Miracle-dz/UniFAR-FTUs huggingface dataset:
Modeled Rat Hepatic and Plasma Concentrations of Chemicals after Virtual Administrations Using Two Sets of in silico Liver-to-Plasma Partition Coefficients.

The hepatic elimination of chemical substances in pharmacokinetic models requires hepatic intrinsic clearance (CLh,int) parameters for unbound drug in the liver, and these are regulated by the liver-to-plasma partition coefficients (Kp,h). Both Poulin and Theil and Rodgers and Rowland have proposed in silico expressions for Kp,h for a variety of chemicals. In this study, two sets of in silico Kp,h values for 14 model substances were assessed using experimentally reported in vivo steady-state Kp,h data and time-dependent virtual internal exposures in the liver and plasma modeled by forward dosimetry in rats. The Kp,h values for 14 chemicals independently calculated using the primary Poulin and Theil method in this study were significantly correlated with those obtained using the updated Rodgers and Rowland method and with reported in vivo steady-state Kp,h data in rats. When pharmacokinetic parameters were derived based on individual in vivo time-dependent data for diazepam, phenytoin, and nicotine in rats, the modeled liver and plasma concentrations after intravenous administration of the selected substrates in rats using two sets of in silico Kp,h values were mostly similar to the reported time-dependent in vivo internal exposures. Similar results for modeled liver and plasma concentrations were observed with input parameters estimated by machine-learning systems for hexobarbital, fingolimod, and pentazocine, with no reference to experimental pharmacokinetic data. These results suggest that the output values from rat pharmacokinetic models based on in silico Kp,h values derived from the primary Poulin and Theil model would be applicable for estimating toxicokinetics or internal exposure to substances.
Dysregulated neutrophil extracellular traps formation in sepsis

The migration and antimicrobial functions of neutrophils seem to be impaired during sepsis and contribute to the dysregulation of immune responses and disease pathogenesis. However, the role of neutrophil extracellular traps (NETs) remains to be clarified. The study aimed to analyse sequential phenotypic and functional changes of neutrophils during the time following the diagnosis of sepsis. We prospectively enrolled 49 septic and 18 non‐septic patients from the intensive care unit (ICU) and emergency room (ER) and 20 healthy volunteers (HV). Baseline blood samples from septic and non‐septic patients were collected within 12 h of admission to the hospital. Additional septic samples were drawn at 24, 48 and 72 h after baseline. Neutrophil phenotype and degranulation capacity were assessed by flow cytometry and NET formation was quantified by fluorescence. Neutrophils from septic patients exhibited increased CD66b, CD11b and CD177 expression but displayed reduced NET formation at baseline compared with non‐septic patients and HV controls. Neutrophils expressing CD177 interacted less with platelets, were related to reduced NETosis and tended to indicate a worse sepsis outcome. In vitro experiments revealed that neutrophil function is compromised by the origin of sepsis, including the pathogen type and the affected organ. Assessing a decision tree model, our study showed that CD11b expression and NETosis values are useful variables to discriminate septic from non‐septic patients. We conclude that sepsis induces changes in neutrophil phenotype and function that may compromise the effective capacity of the host to eliminate pathogens.
The Limit Is Zero: A Prospective Evaluation of Ketorolac in Patients Undergoing Primary Palatoplasty to Reduce Narcotic Utilization

Background: Patients undergoing primary palatoplasty rely on narcotics for pain control, but narcotics can lead to sedation and respiratory depression. Recent research into Enhanced Recovery After Surgery (ERAS) pathways utilizing multimodal pain therapy has yielded promising results for patients undergoing palatoplasty in terms of decreased hospital length of stay (LOS), increased oral intake, and decreased narcotic usage. Despite the potential benefit of ketorolac after palatoplasty, there is a paucity of data regarding its use. Methods: A single-center cohort study of patients undergoing primary palatoplasty was performed using 2 cohorts: a retrospective cohort treated with our institution’s prior ERAS protocol from 2016 to 2018 and a prospective group of patients who also received ketorolac (ERAS+K) postoperatively from 2020 to 2022. Results: A total of 85 patients (57 ERAS and 28 ERAS+K) were included. Compared with the ERAS group, the ERAS+K cohort had significantly decreased LOS (31.8 versus 55 h, P=0.02), decreased morphine milligram equivalents administered at 24 hours (1.5 versus 2.5, P=0.003), 48 hours (0 versus 1.5, P<0.001), and total inpatient morphine milligram equivalents (1.9 versus 3.8, P=0.001). The ERAS+K group also had a significant decrease in the prescribed narcotic rate (32.1% versus 61.4%, P=0.006). No bleeding issues, blood transfusions, or reoperations were noted in either cohort. Conclusions: This study illustrates many potential benefits of using ketorolac as a pain management adjunct in combination with a multimodal pain regimen. Our results demonstrated favorable outcomes, including decreased narcotic usage and LOS as well as increased hourly oral intake, without increasing bleeding complications.
Factors associated with blue-collar workers’ participation in Worksite Health Promotion Programs: a scoping literature review

Abstract A growing number of employers implement worksite health promotion programs (WHPPs). In particular, blue-collar workers may benefit from these WHPPs. However, they are less likely than other workers to participate and little is known about which factors affect their participation. The aim of this scoping literature review is to produce an overview of studies on factors associated with blue-collar workers’ participation in WHPPs. Five databases were searched: BSU, PsycINFO, Medline, Web of Science and CINAHL. The review included peer-reviewed empirical studies on determinants associated with blue-collar workers’ participation in WHPPs. Factors were extracted and categorized. Similar determinants were clustered and the direction of the associations was further examined. Nineteen papers describing 11 qualitative and 4 quantitative studies met the eligibility criteria. Seventy-seven determinants were analyzed (in quantitative studies) or reported (in qualitative studies). In most studies, only participant characteristics were investigated. Participation may be enhanced by addressing needs, tailoring from a broad range of activities, offering group activities, requiring little effort and commitment at the start, using incentives, leading by example and combining WHPPs with occupational safety interventions. WHPPs seem to be able to reach blue-collar workers, but it remains particularly challenging to reach shift workers and those who do not yet experience health complaints.
Treatment and outcome of the Dutch Childhood Craniopharyngioma Cohort study: First results after centralization of care

Abstract Background Childhood craniopharyngioma (cCP) has excellent survival, but quality of life may be severely hampered by hypothalamic dysfunction. We aimed to evaluate treatment and hypothalamic outcomes of a Dutch cCP cohort, and evaluate the effect of centralization of care. Methods A retrospective cohort study was performed, including cCP patients diagnosed between 2004 and 2021. Treatment characteristics and hypothalamic outcomes were evaluated and compared before and since centralization of care in May 2018. Results We included 87 cCP patients. Cyst drainage/fenestration was performed in 29.9%, limited resection in 27.6%, near-total resection in 16.1%, and gross total resection (GTR) in 25.4%. Radiotherapy was given in 46.0%. After a median follow-up of 6.5 years, hypothalamic obesity (HO) was present in 24.7% and panhypopituitarism with diabetes insipidus in 71.3%. Higher body mass index (BMI) SDS at diagnosis and Muller grade II at last magnetic resonance imaging of follow-up were associated with overweight/obesity. No association was found between extensiveness of resection and overweight/obesity at last follow-up. When comparing before and after centralization of care, rates of GTR remained similar, but BMI outcomes changed; mean ΔBMI SDS 1 year after diagnosis from 1.12 (SD 1.15) to 0.81 (SD 1.24), and HO after 1 year decreased from 33.3% to 12.0% (P = .067), and after 2 years from 28.6% to 6.7% (P = NS). Conclusions In our nationwide cohort, GTR was performed in a relatively low percentage of patients and extensiveness of resection was no longer associated with HO at follow-up. A trend toward improvement of BMI is observed since centralization of care, which needs further exploration.
A novel risk signature for predicting brain metastasis in patients with lung adenocarcinoma

Abstract Background Brain metastasis (BM) are a devastating consequence of lung cancer. This study was aimed to screen risk factors for predicting BM. Methods Using an in vivo BM preclinical model, we established a series of lung adenocarcinoma (LUAD) cell subpopulations with different metastatic ability. Quantitative proteomics analysis was used to screen and identify the differential protein expressing map among subpopulation cells. Q-PCR and Western-blot were used to validate the differential proteins in vitro. The candidate proteins were measured in LUAD tissue samples (n = 81) and validated in an independent TMA cohort (n = 64). A nomogram establishment was undertaken by performing multivariate logistic regression analysis. Results The quantitative proteomics analysis, qPCR and Western blot assay implied a five-gene signature that might be key proteins associated with BM. In multivariate analysis, the occurrence of BM was associated with age ≤ 65 years, high expressions of NES and ALDH6A1. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.934 (95% CI, 0.881–0.988) in the training set. The validation set showed a good discrimination with an AUC of 0.719 (95% CI, 0.595–0.843). Conclusions We have established a tool that is able to predict occurrence of BM in LUAD patients. Our model based on both clinical information and protein biomarkers will help to screen patient in high-risk population of BM, so as to facilitate preventive intervention in this part of the population.
Traumatic Experiences and Obsessive-Compulsive Symptoms

Abstract Accumulating evidence suggests that obsessive-compulsive symptoms (OCSs) are positively associated with exposure to traumatic experiences and dissociative symptoms in both clinical and community samples. The current study was aimed at investigating the relationships between traumatic experiences, dissociation, and OCSs. A sample of 333 community adults (56.8% females) aged from 18 to 56 years (mean [SD], 25.64 [6.70] years) completed measures on traumatic experiences, dissociative symptoms, and OCSs. A structural equation modeling (SEM) framework was used to test if dissociative symptoms mediated the relationship between traumatic experiences and OCSs. SEM analyses showed that dissociation fully mediated the predictive association between traumatic experiences of emotional neglect and abuse and OCSs in the sample. Accordingly, some individuals suffering from OCSs might benefit from clinical interventions aimed at processing and integrating traumatic experiences.
Acute effects of fatigue on internal and external load variables determining cyclists’ power profile

ABSTRACT The aim of the present study was to determine whether fatigue affects internal and external load variables determining power profile in cyclists. Ten cyclists performed outdoor power profile tests (lasting 1-, 5 and 20-min) on two consecutive days, subject either to a fatigued condition or not. Fatigue was induced by undertaking an effort (10-min at 95% of average power output obtained in a 20-min effort followed by 1-min maximum effort) until the power output decreased by 20% compared to the 1-min power output. Fatigued condition decreased power output (p < 0.05, 1-min: 9.0 ± 3.8%; 5-min: 5.9 ± 2.5%; 20-min: 4.1 ± 1.9%) and cadence in all test durations, without differences in torque. Lactate decreased in longer efforts when a fatigue protocol had previously been conducted (e.g., 20-min: 8.6 ± 3.0 vs. 10.9 ± 2.7, p < 0.05). Regression models (r2 ≥ 0.95, p < 0.001) indicated that a lower variation in load variables of 20-min in fatigued condition compared with the non-fatigued state resulted in a lower decrease in critical power after the fatigue protocol. The results suggest that fatigued condition on power was more evident in shorter efforts and seemed to rely more on a decrease in cadence than on torque. GRAPHICAL ABSTRACT
Bacillus subtilis extracellular protease production incurs a context‐dependent cost

Microbes encounter a wide range of polymeric nutrient sources in various environmental settings, which require processing to facilitate growth. Bacillus subtilis, a bacterium found in the rhizosphere and broader soil environment, is highly adaptable and resilient due to its ability to utilise diverse sources of carbon and nitrogen. Here, we explore the role of extracellular proteases in supporting growth and assess the cost associated with their production. We provide evidence of the essentiality of extracellular proteases when B. subtilis is provided with an abundant, but polymeric nutrient source and demonstrate the extracellular proteases as a shared public good that can operate over a distance. We show that B. subtilis is subjected to a public good dilemma, specifically in the context of growth sustained by the digestion of a polymeric food source. Furthermore, using mathematical simulations, we uncover that this selectively enforced dilemma is driven by the relative cost of producing the public good. Collectively, our findings reveal how bacteria can survive in environments that vary in terms of immediate nutrient accessibility and the consequent impact on the population composition. These findings enhance our fundamental understanding of how bacteria respond to diverse environments, which has importance to contexts ranging from survival in the soil to infection and pathogenesis scenarios.
Intra and inter-rater repeatability of brachial artery ultrasound estimates of flow-mediated slowing and flow-mediated dilation

Flow-mediated slowing (FMS) is a non-invasive measure of endothelial function measured through reactive hyperemia-induced changes in pulse wave velocity (PWV). FMS is suggested to mitigate known pitfalls of flow-mediated dilation (FMD) including suboptimal repeatability and high-operator dependency. However, the few single-rater studies that examined FMS repeatability have shown controversial results and used only regional measurements of PWV, which might not reflect local brachial artery stiffness responses to reactive hyperemia. We assessed the inter- and intra-rater repeatability of ultrasound-based changes in local PWV (FMS) and diameter (FMD). Twenty-four healthy male participants aged 23–75 yr, were examined on two separate days. Reactive hyperemia-induced changes in PWV were calculated using a tailored R-script. The inter- and intra-rater repeatability were tested with the intraclass correlation coefficient (ICC), coefficient of variation (CV), and the Bland-Altman plot estimates. The inter-rater repeatability of FMS (bias: -0.08%; ICC: 0.85; 95% CI: 0.65 to 0.93; CV: 11%) and FMD (bias: -0.02%; ICC: 0.98; 95% CI: 0.97 to 0.99; CV: 7%) showed overall good repeatability over different days. The intra-rater repeatability of FMD (1st rater: bias: 0.27%; ICC: 0.90; 95% CI: 0.78 to 0.96; CV: 14%; 2nd rater: bias: 0.60%; ICC: 0.85; 95% CI: 0.64 to 0.94; CV: 18%) was better than FMS (1st rater: bias: -1.03%; ICC: 0.76; 95% CI: 0.44 to 0.91; CV: 21%; 2nd rater: bias:-0.49%; ICC: 0.70; 95% CI: 0.34 to 0.80; CV: 23%) but not different between raters. Ultrasound-based local measurements of PWV deceleration reactive hyperemia were repeatable among the raters.
Vitamin D status & associations with inflammation in older adults

Research studies have observed associations of vitamin D with inflammation but data in representative older adult studies is lacking. We aimed to investigate the association of C-reactive protein (CRP) with vitamin D status in a representative sample of the older Irish population. The concentrations of 25-hydroxyvitamin D (25(OH)D) and CRP was measured in 5,381 community dwelling Irish adults aged ≥50 years from the Irish Longitudinal Study on Ageing (TILDA). Demographic, health and lifestyle variables were assessed by questionnaire and categorical proportions of CRP were generated by vitamin D status and age. Multi-nominal logistic regression was used to investigate the association of 25(OH)D and CRP status. The prevalence (mean; 95% confidence interval (95% CI)) of normal CRP status (0–5 mg/dL) was 83.9% (82.6–85.0%), elevated status (5–10 mg/dL) 11.0% (9.9–12.0%) and high status (>10 mg/dL) was 5.1% (4.5–5.8%). Mean (95% CI) CRP concentrations were lower in those with normal vs. deficient 25(OH)D status (2.02 mg/dL (1.95–2.08) vs. 2.60 mg/dL (2.41–2.82); p<0.0001). In a logistic regression analysis, those with insufficient or sufficient 25(OH)D status were less likely to have a high CRP status compared to those with deficient 25(OH)D status (insufficient: coefficient (CE) -0.732, 95% CI -1.12–0.33, p<0.0001; sufficient: CE -0.599, 95% CI -0.95–0.24, p = 0.001). In conclusion older adults with deficient vitamin D status had higher levels of inflammation as measured by CRP. Given that inflammation is an important pathological driver of chronic diseases of ageing, and that emerging evidence suggests that vitamin D therapy can reduce inflammation in some disease settings, optimising vitamin D status could represent an effective low risk/low-cost pathway to modulate inflammation in community dwelling older adults.
Intranasal trigeminal function in chronic rhinosinusitis: a review

ABSTRACT Introduction Chronic rhinosinusitis (CRS) affects 5–12% of the general population with significant effects on quality of life. Chronic inflammation also seems to affect intranasal trigeminal sensitivity. Areas covered A systematic literature search was done in Scopus, Web of Science, and PubMed in February 2023. The review addressed intranasal trigeminal function in patients with CRS and summarized current knowledge on trigeminal function as it relates to the symptoms, assessment, and treatment of CRS. Expert opinion Olfaction and trigeminal function are synergistic and this interaction may contribute to trigeminal dysfunction in CRS. Aside from anatomic blockage through polypoid mucosal changes, trigeminal dysfunction may affect the perception of nasal obstruction in CRS. Upregulated immune defense mechanisms leading to damage of nerve endings, changes in nerve growth factor release or other mechanisms may be responsible for trigeminal dysfunction in CRS. Since the pathophysiology of trigeminal dysfunction in CRS is poorly understood, current treatment recommendations are directed toward the therapy of CRS as an underlying cause, although the effect of surgery and corticosteroids on trigeminal function remains unclear. A standardized and validated trigeminal test that is accessible and easy to use in clinical settings would be beneficial for future studies.
Unlocking Endocrown Restoration Expertise Among Dentists: Insights from a Multi-Center Cross-Sectional Study

Background This study, employing an online questionnaire, aimed to assess and contrast the awareness, knowledge, and perceptions of dentists in Saudi Arabia (SA) regarding endocrowns (EC) as post-endodontic restorations with those of dentists educated in various other countries. Material/Methods We conducted a cross-sectional survey among dental interns and practicing dentists in government facilities, private dental centers, and dental colleges in SA, including participants of diverse nationalities. We disseminated validated, closed-ended questionnaires through WhatsApp via Google Forms. The Chi-square test was applied to assess associations between categorical variables, with a P-value of ≤0.05 indicating statistical significance. Results The majority of participants (61.2%) indicated that EC restorations are best suited for molar teeth. Furthermore, 69.6% asserted that the primary objective of employing EC is to accomplish minimally invasive preparations while preserving the existing tooth structure. Among the responses, 68.3% pinpointed debonding of ECs as a significant cause of failure. Notably, substantial differences were observed in responses concerning the knowledge or practice of EC across various factors such as gender, educational attainment, country of graduation, and workplace. Conclusions The findings reveal a comparatively low adoption of ECs among the participants, irrespective of experience or country of education. This underscores the need for incorporating ECs into dental curricula through theoretical and clinical discussions or considering them as a subject for post-graduate continuing education programs.
Valproic acid reduces muscle susceptibility to contraction‐induced functional loss but increases weakness in two murine models of Duchenne muscular dystrophy

Skeletal muscles in animal models of Duchenne muscular dystrophy (DMD) are more susceptible to contraction‐induced functional loss, which is not related to fatigue. Valproic acid (VPA) reportedly improves serological and histological markers of damage in dystrophin‐deficient murine muscle. Here, we tested whether VPA would reduce the susceptibility to contraction‐induced functional loss in two murine DMD models. Adult female mdx (mild) and D2‐mdx (severe) DMD murine models were administered VPA (240 mg/kg) or saline for 7 days. Some VPA‐treated mdx mice also performed voluntary running in a wheel, which is known to reduce the susceptibility to contraction‐induced functional loss; that is, isometric force drop following eccentric contractions. In situ muscle function was assessed before, during and after eccentric contractions. Muscle utrophin and desmin expression were also evaluated using immunoblotting. Interestingly, VPA reduced the isometric force drop following eccentric contractions in both murine models, without change in the relative eccentric maximal force and in the expression of utrophin and desmin. VPA for 7 days combined with voluntary running had no additive effect compared to VPA alone. Furthermore, VPA reduced the absolute isometric maximal force before eccentric contractions in both murine models. The results of our study indicated that VPA in both murine DMD models reduced the susceptibility to contraction‐induced functional loss but increased muscle weakness.
A PI(3,5)P2 reporter reveals PIKfyve activity and dynamics on macropinosomes and phagosomes

In this work, the authors describe a new biosensor for the phosphoinositide signaling lipid PI(3,5)P2. They demonstrate that this reporter faithfully reports PI(3,5)P2 dynamics in both Dictyostelium amoebae and mammalian cells and uncover details of how PI(3,5)P2 formation is regulated during phagosome maturation.