Publications by authors named "Shannon Hunter"

25 Publications

  • Page 1 of 1

Rapid methodologies for assessing colonization and effector-mediated hypersensitive response in kiwifruit.

Mol Plant Microbe Interact 2021 Apr 9. Epub 2021 Apr 9.

Plant and Food Research Ltd, 1413, 120 Mt Albert road, Sandringham, Auckland, New Zealand, 1142;

The infection of in kiwifruit is currently assessed by numerous methodologies, each with their own limitations. Most studies are based on either a laborious method of growth quantification of the pathogen or qualitative assessments by visual scoring following stem or cutting inoculation. Additionally, when assessing for resistance against specific pathogen effectors, confounding interactions between multiple genes in the pathogen can make mapping resistance phenotypes nearly impossible. Here we present robust alternative methods to quantify pathogen load based on rapid bacterial DNA quantification by PCR, the use of (), and a transient reporter eclipse assay, for assessing resistance conferred by isolated bacterial avirulence genes. These assays compare well with bacterial plate counts to assess bacterial colonization as a result of plant resistance activation. The DNA-based quantification, when coupled with the and reporter eclipse assays to independently identify bacterial avirulence genes, is rapid, highly reproducible, and scalable for high-throughput screens of multiple cultivars or genotypes. Application of these methodologies will allow rapid and high-throughput identification of resistant cultivars and the bacterial avirulence genes they recognize, facilitating resistance gene discovery for plant breeding programs.
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http://dx.doi.org/10.1094/MPMI-02-21-0043-RDOI Listing
April 2021

Design of the Association of Uterine Perforation and Expulsion of Intrauterine Device study: a multisite retrospective cohort study.

Am J Obstet Gynecol 2021 Jan 15. Epub 2021 Jan 15.

Bayer AG, Berlin, Germany.

Background: Intrauterine devices are effective and safe, long-acting reversible contraceptives, but the risk of uterine perforation occurs with an estimated incidence of 1 to 2 per 1000 insertions. The European Active Surveillance Study for Intrauterine Devices, a European prospective observational study that enrolled 61,448 participants (2006-2012), found that women breastfeeding at the time of device insertion or with the device inserted at ≤36 weeks after delivery had a higher risk of uterine perforation. The Association of Uterine Perforation and Expulsion of Intrauterine Device (APEX-IUD) study was a Food and Drug Administration-mandated study designed to reflect current United States clinical practice. The aims of the APEX-IUD study were to evaluate the risk of intrauterine device-related uterine perforation and device expulsion among women who were breastfeeding or within 12 months after delivery at insertion.

Objective: We aimed to describe the APEX-IUD study design, methodology, and analytical plan and present population characteristics, size of risk factor groups, and duration of follow-up.

Study Design: APEX-IUD study was a retrospective cohort study conducted in 4 organizations with access to electronic health records: Kaiser Permanente Northern California, Kaiser Permanente Southern California, Kaiser Permanente Washington, and Regenstrief Institute in Indiana. Variables were identified through structured data (eg, diagnostic, procedural, medication codes) and unstructured data (eg, clinical notes) via natural language processing. Outcomes include uterine perforation and device expulsion; potential risk factors were breastfeeding at insertion, postpartum timing of insertion, device type, and menorrhagia diagnosis in the year before insertion. Covariates include demographic characteristics, clinical characteristics, and procedure-related variables, such as difficult insertion. The first potential date of inclusion for eligible women varies by research site (from January 1, 2001 to January 1, 2010). Follow-up begins at insertion and ends at first occurrence of an outcome of interest, a censoring event (device removal or reinsertion, pregnancy, hysterectomy, sterilization, device expiration, death, disenrollment, last clinical encounter), or end of the study period (June 30, 2018). Comparisons of levels of exposure variables were made using Cox regression models with confounding adjusted by propensity score weighting using overlap weights.

Results: The study population includes 326,658 women with at least 1 device insertion during the study period (Kaiser Permanente Northern California, 161,442; Kaiser Permanente Southern California, 123,214; Kaiser Permanente Washington, 20,526; Regenstrief Institute, 21,476). The median duration of continuous enrollment was 90 (site medians 74-177) months. The mean age was 32 years, and the population was racially and ethnically diverse across the 4 sites. The mean body mass index was 28.5 kg/m, and of the women included in the study, 10.0% had menorrhagia ≤12 months before insertion, 5.3% had uterine fibroids, and 10% were recent smokers; furthermore, among these women, 79.4% had levonorgestrel-releasing devices, and 19.5% had copper devices. Across sites, 97,824 women had an intrauterine device insertion at ≤52 weeks after delivery, of which 94,817 women (97%) had breastfeeding status at insertion determined; in addition, 228,834 women had intrauterine device insertion at >52 weeks after delivery or no evidence of a delivery in their health record.

Conclusion: Combining retrospective data from multiple sites allowed for a large and diverse study population. Collaboration with clinicians in the study design and validation of outcomes ensured that the APEX-IUD study results reflect current United States clinical practice. Results from this study will provide valuable information based on real-world evidence about risk factors for intrauterine devices perforation and expulsion for clinicians.
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http://dx.doi.org/10.1016/j.ajog.2021.01.003DOI Listing
January 2021

Later sleep timing is associated with an increased risk of preterm birth in nulliparous women.

Am J Obstet Gynecol MFM 2019 11 9;1(4):100040. Epub 2019 Sep 9.

Department of Obstetrics, Gynecology-Maternal Fetal Medicine & Preventive Medicine, Northwestern University, Chicago, IL.

Background: Although uterine contractions have a diurnal periodicity and increase in frequency during hours of darkness, data on the relationship between sleep duration and sleep timing patterns and preterm birth are limited.

Objective: We sought to examine the relationship of self-reported sleep duration and timing in pregnancy with preterm birth.

Study Design: In the prospective Nulliparous Pregnancy Outcome Study: Monitoring Mothers-to-be cohort, women completed a survey of sleep patterns at 6-13 weeks gestation (visit 1) and again at 22-29 weeks gestation (visit 3). Additionally, at 16-21 weeks gestation (visit 2), a subgroup completed a weeklong actigraphy recording of their sleep. Weekly averages of self-reported sleep duration and sleep midpoint were calculated. A priori, sleep duration of <7 hours was defined as "short," and sleep midpoint after 5 am was defined as "late." The relationships among these sleep characteristics and all preterm birth and spontaneous preterm birth at <37 weeks gestation were examined in univariate analyses. Multivariable logistic regressions that controlled for age and body mass index alone (model 1) and with additional covariates (race, smoking, insurance, and employment schedule) following a backward elimination process (model 2) were performed.

Results: Of the 10,038 women who were enrolled, sleep survey data were available on 7524 women at visit 1 and 7668 women at visit 3. The rate of short sleep duration was 17.1% at visit 1 and 20.7% at visit 3. The proportion with a late sleep midpoint was 11.6% at visit 1 and 12.2% at visit 3. There was no significant relationship between self-reported short sleep and preterm birth across all visits. However, self-reported late sleep midpoint (>5 am) was associated with preterm birth . Women with a late sleep midpoint (>5 am) in early pregnancy had a preterm birth rate of 9.5%, compared with 6.9% for women with sleep midpoint ≤5 am (P=.005). Similarly, women with a late sleep midpoint had a higher rate of spontaneous preterm birth (6.2% vs 4.4%; P=.019). Comparable results were observed for women with a late sleep midpoint at visit 3 (all preterm birth 8.9% vs 6.6%; P=.009; spontaneous preterm birth 5.9% vs 4.3%; P=.023). All adjusted analyses on self-reported sleep midpoint (models 1 and 2) maintained statistical significance (P<.05), except for visit 1, model 2 for spontaneous preterm birth (P=.07). The visit 2 objective data from the smaller subgroup (n=782) demonstrated similar trends in preterm birth rates by sleep midpoint status.

Conclusion: Self-reported late sleep midpoint in both early and late pregnancy, but not short sleep duration, is associated with an increased rate of preterm birth.
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http://dx.doi.org/10.1016/j.ajogmf.2019.100040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757682PMC
November 2019

Real-time PCR and droplet digital PCR are accurate and reliable methods to quantify pv. biovar 3 in kiwifruit infected plantlets.

Plant Dis 2020 Nov 18. Epub 2020 Nov 18.

New Zealand Institute for Plant and Food Research Ltd, 1413, New Cultivar Innovation, Private Bag 92169, Auckland, New Zealand, 1142;

pv. (Psa) is the etiological agent of kiwifruit canker disease, causing severe economic losses in kiwifruit production areas around the world. Rapid diagnosis, understanding of bacterial virulence and rate of infection in kiwifruit cultivars is important in applying effective measures of disease control. Psa load in kiwifruit is currently determined by a labor-intense colony counting method with no high-throughput and specific quantification method being validated. In this work we used three alternative Psa quantification methods in two infected kiwifruit cultivars: start of growth time, quantitative qPCR (qPCR), and droplet digital PCR (ddPCR). Method performance in each case was compared to the colony counting method. Methods were validated using calibration curves obtained with serial dilutions of Psa3 inoculum and standard growth curves obtained from kiwifruit samples infected with Psa3 inoculum. All three alternative methods showed high correlation (r > 0.85) with the colony counting method. qPCR and ddPCR were very specific, sensitive (5 × 10 CFU/cm2), highly correlated to each other (r = 0.955) and flexible allowing for sample storage. The inclusion of a kiwifruit biomass marker increased the methods' accuracy. The qPCR method was efficient and allowed for high-throughput processing and the ddPCR method showed highly accurate results but was more expensive and time consuming. While not ideal for high-throughput processing, ddPCR was useful in developing accurate standard curves for the qPCR method. The combination of the two methods is high-throughput, specific for Psa3 quantification and useful for research studies e.g. disease phenotyping and host-pathogen interactions.
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http://dx.doi.org/10.1094/PDIS-08-20-1703-REDOI Listing
November 2020

Assessing the incidence of osteosarcoma among teriparatide users based on Medicare Part D and US State Cancer Registry Data.

Pharmacoepidemiol Drug Saf 2020 12 7;29(12):1616-1626. Epub 2020 Sep 7.

RTI Health Solutions, Research Triangle Park, North Carolina, USA.

Purpose: During preclinical testing, teriparatide caused a dose-dependent increase in the incidence of osteosarcoma in rats. This study compared the incidence rate of osteosarcoma among patients aged ≥65 years treated with teriparatide vs a matched-comparator cohort.

Methods: This population-based comparative-cohort study matched exposure details for each teriparatide user, identified via Medicare Part D prescription claims, and up to four comparators based on age, sex, zip code, date of claim for filled prescription, and number of unique therapeutic classes dispensed. Outcomes were identified via linkage with participating cancer registries. All US state cancer registries were invited to participate.

Results: Overall, 153 316 patients in the teriparatide cohort and 613 247 in the comparator cohort were linked to 811 osteosarcoma cases from 26 participating state cancer registries (68% of US patients aged ≥65 years diagnosed 2007-2014). Analysis on a subset of cohorts revealed they were balanced for known osteosarcoma risk factors and Charlson comorbidity index. Mean duration of teriparatide treatment was 10 months. No osteosarcoma cases were observed in the teriparatide cohort; the incidence rate in the comparator cohort was consistent with the background incidence rate among adults aged ≥65 years. The incidence rate ratio was 0.0 (95% confidence interval, 0.0-3.2).

Conclusions: For US patients aged ≥65 years, incidence of osteosarcoma among those treated with teriparatide ranges from 0 to 3.2 times the incidence of osteosarcoma in those treated with other medications. Given low incidence of osteosarcoma, this range of effect is inconsistent with a large absolute increase in osteosarcoma risk.
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http://dx.doi.org/10.1002/pds.5103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754479PMC
December 2020

Patient-reported burden of hereditary angioedema: findings from a patient survey in the United States.

Ann Allergy Asthma Immunol 2020 06 10;124(6):600-607. Epub 2020 Mar 10.

Shire, a Takeda company, Lexington, Massachusetts.

Background: Hereditary angioedema (HAE) with C1-inhibitor deficiency is associated with painful, potentially fatal attacks affecting subcutaneous or submucosal tissues.

Objective: To evaluate HAE burden from the patients' perspective.

Methods: This was a noninterventional survey of patients with HAE in the United States, conducted from March 17 to April 28, 2017. Patients were recruited through the US Hereditary Angioedema Association. Key eligibility criteria included the following: (1) aged 18 years and older, (2) self-reported physician diagnosis of HAE type I or II, (3) 1 or more HAE attacks or prodromal symptoms within the last year, and (4) receipt of HAE medication for an attack within the last 2 years. Descriptive analyses were conducted.

Results: A total of 445 patients completed the survey. Most patients (92.8%) were aged 18 to 64 years with HAE type I (78.4%) and had a positive family history (78.4%). Mean (SD) ages at symptom onset and diagnosis were 12.5 (9.1) and 20.1 (13.7) years, respectively. Most patients (78.7%) experienced an attack within the past month. The abdomen (58.0%) and extremities (46.1%) were commonly affected sites; pain (73.9%) and abdominal (57.0%) and nonabdominal (55.1%) swelling were frequently reported symptoms. Most patients (68.5%) had received or were currently receiving long-term prophylaxis. Most patients (88.8%) reported visiting allergists or immunologists, whereas 9.2% visited emergency departments or urgent care clinics. Per the Hospital Anxiety and Depression Scale, 49.9% and 24.0% of respondents had anxiety and depression, respectively. Mean Hereditary Angioedema-Quality of Life scores were generally lower with higher attack frequency. General health was "poor" or "fair" for 24.8% of patients. Mean (SD) percentage impairments were 5.9% (14.1%) for absenteeism, 23.0% (25.8%) for presenteeism, 25.4% (28.1%) for work productivity loss, and 31.8% (29.7%) for activity impairment.

Conclusion: Despite treatment advances, patients with HAE in the United States continue to have a high burden of illness.
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http://dx.doi.org/10.1016/j.anai.2020.02.018DOI Listing
June 2020

Prospective Evaluation of Maternal Sleep Position Through 30 Weeks of Gestation and Adverse Pregnancy Outcomes.

Obstet Gynecol 2019 10;134(4):667-676

University of Utah, Salt Lake City, Utah; RTI International, Research Triangle Park, North Carolina; Yale University, New Haven, Connecticut; University of Pittsburgh, Pittsburgh, Pennsylvania; Oregon Health & Science University, Portland, Oregon; Northwestern University, Evanston, Illinois; Case Western Reserve University, Cleveland, Ohio; Indiana University, Bloomington, Indiana; University of Pennsylvania, Philadelphia, Pennsylvania; Columbia University, New York, New York; University of South Florida, Tampa, Florida; University of California-Irvine, Irvine, California; Johns Hopkins Medicine, Baltimore, Maryland; University of Texas Medical Branch at Galveston, Galveston, Texas; and Brigham and Women's Hospital, Boston, Massachusetts.

Objective: To examine the relationship between prospectively assessed maternal sleep position and subsequent adverse pregnancy outcomes.

Methods: This was a secondary analysis of a prospective observational multicenter cohort study of nulliparous women with singleton gestations who were enrolled between October 2010 and May 2014. Participants had three study visits that were not part of clinical care. They prospectively completed in-depth sleep questionnaires between 6 0/7 and 13 6/7 weeks of gestation and 22 0/7 and 29 6/7 weeks of gestation, the first and third study visits. A subset of women also underwent level 3 home sleep tests using the Embletta Gold device. The primary outcome was a composite of adverse pregnancy outcomes such as stillbirth, a small-for-gestational-age newborn, and gestational hypertensive disorders.

Results: A total of 8,706 (of 10,038) women had data from at least one sleep questionnaire and for pregnancy outcomes, and they comprised the population for this analysis. The primary outcome occurred in 1,903 pregnancies (22%). There was no association between reported non-left lateral or supine sleep during the last week of the first visit (adjusted odds ratio [aOR] 1.00 [95% CI 0.89-1.14]) or third visit (aOR 0.99 [95% CI 0.89-1.11] and the composite or any individual outcome, except for an apparent protective effect for stillbirth at the third visit (aOR 0.27 (95% CI 0.09-0.75). Women with objectively measured supine sleep position for at least 50% of the time were no more likely than those in the supine position 50% or less of the time to have the composite adverse outcome.

Conclusions: Going to sleep in the supine or right lateral position, as self-reported before the development of pregnancy outcome and objectively assessed through 30 weeks of gestation, was not associated with an increased risk of stillbirth, a small-for-gestational-age newborn, or gestational hypertensive disorders.
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http://dx.doi.org/10.1097/AOG.0000000000003458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768734PMC
October 2019

Genetic and phenotypic variation of Phytophthora crassamura isolates from California nurseries and restoration sites.

Fungal Biol 2019 02 5;123(2):159-169. Epub 2018 Dec 5.

Department of Environmental Science, Policy and Management, University of California, Berkeley, CA, 94720, USA.

Phenotypic and sequence data were used to characterize 28 isolates resembling Phytophthora megasperma from 14 host species in 2 plant production facilities and 10 restoration sites across the San Francisco Bay Area (California; USA). Size of the oogonia and DNA sequences (nuclear internal transcribed spacer (ITS) and mitochondrial cytochrome c oxidase subunit 1 (COX 1)) were compared, and sensitivity to mefenoxam and pathogenicity were measured. Based on ITS 61 % of isolates matched ex-type sequences of Phytophthora crassamura from Italy, and the remainder matched or were close to the P. megasperma ex-type. However, all California P. crassamura genotypes belonged to four unique COX 1 haplotype lineages isolated from both nurseries and restoration sites. Although lineages were sensitive to mefenoxam, a significant difference in sensitivity was identified, and all continued growth in-vitro. These results suggested previous mefenoxam exposure in plant production facilities resulting in tolerance. In conclusion, all evidence pointed to a nursery origin of novel P. crassamura lineages found in California restoration sites. In this study, COX 1 sequences and oogonia size provided information relevant to identify geographic and evolutionary intraspecific variation within P. crassamura, and was additionally used to track the spread of this species from nurseries into wildlands.
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http://dx.doi.org/10.1016/j.funbio.2018.11.012DOI Listing
February 2019

The burden of chronic spontaneous urticaria: unsatisfactory treatment and healthcare resource utilization in France (the ASSURE-CSU study).

Eur J Dermatol 2018 Dec;28(6):795-802

Hospices civils de Lyon, Claude-Bernard University, Lyon, France.

Data on the clinical burden of chronic spontaneous urticaria (CSU) and economic consequences are lacking in France. To characterize the clinical and economic burden of CSU in symptomatic patients despite treatment by analysing data of French patients from the ASSURE-CSU study. ASSURE-CSU was an international observational study that included CSU patients with symptoms that lasted for 12 months or more despite treatment. Disease characteristics and healthcare resource use were obtained from medical records. Data on disease history, health-related quality of life (HR-QoL), and work productivity were collected from a patient survey. A total of 101 patients were analysed (76.2% female; mean age: 48.9 years) with moderate to severe disease (UAS7 score ≥16) in 43.4% and angioedema in 72.3%. The mean (S.D.) total scores of Chronic Urticaria Quality of Life (CU-QoL) and Dermatology Life Quality Index (DLQI) were 37.7 (22.3) and 9.7 (6.9), respectively, thus indicating a significant impact of the disease on HR-QoL. Mean absenteeism and presenteeism were 6.4% and 20.8%, respectively, with a mean loss of work productivity estimated at 20.7%. The mean (S.D.) total direct cost of CSU was €2,397 per patient per year and was mainly driven by therapies (€1,435) and inpatient costs (€859). The indirect costs for four weeks were mainly presenteeism (€421) and loss of work productivity (€420). CSU significantly impairs HR-QoL, which increases with the severity of the disease. The direct and indirect costs for the management of symptomatic CSU are an important economic burden.
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http://dx.doi.org/10.1684/ejd.2018.3446DOI Listing
December 2018

Evidence for rapid adaptive evolution of tolerance to chemical treatments in Phytophthora species and its practical implications.

PLoS One 2018 10;13(12):e0208961. Epub 2018 Dec 10.

Department of Environmental Science, Policy & Management, University of California, Berkeley, CA, United States of America.

Chemical treatments are used widely in agricultural and natural settings to protect plants from diseases; however, they may exert an important selection pressure on plant pathogens, promoting the development of tolerant isolates through adaptive evolution. Phosphite is used to manage diseases caused by Phytophthora species which include a large number of the most economically damaging plant pathogens worldwide. Phosphite controls the growth of Phytophthora species in planta without killing it; as a result, isolates can develop tolerance to phosphite after prolonged exposure. We investigated the inter- and intra-specific variability in phosphite tolerance of eleven Phytophthora species, including P. ramorum, an internationally important, highly regulated pathogen. Phytophthora ramorum is a good model system because it is comprised of multiple genetically homogeneous lineages. Seven species were found to be consistently sensitive to phosphite based on the low Effective Concentration (EC) 50 values of all isolates tested (amount of phosphite required to inhibit mycelial growth by 50% relative to growth in the absence of phosphite). However, P. ramorum, P. lateralis, P. crassamura and P. cambivora showed intraspecific variability in sensitivity to phosphite, with at least one isolate showing significantly higher tolerance than the other isolates. Within the three P. ramorum evolutionarily divergent lineages tested, NA1 was the most susceptible to phosphite, the NA1 and EU1 lineages showed intralineage variability and the NA2 lineage showed a decreased sensitivity to phosphite overall as all isolates were relatively tolerant. This finding is relevant because NA1 is dominant in the wild and can be controlled using phosphite, while the EU1 lineage has recently been identified in the wild and is phosphite-tolerant, making the treatment approach potentially less effective. Phytophthora ramorum, P. lateralis and P. crassamura are either selfing, homothallic species, or are known to reproduce exclusively clonally, indicating tolerance to phosphite can emerge even in the absence of sexual recombination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208961PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287812PMC
May 2019

Association of Adverse Pregnancy Outcomes With Self-Reported Measures of Sleep Duration and Timing in Women Who Are Nulliparous.

J Clin Sleep Med 2018 12 15;14(12):2047-2056. Epub 2018 Dec 15.

Department of Obstetrics and Gynecology Medicine, Northwestern University, Chicago, Illinois.

Study Objectives: To examine the relationship of self-reported sleep during pregnancy with adverse pregnancy outcomes. A secondary objective was to describe the concordance between self-reported and objectively assessed sleep during pregnancy.

Methods: In this prospective cohort, women completed a survey of sleep patterns at 6 to 13 weeks' gestation (visit 1) and again at 22 to 29 weeks' gestation (visit 3). Additionally, at 16 to 21 weeks (visit 2), a subgroup completed a week-long sleep diary coincident with an actigraphy recording. Weekly averages of self-reported sleep duration and sleep midpoint were calculated. A priori, sleep duration < 7 hours was defined as "short," and sleep midpoint after 5:00 AM was defined as "late." The relationship of these sleep abnormalities with hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM) was determined.

Results: Of the 10,038 women enrolled, sleep survey data were available for 7,524 women at visit 1 and 7,668 women at visit 3. A total of 752 women also provided ≥ 5 days of sleep diary data coincident with actigraphy at visit 2. We did not observe any consistent relationship between self-reported short sleep and HDP or GDM. There was an association between self-reported late sleep midpoint and GDM (visit 1 adjusted odds ratio 1.67, 95% confidence interval 1.17, 2.38; visit 2 adjusted odds ratio 1.73, 95% confidence interval 1.23, 2.43). At visit 2, 77.1% of participants had concordance between their diary and actigraphy for short sleep duration, whereas 94.3% were concordant for sleep midpoint.

Conclusions: Self-reported sleep midpoint, which is more accurate than self-reported sleep duration, is associated with the risk of GDM.

Clinical Trial Registration: Registry: ClinicalTrials.gov, Title: Pregnancy as a Window to Future Cardiovascular Health: Adverse Pregnancy Outcomes as Predictors of Increased Risk Factors for Cardiovascular Disease, Identifier: NCT02231398, URL: https://clinicaltrials.gov/ct2/show/NCT02231398.
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http://dx.doi.org/10.5664/jcsm.7534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287730PMC
December 2018

Development of a high throughput optical density assay to determine fungicide sensitivity of oomycetes.

J Microbiol Methods 2018 11 9;154:33-39. Epub 2018 Oct 9.

Forest Protection, Scion, Rotorua 3010, New Zealand. Electronic address:

A high-throughput assay was developed to screen Phytophthora species for fungicide sensitivity using optical density measurements for unbiased, automated measurement of mycelial growth. The efficacy of the optical density assay (OD) to measure phosphite sensitivity in Phytophthora species was compared to two widely used methods, radial growth (RG) and dry weight (DW) assays. Three isolates of each of Phytophthora cinnamomi, P. multivora and P. pluvialis, with known phosphite exposure and three isolates of each species with no prior phosphite exposure, were screened for phosphite sensitivity using the three assays. Mycelial growth measurements were taken after culturing for 6, 14 and 15 days for the OD, DW and RG assays respectively. Mycelial growth inhibition at 15, 80, 200 and 500 μg/mL phosphite relative to growth on control media was used to determine effective concentration values for 50% growth reduction (EC50). The species varied in their tolerance to phosphite with P. cinnamomi being the least sensitive followed by P. multivora and P. pluvialis. No significant differences in tolerance were found between isolates within the same species using any method. The OD assay produced comparable EC50 values to the RG and DW assays. The growth of the three species was more sensitive to phosphite in the DW than the RG and OD assays, however limited sample throughput and greater variation in measuring small amounts of mycelia in the dry weight assessment increase variability and limits throughput. The OD assay offers a fast method to enable an inventory of chemical resistance and is particularly advantageous for slow growing species as it requires less time and offers greater throughput than existing RG and DW methods.
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http://dx.doi.org/10.1016/j.mimet.2018.10.006DOI Listing
November 2018

Cardiovascular Safety During and After Use of Phentermine and Topiramate.

J Clin Endocrinol Metab 2019 02;104(2):513-522

RTI Health Solutions, Research Triangle Park, North Carolina.

Context: Increases in heart rate were seen during the clinical program for fixed-dose combination phentermine (PHEN) and topiramate (TPM), an oral medication indicated for weight management; however, the effect on cardiovascular (CV) outcomes is uncertain.

Objective: The aim of the present study was to determine the extent to which the rates of major adverse CV events (MACE) in patients using PHEN and TPM (including fixed dose) differed from the MACE rates during unexposed periods.

Design: Retrospective cohort study.

Setting: MarketScan, US insurance billing data.

Patients Or Other Participants: Patients aged >18 years with ≥6 months of continuous enrollment in the database before taking PHEN and/or TPM or after stopping these medications.

Interventions: PHEN and TPM, taken separately and together (including fixed dose).

Main Outcome Measures: MACE, a composite of hospitalization for acute myocardial infarction and stroke and in-hospital CV death.

Results: Because the outcomes are rare and the duration of medication use was brief, few events occurred. The MACE rates among current users of PHEN/TPM, fixed-dose PHEN/TPM, and PHEN were lower than those among unexposed former users. In contrast, the rate of MACE among current users of TPM was greater than among unexposed former users [incidence rate ratio: PHEN/TPM, 0.57; 95% CI, 0.19 to 1.78; fixed-PHEN/TPM, 0.24; 95% CI, 0.03 to 1.70; PHEN, 0.56; 95% CI, 0.34 to 0.91; TPM, 1.58; 95% CI, 1.33 to 1.87).

Conclusions: Overall, the data indicated no increased risk of MACE for current PHEN/TPM users; however, the 95% CIs for the PHEN/TPM groups were broad, indicating that the data were compatible with a wide range of possible values.
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http://dx.doi.org/10.1210/jc.2018-01010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318778PMC
February 2019

Comparison of Urticaria Activity Score Over 7 Days (UAS7) Values Obtained from Once-Daily and Twice-Daily Versions: Results from the ASSURE-CSU Study.

Am J Clin Dermatol 2018 Apr;19(2):267-274

Charité-Universitätsmedizin Berlin, Berlin, Germany.

Background: The Urticaria Activity Score summed over 7 days (UAS7) assesses the itch severity and hive count in chronic spontaneous urticaria (CSU) using once- or twice-daily diary-based documentation.

Objective: The aim of this study was to evaluate the comparability of twice-daily versus once-daily versions of the UAS and the resulting UAS7 values.

Methods: Data came from the ASSURE-CSU study. The twice-daily and once-daily UAS7 was calculated from morning and evening ratings, as well as from exact 24-h evening ratings of hive count and itch severity, respectively. Three UAS7 scores were computed: UAS7 twice daily (UAS7), UAS7 once daily for maximum itch (UAS7), and UAS7 once daily for average itch (UAS7). UAS7 values were assigned to five score bands (0, 1-6, 7-15, 16-27, 28-42), reflecting urticaria-free to severe disease activity. The score values and score band ratios of the UAS7 and UAS7 versions were compared and assessed for correlation by weighted Cohen's kappa statistics.

Results: Data from 614 patients were analyzed. All three versions of the UAS7 yielded very similar results, with a mean (standard deviation) UAS7, UAS7, and UAS7 of 17.3 (10.49), 17.7 (8.90), and 16.2 (8.68), respectively. Correlation coefficients between UAS7 and UAS7, UAS7 and UAS7, and UAS7 and UAS7 were 0.94, 0.95, and 0.99, respectively, showing very high positive pairwise correlation. The weighted kappa coefficient, κ (95% confidence interval) was 0.78 (0.75-0.82) for UAS7 versus UAS7, and 0.82 (0.78-0.85) for UAS7 versus UAS7, demonstrating substantial agreement.

Conclusions: The once- and twice-daily UAS7 scores were highly consistent, supporting the use of either version when evaluating CSU activity.
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http://dx.doi.org/10.1007/s40257-017-0331-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978890PMC
April 2018

Racial Disparities in Adverse Pregnancy Outcomes and Psychosocial Stress.

Obstet Gynecol 2018 02;131(2):328-335

Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, North Carolina; the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland; and the Departments of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois, the University of California at Irvine, Irvine, California, the University of Utah Health Sciences Center, Salt Lake City, Utah, Columbia University, New York, New York, the University of Pittsburgh, Pittsburgh, Pennsylvania, the University of Pennsylvania, Philadelphia, Pennsylvania, MetroHealth Medical Center-Case Western Reserve University, Cleveland, Ohio, Indiana University, Indianapolis, Indiana, and the University of Texas Medical Branch, Galveston, Texas.

Objective: To assess the relationships between self-reported psychosocial stress and preterm birth, hypertensive disease of pregnancy, and small-for-gestational-age (SGA) birth and to assess the extent to which these relationships account for racial and ethnic disparities in these adverse outcomes.

Methods: Self-reported measures of psychosocial stress (perceived stress, depression, racism, anxiety, resilience, and social support) were collected during pregnancy among a racially and ethnically diverse cohort of women enrolled in a prospective observational study of nulliparous women with singleton pregnancies, from eight clinical sites across the United States, between October 2010 and May 2014. The associations of preterm birth, hypertensive disease of pregnancy, and SGA birth with the self-reported measures of psychosocial stress as well as with race and ethnicity were evaluated.

Results: The study included 9,470 women (60.4% non-Hispanic white, 13.8% non-Hispanic black, 16.7% Hispanic, 4.0% Asian, and 5.0% other). Non-Hispanic black women were significantly more likely to experience any preterm birth, hypertensive disease of pregnancy, and SGA birth than were non-Hispanic white women (12.2% vs 8.0%, 16.7% vs 13.4%, and 17.2% vs 8.6%, respectively; P<.05 for all). After adjusting for potentially confounding factors, including the six different psychosocial factors singly and in combination, non-Hispanic black women continued to be at greater risk of any preterm birth and SGA birth compared with non-Hispanic white women.

Conclusion: Among a large and geographically diverse cohort of nulliparous women with singleton gestations, non-Hispanic black women are most likely to experience preterm birth, hypertensive disease of pregnancy, and SGA birth. These disparities were not materially altered for preterm birth or SGA birth by adjustment for demographic differences and did not appear to be explained by differences in self-reported psychosocial factors.
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http://dx.doi.org/10.1097/AOG.0000000000002441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785441PMC
February 2018

Objectively measured short sleep duration and later sleep midpoint in pregnancy are associated with a higher risk of gestational diabetes.

Am J Obstet Gynecol 2017 10 7;217(4):447.e1-447.e13. Epub 2017 Jun 7.

Department of Neurology and Center for Circadian and Sleep Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.

Background: Experimental and epidemiologic data suggest that among nonpregnant adults, sleep duration may be an important risk factor for chronic disease. Although pregnant women commonly report poor sleep, few studies objectively evaluated the quality of sleep in pregnancy or explored the relationship between sleep disturbances and maternal and perinatal outcomes.

Objective: Our objective was to examine the relationship between objectively assessed sleep duration, timing, and continuity (measured via wrist actigraphy) and maternal cardiovascular and metabolic morbidity specific to pregnancy.

Study Design: This was a prospective cohort study of nulliparous women. Women were recruited between 16 0/7 and 21 6/7 weeks' gestation. They were asked to wear a wrist actigraphy monitor and complete a daily sleep log for a period of 7 consecutive days. The primary sleep exposure variables were the averages of the following over the total valid nights (minimum 5, maximum 7 nights): short sleep duration during the primary sleep period (<7 h/night), late sleep midpoint (midpoint between sleep onset and sleep offset >5 am), and top quartile of minutes of wake time after sleep onset and sleep fragmentation index. The primary outcomes of interest were a composite of hypertensive disorders of pregnancy (mild, severe, or superimposed preeclampsia; eclampsia; or antepartum gestational hypertension) and gestational diabetes mellitus. We used χ tests to assess associations between sleep variables and categorical baseline characteristics. Crude odds ratios and 95% confidence intervals were estimated from univariate logistic regression models to characterize the magnitude of the relationship between sleep characteristics and hypertensive disorders of pregnancy and gestational diabetes. For associations significant in univariate analysis, multiple logistic regression was used to explore further the association of sleep characteristics with pregnancy outcomes.

Results: In all, 901 eligible women consented to participate; 782 submitted valid actigraphy studies. Short sleep duration and a later sleep midpoint were associated with an increased risk of gestational diabetes (odds ratio, 2.24; 95% confidence interval, 1.11-4.53; and odds ratio, 2.58; 95% confidence interval, 1.24-5.36, respectively) but not of hypertensive disorders. A model with both sleep duration and sleep midpoint as well as their interaction term revealed that while there was no significant interaction between these exposures, the main effects of both short sleep duration and later sleep midpoint with gestational diabetes remained significant (adjusted odds ratio, 2.06; 95% confidence interval, 1.01-4.19; and adjusted odds ratio, 2.37; 95% confidence interval, 1.13-4.97, respectively). Additionally, after adjusting separately for age, body mass index, and race/ethnicity, both short sleep duration and later sleep midpoint remained associated with gestational diabetes. No associations were demonstrated between the sleep quality measures (wake after sleep onset, sleep fragmentation) and hypertensive disorders or gestational diabetes.

Conclusion: Our results demonstrate a relationship between short sleep duration and later sleep midpoint with gestational diabetes. Our data suggest independent contributions of these 2 sleep characteristics to the risk for gestational diabetes in nulliparous women.
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http://dx.doi.org/10.1016/j.ajog.2017.05.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783638PMC
October 2017

Sleep During Pregnancy: The nuMoM2b Pregnancy and Sleep Duration and Continuity Study.

Sleep 2017 05;40(5)

Department of Neurology and Center for Circadian and Sleep Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.

Study Objectives: To characterize sleep duration, timing and continuity measures in pregnancy and their association with key demographic variables.

Methods: Multisite prospective cohort study. Women enrolled in the nuMoM2b study (nulliparous women with a singleton gestation) were recruited at the second study visit (16-21 weeks of gestation) to participate in the Sleep Duration and Continuity substudy. Women <18 years of age or with pregestational diabetes or chronic hypertension were excluded from participation. Women wore a wrist activity monitor and completed a sleep log for 7 consecutive days. Time in bed, sleep duration, fragmentation index, sleep efficiency, wake after sleep onset, and sleep midpoint were averaged across valid primary sleep periods for each participant.

Results: Valid data were available from 782 women with mean age of 27.3 (5.5) years. Median sleep duration was 7.4 hours. Approximately 27.9% of women had a sleep duration of <7 hours; 2.6% had a sleep duration of >9 hours. In multivariable models including age, race/ethnicity, body mass index, insurance status, and recent smoking history, sleep duration was significantly associated with race/ethnicity and insurance status, while time in bed was only associated with insurance status. Sleep continuity measures and sleep midpoint were significantly associated with all covariates in the model, with the exception of age for fragmentation index and smoking for wake after sleep onset.

Conclusions: Our results demonstrate the relationship between sleep and important demographic characteristics during pregnancy.
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http://dx.doi.org/10.1093/sleep/zsx045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396817PMC
May 2017

Predictive Accuracy of Serial Transvaginal Cervical Lengths and Quantitative Vaginal Fetal Fibronectin Levels for Spontaneous Preterm Birth Among Nulliparous Women.

JAMA 2017 03;317(10):1047-1056

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland.

Importance: Spontaneous preterm birth is a leading cause of infant mortality. Prediction, largely based on prior pregnancy outcomes, is not possible in women pregnant for the first time.

Objective: To assess the accuracy of universal screening to predict spontaneous preterm birth in nulliparous women using serial measurements of vaginal fetal fibronectin levels and cervical length.

Design, Settings, And Participants: A prospective observational cohort study of nulliparous women with singleton pregnancies, from 8 clinical sites across the United States between October 2010 and May 2014. Women and clinicians were blinded to results unless cervical shortening less than 15 mm was identified.

Exposures: Transvaginal cervical length and quantitative vaginal fetal fibronectin levels were reviewed at 2 study visits 4 or more weeks apart.

Main Outcomes And Measures: Spontaneous preterm birth at less than 37 weeks was the primary outcome. Cervical length and quantitative fetal fibronectin were considered independently and together at each visit. Measurement distributions were compared for spontaneous preterm birth vs all other births. Spontaneous preterm birth before 32 weeks was a secondary outcome.

Results: The study included 9410 women (median age, 27.0 [interquartile range, 9.0] years; 60.7% non-Hispanic white, 13.8% non-Hispanic black, 16.5% Hispanic, 4.0% Asian, and 5.1% other), of whom 474 (5.0%) had spontaneous preterm births, 335 (3.6%) had medically indicated preterm births, and 8601 (91.4%) had term births. Among women with spontaneous preterm birth, cervical length of 25 mm or less occurred in 35 of 439 (8.0%) at 16 to 22 weeks' gestation and in 94 of 403 (23.3%) at 22 to 30 weeks' gestation. Fetal fibronectin levels of 50 ng/mL or greater at 16 to 22 weeks identified 30 of 410 women (7.3%) with spontaneous preterm birth and 31 of 384 (8.1%) at 22 to 30 weeks. The area under the receiver operating characteristic curve for screening between 22 and 30 weeks for fetal fibronectin level alone was 0.59 (95% CI, 0.56-0.62), for transvaginal cervical length alone was 0.67 (95% CI, 0.64-0.70), and for the combination as continuous variables was 0.67 (95% CI, 0.64-0.70).

Conclusions And Relevance: Among nulliparous women with singleton pregnancies, quantitative vaginal fetal fibronectin and serial transvaginal ultrasound cervical length had low predictive accuracy for spontaneous preterm birth. These findings do not support routine use of these tests in such women.
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http://dx.doi.org/10.1001/jama.2017.1373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828036PMC
March 2017

Association Between Sleep-Disordered Breathing and Hypertensive Disorders of Pregnancy and Gestational Diabetes Mellitus.

Obstet Gynecol 2017 01;129(1):31-41

University of Pittsburgh, Pittsburgh, and the University of Pennsylvania, Philadelphia, Pennsylvania; RTI International, Washington, DC; the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland; the University of Utah, Salt Lake City, Utah; Case Western Reserve University, Cleveland, Ohio; Columbia University, New York, New York; the University of California-Irvine, Irvine, California; Johns Hopkins University School of Medicine, Baltimore, Maryland; Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts; Northwestern University, Chicago, Illinois; Indiana University, Bloomington, Indiana; and the University of Texas Medical Branch, Galveston, Galveston, Texas.

Objective: To estimate whether sleep-disordered breathing during pregnancy is a risk factor for the development of hypertensive disorders of pregnancy and gestational diabetes mellitus (GDM).

Methods: In this prospective cohort study, nulliparous women underwent in-home sleep-disordered breathing assessments in early (6-15 weeks of gestation) and midpregnancy (22-31 weeks of gestation). Participants and health care providers were blinded to the sleep test results. An apnea-hypopnea index of 5 or greater was used to define sleep-disordered breathing. Exposure-response relationships were examined, grouping participants into four apnea-hypopnea index groups: 0, greater than 0 to less than 5, 5 to less than 15, and 15 or greater. The study was powered to test the primary hypothesis that sleep-disordered breathing occurring in pregnancy is associated with an increased incidence of preeclampsia. Secondary outcomes were rates of hypertensive disorders of pregnancy, defined as preeclampsia and antepartum gestational hypertension, and GDM. Crude and adjusted odds ratios and 95% confidence intervals (CIs) were calculated from univariate and multivariate logistic regression models.

Results: Three thousand seven hundred five women were enrolled. Apnea-hypopnea index data were available for 3,132 (84.5%) and 2,474 (66.8%) women in early and midpregnancy, respectively. The corresponding prevalence of sleep-disordered breathing was 3.6% and 8.3%. The prevalence of preeclampsia was 6.0%, hypertensive disorders of pregnancy 13.1%, and GDM 4.1%. In early and midpregnancy the adjusted odds ratios for preeclampsia when sleep-disordered breathing was present were 1.94 (95% CI 1.07-3.51) and 1.95 (95% CI 1.18-3.23), respectively; hypertensive disorders of pregnancy 1.46 (95% CI 0.91-2.32) and 1.73 (95% CI 1.19-2.52); and GDM 3.47 (95% CI 1.95-6.19) and 2.79 (95% CI 1.63-4.77). Increasing exposure-response relationships were observed between apnea-hypopnea index and both hypertensive disorders and GDM.

Conclusion: There is an independent association between sleep-disordered breathing and preeclampsia, hypertensive disorders of pregnancy, and GDM.
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http://dx.doi.org/10.1097/AOG.0000000000001805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512455PMC
January 2017

Racial/Ethnic Disparities in Measures of Self-reported Psychosocial States and Traits during Pregnancy.

Am J Perinatol 2016 12 8;33(14):1426-1432. Epub 2016 Aug 8.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.

 The aim of this study was to determine whether racial/ethnic differences in psychosocial measures, independent of economic status, exist among a large population of pregnant nulliparas.  Between October 2010 and September 2013, nulliparous women at eight U.S. medical centers were followed longitudinally during pregnancy and completed validated instruments to quantify several psychosocial domains: Cohen Perceived Stress Scale, trait subscale of the Spielberger Anxiety Inventory, Connor-Davidson Resilience Scale, Multidimensional Scale of Perceived Social Support, Krieger Racism Scale, Edinburgh Postnatal Depression Scale, and the Pregnancy Experience Scale. Scores were stratified and compared by self-reported race, ethnicity, and income.  Complete data were available for 8,128 of the 10,038 women enrolled in the study. For all measures, race and ethnicity were significantly associated ( < 0.001) with survey scores. Non-Hispanic black (NHB) women were most likely to score in the most unfavorable category for all measures, with the exception of the Pregnancy Experience Scale. The magnitude of these differences did not differ by income status (interaction,  > 0.05) except on the Krieger racism survey and the Edinburgh depression survey, which were exacerbated among NHB women with higher income (interaction,  < 0.001).  Significant racial/ethnic disparities, independent of income status, exist in psychosocial measures during pregnancy.
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http://dx.doi.org/10.1055/s-0036-1586510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821109PMC
December 2016

Radiation dose response simulation for biomechanical-based deformable image registration of head and neck cancer treatment.

Phys Med Biol 2015 Nov 20;60(21):8481-9. Epub 2015 Oct 20.

Civil and Environmental Engineering/Mechanical and Mechatronics Engineering, University of Waterloo, Waterloo, ON, N2L 3G1, Canada.

Biomechanical-based deformable image registration is conducted on the head and neck region. Patient specific 3D finite element models consisting of parotid glands (PG), submandibular glands (SG), tumor, vertebrae (VB), mandible, and external body are used to register pre-treatment MRI to post-treatment MR images to model the dose response using image data of five patients. The images are registered using combinations of vertebrae and mandible alignments, and surface projection of the external body as boundary conditions. In addition, the dose response is simulated by applying a new loading technique in the form of a dose-induced shrinkage using the dose-volume relationship. The dose-induced load is applied as dose-induced shrinkage of the tumor and four salivary glands. The Dice Similarity Coefficient (DSC) is calculated for the four salivary glands, and tumor to calculate the volume overlap of the structures after deformable registration. A substantial improvement in the registration is found by including the dose-induced shrinkage. The greatest registration improvement is found in the four glands where the average DSC increases from 0.53, 0.55, 0.32, and 0.37 to 0.68, 0.68, 0.51, and 0.49 in the left PG, right PG, left SG, and right SG, respectively by using bony alignment of vertebrae and mandible (M), body (B) surface projection and dose (D) (VB+M+B+D).
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http://dx.doi.org/10.1088/0031-9155/60/21/8481DOI Listing
November 2015

Deformable image registration of heterogeneous human lung incorporating the bronchial tree.

Med Phys 2010 Sep;37(9):4560-71

Radiation Medicine Program, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.

Purpose: To investigate the effect of the bronchial tree on the accuracy of biomechanical-based deformable image registration of human lungs.

Methods: Three dimensional finite element models have been developed using four dimensional computed tomography image data of ten lung cancer patients. Each model is built of a body, left and right lungs, tumor, and bronchial trees. Triangular shell elements are used for the bronchial trees while tetrahedral elements are used for other components. Hyperelastic material properties based on experimental investigation on human lungs are used for the lung parenchyma. Different material properties are assigned for the bronchial tree using five values for the modulus of elasticity of 0.01, 0.12, 0.5, 10, and 18 MPa. Lungs are modeled to slide inside chest cavities by applying frictionless contact surfaces between each lung and corresponding chest cavity. The accuracy of the models is examined using an average of 40 bronchial bifurcation points identified on inhale and exhale images. Relative accuracy is evaluated by comparing the displacement of all nodes within the lungs as well as the dosimetric difference at the exhale position predicted by the model.

Results: There is no significant effect of bronchial tree on the model accuracy based on the bifurcation points analysis. However, on the local level, using an average of 38 000 nodes, there is a maximum difference of 8.5 mm in the deformation of the bronchial trees, as the modulus of elasticity of the bronchial trees increases from 0.01 to 18 MPa; however, more than 96% of nodes are within a 2.5 mm difference in each direction. The average dose difference at the predicted exhale position is less than 35 cGy between the models.

Conclusions: The bronchial tree has little effect on the global deformation and the accuracy of deformable image registration of lungs. Hence, the homogenous model is a reasonable assumption. Since there are some local deformation differences between nodes as the material properties of the bronchial tree change that may affect the accuracy of dosimetric results, heterogeneity may be required for a smaller scale modeling of lungs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933251PMC
http://dx.doi.org/10.1118/1.3471020DOI Listing
September 2010

Biomechanical-based image registration for head and neck radiation treatment.

Phys Med Biol 2010 Nov 19;55(21):6491-500. Epub 2010 Oct 19.

Radiation Medicine Program, Princess Margaret Hospital, 610 University Ave., Toronto, Ontario M5G2M9, Canada.

Deformable image registration of four head and neck cancer patients has been conducted using a biomechanical-based model. Patient-specific 3D finite element models have been developed using CT and cone-beam CT image data of the planning and a radiation treatment session. The model consists of seven vertebrae (C1 to C7), mandible, larynx, left and right parotid glands, tumor and body. Different combinations of boundary conditions are applied in the model in order to find the configuration with a minimum registration error. Each vertebra in the planning session is individually aligned with its correspondence in the treatment session. Rigid alignment is used for each individual vertebra and the mandible since no deformation is expected in the bones. In addition, the effect of morphological differences in the external body between the two image sessions is investigated. The accuracy of the registration is evaluated using the tumor and both parotid glands by comparing the calculated Dice similarity index of these structures following deformation in relation to their true surface defined in the image of the second session. The registration is improved when the vertebrae and mandible are aligned in the two sessions with the highest average Dice index of 0.86 ± 0.08, 0.84 ± 0.11 and 0.89 ± 0.04 for the tumor, left and right parotid glands, respectively. The accuracy of the center of mass location of tumor and parotid glands is also improved by deformable image registration where the errors in the tumor and parotid glands decrease from 4.0 ± 1.1, 3.4 ± 1.5 and 3.8 ± 0.9 mm using rigid registration to 2.3 ± 1.0, 2.5 ± 0.8 and 2.0 ± 0.9 mm in the deformable image registration when alignment of vertebrae and mandible is conducted in addition to the surface projection of the body.
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http://dx.doi.org/10.1088/0031-9155/55/21/010DOI Listing
November 2010

Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer.

Int J Radiat Oncol Biol Phys 2004 Apr;58(5):1418-23

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Purpose: Neck dissection has traditionally played an important role in the treatment of patients with squamous cell carcinoma of the head and neck who present with regionally advanced neck disease (N2-N3). Radiotherapy and concurrent chemotherapy improves overall survival in advanced head-and-neck cancer compared with radiotherapy alone. The necessity for postchemoradiation neck dissection is controversial. The intent of this report was to define the value of neck dissection in this patient population better.

Methods And Materials: Patients with locally advanced squamous carcinoma of the head and neck who also presented with nodal disease and underwent hyperfractionated radiotherapy and concurrent cisplatin/5-fluorouracil chemotherapy constituted the study population. Adjuvant modified neck dissection (MND) was planned 6 to 8 weeks after completion of chemoradiation in those patients who had a biopsy-proven pathologically complete response at the primary tumor site, irrespective of the clinical/radiographic neck response. A cohort of patients underwent electrode assessment of tumor oxygenation. Pathologic findings from the MND were used to compute the negative and positive predictive values and overall accuracy of the clinical/radiographic response (cCR). Regional control, failure-free survival, and survival were compared according to whether patients actually underwent MND.

Results: A total of 154 patients received concurrent chemoradiation. Of these, 108 presented with nodal disease: N1, n = 30; and N2-N3, n = 78. MND was performed in 65 (60%) of 108 patients, including 13 (43%) of 30 with Stage N1 and 52 (66%) of 78 with Stage N2-N3. For N1 patients, the negative predictive value of a cCR, positive predictive value of less than a cCR, and the overall accuracy for clinical response was 92%, 100%, and 92%, respectively. For N2-N3 patients, the corresponding values were 74%, 44%, and 60%. Patients with poorly oxygenated tumors were more likely to have residual disease at MND. The median follow-up was 4 years. The 4-year disease-free survival rate was 70% for N1 patients, irrespective of the clinical response or whether MND was performed. The 4-year disease-free survival rate was 75% for N2-N3 patients who had a cCR and underwent MND vs. 53% for patients who had a cCR but did not undergo MND (p = 0.08). The 4-year overall survival rate was 77% vs. 50% for these two groups of patients (p = 0.04).

Conclusion: The clinical and pathologic responses in the neck correlated poorly with one another for patients with N2-N3 neck disease undergoing concurrent chemoradiation for advanced head-and-neck cancer. MND still appears to confer a disease-free survival and overall survival advantage with acceptably low morbidity. Tumor oxygenation assessment may be useful in selecting patients who are especially prone to have residual disease. Better tools need to be developed to determine prospectively whether this procedure is required for individual patients.
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http://dx.doi.org/10.1016/j.ijrobp.2003.09.004DOI Listing
April 2004

Clinical implications of radionecrosis to the head and neck surgeon.

Curr Opin Otolaryngol Head Neck Surg 2003 Apr;11(2):103-6

Duke University Medical Center, Durham, NC 27709, USA.

Radiation necrosis is one of the most serious complications in the treatment of malignancies of the head and neck. As radiotherapy becomes more frequently used as a primary modality and in combination with chemotherapy and surgery, the head and neck surgeon needs to be able to prevent and recognize the often subtle signs and symptoms of radiation necrosis. The symptoms of necrosis can mimic the recurrence of cancer, which presents a diagnostic dilemma, because aggressive surgical biopsy may worsen necrosis and contribute to the formation of a fistula. This review provides a brief discussion of the diagnostic and treatment options for osteoradionecrosis and chondroradionecrosis in the head and neck.
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http://dx.doi.org/10.1097/00020840-200304000-00007DOI Listing
April 2003