Accuracy of Antepartum Ultrasound in Evaluating Placental

Posted on Authorea 21 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160856757.72561367/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. vsuaiyo h eihrlvloste n ogse tmvsesuigSMI using spiral the vessels previously the also stem we but from contrast, congested tissue, In space and placental invasive intervillous mothers. tree with insertion the villous the myometrium of cord peripheral in thin rate umbilical the the flow heart only of the the blood avascularity not matches from slow increta, that visualized placenta Additionally, ”scatter” in a be demonstrated, as villi. can visualized terminal vessels also the and is blood investigated artery villi villous we stem placenta, Therefore, the normal it to prognosis. a examination, the in predict ultrasound SMI, SMI. and using Using using state antenatally findings disease findings pathologic the pathological placental understand the of evaluation to predict pregnancy. useful to during performed be possible complications retrospectively in would is resulted is have it can examination could if SMI that pathological However, abnormalities methods, Placental placental evaluate imaging to abnormalities. Doppler delivery after placental on color conventional of based vessels small signals the diagnoses Medical in eliminating to flow and Canon by blood Compared by low-velocity artifacts visualize produced movement. motion better significantly technique minimize tissue to of imaging algorithm flow analysis unique the blood a recent employs a (Japan), Systems (SMI), Imaging microvascular Superb The improve respectively. Introduction may modality 0.920, This and abnormalities. villi. placental 80%, avascular of 80%, and cases (AUC infarction of and in insufficient placental preeclampsia, cases management as were 57%, with such perinatal chorangiosis in 100%, findings, cases the and AUC were pathologic in villi placental villi and stem predictive 0.780 detect avascular sensitivity, of accurately and (positive for can congestion PPV, 67%, FGR AUC of 67%, whereas and predictive in FGR, sensitivity, 0.945), accuracies infarction with PPV, diagnostic [AUC], cases placental Additionally, curve in with 0.540). the 0.785 observed (AUC and under was low area relatively accuracy pre-eclampsia, were 89%; (FGR), of highest restriction preeclampsia sensitivity, detection The growth ultrasound 100%; fetal antenatal to Results: [PPV], of due value accuracy admitted The indications. were who microscopic other findings. for women ultrasound and between clipped obtained was compared placenta tissue was the placental pathologies identify the of placental delivery, to location examinations After Ultrasound the delivery. before as enrolled. were performed examination, management pregnant were antenatal (STROBE), perinatal SMI for study detect using center observational pathologies can perinatal diagnostic placental our prospective imaging) to this microvascular admitted In were superb who Methods: (SMI: women placentas. Doppler pathologic ultrasound in microvascular findings histological whether clarify To Objectives: Abstract 2020 21, December 3 2 1 Suzuki Furuya Natsumi research main article imaging: microvascular superb placental using evaluating pathology in ultrasound antepartum of Accuracy ffiito o available Medicine not of Affiliation School University Marianna St. Daigaku Ika Marianna Sei 3 1 UIH HASEGAWA JUNICHI , 2 aaooDoi Masatomo , 1 1 hc losdpcino h pathology the of depiction allows which , 2 uk Koike Junki , 2 . < .0) ocuin:SMI Conclusions: 0.700). 2 n Nao and , Posted on Authorea 21 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160856757.72561367/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. eia ytm,Jpn.Stigfrvsaiaini -oeadSI nldn an yai range, dynamic gain, including SMI, and (Canon B-mode probe Convex in MHz visualization 1–8 with for i700 Setting Aplio an was and Japan). study villi present Systems, standard the the Medical in with used compared equipment ultrasound villi The terminal high-echoic as defined is ”fluffy”. findings appear SMI a as Chorangiosis the with (Chorangiosis) compared villi villi terminal stem Hyper-vascular dilated clearly S4). as Appendix defined 2c, is (Figure finding SMI vessels an stem as villous vessels surrounding stem the of (Congestion) Congestion villi ”scatter” stem background the of only Dilatation present, is c. space trees intervillous villous the normal but absent without is observed flow is and blood villous ”scatter” the background only Since the space both villi echoic an terminal disappear, Avascular in space resulting b. intervillous thus, and detected, not vessels are blood tree” villous “villous the both Since space intervillous flow the blood in Tertiary follows. maternal Infarction ’scatter’ Additionally, as side. as defined diminished. maternal the were observed sharply side—from the findings is and fetal into abnormal artery the homogenous contrast, villi on are spiral terminal identified tree the the are villous to from trees the villi—connecting villous in stem and the vessels placenta the SMI, stem the using to placenta of insertion the form cord of and umbilical findings location site. normal the findings insertion the on exhibited cord In based the umbilical placenta found, the the were from with findings on cord relationship SMI ultrasound location velamentous spatial using some respective the as precisely When the evaluated such to placenta plate. then abnormalities, chorionic mapped The was the were gross JH). placenta to detect and The layer to (NF decidual entanglement. the authors B-mode and two using cord, by evaluated hyper-coiled performed insertion, were were cord study umbilical present and the in examinations Ultrasound those to compared SMI were the using SMI in findings on examination. findings findings Ultrasound pathological SMI The for the delivery. submitted before Therefore, weeks placenta perinatal weeks. 1–2 the 1–2 our within of every those to ultrasound of pregnancy Placental were admitted during analysis enrolled. were performed present were was who 2020 February SMI women and using 2019 pregnant evaluation March between study, management observational perinatal for diagnostic center prospective, this In to findings. population was Patient pathological study placental present of for the accuracies SMI of diagnostic using aim evaluation the Methods The ultrasound reproducibility, evaluated. antenatal and were of placenta objectivity accuracy was pathologic the demonstrate the it clarify to Consequently, of order findings SMI. in ultrasound in various findings. study, expressed pathological present was the background the ’scatter’ match and In background SMI trees of only villous findings villi, both the avascular without that of space confirmed cases echo-free In in expressed scatters. are findings SMI infarctions pathological using placental antenatally placental findings confirmed with pathological them placental various compared demonstrated and we study, pilot a in Furthermore, Fgr -,Apni S5). Appendix 2-d, (Figure Fgr b pedxS3). Appendix 2b, (Figure 2 3 codn oorivsiain,pathologically investigations, our to According . Fgr a pedxS2). Appendix 2a, (Figure Fgr ,Apni S1) Appendix 1, (Figure In . Posted on Authorea 21 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160856757.72561367/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. h atcpnsicue 9csso G n/rpecapi n 5csso disosdet other to due admissions of cases 15 and preeclampsia and/or FGR enrolled. of were cases hospital 19 our in in included presented unit) participants are care participants The intensive the (Maternal-fetal of MFICU characteristics the The to admitted women pregnant the Kawasaki, pre-evaluated of Medicine, principles The patients. the of all with School accordance from University in obtained was Marianna conducted Results was consent investigation informed St. Written This of Helsinki. 2019). board 27, of ethics Declaration Sep. the 4543; by (No. approved Japan at was twice findings study of This types 4 22 as in JH) places statement and 22 Ethics (NF of error. examiners findings intra-observer two the the the evaluated calculated between (NF) findings and intervals, of inspector inter-observer types an An four Additionally, agreement. the inter-observer findings. examining the by calculate determined to was used were error placentas pathological in findings binomial SMI the error inter-observer under area and of (ROC) intra- the values using of characteristics finding Analysis predictive operating each (NPV) of Receiver accuracy negative sections diagnostic (AUC). cotyledon and calculated. curve the random ROC estimate (PPV) were to 3 positive findings generated were as pathological [?] curves well and in as findings found specificity ultrasound are villi and them these sensitivity of of Diagnostic more more or or 10 10 villus; and intermediate analysis Accuracy or 10x terminal at one field in visual found 3d). a are (Figure vessels in blood found more are or 10 least At villi to vessel terminal villous Hyper-vascular stem a c. of enlargement caliber an similar as defined of is vessels villi stem of Dilatation villi stem of Dilatation d. and 3b). vessels (Figure blood all of disappearance vitrified with and villi karyorrhexis stromal-vascular Villous villi coagulative terminal infiltration Avascular and neutrophil by aggregation b. accompanied villous are They associated time. with 3a). over space (Figure disappear intervillous structures nuclear the all of and collapse necrosis, a reveal Infarctions by performed were examinations KJ). findings Infarction to and Pathological pathological a. according MD, following delivery. JH, locations The after (NF, the placenta pathologists placenta. in and the the examination obstetricians in of microscopic confirmed investigation for histologically macroscopic were clipped and was mapped tissue ultrasonically placental the delivery, parameters. preset After these using performed was for findings case determined Pathological each and adjusted in investigation preliminarily were The sensitivity evaluation. Doppler placental and Frequency), Repectition (Pulse PRF stroma κ- auso ne-aditaosre roswr .6ad08,rsetvl.Thirty-four respectively. 0.88, and 0.76 were errors intra-observer and inter- of values Fgr 3c). (Figure 3 al 1 Table h einmtra g a 35years. 33.5 was age maternal median The . > ie hto neighboring of that times 4 nfrl fibrotic uniformly Posted on Authorea 21 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160856757.72561367/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ml nacin ih edffiutt itnus rmaaclrvliepesda cte ihu villous without Diffuse scatter detected. as easily expressed be villi the could avascular in lesions findings from larger pathologic distinguish much large to that and/or difficult many reason malperfusion, trees be have the maternal might to by be likely infarctions affected might are small adversely cases believe preeclampsia, more in we and Cases higher which FGR was pre-eclampsia. placenta, with SMI with using those cases villi as in avascular such and that FGR infarction than and predicting FGR for preeclampsia with masses accuracy severe intra-placental diagnostic echogenic plate in the complex basal However, found as the lesions are large to central deposition these multiple close detect however, infarction fibrin can placental pregnancies; intervillous ultrasound in uncomplicated conventional with resulting in Although thus, associated pathologically trimester, found often first be the infarcts can in due infarcts arteries disorder study. hypoxic spiral small current utero-placental the the Isolated cause of of with FGR, outcome flow, remodeling and space breakthrough incomplete pre-eclampsia minute intervillous a to as the such is such be of in this malperfusion, can detect flow that expression vascular villi believe to Maternal blood avascular the We lowered maternal of enables vessels. congested diagnosis is SMI blood slow ultrasound However, villous range of Therefore, peripheral presence velocity absent flow. vessels. the flow blood blood identifying villous flow the real by terminal blood established If of sharp minute expression and the the villi. thin visualize such disturb to terminal villi, would difficult the avascular is artifacts with in it motion infarction tissues capillaries Doppler, placental in color the of conventional tissue contrast, of lesions with villous In Even identify the flow. help ultrasound. in blood infarction easily B-mode absent placental placental can are normal induced it capillaries surrounding and therefore, the only vascularity placenta flow; of of the transformation blood lack of minute incomplete as hypoperfusion visualizing with for in associated result good are which FGR placenta-related arteries, and spiral preeclampsia onset Early pathological and of exact placental method The more of abnormalities. be distinguished. strength placental would be Interpretation evaluation, of the can quantitative management fetus that of perinatal and believe instead the mother pathology, the in we the from useful However, flow on based blood Doppler evaluation . the inter- qualitative that placental flow few is evaluated the SMI blood though quantitatively using regarding even index intervillous evaluation have flow pathologists SMI gross studies and between using and Previous index achieved diagnosing flow vascular is for as established. consensus consensus such been intensity, of established have degree no errors certain evaluations. is observer subjective a there on that findings, based both of considered performed evaluation pathological usually subjective is on are based it evaluations examined pathologic While were results although the pathology, that and are SMI study current the of limitations avascular The and SMI. infarction using especially, PPV limitation high findings, and with pathological Strength pregnancy placental during is detected study be present could villi, the in outcomes Main respectively. 0.920, findings and Main 80%, FGR, with 80%, cases and in preeclampsia, 0.785 with were and Discussion cases 57.1%, preeclampsia 100%, in with were 0.780 cases villi and avascular in for 66.7%, AUC AUC 66.7%, and and sensitivity, sensitivity, PPV, PPV, in whereas low. presented relatively 0.945), are AUC, in curves 88.9%; ROC presented sensitivity, and 100%; are 4 findings of findings pathological weeks Figure histological placental 33 and of with and detection findings 34 ultrasound was SMI antenatal examination of ultrasound comparisons at The age gestational median the respectively. cases, gestation, these in indications; Fgr ,Apni S6) Appendix 5, (Figure h otacrt igotcfidn a lcna nacini ae ihFR(PPV, FGR with cases in infarction placental was finding diagnostic accurate most The . 9 M nbe h eeto fteesallsosee ntrir ilu tissues. villous tertiary in even lesions small these of detection the enables SMI , . 7 hc sntdsigihbefo omlpaet using placenta normal from distinguishable not is which , 4 ovninlclrDplrdtcsbt ilu blood villous both detects Doppler color Conventional . 4 al 2 Table h cuayof accuracy The . ,6 5, M is SMI . al 3 Table 7 8 . . Posted on Authorea 21 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160856757.72561367/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. pcrmuigutahg-rqec rb n uebMcoaclrIaig lrsudOse Gynecol. Obstet Ultrasound Imaging. Microvascular Superb and probe ultra-high-frequency using spectrum 2 was records/information 1 patients’ retrospec- All was analysis protected. the was References The analysis. Although involved to patients prior hospital standards. patients. the university de-identified ethical from of Marianna and comparable anonymized confidentiality St obtained of or the was (IRBs) and amendments consent Boards tive later informed Review Written Institutional its committee research the and national by (No.4543). declaration approved and/or was institutional Helsinki the protocol 1964 of study standards the ethical with the and with accordance in were consent: pants informed and approval Ethical data confidentiality the of integrity availability: the Data for responsibility take statement: each study. and Interest the study analyzed for financial the All analysis. guarantors and in Competing the data data. data data are the the the NS collected of analyzed of and accuracy and all authors JK the to database MD, All access and JH, the full developed manuscript. had manuscript. the and authors of study the All drafting the the of coordinated to draft contributed JH authors and first NF the death. prepared maternal and data, the contributions Author present the using future. pregnancy the during in Acknowledgments formation management villi perinatal maternal terminal the of with improve determination problems can prospective is or that method SMI believe malperfusion using We vascular pathology placental villi. fetal avascular the or and predicting infarction in placental diagnosis in ultrasound guaranteed antenatal of accuracy diagnostic The Conclusion normal from standard chorangiosis the hyperbranching with when exact echogenicity made reconsidered. the pathologically of be comparison distinguish should than relative chorangiosis confirmed to the higher of is of difficult was diagnosis because the SMI was Originally, is of it this findings. strength villous that However, believe Doppler hypoxia We the villi. placental tissue. when surrounding to placental finding the response ultrasonographic preeclampsia. adaptive of of an an that cases as to and in chorangiosis due in placenta ultrasound defined form the findings findings. we B-mode in to other histological investigated the believed and the often is between SMI are to between Chorangiosis chorangiosis comparison compared of comparison cen- evaluation, large findings the the relatively histological vascular to Placental in are superior large findings vessel villi be a histological might blood stem such sliced findings the in In and placental of congestion macroscopic findings section of study. ultrasound cross findings present the the The between histological the the include in discrepancy large. of always Furthermore, the be one not enhanced. believe to as is does easily we SMI villi tissue be Therefore, Since can the stem low. vascular image ter. of of was flow fetal slice diagnosis dilatation blood and ultrasound the the SMI maternal of evaluation, method, on accuracy both Doppler the focused FGR, however, ultrasound We of FGR malperfusion; an SMI. in vascular causes result fetal placental using of stasis various distinguished flow findings that be blood hypothesized cord could we umbilical malperfusion, FGR, to hyper- of due as villi cases such villi ischemic cord, stem in and umbilical of thrombosis the dilation by of a terized compression cause or can occlusion cord, malperfusion, coiled vascular maternal to Contrary aeaaJ uuiN M o mgn fpaetlifrto.Paet.2016;47:96-8. Placenta. infarction. placental of imaging for SMI N. Suzuki J, Hasegawa aeaaJ uaaiA aaT om ,MuaA od ,e l igoi fpaet accreta placenta of Diagnosis al. et H, Kondo A, Miura C, Homma T, Hata A, Kurasaki J, Hasegawa 12 . aial,w oie httedfiiino lrsudfidnso hrnisssol be should chorangiosis of findings ultrasound of definition the that noticed we Radically, . h aarltdt hssuywscletdfo eia eod,pyn teto to attention paying records, medical from collected was study this to related data The FadJ ocie h td.N n Hdatdteiiilpooo,analyzed protocol, initial the drafted JH and NF study. the conceived JH and NF : 7 l rcdrspromdi tde novn ua partici- human involving studies in performed procedures All osqety ea aclrmlefso,wihi charac- is which malperfusion, vascular fetal Consequently, . l uhr elr htte aen oflc finterest. of conflict no have they that declare authors All 5 11 ntepeetstudy, present the In . 10 Therefore, . Posted on Authorea 21 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160856757.72561367/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. - + ------+ + - - + + - + + + + + + + + + + + - + - + - - + + - - - - - + + findings Histological + + + + findings Histological + + + ------+ + + 6 + 5 + 4 + findings 3 SMI 2 findings SMI 1 Background Background findings histological Case with findings SMI of Comparison 2: Table participants the of Characteristics 1. Table Interest: of Conflict 1984;108:71-4. Med. Lab 12 2016;140:588-93. 11 10 2018;218:S745-s61. Gynecol. 9 late-onset and 8 early- in 2020;33:564-9. Doppler Med. artery Neonatal 7 Fetal uterine Matern and J volume restriction. placental growth ultrasound fetal three-dimensional the of 6 2003;22:143-8. 5 2011;32:105-15. 2020:1- 4 Med. Neonatal Fetal Matern J imaging. microvascular 4. superb using function pathological placental of 3 2019;54:705-7. uuaN aeaaJ om ,Kwhr ,IaaaY wht ,e l oe lrsudassessment ultrasound Novel al. et H, Iwahata Y, Iwahata T, Kawahara C, Homma J, Hasegawa N, Furuya aaT aaaH ouh ,Ht .Tredmninlutaon vlaino h lcna Placenta. placenta. the of evaluation ultrasound Three-dimensional K. Hata J, Noguchi H, Tanaka T, Hata rs M aenlvsua apruino h lcna e.Ams 2018;126:551-60. Apmis. bed. placental 2018. the ed; of 2nd malperfusion vascular Placenta. Maternal Pathology: LM. Diagnostic Ernst Paepe. De Monique EP, Heerema-McKenney Amy rkk ,Hsgw ,Nkmr ,Tkt ,Hmd ,OaT ta.Frttietrmeasurements First-trimester al. et T, Oba S, Hamada H, Takita M, Nakamura J, Hasegawa T, Arakaki utnG,Juiu .Ptohsooyo lcna-eie ea rwhrsrcin mJObstet J Am restriction. growth fetal placental-derived of Pathophysiology E. Jauniaux GJ, Burton o aese ,MgeL,RbrsJ.Sblsicto fpecapi.HpresPregnancy. Hypertens preeclampsia. of Subclassification JM. Roberts LA, Magee P, Dadelszen von lsue .Coagoi.A motn lcna ino entlmriiyadmraiy rhPathol Arch mortality. and morbidity neonatal of sign placental important An Chorangiosis. G. Altshuler eln W aihna .Ftlvsua apruin nudt.AMS 2018;126:561-9. APMIS. update. an malperfusion, vascular Fetal S. Ravishankar RW, Redline tnkJ hrnisso hroi il:Wa osI elyMa?Ac ahlLbMed. Lab Pathol Arch Mean? Really It Does What Villi: Chorionic of Chorangiosis J. Stanek G EIfrto vsua il ogsinCoagoi nacinAaclrvliCneto Chorangiosis Congestion villi Avascular Infarction Chorangiosis Congestion villi Avascular Infarction PE FGR hr r ocnit fitrs odeclare. to interest of conflicts no are There miia reyp .0(7.10–7.47) 7.30 (4–10) (0–3) 9 0 (467–3102) (2–9) 1754 8 (1–4) 1.5 pH artery min Umbilical 5 at score (24–40) min Apgar 34 1 at score Apgar (22–44) 33.5 (g) weight (23–38) Birth 33 delivery at weeks Gestational ultrasound at weeks Gestational Para Gravida (years) age Maternal 6 ae (n=34) Cases Posted on Authorea 21 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160856757.72561367/v1 — This a preprint and has not been peer reviewed. 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160856757.72561367/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. saaclrvilli avascular as S6 Appendix S5 Appendix S4 Appendix S3 Appendix S2 Appendix pathologically. S1 detected Appendix are infarctions diffuse small of Diffuse case (b) Appendix in tree. villous findings without pathological villi: scatter avascular and only as of findings diagnosed imaging infarctions microvascular small Superb 5: Figure findings pathologic placental of detection ultrasound antenatal of Accuracy 4: Figure findings Pathological 3: Figure placental abnormal of imaging microvascular superb of background using the findings as mother Ultrasound the pathology of rate 2: heart the Figure matches which ”scatter,” (triangle). as tree like villous visualized also is artery RCcrepeitn chrangiosis predicting curve ROC congestion 4. predicting curve ROC villi avascular infarction 3. predicting predicting curve curve ROC (ROC) 2. Characteristic Operating Receiver 1. 4. 3. 2. 1. 4. 3. 2. 1. ils ? 0o hs il r on navsa eda 0;ad[]1 fte r on n[]3 [?] in found are them of 10 [?] and 10x; at field visual a in found are villi these sections. cotyledon of random 10 [?] villus; villi: terminal Hyper-vascular > villi: stroma. by stem vitrified accompanied of and Dilatation are fibrotic They uniformly and disappear. vessels villi: structures terminal nuclear all Avascular time over infiltration. and neutrophil necrosis, coagulative and Infarction: (triangle). ”fluffy” be to appear and villi (Chorangiosis): standard villi terminal Hyper-vascular vessels. (Congestion): stem villi villous surrounding stem of Dilatation villi: terminal Avascular (triangle). space Infarction: ie hto egbrn esl fsmlrcaliber. similar of vessels neighboring of that times 4 uebmcoaclriaig(M)fidnsi aeo iuesalifrtosdiagnosed infarctions small diffuse of case in findings (SMI) imaging microvascular Superb : hrnissdpce sn uebmcoaclriaig(SMI) imaging microvascular (SMI) superb imaging using microvascular depicted superb Chorangiosis using : depicted villi stem (SMI) of imaging Congestion microvascular : superb using depicted villi (SMI) Avascular imaging microvascular : superb using (SMI) depicted imaging Infarction microvascular : superb using depicted placenta Normal : ete h akrud”cte”ad“ilu re eedtce,rsligi nechoic an in resulting detected, were tree” “villous and ”scatter” background the Neither nacin hwclas fteitrilu pc n soitdvlosaggregation villous associated and space intervillous the of collapse show Infarctions iaaino tmvlii enda h nagmn fase ilu vessel villous stem a of enlargement the as defined is villi stem of Dilatation nytebcgon satr sosre ihu omlvlostrees. villous normal without observed is ”scatter” background the Only ilu toa-aclrkrorei ihdsperneo l blood all of disappearance with karyorrhexis stromal-vascular Villous tlat[]1 lo esl r on noetria rintermediate or terminal one in found are vessels blood 10 [?] least At h tmvliwr lal iae oprdwt the with compared dilated clearly were villi stem The 8 a vsua il a upce eas fdetection of because suspected was villi Avascular (a) emnlvliaehgl coccmae with compared echoic highly are villi Terminal Posted on Authorea 21 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160856757.72561367/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 9 Posted on Authorea 21 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160856757.72561367/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 10