Miracle-dz/UniFAR-FTUs huggingface dataset:
Recent developments in in vitro and in vivo models for improved translation of preclinical pharmacokinetics and pharmacodynamics data

Abstract Improved pharmacokinetics/pharmacodynamics (PK/PD) prediction in the early stages of drug development is essential to inform lead optimization strategies and reduce attrition rates. Recently, there have been significant advancements in the development of new in vitro and in vivo strategies to better characterize pharmacokinetic properties and efficacy of drug leads. Herein, we review advances in experimental and mathematical models for clearance predictions, advancements in developing novel tools to capture slowly metabolized drugs, in vivo model developments to capture human etiology for supporting drug development, limitations and gaps in these efforts, and a perspective on the future in the field.
Ethical issues in therapeutic use and research in pregnant and breastfeeding women

Pregnant or potentially pregnant women have historically been excluded from clinical trials of new medications. However, it is increasingly recognised that it is imperative to generate evidence from the population in whom the drugs are likely to be used to inform safe, evidence‐based shared clinical decision making. Reluctance by researchers and regulators to perform such studies often relates to concerns about risk, particularly to the foetus. However, this must be offset against the risk of untreated disease or using a drug in pregnancy where safety, efficacy and dosing information are not known. This review summarises the historical perspective, and the ethical and legal frameworks that inform the conduct of such research, then highlights examples of innovative practice that have enabled high quality, ethical research to proceed to inform the evidence‐based use of medication in pregnancy.
Nitric Oxide Signaling for Actinorhodin Production in Streptomyces coelicolor A3(2) via the DevS/R Two-Component System

Diverse organisms, such as mammals, plants, and bacteria, utilize NO via well-known signal transduction mechanisms. Many useful secondary metabolite-producing bacteria of the Streptomyces genus had been also suggested for the metabolism regulated by endogenously produced NO; however, the regulatory mechanisms remain to be elucidated. ABSTRACT Nitric oxide (NO) is an important signaling molecule in eukaryotic and prokaryotic cells. A previous study revealed an NO synthase-independent NO production metabolic cycle in which the three nitrogen oxides, nitrate (NO3−), nitrite (NO2−), and NO, were generated in the actinobacterium Streptomyces coelicolor A3(2). NO was suggested to act as a signaling molecule, functioning as a hormone that regulates secondary metabolism. Here, we demonstrate the NO-mediated regulation of the production of the blue-pigmented antibiotic actinorhodin (ACT), via the heme-based DevS/R two-component system (TCS). Intracellular NO controls the stabilization or inactivation of DevS, depending on the NO concentration. An electrophoretic mobility shift assay and chromatin immunoprecipitation-quantitative PCR analysis revealed the direct binding between DevR and the promoter region of actII-ORF4, resulting in gene expression. Our results indicate that NO regulates the DevS/R TCS, thereby strictly controlling the secondary metabolism of S. coelicolor A3(2). IMPORTANCE Diverse organisms, such as mammals, plants, and bacteria, utilize NO via well-known signal transduction mechanisms. Many useful secondary metabolite-producing bacteria of the Streptomyces genus had been also suggested for the metabolism regulated by endogenously produced NO; however, the regulatory mechanisms remain to be elucidated. In this study, we demonstrated the molecular mechanism by which endogenously produced NO regulates antibiotic production via the DevS/R TCS in S. coelicolor A3(2). NO serves as both a stabilizer and a repressor in the regulation of antibiotic production. This report shows the mechanism by which Streptomyces utilizes endogenously produced NO to modulate its normal life cycle. Moreover, this study implies that studying NO signaling in actinobacteria can help in the development of both clinical strategies against pathogenic actinomycetes and the actinobacterial industries.
Atherogenic Index of Plasma, Triglyceride-Glucose Index and Monocyte-to-Lymphocyte Ratio for Predicting Subclinical Coronary Artery Disease.

BACKGROUND The atherogenic index of plasma (AIP), triglyceride-glucose (TyG) index, and monocyte-to-lymphocyte ratio (MLR) are strongly associated with atherogenesis of the coronary artery. This study aimed to investigate the association of the AIP, TyG index, and MLR with subclinical coronary artery disease (CAD) and evaluate their ability to predict subclinical CAD. METHODS A total of 697 asymptomatic patients were enrolled in this study and assigned to the subclinical CAD group (n=332) and control group (n=365). The clinical data, coronary artery calcification score, and calculated AIP, TyG index, and MLR were collected by graduate students in the cardiology division. Multivariate logistic regression models were set up to assess the risk factors for subclinical CAD. RESULTS The AIP, TyG index and MLR values were higher in the subclinical CAD group than in the control group (all P<0.05). In addition to the classic independent clinical risk factors, increased AIP, TyG index and MLR values were all independent risk factors for subclinical CAD (all P<0.05). The AUCs were higher after combining clinical risk factors than the AIP, TyG index, or MLR alone (all P<0.05). CONCLUSIONS The AIP, TyG index and MLR are independent risk factors for subclinical CAD, which can be useful for improving the diagnosis and prevention of CAD.
Hybrid Face Reflectance, Illumination, and Shape From a Single Image

We propose HyFRIS-Net to jointly estimate the hybrid reflectance and illumination models, as well as the refined face shape from a single unconstrained face image in a pre-defined texture space. The proposed hybrid reflectance and illumination representation ensure photometric face appearance modeling in both parametric and non-parametric spaces for efficient learning. While forcing the reflectance consistency constraint for the same person and face identity constraint for different persons, our approach recovers an occlusion-free face albedo with disambiguated color from the illumination color. Our network is trained in a self-evolving manner to achieve general applicability on real-world data. We conduct comprehensive qualitative and quantitative evaluations with state-of-the-art methods to demonstrate the advantages of HyFRIS-Net in modeling photo-realistic face albedo, illumination, and shape.
A spatial model of YAP/TAZ signaling reveals how stiffness, dimensionality, and shape contribute to emergent outcomes

Significance The YAP/TAZ pathway plays a fundamental role in integrating a variety of cellular cues to control important physiological processes. Here, we develop a spatial model of this pathway that contributes quantitative understanding and disentangles the role various stimuli play that are difficult to distinguish experimentally. The model integrates key spatial and physical inputs, namely cell and nuclear shape, surface area-to-volume ratios of cytoplasmic and nuclear compartments, substrate dimensionality, substrate activation area, and substrate stiffness, through membrane-proximal, cytoskeletal, and nuclear mechanotransduction modules. The resulting model accounts for seemingly contradictory experimental trends and lends new insight into controlling YAP/TAZ signaling. YAP/TAZ is a master regulator of mechanotransduction whose functions rely on translocation from the cytoplasm to the nucleus in response to diverse physical cues. Substrate stiffness, substrate dimensionality, and cell shape are all input signals for YAP/TAZ, and through this pathway, regulate critical cellular functions and tissue homeostasis. Yet, the relative contributions of each biophysical signal and the mechanisms by which they synergistically regulate YAP/TAZ in realistic tissue microenvironments that provide multiplexed input signals remain unclear. For example, in simple two-dimensional culture, YAP/TAZ nuclear localization correlates strongly with substrate stiffness, while in three-dimensional (3D) environments, YAP/TAZ translocation can increase with stiffness, decrease with stiffness, or remain unchanged. Here, we develop a spatial model of YAP/TAZ translocation to enable quantitative analysis of the relationships between substrate stiffness, substrate dimensionality, and cell shape. Our model couples cytosolic stiffness to nuclear mechanics to replicate existing experimental trends, and extends beyond current data to predict that increasing substrate activation area through changes in culture dimensionality, while conserving cell volume, forces distinct shape changes that result in nonlinear effect on YAP/TAZ nuclear localization. Moreover, differences in substrate activation area versus total membrane area can account for counterintuitive trends in YAP/TAZ nuclear localization in 3D culture. Based on this multiscale investigation of the different system features of YAP/TAZ nuclear translocation, we predict that how a cell reads its environment is a complex information transfer function of multiple mechanical and biochemical factors. These predictions reveal a few design principles of cellular and tissue engineering for YAP/TAZ mechanotransduction.
Examining the effect of wound cleansing on the microbiome of venous stasis ulcers

Common treatment for venous leg wounds includes topical wound dressings with compression. At each dressing change, wounds are debrided and washed; however, the effect of the washing procedure on the wound microbiome has not been studied. We hypothesized that wound washing may alter the wound microbiome. To characterize microbiome changes with respect to wound washing, swabs from 11 patients with chronic wounds were sampled before and after washing, and patient microbiomes were characterized using 16S rRNA sequencing and culturing. Microbiomes across patient samples prior to washing were typically polymicrobial but varied in the number and type of bacterial genera present. Proteus and Pseudomonas were the dominant genera in the study. We found that washing does not consistently change microbiome diversity but does cause consistent changes in microbiome composition. Specifically, washing caused a decrease in the relative abundance of the most highly represented genera in each patient cluster. The finding that venous leg ulcer wound washing, a standard of care therapy, can induce changes in the wound microbiome is novel and could be potentially informative for future guided therapy strategies.
Effect of focused cardiopulmonary ultrasonography on clinical outcome of septic shock: a randomized study

Objective To investigate the effect of focused ultrasonography on clinical outcomes of septic shock. Methods Patients with septic shock were randomized into an integrated cardiopulmonary ultrasonography (ICUS) group and conventional (CON) group. Within 1 hour of admission, the ICUS group underwent ICUS examination for hemodynamic decision-making, while the CON group received standard treatment. The primary endpoint was 28-day mortality after admission. The secondary endpoints were cumulative fluid administration in the first 6, 24, and 72 hours; use of vasoactive drugs; lactate clearance; duration of ventilation; and ICU stay. Results Ninety-four qualified patients were enrolled (ICUS group, 49; CON group, 45). ICUS showed no significant effect on 28-day mortality. Within the initial 6 hours, the ICUS group tended to have a higher fluid balance and fluid intake than the CON group. The duration of vasopressor support was shorter in the ICUS group. There were no differences in the cumulative fluid infusion within 24 or 72 hours, lactate clearance, ICU stay, or duration of ventilation. Conclusions The initially focused ICUS did not affect the clinical outcomes of septic shock, but it tended to be associated with a higher fluid balance within the initial 6 hours and shorter duration of vasopressor support.
Off-label postpartum use of domperidone in Canada: a multidatabase cohort study

Background: Trends in off-label postpartum use of domperidone and the impact of safety advisories on its use remain unknown. Our objectives were to describe postpartum use of domperidone in Canada, to evaluate the impact of Health Canada advisories on prescribing patterns, and to describe the association between domperidone use and a composite end point of sudden cardiac death or ventricular tachycardia (VT) among postpartum patients. Methods: We conducted a multidatabase cohort study involving pregnant patients with live births between 2004 and 2017 using administrative health databases from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba and Ontario). We excluded patients with less than 1 year of prepregnancy database history and with approved indications for domperidone. We assessed domperidone use in the 6 months postpartum and the impact of the 2012 and 2015 Health Canada advisories on prescribing via interrupted time series analysis. We estimated crude rates of VT and sudden cardiac death. Results: We included 1 190 987 live births. Mean maternal age was 28.6 (standard error 0.6) years. Domperidone use increased over time, from 7% in 2003–2005 to 12% in 2009–2011, when it plateaued. The 2012 advisory was followed by a drop in use and a reduction in slope, and the 2015 advisory had a more modest impact. Crude analysis suggests that domperidone may be associated with increased VT or sudden cardiac death (0.74 v. 0.37 per 10 000 person-years; difference per 10 000 person-years: 0.37, 95% confidence interval −0.67 to 1.41). Interpretation: Postpartum domperidone use increased between 2004 and 2017, with prescribing attenuated after Health Canada advisories and a very low absolute rate of VT or sudden cardiac death. These findings suggest that Health Canada advisories affected prescribing; any potential increase in VT or sudden cardiac death with use of domperidone is small and could not be confirmed in this large study Study registration: ClinicalTrials.gov, no. NCT04024865
Predicting related factors of immunological response to hepatitis B vaccine in hemodialysis patients based on integration of decision tree classification and logistic regression

ABSTRACT The non/hypo-response rate of the hepatitis B vaccine among hemodialysis (HD) patients is still high, it is of great significance to explore the influencing factors and their relationships. To study the related factors and their relationships using logistic regression model and Chi-squared Automatic Interaction Detection (CHAID) decision tree model. A randomized controlled trial was conducted between February 2014 and May 2015 in China. HD patients being serologically negative for HBsAg and anti-HBs were randomly assigned to receive three intramuscular injections of the standard dose (20 µg) or high dose (60 µg) of recombinant hepatitis B vaccine at months 0, 1, and 6. Those with anti-HBs concentrations <100 mIU/mL, and ≥100 mIU/mL at month 7 were considered as non/hypo-response and high-level response, respectively. The non/hypo-response was 31.34% (89/284). After adjustment for confounders, logistic analysis showed that males (OR = 2.203, 95%CI: 1.109–4.367) and those with higher dialysis frequency (>4 times per 2 weeks) (OR = 1.918, 95%CI: 1.015–3.626) had a significant risk of non/hypo-response. While the CHAID analysis showed that gender, dose, and dialysis frequency were influencing factors of non/hypo-response, and gender is most important. The interaction between gender and dialysis frequency had the greatest effect on immunization, and followed by the interaction between dialysis frequency and vaccine dose. Taken together, gender, dose and dialysis frequency were influencing factors of hepatitis B vaccine in HD patients.
Automated NLP Extraction of Clinical Rationale for Treatment Discontinuation in Breast Cancer.

PURPOSE Key oncology end points are not routinely encoded into electronic medical records (EMRs). We assessed whether natural language processing (NLP) can abstract treatment discontinuation rationale from unstructured EMR notes to estimate toxicity incidence and progression-free survival (PFS). METHODS We constructed a retrospective cohort of 6,115 patients with early-stage and 701 patients with metastatic breast cancer initiating care at Memorial Sloan Kettering Cancer Center from 2008 to 2019. Each cohort was divided into training (70%), validation (15%), and test (15%) subsets. Human abstractors identified the clinical rationale associated with treatment discontinuation events. Concatenated EMR notes were used to train high-dimensional logistic regression and convolutional neural network models. Kaplan-Meier analyses were used to compare toxicity incidence and PFS estimated by our NLP models to estimates generated by manual labeling and time-to-treatment discontinuation (TTD). RESULTS Our best high-dimensional logistic regression models identified toxicity events in early-stage patients with an area under the curve of the receiver-operator characteristic of 0.857 ± 0.014 (standard deviation) and progression events in metastatic patients with an area under the curve of 0.752 ± 0.027 (standard deviation). NLP-extracted toxicity incidence and PFS curves were not significantly different from manually extracted curves (P = .95 and P = .67, respectively). By contrast, TTD overestimated toxicity in early-stage patients (P < .001) and underestimated PFS in metastatic patients (P < .001). Additionally, we tested an extrapolation approach in which 20% of the metastatic cohort were labeled manually, and NLP algorithms were used to abstract the remaining 80%. This extrapolated outcomes approach resolved PFS differences between receptor subtypes (P < .001 for hormone receptor+/human epidermal growth factor receptor 2- v human epidermal growth factor receptor 2+ v triple-negative) that could not be resolved with TTD. CONCLUSION NLP models are capable of abstracting treatment discontinuation rationale with minimal manual labeling.
Regioselective Chain Shuttling Polymerization of Isoprene: An Approach To Access New Materials from Single Monomer

Chain shuttling polymerization (CSP) has exhibited unique privilege to combine monomer sequences of different properties into one macromolecular chain, which, however, is difficult to achieve because of low chain transfer efficiency and thus lead to poor architecture control over the resulting polymers. Herein, we reported that the pyridyl–methylene fluorenyl scandium complex 1 in combination with [Ph3C][B(C6F5)4] and AliBu3 showed a high transfer efficiency (93.8%) in the presence of 10 equiv of AliBu3 toward the chain-transfer polymerization (CTP) of isoprene (IP) in high 1,4-selectivity (83%). Meanwhile, under the same conditions, the analogous lutetium precursor 3 based system was 3,4-regioselective and exhibited almost perfect chain transfer efficiency (96.5–100%) in a wide range of AliBu3-to-Lu ratios from 10:1 to 100:1, indicating that each Lu generated apparently 100 polyisoprene (PIP) macromolecules. Both CTPs performed fluently without compromising the selectivity and the activity and had compar.
Extraordinary behavior of β-hydroxy sulfoxides and sulfone of pinane series

GRAPHICAL ABSTRACT ABSTRACT The “racemic compound-like” behavior, low-temperature conformational rearrangement and “crystallization-induced diastereomerization” of β-hydroxysulfoxides and sulfone of pinane series have been studied. It was established, that the sample of sulfoxide crystallizes as an asymmetric dimer containing a supramolecularcentro-symmetric moiety formed through S=O···H‒O interactions between two independent molecules. Moreover, it was found that this dimer can crystallize in two so-called “packing polymorphs”—monoclinic and triclinic ones. By transition from the room temperature to 150 К for both polymorphic forms conformational restructuring of a stable hydrogen-bonded synthon from “unfolded” form to “folded” one has been observed. The sample of sulfoxide is interesting as the first example of the co-crystallization of chiral sulfur compounds. Surprisingly we have found a similar H-bonded dimer, formed by independent molecules, where all sulfone molecules are identical in stereochemical aspect. We suggested to use the new term “crystallization-induced diastereomerization” for the description of the stereochemical process leading to the formation of sulfone dimer. From a supramolecular chemistry point of view, we can speak of the finding of a new robust and reproducible synthon. From a stereochemical point of view, an “enantiophilic” fragment was discovered—a β-hydroxysulfoxide or sulfone group, capable of recognizing its mirror image.
Circulating neprilysin hypothesis: A new opportunity for sacubitril/valsartan in patients with heart failure and preserved ejection fraction?

Background Circulating Neprilysin (sNEP) has emerged as a potential prognostic biomarker in heart failure (HF). In PARAGON-HF benefit of sacubitril/valsartan was only observed in patients with left ventricular ejection fraction (LVEF) ≤57%. We aimed to assess the prognostic value of sNEP in outpatients with HF and LVEF >57%, in comparison with patients with LVEF ≤57%. Methods Consecutive HF outpatients were included from May-2006 to February-2016. The primary endpoint was the composite of all-cause death or HF hospitalization and the main secondary endpoint was the composite of cardiovascular death or HF hospitalization. For the later competing risk methods were used. Results sNEP was measured in 1428 patients (age 67.7±12.7, 70.3% men, LVEF 35.8% ±14), 144 of which had a LVEF >57%. sNEP levels did not significantly differ between LVEF groups (p = 0.31). During a mean follow-up of 6±3.9 years, the primary endpoint occurred in 979 patients and the secondary composite endpoint in 714 (in 111 and 84 of the 144 patients with LVEF >57%, respectively). sNEP was significantly associated with both composite endpoints. Age- and sex- adjusted Cox regression analyses showed higher hazard ratios for sNEP in patients with LVEF >57%, both for the primary (HR 1.37 [1.16–1.61] vs. 1.04 [0.97–1.11]) and the secondary (HR 1.38 [1.21–1.55] vs. 1.11 [1.04–1.18]) composite endpoints. Conclusions sNEP prognostic value in patients with HF and LVEF >57% outperforms that observed in patients with lower LVEF. Precision medicine using sNEP may identify HF patients with preserved LVEF that may benefit from treatment with sacubitril/valsartan.
Aeration in sludge holding tanks as an economical means for biosolids odor control—A case study

Abnormally high‐odor detection threshold (DT) values were detected for biosolids produced at one of the water resource recovery facilities (WRRFs) of Washington Suburban Sanitary Commission. As an inexpensive countermeasure, aeration of thickened sludge holding tanks (SHTs) was tested as a solution for mitigating the subsequent biosolids odor emission. Experimental results indicated that the extremely low‐oxidation reduction potential (ORP) in the SHTs and the fermentation of high‐rate‐activated sludge were primarily contributors to the odor emission from the dewatered cake. Two rounds of bench‐scale experiments on different days confirmed that aerating the sludge in holding tanks reduced peak emission concentrations of sulfurous odorous compounds such as hydrogen sulfide (H2S), methanethiol (MT), and dimethyl sulfide (DMS) from 203, 110, and 20 mg m−3 g−1 dry to 119, 70, and 14 mg m−3 g−1 dry, respectively. Further preliminary full‐scale validation study showed that even a slight ORP improvement from −180 mV to −162 mV reduced the peak H2S concentration from 87 to 48 mg m−3 g−1 dry and decreased the biosolids DT value from 4266 to 1862. It was concluded that lifting ORP in SHTs through aeration can be used by utilities as a simple means for biosolids odor control.