Publications by authors named "Michael Stephens"

117 Publications

Groundwater Quality of Aquifers Overlying the Oxnard Oil Field, Ventura County, California.

Sci Total Environ 2021 Jun 26;771:144822. Epub 2021 Jan 26.

U.S. Geological Survey, San Diego, CA, USA.

Groundwater samples collected from irrigation, monitoring, and municipal supply wells near the Oxnard Oil Field were analyzed for chemical and isotopic tracers to evaluate if thermogenic gas or water from hydrocarbon-bearing formations have mixed with surrounding groundwater. New and historical data show no evidence of water from hydrocarbon-bearing formations in groundwater overlying the field. However, thermogenic gas mixed with microbial methane was detected in 5 wells at concentrations ranging from 0.011-9.1 mg/L. The presence of these gases at concentrations <10 mg/L do not indicate degraded water quality posing a known health risk. Analysis of carbon isotopes (δC-CH) and hydrogen isotopes (δH-CH) of methane and ratios of methane to heavier hydrocarbon gases were used to differentiate sources of methane between a) microbial, b) thermogenic or c) mixed sources. Results indicate that microbial-sourced methane is widespread in the study area, and concentrations overlap with those from thermogenic sources. The highest concentrations of thermogenic gas were observed in proximity to relatively high density of oil wells, large injection volumes of water disposal and cyclic steam, shallow oil development, and hydrocarbon shows in sediments overlying the producing oil reservoirs. Depths of water wells containing thermogenic gas were within approximately 200 m of the top of the Vaca Tar Sand production zone (approximately 600 m below land surface). Due to the limited sampling density, the source and pathways of thermogenic gas detected in groundwater could not be conclusively determined. Thermogenic gas detected in the absence of co-occurring water from hydrocarbon-bearing formations may result from natural gas migration over geologic time from the Vaca Tar Sand or deeper formations, hydrocarbon shows in sediments overlying producing zones, and/or gas leaking from oil-field infrastructure. Denser sampling of groundwater, potential end-members, and pressure monitoring could help better distinguish pathways of thermogenic gases.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144822DOI Listing
June 2021

Arterio-venous fistula surgery can be safely delivered in the COVID-19 pandemic era.

J Vasc Access 2020 Dec 27:1129729820983166. Epub 2020 Dec 27.

Vascular Access Service, Cardiff & Vale University Health Board, University Hospital of Wales, Cardiff, UK.

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http://dx.doi.org/10.1177/1129729820983166DOI Listing
December 2020

Using electronic AKI alerts to define the epidemiology of acute kidney injury in renal transplants.

J Nephrol 2020 Dec 1. Epub 2020 Dec 1.

Institute of Nephrology, Cardiff University School of Medicine, University Hospital, Heath Park, Cardiff, CF14 4XN, UK.

Background: Little is known regarding the impact of acute kidney injury (AKI) on renal transplant outcome. Our aim was to define the incidence and outcome of AKI in renal transplant patients using data collected from a national AKI electronic alert system METHODS: The study represents a prospective national cohort study collecting data on 1224 renal transplants recipients with a functioning renal transplant, between April 2015 and March 2019.

Results: Four hundred forty patients experienced at least one episode of AKI giving an incidence rate of 35.4%. Sixty-four point seven% of episodes were AKI stage 1, 7.3% AKI stage 2 and 28% AKI stage 3. Only 6.2% of episodes occurred in the context of rejection. Forty-three point five% of AKI episodes were associated with sepsis. AKI was associated with pre-existing renal dysfunction, and a primary renal diagnosis of diabetic nephropathy. AKI was more prevalent in recipients from a donor after cardiac death (26.4% vs. 21.4%, p < 0.05) compared to the non-AKI cohort. Following AKI, 30-day mortality was 19.8% and overall mortality was 34.8%, compared to 8.4% in the non AKI cohort (RR 4.06, 95% CI 3.1-5.3, p < 0.001). Graft survival (GS), and death censored graft survival (DCGS) censored at 4 years, in the AKI cohort were significantly lower than in the non AKI group (p < 0.0001 for GS and DCGS).

Conclusion: The study provides a detailed characterisation of AKI in renal transplant recipients highlighting its significant negative impact on patient and graft survival.
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http://dx.doi.org/10.1007/s40620-020-00869-zDOI Listing
December 2020

Mucosal Inflammatory and Wound Healing Gene Programs Reveal Targets for Stricturing Behavior in Pediatric Crohn's Disease.

J Crohns Colitis 2020 Aug 8. Epub 2020 Aug 8.

Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background And Aims: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures.

Methods: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied.

Results: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)).

Conclusion: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904088PMC
August 2020

Successful Treatment of Skewed Lyonization Associated with X-Linked CGD in a Female Presenting with Recalcitrant Crohn's Disease.

J Clin Immunol 2020 10 27;40(7):1056-1061. Epub 2020 Jul 27.

Division of Pediatric Allergy and Immunology, Mayo Clinic Childrens Center, 200 First St SW, Rochester, MN, 55905, USA.

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http://dx.doi.org/10.1007/s10875-020-00822-6DOI Listing
October 2020

Potential long-term impacts of surgical placement cancellations.

Med Educ Online 2020 12;25(1):1787309

Cardiff Transplant Unit, University Hospital of Wales , Cardiff, UK.

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http://dx.doi.org/10.1080/10872981.2020.1787309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482893PMC
December 2020

Gastrointestinal motility evaluation in children with orthostatic intolerance: Mayo Clinic experience.

Neurogastroenterol Motil 2020 08 1;32(8):e13863. Epub 2020 Jun 1.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Objective: Orthostatic intolerance (OI) and autonomic dysfunction (AD) are common in adolescents and young adults. Patients experience multisystem symptoms including gastrointestinal (GI), postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension (OH), or only symptoms of OI (SOI) without significant findings on 70-degree head-up tilt testing (HUT). We hypothesize that patients with POTS, OH, and SOI show differences in GI symptoms and motility test and that heart rate (HR) changes on HUT predict severity of GI dysmotility.

Study Design: From medical records of patients (<18 years) with OI, we collected demographics, presenting symptoms, GI manifestations, and GI motility testing. Data were compared between the 3 groups (POTS, OH, and SOI). We assessed changes in HR on HUT with changes on GI motility evaluation.

Results: Two hundred twenty-nine patients were included (73% females). Abdominal pain (65%), nausea (49%), vomiting (18%), and constipation (24%) were the most common GI symptoms. In patients who had motility evaluation, there were 27% (53/193) with delayed gastric emptying (GE) at 4 hours, 35% (32/92) with delayed colonic transit (CT), 55% (17/31) with reduced gastric accommodation (GA), and 75% (21/28) with dyssynergic defecation (DD). Among 100 POTS, 34 OH, and 95 SOI patients, no significant differences in GI symptoms or motility tests were identified and HR changes on HUT were not associated with changes on motility tests.

Conclusion: GI symptoms are frequent in adolescents with OI and are associated with delayed GE, reduced GA, delayed CT, and presence of DD.
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http://dx.doi.org/10.1111/nmo.13863DOI Listing
August 2020

Single-cell amplicon sequencing reveals community structures and transmission trends of protist-associated bacteria in a termite host.

PLoS One 2020 15;15(5):e0233065. Epub 2020 May 15.

Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, United States of America.

The hindgut protists of wood-feeding termites are usually colonized by prokaryotic symbionts. Many of the hurdles that have prevented a better understanding of these symbionts arise from variation among protist and termite host species and the inability to maintain prominent community members in culture. These issues have made it difficult to study the fidelity, acquisition, and differences in colonization of protists by bacterial symbionts. In this study, we use high throughput amplicon sequencing of the V4 region of 16S rRNA genes to determine the composition of bacterial communities associated with single protist cells of six protist species, from the genera Pyrsonympha, Dinenympha, and Trichonympha that are present in the hindgut of the termite Reticulitermes flavipes. By analyzing amplicon sequence variants (ASVs), the diversity and distribution of protist-associated bacteria was compared within and across these six different protist species. ASV analysis showed that, in general, each protist genus associated with a distinct community of bacterial symbionts which were conserved across different termite colonies. However, some ASVs corresponding to ectosymbionts (Spirochaetes) were shared between different Dinenympha species and to a lesser extent with Pyrsonympha and Trichonympha hosts. This suggested that certain bacterial symbionts may be cosmopolitan to some degree and perhaps acquired by horizontal transmission. Using a fluorescence-based cell assay, we could observe the horizontal acquisition of surface-bound bacteria. This acquisition was shown to be time-dependent, involve active processes, and was non-random with respect to binding locations on some protists.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233065PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228121PMC
August 2020

Natural History of  Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study.

Inflamm Bowel Dis 2021 Feb;27(3):295-302

The Hospital for Sick Children, Toronto, ON, Canada.

Background: The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described.

Methods: We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years.

Results: The study population included 269 children (105 [39%] Crohn's disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9-5.2). Most (94%) Crohn's disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn's disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis.

Conclusions: Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%-15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population.
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http://dx.doi.org/10.1093/ibd/izaa080DOI Listing
February 2021

An Intrapatient Concordance Study of Mismatch Repair Protein Immunohistochemical Staining Patterns in Patients With Muir-Torre Syndrome.

JAMA Dermatol 2020 06;156(6):676-680

Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia.

Importance: Appropriate use criteria for Muir-Torre syndrome (MTS) screening suggest that mismatch repair protein (MMRP) immunohistochemical (IHC) testing is usually appropriate in patients with 2 or more sebaceous neoplasms (SNs). While MTS is known to be caused by a germline mutation in mismatch repair genes, data are limited as to whether individual sebaceous tumors in these patients with multiple lesions show identical MMRP IHC staining patterns.

Objective: To determine concordance of MMRP IHC staining patterns in lesions of patients with MTS who have multiple SNs.

Design, Setting, And Participants: This retrospective single-center case series evaluated 38 SNs in 11 patients with MTS confirmed by genetic testing for MMRP IHC staining patterns. Tumor sites were classified as either facial or extrafacial. Data were collected between January 1, 2007, and January 1, 2018.

Main Outcomes And Measures: In each patient, MMRP IHC staining patterns for SNs were compared with one another to evaluate intrapatient concordance between lesions, and to the patient's known germline mutation.

Results: A total of 11 patients (7 women and 4 men) with MTS, with a mean (SD) age of 59.3 (10.6) years at time of SN biopsy, were identified. There was high concordance between MMRP IHC staining results (2-4 lesions per patient) and the patient's mutation status, with 36 of 38 total lesions (95%) matching (sensitivity, 94.7%; 95% CI, 82.3%-99.4%). Extrafacial site tumors represented 16 of 38 total lesions (42%) and demonstrated 100% concordance of IHC results to germline mutation. Only 1 of 11 patients (9%) demonstrated discordant results, with both lesions in this patient occurring on a facial site.

Conclusions And Relevance: In patients with known MTS, SNs present with highly concordant MMRP IHC staining profiles across multiple lesions. There is also a strong association with underlying germline mutations. A diagnosis of MTS might be supported by MMRP IHC when the pretest probability is high.
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http://dx.doi.org/10.1001/jamadermatol.2020.0433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142808PMC
June 2020

The Role of Oral Administration of Immunoglobulin in Managing Diarrheal Illness in Immunocompromised Children.

Paediatr Drugs 2020 Jun;22(3):331-334

Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Introduction: Immunocompromised children are susceptible to infectious diarrhea. Oral administration of human serum immunoglobulins to treat immunocompromised patients with viral gastroenteritis caused by viruses like rotavirus and norovirus has been reported.

Objective: The aim of this study was to assess the efficacy of oral immunoglobulin (OIG) in treating hospitalized immunocompromised children with diarrheal illness.

Methods: We conducted a retrospective cohort review of the Mayo Clinic electronic medical records from January 1, 2005, through April 30, 2019. We included children who were immunocompromised and received OIG as a treatment for a diarrheal illness that was classified as acute (< 4 weeks) or chronic (> 4 weeks) at the time of their treatment. Response to therapy was defined by 50% reduction in stool output.

Results: Nineteen children were identified (11 males); average age at the time of treatment was 11 (0.25-18) years. In the acute diarrhea cohort, the mean duration of symptoms was 9.5 days (4-21). In the chronic diarrhea cohort, the mean duration of symptoms was 41 days (28-90). All 19 children were treated with OIG with doses in the range of 100-300 mg/kg/day for 1-5 days. Eighteen patients (95%) had improvement. Overall average time to response was 3.1 (1-9) days after receiving the OIG.

Conclusion: Oral administration of human serum immunoglobulin in immunocompromised children presenting with acute and chronic diarrheal illness appeared helpful in reducing stool output by 50% in the majority of patients.
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http://dx.doi.org/10.1007/s40272-020-00389-0DOI Listing
June 2020

Verruciform xanthoma in a patient with recessive dystrophic epidermolysis bullosa: Case report and literature review.

Pediatr Dermatol 2020 Mar 26;37(2):355-357. Epub 2019 Dec 26.

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Verruciform xanthoma (VX) is a rare finding thought to be caused by epidermal damage from trauma or inflammation and has been reported in a limited number of patients with recessive dystrophic epidermolysis bullosa (RDEB). Herein, we describe a 20-year-old woman with RDEB who developed a large, verrucous, pink plaque on the posterior thigh that was histologically proven to be a VX. We review cases of VX in patients with RDEB and summarize the clinical features, pathophysiology, and management principles.
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http://dx.doi.org/10.1111/pde.14079DOI Listing
March 2020

Genetic variants in DGAT1 cause diverse clinical presentations of malnutrition through a specific molecular mechanism.

Eur J Med Genet 2020 Apr 25;63(4):103817. Epub 2019 Nov 25.

Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA; Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. Electronic address:

Background: DGAT1, a gene encoding a protein involved in lipid metabolism, has been recently implicated in causing a rare nutritional and digestive disease presenting as Congenital Diarrheal Disorder (CDD). Genetic causes of malnutrition can be classified as metabolic disorders, caused by loss of a specific enzyme's function. However, disease driven by genetic variants in lipid metabolism genes is not well understood, and additional information is needed to better understand these effects.

Methods: We gathered a multi-institutional cohort of undiagnosed patients with a constellation of phenotypes presenting as malnutrition and metal ion dysregulation. Clinical Whole Exome Sequencing (WES) was performed on four patients and their unaffected parents. We prioritized genetic variants based on multiple criteria including population allele frequency and presumed inheritance pattern, and identified a candidate gene. Computational modeling was used to investigate if the altered amino acids are likely to result in a dysfunctional enzyme.

Results: We identified a multi-institutional cohort of patients presenting with malnutrition-like symptoms and likely pathogenic genomic variants within DGAT1. Multiple approaches were used to profile the effect these variants have on protein structure and function. Laboratory and nutritional intervention studies showed rapid and robust patient responses.

Conclusions: This report adds on to the database for existing mutations known within DGAT1, a gene recently implicated with CDD, and also expands its clinical spectrum. Identification of these DGAT1 mutations by WES has allowed for changes in the patients' nutritional rehabilitation, reversed growth failure and enabled them to be weaned off of total parenteral nutrition (TPN).
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http://dx.doi.org/10.1016/j.ejmg.2019.103817DOI Listing
April 2020

A Community-Based Participatory Approach to Promote Healthy Eating Among Marshallese.

Hawaii J Health Soc Welf 2019 11;78(11):332-337

Office of Community Health and Research, University of Arkansas for Medical Sciences, Fayetteville, AR.

This article describes changes made to the menu served during the 2015 Marshallese May Day celebration in Northwest Arkansas, an annual Marshallese community event. The menu changes were part of a community-based participatory collaborative to improve nutrition and health in the Marshallese community. The 2015 May Day menu significantly reduced the 2014 May Day menu amount of calories, fat, carbohydrates, sodium, and cholesterol of foods offered by incorporating healthier ingredients and reducing portion sizes. Compared to the 2014 May Day menu, the total caloric value of the revised menu was reduced by more than 63%, declining from 1369 calories to 499 calories. The menu change affected an estimated 1,800 Marshallese in attendance for the 2015 May Day celebration. The successful implementation of the menu changes, which resulted in reductions in calories, fat, carbohydrates, sodium, and cholesterol offered to participants demonstrates the effectiveness of community-based participatory approaches in the implementation of policy, systems, and environmental strategies to promote health.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848001PMC
November 2019

Draining dorsal hand pustules, nodules, and ulcers in a patient with immunosuppression.

JAAD Case Rep 2019 Oct 24;5(10):846-848. Epub 2019 Sep 24.

Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1016/j.jdcr.2019.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804474PMC
October 2019

Acquired port-wine stains in six pediatric patients.

Pediatr Dermatol 2020 Jan 20;37(1):93-97. Epub 2019 Oct 20.

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Background/objectives: Port-wine stains, also known as capillary malformations, are due to dermal vascular ectasia and dilation and are most commonly congenital; however, acquired port-wine stains (APWS) developing later in life have been noted in the literature, most commonly in the context of trauma.

Methods/results: This case series presents 6 pediatric patients with APWS who first developed lesions between ages 3 and 11 years in the absence of a traumatic or other etiologic trigger.

Conclusions: The epidemiology, clinical features, and treatment response of these patients are compared to what has been previously described in other cases in the literature.
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http://dx.doi.org/10.1111/pde.14019DOI Listing
January 2020

Numerous Pink-Purple Papules in a Middle-aged Man.

JAMA Dermatol 2019 Nov;155(11):1308-1309

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1001/jamadermatol.2019.2949DOI Listing
November 2019

Predicting future dermatology academic productivity from medical school publications.

J Am Acad Dermatol 2020 Aug 6;83(2):624-626. Epub 2019 Sep 6.

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2019.08.076DOI Listing
August 2020

Wait times, health care touchpoints, and nonattendance in an academic pediatric dermatology clinic.

Pediatr Dermatol 2019 Nov 23;36(6):893-897. Epub 2019 Aug 23.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background And Objectives: Timely access to pediatric dermatology care remains a challenge. While awaiting appointments, many patients and families utilize so-called health care touchpoints outside of the dermatology clinic such as primary care or emergency department visits to address dermatologic concerns. Long waiting periods also factor into nonattendance rates at pediatric dermatology appointments. This observational retrospective study investigated wait times, relevant health care touchpoints, and factors related to nonattendance at a pediatric dermatology clinic.

Methods: We reviewed demographic, health care touchpoint, and nonattendance data for patients referred by a primary care affiliate to the Children's Hospital of Philadelphia (CHOP) pediatric dermatology clinic from February 2016 to May 2017. Descriptive statistics were used to identify trends among analyzed variables.

Results: We reviewed 250 patient records. The average number of touchpoints per patient was 0.56, and factors that significantly correlated with increased numbers of touchpoints included younger patient age and longer wait time while payer, primary diagnosis, and time of year were not associated. The nonattendance rate was 26%, and factors significantly associated with increased nonattendance rate included longer wait times and winter and spring appointments.

Conclusion: Long wait times impact numbers of touchpoints and appointment attendance rate when referring to pediatric dermatology. A platform such as teledermatology may represent an opportunity to improve access to care by allowing for earlier input from the pediatric dermatologist.
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http://dx.doi.org/10.1111/pde.13943DOI Listing
November 2019

Process evaluation of specialist nurse implementation of a soft opt-out organ donation system in Wales.

BMC Health Serv Res 2019 Jun 24;19(1):414. Epub 2019 Jun 24.

NHS Blood and Transplant, South Wales, South West and South Central, Unit 3 Cae Gwyrdd, Greenmeadow Springs Business Park, Tongwynlais, Cardiff, CF15 7AB, UK.

Background: Wales introduced a soft opt-out organ donation system on 1st December 2015 with the aim of improving consent rates. In the first 18 months consent rates improved but the difference could not solely be attributed to the soft opt-out system when compared with similar improvements in consent rates in other UK nations.

Methods: We conducted an 18 month post-intervention qualitative process evaluation involving 88 family members of 60/211 potential organ donor cases, and 19 professionals. Views and experiences of Specialist Nurses in Organ Donation who implemented the new system and family members who were involved in decision making were collected to see how their respective behaviours impacted on implementation. Data collection included interviews, focus groups and qualitative questionnaire data.

Results: Implementation was considered a success by Specialist Nurses in Organ Donation. The bespoke retraining programme and responsive approach to addressing initial implementation issues were identified as examples of best practice. Specialist Nurses in Organ Donation were valued by family members. Six implementation issues had an impact on consent rates - the media campaign had gaps, the system was more complex, challenges in changing professional behaviours, inability to obtain the required standard of evidence from family members to overturn a donation decision, increased complexity of consent processes, and additional health systems issues.

Conclusion: This is the first comprehensive process evaluation of implementing a soft opt-out system of organ donation. Specific elements of good implementation practice (such as investment in the retraining programme and the responsiveness of Specialist Nurses in Organ Donation and managers to feedback) were identified. The key message is that despite retraining, nursing practice did not radically change overnight to accommodate the new soft opt-out system. Policy makers and health service managers should not assume that nurses simply need more time to implement the soft-out as intended. Additional responsive modification of processes, ongoing training and support is required to help with implementation as originally intended. Scotland, England and the Netherlands are introducing soft opt-out systems. There is an opportunity to learn from initial implementation in Wales, by acknowledging gaps, good practice and opportunities to further improve processes and nursing practices.
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http://dx.doi.org/10.1186/s12913-019-4266-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591913PMC
June 2019

Petroleum as source and carrier of metals in epigenetic sediment-hosted mineralization.

Sci Rep 2019 06 4;9(1):8283. Epub 2019 Jun 4.

Department of Earth Sciences, University of Geneva, Rue des Maraîchers 13, 1205, Geneva, Switzerland.

Sediment-hosted ore deposits contribute a significant amount (up to 65%) of the global resources of lead and zinc. Among them, the Mississippi-Valley type deposits and related oil fields often comprise large-scale hydrothermal systems where regional host rocks are stained with disseminated liquid petroleum (crude oil) and other organic compounds. Current models for the formation of those epigenetic Pb-Zn sulphide deposits consider that metals are mostly leached from basement rocks and their detrital erosional products, and transported by oxidized basinal hydrothermal fluids as chloride complexes. Sulphide precipitation mainly occurs when these basinal brines interact with fluids rich in reduced sulphur species produced mostly by thermochemical sulphate reduction (TSR) mediated by hydrocarbons. Here, using organic geochemistry and Pb isotopes, we provide evidence that petroleum and associated water were key for the formation of sulphide mineralization in the world-class sandstone-hosted ore deposit at Laisvall, not only by supplying reduced sulphur but also by contributing metals in significant amounts. The lead originally found in bitumen of the Alum Shale Formation was transported -during an arc-continent collisional event- by liquid petroleum and associated water to the site of sulphide mineralization. The alteration of petroleum by TSR made lead available for precipitation as sulphide. The petroleum-associated lead represents 40 to 60% of the metal budget in the deposit, the remainder being sourced by leaching of basement rocks.
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http://dx.doi.org/10.1038/s41598-019-44770-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547663PMC
June 2019

Designing a co-productive study to overcome known methodological challenges in organ donation research with bereaved family members.

Health Expect 2019 08 6;22(4):824-835. Epub 2019 May 6.

NHS Blood and Transplant, South Wales, South West and South Central, Cardiff, UK.

Background: Co-production of research into public health services has yet to demonstrate tangible benefits. Few studies have reported the impact of co-production on research outcomes. The previous studies of organ donation have identified challenges in engaging with public organizations responsible, gaining ethical approval for sensitive studies with the recently bereaved and difficulty in recruiting bereaved family members who were approached about organ donation.

Objective: To address these challenges, we designed the first large co-productive observational study to evaluate implementation of a new system of organ donation in Wales. This paper outlines the co-productive strategies that were designed to overcome known methodological challenges and reports what impact they had on resolving these challenges.

Design: Two-year co-produced study with multiple stakeholders with the specific intention of maximizing engagement with the National Health Service arm in Wales responsible for organ donation, and recruitment of bereaved family members whose perspectives are essential but commonly absent from studies.

Setting And Participants: NHS Blood and Transplant, Welsh Government and multiple patient and public representatives who served as co-productive partners with the research team.

Results: Co-productive strategies enabled a smooth passage through four different ethics processes within the 10-week time frame, family member recruitment targets to be surpassed, sharing of routinely collected data on 100% of potential organ donor cases and development of further research capacity and capability in a critically under researched area.

Discussion And Conclusion: Although expensive and time consuming, co-production was effective and added value to research processes and study outcomes.
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http://dx.doi.org/10.1111/hex.12894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737840PMC
August 2019

Short-term impact of introducing a soft opt-out organ donation system in Wales: before and after study.

BMJ Open 2019 04 3;9(4):e025159. Epub 2019 Apr 3.

Department of Nephrology and Transplantation, Cardiff and Vale University Health Board, University Hospital of Wales, Cardiff, UK.

Objectives: To determine the short-term impact of a soft opt-out organ donation system on consent rates and donor numbers.

Design: Before and after observational study using bespoke routinely collected data.

Setting: National Health Service Blood and Transplant.

Participants: 205 potential organ donor cases in Wales.

Interventions: The Act and implementation strategy.

Primary And Secondary Outcomes: Consent rates at 18 months post implementation compared with 3 previous years, and organ donor numbers 21 months before and after implementation. Changes in organ donor register activity post implementation for 18 months.

Results: The consent rate for all modes of consent was 61.0% (125/205), showing a recovery from the dip to 45.8% in 2014/2015. 22.4% (46/205) were deemed consented donors: consent rate 60.8% (28/46). Compared with the 3 years before the switch there was a significant difference in Welsh consent rates (χ p value=0.009). Over the same time period, rest of the UK consent rates also significantly increased from 58.6% (5256/8969) to 63.1% (2913/4614) (χ p value<0.0001), therefore the Wales increase cannot be attributed to the Welsh legislation change. Deceased donors did not increase: 101 compared with 104. Organ donation registration increased from 34% to 38% with 6% registering to opt-out.

Conclusion: This is the first rigorous initial evaluation with bespoke data collected on all cases. The longer-term impact on consent rates and donor numbers is unclear. Concerns about a potential backlash and mass opting out were not realised. The move to a soft opt-out system has not resulted in a step change in organ donation behaviour, but can be seen as the first step of a longer journey. Policymakers should not assume that soft opt-out systems by themselves simply need more time to have a meaningful effect. Ongoing interventions to further enhance implementation and the public's understanding of organ donation are needed to reach the 2020 target of 80% consent rates. Further longitudinal monitoring is required.
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http://dx.doi.org/10.1136/bmjopen-2018-025159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500329PMC
April 2019

Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation.

Gastroenterology 2019 06 16;156(8):2254-2265.e3. Epub 2019 Feb 16.

Genetics and Molecular Biology Program, Emory University, Atlanta, Georgia; Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia; Department of Human Genetics, Emory University, Atlanta, Georgia. Electronic address:

Background & Aims: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression.

Methods: We obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease.

Results: We identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease.

Conclusions: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.
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http://dx.doi.org/10.1053/j.gastro.2019.01.270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529254PMC
June 2019

Comparison of 4 different techniques in first metatarsophalangeal joint arthrodesis.

Ir J Med Sci 2019 Aug 8;188(3):885-891. Epub 2019 Jan 8.

Orthopaedic Department, St. James's Hospital, James's Street, Dublin, D08 NHY1, Ireland.

Aims: The aim of this study was to evaluate outcomes and fusion rates of 4 different methods of first metatarsophalangeal joint (MTPJ) arthrodesis.

Methods: We performed a retrospective analysis of first MTPJ fusion using Bold® and Acutrak® compression screws, universal 1/3 tubular plate and Hallu®-S non-locking plate in 6 hospitals in Dublin over 4 years. A cohort of 300 patients (351 feet) was operated on by 3 feet and ankle fellowship trained orthopaedic surgeons (PK, MMS, JVMcK) over 4 years. Mean age was 62.4 years. There were 261 females and 39 males. One hundred three patients had a fusion of first MTPJ using two Acutrak® screws and 90 with two Bold® screws. Sixty-five were fused with the Hallu-S® plate and 42 with the universal 1/3 tubular plate. Patients were evaluated clinically and radiographically at 6 weeks, 3 months and 12 months.

Results: Functional outcome scores performed using Manchester-Oxford Foot Questionnaire (MOXFQ). Failure rate in those fused with the Hallu®-S plate was 0%, Acutrak® screws 2.4%, Bold® screws 9.5% and universal 1/3 tubular plate 12.5% (p > 0.12). All treatment groups demonstrated significantly reduced MOXFQ scores (p value < 0.05).

Conclusion: In this retrospective study for first MTPJ fusion, a low profile, pre-contoured plate in combination with a screw mode had the best results with no failure rates and improved MOXFQ scores.

Level Of Clinical Evidence: IV, retrospective study.
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http://dx.doi.org/10.1007/s11845-018-01961-xDOI Listing
August 2019

Transverse melanonychia in a child receiving chemotherapy.

Pediatr Dermatol 2019 Jan 12;36(1):e60-e61. Epub 2018 Dec 12.

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Transverse melanonychia is a rare finding often secondary to chemotherapy, orally ingested medications, or other iatrogenic interventions. A 19-month-old boy with hemophagocytic lymphohistiocytosis treated with biweekly etoposide and dexamethasone developed transverse bands of pigment in all toenail and fingernail units consistent with transverse melanonychia. We review the literature for reported cases of transverse melanonychia and summarize suspected etiologies.
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http://dx.doi.org/10.1111/pde.13721DOI Listing
January 2019

The Effect of Early-Life Environmental Exposures on Disease Phenotype and Clinical Course of Crohn's Disease in Children.

Am J Gastroenterol 2018 10 28;113(10):1524-1529. Epub 2018 Sep 28.

Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, GA, USA. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA. Department of Pediatric Gastroenterology, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH, USA. Department of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA. Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Department of Pediatrics, Goryeb Children's Hospital, Morristown, NJ, USA. Division of Pediatric Gastroenterology, Hasbro Children's Hospital/The Rhode Island Hospital, Providence, RI, USA. Department of Pediatrics, University of Utah, Salt Lake City, UT, USA. Department of Pediatrics, Children's Hospital of Eastern Ontario IBD Centre and University of Ottawa, Ottawa, ON, Canada. Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA. Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA. Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA. Department of Gastroenterology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA. Children's Healthcare of Atlanta, Atlanta, GA, USA. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. Department of Pediatrics, Dalhousie University, Halifax, NS, Canada. Department of Digestive Diseases and Nutrition Center, University at Buffalo, Buffalo, NY, USA. Department of Pediatrics, Nemours Children's Specialty Care, Jacksonville, FL, USA. Department of Pediatrics, University of Chicago Medicine Comer Children's Hospital, Chicago, IL, USA. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. Department of Pediatric Gastroenterology, Mayo Clinic, Rochester, MN, USA. Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA. Department of Pediatrics, Mount Sinai Hospital, New York, NY, USA. Department of Pediatrics, Northwell Health, New York, NY, USA. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.

Objectives: Environmental factors play an important role in the pathogenesis of Crohn's Disease (CD). In particular, by virtue of the instability of the microbiome and development of immunologic tolerance, early life factors may exert the strongest influence on disease risk and phenotype.

Methods: We used data from 1119 CD subjects recruited from RISK inception cohort to examine the impact of early life environment on disease progression. Our primary exposures of interest were breastfeeding in infancy and exposure to maternal, active, or passive smoke. Our primary outcomes were development of complicated (stricturing or penetrating) disease, and need for CD-related hospitalization, and surgery. Multivariable logistic regression models were used to define independent associations, adjusting for relevant covariates.

Results: Our study cohort included 1119 patients with CD among whom 15% had stricturing (B2) or penetrating disease (B3) by 3 years. 331 patients (35%) and 95 patients (10.6%) required CD-related hospitalizations and surgery respectively. 74.5% were breastfed in infancy and 31% were exposed to smoking among whom 7% were exposed to maternal smoke. On multivariable analysis, a history of breastfeeding was inversely associated with complicated (B2/B3 disease) 0.65, CI 95% 0.44-96; P = 0.03) in pediatric CD. Maternal smoking during pregnancy was associated with increased risk of hospitalization during the 3-year follow-up period (OR 1.75, CI 95% 1.05-2.89; P = 0.03).

Conclusions: Early life environmental factors influence the eventual phenotypes and disease course in CD.
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http://dx.doi.org/10.1038/s41395-018-0239-9DOI Listing
October 2018

Microbiota-sensitive epigenetic signature predicts inflammation in Crohn's disease.

JCI Insight 2018 09 20;3(18). Epub 2018 Sep 20.

Division of Immunobiology, Center for Inflammation and Tolerance.

Altered response to the intestinal microbiota strongly associates with inflammatory bowel disease (IBD); however, how commensal microbial cues are integrated by the host during the pathogenesis of IBD is not understood. Epigenetics represents a potential mechanism that could enable intestinal microbes to modulate transcriptional output during the development of IBD. Here, we reveal a histone methylation signature of intestinal epithelial cells isolated from the terminal ilea of newly diagnosed pediatric IBD patients. Genes characterized by significant alterations in histone H3-lysine 4 trimethylation (H3K4me3) showed differential enrichment in pathways involving immunoregulation, cell survival and signaling, and metabolism. Interestingly, a large subset of these genes was epigenetically regulated by microbiota in mice and several microbiota-sensitive epigenetic targets demonstrated altered expression in IBD patients. Remarkably though, a substantial proportion of these genes exhibited H3K4me3 levels that correlated with the severity of intestinal inflammation in IBD, despite lacking significant differential expression. Collectively, these data uncover a previously unrecognized epigenetic profile of IBD that can be primed by commensal microbes and indicate sensitive targets in the epithelium that may underlie how microbiota predispose to subsequent intestinal inflammation and disease.
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http://dx.doi.org/10.1172/jci.insight.122104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237229PMC
September 2018

Improving Health while Alleviating Hunger: Best Practices of a Successful Hunger Relief Organization.

Curr Dev Nutr 2018 Sep 22;2(9):nzy057. Epub 2018 Jun 22.

College of Medicine, University of Arkansas for Medical Sciences Northwest, Fayetteville, AR.

Background: Food insecurity affects millions each year in the United States. Hunger relief organizations work to reduce hunger and food insecurity; however, the foods they provide are often unhealthy.

Objective: The objective of this article is to document the policy, systems, and environmental changes that Samaritan Community Center made to their programs in order to better serve Washington County and Benton County, Arkansas.

Methods: With the use of a case-study approach, researchers held 17 meetings with key members of the organization and conducted >30 h of observations to document policy, systems, and environmental changes and best practices for implementing those changes.

Results: Researchers identified emergent themes and grouped best practices in the following categories: ) removing stigma and empowering clients, ) incremental steps to increase access to healthy foods, ) embracing multiculturalism, ) donation policies and procurement, ) collaboration is key, ) organizational culture, and ) challenges and resolutions.

Conclusions: Samaritan Community Center has successfully implemented and adopted new programs and practices in order to improve the health of their clients. To our knowledge, this is the first case study to document best practices for making policy, systems, and environmental changes by a hunger relief organization to improve the nutritional quality of foods provided to their clients.
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http://dx.doi.org/10.1093/cdn/nzy057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121129PMC
September 2018