bluuebunny/crossref_metadata_2025 huggingface dataset:
Coagulopathy is a major extrapulmonary risk factor for mortality in hospitalized patients with COVID-19 with type 2 diabetes
Authors: Chen Xiaoyan , Chen Ying , Wu Chaomin , Wei Ming , Xu Jie , Chao Yen-cheng , Song Juan , Hou Dongni , Zhang Yuye , Du Chunling , Li Xiaoying , Song Yuanlin
Published: November 2020

Introduction

To investigate the risk factors for the death in patients with COVID-19 with type 2 diabetes mellitus (T2DM).

Research design and methods

We retrospectively enrolled inpatients with COVID-19 from Wuhan Jinyintan Hospital (Wuhan, China) between December 25, 2019, and March 3, 2020. The epidemiological and clinical data were compared between non-T2DM and T2DM or between survivors and non-survivors. Univariable and multivariable Cox regression analyses were used to explore the effect of T2DM and complications on in-hospital death.

Results

A total of 1105 inpatients with COVID-19, 967 subjects with without T2DM (n=522 male, 54.0%) and 138 subjects with pre-existing T2DM (n=82 male, 59.4%) were included for baseline characteristics analyses. The complications were also markedly increased in patients with pre-existing T2DM, including acute respiratory distress syndrome (ARDS) (48.6% vs 32.3%, p<0.001), acute cardiac injury (ACI) (36.2% vs 16.7%, p<0.001), acute kidney injury (AKI) (24.8% vs 9.5%, p<0.001), coagulopathy (24.8% vs 11.1%, p<0.001), and hypoproteinemia (21.2% vs 9.4%, p<0.001). The in-hospital mortality was significantly higher in patients with pre-existing T2DM compared with those without T2DM (35.3% vs 17.4%, p<0.001). Moreover, in hospitalized patients with COVID-19 with T2DM, ARDS and coagulopathy were the main causes of mortality, with an HR of 7.96 (95% CI 2.25 to 28.24, p=0.001) for ARDS and an HR of 2.37 (95% CI 1.08 to 5.21, p=0.032) for coagulopathy. This was different from inpatients with COVID-19 without T2DM, in whom ARDS and cardiac injury were the main causes of mortality, with an HR of 12.18 (95% CI 5.74 to 25.89, p<0.001) for ARDS and an HR of 4.42 (95% CI 2.73 to 7.15, p<0.001) for cardiac injury.

Conclusions

Coagulopathy was a major extrapulmonary risk factor for death in inpatients with COVID-19 with T2DM rather than ACI and AKI, which were well associated with mortality in inpatients with COVID-19 without T2DM.
‘I do what a woman should do’: a grounded theory study of women’s menstrual experiences at work in Mukono District, Uganda
Authors: Hennegan Julie , Kibira Simon P S , Exum Natalie G , Schwab Kellogg J , Makumbi Fredrick E , Bukenya Justine
Published: November 2020

Menstrual health has received increasing recognition as an essential issue for public health and gender equality. A growing body of research has elucidated adolescent girls’ menstrual needs and informed policy and practice responses. However, the experiences of adult women have received little attention, particularly in the workplace where many spend a significant proportion of their lives. To address this gap, we took a grounded theory approach to generate a nuanced understanding of working women’s menstrual experiences, and the impact of menstruation on their work and health in Mukono District, Uganda. In-depth interviews were undertaken with 35 women aged 18–49. This included 21 women working in markets, 7 teachers and 7 healthcare facility workers. Frequent collaborative analysis sessions throughout data collection, coding of interview transcripts, and generation of participant, workplace, and category memos facilitated analysis. Our core category and underlying theory,‘being a responsible woman’, underpinned women’s experiences.‘Being responsible’ meant keeping menstruation secret, and the body clean, at all times. These gendered expectations meant that any difficulty managing menses represented a failure of womanhood, met with disgust and shame. Difficulties with menstrual pain and heavy bleeding were excepted from these expectations and perceived as requiring compassion. Commercial menstrual products were expensive for most women, and many expressed concerns about the quality of cheaper brands. Workplace infrastructure, particularly unreliable water supply and cleanliness, was problematic for many women who resorted to travelling home or to other facilities to meet their needs. Menstruation presented a burden at work, causing some women to miss work and income, and many others to endure pain, discomfort and anxiety throughout their day. Our findings can inform norm and resource-focused responses to improve experiences and should provoke critical reflection on the discourse used in menstrual health advocacy in Uganda.
New Onset of DiabetEs in aSsociation with pancreatic ductal adenocarcinoma (NODES Trial): protocol of a prospective, multicentre observational trial
Authors: Illés Dóra , Ivány Emese , Holzinger Gábor , Kosár Klára , Adam M Gordian , Kamlage Beate , Zsóri Gábor , Tajti Máté , Svébis Márk M , Horváth Viktor , Oláh Ilona , Márta Katalin , Váncsa Szilárd , Zádori Noémi , Szentesi Andrea , Czakó Bálint , Hegyi Péter , Czakó László
Published: November 2020

Introduction

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with an overall 5-year survival of approximately 8%. The success in reducing the mortality rate of PDAC is related to the discovery of new therapeutic agents, and to a significant extent to the development of early detection and prevention programmes. Patients with new-onset diabetes mellitus (DM) represent a high-risk group for PDAC as they have an eightfold higher risk of PDAC than the general population. The proposed screening programme may allow the detection of PDAC in the early, operable stage. Diagnosing more patients in the curable stage might decrease the morbidity and mortality rates of PDAC and additionally reduce the burden of the healthcare.

Methods and analysis

This is a prospective, multicentre observational cohort study. Patients ≥60 years old diagnosed with new-onset (≤6 months) diabetes will be included. Exclusion criteria are (1) Continuous alcohol abuse; (2) Chronic pancreatitis; (3) Previous pancreas operation/pancreatectomy; (4) Pregnancy; (5) Present malignant disease and (6) Type 1 DM. Follow-up visits are scheduled every 6 months for up to 36 months. Data collection is based on questionnaires. Clinical symptoms, body weight and fasting blood will be collected at each, carbohydrate antigen 19–9 and blood to biobank at every second visit. The blood samples will be processed to plasma and analysed with mass spectrometry (MS)-based metabolomics. The metabolomic data will be used for biomarker validation for early detection of PDAC in the high-risk group patients with new-onset diabetes. Patients with worrisome features will undergo MRI or endoscopic ultrasound investigation, and surgical referral depending on the radiological findings. One of the secondary end points is the incidence of PDAC in patients with newly diagnosed DM.

Ethics and dissemination

The study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (41085-6/2019). We plan to disseminate the results to several members of the healthcare system includining medical doctors, dietitians, nurses, patients and so on. We plan to publish the results in a peer-reviewed high-quality journal for professionals. In addition, we also plan to publish it for lay readers in order to maximalise the dissemination and benefits of this trial.

Trial registration number

ClinicalTrials.govNCT04164602
Longitudinal study of symptom burden in outpatients with advanced cancers based on electronic Patient-Reported Outcome (ePRO) platform: a single institution, prospective study protocol
Authors: Tang Lili , Pang Ying , He Yi , Shi Qiuling , Han Xinkun , Li Zimeng , Zhou Chengcheng , Zhou Yuhe , He Shuangzhi , Wang Yan , Zhang Yening , Song Lili , Wang Bingmei , Li Xiumin
Published: November 2020

Introduction

An electronic Patient-Reported Outcome (ePRO) platform is needed for implementing evidence-based symptom management in outpatients with advanced cancer. We describe the overall protocol and the methodology for measuring symptom burden, to provide critical parameters needed to implement symptom management on the ePRO platform.

Methods and analysis

The study focusses on patients with advanced lung cancer, stomach cancer, oesophagus cancer, liver cancer, colorectal cancer or breast cancer. The primary outcome is the change of symptom burden. MD Anderson Symptom Inventory, and other PRO instruments (Insomnia Severity Index, Hospital Anxiety and Depression Scale, 9-item Patient Health Questionnaire and EuroQol-5 dimensions-5 levels version) were used. The secondary outcomes include feasibility of using ePRO, symptom-related quality of life, reasons for no improvement of symptoms, defining frequency of PRO assessments and cut-points, items for screening and management of comorbidity and satisfaction with ePRO platform in patients and health providers. After initial outpatient visit for baseline assessment, ePRO system will automatically send follow-up notification seven times over 4 weeks to patients. The characteristics and changing trajectory of symptoms of patients will be described. Parameters for using PROs, such as optimal time points for follow-up and cut-off point for alert will be determined. The feasibility of ePRO platform to track the changes of target symptoms in outpatients will be evaluated.

Ethics and dissemination

The study protocol and related documents were approved by the Institutional Research Board (IRB) of Peking University Cancer Hospital on 13 February 2019 (2019YJZ07). The results of this study will be disseminated through academic workshops, peer-reviewed publications and conferences.

Trial registration number

ChiCTR1900023560.
Mental health recovery for survivors of modern slavery: grounded theory study protocol
Authors: Wright Nicola , Hadziosmanovic Emina , Dang Minh , Bales Kevin , Brookes Caroline , Jordan Melanie , Slade Mike
Published: November 2020

Introduction

Slavery and human trafficking are crimes involving the violation of human rights and refer to exploitative situations where an individual cannot refuse or leave due to threats, coercion or abuse of power. Activities involving slavery include forced labour exploitation, forced sexual exploitation, forced marriage and servitude. Epidemiological studies show high levels of mental health need and poor provision of appropriate support for survivors. What mental health recovery means to victims/survivors and how it could be promoted is under-researched.

Methods and analysis

A grounded theory study based on individual interviews will be undertaken. Survivors across the UK will be identified and recruited from non-governmental organisations and via social media. As per grounded theory methodology, data collection and analysis will be undertaken concurrently and recruitment will continue until theoretical saturation is reached. It is anticipated that approximately 30 participants will be recruited. Interviews will be audio recorded, transcribed verbatim and uploaded to NVivo V.11. The constant comparative method will be used to analyse the data, in order to produce a theoretical framework for mental health recovery that is grounded in the experiences of survivors.

Ethics and dissemination

Ethical approval has been obtained from the Faculty of Medicine and Health Sciences Ethics Committee at the University of Nottingham. The findings of the study will be disseminated to academic, professional and survivor-based audiences to inform future policy developments and the provision of mental health recovery support to this population.
Effect of spironolactone on cardiovascular morbidity and mortality in patients with hypertension and glucose metabolism disorders (ESCAM): a study protocol for a pragmatic randomised controlled trial
Authors: Li Nanfang , Lin Mengyue , Heizhati Mulalibieke , Wang Lin , Luo Qin , Li Yuanyuan , Yili Jina , Hong Jing , Yao Xiaoguang , Zhu Qing
Published: November 2020

Introduction

Hypertension combined with diabetes and hypokalemia is more likely to develop hyperaldosteronism and is at higher risk of cardiovascular events. There is evidence that activation of aldosterone and mineralocorticoid receptors may play a significant role in the occurrence of cardiovascular events in patients with hypertension and diabetes. Clinical studies have demonstrated that spironolactone can reduce the incidence of cardiovascular events in patients with chronic kidney diseases or severe heart failure. However, the effect of spironolactone on cardiovascular risk in patients with hypertension and glucose metabolism disorders (GMD) and low potassium has been scarcely studied. Therefore, this study aims to evaluate whether add-on spironolactone (conventional antihypertensive drugs alone vs conventional antihypertensive drugs+spironolactone) can reduce the morbidity and mortality of cardiovascular events in this population.

Methods and analysis

In this multicentre, randomised, parallel-controlled study, a total of 7140 hypertensive patients aged 45–75 years with GMD and low potassium will be randomised in a 1:1 manner to the control or the spironolactone group (20 mg/day or with a maximum dose of 40 mg). The primary objective is to estimate the difference in the HR of composite cardiovascular events between the two groups. We will also assess the effects of spironolactone on individual cardiovascular events and the progression of diabetes and renal dysfunction.

Ethics and dissemination

This protocol was approved by the Independent Ethics Committee of People’s Hospital of Xinjiang Uygur Autonomous Region (no. 2020020618). The results will be disseminated in peer-reviewed journals and at scientific conferences.

Trial registration number

ChiCTR2000028909.
Use of dating sites and applications by women and their risk of sexually transmitted infections: a systematic review and meta-analysis protocol
Authors: Queiroz Janice França , Medeiros Kleyton Santos , Sarmento Ayane Cristine Alves , Monteiro Michelly Nóbrega , Cobucci Ricardo Ney , Stransky Beatriz , Gonçalves Ana Katherine
Published: November 2020

Introduction

The use of social networks has been increasing worldwide. Mobile websites and applications (apps) allow people to network more quickly and have more partners for sex. This can facilitate risky sexual behaviours, such as having multiple partners and unprotected sex, which can lead to a higher incidence of sexually transmitted infections. This systematic review/meta-analysis will assess the effects of the use of dating sites and apps by women on their level of engagement in risky sexual behaviours and their incidence of sexually transmitted infections.

Methods and analysis

The Cochrane Central Controlled Trials Registry, ClinicalTrials.gov, MEDLINE, Embase, SciELO, Web of Science, Scopus and Cumulative Index to Nursing & Allied Health Literature will be searched for cross-sectional studies, clinical trials and observational studies published between January 1990 and July 2020. This systematic review and meta-analysis will include studies investigating the use of mobile apps by women, risky sexual behaviour and sexually transmitted infections. The outcome will be an increase in new cases of sexually transmitted infections and HIV among women using dating sites and apps. Three independent reviewers will select the studies and extract data from the original articles. The risk of bias will be assessed using the Cochrane risk of bias tool and Risk Of Bias in Non-randomized Studies of Interventions. Data synthesis will be performed using Review Manager software (RevMan V.5.2.3). To assess heterogeneity, we will compute the I2statistic. In addition, a quantitative synthesis will be carried out if the included studies are sufficiently homogeneous.

Ethics and dissemination

This study will be a review of the published data, and thus ethical approval is not required. The findings of this systematic review will be published in a peer-reviewed journal.

PROSPERO registration number

CRD42019120494.
Active and passive work breaks during simulated laparoscopy among laparoscopic surgeons: study protocol for a controlled, randomised cross-over laboratory trial
Authors: Luger Tessy , Rieger Monika A , Bonsch Rosina , Krämer Bernhard , Seibt Robert , Steinhilber Benjamin
Published: November 2020

Introduction

Laparoscopy has partially replaced open surgery due to the lower infection rate for the patient and hence better and shorter recovery. However, the surgeon’s physical load is higher due to longer duration static and awkward body postures, increasing the risk for developing work-related musculoskeletal disorders. Interventions of an organisational nature are work breaks, being either passive or active. The primary objectives of this study are to determine whether passive and active work breaks lead to less discomfort than no work breaks and whether active work breaks lead to less discomfort than passive work breaks.

Methods and analysis

A controlled, randomised cross-over trial will be performed in the laboratory, of which its protocol is described here according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement. Recruitment of 21 laparoscopic surgeons started in April 2019 and the study is ongoing. The participating surgeons will perform three 1.5 hour experimental conditions, one without work breaks, one with 2.5 min passive work breaks including rest, and one with 2.5 min active work breaks including mobility and stretching exercises. The work breaks will be taken after 30 and 60 min of work. During the experiments, outcomes will be recorded. The primary outcome is rating of perceived discomfort measured on an 11-point numeric rating scale. The secondary outcomes are performance, muscle activity of selected muscles, upper body angles, heart rate, workload and subjective evaluation of both interventions. The collected data will be tested using a one-way or two-factorial repeated-measures analysis of variance.

Ethics and dissemination

Ethical approval of the study protocol was received by the local medical ethical committee of the University of Tübingen in February 2019 (no 618/2018BO2). The results of this study will be presented at national and international conferences, submitted for publications in peer-reviewed journals and serve as the starting point for a feasibility study.

Trial registration number

NCT03715816.
Valuing health-related quality of life among the Indian population: a protocol for the Development of an EQ-5D Value set for India using an Extended design (DEVINE) Study
Authors: Jyani Gaurav , Prinja Shankar , Kar Sitanshu Sekhar , Trivedi Mayur , Patro Binod , Purba Fredrick , Pala Star , Raman Swati , Sharma Atul , Jain Shalu , Kaur Manmeet
Published: November 2020

Introduction

Quality-adjusted life year (QALY) has been recommended by the government as preferred outcome measure for Health Technology Assessment (HTA) in India. As country-specific health-related quality of life tariff values are essential for accurate measurement of QALYs, the government of India has commissioned the present study. The aim of this paper is to describe the methods for the Development of an EQ-5D Value set for India using an Extended design (DEVINE) Study. Additionally, this study aspires to establish if the design of 10-time trade-off (TTO) blocks is enough to generate valid value sets.

Methods and analysis

A cross-sectional survey using the EuroQol Group’s Valuation Technology (EQ-VT) will be undertaken in a sample of 2700 respondents selected from six different states of India using a multistage stratified random sampling technique. The participants will be interviewed using computer-assisted personal interviewing technique. The TTO valuation will be done using 10 composite TTO (c-TTO) tasks and 7 discrete choice experiment (DCE) tasks. Hybrid modelling approach using both c-TTO and DCE data to estimate the potential value set will be applied. Values of all 3125 health states will be predicted using both the conventional EQ-VT design of 10 blocks of 10 TTO tasks, and an extended design of 18 blocks of 10 TTO tasks. The potential added value of the eight additional blocks in overall validity will be tested. The study will deliver value set for India and assess the adequacy of existing 10-blocks design to be able to correctly predict the values of all 3125 health states.

Ethics and dissemination

The ethical approval has been obtained from Institutional Ethics Committee of PGIMER, Chandigarh, India. The anonymised EQ-5D-5L value set will be available for general use and in the HTAs commissioned by India’s central HTA Agency.
Risk assessment and identification of HIV infection among men who have sex with men: a cross-sectional study in Southwest China
Authors: Zheng Min , He Jiayu , Yuan Zhi , Zhang Xinhui , Yao Yongming , Fang Xing , Fu Lin , Ding Yingying , He Na , Zhang Yuqiong
Published: November 2020

Objectives

The HIV epidemic is around 7%–20% among men who have sex with men (MSM) in Southwest China. The low HIV-testing rate highlights the need for tools to identify high-risk MSM in resource-limited regions. Our aim was, therefore, to evaluate the HIV RISK Assessment Tool for HIV prediction and to characterise the primary infection among MSM in Southwest China.

Design

A cross-sectional survey was conducted in Guizhou province between January and December 2018. Participants were recruited from gay communities, among whom the HIV RISK Assessment Tool was evaluated. Logistic regression was used to analyse items associated with HIV and the area under the curve (AUC) of the receiver operating curve was calculated to quantify discrimination performance.

Participants

1330 MSM participants, of which 83 (6.2%) tested as HIV positive.

Results

A higher composite score of the tool (adjusted OR (aOR) 9.33, 95% CI 4.57 to 19.05) was independently associated with HIV infection. Items positively associated with HIV infection included having 2–5 same sex partners (aOR 2.43, 95% CI 1.28 to 4.64), always (aOR 5.93, 95% CI 1.59 to 22.13) or sometimes (aOR 4.25, 95% CI 2.09 to 8.64) having unprotected anal intercourse, taking both insertive and receptive sex roles (aOR 4.95, 95% CI 2.57 to 9.53) or only the receptive sex role (aOR 2.26, 95% CI 1.21 to 4.24). The tool showed an optimal discrimination ability (AUC=0.827), with a specificity of 0.747 and sensitivity of 0.785. Five MSM were identified with primary infection and had similar sexual risk behaviors as HIV-positive participants.

Conclusions

The HIV RISK Assessment Tool showed an overall good performance in predicting HIV risk among MSM in Guizhou province where the prevalence is still severe. This tool also demonstrated a potential to identify primary infection and is worth being promoted in resource-limited regions.
Evaluating the impact of the Bolsa Familia conditional cash transfer program on premature cardiovascular and all-cause mortality using the 100 million Brazilian cohort: a natural experiment study protocol
Authors: Pescarini Julia M , Craig Peter , Allik Mirjam , Amorim Leila , Ali Sanni , Smeeth Liam , Barreto Mauricio L , Leyland Alastair H , Aquino Estela M L , Katikireddi Srinivasa Vittal
Published: November 2020

Introduction

Brazil’s Bolsa Familia Program (BFP) is the world’s largest conditional cash transfer scheme. We shall use a large cohort of applicants for different social programmes to evaluate the effect of BFP receipt on premature all-cause and cardiovascular mortality.

Methods and analysis

We will identify BFP recipients and non-recipients among new applicants from 2004 to 2015 in the 100 Million Brazilian Cohort, a database of 114 million individuals containing sociodemographic and mortality information of applicants to any Brazilian social programme. For individuals applying from 2011, when we have better recorded income data, we shall compare premature (age 30–69) cardiovascular and all-cause mortality among BFP recipients and non-recipients using regression discontinuity design (RDD) with household monthly per capita income as the forcing variable. Effects will be estimated using survival models accounting for individuals follow-up. To test the sensitivity of our findings, we will estimate models with different bandwidths, include potential confounders as covariates in the survival models, and restrict our data to locations with the most reliable data. In addition, we will estimate the effect of BFP on studied outcomes using propensity score risk-set matching, separately for individuals that applied ≤2010 and >2011, allowing comparability with RDD. Analyses will be stratified by geographical region, gender, race/ethnicity and socioeconomic position. We will investigate differential impacts of BFP and the presence of effect modification for a combination of characteristics, including gender and race/ethnicity.

Ethics and dissemination

The study was approved by the ethics committees of Oswaldo Cruz Foundation and the University of Glasgow College of Medicine and Veterinary Life Sciences. The deidentified dataset will be provided to researchers, and data analysis will be performed in a safe computational environment without internet access. Study findings will be published in high quality peer-reviewed research articles. The published results will be disseminated in the social media and to policy-makers.
How to prioritise in quality improvement? Targeted implementation as a key for quality improvement in Kenyan health facilities
Authors: Nitschke Christine , Nafula Maureen , Brodowski Marc , Marx Irmgard , Kandie Charles , Omogi Irene , Paul-Fariborz Friederike , Szecsenyi Joachim , Brugnara Lucia , Marx Michael
Published: November 2020

Background

Data from national surveys of low- and middle income countries indicates that there is still a need to improve the quality of healthcare in resource-poor settings. This study aims to understand the benefit of an integral, facility-driven, indicator-based approach used as a decision-making tool to define effective quality improvement interventions in Kenya.

Objective

The aim of the study is to understand whether the integral approach developed leads to effective interventions.

Methods

Categorical data is collected from ten health facilities covered by the Integrated Quality Management System (IQMS) project in Kenya. First the information on concrete improvement interventions implemented within the facilities is collected and merged into five different intervention topics. Second, groups of facilities with similar quality improvement interventions are selected to compare between the first and second quality assessment rounds. Those IQMS indicators matching the content of the intervention topic are extracted from the software VISOTOOL. In a third step, the data is summarised using means and SD. A one sample T-test is applied on the mean changes and SD. Frequency counts and percentages were used for the presentation of categorical data.

Results

All improvement interventions resulted in positive and higher change values (T2-T1). Four of five intervention topics, show statistically significant improvements including neonatal mortality (42%; p<0.0001), waiting time (39%; p=0.0490), infection prevention control (28%; p=0.0007) and with shortages of staffing and transport in remote areas (32%; p=0.0194).

Conclusions

In all facilities the interventions selected have a positive impact, some of which markedly improved. It demonstrates that this integral quality improvement approach in Kenya can serve as an effective decision-making tool for identification and prioritisation of interventions. Those targeted interventions, being performed under institutionalisation in form of coaching and tutoring, effectively contribute to improving the quality of care in resource poor settings.
Neutrophils interact with cholangiocytes to cause cholestatic changes in alcoholic hepatitis
Authors: Takeuchi Masahiro , Vidigal Paula T , Guerra Mateus T , Hundt Melanie A , Robert Marie E , Olave-Martinez Maria , Aoki Satoshi , Khamphaya Tanaporn , Kersten Remco , Kruglov Emma , de la Rosa Rodriguez Randolph , Banales Jesus M , Nathanson Michael H , Weerachayaphorn Jittima
Published: November 2020

Background & objectives

Alcoholic hepatitis (AH) is a common but life-threatening disease with limited treatment options. It is thought to result from hepatocellular damage, but the presence of cholestasis worsens prognosis, so we examined whether bile ducts participate in the pathogenesis of this disease.

Design

Cholangiocytes derived from human bile ducts were co-cultured with neutrophils from patients with AH or controls. Loss of type 3 inositol 1,4,5-trisphosphate receptor (ITPR3), an apical intracellular calcium channel necessary for cholangiocyte secretion, was used to reflect cholestatic changes. Neutrophils in contact with bile ducts were quantified in liver biopsies from patients with AH and controls and correlated with clinical and pathological findings.

Results

Liver biopsies from patients with AH revealed neutrophils in contact with bile ducts, which correlated with biochemical and histological parameters of cholestasis. Cholangiocytes co-cultured with neutrophils lost ITPR3, and neutrophils from patients with AH were more potent than control neutrophils. Biochemical and histological findings were recapitulated in an AH animal model. Loss of ITPR3 was attenuated by neutrophils in which surface membrane proteins were removed. RNA-seq analysis implicated integrin β1 (ITGB1) in neutrophil-cholangiocyte interactions and interference with ITGB1 on cholangiocytes blocked the ability of neutrophils to reduce cholangiocyte ITPR3 expression. Cell adhesion molecules on neutrophils interacted with ITGB1 to trigger RAC1-induced JNK activation, causing a c-Jun-mediated decrease in ITPR3 in cholangiocytes.

Conclusions

Neutrophils bind to ITGB1 on cholangiocytes to contribute to cholestasis in AH. This previously unrecognised role for cholangiocytes in this disease alters our understanding of its pathogenesis and identifies new therapeutic targets.
Integrated immunological analysis of a successful conversion of locally advanced hepatocellular carcinoma to resectability with neoadjuvant therapy
Authors: Ho Won Jin , Sharma Gaurav , Zhu Qingfeng , Stein-O'Brien Genevieve , Durham Jennifer , Anders Robert , Popovic Aleksandra , Mo Guanglan , Kamel Ihab , Weiss Matthew , Jaffee Elizabeth , Fertig Elana J , Yarchoan Mark
Published: November 2020

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide with a minority of patients being diagnosed early enough for curative-intent interventions. We report the first use of preoperative cabozantinib plus nivolumab to successfully downstage what presented as unresectable HCC as part of an ongoing phase 1b study. Preoperative treatment with cabozantinib and nivolumab led to >99% reduction in alpha-fetoprotein, −37.3% radiographic reduction by RECIST 1.1 and a near complete pathologic response (80% to 100% necrosis). An integrated immunological analysis was performed on the post-treatment surgical tumor sample and matched pre-treatment and post-treatment peripheral blood samples with high-dimensional imaging and cytometry techniques. Bayesian non-negative matrix factorization (CoGAPS, Coordinated Gene Activity in Pattern Sets) and self-organizing map (FlowSOM) algorithms were used to distinguish changes in functional markers across cellular neighborhoods in the single cell data sets. Brisk immunological infiltration into the tumor microenvironment was observed in non-random, organized cellular neighborhoods. Systemically, combination therapy led to marked promotion of effector cytotoxic T cells and effector memory helper T cells. Natural killer cells also increased with therapy. The patient remains without disease recurrence and with a normal alpha-fetoprotein approximately 2 years from presentation. Our study provides proof-of-concept that borderline resectable or locally advanced HCC warrants consideration of downstaging with effective neoadjuvant systemic therapy for subsequent curative resection.
Eftilagimod alpha, a soluble lymphocyte activation gene-3 (LAG-3) protein plus pembrolizumab in patients with metastatic melanoma
Authors: Atkinson Victoria , Khattak Adnan , Haydon Andrew , Eastgate Melissa , Roy Amitesh , Prithviraj Prashanth , Mueller Christian , Brignone Chrystelle , Triebel Frederic
Published: November 2020

Background

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, in combination with the programmed cell death-1 (PD-1) antagonist pembrolizumab.

Methods

The study was divided into two parts; parts A and B, where part A was the dose escalation part and part B was an extension part of the study. Patients with metastatic melanoma were treated with efti plus the standard dose of pembrolizumab. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect efti antibody formation and determine long-lived CD8 T cell responses and associated pharmacodynamic parameters.

Results

Twenty-four patients with melanoma received pembrolizumab and bi-weekly subcutaneous (s.c.) injections of efti at doses 1 mg, 6 mg or 30 mg/injection for up to 6 months (part A) or 30 mg/injection for up 12 months (part B). No dose-limiting toxicities were reported and the main adverse event for efti was injection site reactions. Sustained systemic exposure to the product was obtained in all patients following s.c. injections of 30 mg dose. Treatment induced an increase in activated CD8 and CD4 T cell counts, and in some of the soluble biomarkers, particularly interferon (IFN)-γ, a Th1 signature cytokine. An overall response rate (ORR) of 33% was observed in patients partly with pembrolizumab-refractory of part A and ORR of 50% was observed in patients with PD-1 naïve of part B.

Conclusions

Efti was well tolerated in combination with pembrolizumab with encouraging antitumor activity. This warrants further clinical studies of this new combination therapy combining an antigen-presenting cell activator with an immune checkpoint inhibitor.
Screening of CNVs using NGS data improves mutation detection yield and decreases costs in genetic testing for hereditary cancer
Authors: Moreno-Cabrera José Marcos , del Valle Jesús , Feliubadaló Lidia , Pineda Marta , González Sara , Campos Olga , Cuesta Raquel , Brunet Joan , Serra Eduard , Capellà Gabriel , Gel Bernat , Lázaro Conxi
Published: November 2020

Introduction

Germline CNVs are important contributors to hereditary cancer. In genetic diagnostics, multiplex ligation-dependent probe amplification (MLPA) is commonly used to identify them. However, MLPA is time-consuming and expensive if applied to many genes, hence many routine laboratories test only a subset of genes of interest.

Methods and results

We evaluated a next-generation sequencing (NGS)-based CNV detection tool (DECoN) as first-tier screening to decrease costs and turnaround time and expand CNV analysis to all genes of clinical interest in our diagnostics routine. We used DECoN in a retrospective cohort of 1860 patients where a limited number of genes were previously analysed by MLPA, and in a prospective cohort of 2041 patients, without MLPA analysis. In the retrospective cohort, 6 new CNVs were identified and confirmed by MLPA. In the prospective cohort, 19 CNVs were identified and confirmed by MLPA, 8 of these would have been lost in our previous MLPA-restricted detection strategy. Also, the number of genes tested by MLPA across all samples decreased by 93.0% in the prospective cohort.

Conclusion

Including an in silico germline NGS CNV detection tool improved our genetic diagnostics strategy in hereditary cancer, both increasing the number of CNVs detected and reducing turnaround time and costs.
New perspectives on brain death
Authors: Kirschen Matthew P. , Lewis Ariane , Rubin Michael , Kurtz Pedro , Greer David M
Published: November 2020

Brain death, or death by neurological criteria (BD/DNC), has been accepted conceptually, medically and legally for decades. Nevertheless, some areas remain controversial or understudied, pointing to a need for focused research to advance the field. Multiple recent contributions have increased our understanding of BD/DNC, solidified our practice and provided guidance where previously lacking. There have also been important developments on a global scale, including in low-to-middle income countries such as in South America. Although variability in protocols and practice still exists, new efforts are underway to reduce inconsistencies and better train practitioners in accurate and sound BD/DNC determination. Various legal challenges have required formal responses from national societies, and the American Academy of Neurology has filled this void with much needed guidance. Questions remain regarding concepts such as ‘whole brain’ versus ‘brainstem’ death, and the intersection of BD/DNC and rubrics of medical futility. These concepts are the subject of this review.
Risk of chronic opioid use after simultaneous versus staged bilateral knee arthroplasty
Authors: Wilson Lauren , Fiasconaro Megan , Liu Jiabin , Poeran Jashvant , Poultsides Lazaros , Memtsoudis Stavros G
Published: November 2020

Background

Several studies have identified excess risk associated with undergoing simultaneous (compared with unilateral or staged) bilateral total knee arthroplasty (BTKA). However, few have addressed subsequent chronic opioid use. Given the substantial morbidity and mortality associated with prolonged opioid use, we evaluated the incidence of postoperative chronic opioid use following simultaneous versus staged BTKA, based on the different timing strategies of staged procedures.

Methods

In this retrospective cohort study, patients who underwent BTKA procedures (2012–2016; Truven Health MarketScan; n=14 407) were classified as having undergone simultaneous or staged BTKA (<3 months, 3–6 months or 6–12 months apart). Outcomes were postoperative chronic opioid use and oral morphine equivalents prescribed on discharge. Multivariable regression models measured associations between type/timing of BTKA and outcomes. ORs and 95% CIs were reported.

Results

Unadjusted frequency of chronic opioid use did not differ between groups, (Simultaneous: 11.3%, staged <3 months: 10.7%, staged 3–6 months: 11.7%, staged >6 months: 10.2%; p=0.247). In an adjusted model, there was no significant difference in the odds of becoming chronic opioid users between staged and simultaneous BTKA (staged <3 months OR 1.03, 95% CI 0.88 to 1.21/staged 3–6 months OR 0.94, 95% CI 0.79 to 1.12/staged >6 months OR 0.96, 95% CI 0.82 to 1.13; p=0.755). Patients undergoing staged BTKAs <6 months apart (compared with simultaneous) were prescribed slightly greater oral morphine equivalents on hospital discharge (staged <3 months 6% increase, 95% CI 3% to 10%; staged 3–6 months 4%, 95% CI 1% to 8%; p=0.002).

Conclusion

Although patients undergoing staged BTKA <6 months apart were prescribed greater quantities of opioids on discharge, there was no significant difference in the odds of postoperative chronic opioid use compared with simultaneous BTKA. The timing of BTKA procedures does not appear to influence the likelihood of postoperative chronic opioid dependence.
Characterisation of the novel clinical isolate X-4 containing a new
tp0548
sequence-type
Authors: Liu Dan , Tong Man-Li , Liu Li-Li , Lin Li-Rong , Zhang Hui-Lin , Yang Tian-Ci
Published: November 2020

Objectives

A novel
tp0548
sequence-type was identified in one clinical isolate (X-4) from a patient diagnosed with primary syphilis in Xiamen, China. To precisely define and characterise a new clinical isolate, we performed further genome-scale molecular analysis.

Methods

The pooled segment genome sequencing method followed by Illumina sequencing was performed.

Results

This novel sequence-type contained a unique nucleotide substitution ‘T’ at position 167 and belonged to the SS14-like clade of TPA strains, as determined by phylogenetic analysis. Multi-locus sequence analysis of nine chromosomal loci demonstrated that the X-4 isolate was clustered within a monophyletic group of TPA strains. Whole-genome phylogenetic analysis subsequently corroborated the TPA strain classification of the X-4 isolate and revealed that the isolate was closely related to the SS14 strain, with 42 single-nucleotide variations and 12 insertions/deletions. In addition, high intrastrain heterogeneity in the length of the poly G/C tracts was found in the TPAChi_0347 locus, which might indicate that this gene of the X-4 isolate is likely involved in phase variation events. The length heterogeneity of the poly A/T tracts was lower than the genetic variability of the poly G/C tracts, and all the observed intrastrain variations fell within coding regions.

Conclusion

The novel
tp0548
sequence-type was determined to belong to a new TPA isolate, X-4. The identification of variable length in homopolymetic tracts (G/C and A/T) could provide a snapshot of the genes that potentially involved in genotype–phenotype variations. These findings provide an unequivocal characterisation for better understanding the molecular variation of this emerging isolate.
Effects of nutrition supplementation and physical exercise on muscle mass, muscle strength and fat mass among sarcopenic elderly: a randomized controlled trial
Authors: Li Zhuo , Cui Min , Yu Kang , Zhang Xiao-wei , Li Chun-wei , Nie Xiao-dong , Wang Fang
Published: November 2020

This study aimed to determine the impact of nutrition supplementation (whey protein, fish oil, vitamin D) and physical exercise (resistance and aerobic exercise) on muscle mass, muscle strength and fat mass among sarcopenic elderly. Participants (N = 241) with sarcopenia (aged ≥ 60 y) enrolled from 2 centers were randomized into groups undergoing nutrition supplementation (Nutr), physical exercise (Ex), nutrition combined with exercise (Nutr+Ex), or routine consultation for 12 weeks. Muscle-related indicators, grip strength as well as fat-related indicators were compared pre- and post-intervention. The per-protocol analysis showed that all indicators were significantly different between groups (P < 0.001). Further pairwise comparisons showed that compared with controls, appendicular muscle mass and grip strength were significantly higher in Nutr (P < 0.001, 95% CI: 0.578, 1.475; P < 0.001, 95% CI: 3.614∼9.118), Ex (P = 0.010, 95% CI: 0.157, 1.153; P < 0.001, 95% CI: 2.904, 8.732), and Nutr+Ex (P < 0.001, 95% CI: 0.564, 1.471; P < 0.001, 95% CI: 3.441, 8.907) groups, while fat mass was significantly lower in the Nutr (P < 0.001, 95% CI: −4.676, −2.358) and Nutr+Ex (P < 0.001, 95% CI: −4.717,−1.790) groups. When compared with Ex, fat mass decreased significantly in the Nutr (P = 0.001, 95% CI: −4.856,−1.359) and Nutr+Ex (P = 0.005, 95% CI: −4.810, −0.878) groups. The findings indicate that nutrition supplementation and physical exercise could improve muscle mass, strength and fat mass among sarcopenic elderly. Nutrition supplementation might be better at decreasing fat mass in this population. ClinicalTrials.gov registration no.: NCT02873676.

Novelty: Nutrition supplementation improved muscle mass, strength and fat mass among sarcopenic elderly. Aerobic and resistance exercise improved muscle mass and strength in sarcopenic elderly. Combined nutrition supplementation and physical exercise improved muscle mass, strength and fat mass among sarcopenic elderly.
Channel Selection for Optimal EEG Measurement in Motor Imagery-Based Brain-Computer Interfaces
Authors: Arpaia Pasquale , Donnarumma Francesco , Esposito Antonio , Parvis Marco
Published: November 2020

A method for selecting electroencephalographic (EEG) signals in motor imagery-based brain-computer interfaces (MI-BCI) is proposed for enhancing the online interoperability and portability of BCI systems, as well as user comfort. The attempt is also to reduce variability and noise of MI-BCI, which could be affected by a large number of EEG channels. The relation between selected channels and MI-BCI performance is therefore analyzed. The proposed method is able to select acquisition channels common to all subjects, while achieving a performance compatible with the use of all the channels. Results are reported with reference to a standard benchmark dataset, the BCI competition IV dataset 2a. They prove that a performance compatible with the best state-of-the-art approaches can be achieved, while adopting a significantly smaller number of channels, both in two and in four tasks classification. In particular, classification accuracy is about 77–83% in binary classification with down to 6 EEG channels, and above 60% for the four-classes case when 10 channels are employed. This gives a contribution in optimizing the EEG measurement while developing non-invasive and wearable MI-based brain-computer interfaces.
COMBINING FRACTIONAL DERIVATIVES TO PREDICT BLOOD ALCOHOL CONCENTRATION
Authors: ROSALES J. J. , GODÍNEZ F. A. , MARTÍNEZ L. , CHÁVEZ O.
Published: November 2020

This paper focuses on the analysis of the system of equations that describes the blood alcohol concentration (BAC) involving two linked absorption processes, first in the stomach and then in the blood. Each process was modeled with conformable and Caputo derivatives; thus, in this way, the BAC was simulated via four different derivative combinations. In the analysis, the dimensional homogeneity of the equations was maintained. The efficiency (with respect to the classical integer order model) of the obtained solutions was estimated by fitting them to experimental data. The Caputo-conformable combination leads to the highest efficiency followed by the conformable-conformable combination.
On maps which preserve semipositivity and quantifier elimination theory for real numbers
Authors: Pastuszak Grzegorz , Skowyrski Adam , Jamiołkowski Andrzej
Published: November 2020

Assume that [Formula: see text] is a superoperator which preserves hermiticity. We give an algorithm determining whether [Formula: see text] preserves semipositivity (we call [Formula: see text] positive in this case). Our approach to the problem has a model-theoretic nature, namely, we apply techniques of quantifier elimination theory for real numbers. An approach based on these techniques seems to be the only one that allows to decide whether an arbitrary hermiticity-preserving [Formula: see text] is positive. Before we go to detailed analysis of the problem, we argue that quantifier elimination for real numbers (and also for complex numbers) can play a significant role in quantum information theory and other areas as well.
Comparative of Influence of Noise on Frequency Estimation Provided by Three Points Interpolated Discrete Fourier Transform
Authors: Shao Xirui , Wen He
Published: November 2020

The paper compares the accuracy of two different three points Interpolated Discrete Fourier Transform (M3IpDFT and C3IpDFT) algorithms in the presence of Gaussian white noise. The above two algorithms use the magnitude and the complex value of spectrum line for interpolation, respectively. The theoretical expressions of variances of frequency estimation due to noise are derived and then verified by simulations. From the theoretical and simulation results, the variances of frequency estimation are inversely proportional to the signal-to-noise ratio (SNR) and the length of DFT. Simulation shows that the C3IpDFT outperforms the M3IpDFT.