Kidney and liver transplantation in childrenwith fibrocystic liver–kidney disease: Datafrom the US Scientific Registry ofTransplant Recipients: 1990–2010

Wen JW, Furth SL, Ruebner RL. (2014) Kidney and livertransplantation in children with fibrocystic liver–kidney disease: Datafrom the US Scientific Registry of Transplant Recipients: 1990–2010.Pediatr Transplant, 18: 726–732. DOI: 10.1111/petr.12330.

Abstract: The natural history and survival of children with fibrocysticliver–kidney disease undergoing solid organ transplantation haveinfrequently been described. We report outcomes in a cohort of USchildren with fibrocystic liver–kidney disease receiving solid organtransplants over 20 yr. Retrospective cohort study of pediatrictransplant recipients with diagnoses of fibrocystic liver–kidney diseasefrom 1/1990 to 3/2010, using data from the SRTR. Subjects werecategorized by the first transplanted organ: LT, KT, or SLK. Primaryoutcomes were death, re-transplant, transplant of the alternate organ,or initiation of dialysis. Seven hundred and sixteen subjects weretransplanted in this period. Median age at first transplant was 9.7 yr.Of the LT, 14 (19%) required a second liver transplant at median of0.2 yr, and five (7%) required kidney transplant or dialysis at a medianof 9.0 yr. Of the KT, 188 (31%) required a second kidney transplant ordialysis at a median of 5.9 yr. Twenty-nine (5%) subsequently receivedliver transplant at a median of 6.0 yr. Among patients in this registry,far more children underwent kidney than liver transplants. The risk ofsubsequently needing transplantation of an alternate organ was low.

Jessica W. Wen1, Susan L. Furth2 andRebecca L. Ruebner21Division of Gastroenterology, Hepatology andNutrition, The Children’s Hospital of Philadelphia,Philadelphia, PA, USA, 2Division of Nephrology, TheChildren’s Hospital of Philadelphia, Philadelphia, PA,USA

Key words: liver fibrocystic disease – congenitalhepatic fibrosis – kidney transplantation – livertransplantation – pediatric – autosomal recessivepolycystic kidney – Caroli’s syndrome

Jessica W. Wen, MD, Division of Gastroenterology,Hepatology & Nutrition, The Children’s Hospital ofPhiladelphia, 34th St & Civic Center Blvd,Philadelphia, PA 19104, USATel.: +1 215 590 9146Fax: +1 215 590 3680E-mail: wenj@email.chop.edu

Accepted for publication 12 July 2014

Fibrocystic liver–kidney disease is caused by agroup of rare and genetically diverse disordersthat are associated with kidney cysts or dysplasiaand DPM in the liver. With the identification ofassociated genes and understanding of gene func-tion, this group of diseases is often collectively

referred to as ciliopathies (1) because defects inproteins localizing the primary cilia play a majorrole in pathogenesis. There is a wide range ofpresentation for fibrocystic liver–kidney diseasefrom relatively asymptomatic to lethality in theperinatal period due to pulmonary hypoplasia.The kidney disease in ciliopathies includes cysticand cystic dysplastic kidneys. ADPKD and AR-PKD are the most common of the ciliopathies,but the group of disorders also includes NPHP,glomerulocystic kidney disease, and Joubert’s,Bardet–Biedl, Meckel–Gruber, and oral–facial–digital syndromes. The common thread in thesedisorders is abnormal epithelial tubulogenesis,which manifests as both kidney disease, includ-ing progressive CKD in some patients, and liverdisease. DPM, a developmental abnormality ofthe portobiliary system, is the basis of the liverdisease, presenting as CHF and CS. The liverdisease has characteristic pathologic findings of

Abbreviations: ADPKD, autosomal dominant polycystickidney disease; ARPKD, autosomal recessive polycystickidney disease; CHF, congenital hepatic fibrosis; CKD,chronic kidney disease; CMS, Centers for Medicare andMedicaid Services; CS, Caroli’s syndrome; DPM, ductalplate malformation; eGFR, estimated glomerular filtrationrate; ESKD, end-stage kidney disease; HRSA, HealthResources and Services Administration; IQR, interquartile;KT, kidney alone; LT, liver alone; MELD, model for end-stage liver disease; MMRF, Minneapolis Medical ResearchFoundation; NPHP, nephronophthisis; OPTN, Organ Pro-curement and Transplantation Network; SLK, simulta-neous liver–kidney; SRTR, Scientific Registry of TransplantRecipients; USRDS, US Renal Data System.

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Pediatr Transplantation 2014: 18: 726–732 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Pediatric TransplantationDOI: 10.1111/petr.12330

dilated bile ducts accompanied by dense peripor-tal fibrosis that results from the disruption of thenormally developing ductal plate in utero (2).Affected patients often have variable presenta-

tion and progression in their liver and kidney dis-eases, with patients often having more severeinvolvement of one organ (3–5). Some patientsmay develop ESKD, while others may developcomplications from portal hypertension or recur-rent cholangitis requiring liver transplantation.A small subset of patients requires transplanta-tion in both organs, either sequentially or incombination. It is difficult to predict whichpatients may require transplantation in bothorgans (6, 7). When a patient requires either aliver or kidney transplant, clinicians often facethe question of whether simultaneous liver/kid-ney transplantation is indicated. As small num-bers of patients affected with these disorders arefollowed at any single center, it has been difficultto describe the natural history of kidney and liverdysfunction and outcomes of transplantation inthis group. To address these limitations, we uti-lized data from the SRTR to perform a retro-spective cohort study of children receivingkidney and liver transplants in the United Statesfrom 1990 to 2010 with diagnoses consistent withfibrocystic liver–kidney disease. Our primaryobjective was to describe the outcomes of kidneyand liver transplantation in children with thisgroup of diagnoses in the modern era of trans-plantation.

Methods

Sources of data

This study used data from the SRTR linked to the USRDS,a national registry of patients with ESKD. The SRTRincludes data on all donors, wait-listed candidates, andtransplant recipients in the United States, submitted by themembers of the OPTN. The HRSA, US Department ofHealth and Human Services, provides oversight to the activ-ities of the OPTN and SRTR contractors. Outcomes ofdeath in SRTR are determined through center reports aswell as through linkage to the Social Security Death MasterFile. ESKD outcomes were ascertained through SRTR dataon kidney transplantation and CMS form 2728 for chronicdialysis submitted to USRDS. The Institutional ReviewBoard at the Children’s Hospital of Philadelphia deemedthis study exempt under provisions of the Code of FederalRegulations 45 CFR 46.101, category 4.

Study population

The study population included children ≤18 yr at initialliver or kidney transplant between January 1, 1990, andMarch 1, 2010, identified in the SRTR database. In theSRTR database, there are no specific diagnosis codes forARPKD or fibrocystic liver–kidney disease, and availablediagnosis codes differ between the liver and kidney

databases. Subjects were included in the cohort if theirprimary diagnosis codes were consistent with fibrocysticliver–kidney disease, although these codes may not be spe-cific for these disorders. In the liver transplant database, thediagnosis codes used for inclusion were “CHF” or “Caroli’sdisease.” In the kidney transplant database, the diagnosiscodes used for inclusion were “polycystic kidney disease” or“NPHP.” Subjects were excluded if they had an initialtransplant prior to the study period. Subjects were catego-rized by their first transplanted organ: KT, LT, or simulta-neous liver/kidney (SLK).

Analytic approach

We assessed baseline demographic characteristics of thestudy population using median and IQR ranges for continu-ous variables and distributions for categorical variables.Baseline characteristics included age at transplant, sex, race,year of transplant, diagnosis, type of donor (living ordeceased), hypertension, diabetes, location at the time oftransplant (not hospitalized, hospitalized, or hospitalized inan intensive care unit), and eGFR at the time of transplant,calculated using the bedside CKiD formula (0.413*height/serum creatinine) with the creatinine reported in SRTR atthe time of transplant (8).

The primary end-points were death, need for alternateorgan transplant after initial transplant (defined as ESKD –initiation of chronic dialysis or receipt of KT – after initialLT or LT after initial KT), and failure of the initial trans-plant (defined as ESKD after initial KT or second LT afterinitial LT). Date of ESKD was considered the first datereported on CMS form 2728 for chronic dialysis submittedto USRDS or date of kidney transplant reported in SRTR,whichever occurred first. Subjects were followed from thedate of initial transplant until ESKD, death, or March 1,2010, whichever occurred first.

We calculated overall mortality, median time to death,rate of failure of the initial transplant, and rate of transplantin the alternate organ. Categorical variables were comparedusing the Pearson’s chi-square test. Nonparametric continu-ous variables were compared using the Wilcoxon’s rank-sum test. We created Kaplan–Meier curves for patient andgraft survival after initial KT, LT, or SLK in this study pop-ulation. Survival was compared using the log-rank test.Analyses were conducted using STATA 12.0 (StataCorp, Col-lege Station, TX, USA). All reported p values were two-sided, and a p value of <0.05 was the threshold for statisticalsignificance.

Results

Baseline characteristics

A total of 716 pediatric subjects with a diagnosisof polycystic kidney disease, NPHP, CHF, orCaroli’s disease received a liver and/or kidneytransplant during the study period. Seventy-threesubjects received an LT, 602 subjects received aKT, and 41 subjects received an SLK. The over-all median follow-up time was 8.5 yr (IQR 4.7,13.3).Baseline demographic characteristics of the

cohort are shown in Table 1. The median ageat initial transplant was 8.7 yr for LT, 9.9 yr

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for KT, and 9.2 yr for SLK. Male and femaledistributions were similar among the threegroups. Almost 40% of the LT recipients werehospitalized at the time of LT, while only 5%of KT recipients were hospitalized at the timeof transplant. The majority of the LTrecipients had an eGFR ≥60 mL/min/1.73 m2

at the time of LT. The relative normal albu-min and total bilirubin in LT and SLK recipi-ents are consistent with previous reports that

complications of portal hypertension andcholangitis are the most common manifesta-tions of liver disease in these disorders, ratherthan cirrhosis (9).

Mortality after transplant

The overall mortality was 23% (17 deaths) forLT recipients, with a median time to death of 0.7(IQR 0.04, 5.6) yr. The overall mortality for KTrecipients was lower at 10% (59 deaths)(p = 0.001). Death occurred later after KT thanLT, with median time to death of 4.8 (IQR 1.0,10.4) yr (p = 0.01). The overall mortality forSLK recipients was 12% with median time todeath of 5.1 (IQR 0.3, 11.3) yr. Survival was notsignificantly different between SLK vs. LT andSLK vs. KT, although the number of SLK wassmall. Fig. 1 shows Kaplan–Meier curves ofpatient survival by transplant organ type.To address whether the overall mortality has

improved in the last decade due to advance-ment in immunosuppressive regimen and peri-operative patient survival, we determined themortality rate by decades (1990–2000 vs. 2000–2010) for each type of organ transplant. Themortality rate improved in KT, 13.6 (95% CI10.2–18.0) per 1000 person-years in the earlierdecade compared with 5.8 (3.3–10.1) in themore recent decade (p = 0.005). Mortality rateappears relatively unchanged in LT, 23.1 (13.4–39.7) in the earlier decade compared with 29.5(11.1–78.7) in the last decade (p = 0.65). InSLK, the mortality is 9.4 (2.3–37.4) in the ear-lier decade compared with 20.7 (6.7–64.1) inthe last decade (p = 0.42), although the numberof cases may be too small to draw any mean-ingful conclusion in this group.

Table 1. Baseline characteristics

Characteristic Liver (n = 73)Kidney(n = 602) SLK (n = 41)

Age in years attransplant,med (IQR)

8.7 (2.3, 13.3) 9.9 (3.5, 14.8) 9.2 (5.3, 13.8)

Male sex, n (%) 38 (52) 311 (52) 20 (49)Race, n (%)White 49 (67) 413 (69) 29 (71)Black 13 (18) 58 (10) 2 (5)Asian 0 (0) 23 (4) 0 (0)Other 11 (15) 108 (18) 10 (24)

Year of transplant, n (%)1990–1994 20 (27) 113 (19) 4 (10)1995–1999 25 (34) 135 (22) 11 (27)2000–2004 11 (15) 177 (29) 14 (34)2005–2010 17 (23) 177 (29) 12 (29)

Diagnosis, n (%)Caroli’s disease 21 (29) N/A *CHF 52 (71) N/APolycystickidney disease

N/A 484 (80)

NPHP N/A 118 (20)Living donor,n (%)

10 (14) 371 (62) 2 (5)

Diabetes, n (%) 0 (0) 2 (0.3) 0 (0)Hypertension,n (%)

5 (7) 228 (38) 10 (24)

Location at time of transplant, n (%)Not hospitalized 46 (63) 571 (95) 35 (85)Hospitalized,non-intensivecare

13 (18) 19 (3) 5 (12)

Intensivecare unit

14 (19) 12 (2) 1 (2)

Pretransplant eGFR mL/min/1.73 m2, n (%)≥60 50 (68) 1 (0.2) 1 (2)30–59 6 (8) 0 (0) 7 (17)<30 3 (4) 178 (30) 14 (34)Dialysis 1 (1) 386 (64) 14 (34)Missing 13 (18) 37 (6) 5 (12)

Total bilirubinprior to livertransplant,mg/dL, med (IQR)

1.9 (1.0, 8.0) N/A 0.7 (0.5, 1.2)

Albumin prior toliver transplant,g/dL, med (IQR)

3.3 (3.0, 3.9) N/A 3.8 (2.9, 4.2)

*The SLK recipients had diagnosis codes from both the liver and the kidneytransplant datasets. All SLK recipients had codes for CHF and/or polycystic kid-ney disease. None had codes for Caroli’s disease or NPHP.

Fig. 1. Kaplan–Meier patient survival estimates by trans-plant type: Comparison of patient survival after initial LTvs. KT vs. SLK. *p Value comparing survival of LT vs. KT.

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Failure of primary transplant allograft

Of the 73 LT recipients, 14 (19%) received a sec-ond LT at a median of 0.2 yr (0.01, 3.6) after ini-tial transplant. All were liver-alone transplants(no SLK). Median age at second transplant was11.8 yr (IQR 5.2, 14.2). Of the 41 SLK recipients,two (5%) were re-transplanted (one liver thenkidney, one SLK).Of the 602 KT recipients, 188 (31%) had graft

failure requiring dialysis or repeat KT (p = 0.034compared with LT recipients requiring a secondLT) at a median of 5.9 yr (IQR 1.7, 9.6) after ini-tial transplant. Median age at second ESKDevent was 17.1 yr (IQR 11.0, 20.8). Of these 188subjects, 29 received a second KT without a per-iod on dialysis. The remaining 159 requiredchronic dialysis, 94 subsequently received a KT,while 65 remained on dialysis until death or lastfollow-up. Fig. 2 shows Kaplan–Meier curves ofallograft survival by transplant organ type. SLKis not included in the figure as the numbers werevery small (only two events), the follow-up timemore limited, and either the liver or kidney allo-graft could fail.

Need for alternate organ transplant after initial transplant

Of the 73 LT recipients, five (7%) had ESKDafter transplant at a median of 9.0 yr (7.0, 11.9)after LT. Of these, three received a preemptiveKT, one received a KT after a period on dialysis,and one remained on chronic dialysis until lastfollow-up. Median age at ESKD was 16.8 yr(IQR 12.3, 19.5).Of the 602 KT recipients, 29 (5%) subse-

quently received a liver transplant (p = 0.45 com-pared with LT recipients who developed ESKD)at a median of 6.0 yr (IQR 3.6, 8.6) after KT. Of

these, 14 were SLK and 15 were LT. Median ageat liver transplant was 10.8 yr (IQR 7.6, 17.1)(Fig. 3).

Discussion

In this 20-yr national cohort study, we report ontransplantation outcomes in children with fibro-cystic liver–kidney disease. We found that chil-dren with these diagnoses more often receivedkidney than liver transplants, but approximatelyone-third of those receiving liver transplantsreceived a kidney and a liver simultaneously. Themortality after liver transplantation was higherthan after kidney transplantation, and the mor-tality of those selected for SLK was similar tothat of those with KT alone. Relatively few indi-viduals in this cohort required transplantation inan alternate organ (7% of LT recipients and 5%of KT recipients) after the initial transplant.To our knowledge, this study is the first to

assess transplant outcomes, spanning 20 yr, in amulticenter, national cohort of children withdiagnoses consistent with fibrocystic liver–kidneydisease. We found that children receiving LT orKT were unlikely to require transplantation ofthe alternate organ. Although these data areobservational and subject to selection bias, thisfinding supports the concept of isolated orsequential organ transplant rather than preemp-tive simultaneous liver/kidney transplant in thisunique patient population. This is in agreementwith previous reports showing that end-stage dis-ease is unlikely to affect both the liver and thekidney in patients with fibrocystic liver–kidneydisease, and patients usually have more severeinvolvement in only one organ (4). Furthermore,in another natural history study of a large cohort

Fig. 2. Kaplan–Meier graft survival estimates by transplanttype: Comparison of graft survival after initial LT vs. KT,censored at death.

Fig. 3. Failure of the initial transplant and need for trans-plant in an alternate organ.

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with genetically confirmed PKHD1 mutation, itdemonstrated the independent progression ofthe kidney and liver diseases, as well as failureof genotype–phenotype association (10, 11).Together, these data appear to favor isolatedtransplantation rather than SLK in anticipationof disease progression. The strengths of ourstudy include an objective measure of ESKDoutcomes by linking the SRTR to the USRDS,which should allow for near-complete capture ofall ESKD events, a unique feature of this dataset.Overall, we observed a similar mortality rate

in patients with fibrocystic liver–kidney diseaseundergoing LT or KT compared with all otherpediatric patients undergoing these transplantsduring the same time period. To compare withreported five-yr mortality rates in the generaltransplant population, we calculated five-yr mor-tality among 563 of 716 subjects in this cohortwho had at least five yr of follow-up time or diedwithin five yr of transplant. The five-yr mortalityin this cohort was 20% for LT recipients, 6% forKT recipients, and 6% for SLK recipients. TheOPTN reported similar five-yr mortality data forpediatric transplants between 1997 and 2004:21% for all pediatric LT recipients and 4% forall pediatric KT recipients (http://optn.trans-plant.hrsa.gov). Although there is no OPTN-reported outcomes for SLK in children, a Euro-pean single-center case series of children withfibrocystic liver disease over the same approxi-mate time frame as our study (1990–2009), inwhich 90% of the children who had undergonesolid organ transplants in this series had SLK(12), the one- and five-yr mortality was 10% and29%, respectively. This is higher than the mortal-ity observed in our cohort.The timing of organ transplantation in fibro-

cystic liver–kidney disease often poses a dilemmafor clinicians given variability in the degree ofliver and kidney involvement and uncertaintyabout disease progression (13–15). It can be espe-cially challenging for clinicians to decide whethera SLK transplant provides better outcomes com-pared with isolated or sequential organ trans-plant, particularly because transplanting oneorgan has potential side effects on the otherorgan (16).Although in these data we observed successful

outcomes with sequential solid organ transplant,and a low rate of alternate organ transplantationafter either LT or KT, there may be situations inwhich a child may benefit from consideration ofan SLK. In this cohort, 34% of children whoreceived an SLK were already on dialysis priorto transplant, while an additional 34% had anestimated GFR <30 mL/min/1.73 m2, suggesting

that the majority of these patients had severe kid-ney disease at the time of transplant. In compari-son, only 5% of those children undergoingisolated LT had an estimated GFR <30 mL/min/1.73 m2. SLK is also sometimes considered inclinical practice if there is a concern for ascend-ing cholangitis after KT alone. This was high-lighted in a systematic review combining datafrom all published case reports and case series ofCHF, ARPKD, Caroli’s disease, and type Vcholedochal cyst (17). Among the published 173patients with CHF who received an isolated KT,there were 23 (25%) cases of sepsis after trans-plant, with 13 deaths. Three of the deaths weredefinitively attributed to cholangitis. Otherreports have also noted ascending cholangitis asa complication after isolated renal transplants inthese patients (12, 18). Although the actual num-ber of reported cases of cholangitis after isolatedkidney transplant is small, it is a unique cause ofmorbidity and mortality after isolated KT inpatients with fibrocystic liver–kidney disease andhas been suggested as a rationale for SLK trans-plant. Another consideration for SLK is thepotential immunological advantage for the kid-ney when a liver is transplanted at the same time.Even in individuals who are highly sensitizedand/or cross-match positive, SLK may providebetter outcomes in both kidney graft rejectionepisodes and graft survival both in adults and inchildren (19–22). In a database review of 111pediatric SLK from UNOS database, there is amuch higher loss of kidney graft within the firstsix months compared with KT, likely explainedby early surgical complications. However, thereis significant improvement in the late kidneygraft survival in SLK compared with isolatedKT, attributed to the liver-protective effect anddecreased episodes of antibody-mediated rejec-tions (22). Due to limitations in the SRTR data-set, we were not able to determine indications forSLK vs. KT or LT alone or ascertain sepsis orcholangitis as a complication after isolated KT.We observed low mortality and graft failure afterSLK in this cohort; however, there were only 41subjects who underwent SLK, and these werelikely a highly selected group. Therefore, giventhe small cohort and the possible selection bias,it is difficult to infer whether these favorable out-comes would be generalizable.Allocation of SLKs is a pertinent topic in the

current environment of scarce allografts andincreasing number of patients on the wait-list forliver and kidney transplants (OPTN Data Reporthttp://optn.transplant.hrsa.gov/, Accessed Feb11, 2014). Since the institution of the MELDsystem in 2002, which gives priority to LT

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candidates with kidney dysfunction, there hasbeen a significant increase in the number of SLKsperformed, up to a three-fold increase comparedwith the pre-MELD era (23). There is also signif-icant center and regional variability in the selec-tion of candidates for SLK (24). This has led tothe concern that deceased donor kidney allo-grafts are being diverted away from candidateson the wait-list for an isolated kidney transplant(25). In addition, adult SLK recipients not ondialysis may not gain a survival benefit by theaddition of a kidney when a liver transplant isrequired (26). This has not been closely studiedin the pediatric population. Given the limitedorgan supply, the appropriate indications forSLK in children with fibrocystic liver–kidney dis-ease need to be further studied.The main limitation of this study is due to its

observational nature using an administrativedatabase. Not all variables of interest are col-lected, such as information on specific diagnoses,indications for transplant, or causes of graft fail-ure after transplant. Data entered into SRTRmay be incomplete, such as missing GFR forsome transplant recipients (Table 1). Impor-tantly, there may be the potential for misclassifi-cation based on the primary diagnosis codes inSRTR. As there is no specific diagnosis code forARPKD, we identified subjects using the diagno-sis code of polycystic kidney disease, which doesnot distinguish between ARPKD and ADPKD.ADPKD primarily affects the kidney and doesnot progress to ESKD until the fifth or sixth dec-ades of life (27). Therefore, we think it is unlikelythat there are a significant number of subjectswho actually have ADPKD in this cohort, inwhich the median age at KT was 9.9 yr. Further-more, the diagnosis of fibrocystic liver–kidneydisease prior to the era of genetic testing can bevague or incorrect. For example, patients withmild renal manifestation can be misdiagnosed asprimary sclerosing cholangitis due to dense peri-portal fibrosis. The lack of genetic testing in thisdataset also contributes to the potential for mis-classification. Additionally, the median follow-up time in this study was 8.5 yr. It is possiblethat with longer follow-up time, a greater num-ber of subjects would require transplant in thealternate organ. Finally, the data presented hereonly represent outcomes of those children withfibrocystic liver–kidney disease who underwenttransplantation, and the outcomes are not neces-sarily generalizable to all children with these dis-eases who do not require or are not selected fortransplant.In summary, we have shown that children

with fibrocystic liver–kidney disease who

develop end-stage disease in one organ are unli-kely to require transplantation of the alternateorgan. Careful consideration regarding the useof SLK transplantation is required in this popu-lation. Future prospective studies are requiredto understand indications for transplantation inthis population and to help guide clinicians todetermine which patients would benefit fromSLK transplantation.

Acknowledgments

The data reported here have been supplied by the MMRFas the contractor for the SRTR. The interpretation andreporting of these data are the responsibility of the authorsand in no way should be seen as an official policy of or inter-pretation by the SRTR or the US Government. The authorswish to acknowledge David Piccoli, M.D., for his thought-ful discussion in the concept and design of the project.

Authors’ contributions

Jessica Wen: Participated in concept/design, data analysis/interpretation, and drafting the article; Susan Furth: Partici-pated in concept/design, and critical revision of the article;Rebecca Ruebner: Participated in concept/design, dataanalysis/interpretation, and critical revision of the article.

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