bluuebunny/crossref_metadata_2025_split huggingface dataset:
Levers for Change and Unexpected Outcomes of a Participatory Research Partnership: Toward Fostering Older adults’ Social Participation to Promote Health Equity
Authors: Turcotte Pier‐Luc , Carrier Annie , Levasseur Mélanie 
Published: July 2020

AbstractPromoting health equity in aging requires ensuring older adults’ effective access to community‐based services fostering their social participation. This study aimed to (a) identify levers for change in community‐based services to foster older adults’ social participation and (b) explore unexpected outcomes of stakeholder engagement. Based in a large Canadian city, a critical participatory research partnership was formed in a district experiencing considerable health disparities. Four focus groups and seven individual interviews were followed by a collaborative workshop with 28 community stakeholders. Participants identified mainly systemic and organizational levers for change. These levers comprised changing performance indicators and the institutional culture of homecare to value services fostering social participation opportunities. Other levers included supporting individual change agency through participatory research involving community members. Stakeholder engagement led to five unexpected outcomes: “Marking a new beginning,” “Expressing ourselves,” “Feeling better,” “Working together,” and “Influencing the community.” Recognizing levers for change is essential to understand how to develop services fostering social participation to promote health equity, with whom and in which contexts.
The CYB5R3c.350C>G and G6PD A alleles modify severity of anemia in malaria and sickle cell disease
Authors: Gordeuk Victor R. , Shah Binal N. , Zhang Xu , Thuma Philip E. , Zulu Stenford , Moono Rodgers , Reading N. Scott , Song Jihyun , Zhang Yingze , Nouraie Mehdi , Campbell Andrew , Minniti Caterina P. , Rana Sohail R. , Darbari Deepika S. , Kato Gregory J. , Niu Mei , Castro Oswaldo L. , Machado Roberto , Gladwin Mark T. , Prchal Josef T. 
Published: July 2020

AbstractGenetic modifiers of anemia in Plasmodium falciparum infection and sickle cell disease (SCD) are not fully known. Both conditions are associated with oxidative stress, hemolysis and anemia. The CYB5R3 gene encodes cytochrome b5 reductase 3, which converts methemoglobin to hemoglobin through oxidation of NADH. CYB5R3c.350C > G encoding CYB5R3T117S, the most frequent recognized African‐specific polymorphism, does not have known functional significance, but its high allele frequency (23% in African Americans) suggests a selection advantage. Glucose‐6‐phosphate dehydrogenase (G6PD) is essential for protection from oxidants; its African‐polymorphic X‐linked A+ and A‐ alleles, and other variants with reduced activity, coincide with endemic malaria distribution, suggesting protection from lethal infection. We examined the association of CYB5R3c.350C > G with severe anemia (hemoglobin <5 g/dL) in the context of G6PD A+ and A‐ status among 165 Zambian children with malaria. CYB5R3c.350C > G offered protection against severe malarial anemia in children without G6PD deficiency (G6PD wild type or A+/A‐ heterozygotes) (odds ratio 0.29, P = .022) but not in G6PD A+ or A‐ hemizygotes/homozygotes. We also examined the relationship of CYB5R3c.350C > G with hemoglobin concentration among 267 children and 321 adults and adolescents with SCD in the US and UK and found higher hemoglobin in SCD patients without G6PD deficiency (β = 0.29, P = .022 children; β = 0.33, P = .004 adults). Functional studies in SCD erythrocytes revealed mildly lower activity of native CYB5R3T117S compared to wildtype CYB5R3 and higher NADH/NAD+ ratios. In conclusion, CYB5R3c.350C > G appears to ameliorate anemia severity in malaria and SCD patients without G6PD deficiency, possibly accounting for CYB5R3c.350C > G selection and its high prevalence.
Divergent Total Synthesis of Euphoranginol C, Euphoranginone D, ent‐Trachyloban‐3β‐ol, ent‐Trachyloban‐3‐one, Excoecarin E, and ent‐16α‐Hydroxy‐atisane‐3‐one
Authors: Xu Ze‐Jun , Zong Yan , Qiao Ya‐Nan , Zhang Jiao‐Zhen , Liu Xuyuan , Zhu Ming‐Zhu , Xu Yuliang , Zheng Hongbo , Fang Liyuan , Wang Xiao‐ning , Lou Hong‐Xiang 
Published: July 2020

AbstractA divergent synthetic approach to biogenetically related diterpenoids such as ent‐kauranes, ent‐trachylobanes, ent‐beyerane, and ent‐atisane has been developed. The unified synthetic route involves the De Mayo reaction to rapidly generate the bicyclo[3.2.1]‐octane moiety of ent‐kaurane. The key reactions also include bioinspired nucleophilic cyclopropanation generating the [3.2.1.02,7]‐tricyclic core of ent‐trachylobane and regioselective cyclopropane fragmentation furnishing ent‐beyerane and ent‐atisane through the nucleophilic attack and protonation of the cyclopropane ring. This strategy enables the asymmetric total syntheses of six diterpenoids from the commercially available geraniol.
Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX‐2/5‐LOX inhibitors
Authors: Shaaban Mohamed A. , Kamal Aliaa M. , Faggal Samar I. , Farag Nahla A. , Aborehab Nora M. , Elsahar Ayman E. , Mohamed Khaled O. 
Published: July 2020

AbstractA new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through 1H nuclear magnetic resonance (NMR), 13C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone‐privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase‐2 (COX‐2)/5‐lipoxygenase (5‐LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5‐LOX inhibitory activity and COX‐2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti‐inflammatory activity. Compound 3j was found to be the most promising derivative, with IC50 values of 667 and 47 nM against COX‐1 and COX‐2, respectively, which are superior to that of celecoxib (IC50 value against COX‐2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX‐1 inhibition, with IC50 values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5‐LOX, with IC50 values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC50 values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC50 = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti‐inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX‐2 and 5‐LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX‐2 and 5‐LOX as dual inhibitors, as a new avenue in anti‐inflammatory therapy.
DAS‐IICognitive Profiles Are Not Diagnostically Meaningful For Autism: AROCAnalysis
Authors: Clements Caitlin C. , Sparding Timea , Schultz Robert T. , Yerys Benjamin E. , Watkins Marley W. 
Published: July 2020

Intelligence assessment is an integral part of a comprehensive autism evaluation. Many past studies have described a cognitive profile of autistic individuals characterized by higher nonverbal than verbal IQ scores. The diagnostic utility of this profile, however, remains unknown. We leveraged receiver operating characteristic methods to determine the sensitivity, specificity, and area under the curve (AUC) of three different IQ profiles in a large sample of children who have an autism spectrum disorder diagnosis (N= 1,228, Simons Simplex Collection) who completed the Differential Ability Scales—Second Edition (DAS‐II), School Age compared to the normative sample provided by the DAS‐II publisher (N= 2,200). The frequently discussed nonverbal > verbal IQ profile performed near chance at distinguishing ASD from normative individuals (AUC: 0.54, 95% CI [0.52–0.56]), and performed significantly worse for females than males (AUC: females: 0.46 [0.41–0.52]; males: 0.55 [0.53–0.58]). All cognitive profiles showed AUC < 0.56. We conclude that while significant differences between verbal and nonverbal IQ scores exist at the group level, these differences are small in an absolute sense and not meaningful at an individual level. We do not recommend using cognitive profiles to aid in autism diagnostic decision‐making.Lay SummarySome researchers and clinicians have reported an “autistic cognitive profile” of higher nonverbal intelligence than verbal intelligence. In an analysis of over 1,000 autistic children, we found that thegroup'saverage nonverbal intelligence is usually higher than their verbal intelligence. However, this pattern should not be used by clinicians to make anindividualdiagnosis of autism because our results show it is not helpful nor accurate.
Bayesian inference for quantiles of the log‐normal distribution
Authors: Gardini Aldo , Trivisano Carlo , Fabrizi Enrico 
Published: July 2020

AbstractThe log‐normal distribution is very popular for modeling positive right‐skewed data and represents a common distributional assumption in many environmental applications. Here we consider the estimation of quantiles of this distribution from a Bayesian perspective. We show that the prior on the variance of the log of the variable is relevant for the properties of the posterior distribution of quantiles. Popular choices for this prior, such as the inverse gamma, lead to posteriors without finite moments. We propose the generalized inverse Gaussian and show that a restriction on the choice of one of its parameters guarantees the existence of posterior moments up to a prespecified order. In small samples, a careful choice of the prior parameters leads to point and interval estimators of the quantiles with good frequentist properties, outperforming those currently suggested by the frequentist literature. Finally, two real examples from environmental monitoring and occupational health frameworks highlight the improvements of our methodology, especially in a small sample situation.
Highly sensitive spectrofluorimetric procedure for the assay of phenothiazine derivatives in the presence of their sulfoxide oxidized product
Authors: Omar Mahmoud A. , Mohamed Abdel‐Maaboud , Nagy Dalia M. , Salem Hesham , Abdelmageed Osama H. 
Published: July 2020

AbstractA validated straightforward and sensitive spectrofluorimetric procedure was developed to assay trifluoperazine hydrochloride, promethazine hydrochloride, and perazine maleate. The procedure was dependent on oxidation of the investigated phenothiazines using a known excess of ammonium cerium sulfate as oxidizing agent and overseeing the fluorescence intensity of the resultant Ce3+ion as the product of this reaction at λcx= 254 nm. and λem= 355 nm. Various parameters controlling the reaction were investigated and optimized. Linear calibration graphs were found in the general concentration range 5–30 ng/ml with a general correlation coefficient range 0.9994–0.9995. Limits of detection were 0.97, 0.70 and 0.56 ng/ml, whereas limits of quantification were 3.24, 2.12 and 1.89 ng/ml for trifluoperazine hydrochloride, promethazine hydrochloride and perazine maleate, respectively. The procedure was implemented successfully for analyses of the cited drugs in their trade dosage preparations such as tablets and syrups. The effect of possible interference from common excipients and their sulfoxide oxidized product was studied and the procedure showed good recovery of the drugs under study in their available dosage preparations. The possible effect of structure variation of the studied drugs on the experimental conditions and sensitivity observed with each one was also discussed.
Forskolin Increases cAMP Levels and Enhances Recombinant Antibody Production in CHO Cell Cultures
Authors: Yoon Chansik , Kim Dongil , Lim Ju Hyeon , Lee Gyun Min 
Published: July 2020

AbstractCyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger essential to many biological processes. Forskolin, a labdane diterpene, is widely used to increase cAMP levels in various cell types. When 5 µm of forskolin is added to recombinant Chinese hamster ovary (rCHO) cell cultures producing monoclonal antibody (mAb) (GSR cell line), it decreases specific growth rate (μ), but increases culture longevity and specific mAb productivity (qmAb). The beneficial effect of forskolin on culture longevity and qmAb outweighs its detrimental effect on μ, resulting in 1.5‐fold increase in the maximum mAb concentration (MMC) without an adverse effect on mAb quality attributes such as aggregation, charge variation, and galactosylation. Forskolin induces cell cycle arrest at the G0/G1 phase via the LKB1/AMPK pathway and inhibits apoptosis via the CREB/Bcl‐2 pathway. The beneficial effect of forskolin on mAb production is also demonstrated with another rCHO cell line (ABTAA). Addition of 5 µm forskolin to ABTAA cell cultures also results in 1.5‐fold increase in the MMC. Taken together, the results obtained demonstrate that forskolin is an efficient chemical reagent to increase mAb production in rCHO cell cultures.
Neutrophil‐to‐lymphocyte ratio, hyperglycemia, and outcomes in ischemic stroke patients treated with intravenous thrombolysis
Authors: Cheng Yani , Ying Anna , Lin Yanyan , Yu Junru , Luo Ji , Zeng Yifan , Lin Yuanshao 
Published: July 2020

AbstractIntroductionIncreased neutrophil‐to‐lymphocyte ratio (NLR) and hyperglycemia on admission are associated with poor outcomes in acute ischemic stroke (AIS) patients. We sought to evaluate the combined effect of increased NLR and hyperglycemia on the prognosis of ischemia stroke treated with intravenous thrombolysis (IVT).MethodsPatients with acute ischemic stroke receiving IVT treatment were prospectively enrolled. All participants were followed for 3 months. According to the levels of NLR and blood glucose, patients were categorized into four groups: high NLR or nonhigh NLR with or without hyperglycemia. The associations between NLR values with or without hyperglycemia and outcomes of stroke after thrombolysis were assessed by multivariable logistic regression analysis.ResultsAmong the 381 stroke patients (median age 68 years, 61.68% man) included, 155 (40.68%) had a poor outcome (modified Rankin Scale score 3–6) during 3 months. After multivariate adjustment, high NLR with hyperglycemia increased the risk of 3‐month poor outcome (OR = 4.42; 95% CI, 2.13–9.16), early neurological deterioration (END) (OR = 4.81; 95% CI, 2.08–11.12), and 3‐month mortality (OR = 6.56; 95% CI, 1.92–22.40). A significant multiplicative interaction of NLR and blood glucose on 3‐month poor outcome in ischemic stroke patients after thrombolysis was observed.ConclusionsIschemic stroke patients with concurrent high NLR and hyperglycemia increased risks of END, 3‐month poor outcome, and mortality after thrombolysis.
Total Synthesis and Structural Revision of Kasumigamide, and Identification of a New Analogue
Authors: Kuranaga Takefumi , Matsuda Kenichi , Takaoka Masachika , Tachikawa Chisato , Sano Ayae , Itoh Kosei , Enomoto Ayumu , Fujita Kei , Abe Ikuro , Wakimoto Toshiyuki 
Published: July 2020

AbstractKasumigamide is an antialgal hybrid peptide–polyketide isolated from the freshwater cyanobacterium Microcystis aeruginosa (NIES‐87). The biosynthetic gene cluster was identified from not only the cyanobacterium but also Candidatus “Entotheonella”, associated with the Japanese marine sponge Discodermia calyx. Therefore, kasumigamide is considered to play a key role in microbial ecology, regardless of the terrestrial and marine habitats. We now report synthetic studies on this intriguing natural product that have led to a structural revision and the first total synthesis. During this study, a new analogue, deoxykasumigamide, was also isolated and structurally validated. This study confirmed the presence of the unusual pathway in the biosynthesis of a hybrid peptide–polyketide natural product.
Active Bicomponent Nanoparticle Assembly with Temporal, Microstructural, and Functional Control
Authors: Dhiman Shikha , Singh Akanksha , George Subi J. 
Published: July 2020

AbstractTransient supramolecular self‐assembly has evolved as a tool to create temporally programmable smart materials. Yet, so far single‐component self‐assembly has been mostly explored. In contrast, multicomponent self‐assembly provides an opportunity to create unique nanostructures exhibiting complex functional outcomes, newer and different than individual components. Even two‐component can result in multiple organizations, such as self‐sorted domains or co‐assembled heterostructures, can occur, thus making it highly complex to predict and reversibly modulate these microstructures. In this study, we attempted to create active bicomponent nanoparticle assemblies of orthogonally pH‐responsive‐group‐functionalized gold and cadmium selenide nanoparticles with temporal microstructural control on their composition (self‐sorted or co‐assembly) in order to harvest their emergent transient photocatalytic activity by coupling to temporal changes in pH. Moving towards multicomponent systems can deliver next level control in terms of structural and functional outcomes of supramolecular systems.
A quality‐adjusted survival time without symptoms or toxicities analysis of glasdegib plus low‐dose cytarabine versus low‐dose cytarabine as initial therapy for acute myeloid leukemia in patients who are not considered candidates for intensive chemotherapy
Authors: Solem Caitlyn T. , Bell Timothy J. , Kwon Youngmin , Cappelleri Joseph C. , Johnson Courtney , Bhattacharyya Helen , Hoang Caroline J. , Cortes Jorge E. 
Published: July 2020

BackgroundIn a randomized study, glasdegib (a hedgehog inhibitor) plus low‐dose cytarabine (LDAC) significantly prolonged survival in comparison with LDAC in patients with acute myeloid leukemia (AML). A quality‐adjusted time without symptoms of disease progression or toxicity (Q‐TWiST) approach was used to evaluate comparative quality‐adjusted survival.MethodsOverall survival was partitioned into the following: time with any treatment‐emergent grade 3 or higher adverse events (TOX); time without symptoms of disease progression or toxicity (TWiST); and time after treatment discontinuation due to insufficient clinical response, relapse, or death time after progression (REL). Q‐TWiST was calculated by multiplying the restricted mean time in each state by respective utilities and then summing up the utility‐adjusted time.ResultsAt 20 months of follow‐up, the survival probabilities for the glasdegib‐LDAC arm and the LDAC arm were 28.2% and 7.9%, respectively. Glasdegib‐LDAC patients (n = 78), in comparison with LDAC patients (n = 38), had significantly longer mean TWiST (+3.4 months; 95% confidence interval [CI], 1.8‐5.2 months) and TOX (+0.8 months; 95% CI, 0.1‐1.6 months) and longer but nonsignificant REL (+0.3 months; 95% CI, −1.9 to 2.3 months). Q‐TWiST was 4.0 months (95% CI, 2.1‐5.8 months) longer with glasdegib plus LDAC, and this translated into a 75% relative improvement in quality‐adjusted survival with respect to LDAC. Results were robust to the length of follow‐up (6‐24 months) and remained significant when all adverse events, regardless of grade, were included.ConclusionsThese results suggest that most of the survival benefit from glasdegib plus LDAC versus LDAC alone is TWiST, and this represents added time in relatively “good” health. These results support the clinical value of glasdegib plus LDAC as initial therapy for AML in patients for whom intensive chemotherapy is not an option.
Clinical benefit and cost of breakthrough cancer drugs approved by the US Food and Drug Administration
Authors: Molto Consolación , Hwang Thomas J. , Borrell Maria , Andres Marta , Gich Ignasi , Barnadas Agustí , Amir Eitan , Kesselheim Aaron S. , Tibau Ariadna 
Published: July 2020

BackgroundThe clinical benefit and pricing of breakthrough‐designated cancer drugs are uncertain. This study compares the magnitude of the clinical benefit and monthly price of new and supplemental breakthrough‐designated and non–breakthrough‐designated cancer drug approvals.MethodsA cross‐sectional cohort comprised approvals of cancer drugs for solid tumors from July 2012 to December 2017. For each indication, the clinical benefit from the pivotal trials was scored via validated frameworks: the American Society of Clinical Oncology Value Framework (ASCO‐VF), the American Society of Clinical Oncology Cancer Research Committee (ASCO‐CRC), the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO‐MCBS), and the National Comprehensive Cancer Network (NCCN) Evidence Blocks. A high clinical benefit was defined as scores ≥ 45 for the ASCO‐VF, overall survival gains ≥ 2.5 months or progression‐free survival gains ≥ 3 months for all cancer types for the ASCO‐CRC criteria, a grade of A or B for trials of curative intent and a grade of 4 or 5 for trials of noncurative intent for the ESMO‐MCBS, and scores of 4 and 5 and a combined score ≥ 16 for the NCCN Evidence Blocks. Monthly Medicare drug prices were calculated with Medicare prices and DrugAbacus.ResultsThis study identified 106 trials supporting approval of 52 drugs for 96 indications. Forty percent of these indications received the breakthrough designation. Among the included trials, 33 (43%), 46 (73%), 35 (34%), and 67 (69%) met the thresholds established by the ASCO‐VF, ASCO‐CRC, ESMO‐MCBS, and NCCN, respectively. In the metastatic setting, there were higher odds of clinically meaningful grades in trials supporting breakthrough drugs with the ASCO‐VF (odds ratio [OR], 3.69; P = .022) and the NCCN Evidence Blocks (OR, 5.80; P = .003) but not with the ASCO‐CRC (OR, 3.54; P = .11) or version 1.1 (v1.1) of the ESMO‐MCBS (OR, 1.22; P = .70). The median costs of breakthrough therapy drugs were significantly higher than those of nonbreakthrough therapies (P = .001).ConclusionsIn advanced solid cancers, drugs that received the breakthrough therapy designation were more likely than nonbreakthrough therapy drugs to be scored as providing a high clinical benefit with the ASCO‐VF and the NCCN Evidence Blocks but not with the ESMO‐MCBS v1.1 or the ASCO‐CRC scale.