bluuebunny/crossref_metadata_2025_split huggingface dataset:
Barriers and facilitators to use of a digital clinical decision support tool: a cohort study combining clickstream and survey data
Authors: Rosenberg Julie , Miller Kate , Pickard Olivia , Henrich Natalie , Karlage Ami , Weintraub Rebecca 
Published: November 2022

ObjectivesThis research aimed to understand the barriers and facilitators clinicians face in using a digital clinical decision support tool—UpToDate—around the globe.DesignWe used a mixed-methods cohort study design that enrolled 1681 clinicians (physicians, surgeons or physician assistants) who applied for free access to UpToDate through our established donation programme during a 9-week study enrolment period. Eligibility included working outside of the USA for a limited-resource public or non-profit health facility, serving vulnerable populations, having at least intermittent internet access, completing the application in English; and not being otherwise able to afford the subscription.InterventionAfter consenting to study participation, clinicians received a 1-year subscription to UpToDate. They completed a series of surveys over the year, and we collected clickstream data tracking their use of the tool.Primary and secondary outcome measures(1) The variation in use by demographic; (2) the prevalence of barriers and facilitators of use; and (3) the relationship between barriers, facilitators and use.ResultsOf 1681 study enrollees, 69% were men and 71% were between 25 and 35 years old, with the plurality practicing general medicine and the majority in sub-Saharan Africa or Southeast Asia. Of the 11 barriers we assessed, fitting the tool into the workflow was a statistically significant barrier, making clinicians 50% less likely to use it. Of the 10 facilitators we assessed, a supportive professional context and utility were significant drivers of use.ConclusionsThere are several clear barriers and facilitators to promoting the use of digital clinical decision support tools in practice. We recommend tools like UpToDate be implemented with complementary services. These include generating a supportive professional context, helping clinicians realise the tools’ use and working with health systems to better integrate digital, clinical decision support tools into workflows.
Quality improvement project to improve the standardisation and efficiency of occupational therapy initial contact and assessment within a mental health inpatient service
Authors: Ige Joshua Jesudunsin , Hunt David Fancis 
Published: November 2022

Timely contact and assessment between occupational therapists (OTs) and patients are vital to understanding their needs and creating person-centred interventions. Any delays in completing contact and assessment will likely impact patients’ experience and outcomes. The aim of this study was to ensure that 90% of all patients in a male and female ward received OT initial contact within two working days of admission by the end of June 2020.With the teams working in collaboration, the first change idea of increasing the initial contact in two working days was introduced and the impact assessed on two of the five wards. The Plan–Do–Study–Act cycles used for this test of change included: Standardising the initial contact, informal training for the audit tool created to measure the admission process, increasing efficiency for documenting OT contact, updated exclusion/inclusion criteria for OT initial contact, refining documentation for contact and assessment, and the impact of COVID-19 on initial contact and admission processes.Our test of change resulted in an increase in the average initial contact from 12.5% to 71.24%. Following this success, we spread the project to the three remaining wards. Feedback from OTs using the tools we introduced ensured that we made tools as user-friendly as possible. Likewise, teams who achieved particularly high compliance noted the importance of dedicating time to conduct initial contact.Our team embarked on a quality improvement project that aimed to set a standard and increase compliance for achieving this standard. Alongside this, we developed an appropriate and pragmatic measure to track our progress. While we did not achieve 90%, we observed substantial improvements made across the participating service. Using the findings from the project, we have spread this approach to other wards and believe that it could easily be transferrable as a discreet package to other mental health settings.
Dose selection for a phase III study evaluating gepotidacin (GSK2140944) in the treatment of uncomplicated urogenital gonorrhoea
Authors: Scangarella-Oman Nicole E , Hossain Mohammad , Perry Caroline R , Tiffany Courtney , Powell Marcy , Swift Brandon , Dumont Etienne F 
Published: November 2022

BackgroundGepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and is active against most strains ofNeisseria gonorrhoeae(N. gonorrhoeae). Phase II data suggested higher exposures were needed for efficacy and to suppress resistance development. A translational approach using in vitro pharmacokinetic/pharmacodynamic (PK/PD) and clinical data was used to select a gepotidacin dose for a phase III study. In this narrative review of previously shown data, we summarise how a translational approach based on in vitro PK/PD and population PK modelling and simulation data was undertaken to select a dosing regimen for the ongoing phase III gepotidacin study in participants with uncomplicated urogenital gonorrhoea.MethodsFor dose selection, prior in vitro minimum inhibitory concentrations (MICs) and PK/PD data were available. PK modelling was conducted to determine a dose that would limit plasma concentrations to less than 14 µg/mL (as concentrations above this are associated with QT prolongation and effects associated with acetylcholinesterase inhibition) while maintaining ≥90% probability of target attainment (PTA) for efficacy and resistance suppression againstN. gonorrhoeaeisolates with gepotidacin MICs ≤1 µg/mL.ResultsTwo 3000 mg gepotidacin doses, administered 10–12 hours apart, resulted in PTA of ≥97.5% and ≥91.7% for gepotidacin MICs ≤1 µg/mL for the ratio of the area under the free drug plasma concentration–time curve over 24 hours to the MIC (fAUC0–24/MIC) efficacy, and resistance suppression targets of 40 and 46, respectively, but limited the occurrence of maximum plasma concentrations ≥14 µg/mL.ConclusionsTwo gepotidacin 3000 mg oral doses 10–12 hours apart provide ~2-fold higher systemic exposures, increase efficacy for higher gepotidacin MICN. gonorrhoeaeisolates, reduce resistance potential and limit plasma concentrations of potential safety concern, compared with higher doses.
20(S)-Protopanaxadiol fromPanax ginsengInduces Apoptosis and Autophagy in Gastric Cancer Cells by Inhibiting Src
Authors: Song Chaoran , Shen Ting , Kim Han Gyung , Hu Weicheng , Cho Jae Youl 
Published: November 2022

20(S)-protopanaxadiol (PPD), a metabolite of Panax ginseng, has multiple pharmacological properties. However, the effects of PPD against human gastric cancer have not been elucidated. Our purpose in this study was to investigate if PPD has anticancer effects against human gastric cancer in vitro. Cell viability, migration, clone formation, and invasion were assessed to explore the effects of PPD on cancer cells. PI and annexin V staining as well as immunoblotting were employed to determine if PPD-induced apoptosis and autophagy of MKN1 and MKN45 cells. The target of PPD was identified using immunoblotting, overexpression analysis, and flow cytometric analysis. PPD exhibited significantly suppressed cell viability, migration, colony formation, and invasion. Phosphorylation of Src and its down-stream effectors were inhibited by PPD. PPD-enhanced apoptosis and autophagy in a dose- and time-dependent manner by inhibiting Src. Collectively, our results demonstrate that PPD induces apoptosis and autophagy in gastric cancer cells in vitro by inhibiting Src.
The Impact of Flooding on Education of Children and Adolescents: Evidence from Pakistan
Authors: Ahmed Riaz , Barkat Waseem , Ahmed Adeel , Tahir Muhammad , Nasir Abdul Majid 
Published: November 2022

This study traces short- to long-term adverse effects of the colossal flood 2010 on educational outcomes of children and adolescents (age 5–16 years) in the flooded districts of Pakistan. Taking advantage of the flood — a type of quasi-natural experimental research design we utilized a difference-in-differences (DID) approach with inverse probability of treatment weights (IPTWs) to estimate the impact of the flood on educational outcomes by using a household surveys’ dataset (six waves). We compare educational outcomes out-of-school or dropout from school of — children and adolescents in the flooded households with the educational outcomes of individuals of same age groups in the non-flooded households before, during and after the flood. Our findings reveal that, on an average, 39 out of 1000 children and adolescents in the flooded districts, compared with their counterparts in the non-flooded districts, were not admitted in any educational institutions and 16 of them dropped out from schools during the flood. The effect of flood on education of children and adolescents, then, disappeared after 2–4 years after the flood. The education outcomes of children and adolescents in flooded households in rural areas compared with their peers in non-flooded districts were severely affected by the flood. Mirroring the impact of flood on education sector to the current heavy flood 2022 in Pakistan or pandemic COVID-19 is similarly compelling nations around the world for closure of their schools and educational institutions. The findings of this study may have some policy implications in terms of identifying the most vulnerable children and adolescents to mitigate the adverse impact of the natural disasters such as flood or pandemic on education outcomes and particularly significant to pinpoint shocks of disasters that have large and long-run impacts on human capital accumulation.
Comparison of Adjuvant Hypertonic Saline and Normal Saline for Epidural Block in Patients with Postherpetic Neuralgia: A Double-Blind, Randomized Trial
Authors: Kwon Hyun-Jung , Kim Doo-Hwan , Cho Seong-Sik , Jeon Bokyoung , Karm Myong-Hwan , Choi Seong-Soo 
Published: November 2022

Background. In patients with postherpetic neuralgia (PHN), the effectiveness of epidural block and the benefits of adjuvant hypertonic saline (HS) have not been fully determined. Therefore, we investigated these issues in this study. Methods. At a tertiary medical center’s single pain clinic in Seoul, Republic of Korea, patients complaining of PHN even after 4 months of herpes zoster onset were enrolled and randomly assigned to either the HS or normal saline (NS) group. After epidural block with adjuvant HS or NS administration according to each protocol, outcomes were assessed at baseline and one and three months after the intervention. The primary outcome was pain intensity on the numerical rating scale (NRS). The secondary outcomes were the insomnia severity index (ISI), the medication quantification scale (MQS), and the global perceived effect of satisfaction (GPES). Results. Thirty-six patients (NS: 17, HS: 19) were included in the intention-to-treat analysis. The estimated pain intensity decreased in both groups at one and three months after the procedure (

P

< 0.001), without a significant group difference. The estimated ISI and MQS were not significantly different at 1 month compared with baseline but significantly decreased at 3 months in each group (

P

< 0.001 and

P

< 0.001, respectively), without group differences. In addition, there was no difference between the groups on the GPES scale at one and three months after the procedure. Conclusions. Epidural steroid injection may have the advantages of short-term pain relief, improved sleep quality, and decreased medication usage in patients with PHN. In addition, adjuvant HS administration with epidural steroid injection did not show beneficial effects in patients with PHN. Further studies are needed to clarify the potential effectiveness of HS in treating neuropathic pain such as PHN. This trial is registered with KCT0002845.
JAK–STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States
Authors: Stevens Laura E. , Peluffo Guillermo , Qiu Xintao , Temko Daniel , Fassl Anne , Li Zheqi , Trinh Anne , Seehawer Marco , Jovanović Bojana , Alečković Maša , Wilde Callahan M. , Geck Renee C. , Shu Shaokun , Kingston Natalie L. , Harper Nicholas W. , Almendro Vanessa , Pyke Alanna L. , Egri Shawn B. , Papanastasiou Malvina , Clement Kendell , Zhou Ningxuan , Walker Sarah , Salas Jacqueline , Park So Yeon , Frank David A. , Meissner Alexander , Jaffe Jacob D. , Sicinski Piotr , Toker Alex , Michor Franziska , Long Henry W. , Overmoyer Beth A. , Polyak Kornelia 
Published: November 2022

Abstract

Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24− cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24−pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24− cells are the most frequent cell type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy-resistant derivatives. Integrated pSTAT3 chromatin immunoprecipitation sequencing and RNA sequencing (RNA-seq) analyses showed pSTAT3 regulates genes related to inflammation and epithelial-to-mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare preexisting subpopulations or an acquired change. Finally, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC.

Significance:
Chemotherapy resistance in inflammatory breast cancer is driven by the JAK2/STAT3 pathway, in part via cAMP/PKA signaling and a cell state switch, which can be overcome using paclitaxel combined with JAK2 inhibitors.
Aberrant L-Fucose Accumulation and Increased Core Fucosylation Are Metabolic Liabilities in Mesenchymal Glioblastoma
Authors: Pieri Valentina , Gallotti Alberto L. , Drago Denise , Cominelli Manuela , Pagano Ilaria , Conti Valentina , Valtorta Silvia , Coliva Angela , Lago Sara , Michelatti Daniela , Massimino Luca , Ungaro Federica , Perani Laura , Spinelli Antonello , Castellano Antonella , Falini Andrea , Zippo Alessio , Poliani Pietro L. , Moresco Rosa Maria , Andolfo Annapaola , Galli Rossella 
Published: November 2022

Abstract

Glioblastoma (GBM) is a common and deadly form of brain tumor in adults. Dysregulated metabolism in GBM offers an opportunity to deploy metabolic interventions as precise therapeutic strategies. To identify the molecular drivers and the modalities by which different molecular subgroups of GBM exploit metabolic rewiring to sustain tumor progression, we interrogated the transcriptome, the metabolome, and the glycoproteome of human subgroup-specific GBM sphere-forming cells (GSC). L-fucose abundance and core fucosylation activation were elevated in mesenchymal (MES) compared with proneural GSCs; this pattern was retained in subgroup-specific xenografts and in subgroup-affiliated human patient samples. Genetic and pharmacological inhibition of core fucosylation significantly reduced tumor growth in MES GBM preclinical models. Liquid chromatography-mass spectrometry (LC-MS)–based glycoproteomic screening indicated that most MES-restricted core-fucosylated proteins are involved in therapeutically relevant GBM pathological processes, such as extracellular matrix interaction, cell adhesion, and integrin-mediated signaling. Selective L-fucose accumulation in MES GBMs was observed using preclinical minimally invasive PET, implicating this metabolite as a potential subgroup-restricted biomarker.
Overall, these findings indicate that L-fucose pathway activation in MES GBM is a subgroup-specific dependency that could provide diagnostic markers and actionable therapeutic targets.

Significance:
Metabolic characterization of subgroup-specific glioblastoma (GBM) sphere-forming cells identifies the L-fucose pathway as a vulnerability restricted to mesenchymal GBM, disclosing a potential precision medicine strategy for targeting cancer metabolism.
Serrated Polyp Yield at Colonoscopy in Patients with Positive FIT, Positive mt-sDNA, and Colonoscopy Only: Data from the New Hampshire Colonoscopy Registry
Authors: Anderson Joseph C. , Hisey William M. , Robinson Christina M. , Limburg Paul J. , Kneedler Bonny L. , Butterly Lynn F. 
Published: November 2022

Abstract

Background:
Stool-based screening with fecal immunochemical (FIT) or multitarget-stool DNA (mt-sDNA) tests is associated with increased colonoscopy polyp yield. mt-sDNA includes methylated markers, which improve detection of serrated polyps (SP) versus FIT. We compared SP detection in colonoscopies performed for positive FIT or mt-sDNA tests, as well as in colonoscopies without a preceding stool test, using the New Hampshire Colonoscopy Registry, a comprehensive statewide population-based registry.

Methods:
Across the three groups, we compared the frequency of clinically relevant SPs (CRSP: sessile SPs, hyperplastic polyps ≥10 mm, and traditional serrated adenomas). We also compared SP size, histology, number, and bulk (combined sizes).

Results:
Our sample included 560 mt-sDNA+ (age ± SD: 66.5 ± 7.9), 414 FIT+ (age ± SD: 66.3 ± 8.8), and 59,438 colonoscopy-only patients (age ± SD: 61.7 ± 8.0). mt-sDNA+ patients were more likely to have a higher yield of CRSPs and CRSP bulk than FIT+ (P &lt; 0.0001) or colonoscopy-only patients (P &lt; 0.0001). More mt-sDNA+ patients had CRSPs without large adenomas or colorectal cancers (17.9% vs. 9.9% of FIT+ and 8% of colonoscopy-only patients). After adjusting for synchronous large adenomas, colorectal cancers, and other risk factors, mt-sDNA+ patients were more likely (OR, 1.82; 95% CI, 1.18–2.85) than FIT+ patients to have CRSPs.

Conclusions:
mt-sDNA+ patients had a higher SP yield than FIT+ or colonoscopy-only patients, particularly in the absence of synchronous large adenomas or colorectal cancer.

Impact:
Our results suggest that screening with mt-sDNA tests could improve colorectal cancer screening by identifying more patients at increased risk from the serrated pathway.
Multimarker Analysis of Serially Measured GDF-15, NT-proBNP, ST2, GAL-3, cTnI, Creatinine, and Prognosis in Acute Heart Failure
Authors: Gürgöze Muhammed T. , van Vark Laura C. , Baart Sara J. , Kardys Isabella , Akkerhuis K. Martijn , Manintveld Olivier C. , Postmus Douwe , Hillege Hans L. , Lesman-Leegte Ivonne , Asselbergs Folkert W. , Brunner-la-Rocca Hans-Peter , van den Bos Ewout J. , Orsel Joke G. , de Ridder Stijn P.J. , Pinto Yigal M. , Boersma Eric 
Published: November 2022

Background:
Studies on serially measured GDF-15 (growth differentiation factor 15) in acute heart failure (HF) are limited. Moreover, several pathophysiological pathways contribute to HF. Therefore, we aimed to explore the (additional) prognostic value of serially measured GDF-15 using a multi-marker approach to more accurately predict HF risk.

Methods:
TRIUMPH (Translational Initiative on Unique and Novel Strategies for Management of Patients With Heart Failure) is a prospective cohort of 496 patients with acute HF who were enrolled in 14 hospitals in the Netherlands between 2009 and 2014. Blood sampling was scheduled at 7 moments during 1-year follow-up. GDF-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), ST2 (suppression of tumorigenicity 2), galectin-3, troponin I, and creatinine were measured in a central laboratory. We associated repeated measurements of these biomarkers with the composite primary end point of all-cause mortality and HF rehospitalization, using multivariable joint modeling.

Results:
Median age was 74 years, and 37% were women. Median baseline GDF-15 was 4632 pg/mL. The primary end point was reached in 188 (40%) patients. The average estimated GDF-15 level increased weeks before the primary end point was reached. The hazard ratio per 1 SD difference in log-GDF-15 was 2.14 (95% CI, 1.78–2.57) unadjusted, 1.96 (1.49–2.53) after adjustment for clinical confounders and 1.44 (1.05–1.91) when jointly modeled with all biomarkers. The adjusted HRs for NT-proBNP were 2.38 (1.78–3.33) and 1.52 (1.15–2.08), respectively. The multimarker model combining GDF-15, NT-proBNP, and troponin I provided a favorable risk discrimination (area under the curve=0.785).

Conclusions:
Sequentially measured GDF-15 independently and dynamically predicts risk of adverse outcomes during 1-year follow-up after index admission for acute HF. NT-proBNP remains a robust predictor among potential candidates. Multiple biomarkers should be considered for stratification in clinical practice.

Registration:

URL:
https://www.trialregister.nl/trial/1783
; Unique Identifier: NTR1893. (The trial can be found temporarily at
https://trialsearch.who.int/Trial2.aspx?TrialID=NTR1893
.)
The Late 1970s Shift in ENSO Persistence Barrier Modulated by the Seasonal Amplitude of ENSO Growth Rate
Authors: Jiang Ning , Yu Minjie , Lu Bo , Leung Jeremy Cheuk-Hin , Zhu Congwen 
Published: November 2022

Abstract
The persistence barrier (PB), one of the El Niño–Southern Oscillation (ENSO) properties, has exhibited a significant decadal variability, showing enhanced and weakened behavior before and after the late 1970s, respectively. In the present study, both the theoretical solution and the observations indicate that the variability of PB intensity is linearly proportional to the seasonal amplitude of ENSO growth rate, which accounts for the ENSO PB decadal variability. With further use of the Bjerknes–Jin (BJ) index analysis, we find that the decadal reduction in PB intensity since the late 1970s is mainly attributed to the mean advection and the thermocline feedback. In addition, the stronger spring thermal damping delayed the timing of PB in the 1980s and 1990s. Our study establishes a linear relationship between PB intensity and ENSO growth rate, which carries implications for understanding the ENSO predictability and the systematic changes in ENSO properties under climate change.