bluuebunny/crossref_metadata_2025_split huggingface dataset:
A laboratory framework for ongoing optimization of amplification-based genomic surveillance programs
Authors: Lam Connie , Johnson-Mackinnon Jessica , Basile Kerri , Fong Winkie , Suster Carl J.E. , Gall Mailie , Agius Jessica , Chandra Shona , Draper Jenny , Martinez Elena , Drew Alexander , Wang Qinning , Chen Sharon C. , Kok Jen , Dwyer Dominic E. , Sintchenko Vitali , Rockett Rebecca J. 
Published: November 2023

ABSTRACT
Constantly evolving viral populations affect the specificity of primers and the quality of genomic surveillance. This study presents a framework for the continuous optimization of sequencing efficiency for public health surveillance based on the ongoing evolution of the COVID-19 pandemic. SARS-CoV-2 genomic clustering capacity based on three amplification-based whole genome sequencing schemes was assessed using decreasing thresholds of genome coverage and measured against epidemiologically linked cases. The overall genome coverage depth and individual amplicon depth were used to calculate an amplification efficiency metric. Significant loss of genome coverage over time was documented, which was recovered by optimization of primer pooling or implementation of new primer sets. A minimum of 95% genome coverage was required to cluster 94% of epidemiologically defined SARS-CoV-2 transmission events. Clustering resolution fell to 70% when only 85% genome coverage was achieved. The framework presented in this study can provide public health genomic surveillance programs with a systematic process to ensure an agile and effective laboratory response during rapidly evolving viral outbreaks.

IMPORTANCE
This study provides a laboratory framework to ensure ongoing relevance and performance of amplification-based whole genome sequencing to strengthen public health surveillance during extended outbreaks or pandemics. The framework integrates regular reviews of the performance of a genomic surveillance system and highlights the importance of ongoing monitoring and the identification and implementation of improvements to whole genome sequencing methods to enhance public health responses to pathogen outbreaks.
Efficient cross-protection against serotype 4/8a fowl adenoviruses (FAdVs): recombinant FAdV-4 with FAdV-8a Fiber
Authors: Lu Yixuan , Yuan Yaqin , Jiang Huiru , Xu Zhenqi , Guo Yiwen , Cao Xudong , Li Tuofan , Wan Zhimin , Shao Hongxia , Qin Aijian , Xie Quan , Ye Jianqiang 
Published: November 2023

ABSTRACT
Recently, the infection of fowl adenoviruses (FAdVs) in chicken flocks has caused huge economic losses to the poultry industry in China. Although immunization with Fiber protein can provide autogenous protection of FAdVs, no commercial multivalent vaccines are available for the prevention and control of FAdVs. In this study, a novel recombinant virus FAdV4-F/8a-rF2 expressing the Fiber of FAdV-8a was generated through CRISPR-Cas9 and Cre-LoxP system by using the template virus FA4-EGFP. FAdV4-F/8a-rF2 not only exhibited a similar replication capacity to the wild-type FAdV-4 in Leghorn male hepatoma (LMH) cells but was also highly attenuated to specific pathogen free (SPF) chickens. Moreover, the inoculation of FAdV4-F/8a-rF2 could induce high neutralizing antibodies and provide full protection against both FAdV-4 and FAdV-8a. All these data demonstrate that the recombinant virus FAdV4-F/8a-rF2 developed here can be used as an attenuated bivalent vaccine candidate for the prevention and control of both FAdV-4 and FAdV-8a.

IMPORTANCE
Epidemiological data reveal that FAdV-4 and FAdV-8a are the dominant serotypes of FAdVs in the poultry industry in China. Although three commercial inactivated vaccines against FAdV-4 have been licensed in China, the bivalent vaccine against both FAdV-4 and FAdV-8a is not available. Here, we used CRISPR-Cas9 and Cre-LoxP system to generate a recombinant virus FAdV4-F/8a-rF2 expressing the Fiber of FAdV-8a. Notably, FAdV4-F/8a-rF2 was highly attenuated and could provide efficient protection against both FAdV-4 and FAdV-8a in the chicken infection model, highlighting the applaudable application of FAdV4-F/8a-rF2 as a novel live-attenuated bivalent vaccine against the diseases caused by the infection of FAdV-4 and FAdV-8a.
Determinants of practice for providing decision coaching to facilitate informed values-based decision-making: protocol for a mixed-methods systematic review
Authors: Berger-Höger Birte , Lewis Krystina B , Cherry Katherine , Finderup Jeanette , Gunderson Janet , Kaden Jana , Kienlin Simone , Rahn Anne C , Sikora Lindsey , Stacey Dawn , Steckelberg Anke , Zhao Junqiang 
Published: November 2023

IntroductionDecision coaching is a non-directive approach to support patients to prepare for making health decisions. It is used to facilitate patients’ involvement in informed values-based decision-making and use of evidence-based health information. A recent systematic review revealed low certainty evidence for its effectiveness with and without evidence-based information. However, there may be opportunities to improve the study and use of decision coaching in clinical practice by systematically investigating its determinants of practice. We aim to conduct a systematic review to identify and synthesise the determinants of practice for providing decision coaching to facilitate patient involvement in decision-making from multiple perspectives that influence its use.Methods and analysisWe will conduct a mixed-methods systematic review guided by the Cochrane’ Handbook of Systematic Reviews. We will include studies reporting determinants of practice influencing decision coaching with or without evidence-based patient information with adults making a health decision for themselves or a family member. Systematic literature searches will be conducted in Medline, EMBASE, Cochrane CENTRAL and PsycINFO via Ovid and CINAHL via EBSCO including quantitative, qualitative and mixed-methods study designs. Additionally, experts in the field will be contacted.Two reviewers will independently screen and extract data. We will synthesise determinants using deductive and inductive qualitative content analysis and a coding frame developed specifically for this review based on a taxonomy of barriers and enablers of shared decision-making mapped onto the major domains of the Consolidated Framework for Implementation Research. We will assess the quality of included studies using the Mixed Methods Appraisal Tool.Ethics and disseminationEthical approval is not required as this systematic review involves only previously published literature. The results will be published in a peer-reviewed journal, presented at scientific conferences and disseminated to relevant consumer groups.PROSPERO registration numberCRD42022338299.
Assessing the burden of HPV-related head and neck cancers in mainland China: protocol of a nationwide, multisite, cross-sectional study
Authors: Wang Wei , Song Cheng , Su Zheng , Kothari Smita , Chen Ya-Ting , Liu Yin , Wu Shu-Yu , Panchal Ravi , Morais Edith , Zhang Shao-Kai , Yin Jian , Qiao You-Lin , Roberts Craig 
Published: November 2023

BackgroundPersistent human papillomavirus (HPV) infection is a known cause of a subset of head and neck cancers (HNCs). In the last two decades, the proportion of HNCs attributable to HPV infection has increased worldwide, notably the oropharyngeal cancers. However, the trend of HPV-related HNC burden is not clearly understood yet in China. Thus, the absoluteburdenof HPV-related head andneck cancers in China (BROADEN-China) will be conducted to estimate the proportion of HNCs attributable to HPV infection, per anatomic site, by genotype, in three time periods (2008–2009, 2013–2014 and 2018–2019).Methods and analysisBROADEN-China is a nationwide, multisite, cross-sectional study. A stratified, multistage, non-randomised cluster sampling method will be used to select 2601 patients with HNC from 14 hospitals across seven regions, based on population density in China. Patients with formalin-fixed paraffin-embedded tissue samples collected prior to treatment induction during three time periods will be included, and factors (eg, smoking status, alcohol consumption, betel nut chewing, Epstein-Barr virus, teeth loss, etc) associated with HNC will be assessed. HPV testing (HPV-DNA, HPV-mRNA and p16INK4aimmunohistochemistry) and histological diagnosis of the tissue samples will be conducted at a central laboratory.The study protocol and all required documents have been submitted for review and approval to the Independent Ethics Committees of all the participating sites. The informed consent was waived for all participants and all the recorded data will be treated as confidential.We have included 14 hospitals as our participating sites, of which Henan Cancer Hospital is the leading site. The study has been approved by the independent ethics committees of the leading site on 3 December 2020. The other 13 participating site names of ethics committee and IRB that have approved this study.
Continuity of care and consultation mode in general practice: a cross-sectional and longitudinal study using patient-level and practice-level data from before and during the COVID-19 pandemic in England
Authors: Parry Will , Fraser Caroline , Crellin Elizabeth , Hughes Jay , Vestesson Emma , Clarke Geraldine M. 
Published: November 2023

ObjectivesInvestigate trends in continuity of care with a general practitioner (GP) before and during the COVID-19 pandemic. Identify whether continuity of care is associated with consultation mode, controlling for other patient and practice characteristics.DesignRetrospective cross-sectional and longitudinal observational studies.SettingPrimary care records from 389 general practices participating in Clinical Practice Research Datalink Aurum in England.ParticipantsIn the descriptive analysis, 100 000+ patients were included each month between April 2018 and April 2021. Modelling of the association between continuity of care and consultation mode focused on 153 475 and 125 298 patients in index months of February 2020 (before the pandemic) and February 2021 (during the pandemic) respectively, and 76 281 patients inbothindex months.Primary and secondary outcomes measuresThe primary outcome measure was the Usual Provider of Care index. Secondary outcomes included the Bice-Boxerman index and count of consultations with the most frequently seen GP.ResultsContinuity of care was gradually declining before the pandemic but stabilised during it. There were consistent demographic, socioeconomic and regional differences in continuity of care. An average of 23% of consultations were delivered remotely in the year to February 2020 compared with 76% in February 2021. We found little evidence consultation mode was associated with continuity at the patient level, controlling for a range of covariates. In contrast, patient characteristics and practice-level supply and demand were associated with continuity.ConclusionsWe set out to examine the association of consultation mode with continuity of care but found that GP supply and patient demand were much more important. To improve continuity for patients, primary care capacity needs to increase. This requires sufficient, long-term investment in clinicians, staff, facilities and digital infrastructure. General practice also needs to transform ways of working to ensure continuity for those that need it, even in a capacity-constrained environment.
Variation in the Incidence and Type of Full versus Mosaic Segmental Aneuploidies Identified in Blastocysts Undergoing PGT-A
Authors: Cuman Carly , Green Mark P. , Willats Elissa , Hardy Tristan , Zander-Fox Deirdre 
Published: November 2023

Objectives: The primary aim of this study was to investigate the incidence of segmental aneuploidies (full vs. mosaic) in embryos biopsied for Preimplantation Genetic Testing with Aneuploidy (PGT-A) screening using low-coverage whole genome sequencing (WGS). The secondary aim was to investigate factors that may be associated with segmental aneuploidy rates, including blastocyst developmental stage and quality. Methods: This study involved a retrospective analysis of cycle and PGT-A data from 8,153 blastocysts biopsied from 2,522 patients at four Monash IVF Victorian clinics between January 2015 and June 2021. All biopsies were processed using the Veriseq PGS Kit (Illumina) and analyzed using Bluefuse Multi software (Illumina) with a conclusive PGT-A result. Segmental aneuploidy was reported with a minimum resolution of greater than or equal to 10[Formula: see text]Mb. The reporting range for mosaicism was 20%–70% loss/gain in copy number. Statistical significance was established at a P-value of less than 0.05. Results: Segmental aneuploidies (full and/or mosaic) were reported in 682/8,153 (8.4%) biopsied embryos. Analysis of the types of segmental aneuploidy showed a higher proportion of deletions (423/8,153; 5.2%) compared to duplications (210/8,153; 2.6% [[Formula: see text]] plus a small portion with both duplications and deletions detected 49/8153; 0.6% [[Formula: see text]]). The incidence of segmental aneuploidies appeared to increase in correlation with chromosome size. Segregation of embryos by blastocyst stage indicated an increase in the incidence of segmental aneuploidies in early blastocysts (9/64; 14.1%) compared with expanding/expanded (39/475, 8.2%, [[Formula: see text]] and hatching/hatched blastocysts [634/7614, 8.3%; [Formula: see text]]). Furthermore, the incidence of segmental aneuploidies significantly increased as blastocyst overall grade decreased (Grade A 71/1,429, 5.0%; Grade B 298/3,764, 7.9%; Grade C 313/2,960, 10.6%; [Formula: see text]). Of the segmental aneuploidies detected, 425/682 (62.3%) were present at a mosaic level. Conclusions: Segmental aneuploidy rates varied between blastocyst stage and grades, with a significant proportion of segmental aneuploidies being detected at the mosaic level. Our data highlights that segmental aneuploidies, both at the full and mosaic level, are associated with lower blastocyst quality and poorer embryo development.
Progestin-Primed Ovarian Stimulation versus GnRH Antagonist Protocol for Ovarian Stimulation in IVF: A Prospective Pilot Study
Authors: Le Tien K. , Le Xuyen H. , Nguyen Duy L. , Vu Anh L. , Vuong Lan N. 
Published: November 2023

Background: Progestin-primed ovarian stimulation (PPOS) has been proposed as an alternative to conventional gonadotropin-releasing hormone (GnRH) antagonist protocol for ovarian stimulation in in vitro fertilization (IVF). The aim of PPOS is to provide an effective, patient-friendly treatment. However, studies comparing outcomes after the use of PPOS and GnRH antagonist protocol in IVF have shown mixed results. This study compared ongoing pregnancy rates after the use of PPOS versus GnRH antagonist protocol for ovarian stimulation in IVF. Methods: This prospective pilot study was conducted at a single IVF center. Women aged 18–35 years old with an anti-Müllerian hormone (AMH) level greater than or equal to 1.2[Formula: see text]ng/mL or an antral follicle count (AFC) greater than or equal to 5 who were undergoing their first IVF cycle were allocated to undergoing ovarian stimulation using PPOS (dydrogesterone 20[Formula: see text]mg/day started on the day of gonadotropin) or a GnRH antagonist protocol (fixed regimen from stimulation day 5). The primary outcome was the ongoing pregnancy rate (at 12 weeks’ gestation). Results: The study included 30 women (15 in each treatment group). Baseline characteristics were similar between groups. The ongoing pregnancy rate was 7/15 (46.7%) in the PPOS group and 8/15 (53.3%) in the GnRH antagonist group ([Formula: see text]); the number of oocytes retrieved and fertilization rates were also comparable between groups. One case of mild ovarian hyperstimulation syndrome (OHSS) occurred in the GnRH antagonist group. Conclusions: This pilot study showed similar ongoing pregnancy rates after the use of a PPOS protocol and a conventional GnRH antagonist protocol for ovarian stimulation in IVF. Additional studies with larger sample sizes are needed to confirm these findings.
Association of Molecular Subtypes with Pathologic Response, PFS, and OS in a Phase II Study of COXEN with Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer
Authors: Lerner Seth P. , McConkey David J. , Tangen Catherine M. , Meeks Joshua J. , Flaig Thomas W. , Hua Xing , Daneshmand Siamak , Alva Ajjai Shivaram , Lucia M. Scott , Theodorescu Dan , Goldkorn Amir , Milowsky Matthew I. , Choi Woonyoung , Bangs Rick , Gustafson Daniel L. , Plets Melissa , Thompson Ian M. 
Published: November 2023

Abstract

Purpose:
The Coexpression Extrapolation (COXEN) gene expression model with chemotherapy-specific scores [for methotrexate, vinblastine, adriamycin, cisplatin (ddMVAC) and gemcitabine/cisplatin (GC)] was developed to identify responders to neoadjuvant chemotherapy (NAC). We investigated RNA-based molecular subtypes as additional predictive biomarkers for NAC response, progression-free survival (PFS), and overall survival (OS) in patients treated in S1314.

Experimental Design:
A total of 237 patients were randomized between four cycles of ddMVAC (51%) and GC (49%). On the basis of Affymetrix transcriptomic data, we determined subtypes using three classifiers: TCGA (k = 5), Consensus (k = 6), and MD Anderson (MDA; k = 3) and assessed subtype association with path response to NAC and determined associations with COXEN. We also tested whether each classifier contributed additional predictive power when added to a model based on predefined stratification (strat) factors (PS 0 vs. 1; T2 vs. T3, T4a).

Results:
A total of 155 patients had gene expression results, received at least three of four cycles of NAC, and had pT-N response based on radical cystectomy. TCGA three-group classifier basal-squamous (BS)/neuronal, luminal (Lum), Lum infiltrated, and GC COXEN score yielded the largest AUCs for pT0 (0.59, P = 0.28; 0.60, P = 0.18, respectively). For downstaging (&lt;pT2), the three-category Consensus classifier [BS/neuroendocrine (NE)-like, Lum, stroma-rich] increased the AUC from 0.57 (strat factors alone) to 0.61 (P = 0.10). The MDA classifier AUC was 0.63 (P = 0.18) and the GC COXEN score AUC was 0.62 (P = 0.23), but neither significantly improved the AUC. There was no statistically significant association of stratification factors and subtypes with PFS or OS.

Conclusions:
The Consensus classifier, based in part on the TCGA and MDA classifiers, modestly improved prediction for pathologic downstaging but subtypes were not associated with PFS or OS.
Preclinical Characterization of AZD9574, a Blood–Brain Barrier Penetrant Inhibitor of PARP1
Authors: Staniszewska Anna D. , Pilger Domenic , Gill Sonja J. , Jamal Kunzah , Bohin Natacha , Guzzetti Sofia , Gordon Jacob , Hamm Gregory , Mundin Gill , Illuzzi Giuditta , Pike Andy , McWilliams Lisa , Maglennon Gareth , Rose Jonathan , Hawthorne Glen , Cortes Gonzalez Miguel , Halldin Christer , Johnström Peter , Schou Magnus , Critchlow Susan E. , Fawell Stephen , Johannes Jeffrey W. , Leo Elisabetta , Davies Barry R. , Cosulich Sabina , Sarkaria Jann N. , O'Connor Mark J. , Hamerlik Petra 
Published: November 2023

Abstract

Purpose:
We evaluated the properties and activity of AZD9574, a blood–brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models.

Experimental Design:
AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models. Mouse, rat, and monkey were used to assess AZD9574 BBB penetration and rat models were used to evaluate potential hematotoxicity for AZD9574 monotherapy and the TMZ combination.

Results:
AZD9574 demonstrated PARP1-selectivity in fluorescence anisotropy, PARylation, and PARP-DNA trapping assays and in vivo experiments demonstrated BBB penetration. AZD9574 showed potent single agent efficacy in preclinical models with homologous recombination repair deficiency in vitro and in vivo. In an O6-methylguanine-DNA methyltransferase (MGMT)–methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared with TMZ alone.

Conclusions:
The combination of three key features—PARP1 selectivity, PARP1 trapping profile, and high central nervous system penetration in a single molecule—supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anticancer efficacy as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594).
See related commentary by Lynce and Lin, p. 1217
Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression
Authors: Hasselluhn Marie C. , Decker-Farrell Amanda R. , Vlahos Lukas , Thomas Dafydd H. , Curiel-Garcia Alvaro , Maurer H. Carlo , Wasko Urszula N. , Tomassoni Lorenzo , Sastra Stephen A. , Palermo Carmine F. , Dalton Tanner C. , Ma Alice , Li Fangda , Tolosa Ezequiel J. , Hibshoosh Hanina , Fernandez-Zapico Martin E. , Muir Alexander , Califano Andrea , Olive Kenneth P. 
Published: November 2023

AbstractThe sparse vascularity of pancreatic ductal adenocarcinoma (PDAC) presents a mystery: What prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of noncanonical WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues.Significance:We present a key mechanism of tumor angiosuppression, a process that sculpts the physiologic, cellular, and metabolic environment of PDAC. We further present a computational and experimental framework for the dissection of complex signaling cascades that propagate among multiple cell types in the tissue environment.This article is featured in Selected Articles from This Issue, p. 201