bluuebunny/crossref_metadata_2025 huggingface dataset:
A Numerical Approach to Investigate the Impact of Acid-Asphaltene Sludge Formation on Wormholing During Carbonate Acidizing
Authors: Khurshid Ilyas , Al-Shalabi Emad W. , Afgan Imran , Al-Attar Hazim
Published: July 2021

Carbonate acidization is the process of creating wormholes by injecting acid to increase reservoir permeability and oil production. Nevertheless, some reservoir oils are problematic with low asphaltene stability, which affects the wormholing process. The interactions between acid, rock, and asphaltene lead to acid-asphaltene sludge formation, which reduces oil productivity and acid injectivity. Neglecting this sludge formation leads to over predicting the depth of the wormhole penetration. Therefore, a numerical model was developed in this study to provide a better understanding of acid-asphaltene sludge formation effect on wormhole creation and propagation in carbonates. A one-dimensional radial model was developed by coupling fluid flow equations in porous media with asphaltene deposition and acid-asphaltene reactions. Then, the developed model was validated and utilized to investigate the effects of different parameters on wormholing including asphaltene presence, acid injection volume and concentration, formation temperature and porosity, and asphaltene concentration. Results showed that acid injection in carbonates with asphaltenic oils reduce wormhole penetration from 40% to total pore blockage as opposed to reservoirs without asphaltene deposition. The findings also highlighted that shallow wormhole penetration is more pronounced with a high volume of acid injection, high porous formations, less diluted acid, and a high concentration of asphaltene. In addition, there is an optimum acid injection volume at which wormhole penetration is high and its infiltration is deep into the formation. This is the first work to discuss modeling of acid-asphaltene sludge formation and subsequent wormhole development in carbonates, which is particularly important for problematic crude oils.
Pressure Transient Analysis for Fracture-Cavity Carbonate Reservoirs With Large-Scale Fractures–Caves in Series Connection
Authors: Xing Cuiqiao , Yin Hongjun , Yuan Hongfei , Fu Jing , Xu Guohan
Published: July 2021

Fracture-cavity carbonate reservoirs are noncontinuous and highly heterogeneous with the present of large-scale fractures, cavities, and erosion pores. The multiscale and diversity of medium in reservoirs have a noticeable influence on the transient pressure analysis. In the typical curve matching, the connection between large-scale fractures and cavities must be considered. Unfortunately, the current well-testing model cannot be used to analyze the date of fracture-cavity carbonate reservoirs. The aim of this study is to develop an efficient well-testing model to obtain parameters and number of large-scale fractures and cavities. To solve the aforementioned problem, a pressure-transient analysis model for fracture-cavity carbonate reservoir with radial composite reservoir, multiscale fractures–caves in series connection, and dual-porosity medium (fracture and erosion pore) is established in this study. Laplace transformation is used to solve the mathematical model. The linear flow in the main fractures and the radial flow of caves drainage area are solved by coupling. The pressure-transient curves of the bottom hole have been obtained with the numerical inversion algorithms. The typical curves for the well-testing model are drawn. Nine flow stages and variation characteristics of typical curves are analyzed. The sensitivity analyses for different parameters are carried out. From the calculations, with the increasing in the length of large-scale fractures, the duration of linear flow is increased. While the radius of cave is the bigger, the convex and concave are the larger. Therefore, the location and the size of caves and large-scale fractures can be analyzed. As a field example, actual test data are analyzed by the established model. An efficient well-testing model is developed, and it can be used to interpret the actual pressure data for fracture-cavity carbonate reservoirs.
The Influence of Pressure on Flame-Flow Characteristics of a Reacting Jet in Crossflow
Authors: Otero Michelle , Genova Tommy , Stiehl Bernhard , Morales Anthony J. , Martin Scott , Ahmed Kareem A.
Published: July 2021

This work experimentally investigates the effects of elevated combustor pressures on the characteristics of a lean premixed reacting methane/air jet injected into a lean vitiated crossflow using a 12.7 mm axial jet. Experiments were conducted in an axially staged combustor, which implements a reacting jet in crossflow (RJIC) configuration and operates over a pressure range of 1−5 atmospheres. Simultaneous CH* chemiluminescence and particle image velocimetry (PIV) are used to study the flow field and flame behavior. The results show that the reacting jet trajectory exhibits greater penetration with elevated pressure, which is a novel finding compared to available data in the literature. However, the flame liftoff point and ignition delay time both decreased with elevated pressure, which was attributed to decreased vorticity along the flame boundary which corresponds to increased Damköhler numbers (Da). Emissions measurements confirm the NOx increase with pressure as reported in the literature for single-stage gas turbine combustors. Concurrently, emission measurements for the staged configuration show the strong NOx benefit of the RJIC system: the data prove a reduction of global outlet emission levels at elevated pressure with the axially staged configuration. The axial emission reduction was attributed to the decreasing liftoff at elevated pressure levels. Hence, the research emphasizes that the flame and emission characteristics are coupled; they are not only dependent on the geometric parameters and momentum flux ratios but are also a function of pressure.
Nikkomycin Z against Disseminated Coccidioidomycosis in a Murine Model of Sustained-Release Dosing
Authors: Sass Gabriele , Larwood David J. , Martinez Marife , Chatterjee Paulami , Xavier Melissa O. , Stevens David A.
Published: July 2021

Nikkomycin Z (nikZ) is a chitin synthase inhibitor. Efficacy against
Coccidioides
has been demonstrated in animal models of pulmonary or brain infection.
Pharmacokinetics, Safety, and Tolerability of Ravidasvir, with and without Danoprevir/Ritonavir, in Healthy Subjects
Authors: Wu Guolan , Zhou Huili , Wu Jing , Lv Duo , Wu Lihua , Zhai You , Lin Meihua , Wu Jingzi J. , Shentu Jianzhong
Published: July 2021

Ravidasvir (RDV) is a novel oral hepatitis C virus NS5A inhibitor. This study aimed to evaluate the pharmacokinetics and safety of RDV and the drug-drug interactions between RDV and ritonavir-boosted danoprevir (DNVr) in healthy adults.
Pharmacokinetics of Polymyxin B in Hospitalized Adults with Cystic Fibrosis
Authors: Crass Ryan L. , Al Naimi Tamara , Wen Bo , Souza Ernane , Murray Susan , Pai Manjunath P. , Jia Shijing
Published: July 2021

The optimal polymyxin B dosage needed to achieve an efficacy target of 50 to 100 mg · h/liter when treating multidrug-resistant bacterial infections in adult cystic fibrosis (CF) patients is unclear. The pharmacokinetics of intravenous polymyxin B were evaluated to better inform dosing.
Copper Intoxication in Group B Streptococcus Triggers Transcriptional Activation of the
cop
Operon That Contributes to Enhanced Virulence during Acute Infection
Authors: Sullivan Matthew J. , Goh Kelvin G. K. , Gosling Dean , Katupitiya Lahiru , Ulett Glen C.
Published: July 2021

Understanding how bacteria manage cellular levels of metal ions, such as copper, helps to explain how microbial cells can survive in different stressful environments. We show the opportunistic pathogen group B streptococcus (GBS) achieve homeostasis of intracellular copper through the activities of the genes that comprise the
cop
operon, and we describe how this helps GBS survive in stressful environments, including in the mammalian host during systemic disseminated infection.
Tectonic pressure gradients during viscous creep drive fluid flow and brittle failure at the base of the seismogenic zone
Authors: Menegon Luca , Fagereng Åke
Published: July 2021

Fluid-pressure cycles are commonly invoked to explain alternating frictional and viscous deformation at the base of the seismogenic crust. However, the stress conditions and geological environment of fluid-pressure cycling are unclear. We address this problem by detailed structural investigation of a vein-bearing shear zone at Sagelvvatn, northern Norwegian Caledonides. In this dominantly viscous shear zone, synkinematic quartz veins locally crosscut mylonitic fabric at a high angle and are rotated and folded with the same sense of shear as the mylonite. Chlorite thermometry indicates that both veining and mylonitization occurred at ∼315–400 °C. The vein-filled fractures are interpreted as episodically triggered by viscous creep in the mylonite, where quartz piezometry and brittle failure modes are consistent with low (18–44 MPa) differential stress. The Sagelvvatn shear zone is a stretching shear zone, where elevated pressure drives a hydraulic gradient that expels fluids from the shear zone to the host rocks. In low-permeability shear zones, this hydraulic gradient facilitates build-up of pore-fluid pressure until the hydrofracture criterion is reached and tensile fractures open. We propose that hydraulic gradients established by local and cyclic pressure variations during viscous creep can drive episodic fluid escape and result in brittle-viscous fault slip at the base of the seismogenic crust.
Stereotactic body radiotherapy and checkpoint inhibitor for locally recurrent unresectable nasopharyngeal carcinoma
Authors: Wu Jia-Shing , Jen Chung-Wen , Chen Hsin-Hsuan , Cheng Skye Hung-Chun
Published: July 2021

The treatment of local recurrence of nasopharyngeal carcinoma (NPC) is challenging, and the role of reirradiation is controversial regarding the high risk for severe toxicity. Stereotactic body radiotherapy (SBRT) is a high-precision radiation technique that can spare surrounding normal tissues. Studies have demonstrated the high activity and low toxicity of both SBRT and anti-programmed-cell-death-1 immune checkpoint inhibitors for head and neck cancers. There has been preclinical and clinical evidence suggesting synergy between radiotherapy and checkpoint inhibitors. We report two patients with locally recurrent unresectable rT4 NPC both involving the retro-orbital areas. They received the same treatment with low-dose SBRT (28 Gy in 5 fractions) and pembrolizumab, and showed a remarkable tumour response without untoward radiation toxicity. SBRT plus an immune checkpoint inhibitor may provide a new treatment option for locally recurrent NPC. We propose further investigation with a formal clinical trial.
Stepwise multidisciplinary approach in very low birthweight infant with bronchopleural fistula
Authors: Milan Anna , Yardley Iain , Fox Grenville , Meau-Petit Virginie
Published: July 2021

A 25-week gestation infant experienced chest infection complicated by septic shock and tension pneumothorax. Despite multiple drains, it was impossible to reinflate the lung, thus suggesting a bronchopleural fistula. Multidisciplinary meetings were arranged, involving the parents, and a stepwise approach was agreed. Chest drain repositioning, single lung ventilation and pleurodesis proved unsuccessful. In a rare window of relative stability, open chest surgery was performed at the cot-side by the paediatric general and cardiothoracic surgical teams. A large tear was identified at the carina, extending along the left main bronchus. This was repaired, with immediate clinical improvement. He was extubated 7 days later and discharged home on day 94 (CGA 39+0). This case report describes a successful stepwise multidisciplinary approach to a bronchopleural fistula in a very low birthweight infant, highlighting the potential for surgical intervention at cot-side and the value of involving the surgical team early on.
Diagnostic conundrum: an elusive bleeding source in patient with recurrent gastrointestinal bleeding
Authors: Shannon Laura , Campbell David , Tham Tony C K , Caddy Grant R
Published: July 2021

Over a 6-month period, a 69-year-old woman presented with recurrent symptomatic anaemia, melaena and haematochezia. Extensive investigations were carried out, including CT of the abdomen and pelvis, oesophagogastroduodenoscopy, colonoscopy, two capsule endoscopies and two CT angiograms. The lack of active bleeding at the time of both CT angiograms meant a diagnosis was only made following retrospective examination of images by interventional radiology once fresh ampullary bleeding was identified on capsule endoscopy. The unifying diagnosis was haemosuccus pancreaticus given the combination of the left gastric artery pseudoaneurysm, fresh bleeding identified from ampulla and the patient’s history of chronic alcohol-related pancreatitis. Subsequent coil embolisation was performed to an optimal result with no recurrence of symptoms to date.
Congenital cytomegalovirus infection in twin pregnancy
Authors: Carvalho Ana Araújo , Silva Cláudia B , Martins Maria Luísa , Santos Gonçalo Cassiano
Published: July 2021

Cytomegalovirus (CMV) infection is one of the preeminent congenital viral infections, and despite its potential morbidity, uncertainty about its physiopathology, prevention and treatment remains until now. We report a case of a dichorionic and diamniotic twin pregnancy in which only one of the fetus had signs of being affected. The first twin had prenatal diagnosis of intrauterine growth restriction and hyperechogenic bowel, attributable to CMV infection, while there was no evidence of infection of the second one. Prenatal treatment was done with maternal administration of valacyclovir and postnatal treatment of the infected newborn with oral valganciclovir with normal neurodevelopment assessment at 12 months corrected age. In this case, maternal CMV infection was not equally transmitted to both fetuses, suggesting that there may be intrinsic fetal and placental factors influencing both transmission and the clinical features of the infection.
Hypoplastic internal carotid artery ending as an ophthalmic artery with multiple cerebral aneurysms, fenestrated Acom and triple A2
Authors: Türk Yaşar , Küskün Atakan
Published: July 2021

A rare case of a hypoplastic internal carotid artery (ICA) terminating in the ophthalmic artery with multiple intracranial saccular aneurysms in the contralateral ICA, anterior communicating artery fenestration and triple A2 was identified. The aetiology and pathogenesis of ICA hypoplasia are subjected to certain hypotheses. Developing several collaterals to preserve the blood supply of the ipsilateral cerebral hemisphere could result in aneurysm formation due to flow overload on the contralateral vasculature, but it could also result in hemicranial hypoplasia, cerebral atrophy and deep watershed infarcts, as in our case.
Squamous cell carcinoma of uterine cervix metastatic to the axillary lymph node
Authors: Chundriger Qurratulain , Chishti Uzma , Idrees Romana
Published: July 2021

We report a case of an elderly woman, presenting with vesicouterine fistula and enlarged axillary lymph nodes. She had been diagnosed with cervical squamous cell carcinoma (SCC) in April 2015, for which she had received brachytherapy and concurrent chemoradiation therapy. The presence of enlarged axillary lymph nodes raised a suspicion for breast cancer with axillary metastases, but the bilateral mammograms did not show any discrete lesion in both breasts. The biopsy from axillary lymph node showed metastatic SCC, with block positivity for P16, confirming the origin from known cervical primary. Axillary lymph nodes are the least likely to be involved by tumours arising in the pelvis, as the lymphatic drainage of this region goes directly to the systemic circulation via the para-aortic lymph nodes and thoracic ducts. A complete clinical history is essential in such cases, to avoid misdiagnosis. Positron emission tomography CT helps in this regard.
Decolonising human rights: how intellectual property laws result in unequal access to the COVID-19 vaccine
Authors: Sekalala Sharifah , Forman Lisa , Hodgson Timothy , Mulumba Moses , Namyalo-Ganafa Hadijah , Meier Benjamin Mason
Published: July 2021

The recent rapid development of COVID-19 vaccines offers hope in addressing the worst pandemic in a hundred years. However, many countries in the Global South face great difficulties in accessing vaccines, partly because of restrictive intellectual property law. These laws exacerbate both global and domestic inequalities and prevent countries from fully realising the right to health for all their people. Commodification of essential medicines, such as vaccines, pushes poorer countries into extreme debt and reproduces national inequalities that discriminate against marginalised groups. This article explains how a decolonial framing of human rights and public health could contribute to addressing this systemic injustice. We envisage a human rights and global health law framework based on solidarity and international cooperation that focuses funding on long-term goals and frees access to medicines from the restrictions of intellectual property law. This would increase domestic vaccine production, acquisition and distribution capabilities in the Global South.
Decision aids for female BRCA mutation carriers: a scoping review protocol
Authors: McGarrigle Sarah A , Prizeman Geraldine , Spillane Carol , Byrne Niamh , Drury Amanda , Mockler David , Connolly Elizabeth M , Brady Anne-Marie , Hanhauser Yvonne P
Published: July 2021

Introduction

Women who inherit a pathogenic mutation in Breast Cancer Susceptibility Genes 1 or 2 (BRCA1 or BRCA2) are at substantially higher risk of developing breast and ovarian cancer than the average woman. Several cancer risk management strategies exist to address this increased risk. Decisions about which risk management strategies to choose are complex, personal and multifactorial for these women. This scoping review will map evidence relevant to cancer risk management decision making in BRCA mutation carriers without a personal history of cancer. The objective is to identify and describe the features of patient decision aids that have been developed for BRCA mutation carriers. This information may be beneficial for designing new decision aids or adapting existing decision aids to support decision making in this population.

Methods and analysis

This scoping review will be conducted according to the Joanna Briggs Institute’s scoping review methodological framework. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist will be used for guidance. Studies on decision aids for women with a BRCA mutation who are unaffected by breast or ovarian cancer will be considered for inclusion. Five electronic databases will be searched (MEDLINE, EMBASE, Cochrane Library, CINAHL, Web of Science) with no restrictions applied for language or publication date. Studies for inclusion will be selected independently by two review authors. Data will be extracted using a predefined data extraction form. Findings will be presented in tabular form. A narrative description of the evidence will complement the tabulated results.

Ethics and dissemination

Ethical approval for conducting this scoping review is not required as this study will involve secondary analysis of existing literature. Findings will be published in a peer-reviewed journal and presented at relevant conferences.
Study protocol for endoscopic ultrasonography-guided ethanol injection therapy for patients with pancreatic neuroendocrine neoplasm: a multicentre prospective study
Authors: Matsumoto Kazuyuki , Kato Hironari , Kitano Masayuki , Hara Kazuo , Kuwatani Masaki , Ashida Reiko , Takenaka Mamoru , Yamazaki Tatsuhiro , Sakurai Jun , Yoshida Michihiro , Okada Hiroyuki
Published: July 2021

Introduction

The management of small pancreatic neuroendocrine neoplasms (PNENs) remains controversial. The standard treatment for PNENs is surgical resection; however, invasiveness of surgical procedure remains higher and the incidence of postoperative adverse events is still high. Recently, the efficacy and safety of endoscopic ultrasonography (EUS)-guided ethanol injection for small PNENs has been preliminarily demonstrated. Thus, a multicentre prospective study is being conducted to evaluate the efficacy and safety of EUS-guided ethanol injection therapy for small PNENs.

Methods and analysis

The major eligibility criteria are the presence of pathologically diagnosed grade (G) 1 tumour, a tumour size of ≤15 mm and non-functional PNEN or insulinoma. For treatment, we will use a 25-gauge needle and pure ethanol. Contrast-enhanced CT (CE-CT) will be performed on postoperative day 3–5, and if enhanced areas of the tumour are still apparent, an additional session is scheduled during the same hospitalisation period. We set the total amount of ethanol per session to 2 mL. To evaluate the efficacy and safety, CE-CT will be performed at 1 and 6 months after treatment. The primary endpoint is the percentage of subjects who achieved all of the following evaluated points. Efficacy will be evaluated based on the achievement of complete ablation (defined as no enhanced area within the tumour on CE-CT) at 1 and 6 months. Safety will be evaluated based on the avoidance of severe adverse events within 1 month after treatment, continuing severe pancreatic fistula at 1 month after treatment and the incidence and/or exacerbation of diabetes mellitus at 6 months after treatment.

Ethics and dissemination

This protocol has been approved by Okayama University Certified Review Board (approval number. CRB19-007). The results will be submitted to peer-reviewed journals and will be presented at international conferences.

Trial registration number

jRCTs061200016.
Effects of integrated economic and health interventions with women’s groups on health-related knowledge, behaviours and outcomes in low-income and middle-income countries: a systematic review protocol
Authors: Desai Sapna , Mehta Kala M , Singh Roopal Jyoti , Westley Allie K , Dirisu Osasuyi , Wong Connie , De Hoop Thomas , Darmstadt Gary L
Published: July 2021

Introduction

Economic groups, such as microfinance or self-help groups are widely implemented in low-income and middle-income countries (LMICs). Women’s groups are voluntary groups, which aim to improve the well-being of members through activities, such as joint savings, credit, livelihoods development and/or health activities. Health interventions are increasingly added on to existing women’s economic groups as a public health intervention for women and their families. Here, we present the protocol for a mixed-methods systematic review we will conduct of the evidence on integrated economic and health interventions on women’s groups to assess whether and how they improve health-related knowledge, behaviour and outcomes in LMICs.

Methods and analysis

We will search seven electronic databases for published literature, along with manual searches and consultation. The review will include (1) randomised trials and non-randomised quasiexperimental studies of intervention effects of integrated economic and health interventions delivered through women’s groups in LMICs, and (2) sibling studies that examine factors related to intervention content, context, implementation processes and costs. We will appraise risk of bias and study quality using standard tools. High and moderate quality studies will be grouped by health domain and synthesised without meta-analysis. Qualitative evidence will be thematically synthesised and integrated into the quantitative synthesis using a matrix approach.

Ethics and dissemination

This protocol was reviewed and deemed exempt by the institutional review board at the American Institutes for Research. Findings will be shared through peer-reviewed publication and disseminated with programme implementers and policymakers engaged with women’s groups.

PROSPERO registration number

CRD42020199998.
Understanding factors critical to the implementation of ehealth in chronic disease management: a realist review protocol
Authors: Shahid Nida , Rac Valeria E , Bielecki Joanna , Berta Whitney
Published: July 2021

Introduction

Canadians are living longer, many with multiple chronic conditions. This population of older, frail Canadians continues to grow in size as do concurrent demands for community-based, outpatient and ambulatory models of care. Ideally, a multifaceted, proactive, planned and integrated care model includes ehealth. Although several factors are known to facilitate the implementation of ehealth in chronic disease management (CDM), for example, adequate support, usability, alignment of programme objectives, there is a growing body of inconclusive evidence on what is critical for implementation. We aim to achieve a fulsome understanding of factors critical to implementation by conducting a realist review—an approach suitable for understanding complex interventions. Our proposed review will identify factors critical to the implementation of ehealth in CDM (heart failure, chronic obstructive pulmonary disease, chronic kidney disease and/or diabetes (type 1 or 2)) without limitations to care setting, language, publication year or geography. Findings will be presented in configurations of contexts, mechanisms and outcomes (CMOs).

Methods and analysis

A search strategy will be iteratively developed based on the concepts of ‘implementation’ and ‘adoption’ of ‘ehealth’ interventions used within ‘CDM’ to identify the peer-reviewed and grey literature published before 31 March 2021 from five databases (Medline, Embase, Cochrane, CINAHL and PsychInfo) on ehealth interventions actively involving a healthcare provider for CDM among adults. Data extraction and synthesis will be guided by Realist and Meta-review Evidence Synthesis: Evolving Standards (RAMESES) guidelines informing core concepts of CMOs, and a study output will include a middle-range-theory describing the implementation of ehealth in CDM.

Ethics and dissemination

Findings will be published in an open-access peer-reviewed journal and presented at relevant conferences. A multistakeholder (patients, caregivers, healthcare providers and practitioners, decision-makers and policy-makers) perspective will be used in our dissemination approach. No formal ethics approval is required for this review.

PROSPERO registration number

CRD42020208275.
Retrospective cohort analysis of prescription patterns of cancer medications during periods of drug stockouts in Botswana
Authors: Davey Sonya , Grover Surbhi , Bilker Warren B , Setlhako Dipho I , Ralefala Tlotlo B , Manshimba Patrick , Gross Robert , DeMichele Angela , Shulman Lawrence N , Martei Yehoda M
Published: July 2021

Objective

Cancer drug stockouts occur at high frequencies globally, however, their effects on treatment are understudied in sub-Saharan Africa (SSA). We aimed to determine whether causes of suboptimal cancer treatment prescriptions differed between periods of stockout and full treatment supply.

Design

A retrospective cohort study of systemic therapy prescriptions for patients diagnosed with the twelve most common solid tumour cancers treated in 2016.

Setting

Princess Marina Hospital in Gaborone, Botswana.

Participants

Patients in the retrospective cohort who experienced any suboptimal treatment events, defined as ≥7 days delay or switch from guideline-concordant initiated therapy.

Primary and secondary outcome measures

Frequency of delays and patterns of prescription changes for specific regimens and cancer types.

Results

167/378 patients contributed to 320 suboptimal events (115 therapy switches, 167 delays and 38 events with both), over 1452 total chemotherapy cycles received. Events during stockout were 43% delays, 43% switches and 14% both during stockout periods and 67.2% delays, 24.4% switches and 8.4% both during non-stockout periods (p<0.001). Majority of switches involved de-escalation of initially prescribed guideline-recommended regimens in patients with breast cancer, Kaposi sarcoma and patients with colorectal cancer, which occurred more frequently during periods of drug stockouts. Among patients with breast cancer, substitution of docetaxel for paclitaxel event occurred exclusively during paclitaxel drug stockout. Delays of ≥7 days events were most frequent in breast cancer patients receiving paclitaxel during stockout, and combination doxorubicin and cyclophosphamide even during periods of non-stockout.

Conclusions

The aetiology of suboptimal events differed during stockout and non-stockout periods. Prescription patterns that involved de-escalation of initiated therapy and substitution of paclitaxel with docetaxel occurred frequently during periods of drug stockout. Further research needs to be conducted to understand the impact of stockout on survival and barriers to maintaining essential cancer medicines supplies in SSA, and the factors driving frequent delays in therapy delivery.
Topological analysis of hepatocellular carcinoma tumour microenvironment based on imaging mass cytometry reveals cellular neighbourhood regulated reversely by macrophages with different ontogeny
Authors: Sheng Jianpeng , Zhang Junlei , Wang Lin , Tano Vincent , Tang Jianghui , Wang Xun , Wu Jiangchao , Song Jinyuan , Zhao Yaxing , Rong Jingxia , Cheng Fei , Wang Jianfeng , Shen Yinan , Wen Liang , He Junjun , Zhang Hui , Li Taohong , Zhang Qi , Bai Xueli , Lu Zhimin , Liang Tingbo
Published: July 2021

Objective

Hepatocellular carcinoma (HCC) tumour microenvironment (TME) is highly complex with diverse cellular components organising into various functional units, cellular neighbourhoods (CNs). And we wanted to define CN of HCC while preserving the TME architecture, based on which, potential targets for novel immunotherapy could be identified.

Design

A highly multiplexed imaging mass cytometry (IMC) panel was designed to simultaneously quantify 36 biomarkers of tissues from 134 patients with HCC and 7 healthy donors to generate 562 highly multiplexed histology images at single-cell resolution. Different function units were defined by topological analysis of TME. CN relevant to the patients’ prognosis was identified as specific target for HCC therapy. Transgenic mouse models were used to validate the novel immunotherapy target for HCC.

Results

Three major types of intratumour areas with distinct distribution patterns of tumorous, stromal and immune cells were identified. 22 cellular metaclusters and 16 CN were defined. CN composed of various types of cells formed regional function units and the regional immunity was regulated reversely by resident Kupffer cells and infiltrating macrophages with protumour and antitumour function, respectively. Depletion of Kupffer cells in mouse liver largely enhances the T cell response, reduces liver tumour growth and sensitises the tumour response to antiprogrammed cell death protein-1 treatment.

Conclusion

Our findings reveal for the first time the various topological function units of HCC TME, which also presents the largest depository of pathological landscape for HCC. This work highlights the potential of Kupffer cell-specific targeting rather than overall myeloid cell blocking as a novel immunotherapy for HCC treatment.
Work-related and personal predictors of COVID-19 transmission: evidence from the UK and USA
Authors: Anand Paul , Allen Heidi L , Ferrer Robert L , Gold Natalie , Gonzales Martinez Rolando Manuel , Kontopantelis Evangelos , Krause Melanie , Vergunst Francis
Published: July 2021

Objective

To develop evidence of work-related and personal predictors of COVID-19 transmission.

Setting and respondents

Data are drawn from a population survey of individuals in the USA and UK conducted in June 2020.

Background methods

Regression models are estimated for 1467 individuals in which reported evidence of infection depends on work-related factors as well as a variety of personal controls.

Results

The following themes emerge from the analysis. First, a range of work-related factors are significant sources of variation in COVID-19 infection as indicated by self-reports of medical diagnosis or symptoms. This includes evidence about workplace types, consultation about safety and union membership. The partial effect of transport-related employment in regression models makes the chance of infection over three times more likely while in univariate analyses, transport-related work increases the risk of infection by over 40 times in the USA. Second, there is evidence that some home-related factors are significant predictors of infection, most notably the sharing of accommodation or a kitchen. Third, there is some evidence that behavioural factors and personal traits (including risk preference, extraversion and height) are also important.

Conclusions

The paper concludes that predictors of transmission relate to work, transport, home and personal factors. Transport-related work settings are by far the greatest source of risk and so should be a focus of prevention policies. In addition, surveys of the sort developed in this paper are an important source of information on transmission pathways within the community.
PD-1+CXCR5−CD4+ Th-CXCL13 cell subset drives B cells into tertiary lymphoid structures of nasopharyngeal carcinoma
Authors: Li Jiang-Ping , Wu Chang-You , Chen Ming-Yuan , Liu Shang-Xin , Yan Shu-Mei , Kang Yin-Feng , Sun Cong , Grandis Jennifer R , Zeng Mu-Sheng , Zhong Qian
Published: July 2021

Background

A major current challenge is to exploit tertiary lymphoid structures (TLSs) to promote the lymphocyte infiltration, activation and differentiation by tumor antigens to increase antitumor immune responses. The mechanisms that underlie the role of TLS formation in the adaptive immune responses against nasopharyngeal carcinoma (NPC) remain largely unknown.

Methods

Cell populations and the corresponding markers were identified by single-cell RNA sequencing and fluorescence-activated cell sorting analysis. In vitro differentiation experiments were used to simulate the generation, regulation and function of the Th-CXCL13 cell subset in the tumor microenvironment of NPC. These were followed by histological evaluation of the colocalization of tumor-associated B cells (TABs) and Th-CXCL13 cells within TLSs, and statistical analysis of the relationship between the cells in TLSs and overall survival.

Results

A PD-1+CXCR5−CD4+ Th-CXCL13 cell subset was identified in NPC. This subset was a major source of CXCL13, representing the majority of the CD4+ T cells at levels comparable with Th1 and Tfh cells present in the TLSs. Monocytes activated by toll-like receptor 4 agonists served as the antigen-presenting cells that most efficiently triggered the expansion of Th-CXCL13 cells. Transforming growth factor beta 1 (TGF-β1) stimulation and activation of Sox4 were critical for the induction and polarization of Th-CXCL13 cells in this process. The potential functional contributions of TABs recruited by Th-CXCL13 cells which induced plasma cell differentiation and immunoglobulin production via interleukin-21 and CD84 interactions in the TLSs demonstrated improved survival.

Conclusions

Induction of Th-CXCL13 cells links innate inflammation to immune privilege in tumor-associated TLSs and might predict better survival.
Combining C reactive protein and serum albumin to predict 90-day mortality in systemic lupus erythematosus with serious community-acquired infections
Authors: He Shuangjun , Tang Chao , Yu Jie , Ma Jun , Qiao Minjie , Zhou Wei , Chen Yi , Zhang Xingyu
Published: July 2021

Objective

Serious infections in SLE are common and have emerged as the major cause of death. However, effective methods to identify poor prognosis are still lacking. Therefore, we aimed to determine the predictive value of C reactive protein (CRP) plus albumin (ALB) in SLE with serious infections.

Methods

From May 2015 to December 2018, consecutive patients with SLE presenting with serious infections in our emergency department were prospectively recruited. Serum CRP and ALB were measured within 24 hours of admission. The outcome was defined as mortality rate at 90 days. A CRP plus ALB score (2–6) was assigned based on the CRP and ALB concentrations. We performed univariate and multivariate regression analyses to detect the independent effects of CRP plus ALB on 90-day mortality (all-cause and infection-related). Subgroup analyses were used to show the effects stratified by lupus nephritis.

Results

A total of 150 patients were included, and the all-cause 90-day mortality rate was 38% (n=57), 41 of which was infection-related. The predominant infection sites were pulmonary (79.3%) and bloodstream infection (20.7%). Serum CRP and ALB levels were significantly different in non-surviving patients compared with those in surviving patients (p=0.002 and p<0.001, respectively). In the fully adjusted logistic regression model, the CRP plus ALB score was associated with decreased 90-day survival (adjusted OR 1.52; 95% CI 1.08 to 2.13; p=0.017).

Conclusions

CRP plus ALB was associated with the risk of all-cause and infection-related 90-day mortality in SLE with serious infections. Although this finding requires further verification, the two parameters may be useful for predicting poor outcomes in such patients.
LUPUS-BEST—treat-to-target in systemic lupus erythematosus: study protocol for a three-armed cluster-randomised trial
Authors: Mucke Johanna , Kuss Oliver , Brinks Ralph , Schanze Sabine , Schneider Matthias
Published: July 2021

Introduction

As chronic systemic autoimmune disease, which can affect every organ, SLE is creating significant burden and increased mortality. Despite better outcomes over the past decades by optimising standard of care, new interventions are needed for further improvements. Changing strategy to ‘treat-to-target’ (T2T) may be a promising concept proven successful in other chronic diseases.

Methods and analysis

In this cluster-randomised trial, SLE centres will be assigned 1:1:1 to standard of care (SoC), remission (no clinical disease activity+prednisolone ≤5 mg/day+Physician Global Assessment (PGA 0–3) <0.5±immunomodulatory treatment) or and Lupus Low Disease Activity State (LLDAS, low disease activity+prednisolone ≤7.5 mg/day+PGA ≤1+no new disease activity). Per arm, 424 patients will be included. Intervention centres receive a standardised training on T2T and shared decision-making (SDM). In intervention centres, patients not in target enter a phase of tight control with six weekly visits and treatment adjustments (at least four visits) or until the target is reached and maintained. Patients in target are reassessed every 12 weeks. In case of flare, they can enter tight control based on SDM. In the SoC arm, patients receive their usual three to six monthly controls and treatment adjustments according to the physician’s discretion. Study duration is 120 weeks using change in damage and health-related quality of life (HRQoL) as major outcomes. The primary endpoint will be damage accrual at 120 weeks as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index and will by analysed by a mixed model.

Conclusions

This is the first trial to assess if the implementation of a T2T concept in clinical care minimises damage accrual and improves HRQoL in patients with SLE. Comparison of remission and LLDAS will help to identify the target with the best benefit–risk ratio concerning attainability, adverse events and damage. The emphasis on SDM will strengthen patient autonomy and will improve both their satisfaction and medical condition.
A multianalyte assay panel with cell-bound complement activation products demonstrates clinical utility in systemic lupus erythematosus
Authors: Alexander Roberta Vezza , Rey Daniel Scott , Conklin John , Domingues Vinicius , Ahmed Mansoor , Qureshi Jazibeh , Weinstein Arthur
Published: July 2021

Objective

To evaluate the clinical utility of the multianalyte assay panel (MAP), commercially known as AVISE Lupus test (Exagen Inc.), in patients suspected of SLE.

Methods

A systematic review of medical records of ANA-positive patients with a positive (>0.1) or negative (<−0.1) MAP score was conducted when the MAP was ordered (T0), when the test results were reviewed (T1) and at a later time (T2, ≥8 months after T1). Confidence in the diagnosis of SLE and initiation of hydroxychloroquine (HCQ) were assessed.

Results

A total of 161 patient records from 12 centres were reviewed at T0 and T1. T2 occurred for 90 patients. At T0, low, moderate and high confidence in SLE diagnosis was reported for 58%, 30% and 12% patients, respectively. Confidence in SLE diagnosis increased for the MAP positive, while MAP negative made SLE less likely. Odds of higher confidence in SLE diagnosis increased by 1.74-fold for every unit of increase of the MAP score (p<0.001). Using the MAP-negative/anti-double-stranded DNA-negative patients as reference, the HR of assigning an International Classification of Diseases, Tenth Revision lupus code was 7.02-fold, 11.2-fold and 14.8-fold higher in the low tier-2, high tier-2 and tier-1 positive, respectively (p<0.001). The HR of initiating HCQ therapy after T0 was 2.90-fold, 4.22-fold and 3.98-fold higher, respectively (p<0.001).

Conclusion

The MAP helps increase the confidence in ruling-in and ruling-out SLE in patients suspected of the disease and informs on appropriate treatment decisions.
Research abuses against people of colour and other vulnerable groups in early psychedelic research
Authors: Strauss Dana , de la Salle Sara , Sloshower Jordan , Williams Monnica T
Published: July 2021

There is a growing resurgence in the study of psychedelic medicines for the treatment of mental health and substance use disorders. However, certain early investigations are marred by questionable research methods, abuses against research participants, and covert Central Intelligence Agency financial involvement. The purpose of this study was to understand how and to what extent people of colour and other vulnerable populations, specifically, individuals who were incarcerated or incapacitated due to mental health issues (inpatients with psychotic disorders), were exploited during the first wave of psychedelic research in the USA (1950–1980). To do so, we reviewed available empirical publications according to current ethical standards. Variables of interest included race and ethnicity of participants, population vulnerability, drug administration conditions, informed consent and undue influence. Our findings draw attention to the history of research abuses against people of colour in Western psychedelic research. In light of these findings, we urge a call-to-action to current psychedelic researchers to prioritise culturally inclusive and socially responsible research methods in current and future studies.
COVID-19 vaccination and the right to take risks
Authors: Huang Pei-hua
Published: July 2021

The rare but severe cerebral venous thrombosis occurring in some AstraZeneca vaccine recipients has prompted some governments to suspend part of their COVID-19 vaccination programmes. Such suspensions have faced various challenges from both scientific and ethical angles. Most of the criticisms against such suspensions follow a consequentialist approach, arguing that the suspension will lead to more harm than benefits. In this paper, I propose a rights-based argument against the suspension of the vaccine rollouts amid this highly time-sensitive combat of COVID-19. I argue that by suspending a vaccine rollout, a government infringes people’s right to take the risks they deem worth taking for their health. I also consider four potential objections to my argument and explain why none of them undermines my argument.
Biological DMARDs and disease modification in axial spondyloarthritis: a review through the lens of causal inference
Authors: Sepriano Alexandre , Ramiro Sofia , van der Heijde Desirée , Landewé Robert
Published: July 2021

Axial spondyloarthritis (axSpA) is a chronic rheumatic disease characterised by inflammation predominantly involving the spine and the sacroiliac joints. In some patients, axial inflammation leads to irreversible structural damage that in the spine is usually quantified by the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Available therapeutic options include biological disease-modifying antirheumatic drugs (bDMARDs), which have been proven effective in suppressing inflammation in several randomised controlled trials (RCT), the gold standard for evaluating causal treatment effects. RCTs are, however, unfeasible for testing structural effects in axSpA mainly due to the low sensitivity to change of the mSASSS. The available literature therefore mainly includes observational research, which poses serious challenges to the determination of causality. Here, we review the studies testing the effect of bDMARDs on spinal radiographic progression, making use of the principles of causal inference. By exploring the assumptions of causality under counterfactual reasoning (exchangeability, positivity and consistency), we distinguish between studies that likely have reported confounded treatment effects and studies that, on the basis of their design, have more likely reported causal treatment effects. We conclude that bDMARDs might, indirectly, interfere with spinal radiographic progression in axSpA by their effect on inflammation. Innovations in imaging are expected, so that placebo-controlled trials can in the future become a reality. In the meantime, causal inference analysis using observational data may contribute to a better understanding of whether disease modification is possible in axSpA.
Direct oral anticoagulants versus vitamin K antagonists in patients with antiphospholipid syndrome: systematic review and meta-analysis
Authors: Koval Nazariy , Alves Mariana , Plácido Rui , Almeida Ana G , Fonseca João Eurico , Ferreira Joaquim J , Pinto Fausto J , Caldeira Daniel
Published: July 2021

Background

Despite vitamin K antagonists (VKA) being the gold standard in the prevention of thromboembolic events in antiphospholipid syndrome (APS), non-vitamin K antagonists oral anticoagulants/direct oral anticoagulants (DOACs) have been used off-label.

Objective

We aimed to perform a systematic review comparing DOACs to VKA regarding prevention of thromboembolic events, occurrence of bleeding events and mortality in patients with APS.

Methods

An electronic database search was performed through MEDLINE, CENTRAL and Web of Science. After data extraction, we pooled the results using risk ratio (RR) and 95% CI. Heterogeneity was assessed using the I². The outcomes considered were all thromboembolic events as primary, and major bleeding, all bleeding events and mortality as secondary. Evidence confidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology.

Results

We included 7 studies and a total of 835 patients for analyses. Thromboembolic events were significantly increased in DOACs arm, compared with VKA—RR 1.69, 95% CI 1.09 to 2.62, I²—24%, n=719, 6 studies. In studies using exclusively rivaroxaban, which was the most representative drug in all included studies, the thromboembolic risk was increased threefold (RR 3.36, 95% CI 1.53 to 7.37). The risks of major bleeding, all bleeding events and mortality were not significantly different from control arm. The grade of certainty of our results is very low.

Conclusions

Current evidence suggests DOACs use, particularly rivaroxaban, among patients with APS, is less effective than VKA since it is associated with 69% increased risk of thromboembolic events.

Trial registration number

CRD42020216178.