bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the effectiveness and cost effectiveness of a Community-delivered Integrated Malaria Elimination (CIME) model in Myanmar: protocol for an open stepped-wedge cluster-randomised controlled trial
Authors: Oo Win Han , Thi Aung , Htike Win , Agius Paul A , Cutts Julia C , Win Kyawt Mon , Yi Linn Nay Yi , Than Wint Phyo , Hkawng Galau Naw , Thu Kaung Myat , Oo May Chan , O’Flaherty Katherine , Kearney Ellen , Scott Nick , Phyu Pwint Phyu , Htet Aung Thu , Myint Ohnmar , Lwin Yee Lwin , Thant Zay Phyo , Mon Aung , Htike Soe , Hnin Thet Pan , Fowkes Freya J I 
Published: August 2021

IntroductionIn the Greater Mekong Subregion, community health workers, known as malaria volunteers, have played a key role in reducing malaria in the control phase, providing essential malaria services in areas with limited formal healthcare. However, the motivation and social role of malaria volunteers, and testing rates, have declined with decreasing malaria burden and reorientation of malaria programmes from control to elimination. Provision of additional interventions for common health concerns could help sustain the effectiveness of volunteers and maintain malaria testing rates required for malaria elimination accreditation by the WHO.Methods and analysisThe Community-delivered Integrated Malaria Elimination (CIME) volunteer model, integrating interventions for malaria, dengue, tuberculosis, childhood diarrhoea and malaria Rapid Diagnostic Test (RDT)-negative fever, was developed based on global evidence and extensive stakeholder consultations. An open stepped-wedge cluster-randomised controlled trial, randomised at the volunteer level, will be conducted over 6 months to evaluate the effectiveness of the CIME model in Myanmar. One hundred and forty Integrated Community Malaria Volunteers (ICMVs, current model of care) providing malaria services in 140 villages will be retrained as CIME volunteers (intervention). These 140 ICMVs/villages will be grouped into 10 blocks of 14 villages, with blocks transitioned from control (ICMV) to intervention states (CIME), fortnightly, in random order, following a 1-week training and transition period. The primary outcome of the trial is blood examination rate determined by the number of malaria RDTs performed weekly. Difference in rates will be estimated across village intervention and control states using a generalised linear mixed modelling analytical approach with maximum likelihood estimation.Ethics and disseminationThe study was approved by Institutional Review Board, Myanmar Department of Medical Research (Ethics/DMR/2020/111) and Alfred Hospital Ethics Review Committee, Australia (241/20). Findings will be disseminated in peer-review journals, conferences and regional, national and local stakeholder meetings.Trial registration numberNCT04695886
Study protocol on advance care planning in multiple sclerosis (ConCure-SM): intervention construction and multicentre feasibility trial
Authors: De Panfilis Ludovica , Veronese Simone , Bruzzone Michela , Cascioli Marta , Gajofatto Alberto , Grasso Maria Grazia , Kruger Paola , Lugaresi Alessandra , Manson Leigh , Montepietra Sara , Patti Francesco , Pucci Eugenio , Solaro Claudio , Giordano Andrea , Solari Alessandra 
Published: August 2021

IntroductionMultiple sclerosis (MS) is the most common cause of progressive neurological disability in young adults. The use of advance care planning (ACP) for people with progressive MS (pwPMS) remains limited. The ConCure-SM project aims to assess the effectiveness of a structured ACP intervention for pwPMS. The intervention consists of a training programme on ACP for healthcare professionals caring for pwPMS, and a booklet to be used during the ACP conversation. Herein, we describe the first two project phases.MethodsIn phase 1 we translated and adapted, to the Italian legislation and MS context, the ACP booklet of the National ACP Programme for New Zealand. Acceptability, comprehensibility and usefulness of the booklet were assessed via 13 personal cognitive interviews with pwPMS and significant others (SOs), and one health professional focus group. Based on these findings, we will revise the booklet. In phase 2 we will conduct a single-arm pilot/feasibility trial with nested qualitative study. Participants will be 40 pwPMS, their SOs, health professionals from six MS and rehabilitation centres in Italy. In the 6 months following the ACP conversation, we will assess completion of an advance care plan document (primary outcome), as well as safety of the intervention. Secondary outcomes will be a range of measures to capture the full process of ACP; patient-carer congruence in treatment preferences; quality of patient-clinician communication and caregiver burden. A qualitative process evaluation will help understand the factors likely to influence future implementation and scalability of the intervention.Ethics and disseminationThe project is coleaded by a neurologist and a bioethicist. Phase 1 has received ethical approvals from each participating centre, while phase 2 will be submitted to the centres in May 2021. Findings from both phases will be disseminated widely through peer-reviewed publications, conferences and workshops.Trial registration numberISRCTN48527663; Pre-results.
Comparative effectiveness of interventions for improving adherence to ocular hypotensive therapy in patients with glaucoma or ocular hypertension: protocol for network meta-analysis
Authors: Jang Mirinae , Shim Sung Ryul , Ha Ahnul , Kim Young Kook 
Published: August 2021

IntroductionPoor medication adherence is an important issue in healthcare. Various types of interventions for improved adherence to ocular hypotensive therapy have been proposed, though evidence on the effectiveness of any isolated intervention remains limited. The current protocol is an ongoing network meta-analysis (NMA) design that enables comparative investigation of any and all interventions for which there are available randomised controlled trials (RCTs). Our aim is the systematic comparison of the efficacy of different types of adherence interventions for patients suffering from glaucoma or ocular hypertension (OHT).Methods and analysisStudies of interest will assess the effects of any interventions on medication adherence in adults (age ≥18 years) with either glaucoma or OHT. Four electronic databases (Cochrane Central Register of Controlled Trials, Embase, MEDLINE and Scopus) will be searched for RCTs published in any language, without any time limitation. First, titles and abstracts, and then full-text papers, will be screened by two reviewers, who will extract the useful data. The primary outcome measure is an intervention’s impact on adherence. The two reviewers will also assess, using the relevant domain-based risk-of-bias assessment tool, the internal validity of the studies. The overall quality of the evidence will be assessed by the Confidence in Network Meta-Analysis approach, and will be summarised with network diagrams. To allow for assessment of both direct and indirect evidence, a contribution matrix will be used. For visualisation of the effects of all of the included interventions, forest plots will be constructed. Pairwise effect sizes will be calculated according to all of the evidence available in the network.Ethics and disseminationThis work will synthesise evidence from already published studies and, as such, will not require an ethics review or approval. A manuscript presenting the findings will be submitted to a peer-reviewed scientific journal for publication.PROSPERO registration numberCRD42021253145.
Human gastric microbiota transplantation recapitulates premalignant lesions in germ-free mice
Authors: Kwon Soon-Kyeong , Park Jun Chul , Kim Kwang H , Yoon Jaekyung , Cho Yejin , Lee Buhyun , Lee Jin-Jae , Jeong Haengdueng , Oh Yeseul , Kim Sung-Hee , Lee So Dam , Hwang Bo Ram , Chung Yusook , Kim Jihyun F , Nam Ki Taek , Lee Yong Chan 
Published: August 2021

ObjectiveGastric cancer (GC) is a leading cause of cancer-related mortality. Although microbes besidesHelicobacter pylorimay also contribute to gastric carcinogenesis, wild-type germ-free (GF) mouse models investigating the role of human gastric microbiota in the process are not yet available. We aimed to evaluate the histopathological features of GF mouse stomachs transplanted with gastric microbiota from patients with different gastric disease states and their relationships with the microbiota.DesignMicrobiota profiles in corpus and antrum tissues and gastric fluid from 12 patients with gastric dysplasia or GC were analysed. Thereafter, biopsied corpus and antrum tissues and gastric fluid from patients (n=15 and n=12, respectively) with chronic superficial gastritis, intestinal metaplasia or GC were inoculated into 42 GF C57BL/6 mice. The gastric microbiota was analysed by amplicon sequencing. Histopathological features of mouse stomachs were analysed immunohistochemically at 1 month after inoculation. An independent set of an additional 15 GF mice was also analysed at 1 year.ResultsThe microbial community structures of patients with dysplasia or GC in the corpus and antrum were similar. The gastric microbiota from patients with intestinal metaplasia or GC selectively colonised the mouse stomachs and induced premalignant lesions: loss of parietal cells and increases in inflammation foci, in F4/80 and Ki-67 expression, and in CD44v9/GSII lectin expression. Marked dysplastic changes were noted at 1 year post inoculation.ConclusionMajor histopathological features of premalignant changes are reproducible in GF mice transplanted with gastric microbiota from patients with intestinal metaplasia or GC. Our results suggest that GF mice are useful for analysing the causality of associations reported in human gastric microbiome studies.
VEGFR-2 redirected CAR-T cells are functionally impaired by soluble VEGF-A competition for receptor binding
Authors: Lanitis Evripidis , Kosti Paris , Ronet Catherine , Cribioli Elisabetta , Rota Giorgia , Spill Aodrenn , Reichenbach Patrick , Zoete Vincent , Dangaj Laniti Denarda , Coukos George , Irving Melita 
Published: August 2021

BackgroundThe adoptive transfer of chimeric antigen receptor (CAR)-T cells has emerged as a potent immunotherapy against some hematological malignancies but not yet for epithelial-derived solid tumors. One critical issue is the paucity of broadly expressed solid tumor antigens (TAs), and another is the presence of suppressive mechanisms in the tumor microenvironment (TME) that can impair CAR-T cell homing, extravasation and effector functions. TAs expressed by endothelial cells of the tumor vasculature are of clinical interest for CAR therapy because of their genomic stability and accessibility to circulating T cells, as well as their expression across multiple tumor types. In this study, we sought to explore limitations to the efficacy of second-generation (2G) murine CAR-T cells redirected against the vascular endothelial growth factor receptor-2 (VEGFR-2) with the well-characterized single-chain variable fragment DC101.MethodsPrimary murine T cells were retrovirally transduced to express a 2G anti-VEGFR-2-CAR, and the in vitro binding to VEGFR-2, as well as reactivity against TA-expressing cells, was evaluated in the absence versus presence of exogenous VEGF-A. The CAR-T cells were further tested in vivo for tumor control alone and in combination with anti-VEGF-A antibody. Finally, we performed ex vivo phenotypic analyses of tumor-infiltrating CAR-T cells for the two treatment groups.ResultsIn line with previous reports, we observed poor control of B16 melanoma by the 2G anti-VEGFR-2 CAR-T cells as a monotherapy. We further showed that VEGFR-2 is not downregulated by B16 melanoma tumors post treatment, but that its soluble ligand VEGF-A is upregulated and furthermore competes in vitro with the CAR-T cells for binding to VEGFR-2. This competition resulted in impaired CAR-T cell adhesion and effector function in vitro that could be restored in the presence of anti-VEGF-A antibody. Finally, we demonstrated that coadministration of anti-VEGF-A antibody in vivo promoted CAR-T cell persistence and tumor control and was associated with reduced frequencies of PD-1+Ki67-and LAG-3+Ki67-CAR-T cells in the TME.ConclusionsThis study represents the first example of impaired function of a vasculature-targeted CAR by an angiogenic ligand and rationalizes the use of combinatorial therapies that target the tumor vasculature and augment CAR-T cell effector function.
Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the Accelerating Medicines Partnership RA/SLE Network
Authors: Deonaraine Kristina K , Carlucci Philip M , Fava Andrea , Li Jessica , Wofsy David , James Judith A , Putterman Chaim , Diamond Betty , Davidson Anne , Fine Derek M , Monroy-Trujillo Jose , Atta Mohamed G , Haag Kristin , Rao Deepak A , Apruzzese William , Belmont H Michael , Izmirly Peter M , Wu Ming , Connery Sean , Payan-Schober Fernanda , Furie Richard A , Berthier Celine C , Dall'Era Maria , Cho Kerry , Kamen Diane L , Kalunian Kenneth , Anolik Jennifer , Ishimori Mariko , Weisman Michael H ,   The Accelerating Medicines Partnership RA/SLE network, Petri Michelle A , Buyon Jill P 
Published: August 2021

ObjectivesIn lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.ConclusionsProcurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.
Tocilizumab Effect on Lipid Profile in Correlation to Cardiovascular Events: A Retrospective Cohort Study
Authors: Alsulaim Toka , Alhassan Noor , Khalil Hala , Almutlaq Abdullah 
Published: August 2021

Objective. To study the effect of tocilizumab initiation on the lipid profile, in correlation to a composite of any cardiovascular events. Methods. A retrospective cohort study, using data from the King Faisal Specialist Hospital & Research Centre database, from January 2014 to December 2019. Patients with rheumatoid arthritis or juvenile idiopathic arthritis who were ≥18 years old, initiated either on tocilizumab or other biologic treatment (anti-TNFs or Rituximab), were included, with a follow-up interval duration at a minimum of 6–12 months up to 3-5 years. Any patient with established cardiovascular disease or aged <18 were excluded. Results. Only one cardiovascular mortality was reported in the tocilizumab group. Fifty percent of patients reached

high

cholesterol

levels
≥
5.2

mmol
/
L

and

LDL
≥
3.37

mmol
/
L

in the tocilizumab group at 36 months in a shorter time period compared to controls (60 months),

P

0.001. There were no significant differences between groups for statin use (27% vs. 28%) However, there was a significantly higher mean dose of atorvastatin in the tocilizumab group compared to controls (20.6 mg vs. 16.6 mg,

P

0.03). Conclusion. There was a lack of evidence of increased cardiovascular risk in correlation to hyperlipidemia secondary to tocilizumab treatment.
Isolation and Identification of Escherichia coli O157:H7 Lytic Bacteriophage from Environment Sewage
Authors: Sjahriani Tessa , Wasito Eddy Bagus , Tyasningsih Wiwiek 
Published: August 2021

Escherichia coli O157:H7 is one of the pathogenic bacteria causing foodborne disease. The use of lytic bacteriophages can be a good solution to overcome the disease. This study is aimed at isolating lytic bacteriophages from environmental sewage with E. coli O157:H7 bacterial cells. The sample used in this study was eight bacteriophages, and the technique used in identifying E. coli O157:H7 carriers of the stx1 and stx2 genes was PCR. The double layer plaque technique was used to classify bacteriophages. Plaque morphology, host specificity, and electron micrograph were used to identify the bacteriophages. The result obtained plaque morphology as a clear zone with the largest diameter size of 3.5 mm. Lytic bacteriophage could infect E. coli O157:H7 at the highest titer of

10
×

10

8

PFU
/
mL

. Bacteriophages have been identified as Siphoviridae and Myoviridae. Phage 3, phage 4, and phage 8 could infect Atypical Diarrheagenic E. coli 1 (aDEC1) due to their host specificity. The Friedman statistical tests indicate that lytic bacteriophage can significantly lyse E. coli O157:H7 (

p
=
0.012

). The lysis of E. coli O157:H7 by phage 1, phage 2, phage 3, and phage 5 bacteriophages was statistically significant, according to Conover’s posthoc test (

p
<
0.05

). The conclusion obtained from this study is that lytic bacteriophages from environmental sewage could lyse E. coli O157:H7. Therefore, it could be an alternative biocontrol agent against E. coli O157:H7 that contaminates food causing foodborne disease.
TMB and Inflammatory Gene Expression Associated with Clinical Outcomes following Immunotherapy in Advanced Melanoma
Authors: Hodi F. Stephen , Wolchok Jedd D. , Schadendorf Dirk , Larkin James , Long Georgina V. , Qian Xiaozhong , Saci Abdel , Young Tina C. , Srinivasan Sujaya , Chang Han , Tang Hao , Wind-Rotolo Megan , Rizzo Jasmine I. , Jackson Donald G. , Ascierto Paolo A. 
Published: August 2021

Abstract
Outcomes for patients with melanoma have improved over the past decade as a result of the development and FDA approval of immunotherapies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death ligand 1 (PD-L1). However, these therapies do not benefit all patients, and an area of intensive research investigation is identifying biomarkers that can predict which patients are most likely to benefit from them. Here, we report exploratory analyses of the associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and BRAF mutation status with tumor response, progression-free survival, and overall survival in patients with advanced melanoma treated as part of the CheckMate 066 and 067 phase III clinical trials evaluating immuno-oncology therapies. In patients enrolled in CheckMate 067 receiving the anti–PD-1 inhibitor nivolumab (NIVO) alone or in combination with the anti–CTLA-4 inhibitor ipilimumab (IPI) or IPI alone, longer survival appeared to associate with high (&gt;median) versus low (≤median) TMB and with high versus low inflammatory signature scores. For NIVO-treated patients, the results regarding TMB association were confirmed in CheckMate 066. In addition, improved survival was observed with high TMB and absence of BRAF mutation. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Combined assessment of TMB, inflammatory gene expression signature, and BRAF mutation status may be predictive for response to immune checkpoint blockade in advanced melanoma.
A. Muciniphila Suppresses Colorectal Tumorigenesis by Inducing TLR2/NLRP3-Mediated M1-Like TAMs
Authors: Fan Lina , Xu Chaochao , Ge Qiwei , Lin Yifeng , Wong Chi Chun , Qi Yadong , Ye Bin , Lian Qingwu , Zhuo Wei , Si Jianmin , Chen Shujie , Wang Liangjing 
Published: August 2021

Abstract

The interplay between gut microbiota and the host immune system is emerging as a factor in the pathogenesis of colorectal cancer. Here, we set out to identify the effect of Akkermansia muciniphila (A. muciniphila) on colorectal cancer pathogenesis. A. muciniphila abundance was significantly reduced in patients with colorectal cancer from two independent clinical cohorts and the GMrepo dataset. Supplementation with A. muciniphila suppressed colonic tumorigenesis in ApcMin/+ mice and the growth of implanted HCT116 or CT26 tumors in nude mice. Mechanistically, A. muciniphila facilitated enrichment of M1-like macrophages in an NLRP3-dependent manner in vivo and in vitro. As a consequence, NLRP3 deficiency in macrophages attenuated the tumor-suppressive effect of A. muciniphila. In addition, we revealed that TLR2 was essential for the activation of the NF-κB/NLRP3 pathway and A. muciniphila induced M1-like macrophage response. We observed positive correlations between M1-like macrophages, NLRP3/TLR2 and A. muciniphila in patients with colorectal cancer, which corroborated these findings. In summary, A. muciniphila–induced M1-like macrophages provide a therapeutic target in the colorectal cancer tumor microenvironment.
(In) segurança hídrica: garantindo o direito à água
Authors: Loftus Alex John , Sousa Ana Cristina Augusto de 
Published: August 2021

Este artigo relê os debates sobre segurança e insegurança da água por meio de ferramentas dos estudos geográficos críticos. Ele busca demonstrar o valor dessa perspectiva crítica para a conquista do acesso à água para todos. Embora rejeite a simples desvalorização dos principais discursos sobre segurança hídrica, o artigo observa a falha deles em politizar adequadamente os processos e as relações que reproduzem as desigualdades hídricas. Encontrando lições em escritos recentes sobre ecologia política, o ciclo hidrossocial e sobre o direito à água, o artigo conclui com uma afirmaçãode Gramsci de construir a partir dos conhecimentos fragmentados, mas implícitos nas lutas, a conquista do acesso democrático à água.