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Article ; Online: Exosomal MicroRNAs in Pregnancy Provides Insight into a Possible Cure for Cancer

Preenan Pillay / Kogi Moodley / Manu Vatish / Jagidesa Moodley

International Journal of Molecular Sciences, Vol 21, Iss 5384, p

2020 Volume 5384

Abstract: The biological links between cancer and pregnancy are of recent interest due to parallel proliferative, immunosuppressive and invasive mechanisms between tumour and trophoblast development. Therefore, understanding “cancer-like” mechanisms in pregnancy ... ...

Abstract	The biological links between cancer and pregnancy are of recent interest due to parallel proliferative, immunosuppressive and invasive mechanisms between tumour and trophoblast development. Therefore, understanding “cancer-like” mechanisms in pregnancy could lead to the development of novel cancer therapeutics, however, little is understood on how tumour and trophoblast cells recapitulate similar molecular mechanisms. Based on our observations from a previous study, it was not only evident that exosomal miRNAs are involved in the pathophysiology of preeclampsia but also contained cancer-specific miRNAs, which suggested that “pseudo-malignant-like” exosomal-mediated mechanisms exist in pregnancy. The presented study therefore aimed to identify exosomal miRNAs (exomiR) in pregnancy which can be repurposed towards preventing tumour metastasis and immunosuppression. It was identified that exomiR-302d-3p, exomiR-223-3p and exomiR-451a, commonly associated with cancer metastasis, were found to be highly expressed in pregnancy. Furthermore, computational merging and meta-analytical pathway analysis (DIANA miRPath) of significantly expressed exomiRs between 38 ± 1.9 vs. 30 ± 1.11 weeks of gestation indicated controlled regulation of biological pathways associated with cancer metastasis and immunosuppression. Therefore, the observations made in this study provide the experimental framework for the repurposing of exosomal miRNA molecular mechanisms in pregnancy towards treating and preventing cancer.
Keywords	exosome diagnostics ; cancer therapeutics ; pregnancy ; exosomal microRNA ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610 ; 150
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Exosomal MicroRNAs in Pregnancy Provides Insight into a Possible Cure for Cancer.

Pillay, Preenan / Moodley, Kogi / Vatish, Manu / Moodley, Jagidesa

International journal of molecular sciences

2020 Volume 21, Issue 15

Abstract	The biological links between cancer and pregnancy are of recent interest due to parallel proliferative, immunosuppressive and invasive mechanisms between tumour and trophoblast development. Therefore, understanding "cancer-like" mechanisms in pregnancy could lead to the development of novel cancer therapeutics, however, little is understood on how tumour and trophoblast cells recapitulate similar molecular mechanisms. Based on our observations from a previous study, it was not only evident that exosomal miRNAs are involved in the pathophysiology of preeclampsia but also contained cancer-specific miRNAs, which suggested that "pseudo-malignant-like" exosomal-mediated mechanisms exist in pregnancy. The presented study therefore aimed to identify exosomal miRNAs (exomiR) in pregnancy which can be repurposed towards preventing tumour metastasis and immunosuppression. It was identified that exomiR-302d-3p, exomiR-223-3p and exomiR-451a, commonly associated with cancer metastasis, were found to be highly expressed in pregnancy. Furthermore, computational merging and meta-analytical pathway analysis (DIANA miRPath) of significantly expressed exomiRs between 38 ± 1.9 vs. 30 ± 1.11 weeks of gestation indicated controlled regulation of biological pathways associated with cancer metastasis and immunosuppression. Therefore, the observations made in this study provide the experimental framework for the repurposing of exosomal miRNA molecular mechanisms in pregnancy towards treating and preventing cancer.
MeSH term(s)	Adult ; Biomarkers/blood ; Exosomes/chemistry ; Exosomes/genetics ; Exosomes/metabolism ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Ontology ; Gestational Age ; Humans ; Lymphatic Metastasis ; MicroRNAs/blood ; MicroRNAs/genetics ; Molecular Sequence Annotation ; Molecular Targeted Therapy/methods ; Neoplasms/blood ; Neoplasms/genetics ; Neoplasms/pathology ; Neoplasms/therapy ; Pre-Eclampsia/blood ; Pre-Eclampsia/genetics ; Pre-Eclampsia/pathology ; Pregnancy ; Trophoblasts/chemistry ; Trophoblasts/metabolism
Chemical Substances	Biomarkers ; MIRN223 microRNA, human ; MIRN302A microRNA, human ; MIRN451 microRNA, human ; MicroRNAs
Language	English
Publishing date	2020-07-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21155384
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Article ; Online: Exosomal microRNA profiling in early and late onset preeclamptic pregnant women reflects pathophysiology.

Pillay, Preenan / Vatish, Manu / Duarte, Raquel / Moodley, Jack / Mackraj, Irene

International journal of nanomedicine

2019 Volume 14, Page(s) 5637–5657

Abstract: Background: ...

Abstract	Background:
MeSH term(s)	Adult ; Blood Pressure ; Exosomes/genetics ; Female ; Gene Expression Profiling ; Gene Ontology ; Humans ; MicroRNAs/metabolism ; Pre-Eclampsia/genetics ; Pre-Eclampsia/physiopathology ; Pregnancy ; Reproducibility of Results
Chemical Substances	MicroRNAs
Language	English
Publishing date	2019-07-23
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2364941-0
ISSN	1178-2013 ; 1176-9114
ISSN (online)	1178-2013
ISSN	1176-9114
DOI	10.2147/IJN.S208865
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Article ; Online: Placenta-derived exosomes: potential biomarkers of preeclampsia.

Pillay, Preenan / Moodley, Kogi / Moodley, Jagidesa / Mackraj, Irene

International journal of nanomedicine

2017 Volume 12, Page(s) 8009–8023

Abstract: Preeclampsia remains a leading cause of maternal and fetal mortality, due to ineffective treatment and diagnostic strategies, compounded by the lack of clarity on the etiology of the disorder. Although several clinical and biological markers of ... ...

Abstract	Preeclampsia remains a leading cause of maternal and fetal mortality, due to ineffective treatment and diagnostic strategies, compounded by the lack of clarity on the etiology of the disorder. Although several clinical and biological markers of preeclampsia have been evaluated, they have proven to be ineffective in providing a definitive diagnosis during the various stages of the disorder. Exosomes have emerged as ideal biomarkers of pathological states, such as cancer, and have more recently gained interest in pregnancy-related complications, due to their role in cellular communication in normal and complicated pregnancies. This occurs as a result of the specific placenta-derived exosomal molecular cargo, which may be involved in normal pregnancy-associated immunological events, such as the maintenance of maternal-fetal tolerance. This review provides perspectives on placenta-derived exosomes as possible biomarkers for the diagnosis/prognosis of preeclampsia. Using keywords, online databases were searched to identify relevant publications to review the potential use of placenta-derived exosomes as biomarkers of preeclampsia.
MeSH term(s)	Biomarkers/analysis ; Exosomes/pathology ; Female ; Humans ; Placenta/cytology ; Placenta/pathology ; Pre-Eclampsia/diagnosis ; Pre-Eclampsia/pathology ; Pregnancy ; Prognosis
Chemical Substances	Biomarkers
Language	English
Publishing date	2017-10-31
Publishing country	New Zealand
Document type	Journal Article ; Review
ZDB-ID	2364941-0
ISSN	1178-2013 ; 1176-9114
ISSN (online)	1178-2013
ISSN	1176-9114
DOI	10.2147/IJN.S142732
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Article ; Online: Placental exosomes and pre-eclampsia: Maternal circulating levels in normal pregnancies and, early and late onset pre-eclamptic pregnancies.

Pillay, Preenan / Maharaj, Niren / Moodley, Jagidesa / Mackraj, Irene

Placenta

2016 Volume 46, Page(s) 18–25

Abstract: Introduction and aim: Exosomes are a subtype of extracellular vesicle (20-130 nm) released by biological cells under normal and pathological conditions. Although there have been reports of circulating exosomes in normal pregnancy, the relevance of ... ...

Abstract	Introduction and aim: Exosomes are a subtype of extracellular vesicle (20-130 nm) released by biological cells under normal and pathological conditions. Although there have been reports of circulating exosomes in normal pregnancy, the relevance of placental-derived exosomes in normal and abnormal pregnancies still needs to be elucidated. The aim of this study was to quantify total and placental-derived exosomes in maternal plasma from normal (N), early onset- and late onset-preeclampsia (PE). Method: Plasma samples were obtained from pregnant women in the third trimester, for the isolation of exosomes by differential ultracentrifugation. Total exosomes were quantified using nanoparticle tracking analysis and immuno-reactive exosomal CD63 quantification. Placental-derived exosomes were quantified using placental alkaline phosphatase (PLAP) as a specific marker. The contribution of placental-derived exosomes to total exosomes in maternal plasma was determined by the ratio of PLAP Results: The concentration of total exosomes significantly increased in early onset-PE and late onset-PE compared to N (≤33 weeks) and N (≥34 weeks). The relative concentration of placental-derived exosomes significantly increased in early onset-PE but decreased in late onset-PE compared to N. The ratio of PLAP Conclusion: The differences in the contribution of placental-derived exosomes to total exosomes in maternal circulation suggests a possible pathophysiological role of placental-derived exosomes in pre-eclampsia.
MeSH term(s)	Adult ; Case-Control Studies ; Exosomes ; Female ; Humans ; Placenta/secretion ; Pre-Eclampsia/blood ; Pregnancy ; Young Adult
Language	English
Publishing date	2016-10
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	603951-0
ISSN	1532-3102 ; 0143-4004
ISSN (online)	1532-3102
ISSN	0143-4004
DOI	10.1016/j.placenta.2016.08.078
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Article ; Online: Exosomal Th1/Th2 cytokines in preeclampsia and HIV-positive preeclamptic women on highly active anti-retroviral therapy.

Pillay, Preenan / Moodley, Kogi / Vatish, Manu / Moodley, Jagidesa / Duarte, Raquel / Mackraj, Irene

Cytokine

2019 Volume 125, Page(s) 154795

Abstract: Preeclampsia (PE) is a hypertensive disorder of pregnancy which is a leading cause of maternal and foetal morbidity and mortality. Furthermore, HIV/Highly Active Anti-Retroviral Treatment has been associated with the increased risk of preeclampsia due to ...

Abstract	Preeclampsia (PE) is a hypertensive disorder of pregnancy which is a leading cause of maternal and foetal morbidity and mortality. Furthermore, HIV/Highly Active Anti-Retroviral Treatment has been associated with the increased risk of preeclampsia due to maternal immune reconstitution, which complicates the clinical diagnosis of PE in these patients. It is therefore necessary to identify biomarkers involved in the pathology of both disorders with the intent to diagnose. Exosomal cytokines represent ideal biomarkers of PE and inflammatory conditions due to their immunomodulatory role in pregnancy. We therefore quantified exosomal Th1 (IL-2 and TNF-α) and Th2 cytokines (IL-10) in maternal circulation. A significant dysregulation in total exosomes, placental-derived exosomes and exosomal cytokines in PE and HIV-positive PE pregnant woman on Highly Active Antiretroviral Treatment (HAART) was observed (p < 0.01). Additionally, we observed a significant shift towards Th1 immunity in PE which becomes amplified in HIV-positive PE pregnant woman on HAART (p < 0.01). Moreover, we show the potential application of exosomal Tumor necrosis factor alpha (TNF-α) as a biomarker of PE and PE in HIV-positive pregnant women on HAART (CI: 95%, LHR > 10, sensitivity of 100% and specificity of 90%). These findings are in support of exosome release and exosome cytokine encapsulation as a tightly regulated process in favour of maintaining the immune microenvironment, which can orchestrate either normal pregnancy, or the pathogenesis of preeclampsia and preeclampsia in HIV/HAART pregnancies.
MeSH term(s)	Acetylcholinesterase/metabolism ; Adult ; Antiretroviral Therapy, Highly Active ; Biomarkers/blood ; Cytokines/metabolism ; Exosomes/metabolism ; Exosomes/ultrastructure ; Female ; HIV Infections/blood ; HIV Infections/drug therapy ; Humans ; Interleukin-10/blood ; Interleukin-2/blood ; Microscopy, Electron, Transmission ; Placenta/metabolism ; Pre-Eclampsia/diagnosis ; Pre-Eclampsia/enzymology ; Pre-Eclampsia/virology ; Pregnancy ; Pregnancy Complications, Infectious/diagnosis ; Pregnancy Complications, Infectious/virology ; Risk Factors ; Th1 Cells/metabolism ; Th2 Cells/metabolism ; Tumor Necrosis Factor-alpha/blood
Chemical Substances	Biomarkers ; Cytokines ; IL10 protein, human ; IL2 protein, human ; Interleukin-2 ; Tumor Necrosis Factor-alpha ; Interleukin-10 (130068-27-8) ; Acetylcholinesterase (EC 3.1.1.7)
Language	English
Publishing date	2019-08-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1018055-2
ISSN	1096-0023 ; 1043-4666
ISSN (online)	1096-0023
ISSN	1043-4666
DOI	10.1016/j.cyto.2019.154795
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Article ; Online: Exosomal microRNA profiling in early and late onset preeclamptic pregnant women reflects pathophysiology

Pillay P / Vatish M / Duarte R / Moodley J / Mackraj I

International Journal of Nanomedicine, Vol Volume 14, Pp 5637-

2019 Volume 5657

Abstract: Preenan Pillay,1 Manu Vatish,2 Raquel Duarte,3 Jack Moodley,4 Irene Mackraj51Discipline ...

Abstract	Preenan Pillay,1 Manu Vatish,2 Raquel Duarte,3 Jack Moodley,4 Irene Mackraj51Discipline of Human Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of Kwazulu-Natal, Durban, South Africa; 2Nuffield Department of Women’s and Reproductive Health, Women’s Centre, John Radcliffe Hospital, University of Oxford, Oxford, UK; 3Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 4Women’s Health and HIV Research Group, Department of Obstetrics and Gynaecology, University of Kwazulu-Natal, Durban, South Africa; 5School of Laboratory Medicine and Medical Sciences, University of Kwazulu-Natal, Durban, South AfricaBackground: Preeclampsia is the leading cause of maternal and fetal mortality due to the inability to diagnose and treat the disorder early in pregnancy. This is attributed to the complex pathophysiology and unknown etiology of the disorder, which is modulated by several known and unknown factors. Exosomes have recently been implicated as possible mediators of the pathogenesis of preeclampsia, with, however, no evidence linking these nanovesicles to the pathophysiology of preeclampsia and its subtypes.Methods: To better understand the pathophysiological role of exosomes in preeclampsia, we have analyzed the exosomal microRNA in early and late onset preeclamptic women in comparison to their gestationally matched normotensive controls using Digital Direct Detection (NanoString Technologies).Results: For the first time, distinct exosomal microRNA signatures in early and late onset preeclampsia have been identified. Moreover, these signatures indicate that exosomes are involved in key pathological features associated with preeclampsia and differentiate between the subtypes.Conclusion: This study forms the basis for the diagnostic and functional validation of the identified signatures as biomarkers of preeclampsia and its subtypes.Keywords: biomarkers, preeclampsia, exosomes, microRNA
Keywords	Exosomes ; Exosomal miRNA ; Biomarkers ; Preeclampsia ; Medicine (General) ; R5-920
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Dove Medical Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: The impact of implementing the 2016 WHO Recommendations on Antenatal Care for a Positive Pregnancy Experience on perinatal deaths: an interrupted time-series analysis in Mpumalanga province, South Africa.

Lavin, Tina / Pattinson, Robert Clive / Kelty, Erin / Pillay, Yogan / Preen, David Brian

BMJ global health

2020 Volume 5, Issue 12

Abstract: Objectives: To investigate if the implementation of the 2016 WHO Recommendations for a Positive Pregnancy Experience reduced perinatal mortality in a South African province. The recommendations were implemented which included increasing the number of ... ...

Abstract	Objectives: To investigate if the implementation of the 2016 WHO Recommendations for a Positive Pregnancy Experience reduced perinatal mortality in a South African province. The recommendations were implemented which included increasing the number of contacts and also the content of the contacts. Methods: Retrospective interrupted time-series analysis was conducted for all women accessing a minimum of one antenatal care contact from April 2014 to September 2019 in Mpumalanga province, South Africa. Retrospective interrupted time-series analysis of province level perinatal mortality and birth data comparing the pre-implementation period (April 2014-March 2017) and post-implementation period (April 2018-September 2019). The main outcome measure was unadjusted prevalence ratio (PR) for perinatal deaths before and after implementation; interrupted time-series analyses for trends in perinatal mortality before and after implementation; stillbirth risk by gestational age; primary cause of deaths (and maternal condition) before and after implementation. Results: Overall, there was a 5.8% absolute decrease in stillbirths after implementation of the recommendations, however this was not statistically significant (PR 0.95, 95% CI 0.90% to 1.05%; p=0.073). Fresh stillbirths decreased by 16.6% (PR 0.86, 95% CI 0.77% to 0.95%; p=0.003) while macerated stillbirths (p=0.899) and early neonatal deaths remained unchanged (p=0.499). When stratified by weight fresh stillbirths >2500 g decreased by 17.2% (PR 0.81, 95% CI 0.70% to 0.94%; p=0.007) and early neonatal deaths decreased by 12.8% (PR 0.88, 95% CI 0.77% to 0.99%; p=0.041). The interrupted time-series analysis confirmed a trend for decreasing stillbirths at 0.09/1000 births per month (-0.09, 95% CI -1.18 to 0.01; p=0.059), early neonatal deaths (-0.09, 95% CI -0.14 to 0.04; p=<0.001) and perinatal mortality (-1.18, 95% CI -0.27 to -0.09; p<0.001) in the post-implementation period. A decrease in stillbirths, early neonatal deaths or perinatal mortality was not observed in the pre-implementation period. During the period when additional antenatal care contacts were implemented (34-38 weeks), there was a decrease in stillbirths of 18.4% (risk ratio (RR) 0.82, 95% CI 0.73% to 0.91%, p=0.0003). In hypertensive disorders of pregnancy, the risk of stillbirth decreased in the post-period by 15.1% (RR 0.85; 95% CI 0.76% to 0.94%; p=0.002). Conclusion: The implementation of the 2016 WHO Recommendations for a Positive Pregnancy Experience may be an effective public health strategy to reduce stillbirths in South African provinces.
MeSH term(s)	Female ; Humans ; Infant ; Infant Mortality ; Infant, Newborn ; Perinatal Death/prevention & control ; Pregnancy ; Prenatal Care ; Retrospective Studies ; South Africa/epidemiology ; World Health Organization
Language	English
Publishing date	2020-11-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2059-7908
ISSN	2059-7908
DOI	10.1136/bmjgh-2020-002965
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Article ; Online: Placenta-derived exosomes

Pillay P / Moodley K / Moodley J / Mackraj I

International Journal of Nanomedicine, Vol Volume 12, Pp 8009-

potential biomarkers of preeclampsia

2017 Volume 8023

Abstract: Preenan Pillay,1,2 Kogi Moodley,1 Jagidesa Moodley,3 Irene Mackraj3 1Discipline of Human Physiology ...

Abstract	Preenan Pillay,1,2 Kogi Moodley,1 Jagidesa Moodley,3 Irene Mackraj3 1Discipline of Human Physiology, Nelson R Mandela School of Medicine, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa; 2Pearson Institute of Higher Education, Midrand, South Africa; 3Women’s Health and HIV Research Group, Nelson R Mandela School of Medicine, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban,South Africa Abstract: Preeclampsia remains a leading cause of maternal and fetal mortality, due to ineffective treatment and diagnostic strategies, compounded by the lack of clarity on the etiology of the disorder. Although several clinical and biological markers of preeclampsia have been evaluated, they have proven to be ineffective in providing a definitive diagnosis during the various stages of the disorder. Exosomes have emerged as ideal biomarkers of pathological states, such as cancer, and have more recently gained interest in pregnancy-related complications, due to their role in cellular communication in normal and complicated pregnancies. This occurs as a result of the specific placenta-derived exosomal molecular cargo, which may be involved in normal pregnancy-associated immunological events, such as the maintenance of maternal–fetal tolerance. This review provides perspectives on placenta-derived exosomes as possible biomarkers for the diagnosis/prognosis of preeclampsia. Using keywords, online databases were searched to identify relevant publications to review the potential use of placenta-derived exosomes as biomarkers of preeclampsia. Keywords: placenta-derived exosomes, preeclampsia, biomarkers
Keywords	Placental-derived exosomes ; Preeclampsia ; Biomarkers ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2017-10-01T00:00:00Z
Publisher	Dove Medical Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The impact of implementing the 2016 WHO Recommendations on Antenatal Care for a Positive Pregnancy Experience on perinatal deaths

Yogan Pillay / Tina Lavin / Robert Clive Pattinson / Erin Kelty / David Brian Preen

BMJ Global Health, Vol 5, Iss

an interrupted time-series analysis in Mpumalanga province, South Africa

2020 Volume 12

Abstract: Objectives To investigate if the implementation of the 2016 WHO Recommendations for a Positive Pregnancy Experience reduced perinatal mortality in a South African province. The recommendations were implemented which included increasing the number of ... ...

Abstract	Objectives To investigate if the implementation of the 2016 WHO Recommendations for a Positive Pregnancy Experience reduced perinatal mortality in a South African province. The recommendations were implemented which included increasing the number of contacts and also the content of the contacts.Methods Retrospective interrupted time-series analysis was conducted for all women accessing a minimum of one antenatal care contact from April 2014 to September 2019 in Mpumalanga province, South Africa. Retrospective interrupted time-series analysis of province level perinatal mortality and birth data comparing the pre-implementation period (April 2014–March 2017) and post-implementation period (April 2018–September 2019). The main outcome measure was unadjusted prevalence ratio (PR) for perinatal deaths before and after implementation; interrupted time-series analyses for trends in perinatal mortality before and after implementation; stillbirth risk by gestational age; primary cause of deaths (and maternal condition) before and after implementation.Results Overall, there was a 5.8% absolute decrease in stillbirths after implementation of the recommendations, however this was not statistically significant (PR 0.95, 95% CI 0.90% to 1.05%; p=0.073). Fresh stillbirths decreased by 16.6% (PR 0.86, 95% CI 0.77% to 0.95%; p=0.003) while macerated stillbirths (p=0.899) and early neonatal deaths remained unchanged (p=0.499). When stratified by weight fresh stillbirths >2500 g decreased by 17.2% (PR 0.81, 95% CI 0.70% to 0.94%; p=0.007) and early neonatal deaths decreased by 12.8% (PR 0.88, 95% CI 0.77% to 0.99%; p=0.041). The interrupted time-series analysis confirmed a trend for decreasing stillbirths at 0.09/1000 births per month (−0.09, 95% CI −1.18 to 0.01; p=0.059), early neonatal deaths (−0.09, 95% CI −0.14 to 0.04; p=<0.001) and perinatal mortality (−1.18, 95% CI −0.27 to −0.09; p<0.001) in the post-implementation period. A decrease in stillbirths, early neonatal deaths or perinatal mortality was not observed in ...
Keywords	Medicine (General) ; R5-920 ; Infectious and parasitic diseases ; RC109-216
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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