bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physiologically‐based pharmacokinetic modelling guided dose evaluations of nirmatrelvir/ritonavir in renal impairment for the management of COVID‐19
Authors: Ng Tat Ming , Wang Ziteng , Chan Eric Chun Yong 
Published: April 2024

AbstractWe aimed to address factors contributing to the pharmacokinetic changes of nirmatrelvir/ritonavir in renal impaired (RI) patients and recommend dosing adjustment via a physiologically‐based pharmacokinetic (PBPK) modelling approach. A PBPK model of nirmatrelvir/ritonavir was developed via Simcyp® Simulator. Sensitivity analysis of the influence of hepatic CYP3A4 intrinsic clearance and abundance, as well as hepatic non‐CYP3A4 metabolism (other human liver microsomes [HLM] CLint) was performed to evaluate the effects of RI on oral clearance of nirmatrelvir. Other HLM CLint, the most sensitive parameter, was adjusted, and the simulated plasma concentration profiles of nirmatrelvir in severe RI subjects were within the therapeutic index of 292–10 000 ng/mL for dosing regimens of loading doses of 300/100 mg followed by 150/100 mg or 75/100 mg twice daily of nirmatrelvir/ritonavir. Considering that nirmatrelvir is available as a 150 mg tablet, we recommend 300/100 mg followed by 150/100 mg twice daily as the dosing regimen to be investigated in severe RI.
From the lab to the classroom: Improving children's prospective memory in a natural setting
Authors: Cottini Milvia , Palladino Paola , Basso Demis 
Published: April 2024

AbstractBackgroundLaboratory‐based studies have shown that children's ability to remember intentions (i.e., prospective memory; PM) can be improved by asking them to imagine performing the PM task beforehand (i.e., episodic future thinking; EFT) or to predict their PM performance. Moreover, combining the two strategies resulted in an additional improvement in children's PM performance. However, the effectiveness of these encoding strategies on real‐life PM tasks is still unknown.AimsThe aim of the present study was to evaluate the effect of EFT instructions, performance predictions, and of their combination on children's PM in a natural setting, namely in the classroom.SampleTwelve classes composed by a total of 121 children (53% females) aged between seven and 9 years participated to the study.MethodsAs a PM task, children were asked by their teachers to deliver a letter to their parents and to bring it back to school the next day. Children were divided into four groups: control, prediction, EFT, and the EFT + prediction group. Parent reports on children's everyday prospective and retrospective memory failures were also collected.ResultsResults showed that encoding strategies were effective in enhancing children's PM performance. However, differences compared to previous laboratory‐based findings emerged since predicting PM performance resulted to be most effective in enhancing real‐life PM performance. Moreover, parent reports were related to children's PM performance.ConclusionsThese novel findings highlight the importance of studying PM interventions in natural settings in order to increase their ecological validity and inform educational practices.
Postcards Post‐Petroleras: Exploring Collaborative Ethnography via Mail from the Venezuelan Diaspora
Authors: Irons Rebecca 
Published: April 2024

AbstractPostcards, as ‘travelling communication devices’, have been identified as excellent tools for their ability to collapse ‘the field’ in a new, visually experiential way. Though often presented as a (post)colonial medium that has exoticized ‘the other’, they may also be able to give snapshots of diverse biographies otherwise silenced, and can therefore be utilised as a form of collaborative ethnography. This paper analyses postcards sent from Venezuelans living in Bogota during the pandemic. It will suggest that when migrants express lived‐experience via postcards, the coloniality of the medium is challenged and reimagined as collaborative ethnography.
Synergism between remdesivir and ribavirin leads to SARS‐CoV‐2 extinction in cell culture
Authors: García‐Crespo Carlos , de Ávila Ana Isabel , Gallego Isabel , Soria María Eugenia , Durán‐Pastor Antoni , Somovilla Pilar , Martínez‐González Brenda , Muñoz‐Flores Javier , Mínguez Pablo , Salar‐Vidal Llanos , Esteban‐Muñoz Mario , Cañar‐Camacho Elizabeth , Ferrer‐Orta Cristina , Zuñiga Sonia , Sola Isabel , Enjuanes Luis , Esteban Jaime , Fernández‐Roblas Ricardo , Gadea Ignacio , Gómez Jordi , Verdaguer Nuria , Domingo Esteban , Perales Celia 
Published: April 2024

Background and PurposeThere is a need for effective anti‐COVID‐19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has proved effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID‐19. The purpose of the present study was to find synergistic antiviral combinations for COVID‐19 based on lethal mutagenesis.Experimental ApproachThe effect of combinations of remdesivir and ribavirin on the infectivity of SARS‐CoV‐2 in cell culture has been tested. Viral populations were monitored by ultra‐deep sequencing, and the decrease of infectivity as a result of the treatment was measured.Key ResultsRemdesivir and ribavirin exerted a synergistic inhibitory activity against SARS‐CoV‐2, quantified both by CompuSyn (Chou‐Talalay method) and Synergy Finder (ZIP‐score model). In serial passage experiments, virus extinction was readily achieved with remdesivir‐ribavirin combinations at concentrations well below their cytotoxic 50 value, but not with the drugs used individually. Deep sequencing of treated viral populations showed that remdesivir, ribavirin, and their combinations evoked significant increases of the number of viral mutations and haplotypes, as well as modification of diversity indices that characterize viral quasi‐species.Conclusion and ImplicationsSARS‐CoV‐2 extinction can be achieved by synergistic combination treatments based on lethal mutagenesis. In addition, the results offer prospects of triple drug treatments for effective SARS‐CoV‐2 suppression.
Institutional Investors and ESG Preferences
Authors: Lopez‐de‐Silanes Florencio , McCahery Joseph A. , Pudschedl Paul C. 
Published: April 2024

ABSTRACTResearch Question/IssueWe examine the effect of multiple environmental, social, and governance (ESG) scores on institutional investor ownership of firms and investor portfolio weightings. We are also the first to analyze the three individual components of ESG rankings to estimate the relative preferences of institutional investors.Research Findings/InsightsUsing a unique panel dataset covering US companies and institutional investor portfolios over the 2010–2019 period, we find that while investors are driven to add high‐quality ESG companies to their portfolios, there is a negative relationship with ESG when it comes to taking large ownership stakes. Furthermore, ESG scores are negatively related to the portfolio weightings of institutional investors, which raises concerns of greenwashing. Our analysis of individual ESG scores points to significantly larger effects of G scores in terms of holdings, and G is the only score with no negative impact on portfolio weightings. Finally, in support of systematic stewardship theory, top institutional investors allocate higher proportions of their portfolios to firms with high‐ESG ratings. Our results are robust to the use of a difference‐in‐differences analysis addressing endogeneity concerns.Theoretical/Academic ImplicationsThe findings in this paper offer important policy implications for institutional investors, managers, and policymakers. Given the ongoing debate on ESG scores, this paper shows the importance of examining greenwashing for investors who have a concern regarding the extent to which the valuation of assets might be influenced by unsupported sustainability claims. In addition, our study adds to the debate regarding ESG investing and stewardship theory.
Physiologically based modeling reveals different risk of respiratory depression after fentanyl overdose between adults and children
Authors: Chakravartula Shilpa , Thrasher Bradlee , Mann John , Chaturbedi Anik , Han Xiaomei , Dahan Albert , Florian Jeffry , Strauss David , Li Zhihua 
Published: April 2024

AbstractDespite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose‐dependent impact of opioids on respiratory depression in children, the leading cause of opioid‐associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age‐dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen‐related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric‐specific factors may need to be considered.
Prediction of cardiovascular risk factors from retinal fundus photographs: Validation of a deep learning algorithm in a prospective non‐interventional study in Kenya
Authors: White Tom , Selvarajah Viknesh , Wolfhagen‐Sand Fredrik , Svangård Nils , Mohankumar Gayathri , Fenici Peter , Rough Kathryn , Onyango Nelson , Lyons Kendall , Mack Christina , Nduba Videlis , Noorali Saleh Mansoor , Abayo Innocent , Siddiqui Afrah , Majdanska‐Strzalka Malgorzata , Kaszubska Katarzyna , Hegelund‐Myrback Tove , Esterline Russell , Manzur Antonio , Parker Victoria E. R. 
Published: April 2024

AbstractAimHypertension and diabetes mellitus (DM) are major causes of morbidity and mortality, with growing burdens in low‐income countries where they are underdiagnosed and undertreated. Advances in machine learning may provide opportunities to enhance diagnostics in settings with limited medical infrastructure.Materials and MethodsA non‐interventional study was conducted to develop and validate a machine learning algorithm to estimate cardiovascular clinical and laboratory parameters. At two sites in Kenya, digital retinal fundus photographs were collected alongside blood pressure (BP), laboratory measures and medical history. The performance of machine learning models, originally trained using data from the UK Biobank, were evaluated for their ability to estimate BP, glycated haemoglobin, estimated glomerular filtration rate and diagnoses from fundus images.ResultsIn total, 301 participants were enrolled. Compared with the UK Biobank population used for algorithm development, participants from Kenya were younger and would probably report Black/African ethnicity, with a higher body mass index and prevalence of DM and hypertension. The mean absolute error was comparable or slightly greater for systolic BP, diastolic BP, glycated haemoglobin and estimated glomerular filtration rate. The model trained to identify DM had an area under the receiver operating curve of 0.762 (0.818 in the UK Biobank) and the hypertension model had an area under the receiver operating curve of 0.765 (0.738 in the UK Biobank).ConclusionsIn a Kenyan population, machine learning models estimated cardiovascular parameters with comparable or slightly lower accuracy than in the population where they were trained, suggesting model recalibration may be appropriate. This study represents an incremental step toward leveraging machine learning to make early cardiovascular screening more accessible, particularly in resource‐limited settings.
Combination of retagliptin and henagliflozin as add‐on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double‐blind, active‐controlled, phase 3 trial
Authors: Wang Yao , Jiang Chengxia , Dong Xiaolin , Chen Mingwei , Gu Qin , Zhang Lihui , Fu Yanqin , Pan Tianrong , Bi Yan , Song Weihong , Xu Jing , Lu WeiPing , Sun Xiaodong , Ye Zi , Zhang Danli , Peng Liang , Lin Xiang , Dai Wei , Wang Quanren , Yang Wenying 
Published: April 2024

AbstractAimThis study assessed the efficacy and safety of co‐administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin.MethodsThis multicentre, phase 3 trial consisted of a 24‐week, randomized, double‐blind, active‐controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once‐daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co‐administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24.ResultsBased on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (−1.51%) and R100/H10 (−1.54%) groups compared with those receiving the corresponding doses of individual agents (−0.98% for R100, −0.86% for H5 and −0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2‐h postprandial glucose were also more pronounced in the co‐administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia.ConclusionsFor patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co‐administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.
Geographic variation in sodium‐glucose cotransporter 2 inhibitor and glucagon‐like peptide‐1 receptor agonist use in people with type 2 diabetes in New South Wales, Australia
Authors: de Oliveira Costa Juliana , Lin Jialing , Milder Tamara Y. , Greenfield Jerry R. , Day Richard O. , Stocker Sophie L. , Neuen Brendon L. , Havard Alys , Pearson Sallie‐Anne , Falster Michael O. 
Published: April 2024

AbstractAimSodium‐glucose cotransporter 2 inhibitors (SGLT2is) and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) improve glycaemic control and cardio‐renal outcomes for people with type 2 diabetes (T2D). However, geographic and socio‐economic variation in use is not well understood.MethodsWe identified 367 829 New South Wales residents aged ≥40 years who dispensed metformin in 2020 as a proxy for T2D. We estimated the prevalence of use of other glucose‐lowering medicines among people with T2D and the prevalence of SGLT2i and GLP‐1RA use among people using concomitant T2D therapy (i.e. metformin + another glucose‐lowering medicine). We measured the prevalence by small‐level geography, stratified by age group, and characterized by remoteness and socio‐economic status.ResultsThe prevalence of SGLT2i (29.7%) and GLP‐1RA (8.3%) use in people with T2D aged 40‐64 increased with geographic remoteness and in areas of greater socio‐economic disadvantage, similar to other glucose‐lowering medicines. The prevalence of SGLT2i (55.4%) and GLP‐1RA (15.4%) among people using concomitant T2D therapy varied across geographic areas, with lower SGLT2i use in more disadvantaged areas and localized areas of high GLP‐1RA use (2.5 times the median). Compared with people aged 40‐64 years, the prevalence of SGLT2i and GLP‐1RA use was lower in older age groups, but with similar patterns of variation across geographic areas.ConclusionsThe prevalence of SGLT2i and GLP‐1RA use varied by geography, probably reflecting a combination of system‐ and prescriber‐level factors. Socio‐economic variation in GLP‐1RA use was overshadowed by localized patterns of prescribing. Continued monitoring of variation can help shape interventions to optimize use among people who would benefit the most.
Association of single‐point insulin sensitivity estimator index (SPISE) with future cardiovascular outcomes in patients with type 2 diabetes
Authors: Deng Simin , Hu Xinqun , Zhang Xiangyu 
Published: April 2024

AbstractAimsTo investigate the association of single‐point insulin sensitivity estimator (SPISE) index with future cardiovascular outcomes in patients with type 2 diabetes.Materials and MethodsSPISE index (= 600 × high‐density lipoprotein cholesterol [mg/dL]0.185/triglycerides [mg/dL]0.2 × body mass index [kg/m2]1.338) was calculated in 10 190 participants. Cox proportional hazard regression models were applied to evaluate the association between SPISE index and future cardiovascular outcomes. Restricted cubic spline analyses and two‐piecewise linear regression models were employed to explore the nonlinear association and to determine the threshold value. Subgroup and interaction analyses were conducted to test the robustness of the results.ResultsAfter fully adjusting for well‐established metabolic confounders, higher SPISE index was significantly associated with lower risk of future cardiovascular outcomes in patients with type 2 diabetes (major adverse cardiovascular event [MACE]): hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.90–0.98, p = 0.0026; overall mortality: HR 0.90, 95% CI 0.86–0.93, p < 0.0001; cardiovascular disease [CVD] mortality: HR 0.85, 95% CI 0.79–0.92, p < 0.0001; congestive heart failure (CHF): HR 0.72, 95% CI 0.67–0.78, p < 0.0001; major coronary events: HR 0.91, 95% CI 0.87–0.95, p < 0.0001. There was a nonlinear association between SPISE index and future cardiovascular outcomes (the threshold value was 5.68 for MACE, 5.71 for overall mortality, 4.64 for CVD mortality, 4.48 for CHF, and 6.09 for major coronary events, respectively).ConclusionsHigher SPISE index was independently associated with lower risk of future cardiovascular outcomes in type 2 diabetes patients after full adjustment for well‐established metabolic confounders.
Comparison in microstructure, mechanical properties, and fatigue behavior of 9Cr3W3Co turbine rotor steel and its welded joint
Authors: Mai Jianning , Liu Fulin , Chen Yao , He Chao , Wang Linsen , Zhong Zhengbin , Zhang Wei , Zhang Hong , Wang Chong , Wang Qingyuan , Liu Yongjie 
Published: April 2024

AbstractThe microstructure, mechanical properties, and high/very‐high cycle fatigue behaviors of 9Cr3W3Co turbine rotor steel and its welded joint were investigated. The welded nugget zone (WNZ) exhibited the highest microhardness value, followed by the heat‐affected zone (HAZ), while the base material (BM) showed the lowest hardness value. The WNZ exhibited a higher yield strength compared to the BM with reduced elongation, while maintaining similar ultimate tensile strength. The fatigue strength of the BM at 5 × 107 cycles is roughly 53.7% of the yield strength, whereas that of the WNZ increases to approximately 55.0%. In comparison to the fatigue strength of the BM at 5 × 107 cycles, the WNZ exhibits a notable increase of 10.5%. Smaller grain size and higher dislocation density were observed in the WNZ, which contributed to improved microhardness, yield strength, and fatigue resistance through grain boundary strengthening and dislocation hardening.
Climate‐driven shifts in the diversity of plants in the Neotropical seasonally dry forest: Evaluating the effectiveness of protected areas
Authors: Manrique‐Ascencio Avril , Prieto‐Torres David A. , Villalobos Fabricio , Guevara Roger 
Published: April 2024

AbstractGiven the current environmental crisis, biodiversity protection is one of the most urgent socio‐environmental priorities. However, the effectiveness of protected areas (PAs), the primary strategy for safeguarding ecosystems, is challenged by global climate change (GCC), with evidence showing that species are shifting their distributions into new areas, causing novel species assemblages. Therefore, there is a need to evaluate PAs' present and future effectiveness for biodiversity under the GCC. Here, we analyzed changes in the spatiotemporal patterns of taxonomic and phylogenetic diversity (PD) of plants associated with the Neotropical seasonally dry forest (NSDF) under GCC scenarios. We modeled the climatic niche of over 1000 plant species in five representative families (in terms of abundance, dominance, and endemism) of the NSDF. We predicted their potential distributions in the present and future years (2040, 2060, and 2080) based on an intermediate scenario of shared socio‐economic pathways (SSP 3.70), allowing species to disperse to new sites or constrained to the current distribution. Then, we tested if the current PAs network represents the taxonomic and phylogenetic diversities. Our results suggest that GCC could promote novel species assemblages with local responses (communities' modifications) across the biome. In general, models predicted losses in the taxonomic and phylogenetic diversities of all the five plant families analyzed across the distribution of the NSDF. However, in the northern floristic groups (i.e., Antilles and Mesoamerica) of the NSDF, taxonomic and PD will be stable in GCC projections. In contrast, across the NSDF in South America, some cores will lose diversity while others will gain diversity under GCC scenarios. PAs in some NSDF regions appeared insufficient to protect the NSDF diversity. Thus, there is an urgent need to assess how the PA system could be better reconfigured to warrant the protection of the NSDF.