bluuebunny/crossref_metadata_2025_split huggingface dataset:
Supplementation withBifidobacterium longumsubspeciesinfantisEVC001 for mitigation of type 1 diabetes autoimmunity: the GPPAD-SINT1A randomised controlled trial protocol
Authors: Ziegler Anette-Gabriele , Arnolds Stefanie , Kölln Annika , Achenbach Peter , Berner Reinhard , Bonifacio Ezio , Casteels Kristina , Elding Larsson Helena , Gündert Melanie , Hasford Joerg , Kordonouri Olga , Lundgren Markus , Oltarzewski Mariusz , Pekalski Marcin L , Pfirrmann Markus , Snape Matthew D , Szypowska Agnieszka , Todd John A 
Published: November 2021

IntroductionThe Global Platform for the Prevention of Autoimmune Diabetes-SINT1A Study is designed as a randomised, placebo-controlled, double-blind, multicentre, multinational, primary prevention study aiming to assess whether daily administration ofBifidobacterium infantisfrom age 7 days to 6 weeks until age 12 months to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies in childhood.Methods and analysisInfants aged 7 days to 6 weeks from Germany, Poland, Belgium, UK and Sweden are eligible for study participation if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies by age 6 years as determined by genetic risk score or family history and HLA genotype. Infants are randomised 1:1 to daily administration ofB. infantisEVC001 or placebo until age 12 months and followed for a maximum of 5.5 years thereafter. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies. Secondary outcomes are (1) Any persistent confirmed beta-cell autoantibody, defined as at least one confirmed autoantibody in two consecutive samples, including insulin autoantibodies, glutamic acid decarboxylase, islet tyrosine phosphatase 2 or zinc transporter 8, (2) Diabetes, (3) Transglutaminase autoantibodies associated with coeliac disease, (4) Respiratory infection rate in first year of life during supplementation and (5) Safety. Exploratory outcomes include allergy, antibody response to vaccines, alterations of the gut microbiome or blood metabolome, stool pH and calprotectin.Ethics and disseminationThe study was approved by the local ethical committees of the Technical University Munich, Medical Faculty, the Technische Universität Dresden, the Medizinische Hochschule Hannover, the Medical University of Warsaw, EC Research UZ Leuven and the Swedish ethical review authority. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the study.Trial registration numberNCT04769037.
Maternal perinatal depression and health services utilisation in the first 2 years of life: a cohort study
Authors: Adler Limor , Azuri Joseph 
Published: November 2021

ObjectivesMaternal perinatal depression is a common phenomenon, influencing infants’ development. Studies have shown an inconsistent association between perinatal depression and healthcare resource utilisation. This study aimed to assess whether perinatal depression in mothers is associated with their infants’ healthcare utilisation, during the first 2 years of life.DesignA cohort study based on computerised medical records.SettingNationwide primary care clinics in the second largest health maintenance organisation in Israel.Participants593 children of women with depression (the exposed group) and 2310 children of women without depression.Primary and secondary outcome measuresPrimary outcome variables included general practitioner/paediatrician (GP/Paed) visits (regular and telehealth), emergency room (ER) visits, hospital admission rates and child-development clinic visits. Secondary outcomes included antibiotic use and anaemia status. The exposure variable, perinatal depression, was based on Edinburgh Postnatal Depression Scale. A score of ≥10 was classified as depression.ResultsMultivariable analysis of the number of regular visits and telehealth to the GP/Paed showed an adjusted incidence rate ratio (aIRR) of 1.08, 95% CI 1.03 to 1.13 and aIRR 0.95, 95% CI 0.82 to 1.10, respectively. Children of mothers with perinatal depression had more hospital admissions (aIRR 1.21, 95% CI 1.01 to 1.46) and more visits to child development clinics (aIRR 1.33, 95% CI 1.04 to 1.70). There was a non-significant increase in ER visits (IRR 1.26, 95% CI 0.66 to 2.42), and non-significant decrease in antibiotics prescriptions (IRR 0.95, 95% CI 0.86 to 1.05) and anaemia status (IRR 0.93, 95% CI 0.72 to 1.20).ConclusionThis study shows higher health services utilisation among children of mothers with perinatal depression, including regular GP/Paed visits, hospital admission rates, and child-development clinics.
Effectiveness of interventions to address the negative health outcomes of informal caregiving to older adults: protocol for an umbrella review
Authors: Calderón-Larrañaga Amaia , Kirvalidze Mariam , Dahlberg Lena , Sacco Lawrence B , Morin Lucas 
Published: November 2021

IntroductionInformal (unpaid) caregivers play an essential role in caring for older people, whose care needs are often not fully met by formal services. While providing informal care may be a positive experience, it can also exert a considerable strain on caregivers’ physical and mental health. How to best support the needs of informal caregivers remains largely debated. This umbrella review (review of systematic reviews) aims to evaluate (1) whether effective interventions can mitigate the negative health outcomes of informal caregiving, (2) whether certain types of interventions are more effective than others, (3) whether effectiveness of interventions depends on caregiver/receiver, context or implementation characteristics and (4) how these interventions are perceived in terms of acceptability, feasibility and added value.Methods and analysisWe will include systematic reviews of primary studies focusing on the effectiveness of interventions (public or private, unifaceted or multifaceted, delivered by health or social care professionals or volunteers) aimed at reducing the impact of caregiving on caregivers’ physical or mental health. This will also include quantitative and qualitative syntheses of implementation studies. The literature search will include the following databases: Medline, CINAHL, PsycINFO and Web of Science. A key informant-guided search of grey literature will be performed. Quality appraisal will be conducted with the AMSTAR-2 checklist for quantitative reviews and with anad hocchecklist for qualitative syntheses. Narrative and tabular summaries of extracted data will be produced, and framework synthesis will be employed for weaving together evidence from quantitative studies in effectiveness reviews with findings on implementation from qualitative studies.Ethics and disseminationThis umbrella review will use data from secondary sources and will not involve interactions with study participants; it is thus exempt from ethical approval. Results will be presented at international conferences and will be published in a peer-reviewed journal.PROSPERO registration numberCRD42021252841.
Determinants of change in the inequality and associated predictors of teenage pregnancy in Uganda for the period 2006–2016: analysis of the Uganda Demographic and Health Surveys
Authors: Wasswa Ronald , Kabagenyi Allen , Kananura Rornald Muhumuza , Jehopio Joseph , Rutaremwa Gideon 
Published: November 2021

ObjectiveTeenage pregnancy has become a public health concern in Uganda because of its negative consequences to both the mother and child. The objective of this study was to examine the determinants of change in the inequality and associated predictors of teenage pregnancy in Uganda for the period 2006–2016.Study designA retrospective national cross-sectional study.SettingUganda.ParticipantsUganda Demographic and Health Survey secondary data of only female teenagers aged 15–19 years. The samples selected for analyses were 1936 in 2006; 2048 in 2011 and 4264 in 2016.Outcome measureThe primary outcome was teenage pregnancy. Analysis was performed using the logistic regression, equiplots, concentration curve, normalised concentration index, decomposition of the concentration index and Oaxaca-type decomposition.ResultsThe prevalence of teenage pregnancy has seemingly remained high and almost constant from 2006 to 2016 with the risk worsening to the disadvantage of the poor. Household wealth-index, teenagers’ years of education, early sexual debut and child marriage were the main key predictors and contributors of the large inequality in teenage pregnancy from 2006 to 2016.ConclusionTeenage pregnancy is disproportionately prevalent among different subpopulations of adolescent girls in Uganda. We therefore recommend policy actions to sensitise communities and enforcement of child rights and child protection laws to stop child marriages. There is also need to promote girl child education, improving household incomes, and intensifying mass media awareness on the risks of early pregnancies. Further, ensuring that villages have operational adolescent and youth friendly services as well as incorporating sex education and other different adolescent reproductive health programmes in school curriculum will be key measures in reducing the large inequality in teenage pregnancy.
Interventions to improve early cancer diagnosis of symptomatic individuals: a scoping review
Authors: Okoli George N , Lam Otto L T , Reddy Viraj K , Copstein Leslie , Askin Nicole , Prashad Anubha , Stiff Jennifer , Khare Satya Rashi , Leonard Robyn , Zarin Wasifa , Tricco Andrea C , Abou-Setta Ahmed M 
Published: November 2021

ObjectivesTo summarise the current evidence regarding interventions for accurate and timely cancer diagnosis among symptomatic individuals.DesignA scoping review following the Joanna Briggs Institute’s methodological framework for the conduct of scoping reviews and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist.Data sourcesMEDLINE (Ovid), CINAHL (EBSCOhost) and PsycINFO (Ovid) bibliographic databases, and websites of relevant organisations. Published and unpublished literature (grey literature) of any study type in the English language were searched for from January 2017 to January 2021.Eligibility and criteriaStudy participants were individuals of any age presenting at clinics with symptoms indicative of cancer. Interventions included practice guidelines, care pathways or other initiatives focused on achieving predefined benchmarks or targets for wait times, streamlined or rapid cancer diagnostic services, multidisciplinary teams and patient navigation strategies. Outcomes included accuracy and timeliness of cancer diagnosis.Data extraction and synthesisWe summarised findings graphically and descriptively.ResultsFrom 21 298 retrieved citations, 88 unique published articles and 16 unique unpublished documents (on 18 study reports), met the eligibility for inclusion. About half of the published literature and 83% of the unpublished literature were from the UK. Most of the studies were on interventions in patients with lung cancer. Rapid referral pathways and technology for supporting and streamlining the cancer diagnosis process were the most studied interventions. Interventions were mostly complex and organisation-specific. Common themes among the studies that concluded intervention was effective were multidisciplinary collaboration and the use of a nurse navigator.ConclusionsMultidisciplinary cooperation and involvement of a nurse navigator may be unique features to consider when designing, delivering and evaluating interventions focused on improving accurate and timely cancer diagnosis among symptomatic individuals. Future research should examine the effectiveness of the interventions identified through this review.
Are climate change and mental health correlated?
Authors: Ramadan Abdullah Mohammed Hassan , Ataallah Ahmed G 
Published: November 2021

Climate change is one of the biggest challenges of our time and is likely to affect human beings in substantial ways. Recently, researchers started paying more attention to the changes in climate and their subsequent impact on the social, environmental and economic determinants of health, and the role they play in causing or exacerbating mental health problems. The effects of climate change-related events on mental well-being could be classified into direct and indirect effects. The direct effects of climate change mostly occur after acute weather events and include post-traumatic stress disorder, anxiety, substance abuse disorder, depression and even suicidal ideation. The indirect effects include economic losses, displacement and forced migration, competition over scarce resources and collective violence. The risk factors for developing those mental health issues include young age, female gender, low socioeconomic status, loss or injury of a loved one, being a member of immigrant groups or indigenous people, pre-existing mental illness and inadequate social support. However, in some individuals, especially those undisturbed by any directly observable effects of climate change, abstract awareness and acknowledgement of the ongoing climate crisis can induce negative emotions that can be intense enough to cause mental health illness. Coping strategies should be provided to the affected communities to protect their mental health from collapse in the face of climate disasters. Awareness of the mental health impacts of climate change should be raised, especially in the high-risk groups. Social and global attention to the climate crisis and its detrimental effects on mental health are crucial.This paper was written with the aim of trying to understand the currently, scientifically proven impact of climate change-related disasters on mental health and understanding the different methods of solving the problem at the corporate level, by trying to decrease greenhouse gas emissions to zero, and at the individual level by learning how to cope with the impacts of those disasters.
Virological breakthrough after immune checkpoint inhibitor and nucleos(t)ide analog treatment in patients with hepatitis B surface antigen positive hepatocellular carcinoma: a real-world study
Authors: Wang Kunyuan , Xia Ying , Zhu Yun , Yu Wenxuan , Guo Yabing , Liu Li 
Published: November 2021

BackgroundImmune checkpoint inhibitors (ICIs) have been shown to be a promising and effective treatment for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, there is a lack of evidence-based data demonstrating the impact of ICIs on HBV DNA level in HBV-HCC patients undergoing nucleos(t)ide analog (NA) therapy and of HBV DNA variation on patient survival. In this study, we aimed to investigate this issue in the real world.MethodsIn this single-center retrospective study, we reviewed 182 baseline hepatitis B surface antigen (HBsAg)-positive HBV-HCC patients who were treated with ICIs and pre-emptive NAs. The demographic characteristics, tumor status, treatments, HBV DNA, HBsAg, liver function, antitumor response, and patient survival were investigated. The primary endpoints were the virological breakthrough (VB) rate, HBV reactivation (HBVr) rate, and long-term HBV DNA control; the secondary endpoints were the overall survival (OS) and progression-free survival (PFS).Results(1) VB and HBVr occurred in 18.1% (33/182) and 4.4% (8/182) of patients with a median occurrence time of 3.9 months (range, 0.7–16.0) and 8.0 months (range, 3.0–16.0), respectively. The HBV DNA negative rates were 26.1% and 0 at 24 and 48 weeks in the VB group and 12.5% and 0 in the HBVr group, respectively. A baseline HBsAg level ≥200 IU/mL was the only risk factor for VB (OR 9.9, 95% CI 2.2 to 45.2, p=0.003); (2) patients with VB had much shorter median OS and median PFS than those without (12.3 months vs 18.1 months, p=0.035; 4.5 months vs 7.5 months, p=0.011).ConclusionsThere was a high risk of VB and a moderate risk of HBVr in HBsAg-positive HBV-HCC patients (with poor long-term HBV DNA control) undergoing ICI and pre-emptive NA therapies. The only risk factor for VB was the pretreatment HBsAg level. Further, VB might be considered as a clinical biomarker predicting inferior OS and PFS in the patients.
40 Precise spatial multiplexing for immune profiling in non-small cell lung cancer FFPE samples with ChipCytometry
Authors: Campbell Thomas , Christians Arne , Northcutt Adam , Winkeler Crystal , Gamber Kevin 
Published: November 2021

BackgroundEmergent data indicate that highly multiplexed spatial biomarker analysis has the potential to advance precision medicine in immuno-oncology and inform the discovery of novel biomarkers.MethodsHere we present the analysis of clinical FFPE samples from non-small cell lung cancer patients using ChipCytometry, a novel precise spatial multiplexing technology which combines iterative immuno-fluorescent staining with high-dynamic range imaging to facilitate quantitative phenotyping with single-cell resolution. Standard FCS files are generated from multichannel OME-TIFF images, enabling identification of cellular phenotypes via flow cytometry-like hierarchical gating. In this study, a 27-plex assay was used to identify and quantify more than 30 cellular phenotypes and subtypes in FFPE samples.ResultsThe results show precise expression levels for each marker in the assay in each individual cell in the sample, maintaining spatial information about each cell. Spatial analysis of the samples reveals quantifiable heterogeneity of immune cell infiltration within the tumor samples, demonstrating the utility of the ChipCytometry platform for the in-depth immune profiling in clinical samples.ConclusionsN/A
46 Proximity between cytotoxic antigen-experienced T cells and tumor cells is associated with improved clinical outcomes in early-stage NSCLC
Authors: Luo Qianyun , Parra Edwin , Negrao Marcelo , Akhave Neal , Bayley Erin , Mitchell Kyle , Zhang Jianjun , Heymach John , Sepesi Boris , Wistuba Ignacio , Gibbons Don , Reuben Alexandre 
Published: November 2021

BackgroundWhile the development of immunotherapies has improved the treatment of non-small cell lung cancer (NSCLC), most patients still fail to respond. Immune cell densities have been utilized to predict clinical responses but have largely failed to do so. However, the spatial distribution and interaction of these cells at the tissue level have been less studied. Here, we performed spatial analysis of the cells within the tumor immune microenvironment in order to evaluate their relationship with clinical outcomes in early-stage NSCLC.MethodsMultiplex immunofluorescence was performed on 123 early-stage NSCLC patients from the ICON (Immunogenomic profiling of non-small cell lung cancer) cohort including Cytokeratin (CK), CD3, CD8, CD45RO, FoxP3, CD68, CD20, CD57, Granzyme B (GzmB), PD-1, and PD-L1. Area under the curve (AUC) was calculated using Ripley’s L function, which evaluates the degree of spatial proximity of two cell populations, with a high AUC indicating clustering and low AUC indicating scattering. Findings were integrated with clinical parameters.ResultsAdenocarcinomas demonstrated CD3+PD1+ T cells were closer to CK+ tumor cells (n=60, p=0.035), and B cells were closer to cytotoxic T cells (n=43, p=0.03) than in squamous cell carcinoma. Higher AUC was observed between CD3+PD1+ T cells (n=56, p=0.035), with cytotoxic antigen-experienced T cells (CD45RO+GzmB+) closer to tumor cells (n=35, p=0.017) in stage I and II compared to stage III tumors. Untreated patient tumors exhibited higher proximity between CD20+ B cells and CD57+ NK cells (n=59, p=0.012), CD3+ T cells and PD-L1+ tumor cells (n=56, p=0.027), and CD68+ macrophages and PD-L1+ tumor cells (n=52, p=0.016) than neoadjuvant chemotherapy-treated patients. Patients with no recurrence presented higher AUC in antigen-experienced CD45RO+GzmB+ T cells and tumor cells (n=36, p=0.006), while those with improved survival demonstrated greater proximity between CD68+ macrophages and PD-L1+ tumors (n=52, p=0.016), CD20+ B cells and GzmB+ cells (n=49, p=0.03), and antigen-experienced CD45RO+GzmB+ T cells and tumor cells (n=36, p=0.047). Lastly, patients with improved survival also displayed greater proximity between CD3+CD8+ cytotoxic T cells and PD-L1- epithelial cells (n=76, p=0.04) in tumors versus matched adjacent lungs.ConclusionsOverall, our findings shed light on some of the potential cell interactions at play in the tumor microenvironment of early-stage NSCLC patients and suggest cell distributions could be utilized to predict clinical outcomes in early-stage NSCLC patients.
47 Tertiary lymphoid structures (TLS) in desmoplastic melanomas (DM) differ from non-DM-associated TLS by their intratumoral location and enhanced immune activity
Authors: Mauldin Ileana , Stowman Anne , Hickman Alexandra , Mahmutovic Adela , Gru Alejandro , Lynch Kevin , Young Samuel , Meneveau Max , Wages Nolan , Engelhard Victor , Slingluff Craig 
Published: November 2021

BackgroundTertiary lymphoid structures (TLS) are ectopic lymphoid organs that are localized near tumors and other sites of inflammation, and are commonly believed to support antitumor immunity. We previously published studies that show that most desmoplastic melanomas contain TLS, and that TLS in cutaneous metastatic melanomas varied widely in maturation state, in proportions of proliferating T and B cells, and in markers of B cell function, including AID and CD21. Thus, we hypothesized that there may be diversity in TLS function, or immunologic activity, among melanomas. To address this hypothesis, we evaluated TLS in primary desmoplastic melanomas (DM), and non-desmoplastic melanomas (non-DM) for markers of cell proliferation which are indicative of early immune activity.MethodsDM and non-DM tumor specimens, which included primary melanomas (PM), and cutaneous metastatic melanomas (CMM), were evaluated for TLS by multiplex Immunofluorescence histology, by staining for CD20, CD8, PNAd, Ki67, FoxP3, and DAPI. Lymphoid aggregates were identified in 20x spectrally unmixed images by visual inspection and identified as TLS if possessing organized T-cell and B-cell regions in addition to high endothelial venule-like vasculature (PNAd+). TLS were identified in 30 out of 64 screened (48%) CMM, 4/4 non-DM PM, and 8 out of 11 screened (73%) DM. Immune cells localized in TLS were enumerated using Halo software (Indica Labs). Mann-Whitney tests were used for statistical assessments.ResultsDM commonly contain a dense network of fibroblasts and associated stroma, which are not typical for other non-DM (PM and CMM). TLS in DM are located throughout the tumors, intratumorally, in sharp distinction from the peritumoral location of TLS in non-DM. Furthermore, when compared to TLS of non-DM (PM and CMM), TLS of DM contain increased densities of CD20+ B cells (PM p=0.007; CMM p<0.0001) and CD8+ T cells (PM p=0.017; CMM p=0.0006), and a higher proportion of proliferating (Ki67+) CD20+ B cells (PM p=0.04; CMM p=0.009).ConclusionsRecently published studies have identified tumor-associated fibroblasts as the likely initiating cells for TLS formation in murine melanomas. The intratumoral location of TLS in DM puts them in close proximity to the dense fibroblasts and desmoplastic stroma in these tumors, which may be responsible for their intratumoral location. The increased density of B and T cells, and higher proportion of proliferating (Ki67+) B cells, in DM than in non-DM, suggests that there may be greater immune activation, increased germinal center maturation, or less regulation in TLS of DM.Ethics ApprovalApproval was obtained for these studies under IRB protocol #’s 10598 and 19694.