Publications by authors named "Charles E McCulloch"

395 Publications

Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation.

Mol Genet Genomic Med 2021 Sep 7:e1794. Epub 2021 Sep 7.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.

Background: To investigate whether common variants in EPHB4 and RASA1 are associated with cerebral cavernous malformation (CCM) disease severity phenotypes, including intracranial hemorrhage (ICH), total and large lesion counts.

Methods: Familial CCM cases enrolled in the Brain Vascular Malformation Consortium were included (n = 338). Total lesions and large lesions (≥5 mm) were counted on MRI; clinical history of ICH at enrollment was assessed by medical records. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We tested the association of seven common variants (three in EPHB4 and four in RASA1) using multivariable logistic regression for ICH (odds ratio, OR) and multivariable linear regression for total and large lesion counts (proportional increase, PI), adjusting for age, sex, and three principal components. Significance was based on Bonferroni adjustment for multiple comparisons (0.05/7 variants = 0.007).

Results: EPHB4 variants were not significantly associated with CCM severity phenotypes. One RASA1 intronic variant (rs72783711 A>C) was significantly associated with ICH (OR = 1.82, 95% CI = 1.21-2.37, p = 0.004) and nominally associated with large lesion count (PI = 1.17, 95% CI = 1.03-1.32, p = 0.02).

Conclusion: A common RASA1 variant may be associated with ICH and large lesion count in familial CCM. EPHB4 variants were not associated with any of the three CCM severity phenotypes.
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http://dx.doi.org/10.1002/mgg3.1794DOI Listing
September 2021

Validation of the Surrogate Threshold Effect for Change in BMD as a Surrogate Endpoint for Fracture Outcomes: the FNIH-ASBMR SABRE Project.

J Bone Miner Res 2021 Sep 7. Epub 2021 Sep 7.

Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA.

The surrogate threshold effect (STE) is defined as the minimum treatment effect on a surrogate that is reliably predictive of a treatment effect on the clinical outcome. It provides a framework for implementing a clinical trial with a surrogate endpoint. The aim of this study was to update our previous analysis by validating the STE for change in total hip (TH) BMD as a surrogate for fracture risk reduction; the novelty of this study was this validation. To do so, we used individual patient data from 61,415 participants in 16 RCTs that evaluated bisphosphonates (9 trials), selective estrogen receptor modulators (4 trials), denosumab (1 trial), odanacatib (1 trial) and teriparatide (1 trial) to estimate trial-specific treatment effects on TH BMD and all, vertebral, hip and non-vertebral fractures. We then conducted a random effects meta-regression of the log relative fracture risk reduction against 24-month change in TH BMD, and computed the STE as the intersection of the upper 95% prediction limit of this regression with the line of no fracture reduction. We validated the STE by checking whether the number of fractures in each trial provided 80% power and determining what proportion of trials with BMD changes ≥ STE reported significant reductions in fracture risk. We applied this analysis to 1) the trials on which we estimated the STE; 2) trials on which we did not estimate the STE. We found that the STEs for all, vertebral, hip, and non-vertebral fractures were 1.83, 1.42, 3.18, and 2.13%, respectively. Among trials used to estimate STE, 27/28 were adequately powered, showed BMD effects exceeding the STE, and demonstrated significant reductions in fracture risk. Among the validation set of 11 trials, 10 met these criteria. Thus STE differs by fracture type and has been validated in trials not used to develop the approach.
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http://dx.doi.org/10.1002/jbmr.4433DOI Listing
September 2021

Patterns of Atopic Eczema Disease Activity From Birth Through Midlife in 2 British Birth Cohorts.

JAMA Dermatol 2021 Sep 1. Epub 2021 Sep 1.

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Importance: Atopic eczema is characterized by a heterogenous waxing and waning course, with variable age of onset and persistence of symptoms. Distinct patterns of disease activity such as early-onset/resolving and persistent disease have been identified throughout childhood; little is known about patterns into adulthood.

Objective: This study aimed to identify subtypes of atopic eczema based on patterns of disease activity through mid-adulthood, to examine whether early life risk factors and participant characteristics are associated with these subtypes, and to determine whether subtypes are associated with other atopic diseases and general health in mid-adulthood.

Design, Setting, And Participants: This study evaluated members of 2 population-based birth cohorts, the 1958 National Childhood Development Study (NCDS) and the 1970 British Cohort Study (BCS70). Participant data were collected over the period between 1958 and 2016. Data were analyzed over the period between 2018 and 2020.

Main Outcomes And Measures: Subtypes of atopic eczema were identified based on self-reported atopic eczema period prevalence at multiple occasions. These subtypes were the outcome in models of early life characteristics and an exposure variable in models of midlife health.

Results: Latent class analysis identified 4 subtypes of atopic eczema with distinct patterns of disease activity among 15 939 individuals from the NCDS (51.4% male, 75.4% White) and 14 966 individuals from the BCS70 (51.6% male, 78.8% White): rare/no (88% to 91%), decreasing (4%), increasing (2% to 6%), and persistently high (2% to 3%) probability of reporting prevalent atopic eczema with age. Sex at birth and early life factors, including social class, region of residence, tobacco smoke exposure, and breastfeeding, predicted differences between the 3 atopic eczema subtypes and the infrequent/no atopic eczema group, but only female sex differentiated the high and decreasing probability subtypes (odds ratio [OR], 1.99; 95% CI, 1.66-2.38). Individuals in the high subtype were most likely to experience asthma and rhinitis, and those in the increasing subtype were at higher risk of poor self-reported general (OR, 1.29; 95% CI, 1.09-1.53) and mental (OR 1.45; 95% CI, 1.23-1.72) health in midlife.

Conclusions And Relevance: The findings of this cohort study suggest that extending the window of observation beyond childhood may reveal clear subtypes of atopic eczema based on patterns of disease activity. A newly identified subtype with increasing probability of activity in adulthood warrants additional attention given observed associations with poor self-reported health in midlife.
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http://dx.doi.org/10.1001/jamadermatol.2021.2489DOI Listing
September 2021

Association of Atopic Dermatitis and Mental Health Outcomes Across Childhood: A Longitudinal Cohort Study.

JAMA Dermatol 2021 Sep 1. Epub 2021 Sep 1.

Department of Dermatology, University of California, San Francisco.

Importance: Research has highlighted associations between atopic dermatitis (AD) and mental health conditions in adults. However, literature on the development of mental health comorbidities in children is limited despite the large burden of pediatric AD worldwide.

Objective: To examine the association between AD and internalizing behaviors and symptoms of depression at multiple points across childhood and adolescence and to explore potential mediating factors, including asthma/rhinitis, sleep, and inflammation.

Design, Setting, And Participants: This longitudinal, population-based birth cohort study included children followed up from birth for a mean (SD) duration of 10.0 (2.9) years from the UK Avon Longitudinal Study of Parents and Children. Data were collected from September 6, 1990, to December 31, 2009. Data were analyzed from August 30, 2019, to July 30, 2020.

Exposures: Annual period prevalence of AD assessed at 11 points from 6 months to 18 years of age, measured by standardized questions about flexural dermatitis.

Main Outcomes And Measures: Symptoms of depression, measured using child-reported responses to the Short Moods and Feelings Questionnaire at 5 points from 10 to 18 years of age and internalizing behaviors, measured by maternal report of the Emotional Symptoms subscale of the Strength and Difficulties Questionnaire at 7 points from 4 to 16 years of age.

Results: Among the 11 181 children included in the analysis (5721 male [51.2%]), the period prevalence of symptoms of depression ranged from 6.0% to 21.6%; for internalizing behaviors, from 10.4% to 16.0%. Although mild to moderate AD was not associated with symptoms of depression, it was associated with internalizing behaviors as early as 4 years of age (mean increased odds of 29%-84% across childhood in adjusted models). Severe AD was associated with symptoms of depression (adjusted odds ratio, 2.38; 95% CI, 1.21-4.72) and internalizing symptoms (adjusted odds ratio, 1.90; 95% CI, 1.14-3.16). Sleep quality mediated some of this association, but it was not explained by differences in sleep duration, asthma/rhinitis, or levels of inflammatory markers (interleukin 6 and C-reactive protein).

Conclusions And Relevance: Within this population-based birth cohort study in the UK, severe AD was associated with symptoms of depression and internalizing behaviors throughout childhood and adolescence. Risk of internalizing symptoms was increased even for children with mild AD beginning early in childhood, highlighting the importance of behavioral and mental health awareness in this population.
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http://dx.doi.org/10.1001/jamadermatol.2021.2657DOI Listing
September 2021

Patient Awareness of CKD: A Systematic Review and Meta-analysis of Patient-Oriented Questions and Study Setting.

Kidney Med 2021 Jul-Aug;3(4):576-585.e1. Epub 2021 Jun 1.

Department of Medicine, University of California, San Francisco.

Rationale & Objective: Patient awareness of disease is the first step toward effective management and disease control. Awareness of chronic kidney disease (CKD) has consistently been shown to be low, but studies estimating patient awareness of CKD have used different methods. We sought to determine whether the estimated prevalence of CKD awareness differed by the wording used to ascertain awareness or by setting characteristics.

Study Design: Systematic review and meta-analysis.

Setting & Study Populations: Adults with CKD not receiving dialysis.

Selection Criteria For Studies: We included studies that estimated CKD awareness, determined CKD status by laboratory criteria, and provided the exact question wording used to ascertain awareness.

Data Extraction: 2 reviewers independently extracted data for each study; discordance was resolved by a third independent reviewer.

Analytical Approach: Mixed-effects models were used to calculate pooled CKD awareness estimates and 95% CIs.

Results: 32 studies were included. Publication year ranged from 2004 to 2017, with study populations ranging from 107 to 28,923 individuals. CKD awareness in individual studies ranged from 0.9% to 94.0%. Pooled CKD awareness was 19.2% (95% CI, 10.0%-33.6%) overall and was 26.5% (95% CI, 11.9%-48.9%) among individuals with an estimated glomerular filtration rate < 60 mL/min/1.73 m. "Kidney problem" was the most sensitive question for CKD awareness (58.7%; 95% CI, 32.4%-80.8%); "weak or failing kidneys" was the least sensitive (12.3%; 95% CI, 4.5%-29.4%). CKD awareness was highest among patients from nephrology practices (86.2%; 95% CI, 74.9%-93.0%) and lowest in the general population (7.3%; 95% CI, 5.0%-10.5%).

Limitations: Significant heterogeneity across studies overall and among examined subgroups of wording and study setting.

Conclusions: Differently worded questions may lead to widely different estimates of CKD awareness. Consistent terminology is likely needed to most effectively surveil and leverage CKD awareness to improve management and disease control.
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http://dx.doi.org/10.1016/j.xkme.2021.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350814PMC
June 2021

Seizure Incidence Rates in Children and Adults With Familial Cerebral Cavernous Malformations.

Neurology 2021 Aug 13. Epub 2021 Aug 13.

Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA, USA.

Background And Objectives: Seizure incidence rates related to Familial Cerebral Cavernous Malformation (FCCM) are not well described, especially for children. To measure the seizure incidence rate, examine seizure predictors and characterize epilepsy severity, we studied a cohort of children and adults with FCCM enrolled in the Brain Vascular Malformation Consortium (BVMC).

Methods: Seizure data were collected from participants with FCCM in the BVMC at enrollment and during follow-up. We estimated seizure probability by age, and tested whether cerebral cavernous malformation (CCM) counts or genotype were associated with earlier seizure onset.

Results: The study cohort included 479 FCCM cases. Median age at enrollment was 42.5 years (Interquartile Range [IQR] 22.5-55.0) and 19% were children (<18 years old). Median large CCM count was 3 (IQR: 1-5). Among 393 with genotyping, mutations were: CCM1-Common Hispanic Mutations (88%), another CCM1 mutation (5%), CCM2 mutations (5%), and CCM3 mutations (2%). Prior to or during the study, 202 (42%) had a seizure. The cumulative incidence of a childhood seizure was 20.3% (95% CI 17.0 - 23.4) and by age 80 years was 60.4% (95% CI 54.2-65.7). More total CCMs (Hazard Ratio [HR] 1.24 per SD unit increase, 95% CI 1.1 - 1.4) or more large CCMs (HR=1.5 per SD unit increase, 95% CI 1.2-1.9) than expected for age and sex increased seizure risk. A CCM3 mutation also increased risk compared to other mutations (HR 3.11, 95% CI 1.15-8.45). Individuals with a seizure prior to enrollment had increased hospitalization rates during follow-up (Incidence Rate Ratio 10.9, 95% CI 2.41 - 49.32) compared to patients without a seizure history.

Discussion: Individuals with FCCM have a high seizure incidence, and those with more CCMs or CCM3 genotype are at greater risk. Seizures increase health care utilization in FCCM.
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http://dx.doi.org/10.1212/WNL.0000000000012569DOI Listing
August 2021

Study Designs to Assess Real-World Interventions to Prevent COVID-19.

Front Public Health 2021 27;9:657976. Epub 2021 Jul 27.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States.

In the face of the novel virus SARS-CoV-2, scientists and the public are eager for evidence about what measures are effective at slowing its spread and preventing morbidity and mortality. Other than mathematical modeling, studies thus far evaluating public health and behavioral interventions at scale have largely been observational and ecologic, focusing on aggregate summaries. Conclusions from these studies are susceptible to bias from threats to validity such as unmeasured confounding, concurrent policy changes, and trends over time. We offer recommendations on how to strengthen frequently applied study designs which have been used to understand the impact of interventions to reduce the spread of COVID-19, and suggest implementation-focused, pragmatic designs that, moving forward, could be used to build a robust evidence base for public health practice. We conducted a literature search of studies that evaluated the effectiveness of non-pharmaceutical interventions and policies to reduce spread, morbidity, and mortality of COVID-19. Our targeted review of the literature aimed to explore strengths and weaknesses of implemented studies, provide recommendations for improvement, and explore alternative real-world study design methods to enhance evidence-based decision-making. Study designs such as pre/post, interrupted time series, and difference-in-differences have been used to evaluate policy effects at the state or country level of a range of interventions, such as shelter-in-place, face mask mandates, and school closures. Key challenges with these designs include the difficulty of disentangling the effects of contemporaneous changes in policy and correctly modeling infectious disease dynamics. Pragmatic study designs such as the SMART (Sequential, Multiple-Assignment Randomized Trial), stepped wedge, and preference designs could be used to evaluate community re-openings such as schools, and other policy changes. As the epidemic progresses, we need to move from analyses of available data (appropriate for the beginning of the pandemic) to proactive evaluation to ensure the most rigorous approaches possible to evaluate the impact of COVID-19 prevention interventions. Pragmatic study designs, while requiring initial planning and community buy-in, could offer more robust evidence on what is effective and for whom to combat the global pandemic we face and future policy decisions.
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http://dx.doi.org/10.3389/fpubh.2021.657976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353119PMC
August 2021

Longitudinal Changes in Adiposity and Lower Urinary Tract Symptoms Among Older Men.

J Gerontol A Biol Sci Med Sci 2021 Aug 10. Epub 2021 Aug 10.

Oregon Health and Science University-Portland State University School of Public Health, Portland OR.

Background: Adiposity increases risk for male lower urinary tract symptoms (LUTS), although longitudinal studies have produced conflicting results. No prior studies have evaluated longitudinal associations of changes in adiposity with concurrent LUTS severity among older men.

Methods: We used repeated adiposity measurements from dual-energy x-ray absorptiometry (DXA), body mass index (BMI), and American Urological Association Symptom Index (AUASI) measured at four study visits over a 9-year period among 5949 men enrolled in the Osteoporotic Fractures in Men (MrOS) study. Linear mixed effect models adjusted for age, health-related behaviors, and comorbidities were created to evaluate the association between baseline and change in visceral adipose tissue (VAT) area, total fat mass, and BMI with change in LUTS severity measured by the AUASI.

Results: A non-linear association was observed between baseline VAT area and change in AUASI: men in baseline VAT tertile (T) 2 had a lower annual increase in AUASI score compared to men in T1 and T3 (T2 versus T1: β=-0.07; 95% CI -0.12, -0.03; P= 0.008; T3 versus T1: NS) but differences were small. No significant associations were observed between change in VAT area and change in AUASI score. Neither baseline tertiles nor change in total fat mass or BMI were associated with change in AUASI score.

Conclusions: Changes in VAT area, total fat mass, and BMI were not associated with change in LUTS severity in this cohort. Thus, despite other health benefits, interventions targeting adiposity alone are unlikely to be effective for preventing or treating LUTS among older men.
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http://dx.doi.org/10.1093/gerona/glab227DOI Listing
August 2021

Bariatric surgery prior to transplantation and risk of early hospital re-admission, graft failure, or death following kidney transplantation.

Am J Transplant 2021 Jul 31. Epub 2021 Jul 31.

Division of Nephrology, Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota.

Bariatric surgery has been shown to be safe in the dialysis population. Whether bariatric surgery before kidney transplantation influences posttransplant outcomes has not been examined nationally. We included severely obese (BMI >35) dialysis patients between 18 and 70 years who received a kidney transplant according to the US Renal Data System. We determined the association between history of bariatric surgery and risk of 30-day readmission, graft failure, or death after transplantation using multivariable logistic, Fine-Gray, and Cox models. We included 12 573 patients, of whom 503 (4%) received bariatric surgery before transplantation. Median age at transplant was 53 years; 42% were women. Overall, history of bariatric surgery was not statistically significantly associated with graft failure (HR 1.02; 95% CI 0.77-1.35) or death (HR 1.10; 95% CI 0.84-1.45). However, sleeve gastrectomy (vs. no bariatric surgery) was associated with lower risk of graft failure (HR 0.39; 95% CI 0.16-0.95). In conclusion, history of bariatric surgery prior to kidney transplantation was not associated with allograft or patient survival, but findings varied by surgery type. Sleeve gastrectomy was associated with better graft survival and should be considered in severely obese transplant candidates receiving dialysis.
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http://dx.doi.org/10.1111/ajt.16779DOI Listing
July 2021

Concomitant tamoxifen or letrozole for optimal oocyte yield during fertility preservation for breast cancer: the TAmoxifen or Letrozole in Estrogen Sensitive tumors (TALES) randomized clinical trial.

J Assist Reprod Genet 2021 Jul 26. Epub 2021 Jul 26.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco School of Medicine, San Francisco, CA, USA.

Purpose: To determine whether concomitant tamoxifen 20 mg with gonadotropins (tamoxifen-gonadotropin) versus letrozole 5 mg with gonadotropins (letrozole-gonadotropin) affects mature oocyte yield.

Methods: Open-label, single-institution, randomized trial. Inclusion criteria included the following: females, ages 18-44 years old, with new diagnosis of non-metastatic breast cancer, who were undergoing fertility preservation with either oocyte or embryo cryopreservation. Those with estrogen-receptor-positive (ER+) breast cancer were randomized to tamoxifen-gonadotropin or letrozole-gonadotropin. Another group with estrogen-receptor-negative (ER-) breast cancer was recruited, as a prospectively collected comparison arm who took neither letrozole nor tamoxifen (gonadotropin only). The primary outcome was the number of mature oocytes obtained from the cycle. The randomized groups were powered to detect a difference of three or more mature oocytes.

Results: Forty-five patients were randomized to tamoxifen-gonadotropin and fifty-one to letrozole-gonadotropin. Thirty-eight patients completed gonadotropin only. Age, antral follicle count, and body mass index were similar between the randomized groups. Our primary outcome of mature oocyte yield was similar between the tamoxifen-gonadotropin and letrozole-gonadotropin groups (12±8.6 vs. 11.6±7.5, p=0.81, 95%CI of difference =-2.9 to 3.7). In a pre-specified secondary comparison, mature oocyte yield was also similar with tamoxifen-gonadotropin or letrozole-gonadotropin versus gonadotropin only (12±8.6 vs. 11.6±7.5 vs. 12.4±7.2). There were no serious adverse events in any of the groups.

Conclusions: Tamoxifen-gonadotropin and letrozole-gonadotropin produced a similar number of mature oocytes. Women who received either tamoxifen-gonadotropin or letrozole-gonadotropin had a similar number of oocytes to the gonadotropin-only group.

Trial Registration: NCT03011684 (retrospectively registered 1/5/2017, after 9% enrolled).
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http://dx.doi.org/10.1007/s10815-021-02273-3DOI Listing
July 2021

Recurrent Events Analysis With Data Collected at Informative Clinical Visits in Electronic Health Records.

J Am Stat Assoc 2021 26;116(534):594-604. Epub 2020 Aug 26.

Department of Biostatistics, Columbia University Mailman School of Public Health, New York, NY 10032.

Although increasingly used as a data resource for assembling cohorts, electronic health records (EHRs) pose many analytic challenges. In particular, a patient's health status influences when and what data are recorded, generating sampling bias in the collected data. In this paper, we consider recurrent event analysis using EHR data. Conventional regression methods for event risk analysis usually require the values of covariates to be observed throughout the follow-up period. In EHR databases, time-dependent covariates are intermittently measured during clinical visits, and the timing of these visits is informative in the sense that it depends on the disease course. Simple methods, such as the last-observation-carried-forward approach, can lead to biased estimation. On the other hand, complex joint models require additional assumptions on the covariate process and cannot be easily extended to handle multiple longitudinal predictors. By incorporating sampling weights derived from estimating the observation time process, we develop a novel estimation procedure based on inverse-rate-weighting and kernel-smoothing for the semiparametric proportional rate model of recurrent events. The proposed methods do not require model specifications for the covariate processes and can easily handle multiple time-dependent covariates. Our methods are applied to a kidney transplant study for illustration.
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http://dx.doi.org/10.1080/01621459.2020.1801447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261679PMC
August 2020

Somatic mosaicism in the MAPK pathway in sporadic brain arteriovenous malformation and association with phenotype.

J Neurosurg 2021 Jul 2:1-8. Epub 2021 Jul 2.

Departments of1Anesthesia and Perioperative Care.

Objective: Sporadic brain arteriovenous malformation (BAVM) is a tangled vascular lesion characterized by direct artery-to-vein connections that can cause life-threatening intracerebral hemorrhage (ICH). Recently, somatic mutations in KRAS have been reported in sporadic BAVM, and mutations in other mitogen-activated protein kinase (MAPK) signaling pathway genes have been identified in other vascular malformations. The objectives of this study were to systematically evaluate somatic mutations in MAPK pathway genes in patients with sporadic BAVM lesions and to evaluate the association of somatic mutations with phenotypes of sporadic BAVM severity.

Methods: The authors performed whole-exome sequencing on paired lesion and blood DNA samples from 14 patients with sporadic BAVM, and 295 genes in the MAPK signaling pathway were evaluated to identify genes with somatic mutations in multiple patients with BAVM. Digital droplet polymerase chain reaction was used to validate KRAS G12V and G12D mutations and to assay an additional 56 BAVM samples.

Results: The authors identified a total of 24 candidate BAVM-associated somatic variants in 11 MAPK pathway genes. The previously identified KRAS G12V and G12D mutations were the only recurrent mutations. Overall, somatic KRAS G12V was present in 14.5% of BAVM lesions and G12D was present in 31.9%. The authors did not detect a significant association between the presence or allelic burden of KRAS mutation and three BAVM phenotypes: lesion size (maximum diameter), age at diagnosis, and age at ICH.

Conclusions: The authors confirmed the high prevalence of somatic KRAS mutations in sporadic BAVM lesions and identified several candidate somatic variants in other MAPK pathway genes. These somatic variants may contribute to understanding of the etiology of sporadic BAVM and the clinical characteristics of patients with this condition.
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http://dx.doi.org/10.3171/2020.11.JNS202031DOI Listing
July 2021

Early-life epilepsy after acute symptomatic neonatal seizures: A prospective multicenter study.

Epilepsia 2021 Aug 2;62(8):1871-1882. Epub 2021 Jul 2.

Department of Neurology and Weill Institute for Neuroscience, University of California San Francisco, San Francisco, CA, USA.

Objective: We aimed to evaluate early-life epilepsy incidence, seizure types, severity, risk factors, and treatments among survivors of acute neonatal seizures.

Methods: Neonates with acute symptomatic seizures born 7/2015-3/2018 were prospectively enrolled at nine Neonatal Seizure Registry sites. One-hour EEG was recorded at age three months. Post-neonatal epilepsy and functional development (Warner Initial Developmental Evaluation of Adaptive and Functional Skills - WIDEA-FS) were assessed. Cox regression was used to assess epilepsy-free survival.

Results: Among 282 infants, 37 (13%) had post-neonatal epilepsy by 24-months [median age of onset 7-months (IQR 3-14)]. Among those with post-neonatal epilepsy, 13/37 (35%) had infantile spasms and 12/37 (32%) had drug-resistant epilepsy. Most children with post-neonatal epilepsy had abnormal neurodevelopment at 24-months (WIDEA-FS >2SD below normal population mean for 81% of children with epilepsy vs 27% without epilepsy, RR 7.9, 95% CI 3.6-17.3). Infants with severely abnormal neonatal EEG background patterns were more likely to develop epilepsy than those with mild/moderate abnormalities (HR 3.7, 95% CI 1.9-5.9). Neonatal EEG with ≥3 days of seizures also predicted hazard of epilepsy (HR 2.9, 95% CI 1.4-5.9). In an adjusted model, days of neonatal EEG-confirmed seizures (HR 1.4 per day, 95% CI 1.2-1.6) and abnormal discharge examination (HR 3.9, 95% CI 1.9-7.8) were independently associated with time to epilepsy onset. Abnormal (vs. normal) three-month EEG was not associated with epilepsy.

Significance: In this multicenter study, only 13% of infants with acute symptomatic neonatal seizures developed post-neonatal epilepsy by age 24-months. However, there was a high risk of severe neurodevelopmental impairment and drug-resistant seizures among children with post-neonatal epilepsy. Days of EEG-confirmed neonatal seizures was a potentially modifiable epilepsy risk factor. An EEG at three months was not clinically useful for predicting epilepsy. These practice changing findings have implications for family counseling, clinical follow-up planning, and future research to prevent post-neonatal epilepsy.
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http://dx.doi.org/10.1111/epi.16978DOI Listing
August 2021

Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.

BMJ Neurol Open 2021 17;3(1):e000114. Epub 2021 Mar 17.

Radiology and Biomedical Imaging, UCSF, San Francisco, California, USA.

Brain arteriovenous malformations (bAVMs) are relatively rare, although their potential for secondary intracranial haemorrhage (ICH) makes their diagnosis and management essential to the community. Currently, invasive therapies (surgical resection, stereotactic radiosurgery and endovascular embolisation) are the only interventions that offer a reduction in ICH risk. There is no designated medical therapy for bAVM, although there is growing animal and human evidence supporting a role for bevacizumab to reduce the size of AVMs. In this single-arm pilot study, two patients with large bAVMs (deemed unresectable by an interdisciplinary team) received bevacizumab 5 mg/kg every 2 weeks for 12 weeks. Due to limitations of external funding, the intended sample size of 10 participants was not reached. Primary outcome measure was change in bAVM volume from baseline at 26 and 52 weeks. No change in bAVM volume was observed 26 or 52 weeks after bevacizumab treatment. No clinically important adverse events were observed during the 52-week study period. There were no observed instances of ICH. Sera vascular endothelial growth factor levels were reduced at 26 weeks and returned to baseline at 52 weeks. This pilot study is the first to test bevacizumab for patients with bAVMs. Bevacizumab therapy was well tolerated in both subjects. No radiographic changes were observed over the 52-week study period. Subsequent larger clinical trials are in order to assess for dose-dependent efficacy and rarer adverse drug effects. Trial registration number: NCT02314377.
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http://dx.doi.org/10.1136/bmjno-2020-000114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204171PMC
March 2021

Discordances between pediatric and adult thresholds in the diagnosis of hypertension in adolescents with CKD.

Pediatr Nephrol 2021 Jun 25. Epub 2021 Jun 25.

Division of Pediatric Nephrology, Department of Pediatrics, University of California San Francisco, 550 16th street, 5th Floor, San Francisco, CA, 94158, USA.

Background: Adolescents with chronic kidney disease (CKD) are a unique population with a high prevalence of hypertension. Management of hypertension during the transition from adolescence to adulthood can be challenging given differences in normative blood pressure values in adolescents compared with adults.

Methods: In this retrospective analysis of the Chronic Kidney Disease in Children Cohort Study, we compared pediatric versus adult definitions of ambulatory- and clinic-diagnosed hypertension in their ability to discriminate risk for left ventricular hypertrophy (LVH) and kidney failure using logistic and Cox models, respectively.

Results: Overall, among 363 adolescents included for study, the prevalence of systolic hypertension was 27%, 44%, 12%, and 9% based on pediatric ambulatory, adult ambulatory, pediatric clinic, and adult clinic definitions, respectively. All definitions of hypertension were statistically significantly associated with LVH except for the adult ambulatory definition. Presence of ambulatory hypertension was associated with 2.6 times higher odds of LVH using pediatric definitions (95% CI 1.4-5.1) compared to 1.4 times higher odds using adult definitions (95% CI 0.8-3.0). The c-statistics for discrimination of LVH was statistically significantly higher for the pediatric definition of ambulatory hypertension (c=0.61) compared to the adult ambulatory definition (c=0.54), and the Akaike Information Criterion was lower for the pediatric definition. All definitions were associated with progression to kidney failure.

Conclusion: Overall, there was not a substantial difference in pediatric versus adult definitions of hypertension in predicting kidney outcomes, but there was slightly better risk discrimination of the risk of LVH with the pediatric definition of ambulatory hypertension.
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http://dx.doi.org/10.1007/s00467-021-05166-wDOI Listing
June 2021

An Educational Intervention to Raise Awareness of Contraceptive Options Among Young People.

J Womens Health (Larchmt) 2021 Jun 8. Epub 2021 Jun 8.

Bixby Center for Global Reproductive Health, Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of California, San Francisco, San Francisco, California, USA.

Young people in the United States know little about contraceptive options available to them, although method use is sensitive to individual preferences, and method switching is common. For young people to gain reproductive autonomy, a first step is to be aware of different contraceptives, including hormonal and nonhormonal methods. We tested whether an educational intervention delivered on community college campuses was effective in increasing contraceptive awareness. We developed a low-cost educational intervention featuring youth-friendly visual tools and tested its impact on method awareness and knowledge among 1,051 students of all genders, aged 18-25 years, at five community colleges. We used generalized estimating equations to test changes in awareness of a range of methods, including male and female (internal) condoms, the pill, patch, vaginal ring, shot, intrauterine devices, implant, and emergency contraception. Over 90% of participants were aware of male condoms and the pill at baseline, but fewer had heard of other options (ranging from 31% to 76% for different methods). Across all methods, awareness increased to a mean of 88% among female participants and 82% among male participants postintervention. Awareness of the full range of methods increased from 31% to 55% (adjusted odds ratio [aOR]: 4.4, 95% confidence interval [CI]: 3.1-6.2]) among female participants and 11% to 36% (aOR: 10.8, 95% CI: 5.3-21.8) among male participants postintervention. The intervention was similarly effective by sexual orientation, race/ethnicity, nativity, or insurance coverage. This educational intervention significantly improved all students' awareness of a range of contraceptives, supporting one important aspect of reproductive health for young people in community settings.
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http://dx.doi.org/10.1089/jwh.2020.8753DOI Listing
June 2021

Seizure Control in Neonates Undergoing Screening vs Confirmatory EEG Monitoring.

Neurology 2021 08 2;97(6):e587-e596. Epub 2021 Jun 2.

From the Divisions of Child Neurology and Pediatrics (Neonatology) (C.J.W.) and Division of Neonatal & Developmental Medicine, Department of Pediatrics (S.L.B.), Stanford University; Quantitative Sciences Unit (V.S.), Department of Medicine, Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (N.S.A., S.L.M.), Pediatrics (N.S.A., S.L.M.), and Anesthesia & Critical Care Medicine (N.S.A.), University of Pennsylvania Perelman School of Medicine; Department of Pediatrics (Division of Neurology) (N.S.A., S.L.M.), Children's Hospital of Philadelphia, PA; Departments of Pediatrics and Population Health Sciences (M.E.L.), Duke University School of Medicine, Durham, NC; Department of Pediatrics (C.T.), College of Medicine, Division of Neurology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH; Departments of Epidemiology and Biostatistics (C.E.M., H.C.G.) and Pediatrics (E.E.R.) and Department of Neurology and Weill Institute for Neuroscience and Department of Pediatrics, UCSF Benioff Children's Hospital (H.C.G.), University of California San Francisco; Neurology (T.C.), George Washington University School of Medicine, Children's National Hospital, Washington, DC; Department of Neurology (J.S.S.), Boston Children's Hospital, Harvard Medical School, MA; Department of Neurology (C.J.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Division of Pediatric Neurology (M.R.C.), Department of Pediatrics, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium; and Division of Pediatric Neurology (R.A.S.), Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor.

Objective: To determine whether screening continuous EEG monitoring (cEEG) is associated with greater odds of treatment success for neonatal seizures.

Methods: We included term neonates with acute symptomatic seizures enrolled in the Neonatal Seizure Registry (NSR), a prospective, multicenter cohort of neonates with seizures. We compared 2 cEEG approaches: (1) screening cEEG, initiated for indications of encephalopathy or paralysis without suspected clinical seizures; and (2) confirmatory cEEG, initiated for the indication of clinical events suspicious for seizures, either alone or in addition to other indications. The primary outcome was successful response to initial seizure treatment, defined as seizures resolved without recurrence within 30 minutes after initial loading dose of antiseizure medicine. Multivariable logistic regression analyses assessed the association between cEEG approach and successful seizure treatment.

Results: Among 514 neonates included, 161 (31%) had screening cEEG and 353 (69%) had confirmatory cEEG. Neonates with screening cEEG had a higher proportion of successful initial seizure treatment than neonates with confirmatory cEEG (39% vs 18%; < 0.0001). After adjusting for covariates, there remained a greater odds ratio (OR) for successful initial seizure treatment in the screening vs confirmatory cEEG groups (adjusted OR 2.44, 95% confidence interval 1.45-4.11, = 0.0008).

Conclusions: These findings provide evidence from a large, contemporary cohort of neonates that a screening cEEG approach may improve odds of successful treatment of acute seizures.

Classification Of Evidence: This study provides Class III evidence that for neonates a screening cEEG approach, compared to a confirmatory EEG approach, increases the probability of successful treatment of acute seizures.
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http://dx.doi.org/10.1212/WNL.0000000000012293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424499PMC
August 2021

Changing stimulation protocol on repeat conventional ovarian stimulation cycles does not lead to improved laboratory outcomes.

Fertil Steril 2021 09 24;116(3):757-765. Epub 2021 May 24.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California.

Objective: To evaluate whether physicians' choice of ovarian stimulation protocol is associated with laboratory outcomes.

Design: Retrospective cohort study.

Setting: Single academic center.

Patient(s): The subjects were 4,458 patients who completed more than one in vitro fertilization ovarian stimulation cycle within 1 year. On second stimulation, 49% repeated the same protocol and 51% underwent a different one.

Intervention(s): Estradiol priming antagonist, antagonist +/- oral contraceptive pill priming, long luteal protocol, Lupron (Lupron [AbbVie Inc, North Chicago, IL]) stop protocol, and flare were compared. Logistic or linear regression with cluster robust standard errors to account for covariates and paired data was used.

Main Outcome Measure(s): Oocytes collected (OC), fertilization rate, blastocyst progression (BP), usable embryos (UE), and euploid rate (ER).

Result(s): First stimulation outcomes were comparable across all protocols for FR, BP, UE, and ER but were different for OC, after adjustment for covariates. For OC, the effect of switching protocols differed according to the type of the second stimulation. There was improvement in OC if the same stimulation was repeated, except for flare. In addition, there were slight, significant improvements in fertilization rate (difference in values or coefficient of 0.02; 95% confidence interval [CI], 0.004, 0.4) and UE (coefficient 1.25; 95% CI, 0.79, 1.72) when the same stimulation was repeated. There were no changes in BP (coefficient 0.03; 95% CI, -0.01, 0.08) or ER (coefficient 0.01; 95% CI, -0.04, 0.06) when protocols were changed. In a low-BP subgroup, greater improvement was seen when the same protocol was repeated (coefficient 0.03; 95% CI 0.01, 0.04).

Conclusion(s): There was a slight but significant improvement in laboratory outcomes when the same stimulation protocol was repeated, so careful consideration should be made before switching stimulation protocols for the purpose of improving laboratory outcomes.
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http://dx.doi.org/10.1016/j.fertnstert.2021.04.030DOI Listing
September 2021

Safety of Early Discontinuation of Antiseizure Medication After Acute Symptomatic Neonatal Seizures.

JAMA Neurol 2021 07;78(7):817-825

Department of Pediatrics, University of Michigan, Ann Arbor.

Importance: Antiseizure medication (ASM) treatment duration for acute symptomatic neonatal seizures is variable. A randomized clinical trial of phenobarbital compared with placebo after resolution of acute symptomatic seizures closed early owing to low enrollment.

Objective: To assess whether ASM discontinuation after resolution of acute symptomatic neonatal seizures and before hospital discharge is associated with functional neurodevelopment or risk of epilepsy at age 24 months.

Design, Setting, And Participants: This comparative effectiveness study included 303 neonates with acute symptomatic seizures (282 with follow-up data and 270 with the primary outcome measure) from 9 US Neonatal Seizure Registry centers, born from July 2015 to March 2018. The centers all had level IV neonatal intensive care units and comprehensive pediatric epilepsy programs. Data were analyzed from June 2020 to February 2021.

Exposures: The primary exposure was duration of ASM treatment dichotomized as ASM discontinued vs ASM maintained at the time of discharge from the neonatal seizure admission. To enhance causal association, each outcome risk was adjusted for propensity to receive ASM at discharge. Propensity for ASM maintenance was defined by a logistic regression model including seizure cause, gestational age, therapeutic hypothermia, worst electroencephalogram background, days of electroencephalogram seizures, and discharge examination (all P ≤ .10 in a joint model except cause, which was included for face validity).

Main Outcomes And Measures: Functional neurodevelopment was assessed by the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) at 24 months powered for propensity-adjusted noninferiority of early ASM discontinuation. Postneonatal epilepsy, a prespecified secondary outcome, was defined per International League Against Epilepsy criteria, determined by parent interview, and corroborated by medical records.

Results: Most neonates (194 of 303 [64%]) had ASM maintained at the time of hospital discharge. Among 270 children evaluated at 24 months (mean [SD], 23.8 [0.7] months; 147 [54%] were male), the WIDEA-FS score was similar for the infants whose ASMs were discontinued (101 of 270 [37%]) compared with the infants with ASMs maintained (169 of 270 [63%]) at discharge (median score, 165 [interquartile range, 150-175] vs 161 [interquartile range, 129-174]; P = .09). The propensity-adjusted average difference was 4 points (90% CI, -3 to 11 points), which met the a priori noninferiority limit of -12 points. The epilepsy risk was similar (11% vs 14%; P = .49), with a propensity-adjusted odds ratio of 1.5 (95% CI, 0.7-3.4; P = .32).

Conclusions And Relevance: In this comparative effectiveness study, no difference was found in functional neurodevelopment or epilepsy at age 24 months among children whose ASM was discontinued vs maintained at hospital discharge after resolution of acute symptomatic neonatal seizures. These results support discontinuation of ASM prior to hospital discharge for most infants with acute symptomatic neonatal seizures.
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http://dx.doi.org/10.1001/jamaneurol.2021.1437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145161PMC
July 2021

Opioid users show worse baseline knee osteoarthritis and faster progression of degenerative changes: a retrospective case-control study based on data from the Osteoarthritis Initiative (OAI).

Arthritis Res Ther 2021 05 22;23(1):146. Epub 2021 May 22.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, 185 Berry Street, Lobby 6, Suite 350, San Francisco, CA, 94107, USA.

Background: Opioids are frequently prescribed for pain control in knee osteoarthritis patients, despite recommendations by current guidelines. Previous studies have investigated the chondrotoxicity of different opioid subtypes. However, the impact opioids may have on progression of osteoarthritis in vivo remains unknown. The aim of this study was thus to describe the associations between opioid use and knee structural changes and clinical outcomes, over 4 years.

Methods: Participants with baseline opioid use (n=181) and who continued use for ≥1 year between baseline and 4-year follow-up (n=79) were included from the Osteoarthritis Initiative cohort and frequency matched with non-users (controls) (1:2). Whole-Organ Magnetic Resonance Imaging Scores (WORMS) were obtained, including a total summation score (WORMS total, range 0-96) and subscores for cartilage (0-36), menisci (0-24), and bone marrow abnormalities and subchondral cyst-like lesions (0-18, respectively). Knee Injury Osteoarthritis Outcomes score (KOOS) symptoms, quality of life (QOL), and pain were also obtained at baseline and follow-up (range 0-100; lower scores indicate worse outcomes). Using linear regression models, associations between baseline and longitudinal findings were investigated. As pain may modify observations, a sensitivity analysis was performed for longitudinal findings. All analyses were adjusted for sex, BMI, age, race, and Kellgren-Lawrence grade.

Results: Opioid users had greater structural degeneration at baseline (WORMS total: Coef. [95% CI], P; 7.1 [5.5, 8.8], <0.001) and a greater increase over 4 years (4.7 [2.9, 6.5], <0.001), compared to controls. Cartilage and meniscus scores increased greater in opioid users, compared to controls (P≤0.001), and findings withstood the adjustment for baseline pain (P≤0.002). All baseline KOOS scores were lower in opioid users compared to controls (P<0.001). QOL loss was greater, when adjusted for baseline KOOS pain (QOL -6.9 [-11.6, -2.1], 0.005).

Conclusions: Opioid users had worse baseline knee structural degeneration and faster progression. Opioid use was also associated with worse symptoms, pain, and QOL. Furthermore, QOL loss was greater in opioid users compared to controls, when adjusted for baseline KOOS pain, indicating that opioids may not be suited to prevent subjective disease progression in KOA patients.
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http://dx.doi.org/10.1186/s13075-021-02524-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140460PMC
May 2021

Association of Maternal Immune Activation during Pregnancy and Neurologic Outcomes in Offspring.

J Pediatr 2021 May 7. Epub 2021 May 7.

Division of Neonatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA; Newborn Brain Research Institute, University of California, San Francisco, San Francisco, CA; Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA. Electronic address:

Objective: To evaluate neurologic morbidity among offspring during their first year of life in association with prenatal maternal immune activation (MIA), using an inclusive definition.

Study Design: This retrospective cohort study included singletons born in California between 2011 and 2017. MIA was defined by International Classification of Diseases diagnosis of infection, autoimmune disorder, allergy, asthma, atherosclerosis, or malignancy during pregnancy. Neurologic morbidity in infants was defined by International Classification of Diseases diagnosis of intraventricular hemorrhage, periventricular leukomalacia, seizures, abnormal neurologic examination, or abnormal neurologic imaging. Outcomes of delayed developmental milestones during the first year of life were also explored. Risk of neurologic morbidity in offspring was approximated for women with and without MIA using log link binary regression.

Results: Demographic characteristics among 3 004 166 mother-infant dyads with or without MIA were similar in both groups. Rate of preterm delivery in mothers with MIA (9.4%) was significantly higher than those without MIA (5.6%). Infants of mothers with MIA were more likely to experience neurologic morbidities across all gestational ages. Adjusted relative risk (95% CI) in the exposed infants was 2.0 (1.9-2.1) for abnormal neurologic examination; 1.6 (1.5-1.7) for seizures, and 1.6 (1.4-1.8) for periventricular leukomalacia.

Conclusions: Our results demonstrate that MIA during pregnancy may be associated with considerably higher risk of neurologic morbidity in offspring.
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http://dx.doi.org/10.1016/j.jpeds.2021.04.069DOI Listing
May 2021

Predicting the Need for Phototherapy After Discharge.

Pediatrics 2021 05;147(5)

Division of Research and.

Background And Objectives: Bilirubin screening before discharge is performed to identify neonates at risk for future hyperbilirubinemia. The American Academy of Pediatrics recommends using a graph of bilirubin levels by age (the Bhutani Nomogram) to guide follow-up and a different graph to determine phototherapy recommendations. Our objective was to evaluate predictive models that incorporate the difference between the last total serum bilirubin (TSB) before discharge and the American Academy of Pediatrics phototherapy threshold (Δ-TSB) to predict a postdischarge TSB above the phototherapy threshold by using a single graph.

Methods: We studied 148 162 infants born at ≥35 weeks' gestation at 11 Kaiser Permanente Northern California facilities from 2012 to 2017 whose TSB did not exceed phototherapy levels and who did not receive phototherapy during the birth hospitalization. We compared 3 logistic models (Δ-TSB; Δ-TSB-Plus, which included additional variables; and the Bhutani Nomogram) by using the area under the receiver operating characteristic curve (AUC) in a 20% validation subset.

Results: A total of 2623 infants (1.8%) exceeded the phototherapy threshold postdischarge. The predicted probability of exceeding the phototherapy threshold after discharge ranged from 56% for a predischarge Δ-TSB 0 to 1 mg/dL below the threshold to 0.008% for Δ-TSB >7 mg/dL below the threshold. Discrimination was better for the Δ-TSB model (AUC 0.93) and the Δ-TSB-Plus model (AUC 0.95) than for the Bhutani Nomogram (AUC 0.88).

Conclusions: The use of Δ-TSB models had excellent ability to predict postdischarge TSB above phototherapy thresholds and may be simpler to use than the Bhutani Nomogram.
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http://dx.doi.org/10.1542/peds.2020-019778DOI Listing
May 2021

Weight Cycling and Knee Joint Degeneration in Individuals with Overweight or Obesity: Four-Year Magnetic Resonance Imaging Data from the Osteoarthritis Initiative.

Obesity (Silver Spring) 2021 05 1;29(5):909-918. Epub 2021 Apr 1.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

Objective: The aim of this study was to investigate the associations between weight cycling and knee joint degeneration in individuals with overweight or obesity with different patterns of weight change over 4 years.

Methods: A total of 2,271 individuals from the Osteoarthritis Initiative database were assessed (case-control study). Linear regression models using annual BMI measurements over 4 years were used to classify participants as weight cyclers or noncyclers. 3-T magnetic resonance imaging was used to quantify knee cartilage transverse relaxation time (T2) and cartilage thickness annually over 4 years in all subjects. Whole-Organ Magnetic Resonance Imaging Scores (WORMS) were obtained for cartilage, meniscus, and bone-marrow abnormalities in 958 subjects at baseline and at the 4-year follow-up. The longitudinal differences in cartilage T2 and thickness between weight cyclers and noncyclers were assessed using general estimating equations, whereas the differences in WORMS outcomes were compared using general linear models.

Results: No significant differences in the rate of change of cartilage thickness or T2 were found between weight cyclers and noncyclers. However, increases in maximum cartilage WORMS (P = 0.0025) and bone-marrow abnormalities (P = 0.04) were significantly greater in weight cyclers than in noncyclers.

Conclusions: Although participants' intent for weight cycling in this study was unknown, weight cyclers had significantly greater increases in cartilage and bone-marrow abnormalities over 4 years than noncyclers, independent of weight gain and loss.
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http://dx.doi.org/10.1002/oby.23129DOI Listing
May 2021

Early Identification of Cerebral Palsy Using Neonatal MRI and General Movements Assessment in a Cohort of High-Risk Term Neonates.

Pediatr Neurol 2021 05 15;118:20-25. Epub 2021 Feb 15.

Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, California.

Background: Cerebral palsy (CP) is the most common motor disability of childhood. Its early identification is an important priority for parents and is critical for access to early intervention resources, which may optimize function.

Methods: A prospective cohort of term neonates at high risk for CP was assessed by neonatal magnetic resonance imaging (MRI) to determine myelination of the posterior limb of the internal capsule, General Movements Assessment to assess typical fidgety movements at age three months, and followed to at least age two years to determine diagnosis of CP based on neurological examination.

Results: Seven of 58 children developed CP (12%), two with moderate/severe CP. Sensitivity and specificity for abnormal myelination of the posterior limb of the internal capsule were (PLIC) was 29% and 94%, and for absent fidgety movements, 29% and 98%, respectively. Negative predictive value of both absent myelination of the PLIC and absent fidgety movements was 90% (79% to 96%) for any CP and 98% (90% to 100%) for moderate/severe CP cerebral palsy. None of the children with both normal PLIC and normal fidgety movements had moderate/severe CP.

Conclusion: Normal neonatal MRI and General Movements Assessment at age three months are reassuring that a high-risk term-born child is at low risk for moderate/severe CP. These results are important for counseling parents and individualizing therapy resources in the community.
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http://dx.doi.org/10.1016/j.pediatrneurol.2021.02.003DOI Listing
May 2021

Association between Longer Travel Distance for Transplant Care and Access to Kidney Transplantation and Graft Survival in the United States.

J Am Soc Nephrol 2021 05 12;32(5):1151-1161. Epub 2021 Mar 12.

Division of Nephrology, Department of Medicine, University of California, San Francisco, California.

Background: Transplant candidates may gain an advantage by traveling to receive care at a transplant center that may have more favorable characteristics than their local center. Factors associated with longer travel distance for transplant care and whether the excess travel distance (ETD) is associated with access to transplantation or with graft failure are unknown.

Methods: This study of adults in the United States wait-listed for kidney transplantation in 1995-2015 used ETD, defined as distance a patient traveled beyond the nearest transplant center for initial waiting list registration. We used linear regression to examine patient and center characteristics associated with ETD and Fine-Gray models to examine the association between ETD (modeled as a spline) and time to deceased or living donor transplantation or graft failure.

Results: Of 373,365 patients, 11% had an ETD≥50 miles. Traveling excess distance was more likely among patients who were of non-Black race or those whose nearest transplant center had lower annual living donor transplant volume. At an ETD of 50 miles, we observed a lower likelihood of deceased donor transplantation (subhazard ratio [SHR], 0.85; 95% confidence interval [95% CI], 0.84 to 0.87) but higher likelihood of living donor transplantation (SHR, 1.14; 95% CI, 1.12 to 1.16) compared with those who received care at their nearest center. ETD was weakly associated with higher risk of graft failure.

Conclusions: Patients who travel excess distances for transplant care have better access to living donor but not deceased donor transplantation and slightly higher risk of graft failure. Traveling excess distances is not clearly associated with better outcomes, especially if living donors are unavailable.
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http://dx.doi.org/10.1681/ASN.2020081242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259680PMC
May 2021

Joint-adjacent Adipose Tissue by MRI is Associated With Prevalence and Progression of Knee Degenerative Changes: Data from the Osteoarthritis Initiative.

J Magn Reson Imaging 2021 07 28;54(1):155-165. Epub 2021 Feb 28.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

Background: Adipose tissue has recently gained interest as an independent imaging biomarker for osteoarthritis.

Purpose: To explore 1) cross-sectional associations between local subcutaneous fat (SCF) thickness at the knee and the extent of degenerative changes in overweight and obese individuals and 2) associations between local fat distribution and progression of osteoarthritis over 4 years.

Study Type: Retrospective cohort study.

Population: 338 obese and overweight participants from the Osteoarthritis Initiative cohort without radiographic evidence of osteoarthritis.

Field Strength: 3T: 3D-FLASH-WE; 3D-DESS-WE; T1w-SE; MSME.

Assessment: Baseline SCF thickness was measured in standardized locations medial, lateral and anterior to the knee and the average joint-adjacent SCF (ajSCF) was calculated. Right thigh SCF cross-sectional area was assessed. Quantitative cartilage T relaxation times and semi-quantitative whole organ MRI scores (WORMS) were obtained at baseline and 4-year follow-up. WORMS was calculated as sum of cartilage, bone marrow edema, subchondral cyst, and meniscal scores.

Statistical Tests: Associations of SCF measures with baseline, and 4-year change in T and WORMS were analyzed using regression models. SCF measurements were standardized using the equation . Analyses were adjusted for age, sex, physical activity, and BMI.

Results: Cross-sectionally, significant associations between lateral SCF, lateral compartment WORMS and T were found ( , [95% CI]: 0.53, [0.12-0.95], P < 0.05; ΔT : 0.50, [0.02-0.98], P < 0.05). Moreover, greater lateral SCF was associated with faster progression of lateral WORMS gradings (OR = 1.50, [1.05-2.15], P < 0.05). No significant positive associations were found for thigh SCF and WORMS (P = 0.44) or T measurements (medial: P = 0.15, lateral: 0.39, patellar: P = 0.75).

Data Conclusion: Joint-adjacent SCF thickness was associated with imaging parameters of knee osteoarthritis, both cross-sectionally and longitudinally, while thigh SCF was not, suggesting a spatial association of SCF and knee osteoarthritis. Based on these findings, joint-adjacent SCF may play a role in the development and progression of knee osteoarthritis.

Level Of Evidence: 4 TECHNICAL EFFICACY: Stage 5.
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http://dx.doi.org/10.1002/jmri.27574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211379PMC
July 2021

Racial Disparities in Eligibility for Preemptive Waitlisting for Kidney Transplantation and Modification of eGFR Thresholds to Equalize Waitlist Time.

J Am Soc Nephrol 2021 03;32(3):677-685

Division of Nephrology, Department of Medicine and University of Minnesota, Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota.

Background: Patients may accrue wait time for kidney transplantation when their eGFR is ≤20 ml/min. However, Black patients have faster progression of their kidney disease compared with White patients, which may lead to disparities in accruable time on the kidney transplant waitlist before dialysis initiation.

Methods: We compared differences in accruable wait time and transplant preparation by CKD-EPI estimating equations in Chronic Renal Insufficiency Cohort participants, on the basis of estimates of kidney function by creatinine (eGFR), cystatin C (eGFR), or both (eGFR). We used Weibull accelerated failure time models to determine the association between race (non-Hispanic Black or non-Hispanic White) and time to ESKD from an eGFR of ≤20 ml/min per 1.73 m. We then estimated how much higher the eGFR threshold for waitlisting would be required to achieve equity in accruable preemptive wait time for the two groups.

Results: By eGFR, 444 CRIC participants were eligible for waitlist registration, but the potential time between eGFR ≤20 ml/min per 1.73 m and ESKD was 32% shorter for Blacks versus Whites. By eGFR, 435 participants were eligible, and Blacks had 35% shorter potential wait time compared with Whites. By the eGFR equation, 461 participants were eligible, and Blacks had a 31% shorter potential wait time than Whites. We estimated that registering Blacks on the waitlist as early as an eGFR of 24-25 ml/min per 1.73 m might improve racial equity in accruable wait time before ESKD onset.

Conclusions: Policies allowing for waitlist registration at higher GFR levels for Black patients compared with White patients could theoretically attenuate disparities in accruable wait time and improve racial equity in transplant access.
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http://dx.doi.org/10.1681/ASN.2020081144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920175PMC
March 2021

Recovery of kidney function after dialysis initiation in children and adults in the US: A retrospective study of United States Renal Data System data.

PLoS Med 2021 02 19;18(2):e1003546. Epub 2021 Feb 19.

University of California San Francisco, Division of Nephrology, Department of Medicine, San Francisco, California, United States of America.

Background: Little is known about factors associated with recovery of kidney function-and return to dialysis independence-or temporal trends in recovery after starting outpatient dialysis in the United States. Understanding the characteristics of individuals who may have the potential to recover kidney function may promote better recognition of such events. The goal of this study was to determine factors associated with recovery of kidney function in children compared with adults starting dialysis in the US.

Methods And Findings: We determined factors associated with recovery of kidney function-defined as survival and discontinuation of dialysis for ≥90-day period-in children versus adults who started maintenance dialysis between 1996 and 2015 according to the United States Renal Data System (USRDS) followed through 2016 in a retrospective cohort study. We also examined temporal trends in recovery rates over the last 2 decades in this cohort. Among 1,968,253 individuals included for study, the mean age was 62.6 ± 15.8 years, and 44% were female. Overall, 4% of adults (83,302/1,953,881) and 4% of children (547/14,372) starting dialysis in the outpatient setting recovered kidney function within 1 year. Among those who recovered, the median time to recovery was 73 days (interquartile range [IQR] 43-131) in adults and 100 days (IQR 56-189) in children. Accounting for the competing risk of death, children were less likely to recover kidney function compared with adults (sub-hazard ratio [sub-HR] 0.81; 95% CI 0.74-0.89, p-value <0.001; point estimates <1 indicating increased risk for a negative outcome). Non-Hispanic black (NHB) adults were less likely to recover compared with non-Hispanic white (NHW) adults, but these racial differences were not observed in children. Of note, a steady increase in the incidence of recovery of kidney function was noted initially in adults and children between 1996 and 2010, but this trend declined thereafter. The diagnoses associated with the highest recovery rates of recovery were acute tubular necrosis (ATN) and acute interstitial nephritis (AIN) in both adults and children, where 25%-40% of patients recovered kidney function depending on the calendar year of dialysis initiation. Limitations to our study include the potential for residual confounding to be present given the observational nature of our data.

Conclusions: In this study, we observed that discontinuation of outpatient dialysis due to recovery occurred in 4% of patients with end-stage kidney disease (ESKD) and was more common among those with ATN or AIN as the cause of their kidney disease. While recovery rates rose initially, they declined starting in 2010. Additional studies are needed to understand how to best recognize and promote recovery in patients whose potential to discontinue dialysis is high in the outpatient setting.
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http://dx.doi.org/10.1371/journal.pmed.1003546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935284PMC
February 2021

Diminished ovarian reserve is associated with reduced euploid rates via preimplantation genetic testing for aneuploidy independently from age: evidence for concomitant reduction in oocyte quality with quantity.

Fertil Steril 2021 04 12;115(4):966-973. Epub 2021 Feb 12.

Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California.

Objective(s): To determine whether women with diminished ovarian reserve (DOR) (quantitatively) had lower rates of euploid blastocysts, as a proxy for oocyte quality.

Design: Retrospective cohort study.

Setting: University reproductive health clinic.

Patient(s): A total of 1,152 women aged 19-42 years underwent 1,675 IVF cycles yielding 8,073 blastocysts for biopsy from 2010 to 2019.

Interventions(s): Preimplantation genetic testing for aneuploidy.

Main Outcome Measure(s): Euploid rates, defined as the number of euploid blastocysts divided by the number of biopsied blastocysts per cycle.

Result(s): A total of 225 women (20%) had DOR as infertility diagnosis per the Bologna criteria. Age was higher among the women with DOR (39.5 y vs. 37.0 y). Euploid rates were lower among women with vs. without DOR (29.0% vs. 44.9%). In generalized linear models controlling for age, women with DOR had 24% reduced odds of a biopsied blastocyst being euploid versus women without DOR. In a secondary analysis assigning DOR status to women producing the lowest quartile of age-adjusted mature oocyte yield, this relationship remained. No differences were identified in live birth rates between women with and without DOR after euploid single-embryo transfer independently from age (n = 944 transfers; 56.8% vs. 54.8%, respectively).

Conclusion(s): Blastocysts from women with DOR are less likely to be euploid than those from women without DOR after adjustment for age. Given the concomitant reduction in euploid rates with quantity of oocytes observed in this study, quantitative ovarian reserve assessments (i.e., follicular machinery) may yield insight into relative ovarian aging.
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http://dx.doi.org/10.1016/j.fertnstert.2020.10.051DOI Listing
April 2021

Sex Disparity in Deceased-Donor Kidney Transplant Access by Cause of Kidney Disease.

Clin J Am Soc Nephrol 2021 02 26;16(2):241-250. Epub 2021 Jan 26.

Department of Epidemiology and Biostatistics, University of California, San Francisco, California.

Background And Objectives: Women with kidney failure have lower access to kidney transplantation compared with men, but the magnitude of this disparity may not be uniform across all kidney diseases. We hypothesized that the attributed cause of kidney failure may modify the magnitude of the disparities in transplant access by sex.

Design, Setting, Participants, & Measurements: We performed a retrospective cohort study of adults who developed kidney failure between 2005 and 2017 according to the United States Renal Data System. We used adjusted Cox models to examine the association between sex and either access to waitlist registration or deceased-donor kidney transplantation, and tested for interaction between sex and the attributed cause of kidney failure using adjusted models.

Results: Among a total of 1,478,037 patients, 271,111 were registered on the waitlist and 89,574 underwent deceased-donor transplantation. The rate of waitlisting was 6.5 per 100 person-years in women and 8.3 per 100 person-years for men. In adjusted analysis, women had lower access to the waitlist (hazard ratio, 0.89; 95% confidence interval, 0.89 to 0.90) and to deceased-donor transplantation after waitlisting (hazard ratio, 0.96; 95% confidence interval, 0.94 to 0.98). However, there was an interaction between sex and attributed cause of kidney disease in adjusted models (<0.001). Women with kidney failure due to type 2 diabetes had 27% lower access to the kidney transplant waitlist (hazard ratio, 0.73; 95% confidence interval, 0.72 to 0.74) and 11% lower access to deceased-donor transplantation after waitlisting compared with men (hazard ratio, 0.89; 95% confidence interval, 0.86 to 0.92). In contrast, sex disparities in access to either the waitlist or transplantation were not observed in kidney failure secondary to cystic disease.

Conclusions: The disparity in transplant access by sex is not consistent across all causes of kidney failure. Lower deceased-donor transplantation rates in women compared with men are especially notable among patients with kidney failure attributed to diabetes.
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http://dx.doi.org/10.2215/CJN.09140620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863650PMC
February 2021
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