bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between parental socioeconomic position and health-seeking behaviour for diarrhoea and acute respiratory infection among under-5 children in Myanmar: a cross-sectional study
Authors: Lwin Kaung Suu , Nomura Shuhei , Yoneoka Daisuke , Ueda Peter , Abe Sarah Krull , Shibuya Kenji
Published: March 2020

Objectives

To examine the associations of parental social and economic position with health-seeking behaviour for diarrhoea and acute respiratory infection (ARI) among under-5 children in Myanmar and explore potential underlying mechanisms.

Design

A cross-sectional study.

Setting

A secondary dataset from the nationwide 2015–2016 Myanmar Demographic and Health Survey (MDHS).

Participants

All under-5 children in the sampled households with reported symptoms of diarrhoea and ARI during the 2-week period preceding the MDHS survey interview.

Primary and secondary outcome measures

Four parental health-seeking behaviours: ‘seeking treatment’, ‘formal health provider’, ‘public provider’ and ‘private provider’ were considered. Social and economic positions were determined by confirmatory factor analysis. Multilevel logistic regressions were employed to examine the associations of social and economic positions with health-seeking behaviours for diarrhoea and ARI. Mediation analyses were conducted to explore potential underlying mechanisms in these associations.

Results

Of the 4099 under-5 children from the sampled households in MDHS, 427 (10.4%) with diarrhoea and 131 (3.2%) with ARI were considered for the analyses. For diarrhoea, social position was positively associated with seeking treatment and private provider use (adjusted OR: 1.60 (95% CIs: 1.07 to 2.38) and 1.83 (1.00 to 3.34), respectively). Economic position was positively associated with private provider use for diarrhoea (1.57 (1.07 to 2.30)). Negative associations were observed between social and economic positions with public provider use for diarrhoea (0.55 (0.30 to 0.99) and 0.64 (0.43 to 0.94), respectively). Social position had more influence than economic position on parental health-seeking behaviour for children with diarrhoea. No evidence for a significant association of social and economic position with health-seeking for ARI was observed.

Conclusions

Social and economic positions were possible determinants of health-seeking behaviour for diarrhoea among children; and social position had more influence than economic position. The results of this study may contribute to improve relevant interventions for diarrhoea and ARI among children in Myanmar.
Use of intravenous magnesium sulfate among patients with acute myocardial infarction in China from 2001 to 2015: China PEACE—Retrospective AMI Study
Authors: Wang Xianqiang , Du Xue , Yang Hao , Bucholz Emily , Downing Nicholas , Spertus John A , Masoudi Fredrick A , Li Jing , Guan Wenchi , Gao Yan , Hu Shuang , Bai Xueke , Krumholz Harlan M , Li Xi
Published: March 2020

Objective

In 2001, Chinese guidelines for the care of acute myocardial infarction (AMI) included a new recommendation against the routine use of magnesium. We studied temporal trends and institutional variation in the use of intravenous magnesium sulfate in nationally representative samples of individuals hospitalised with AMI in China between 2001 and 2015.

Methods

In an observational study (China PEACE—Retrospective Study) of AMI care, we used a two-stage, random sampling strategy to create a nationally representative sample of 28 208 patients with AMI at 162 Chinese hospitals in 2001, 2006, 2011 and 2015. The main outcome is use of intravenous magnesium sulfate over time.

Results

We identified 24 418 patients admitted for AMI, without hypokalaemia, in the four study years. Over time, there was a significant initial decrease in intravenous magnesium sulfate use, from 32.1% in 2001 to 17.1% in 2015 (p<0.001 for trend). The decline was greater in the Eastern (from 33.3% to 16.5%) and Western (from 34.8% to 17.2%) regions, as compared with the Central region (from 25.9% to 18.1%), with little difference between rural and urban areas. The proportion of hospitals using intravenous magnesium sulfate did not change over time (from 81.3% to 77.9%). The median ORs, representing hospital-level variation, were 6.03 in 2001, 3.86 in 2006, 4.26 in 2011 and 4.72 in 2015. Intravenous magnesium sulfate use was associated with cardiac arrest at admission and receipt of reperfusion therapy, but no hospital-specific characteristics.

Conclusions

Despite recommendations against its use, intravenous magnesium sulfate is used in about one in six patients with AMI in China. Our findings highlight the need for more efficient mechanisms to stop using ineffective therapies to improve patients’ outcomes and reduce medical waste.

Trial registration number

ClinicalTrials.gov (NCT01624883)
Hilly environment and physical activity among community-dwelling older adults in Japan: a cross-sectional study
Authors: Abe Takafumi , Okuyama Kenta , Hamano Tsuyoshi , Takeda Miwako , Isomura Minoru , Nabika Toru
Published: March 2020

Objectives

We investigated whether a moderate-to-vigorous physical activity (MVPA) level and walking time were associated with a hilly environment in rural Japanese older adults.

Design

Cross-sectional study.

Setting

Unnan city, Ohnan and Okinoshima towns in Shimane, Japan.

Participants

Data were collected from 1115 adults from the Shimane CoHRE study, who were aged 60 years and older and living in rural Japan in 2012.

Measures

We measured the total time spent on MVPA and walking using a Japanese short version of the International Physical Activity Questionnaire. The land slope in 400 or 800 m network buffers was assessed using the geographic information system. A multivariable Poisson regression model examined the prevalence ratios (PR) and 95% CIs of walking time or MVPA levels meeting the WHO guideline (>150 min/week) in the land slope categories (low, middle and high), adjusted for confounders.

Results

Engaging in the recommended level of MVPA was significantly associated with middle land slope (PR=1.07; p=0.03) and high land slope (PR=1.06; p=0.07) compared with low land slope in the 400 m network buffer, as well as with middle land slope (PR=1.02; p=0.48) and high land slope (PR=1.04; p=0.25) compared with the low land slope in the 800 m network buffer. Walking time was significantly associated with middle land slope (PR=1.13; p=0.04) and high land slope (PR=1.17; p=0.01) compared with low land slope in the 400 m network buffer, and with middle land slope (PR=1.09; p=0.16) and high land slope (PR=1.17; p<0.01) compared with low land slope in the 800 m network buffer. The sensitivity analysis found only a positive association between walking time and land slope in the 400 and 800 m network buffers.

Conclusions

This study showed that a hilly environment was positively associated with walking time among older adults living in rural Japan.
Annual rates of and factors influencing inpatient and outpatient transient ischaemic attacks in Chinese population: a nationally representative cross-sectional survey
Authors: Jiang Bin , Sun Dongling , Sun Haixin , Ru Xiaojuan , Liu Hongmei , Ge Siqi , Wang Linhong , Wang Limin , Wang Wenzhi
Published: March 2020

Objectives

To investigate the rates and influencing factors of transient ischaemic attack (TIA) inpatient admissions and outpatient visits in China.

Setting

A door-to-door survey of 178 059 families from 155 urban and rural areas in 31 provinces in China, 2013.

Participants

Total 596 536 people were assessed in the annual rate analysis, and 829 TIA patients were assessed in the influencing factor analysis.

Main outcome measures

The weighted annual rates of TIA inpatient admissions and outpatient visits and the factors influencing inpatient admissions and outpatient visits for TIA patients.

Results

The weighted annual inpatient admission rate per TIA patient was 25.8 (95% CI: 18.4 to 36.2) per 100 000 in the population, whereas the weighted annual inpatient admission rate for patients with TIAs was 32.5 (95% CI: 23.3 to 38.9) per 100 000 in the population. The weighted annual outpatient visit rate per TIA patient was 34.4 (95% CI: 26.2 to 45.1) per 100 000 in the population, whereas the weighted annual outpatient visit rate for patients with TIAs was 149.6 (95% CI: 127.0 to 165.5) per 100 000. The inpatient rate was higher for men than for women (OR: 2.24; 95% CI: 1.40 to 3.59; p=0.001), for TIA patients with stroke than for patients with isolated TIAs (2.93; 2.01 to 4.25; p<0.001), for TIA patients with hypertension than for TIA patients without hypertension (2.60; 1.65 to 4.11; p<0.001). The outpatient rate was higher for TIA patients with stroke than for patients with isolated TIAs (1.88; 1.33 to 2.64; p<0.001), for TIA patients with dyslipidaemia than for TIA patients without dyslipidaemia (1.92; 1.30 to 2.83; p=0.001).

Conclusions

The annual rates of TIA inpatient admissions and outpatient visits in population are low, probably due to the lack of access to inpatient and outpatient services experienced by the majority of TIA patients in the population, and individuals’ socio-demographic characteristics, disease histories and stroke prognosis may be associated with inpatient and outpatient TIAs.
Exploration of stress management interventions to address psychological stress in stroke survivors: a protocol for a scoping review
Authors: Hinwood Madeleine , Ilicic Marina , Gyawali Prajwal , Kluge Murielle Gabriela , Coupland Kirsten , Smith Angela , Nilsson Michael , Walker Frederick Rohan
Published: March 2020

Introduction

Several studies have shown that stroke survivors report experiencing high and unremitting levels of stress, which can negatively affect brain repair processes and psychological outcomes and thereby compromise recovery. However, it is presently unclear which interventions have been trialled to manage stress in stroke survivors and whether they translate to clinically relevant outcomes. The aim of this scoping review will be to examine stress management interventions in stroke survivors in order to map the types of interventions trialled, commonly reported stress outcome measures and whether a reduction in stress contributes to reductions in relevant clinical outcomes.

Methods and analysis

The methodological framework described in Arksey and O’Malley will be applied to this review. A draft search strategy was developed in collaboration with an experienced senior health research librarian. A systematic search of Medline, Embase, CINAHL, Cochrane library, PsycInfo and Clinicaltrials.gov as well as hand searching of reference lists and reviews will identify relevant studies for inclusion. To be eligible for inclusion, studies must report on the outcomes of an intervention targeting stress management and resilience in stroke survivors. Study selection and critical appraisal of selected studies will be carried out independently by two authors, with discrepancies resolved by consensus. Data will be charted using a standard extraction form. Results will be tabulated and narratively summarised to highlight findings relevant to our research questions and to inform recommendations for future research.

Ethics and dissemination

This study does not require ethics approval. This scoping review will provide a synthesis of evidence for stress management interventions in stroke survivors. It will identify and clarify the gaps in stress research specific to stroke pathologies and highlight promising interventions for future research. Findings will be relevant to researchers and healthcare workers and will be disseminated via publications in peer-reviewed journals and presented at conferences.
Valuing hospital investments in nursing: multistate matched-cohort study of surgical patients
Authors: Lasater Karen B , McHugh Matthew , Rosenbaum Paul R , Aiken Linda H , Smith Herbert , Reiter Joseph G , Niknam Bijan A , Hill Alexander S , Hochman Lauren L , Jain Siddharth , Silber Jeffrey H
Published: March 2020

Background

There are known clinical benefits associated with investments in nursing. Less is known about their value.

Aims

To compare surgical patient outcomes and costs in hospitals with better versus worse nursing resources and to determine if value differs across these hospitals for patients with different mortality risks.

Methods

Retrospective matched-cohort design of patient outcomes at hospitals with better versus worse nursing resources, defined by patient-to-nurse ratios, skill mix, proportions of bachelors-degree nurses and nurse work environments. The sample included 62 715 pairs of surgical patients in 76 better nursing resourced hospitals and 230 worse nursing resourced hospitals from 2013 to 2015. Patients were exactly matched on principal procedures and their hospital’s size category, teaching and technology status, and were closely matched on comorbidities and other risk factors.

Results

Patients in hospitals with better nursing resources had lower 30-day mortality: 2.7% vs 3.1% (p<0.001), lower failure-to-rescue: 5.4% vs 6.2% (p<0.001), lower readmissions: 12.6% vs 13.5% (p<0.001), shorter lengths of stay: 4.70 days vs 4.76 days (p<0.001), more intensive care unit admissions: 17.2% vs 15.4% (p<0.001) and marginally higher nurse-adjusted costs (which account for the costs of better nursing resources): $20 096 vs $19 358 (p<0.001), as compared with patients in worse nursing resourced hospitals. The nurse-adjusted cost associated with a 1% improvement in mortality at better nursing hospitals was $2035. Patients with the highest mortality risk realised the greatest value from nursing resources.

Conclusion

Hospitals with better nursing resources provided better clinical outcomes for surgical patients at a small additional cost. Generally, the sicker the patient, the greater the value at better nursing resourced hospitals.
Challenges of opioid deprescribing and factors to be considered in the development of opioid deprescribing guidelines: a qualitative analysis
Authors: Langford Aili V , Gnjidic Danijela , Lin Chung-Wei Christine , Bero Lisa , Penm Jonathan , Blyth Fiona M , Schneider Carl R
Published: March 2020

Background

Chronic prescription opioid use is a major international public health issue associated with significant harms, including increased risk of hospitalisation, morbidity and death. Guidance for healthcare professionals on when and how to deprescribe or reduce opioids is required. A key step for guideline development for deprescribing pharmacotherapy is to understand the perspectives of stakeholders. The aim of this study was to explore the perspectives of healthcare professional stakeholders on the challenges associated with opioid deprescribing and factors to be considered in the development of opioid deprescribing guidelines.

Methods

A qualitative study was undertaken with a purposive sample of healthcare professionals including prescribers, pharmacists and nurses. An initial cohort of participants was identified at the 2018 Australian Deprescribing Network annual meeting and two focus groups were conducted (n=20). Individual interviews were conducted with a further 11 healthcare professionals. Focus groups and interviews were audio-recorded and transcribed verbatim. Data underwent inductive thematic analysis using a phenomenological perspective.

Results

Healthcare professionals viewed opioid deprescribing as a challenge and identified several key barriers to deprescribing in clinical practice. Medication, patient, prescriber and health system level challenges were identified. Participants requested evidence-based guidance on the withdrawal of opioid therapies and suggested that prospective opioid deprescribing guidelines require a multitarget, multimodal intervention strategy that addresses patient psychosocial factors and incorporates behavioural change techniques.

Conclusion

Opioid deprescribing was perceived as a complex and challenging practice with continued prescribing the default behaviour. Evidence-based opioid deprescribing guidelines may be a valuable resource for clinicians to support clinical decision-making and reduce suboptimal opioid use.
Hospice advice and rapid response service for ambulance clinicians
Authors: Dent Tom , Tipping Inderia , Anderson Racquel , Daniels Charles
Published: March 2020

Objective

Patients in the last year of life experience medical emergencies which may lead to an emergency attendance by ambulance clinicians and some patients having a transfer to hospital even when this is unwanted by patients, carers or professionals. Here we report the patient characteristics and outcomes of a 24-hour hospice nursing telephone advice service to support an ambulance service.

Method

An evaluation of the outcomes of ambulance calls to a nursing telephone advice service for people living in northwest London, UK, attended at home during a 6-month period by the London Ambulance Service, whose clinicians then sought advice from the hospice’s 24 hours’ telephone line.

Results

Forty-five attendances of 44 acutely ill people with palliative care needs resulted in a telephone call. Thirteen patients (30%) were male and the median age was over 80 years. Thirty-two attendances (71%) were managed without a transfer to hospital, with telephone advice from the hospice and in some cases arrangements for another clinician to visit. Seven attendances (16%) resulted in a transfer to hospital, of which at least five led to an admission. Six attendances (13%) resulted in a notification of the patient’s death.

Conclusions

This preliminary study shows the feasibility, outcomes and acceptability of telephone advice to support ambulance clinicians attending patients with palliative care needs. The service was associated with low rates of subsequent transfer to hospital. Further controlled research is needed to assess the clinical and cost-effectiveness of the service.
Early specialised palliative care: interventions, symptoms, problems
Authors: Skjoedt Nete , Johnsen Anna Thit , Sjøgren Per , Neergaard Mette Asbjoern , Damkier Anette , Gluud Christian , Lindschou Jane , Fayers Peter , Higginson Irene J , Strömgren Annette S , Groenvold Mogens
Published: March 2020

Background

Few studies have investigated the content of interventions provided in early specialised palliative care (SPC).

Objectives

To characterise the content of interventions delivered in early SPC in the Danish Palliative Care Trial (DanPaCT), a multicentre trial with six participating sites.

Methods

A retrospective qualitative and quantitative study coding all new interventions initiated by the palliative teams and documented in the medical records during the 8-week study period of DanPaCT. Interventions were categorised according to (a) symptom/problem prompting the intervention, (b) type of intervention and (c) professional(s) providing the intervention.

Results

In total, 145 patients were randomised to the SPC teams. According to the medical records, patients received a median of 3.5 (range 0–22) new interventions in the 8-week intervention-period from the palliative teams. For 24 (18%) of the patients there was no documented interventions in the medical records. The most frequent symptom/problems treated were pain, (100 interventions; 20% of interventions given) and impaired physical function (62; 13% of interventions given). The most frequent type of intervention was pharmacological (232; 42% of interventions given).

Conclusions

This is one of the first studies to meticulously investigate the content of interventions documented in the medical records for patients receiving early SPC. Diverse symptoms were treated with many different interventions. However, a relatively low number of interventions were documented. This may explain the lack of effect in DanPaCT but also questions whether all interventions were adequately documented

Trial registration number

NCT01348048
British Society of Gastroenterology (BSG)-led multisociety consensus care bundle for the early clinical management of acute upper gastrointestinal bleeding
Authors: Siau Keith , Hearnshaw Sarah , Stanley Adrian J , Estcourt Lise , Rasheed Ashraf , Walden Andrew , Thoufeeq Mo , Donnelly Mhairi , Drummond Russell , Veitch Andrew M , Ishaq Sauid , Morris Allan John
Published: March 2020

Medical care bundles improve standards of care and patient outcomes. Acute upper gastrointestinal bleeding (AUGIB) is a common medical emergency which has been consistently associated with suboptimal care. We aimed to develop a multisociety care bundle centred on the early management of AUGIB.

Commissioned by the British Society of Gastroenterology (BSG), a UK multisociety task force was assembled to produce an evidence-based and consensus-based care bundle detailing key interventions to be performed within 24 hours of presentation with AUGIB. A modified Delphi process was conducted with stakeholder representation from BSG, Association of Upper Gastrointestinal Surgeons, Society for Acute Medicine and the National Blood Transfusion Service of the UK. A formal literature search was conducted and international AUGIB guidelines reviewed. Evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation tool and statements were formulated and subjected to anonymous electronic voting to achieve consensus. Accepted statements were eligible for incorporation into the final bundle after a separate round of voting. The final version of the care bundle was reviewed by the BSG Clinical Services and Standards Committee and approved by all stakeholder groups.

Consensus was reached on 19 statements; these culminated in 14 corresponding care bundle items, contained within 6 management domains: Recognition, Resuscitation, Risk assessment, Rx (Treatment), Refer and Review.

A multisociety care bundle for AUGIB has been developed to facilitate timely delivery of evidence-based interventions and drive quality improvement and patient outcomes in AUGIB.
Complete response to anti-PD-L1 antibody in a metastatic bladder cancer associated with novel MSH4 mutation and microsatellite instability
Authors: Yang Yuanquan , Jain Rohit K , Glenn Sean T , Xu Bo , Singh Prashant K , Wei Lei , Hu Qiang , Long Mark , Hutson Nicholas , Wang Jianming , Battaglia Sebastiano , George Saby
Published: March 2020

Background

Microsatellite instability (MSI) occurs in 3% of urothelial carcinomas as a result of germline or somatic loss of function mutation in mismatch repair (MMR) proteins.1 Although MSH4 is a member of the DNA MMR mutS family, the association of MSH4 mutation with MSI has not been described. We report a complete responder to PD-L1 blockade who had MSH4 mutated metastatic bladder cancer with mixed histology and MSI. The genomics of urothelial, plasmacytoid and squamous histology was characterized individually through microdissection.

Case presentation

An 81-year-old man was diagnosed with metastatic urothelial carcinoma 8 months after a cystectomy for muscle invasive bladder cancer. His disease was primary refractory to first-line platinum-based chemotherapy but attained complete response to second-line atezolizumab. PCR-based assay revealed MSI high. The tumor mutational burden was elevated to 36.7 mut/Mb. However, immunohistochemistry of MLH1, MSH2, MSH6 and PMS2 was intact. Whole exome sequencing confirmed that the above mentioned four classic MMR genes were wild type but revealed a deleterious MSH4 L359I mutation with variant allele fraction of 30% and Polyphen2 score of 0.873. The association of MSH4 alterations and MSI-H was independently verified in two publicly available MSI-H colorectal cancer datasets.

Conclusions

The novel MSH4 L359I mutation is associated with MSI and high mutational burden leading to remarkable response to PD-L1 blockade. More studies are warranted to establish the causality relationship between MSH4 and MSI.
Immunosuppressant indulges EBV reactivation and related lymphoproliferative disease by inhibiting Vδ2+T cells activities after hematopoietic transplantation for blood malignancies
Authors: Liu Jiangying , Gao Haitao , Xu Lan-Ping , Mo Xiao-Dong , Liu Ruoyang , Liang Shuang , Wu Ning , Wang Ming , Wang Zhidong , Chang Ying-Jun , Wang Yu , Zhang Xiao-Hui , Huang Xiao-Jun
Published: March 2020

Background

Following the extensive use of immunosuppressive drugs in the clinic, immunosuppression-associated side effects have received increasing attention. Epstein-Barr virus (EBV) reactivation and related lymphoproliferative diseases (LPD) are the lethal complications observed after allogeneic hematopoietic cell transplantation (alloHCT). While studies generally suggest an association between immunosuppressants and EBV reactivation, the effects of specific immunosuppressive drugs and which T-cell subsets mediate these correlations are unclear. Vδ2+T cells are correlated with EBV reactivation after alloHCT. Researchers have not determined whether Vδ2+T-cell activities are affected by immunosuppressants and thereby facilitate EBV reactivation and related LPD.

Methods

A clinical cohort study of 170 patients with hematopoietic malignancies who received haploidentical hematopoietic cell transplantation (haploHCT) was performed to investigate whether the early cessation of mycophenolate mofetil (MMF) decreases EBV reactivation and related LPD and to determine whether this change is associated with the recovery of Vδ2+T cells after transplantation. The effects of MMF on the expansion and anti-EBV capacity of Vδ2+T cells were detected in vitro and in an immunodeficient mouse model.

Results

A reduction in the course of MMF significantly improved the recovery of Vδ2+T cells from 30 to 90 days after haploHCT (p=0.002, p=0.042 and p=0.035, respectively), accompanied by a significant decrease in EBV reactivation (from 26% to 13%, p=0.033) and EBV-LPD (from 10.6% to 2.4%, p=0.029). The day-30 Vδ2+T level remained an independent factor for EBV reactivation in patients with different MMF durations (p=0.007). In the in-vitro experiments, MMF inhibited Vδ2+T-cell expansion and its cytotoxicity on EBV-transformed malignant cells. Furthermore, the therapeutic and prophylactic effects of adoptively transferred human Vδ2+T cells were attenuated by the MMF treatment in immunodeficient mice with EBV-LPD.

Conclusions

These results elucidated a negative effect of immunosuppressants on the anti-EBV capacity of Vδ2+T cells. Strategies that appropriately relieve the immunosuppression may improve anti-EBV immunity by increasing the activity of Vδ2+T cells after alloHCT.
EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1
Authors: Park Dong Jun , Sung Pil Soo , Kim Jung-Hee , Lee Gil Won , Jang Jeong Won , Jung Eun Sun , Bae Si Hyun , Choi Jong Young , Yoon Seung Kew
Published: March 2020

Background

Natural killer (NK) cells can recognize and kill cancer cells directly, but their activity can be attenuated by various inhibitory molecules expressed on the surface. The expression of epithelial cell adhesion molecule (EpCAM), a potential marker for cancer stem cells (CSCs), is known to be strongly associated with poor clinical outcomes in hepatocellular carcinoma (HCC). NK cells targeting CSCs may be a promising strategy for anti-tumor therapy, but little is known about how they respond to EpCAMhighCSCs in HCC.

Methods

EpCAM expression was assessed by immunohistochemistry in 280 human HCC tissues obtained from curative surgery. To investigate the functional activity of NK cells against liver CSCs, EpCAMhighand EpCAMlowHuh-7 cells were sorted by flow cytometry. The functional role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is related to NK cells, was determined by in vitro co-culture of NK cells and hepatoma cells using Hepa1–6 mouse hepatoma cells, as well as in vivo experiments using C57/BL6 mice.

Results

The frequency of recurrence after curative surgery was higher in patients with positive EpCAM expression than in those with negative EpCAM expression. In subsequent analysis based on the anatomical location of EpCAM expression, patients with peritumoral EpCAM expression showed worse prognosis than those with pantumoral EpCAM expression. Co-culture experiments demonstrated that CEACAM1 was upregulated on the surface of EpCAMhighHCC cells, resulting in resistance to NK cell-mediated cytotoxicity. Inversely, silencing CEACAM1 restored cytotoxicity of NK cells against EpCAMhighHuh-7 cells. Moreover, neutralizing CEACAM1 on the NK cell surface enhanced killing of Huh-7 cells, suggesting that homophilic interaction of CEACAM1 is responsible for attenuated NK cell–mediated killing of CEACAM1highcells. In mouse experiments with Hepa1–6 cells, EpCAMhighHepa1–6 cells formed larger tumors and showed higher CEACAM1 expression after NK cell depletion. NK-mediated cytotoxicity was enhanced after blocking CEACAM1 expression using the anti-CEACAM1 antibody, thereby facilitating tumor regression. Moreover, CEACAM1 expression positively correlated with EpCAM expression in human HCC tissues, and serum CEACAM1 levels were also significantly higher in patients with EpCAM+HCC.

Conclusion

Our data demonstrated that EpCAMhighliver CSCs resist NK cell–mediated cytotoxicity by upregulation of CEACAM1 expression.
Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients
Authors: Amaral Teresa , Kiecker Felix , Schaefer Sarah , Stege Henner , Kaehler Katharina , Terheyden Patrick , Gesierich Anja , Gutzmer Ralf , Haferkamp Sebastian , Uttikal Jochen , Berking Carola , Rafei-Shamsabadi David , Reinhardt Lydia , Meier Friedegund , Karoglan Ante , Posch Christian , Gambichler Thilo , Pfoehler Claudia , Thoms Kai , Tietze Julia , Debus Dirk , Herbst Rudolf , Emmert Steffen , Loquai Carmen , Hassel Jessica C , Meiss Frank , Tueting Thomas , Heinrich Vanessa , Eigentler Thomas , Garbe Claus , Zimmer Lisa
Published: March 2020

Background

Nivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM.

Methods

Patients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS.

Results

Three hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab. The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively. We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status. In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996). Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119).

Conclusion

Immunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.
The Cohen problem of informed consent
Authors: Simkulet William
Published: March 2020

To avoid potential abuse and respect patient autonomy, physicians have a moral obligation to obtain informed consent before performing any significant medical intervention. To give informed consent, a patient must be competent, understand her condition, options and their expected risks and benefits and must freely and expressly consent to one of those options. Shlomo Cohen challenges this conception of informed consent by constructing cases based on Edmund Gettier’s classic counterexamples to traditional theories of knowledge. In this paper, I argue Cohen-style cases are not genuine threats to the concept of informed consent, however they provide an interesting challenge to theories of conscientious objection.
The right to a self-determined death as expression of the right to freedom of personal development: The German Constitutional Court takes a clear stand on assisted suicide
Authors: Horn Ruth
Published: March 2020

On 26 February 2020, the German Constitutional Court rejected a law from 2015 that prohibited any form of ‘business-like’ assisted suicide as unconstitutional. The landmark ruling of the highest federal court emphasised the high priority given to the rights of autonomy and free personal development, both of which constitute the principle of human dignity, the first principle of the German constitution. The ruling echoes particularities of post-war Germany’s end-of-life debate focusing on patient self-determination while rejecting any discussion of active assistance to die through a lethal injection administered by a doctor. This brief report discusses the ruling in the light of the broader sociopolitical and historical context of the German end-of-life debate.
Effect of weighting for sampling and non-response on estimates of STI prevalence in the third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3)
Authors: Harling Guy , Copas Andrew , Clifton Soazig , Johnson Anne M , Field Nigel , Sonnenberg Pam , Mercer Catherine H
Published: March 2020

Objectives

In addition to researcher-designed sampling biases, population-representative surveys for biomarker measurement of STIs often have substantial missingness due to non-contact, non-consent and other study-implementation issues. STI prevalence estimates may be biased if this missingness is related to STI risk. We investigated how accounting for sampling, interview non-response and non-provision of biological samples affects prevalence estimates in the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3).

Methods

Natsal-3 was a multistage, clustered and stratified probability sample of 16–74 year-olds conducted between 2010 and 2012. Individuals were sampled from all private residential addresses in Britain; respondents aged 16–44 were further sampled to provide a urine specimen based on characteristics including self-reported sexual behaviours. We generated prevalence estimates and confidence intervals for six STIs in five stages: first without accounting for sampling or non-response, then applying inverse-probability weights cumulatively accounting for interview sampling, interview non-response, urine sampling and urine non-response.

Results

Interview non-completion occurred for 42.3% of interview-sampled individuals; urine non-completion occurred for 43.5% of urine-sampled individuals. Interview-sampled individuals, interview respondents, those selected for urine samples and those providing urine samples were each in turn slightly more at-risk for most STIs, leading to lower prevalence estimates after incorporating each set of weights. Researcher-controlled sampling had more impact than respondent-controlled response.

Conclusions

Accounting for both sampling structures and willingness to interview or provide urine specimens can affect national STI prevalence estimates. Using both types of weights, as was done in Natsal-3, is important in reporting on population-based biomarker surveys.
Intracerebral haemorrhage: from clinical settings to animal models
Authors: Bai Qian , Sheng Zhaofu , Liu Yang , Zhang Ruiyi , Yong Voon Wee , Xue Mengzhou
Published: March 2020

Spontaneous intracerebral haemorrhage (ICH) is a devastating type of stroke with high mortality and morbidity and for which no effective treatments are available to date. Much experimental and clinical research have been performed to explore its mechanisms regard the subsequent inflammatory cascade and to seek the potential therapeutic strategies. The aim of this review is to discuss insights from clinical settings that have led to the development of numerous animal models of ICH. Some of the current and future challenges for clinicians to understand ICH are also surveyed.
Multiple cutaneous mast cell tumours in a Boa imperator
Authors: Onkels Ann‐Kathrin , Stadler Christina , Hetzel Udo , Mueller Jana , Herden Christiane
Published: March 2020

Mast cell tumours (MCTs) are common in dogs and cats, but are only rarely reported in reptiles. This case documents the clinical and pathomorphological results from a Boa imperator with multiple cutaneous nodules, diagnosed as MCT based on histopathology, immunohistochemistry and electron microscopy approaches. Grossly, there were multifocal, poorly demarcated, mostly ulcerated nodules ~3 cm in diameter on the skin. Histologically, the dermis and the subcutaneous tissue were infiltrated by round cell populations with eosinophilic granules. Toluidine blue and Giemsa stain revealed metachromatic granules. Using immunohistochemistry, some cells exhibited cytoplasmic immunostaining positive for tryptase. Ultrastructurally, variable quantities of intracytoplasmic, spherical and electron‐dense granules were also detected. The MCT literature on snakes is scarce, especially for the family Boidae, but MCTs should be considered a differential diagnosis for nodular skin lesions in reptiles.
A sexual hybrid and autopolyploids detected in seed from crosses between Neslia paniculata and Camelina sativa (Brassicaceae)
Authors: Martin Sara L. , LaFlamme Michelle L. , James Tracey , Sauder Connie A.
Published: March 2020

It is important to understand the probability of hybridization and potential for introgression of transgenic crop alleles into wild populations as part of pre-release risk assessment. Here we completed bidirectional crosses between the emerging crop, camelina [Camelina sativa (L.) Crantz] and its weedy relative, ball mustard [Neslia paniculata (L.) Desv.]. Ball mustard is a self-compatible annual that produces hard ball-like seeds similar to canola or mustard seed in size and shape. A total of 1593 crosses were completed and collected with camelina as the maternal parent, while 3253 crosses were successfully collected in the reverse direction. Putatively hybrid seedlings were screened with flow cytometry and species-specific nuclear ribosomal internal transcribed spacer (ITS) markers. Three plants had DNA contents close to expectations for hybrids, but only one of these, formed on camelina, had the expected ITS markers. This hybrid exhibited low fertility, and neither self-pollination nor backcrossing produced viable progeny. The other two plants, formed on ball mustard, had high pollen and seed fertility and were identified as ball mustard neoautotetraploids. Therefore, the hybridization rate between camelina and ball mustard is relatively low at one in 20 000 ovules pollinated when camelina is the maternal parent. However, autotetraploids may form frequently in ball mustard, and tetraploid populations may exist in nature.
Double parton scattering in pA collisions at the LHC revisited
Authors: Blok Boris , Ceccopieri Federico Alberto
Published: March 2020

We consider the production of W-boson plus dijet, W-boson plus b-jets and same sign WW via double parton scattering (DPS) in pA collisions at the LHC and evaluate the corresponding cross sections. The impact of a novel DPS contribution pertinent to pA collisions is quantified. Exploiting the experimental capability of performing measurements differential in the impact parameter in pA collisions, we discuss a method to single out this novel DPS contribution. The method allows the subtraction of the leading twist (LT) single parton scattering background and it gives access in a very clean way to double parton distribution functions in the proton. We calculate leading twist and DPS cross sections and study the dependence of the observables on the cuts in the jets phase space. In the Wjj channel the observation of DPS is possible with data already accumulated in pA runs and the situation will greatly improve for the next high luminosity runs. For the $$Wb{\bar{b}}$$Wbb¯ final state, the statistics within the current data is too low, but there is possibility to observe DPS in this channel in future runs, albeit with much reduced sensitivity than in Wjj final state. Finally the DPS observation in the same sign WW channel will require either significant increase of integrated luminosity beyond that foreseen in next pA runs or improved methods for W reconstruction, along with its charge, in hadronic decay channels.
Hong Kong’s Economy Navigating Turbulent Times
Authors: LI Chen
Published: March 2020

Hong Kong’s real gross domestic product (GDP) growth for 2019 was estimated to register the first annual decline since 2009. The economic slowdown and recession in Hong Kong were driven by both weakening domestic and external demand, aggravated by local social unrest which had disrupted social stability, transportation and commerce. Hong Kong’s economic prospects hinge on how its sociopolitical situation and the US–China trade tensions will evolve. Despite short-term headwinds, Hong Kong’s competitiveness in the long term will likely remain strong if it maintains its unique institutional space and advantages in bridging mainland China and the rest of the global economy.
Electrochemical Sensors in Space Missions
Authors: Koehne Jessica E. , Cordeiro Milton , Thomson Seamus D. , Meyyappan M.
Published: March 2020

Electrochemistry offers a wide range of analytical sensing capability and is therefore suited to serve a variety of NASA missions. Advancements in miniaturization and automation in addition to inherent high sensitivity and specificity have made electrochemical sensors especially attractive. Here, we present recent developments for use of electrochemical sensors in planetary exploration and human exploration missions. This article highlights research developments in the area of electrochemical sensors as presented at the Electrochemistry in Space symposium at the 236th ECS Meeting on October 16, 2019 in Atlanta, GA.
Loss of dynamic regulation of G protein-coupled receptor kinase 2 by nitric oxide leads to cardiovascular dysfunction with aging
Authors: Lieu Melissa , Traynham Christopher J. , de Lucia Claudio , Pfleger Jessica , Piedepalumbo Michela , Roy Rajika , Petovic Jennifer , Landesberg Gavin , Forrester Steven J. , Hoffman Matthew , Grisanti Laurel A. , Yuan Ancai , Gao Erhe , Drosatos Konstantinos , Eguchi Satoru , Scalia Rosario , Tilley Douglas G. , Koch Walter J.
Published: March 2020

Research on G protein-coupled receptor kinase 2 (GRK2) in the setting of cardiovascular aging is largely unknown despite its strong established functions in cardiovascular physiology and pathophysiology. This study uses a mouse model of chronic GRK2 overactivity to further investigate the consequences of long-term GRK2 on cardiac function and structure. We report for the first time that chronic GRK2 overactivity was able to cause cardiac dysfunction and remodeling independent of surgical intervention, highlighting the importance of GRK activity in aged-related heart disease.
Fast in vivo detection of myocardial norepinephrine levels in the beating porcine heart
Authors: Chan Shyue-An , Vaseghi Marmar , Kluge Nicholas , Shivkumar Kalyanam , Ardell Jeffrey L. , Smith Corey
Published: March 2020

The sympathetic nervous system modulates cardiac function by controlling key parameters such as chronotropy and inotropy. Sympathetic control of ventricular function occurs through extrinsic innervation arising from the stellate ganglia and thoracic sympathetic chain. In the healthy heart, sympathetic release of norepinephrine (NE) results in positive modulation of chronotropy, inotropy, and dromotropy, significantly increasing cardiac output. However, in the setting of myocardial infarction or injury, sympathetic activation persists, contributing to heart failure and increasing the risk of arrhythmias, including sudden cardiac death. Methodologies for detection of norepinephrine in cardiac tissue are limited. Present techniques rely on microdialysis for analysis by high-performance liquid chromatography coupled to electrochemical detection (HPLC-ED), radioimmunoassay, or other immunoassays, such as enzyme-linked immunosorbent assay (ELISA). Although significant information about the release and action of norepinephrine has been obtained with these methodologies, they are limited in temporal resolution, require large sample volumes, and provide results with a significant delay after sample collection (hours to weeks). In this study, we report a novel approach for measurement of interstitial cardiac norepinephrine, using minimally invasive, electrode-based, fast-scanning cyclic voltammetry (FSCV) applied in a beating porcine heart. The first multispatial and high temporal resolution, multichannel measurements of NE release in vivo are provided. Our data demonstrate rapid changes in interstitial NE profiles with regional differences in response to coronary ischemia, sympathetic nerve stimulation, and alterations in preload/afterload.

NEW & NOTEWORTHY Pharmacological, electrical, or surgical regulation of sympathetic neuronal control can be used to modulate cardiac function and treat arrhythmias. However, present methods for monitoring sympathetic release of norepinephrine in the heart are limited in spatial and temporal resolution. Here, we provide for the first time a methodology and demonstration of practice and rapid measures of individualized regional autonomic neurotransmitter levels in a beating heart. We show dynamic, spatially resolved release profiles under normal and pathological conditions.
Macrophage galectin-3 enhances intimal translocation of vascular calcification in diabetes mellitus
Authors: Sun Zhen , Li Lihua , Zhang Lili , Yan Jinchuan , Shao Chen , Bao Zhengyang , Liu Jia , Li Yalan , Zhou Mengxue , Hou Lina , Jing Lele , Pang Qiwen , Geng Yue , Mao Xiang , Gu Wen , Wang Zhongqun
Published: March 2020

The clinical risks and prognosis of diabetic vascular intimal calcification (VIC) and medial calcification (VMC) are different. This study aims to investigate the mechanism of VIC/VMC translocation. Anterior tibial arteries were collected from patients with diabetic foot amputation. The patients were then divided into VIC and VMC groups. There were plaques in all anterior tibial arteries, while the enrichment of galectin-3 in arterial plaques in the VIC group was significantly higher than that in the VMC group. Furthermore, a macrophage/vascular smooth muscle cell (VSMC) coculture system was constructed. VSMC-derived extracellular vesicles (EVs) was labeled with fluorescent probe. After macrophages were pretreated with recombinant galectin-3 protein, the migration of VSMC-derived EVs and VSMC-derived calcification was more pronounced. And anti-galectin-3 antibody can inhibit this process of EVs and calcification translocation. Then, lentivirus (LV)-treated bone marrow cells (BMCs) were transplanted into apolipoprotein E-deficient (ApoE−/−) mice, and a diabetic atherosclerosis mouse model was constructed. After 15 wk of high-fat diet, ApoE−/−mice transplanted with LV-shgalectin-3 BMCs exhibited medial calcification and a concentrated distribution of EVs in the media. In conclusion, upregulation of galectin-3 in macrophages promotes the migration of VSMC-derived EVs to the intima and induces diabetic vascular intimal calcification.

NEW & NOTEWORTHY The clinical risk and prognosis of vascular intimal and medial calcification are different. Macrophage galectin-3 regulates the migration of vascular smooth muscle cell-derived extracellular vesicles and mediates diabetic vascular intimal/medial calcification translocation. This study may provide insights into the early intervention in diabetic vascular calcification.