Imperial College London

ProfessorMarkJohnson

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Clinical Chair in Obstetrics
 
 
 
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Contact

 

+44 (0)20 8846 7887mark.johnson

 
 
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Location

 

H3.35Chelsea and Westminster HospitalChelsea and Westminster Campus

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Summary

 

Publications

Publication Type
Year
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447 results found

Woon EV, Day A, Bracewell-Milnes T, Male V, Johnson Met al., 2020, Immunotherapy to improve pregnancy outcome in women with abnormal natural killer cell levels/activity and recurrent miscarriage or implantation failure: A systematic review and meta-analysis., Journal of Reproductive Immunology, Vol: 142, Pages: 1-12, ISSN: 0165-0378

There is a trend towards offering immunotherapy to women with unexplained reproductive failure based on abnormal Natural Killer (NK) cell levels. Previous systematic reviews evaluating immunotherapy usage have not focused on women with abnormal level of NK cells. To address the gap in literature, this systematic review aims to evaluate the efficacy of immunotherapy to improve pregnancy outcome in women with recurrent miscarriage (RM) or implantation failure (RIF) specifically selected based on abnormal levels and/or activity of NK cells. Six databases were searched for peer-reviewed studies following PRISMA guidelines. Risk of bias assessment was conducted using RoB2 for randomized controlled trials (RCT) and ROBINS-I for non-RCT. Of 1025 studies identified, seven studies on intravenous immunoglobulin (IVIG) (four), prednisolone (one), etanercept (one) and intralipid (one) were included. Meta-analysis of the non-RCT IVIG studies (557 participants; 312 intervention, 245 controls) showed livebirth in favour of intervention (RR 2.57; 95 % CI = 1.79-3.69; p < 0.05), however there were significant heterogeneity (I2 = 62 %) and moderate to severe risk of bias in these studies. Individual RCTs reported improved livebirth outcome in etanercept, intralipid and prednisolone and this was significant in the former two (p < 0.05). In conclusion, there may be some benefit of immunotherapy, but paucity of high quality evidence means that it is not possible to support the use of immunotherapy even when selected based on abnormal NK cell level/activity. Further research with application of scientifically validated immunological biomarkers in well-planned large scale RCTs will determine whether immunotherapy is beneficial in this subpopulation of women.

Journal article

Maric T, Kanu C, Mandalia S, Johnson MR, Savvidou MDet al., 2020, Fetal fractional limb volumes in pregnancies following bariatric surgery., Acta Obstet Gynecol Scand

INTRODUCTION: Obesity rates have reached an epidemic level and bariatric surgery is the most effective method of sustainable weight loss. Pregnancy following bariatric surgery is associated with an increased prevalence of small babies. The objective of the study is to compare the fetal fat distribution, as assessed by fractional arm and thigh volume using three-dimensional ultrasonography, in pregnancies following maternal bariatric surgery with those without such history. MATERIAL AND METHODS: This is a prospective, longitudinal, observational study conducted in a Maternity Unit in the UK. The study included 189 pregnant women; 63 with previous bariatric surgery [27 restrictive (13 with gastric band, 14 with sleeve gastrectomy) and 36 malabsorptive procedures] and 126 with no previous surgery but similar maternal booking body mass index. Fetal arm and thigh volume were obtained at 30-33 and 35-37 weeks' gestation and fractional limb volumes were calculated using a commercially available software. Women underwent a 75 g, 2 h oral glucose tolerance test at 28-31 weeks of gestation. RESULTS: Overall, adjusted fetal arm and thigh volume were smaller in the post-bariatric, compared to the no surgery, group and this was more marked in women who had undergone a previous sleeve gastrectomy (P < .001 and P = .002, respectively) or a malabsorptive procedure (P < .001 for both). There was a strong positive correlation between maternal fasting/post-prandial (2 h) glucose levels, at the time of the oral glucose tolerance test, and arm and thigh volume at both 30-33 and 35-37 weeks (P < .01 for all). CONCLUSIONS: The study has demonstrated that in the third trimester of pregnancy, fetuses of women with previous bariatric surgery have smaller fractional limb volumes, therefore less soft tissue, compared to fetuses of women without such surgery and this may be related to the lower maternal glucose level

Journal article

Bracewell-Milnes T, Saso S, Jones B, Cato S, Parikh R, Thum M-Y, Johnson M, Almeida P, Norman-Taylor J, Nikolaou Det al., 2020, A systematic review exploring the patient decision-making factors and attitudes towards pre-implantation genetic testing for aneuploidy and gender selection, ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA, ISSN: 0001-6349

Journal article

Sliwa K, Petrie MC, van der Meer P, Mebazaa A, Hilfiker-Kleiner D, Jackson AM, Maggioni AP, Laroche C, Regitz-Zagrosek V, Schaufelberger M, Tavazzi L, Roos-Hesselink JW, Seferovic P, van Spaendonck-Zwarts K, Mbakwem A, Böhm M, Mouquet F, Pieske B, Johnson MR, Hamdan R, Ponikowski P, Van Veldhuisen DJ, McMurray JJV, Bauersachs Jet al., 2020, Clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy: an ESC EORP registry., Eur Heart J

AIMS : We sought to describe the clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy (PPCM) globally. METHODS AND RESULTS : In 2011, >100 national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global registry on PPCM, under the auspices of the ESC EURObservational Research Programme. These societies were tasked with identifying centres who could participate in this registry. In low-income countries, e.g. Mozambique or Burkina Faso, where there are no national societies due to a shortage of cardiologists, we identified potential participants through abstracts and publications and encouraged participation into the study. Seven hundred and thirty-nine women were enrolled in 49 countries in Europe (33%), Africa (29%), Asia-Pacific (15%), and the Middle East (22%). Mean age was 31 ± 6 years, mean left ventricular ejection fraction (LVEF) was 31 ± 10%, and 10% had a previous pregnancy complicated by PPCM. Symptom-onset occurred most often within 1 month of delivery (44%). At diagnosis, 67% of patients had severe (NYHA III/IV) symptoms and 67% had a LVEF ≤35%. Fifteen percent received bromocriptine with significant regional variation (Europe 15%, Africa 26%, Asia-Pacific 8%, the Middle East 4%, P < 0.001). Follow-up was available for 598 (81%) women. Six-month mortality was 6% overall, lowest in Europe (4%), and highest in the Middle East (10%). Most deaths were due to heart failure (42%) or sudden (30%). Re-admission for any reason occurred in 10% (with just over half of these for heart failure) and thromboembolic events in 7%. Myocardial recovery (LVEF > 50%) occurred only in 46%, most commonly in Asia-Pacific (62%), and least commonly in the Middle East (25%). Neonatal death occurred in 5% with marked regional variation (Europe 2%, the Middle East 9%). CONCLUSION&em

Journal article

Baris L, Hakeem A, Moe T, Cornette J, Taha N, Farook F, Gaisin I, Bonanomi C, Parsonage W, Johnson M, Hall R, Roos-Hesselink JW, ROPAC Investigators Groupet al., 2020, Acute Coronary Syndrome and Ischemic Heart Disease in Pregnancy: Data From the EURObservational Research Programme-European Society of Cardiology Registry of Pregnancy and Cardiac Disease., J Am Heart Assoc, Vol: 9

Background The prevalence of ischemic heart disease (IHD) in women of child-bearing age is rising. Data on pregnancies however are scarce. The objective is to describe the pregnancy outcomes in these women. Methods and Results The European Society of Cardiology-EURObservational Research Programme ROPAC (Registry of Pregnancy and Cardiac Disease) is a prospective registry in which data on pregnancies in women with heart disease were collected from 138 centers in 53 countries. Pregnant women with preexistent and pregnancy-onset IHD were included. Primary end point were maternal cardiac events. Secondary end points were obstetric and fetal complications. There were 117 women with IHD, of which 104 had preexisting IHD. Median age was 35.5 years and 17.1% of women were smoking. There was no maternal mortality, heart failure occurred in 5 pregnancies (4.8%). Of the 104 women with preexisting IHD, 11 women suffered from acute coronary syndrome during pregnancy. ST-segment‒elevation myocardial infarction were more common than non‒ST-segment‒elevation myocardial infarction, and atherosclerosis was the most common etiology. Women who had undergone revascularization before pregnancy did not have less events than women who had not. There were 13 women with pregnancy-onset IHD, in whom non‒ST-segment‒elevation myocardial infarction was the most common. Smoking during pregnancy was associated with acute coronary syndrome. Caesarean section was the primary mode of delivery (55.8% in preexisting IHD, 84.6% in pregnancy-onset IHD) and there were high rates of preterm births (20.2% and 38.5%, respectively). Conclusions Women with IHD tolerate pregnancy relatively well, however there is a high rate of ischemic events and these women should therefore be considered moderate- to high-risk. Ongoing cigarette smoking is associated with acute coronary syndrome during pregnancy.

Journal article

West K, Kanu C, Maric T, McDonald J, Nicholson J, Li J, Johnson M, Holmes E, Savvidou Met al., 2020, Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery, Gut, Vol: 69, Pages: 1452-1459, ISSN: 0017-5749

Due to the global increase in obesity rates and success of bariatric surgery in weight reduction, an increasing number of women now present pregnant with a previous bariatric procedure. This study investigates the extent of bariatric-associated metabolic and gut microbial alterations during pregnancy and their impact on fetal development.DesignA parallel metabonomic (1H NMR spectroscopy) and gut bacterial (16S rRNA gene amplicon sequencing) profiling approach was used to determine maternal longitudinal phenotypes associated with malabsorptive/mixed (n=25) or restrictive (n=16) procedures, compared to women with similar early pregnancy body mass index but without bariatric surgery (n=70). Metabolic profiles of offspring at birth were also analysed.ResultsPrevious malabsorptive, but not restrictive, procedures induced significant changes in maternal metabolic pathways involving branched-chain and aromatic amino acids with decreased circulation of leucine, isoleucine and isobutyrate, increased excretion of microbial-associated metabolites of protein putrefaction (phenylacetlyglutamine, p-cresol sulfate, indoxyl sulfate and p-hydroxyphenylacetate), and a shift in the gut microbiota. Urinary concentration of phenylacetylglutamine was significantly elevated in malabsorptive patients relative to controls (P=0.001) and was also elevated in urine of neonates born from these mothers (P=0.021). Furthermore, the maternal metabolic changes induced by malabsorptive surgery were associated with reduced maternal insulin resistance and fetal/birth weight.ConclusionMetabolism is altered in pregnant women with a previous malabsorptive bariatric surgery. These alterations may be beneficial for maternal outcomes, but the effect of elevated levels of phenolic and indolic compounds on fetal and infant health should be investigated further.

Journal article

Ramlakhan KP, Johnson MR, Roos-Hesselink JW, 2020, Pregnancy and cardiovascular disease, Nature Reviews Cardiology, ISSN: 1759-5002

Cardiovascular disease complicates 1-4% of pregnancies - with a higher prevalence when including hypertensive disorders - and is the leading cause of maternal death. In women with known cardiovascular pathology, such as congenital heart disease, timely counselling is possible and the outcome is fairly good. By contrast, maternal mortality is high in women with acquired heart disease that presents during pregnancy (such as acute coronary syndrome or aortic dissection). Worryingly, the prevalence of acquired cardiovascular disease during pregnancy is rising as older maternal age, obesity, diabetes mellitus and hypertension become more common in the pregnant population. Management of cardiovascular disease in pregnancy is challenging owing to the unique maternal physiology, characterized by profound changes to multiple organ systems. The presence of the fetus compounds the situation because both the cardiometabolic disease and its management might adversely affect the fetus. Equally, avoiding essential treatment because of potential fetal harm risks a poor outcome for both mother and child. In this Review, we examine how the physiological adaptations during pregnancy can provoke cardiometabolic complications or exacerbate existing cardiometabolic disease and, conversely, how cardiometabolic disease can compromise the adaptations to pregnancy and their intended purpose: the development and growth of the fetus.

Journal article

Dos Santos F, Baris L, Varley A, Cornette E, Allam J, Steer P, Swan L, Gatzoulis M, Roos-Hesselink J, Johnson MRet al., 2020, Mechanical heart valves and pregnancy: Issues surrounding anticoagulation. Experience from two obstetric cardiac centres, Obstetric Medicine, ISSN: 1753-495X

BackgroundPregnant women with mechanical heart valves are at significant risk of obstetric/cardiac complications. This study compares the anticoagulation management in two obstetric cardiac centres.MethodsRetrospective case-note review from Chelsea and Westminster/Royal Brompton Hospitals (CR) and Erasmus Medical Centre (EMC). Main outcome measure was mechanical heart valve thrombosis.ResultsNineteen pregnancies from CR and 25 pregnancies from EMC were included. Most women were on low-molecular-weight heparin (LMWH) throughout pregnancy at CR, whereas at EMC most had LMWH in the first trimester and vitamin K antagonists in subsequent trimesters. Peak anti-factor Xa were performed monthly at CR, levels 0.39–1.51 IU/mL (mean 0.82 IU/mL). Anticoagulation management peri-partum was inconsistent. Delivery was mainly by Caesarean section at CR (74%) and vaginal delivery at EMC (64%). No maternal deaths and only one mechanical heart valve thrombosis at CR. Two mechanical heart valve thromboses and one maternal death at EMC.ConclusionPeri-partum anticoagulation strategies, anticoagulation monitoring and mode of delivery inconsistencies reported.

Journal article

Maric T, Kanu C, Muller DC, Tzoulaki I, Johnson MR, Savvidou MD, Maric T, Kanu C, Muller DC, Tzoulaki I, Johnson MR, Savvidou MD, Maric T, Kanu C, Muller D, Tzoulaki I, Johnson M, Savvidou Met al., 2020, Fetal growth and fetoplacental circulation in pregnancies following bariatric surgery: a prospective study, Publisher: WILEY, Pages: 839-846, ISSN: 1470-0328

Conference paper

Sliwa K, Azibani F, Johnson MR, Viljoen C, Baard J, Osman A, Briton O, Ntsekhe M, Chin Aet al., 2020, Effectiveness of implanted cardiac rhythm recorders with electrocardiographic monitoring for detecting arrhythmias in pregnant women with symptomatic arrhythmia and/or structural heart disease a randomized clinical trial, JAMA Cardiology, Vol: 5, Pages: 458-463, ISSN: 2380-6583

Importance Arrhythmias are an important cause of maternal morbidity and mortality but remain difficult to diagnose.Objective To compare implantable loop recorder (ILR) plus 24-hour Holter electrocardiographic (ECG) monitoring with standard 24-hour Holter ECG monitoring alone in terms of acceptability, ability to identify significant arrythmias, and effect on management and pregnancy outcome in women who were symptomatic or at high risk of arrythmia because of underlying structural heart disease.Design, Setting, and Participants This single-center, prospective randomized clinical trial recruited 40 consecutive patients from the Cardiac Disease and Maternity Clinic at Groote Schuur Hospital in Cape Town, South Africa. Pregnant patients with symptoms of arrhythmia and/or structural heart disease at risk of arrhythmia were included.Intervention Patients were randomized to standard care (SC; 24-hour Holter ECG monitoring [n = 20]) or standard care plus ILR (SC-ILR; 24-hour Holter ECG monitoring plus ILR [n = 20]). Only 17 consented to ILR insertion, and the 3 who declined ILR were allocated to the SC group.Main Outcomes and Measures Arrhythmias considered included atrial fibrillation, atrial flutter, premature ventricular complexes, supraventricular tachycardia, ventricular tachycardia, or ventricular fibrillation.Results Among the 40 women in this trial, the mean (SD) age was 28.4 (5.5) years. Holter monitoring detected arrhythmias in 3 of 23 patients (13%) in the SC group and 4 of 17 patients (24%) in the SC-ILR group compared with 9 of 17 patients (53%) patients who had arrhythmias detected by ILR. Seven patients (4 with supraventricular tachycardia, 1 with premature ventricular complexes, and 2 with paroxysmal atrial fibrillation recorded by ILR) did not have arrhythmias detected by 24-hour Holter monitoring. Three of these 7 patients (43%) had a change in management as a result of their ILR recordings. There were no maternal deaths.

Journal article

Hua R, Edey LF, O'Dea KP, Howe L, Herbert BR, Cheng W, Zheng X, MacIntyre DA, Bennett PR, Takata M, Johnson MRet al., 2020, CCR2 mediates the adverse effects of LPS in the pregnant mouse, Biology of Reproduction, Vol: 102, Pages: 445-455, ISSN: 0006-3363

In our earlier work, we found that intrauterine (i.u.) and intraperitoneal (i.p.) injection of LPS (10-μg serotype 0111:B4) induced preterm labor (PTL) with high pup mortality, marked systemic inflammatory response and hypotension. Here, we used both i.u. and i.p. LPS models in pregnant wild-type (wt) and CCR2 knockout (CCR2-/-) mice on E16 to investigate the role played by the CCL2/CCR2 system in the response to LPS. Basally, lower numbers of monocytes and macrophages and higher numbers of neutrophils were found in the myometrium, placenta, and blood of CCR2-/- vs. wt mice. After i.u. LPS, parturition occurred at 14 h in both groups of mice. At 7 h post-injection, 70% of wt pups were dead vs. 10% of CCR2-/- pups, but at delivery 100% of wt and 90% of CCR2-/- pups were dead. Myometrial and placental monocytes and macrophages were generally lower in CCR2-/- mice, but this was less consistent in the circulation, lung, and liver. At 7 h post-LPS, myometrial ERK activation was greater and JNK and p65 lower and the mRNA levels of chemokines were higher and of inflammatory cytokines lower in CCR2-/- vs. wt mice. Pup brain and placental inflammation were similar. Using the IP LPS model, we found that all measures of arterial pressure increased in CCR2-/- but declined in wt mice. These data suggest that the CCL2/CCR2 system plays a critical role in the cardiovascular response to LPS and contributes to pup death but does not influence the onset of inflammation-induced PTL.

Journal article

Cauldwell M, Steer PJ, von Klemperer K, Kaler M, Grixti S, Hale J, O'Heney J, Warriner D, Curtis S, Mohan AR, Dockree S, Mackillop L, Head CEG, Sterrenberg M, Wallace S, Freeman LJ, Patridge G, Baalman JH, McAuliffe FM, Simpson M, Walker N, Girling J, Siddiqui F, Bolger AP, Bredaki F, Walker F, Vause S, Gatzoulis MA, Johnson MR, Roberts Aet al., 2020, Maternal and neonatal outcomes in women with history of coronary artery disease, Heart, Vol: 106, Pages: 380-386, ISSN: 1355-6037

Background Pregnancy outcomes in women with pre-existing coronary artery disease (CAD) are poorly described. There is a paucity of data therefore on which to base clinical management to counsel women, with regard to both maternal and neonatal outcomes.Method We conducted a retrospective multicentre study of women with established CAD delivering at 16 UK specialised cardiac obstetric clinics. We included pregnancies of 24 weeks’ gestation or more, delivered between January 1998 and October 2018. Data were collected on maternal cardiovascular, obstetric and neonatal events.Results 79 women who had 92 pregnancies (94 babies including two sets of twins) were identified. 35.9% had body mass index >30% and 24.3% were current smokers. 18/79 (22.8%) had prior diabetes, 27/79 (34.2%) had dyslipidaemia and 21/79 (26.2%) had hypertension. The underlying CAD was due to atherosclerosis in 52/79 (65.8%), spontaneous coronary artery dissection (SCAD) in 11/79 (13.9%), coronary artery spasm in 7/79 (8.9%) and thrombus in 9/79 (11.4%).There were six adverse cardiac events (6.6% event rate), one non-ST elevation myocardial infarction at 23 weeks’ gestation, two SCAD recurrences (one at 26 weeks’ gestation and one at 9 weeks’ postpartum), one symptomatic deterioration in left ventricular function and two women with worsening angina. 14% of women developed pre-eclampsia, 25% delivered preterm and 25% of infants were born small for gestational age.Conclusion Women with established CAD have relatively low rates of adverse cardiac events in pregnancy. Rates of adverse obstetric and neonatal events are greater, highlighting the importance of multidisciplinary care.

Journal article

Cocker A, Shah N, Raj I, Dermont S, Khan W, Mandalia S, Imami N, Johnson Met al., 2020, Pregnancy gestation impacts on HIV-1-specific granzyme B response and central memory CD4 T cells, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224

Pregnancy induces alterations in peripheral T-cell populations with both changes in subset frequencies and anti-viral responses found to alter with gestation. In HIV-1 positive women anti-HIV-1 responses are associated with transmission risk, however detailed investigation into both HIV-1-specific memory responses associated with HIV-1 control and T-cell subset changes during pregnancy have not been undertaken. In this study we aimed to define pregnancy and gestation related changes to HIV-1-specific responses and T-cell phenotype in ART treated HIV-1 positive pregnant women. Eleven non-pregnant and 24 pregnant HIV-1 positive women were recruited, peripheral blood samples taken, fresh cells isolated, and compared using ELISpot assays and flow cytometry analysis. Clinical data were collected as part of standard care, and non-parametric statistics used. Alterations in induced IFNγ, IL-2, IL-10, and granzyme B secretion by peripheral blood mononuclear cells in response to HIV-1 Gag and Nef peptide pools and changes in T-cell subsets between pregnant and non-pregnant women were assessed, with data correlated with participant clinical parameters and longitudinal analysis performed. Cross-sectional comparison identified decreased IL-10 Nef response in HIV-1 positive pregnant women compared to non-pregnant, while correlations exhibited reversed Gag and Nef cytokine and protease response associations between groups. Longitudinal analysis of pregnant participants demonstrated transient increases in Gag granzyme B response and in the central memory CD4 T-cell subset frequency during their second trimester, with a decrease in CD4 effector memory T cells from their second to third trimester. Gag and Nef HIV-1-specific responses diverge with pregnancy time-point, coinciding with relevant T-cell phenotype, and gestation associated immunological adaptations. Decreased IL-10 Nef and both increased granzyme B Gag response and central memory CD4 T cells implies that amplified a

Journal article

Ibeto L, Antonopoulos A, Grassi P, Pang P-C, Panico M, Bobdiwala S, Al-Memar M, Davis P, Davis M, Norman Taylor J, Almeida P, Johnson MR, Harvey R, Bourne T, Seckl M, Clark G, Haslam SM, Dell Aet al., 2020, Insights into the hyperglycosylation of human chorionic gonadotropin revealed by glycomics analysis, PLoS One, Vol: 15, ISSN: 1932-6203

Human chorionic gonadotropin (hCG) is a glycoprotein hormone that is essential for the maintenance of pregnancy. Glycosylation of hCG is known to be essential for its biological activity. "Hyperglycosylated" variants secreted during early pregnancy have been proposed to be involved in initial implantation of the embryo and as a potential diagnostic marker for gestational diseases. However, what constitutes "hyperglycosylation" is not yet fully understood. In this study, we perform comparative N-glycomic analysis of hCG expressed in the same individuals during early and late pregnancy to help provide new insights into hCG function, reveal new targets for diagnostics and clarify the identity of hyperglycosylated hCG. hCG was isolated in urine collected from women at 7 weeks and 20 weeks' gestation. hCG was also isolated in urine from women diagnosed with gestational trophoblastic disease (GTD). We used glycomics methodologies including matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF) mass spectrometry (MS) and MS/MS methods to characterise the N-glycans associated with hCG purified from the individual samples. The structures identified on the early pregnancy (EP-hCG) and late pregnancy (LP-hCG) samples corresponded to mono-, bi-, tri-, and tetra-antennary N-glycans. A novel finding was the presence of substantial amounts of bisected type N-glycans in pregnancy hCG samples, which were present at much lower levels in GTD samples. A second novel observation was the presence of abundant LewisX antigens on the bisected N-glycans. GTD-hCG had fewer glycoforms which constituted a subset of those found in normal pregnancy. When compared to EP-hCG, GTD-hCG samples had decreased signals for tri- and tetra-antennary N-glycans. In terms of terminal epitopes, GTD-hCG had increased signals for sialylated structures, while LewisX antigens were of very minor abundance. hCG carries the same N-glycans throughout pregnancy but in different propo

Journal article

Sliwa K, Baris L, Sinning C, Zengin-Sahm E, Gumbiene L, Yaseen IF, Youssef G, Johnson M, Al-Farhan H, Lelonek M, Hall R, Roos-Hesselink Jet al., 2020, Pregnant women with uncorrected congenital heart disease heart failure and mortality, JACC: Heart Failure, Vol: 8, Pages: 100-110, ISSN: 2213-1779

ObjectivesThe purpose of this work was to study maternal and fetal outcomes of women with uncorrected congenital heart disease (CHD).BackgroundGlobally, CHD is an important cause of maternal morbidity and mortality in women reaching reproductive stage. Data are lacking from larger cohorts of women with uncorrected CHD.MethodsThe 10-year data from the European Society of Cardiology EORP ROPAC (EURObservational Research Programme Registry of Pregnancy and Cardiac disease) registry of women with uncorrected CHD were analyzed.ResultsOf 5,739 pregnancies in 53 countries, 3,295 women had CHD, 1,059 of which were uncorrected cases. Of these, 41.4% were from emerging countries. There were marked differences between the cardiac defects in uncorrected cases versus those in corrected CHD cases with primary shunt lesions (44.7% vs. 32.4%, respectively), valvular abnormalities (33.5% vs. 12.6%, respectively), and Tetralogy of Fallot and pulmonary atresia (0.8% vs. 20.3%, respectively; p < 0.001). In patients with uncorrected CHD, 6.8% were in modified World Health Organization risk class IV, approximately 10% had pulmonary hypertension (PH), and 3% were cyanotic prior to pregnancy. Maternal mortality and heart failure (HF) in the women with uncorrected CHD were 0.7% and 8.7%, respectively. Eisenmenger syndrome was associated with a very high risk of cardiac events (65.5%), maternal mortality (10.3%), and HF (48.3%). Coming from an emerging country was associated with higher pre-pregnancy signs of HF, PH, and cyanosis (p < 0.001) and worse maternal and fetal outcomes, with a 3-fold higher rate of hospital admissions for cardiac events and intrauterine growth retardation (p < 0.001).ConclusionsMarked differences between cardiac conditions in pregnant women with uncorrected CHD and those in corrected CHD were found, with a markedly worse outcome, particularly in women with Eisenmenger syndrome and from emerging countries.

Journal article

Zöllner J, Howe LG, Edey LF, O'Dea KP, Takata M, Leiper J, Johnson MRet al., 2020, LPS-induced hypotension in pregnancy: the effect of progesterone supplementation, Shock, Vol: 53, Pages: 199-207, ISSN: 1073-2322

Our previous work has shown that pregnancy exacerbates the hypotensive response to both infection and LPS. The high levels of progesterone (P4) associated with pregnancy have been suggested to be responsible for the pregnancy-induced changes in the cardiovascular response to infection. Here, we test the hypothesis that P4 supplementation exacerbates the hypotensive response of the maternal cardiovascular to LPS.Female CD1 mice had radiotelemetry probes implanted to measure haemodynamic function non-invasively and were time-mated. From day 14 of pregnancy, mice received either 10 mg of P4 or vehicle alone per day and on day 16, intraperitoneal LPS (10 μg of serotype 0111:B4) was injected. In two identically treated cohorts of mice, tissue and serum (for RNA, protein studies) were collected at 6 and 12 hours.Administration of LPS resulted in a fall in blood pressure in vehicle treated, but not P4 supplemented mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors and in both circulating and tissue inflammatory cell numbers, but with reduced left ventricular expression of cytokines in P4-supplemented mice. However, left ventricular expression of markers of cardiac dysfunction and apoptosis were similar.This study demonstrates that P4 supplementation prevented LPS-induced hypotension in pregnant mice in association with reduced myocardial inflammatory cytokine gene expression. These observations suggest that rather than being detrimental, P4 supplementation has a protective effect on the maternal cardiovascular response to sepsis.

Journal article

Shah NM, Edey LF, Imami N, Johnson MRet al., 2020, Human labour is associated with altered regulatory T cell function and maternal immune activation, Clinical & Experimental Immunology, Vol: 199, Pages: 182-200, ISSN: 0009-9104

During human pregnancy, regulatory T cell (Treg) function is enhanced and immune activation is repressed allowing the growth and development of the feto–placental unit. Here, we have investigated whether human labour is associated with a reversal of the pregnancy‐induced changes in the maternal immune system. We tested the hypothesis that human labour is associated with a decline in Treg function, specifically their ability to modulate Toll‐like receptor (TLR)‐induced immune responses. We studied the changes in cell number, activation status and functional behaviour of peripheral blood, myometrial (myoMC) and cord blood mononuclear cells (CBMC) with the onset of labour. We found that Treg function declines and that Treg cellular targets change with labour onset. The changes in Treg function were associated with increased activation of myoMC, assessed by their expression of major histocompatibility complex (MHC) class II molecules and CBMC inflammatory cells. The innate immune system showed increased activation, as shown by altered monocyte and neutrophil cell phenotypes, possibly to be ready to respond to microbial invasion after birth or to contribute to tissue remodelling. Our results highlight changes in the function of the adaptive and innate immune systems that may have important roles in the onset of human labour.

Journal article

Cífková R, Johnson MR, Kahan T, Brguljan J, Williams B, Coca A, Manolis A, Thomopoulos C, Borghi C, Tsioufis C, Parati G, Sudano I, McManus RJ, van den Born B-JH, Regitz-Zagrosek V, de Simone Get al., 2020, Peripartum management of hypertension: a position paper of the ESC Council on Hypertension and the European Society of Hypertension, European Heart Journal - Cardiovascular Pharmacotherapy, ISSN: 2055-6845

Hypertensive disorders are the most common medical complications in the peripartum period associated with a substantial increase in morbidity and mortality. Hypertension in the peripartum period may be due to the continuation of pre-existing or gestational hypertension, de novo development of pre-eclampsia or it may be also induced by some drugs used for analgesia or suppression of postpartum haemorrhage. Women with severe hypertension and hypertensive emergencies are at high risk of life threatening complications, therefore, despite the lack of evidence-based data, based on expert opinion, antihypertensive treatment is recommended. Labetalol intravenously and metyldopa orally are then the two most frequently used drugs. Short-acting oral nifedipine is suggested to be used only if other drugs or iv access are not available. Induction of labour is associated with improved maternal outcome and should be advised for women with gestational hypertension or mild pre-eclampsia at 37 weeks᾽ gestation. This position paper provides the first interdisciplinary approach to the management of hypertension in the peripartum period based on the best available evidence and expert consensus.

Journal article

Lai PF, Georgiou EX, Tribe RM, Johnson MRet al., 2020, The impact of progesterone and RU-486 on classic pro-labour proteins & contractility in human myometrial tissues during 24-hour exposure to tension & Interleukin-1β, Molecular and Cellular Endocrinology, Vol: 500, ISSN: 0303-7207

Increased expression of pro-labour genes that encode cyclooxygenase-2 (COX-2), oxytocin receptor (OTR) and connexin-43 (Cx43) at parturition is often attributed to P4 functional withdrawal, based on findings from animal models and human primary myometrial cells. However, the cause of reduced myometrial P4 responsiveness that promotes contractions at labour is not fully determined. Uterine stretch occurs with advancing gestation but most in vitro experimental models do not take this into consideration. We aimed to examine whether tissue-level myometrial stretch influences the ability of P4 to regulate pro-labour protein abundance by using myometrial biopsies from term gestation pregnant women to assess the impact of 24 h exposure to combinations of (i) stretch-mediated tension, (ii) P4 (100 nM) and (iii) an anti-progestin, RU-486 (1 μM). Firstly, we observed baseline COX-2 and Cx43 protein levels increased, whereas P4 content along with calponin-1 and progesterone receptor (PR) protein abundance decreased, in vehicle-treated tissues. P4 supplementation subtly reduced COX-2 levels in un-stretched tissues. Spontaneous and oxytocin-augmented contractility were unchanged by tissue culture exposure to P4 and/or RU-486. Interleukin-1β (IL-1β; 1 ng/ml) enhanced COX-2 protein and PGE2 content in un-stretched tissues. Overall, tissue stretch may, in part, regulate P4-sensitive pro-labour protein levels, but this is likely to be reliant on interaction with other in utero factors that were absent in our tissue cultures. More complex culture conditions should be evaluated in future to aid further development of a physiologically relevant model to improve our understanding of in utero myometrial P4 responsiveness.

Journal article

Greer O, Shah NM, Johnson MR, 2020, Maternal sepsis update: current management and controversies, The Obstetrician & Gynaecologist, Vol: 22, Pages: 45-55, ISSN: 1467-2561

•Sepsis is a leading cause of maternal morbidity and mortality, globally and in the UK.•In pregnancy and the puerperium, women may be more susceptible to rapid deterioration of illness following an infection.•Sepsis has a complex pathophysiology and the immunological and cardiovascular adaptations of normal pregnancy may have an adverse impact on the maternal response to infection. Furthermore, physiological changes of pregnancy, which mimic those of sepsis, often delay optimal management.•‘Bedside’ identification of pathogens and their antibiotic resistance patterns may help to improve clinical outcomes.•Recent updates in sepsis management, areas of controversy and the importance of translational research and clinical trials for pregnancy and the puerperium are discussed.

Journal article

Roos-Hesselink J, Baris L, Johnson M, De Backer J, Otto C, Marelli A, Jondeau G, Budts W, Grewal J, Sliwa K, Parsonage W, Maggioni AP, van Hagen I, Vahanian A, Tavazzi L, Elkayam U, Boersma E, Hall Ret al., 2019, Pregnancy outcomes in women with cardiovascular disease: evolving trends over 10 years in the ESC Registry Of Pregnancy And Cardiac disease (ROPAC), European Heart Journal, Vol: 40, Pages: 3848-3855, ISSN: 1522-9645

AIMS: Reducing maternal mortality is a World Health Organization (WHO) global health goal. Although maternal deaths due to haemorrhage and infection are declining, those related to heart disease are increasing and are now the most important cause in western countries. The aim is to define contemporary diagnosis-specific outcomes in pregnant women with heart disease. METHODS AND RESULTS: From 2007 to 2018, pregnant women with heart disease were prospectively enrolled in the Registry Of Pregnancy And Cardiac disease (ROPAC). Primary outcome was maternal mortality or heart failure, secondary outcomes were other cardiac, obstetric, and foetal complications. We enrolled 5739 pregnancies; the mean age was 29.5. Prevalent diagnoses were congenital (57%) and valvular heart disease (29%). Mortality (overall 0.6%) was highest in the pulmonary arterial hypertension (PAH) group (9%). Heart failure occurred in 11%, arrhythmias in 2%. Delivery was by Caesarean section in 44%. Obstetric and foetal complications occurred in 17% and 21%, respectively. The number of high-risk pregnancies (mWHO Class IV) increased from 0.7% in 2007-2010 to 10.9% in 2015-2018. Determinants for maternal complications were pre-pregnancy heart failure or New York Heart Association >II, systemic ejection fraction <40%, mWHO Class 4, and anticoagulants use. After an increase from 2007 to 2009, complication rates fell from 13.2% in 2010 to 9.3% in 2017. CONCLUSION: Rates of maternal mortality or heart failure were high in women with heart disease. However, from 2010, these rates declined despite the inclusion of more high-risk pregnancies. Highest complication rates occurred in women with PAH.

Journal article

Zöllner J, Lambden S, Nasri NM, Johnson M, Leiper Jet al., 2019, Inhibition of dimethylarginine dimethylaminohydrolase 1 improves the outcome of sepsis in pregnant mice., Shock, ISSN: 1073-2322

Sepsis is one of the most important causes of maternal mortality. In our previous work, we established a polymicrobial sepsis (caecal ligation and puncture, [CLP]) model in murine pregnancy and found that pregnant mice had a greater susceptibility to septic shock. In this model, mortality appeared to be associated with the development of early haemodynamic dysfunction and although circulating cytokine levels were similar, "off target" lung inflammatory cell numbers were greater in pregnant mice.Here, we have used the same CLP model to test the hypothesis that inhibiting the metabolism of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine would improve the outcome of sepsis in pregnancy. We used a dimethylarginine dimethylaminohydrolase 1-selective inhibitor (L-257), which reduces vascular nitric oxide synthesis without impairing immune cell function, in combination with a broad-spectrum antibiotic (Imipenem) and studied the outcome of septic shock in pregnant mice. Treatments were administered 3 hours after CLP and samples were taken 3 hours later. Both Imipenem and L-257 treatment alone slightly improved mortality rates from 13% (NaCl) to 20% (Imipenem) and 33% (L-257), while the combination of Imipenem and L-257, significantly improved survival to 50%. Imipenem and L-257 together prevented cardiovascular collapse and improved both organ function and bacterial killing but did not reduce lung inflammatory cell numbers and actually increased lung cytokine levels.These data suggest that conventional management in combination with selective inhibition of DDAH1 may have therapeutic potential in the management of sepsis in pregnancy.

Journal article

Singh N, Herbert B, Sooranna G, Das A, Sooranna SR, Yellon SM, Johnson MRet al., 2019, Distinct preterm labor phenotypes have unique inflammatory signatures and contraction associated protein profiles, Biology of Reproduction, Vol: 101, Pages: 1031-1045, ISSN: 0006-3363

Preterm labor (PTL) is the predominant cause of childhood morbidity and mortality. It has several phenotypes, each with a distinct etiology often involving inflammation. Here, in samples of reproductive tissues obtained in early PTL from women with phenotypically defined PTL, we examined the presence and distribution of inflammation and its relationship with prolabor gene expression. In chorioamnionitis (CA-PTL), cytokine protein concentrations were increased across all tissues; in idiopathic (I-PTL), the inflammatory changes were limited to the choriodecidua; inflammation was not a feature of placental abruption (PA-PTL). CA-PTL was associated with activation of p65 in the myometrium and AP-1 in the choriodecidua, and PA-PTL with CREB in the choriodecidua. In the myometrium, PGHS-2 mRNA level was increased in CA- and I-PTL; in the amnion, PGHS-2 mRNA level was higher in PA- and I-PTL, while in CA-PTL, OT, OTR mRNA, and CX-43 expression were increased. In the choriodecidua, PGHS-2 mRNA level was unchanged, but in CA and I-PTL, OT mRNA level were increased and OTR was reduced. These data show that CA-PTL is associated with widespread inflammation and prolabor gene expression. In contrast, in I-PTL, inflammation is limited to the choriodecidua, with discrete increases in PGHS-2 in the amnion and OT in the choriodecidua. Inflammation is not a feature of PA-PTL, which is associated with increased OT and OTR in the amnion.

Journal article

Shah NM, Imami N, Kelleher P, Barclay WS, Johnson MRet al., 2019, Pregnancy-related immune suppression leads to altered influenza vaccine recall responses, Clinical Immunology, Vol: 208, ISSN: 1521-6616

Pregnancy is a risk factor for severe influenza infection. Despite achieving seroprotective antibody titres post immunisation fewer pregnant women experience a reduction in influenza-like illness compared to non-pregnant cohorts. This may be due to the effects that immune-modulation in pregnancy has on vaccine efficacy leading to a less favourable immunologic response.To understand this, we investigated the antigen-specific cellular responses and leukocyte phenotype in pregnant and non-pregnant women who achieved seroprotection post immunisation. We show that pregnancy is associated with better antigen-specific inflammatory (IFN-γ) responses and an expansion of central memory T cells (Tcm) post immunisation, but low-level pregnancy-related immune regulation (HLA-G, PIBF) and associated reduced B-cell antibody maintenance (TGF-β) suggest poor immunologic responses compared to the non-pregnant.Thus far, studies of influenza vaccine immunogenicity have focused on the induction of antibodies but understanding additional vaccine-related cellular responses is needed to fully appreciate how pregnancy impacts on vaccine effectiveness.

Journal article

Cauldwell M, Steer PJ, Curtis SL, Mohan A, Dockree S, Mackillop L, Parry HM, Oliver J, Sterrenberg M, Wallace S, Malin G, Partridge G, Freeman LJ, Bolger AP, Siddiqui F, Wilson D, Simpson M, Walker N, Hodson K, Thomas K, Bredaki F, Mercaldi R, Walker F, Johnson MRet al., 2019, Maternal and fetal outcomes in pregnancies complicated by Marfan syndrome., Heart, Vol: 105, Pages: 1725-1731, ISSN: 1355-6037

OBJECTIVES: Information to guide counselling and management for pregnancy in women with Marfan syndrome (MFS) is limited. We therefore conducted a UK multicentre study. METHODS: Retrospective observational study of women with MFS delivering between January 1998 and March 2018 in 12 UK centres reporting data on maternal and neonatal outcomes. RESULTS: In total, there were 258 pregnancies in 151 women with MFS (19 women had prior aortic root replacements), including 226 pregnancies ≥24 weeks (two sets of twins), 20 miscarriages and 12 pregnancy terminations. Excluding miscarriages and terminations, there were 221 live births in 139 women. Only 50% of women received preconception counselling. There were no deaths, but five women experienced aortic dissection (1.9%; one type A and four type B-one had a type B dissection at 12 weeks and subsequent termination of pregnancy). Five women required cardiac surgery postpartum. No predictors for aortic dissection could be identified. The babies of the 131 (65.8%) women taking beta-blockers were on average 316 g lighter (p<0.001). Caesarean section rates were high (50%), particularly in women with dilated aortic roots. In 55 women, echocardiographic aortic imaging was available prepregnancy and postpregnancy; there was a small but significant average increase in AoR size of 0.84 mm (Median follow-up 2.3 months) CONCLUSION: There were no maternal deaths, and the aortic dissection rate was 1.9% (mainly type B). There with no identifiable factors associated with aortic dissection in our cohort. Preconception counselling rates were low and need improvement. Aortic size measurements increased marginally following pregnancy.

Journal article

Greer O, Shah NM, Sriskandan S, Johnson MRet al., 2019, Sepsis: precision-based medicine for pregnancy and the puerperium, International Journal of Molecular Sciences, Vol: 20, Pages: 1-18, ISSN: 1422-0067

Sepsis contributes significantly to global morbidity and mortality, particularly in vulnerable populations. Pregnant and recently pregnant women are particularly prone to rapid progression to sepsis and septic shock, with 11% of maternal deaths worldwide being attributed to sepsis. The impact on the neonate is considerable, with 1 million neonatal deaths annually attributed to maternal infection or sepsis. Pregnancy specific physiological and immunological adaptations are likely to contribute to a greater impact of infection, but current approaches to the management of sepsis are based on those developed for the non-pregnant population. Pregnancy-specific strategies are required to optimise recognition and management of these patients. We review current knowledge of the physiology and immunology of pregnancy and propose areas of research, which may advance the development of pregnancy-specific diagnostic and therapeutic approaches to optimise the care of pregnant women and their babies.

Journal article

Viljoen CA, Sliwa K, Azibani F, Johnson MR, Baard J, Osman A, Briton O, Ntsekhe M, Anthony J, Chin Aet al., 2019, Prospective randomized study on implanted cardiac rhythm recorders in pregnant women with symptomatic arrhythmia and/or structural heart disease, Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: Oxford University Press (OUP), Pages: 1496-1496, ISSN: 0195-668X

BackgroundCardiac arrhythmia is an important cause of maternal morbidity and mortality in pregnancy, but is difficult to diagnose.PurposeThe aim of this single-centre, prospective, randomized pilot study was to compare the implantable loop recorder (ILR) with standard assessment of arrhythmia (12-lead ECG; 24-hour Holter ECG) in terms of acceptability, detection of arrhythmias and impact on outcome in pregnant women with symptomatic arrhythmias and/or structural heart disease (SHD).MethodsThe study recruited 40 consecutive patients from a weekly, dedicated cardiac obstetric clinic. Inclusion criteria: symptoms of arrhythmia and/or having SHD at risk of arrhythmia. Patients were randomized to either standard care (SC) or standard care plus ILR (SC-ILR). ILR recordings were read at the monthly visits and/or when presenting with symptoms.ResultsThere were no demographic differences between the study groups. Seventeen patients consented to ILR insertion, all of whom found the procedure acceptable. No arrhythmias were recorded by the 12-lead ECGs. Holter monitoring detected arrhythmias in 10 of 23 patients (43%) from the SC group. In the SC-ILR group, 8 of 17 patients (47%) had arrhythmias detected by Holter, whereas 13 of 17 patients (76%) patients had arrhythmias detected by ILR (p=0.157). One of 4 patients with supraventricular tachycardia, 2 of 3 patients with premature ventricular complexes and 2 patients with paroxysmal atrial fibrillation (AF) recorded by ILR did not have the arrhythmias detected by Holter monitoring (Figure 1A shows a scatter plot of the variable R-R intervals seen in AF and 1B a rhythm strip of AF with irregular RR intervals and the absence of P waves, both downloaded from the ILR). Four of these 5 patients (80%) had a change in management as a direct result of their ILR recordings. There were no maternal deaths up to 42 days postpartum in either of the study groups. Nine babies were born with a low birthweight (<2500g), 5 stillbirth/neonatal

Conference paper

Herbert BR, Markovic D, Georgiou E, Lai PF, Singh N, Yulia A, Johnson MRet al., 2019, Aminophylline and progesterone prevent inflammation-induced preterm parturition in the mouse, Biology of Reproduction, Vol: 101, Pages: 813-822, ISSN: 1529-7268

Although progesterone (P4) supplementation is the most widely used therapy for the prevention of preterm labor (PTL), reports of its clinical efficacy have been conflicting. We have previously shown that the anti-inflammatory effects of P4 can be enhanced by increasing intracellular cAMP levels in primary human myometrial cells. Here we have examined whether adding aminophylline (Am), a non-specific phosphodiesterase (PDE) inhibitor that increases intracellular cyclic adenosine monophosphate (cAMP) levels, to P4 might improve its efficacy using in vivo and in vitro models of PTL. In a mouse model of lipopolysaccharide (LPS)-induced PTL, we found that the combination of P4 and Am delayed the onset of LPS-induced PTL, while the same dose of P4 and Am alone had no effect. Pup survival was not improved by either agent alone or in combination. Myometrial prolabor and inflammatory cytokine gene expression was reduced, but the reduction was similar in P4 and P4/Am treated mice. There was no effect of the combination of P4 and Am on an ex vivo assessment of myometrial contractility. In human myometrial cells and myometrial tissue explants, we found that the combination had marked anti-inflammatory effects, reducing cytokine and COX-2 mRNA and protein levels to a greater extent than either agent alone. These data suggest that the combination of P4 and Am has a more potent anti-inflammatory effect than either agent alone and may be an effective combination in women at high-risk of PTL.

Journal article

Charani E, Cunnington AJ, Yousif AHA, Ahmed MS, Ahmed AEM, Babiker S, Bedri S, Buytaert W, Crawford MA, Elbashir MI, Elhag K, Elsiddig KE, Hakim N, Johnson MR, Miras AD, Swar MO, Templeton MR, Taylor-Robinson SDet al., 2019, In transition: current health challenges and priorities in Sudan, BMJ Global Health, Vol: 4:e001723, ISSN: 2059-7908

A recent symposium and workshop in Khartoum, the capital of the Republic of Sudan, brought together broad expertise from three universities to address the current burden of communicable and non-communicable diseases facing the Sudanese healthcare system. These meetings identified common challenges that impact the burden of diseases in the country, most notably gaps in data and infrastructure which are essential to inform and deliver effective interventions. Non-communicable diseases, including obesity, type 2 diabetes, renal disease and cancer are increasing dramatically, contributing to multimorbidity. At the same time, progress against communicable diseases has been slow, and the burden of chronic and endemic infections remains considerable, with parasitic diseases (such as malaria, leishmaniasis and schistosomiasis) causing substantial morbidity and mortality. Antimicrobial resistance has become a major threat throughout the healthcare system, with an emerging impact on maternal, neonatal, and paediatric populations. Meanwhile, malnutrition, micronutrient deficiency, and poor perinatal outcomes remain common and contribute to a lifelong burden of disease. These challenges echo the UN sustainable development goals and concentrating on them in a unified strategy will be necessary to address the national burden of disease. At a time when the country is going through societal and political transition, we draw focus on the country and the need for resolution of its healthcare needs.

Journal article

Maric T, Kanu C, Johnson MR, Savvidou MDet al., 2019, Maternal, neonatal insulin resistance and neonatal anthropometrics in pregnancies following bariatric surgery, METABOLISM-CLINICAL AND EXPERIMENTAL, Vol: 97, Pages: 25-31, ISSN: 0026-0495

Journal article

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