THA, with accuracy even higher than in urban populations. The model provides an easy-to-use interface, with automation representing a viable tool in helping with shared decision-making regarding postoperative discharge plans.

Note on importance of correct stoichiometric assumptions for modeling of monoclonal antibodies.

Pharmacokinetic modeling of monoclonal antibodies (mAbs) with non-linear binding is based on equations of the target-mediated drug disposition (Mager and Jusko, J Pharmacokinet Pharmacodyn 28:507-532, 2001). These equations demonstrated their utility in countless examples and drug development programs. The model assumes that the mAb drug and the target have only one binding site each while, in reality, most antibodies have two binding sites. Thus, the currently used model does not correspond to the biological process that it aims to describe. The correct mechanistic model should take into account both binding sites. We investigated, using simulations, whether this discrepancy is important and when it is advisable to use a model with correct stoichiometric 2-to-1 ratio. We show that for soluble targets when elimination rate of the drug-target complex is comparable with the elimination rate of the drug or lower, and when measurements of both total drug and total target concentrations are available, the model with 1-to-1 (monovalent) binding cannot describe data simulated from the model with 2-to-1 (bivalent) binding. In these cases, models with correct stoichiometric assumptions may be necessary for an adequate description of the observed data. Also, a model with allosteric binding that encompasses both 2-to-1 and 1-to-1 binding models as particular cases was proposed and applied. It was shown to be identifiable given the detailed concentration data of total drug and total target.

Comparative legal perspectives on voluntary restraints: Analyzing the adaptation of preventive conditions on property rights.

The difficulty of the unique nature of the conditions for preventing action, which deviates from the norm of well-known and established legal systems, has caused great differences among legal jurists. This systematic review examines the preventing condition in the French and Palestinian legal systems, analyzes the justifications presented by jurists, addressing criticisms, clarifies different directions that have emerged, and compares it with the Egyptian legislation. These countries were selected after reviewing the laws related to the phenomenon and realizing the existence of differences between them in this regard. The PRISMA protocol was followed for conducting a review of papers written by Egyptian, French or other writers, and journal articles published in reputed international journals and published in (Sciencedirect, Google Scholar, Researchgate, JSTOR and Google Books). It was conducted during July and August 2023. Moreover, studies that addressed the legal conditions that prevent action were included. The findings reflected that from the initial 431 studies reviewed, 49 met the inclusion criteria. The legal conditions that prevent action have been considered by the relatively small number of studies included in the review. Researchers from different countries examined the phenomenon, and concluded that although jurists have presented several justifications, none has succeeded in explaining the judiciary's doctrine. Accordingly, we find upon examination some jurists expressing their confusion in justifying the passage of the condition of act prevention by invalidity, and concluding that it is an unjustified course of conduct. Therefore, this study gains its uniqueness through its determination of the proper legal adaptation of the preventing condition.