bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract ED02-02: Interaction between genetics, epigenetics, and environment in cancer prevention
Authors: Tycko Benjamin
Published: May 2019

A recent convergence of genomic and epigenomic findings has brought the study of DNA methylation to the forefront of cancer research. In this session I will review our knowledge to date and suggest future directions for translational research and clinical applications in two key areas – (i) dietary methyl donors and DNA methylation in cancer prevention, (ii) allele-specific DNA methylation mapping as a tool for improving the yield of true-positive signals from genome-wide association studies (GWAS) for cancer susceptibility. These topics will highlight the importance of cis- and trans-acting influences of the genetic background on epigenetic patterns and cancer susceptibility.

References:

1. Kerkel K, Spadola A, Yuan E, Kosek J, Jiang L, Hod E, Li K, Murty VV, Schupf N, Vilain E, Morris M, Haghighi F, Tycko B (2008) Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat Genet 40:904-908. PMID:18568024

2. Tycko B (2010). Allele-specific DNA methylation: beyond imprinting. Hum Mol Genet. 19:R210-220.

3. Gonda TA, Kim Y-I, Salas M, Gamble MV, Shibata W, Muthupalani S, Sohn K-J, Abram J, Fox JG, Wang TC, Tycko B (2012). Folic acid increases global DNA methylation and reduces inflammation to prevent Helicobacter-associated gastric cancer in mice. Gastroenterology. 142(4):824-833 PMID:22474448

4. Paliwal A, Temkin A, Kerkel K, Yale A, Yotova I , Drost N, Lax S, Nhan-Chang C-L, Powell C, Borczuk A, Aviv A, Wapner R, Chen X, Nagy P, Schork N, Do C, Torkamani A, Tycko B. (2013) Comparative anatomy of chromosomal domains with imprinted and non-imprinted allele-specific DNA methylation. PLoS Genet. 9(8):e1003622.

Citation Format: Benjamin Tycko. Interaction between genetics, epigenetics, and environment in cancer prevention. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr ED02-02.
Abstract ED03-02: The era of big data informatics for clinical and translational research in cancer prevention
Authors: Pathak Jyotishman
Published: May 2019

Despite considerable progress in prevention and treatment, cancer remains the second leading cause of death in the United States. Cancer researchers around the world are generating massive amounts of clinical and genetic data, although due to its volume, complexity and lack of centralization, much is left unanalyzed. Big Data backed by powerful analytics holds the key to gain important insights from such high volume, variety and velocity data enabling a new understanding of cancer from molecular biology through clinical management. It provides opportunities to ask complex questions and identify novel knowledge from existing data including the study of genetics of an individual's cancer cells, on her response to treatment and sensitivity to side effects. In this session, we will understand the recent developments in Big Data Analytics platforms and how this transformative technology can be harnessed to leverage multidimensional data for developing new preventive measures, diagnostic tools and interventions in cancer research. We will also review success stories from early adopters of Big Data in cancer and highlight the challenges and opportunities for future research and development.

Learning objectives: By the end of this session, the participants should be able to:

1.) Understand the fundamental concepts and principles of Big Data technology

2.) Identify community-based open-source Big Data informatics resources and tools

3.) Recognize the importance of Big Data in cancer prevention research

Citation Format: Jyotishman Pathak. The era of big data informatics for clinical and translational research in cancer prevention. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr ED03-02.
Abstract ED04-02: XCMS cloud-based metabolomics: A platform for the cancer biologist
Authors: Siuzdak Gary
Published: May 2019

Quantitative unbiased analysis of endogenous metabolites from cells, tissues, or fluids - metabolomics, has become an integral part of functional genomics efforts lending itself as a tool for clinical diagnostics, toxicology, agriculture, biofuels, and understanding fundamental biochemistry. Where the genome and proteome represent upstream biochemical events, the metabolites correlate with the most downstream biochemistry and therefore most closely represent the phenotype. This has been proven by the broad success of metabolite analysis in clinical diagnostics and pathogenesis. We have developed a platform to enable these analyses called XCMS, XCMS allows for alignment, statistical evaluation, and metabolite characterization from mass spectrometry data. In addition we have constructed METLIN currently the largest online metabolite MS/MS database. It is worth noting that XCMS, and related papers, enables the initial characterization of endogenous and exogenous metabolites, and has been cited in over a 1200 articles.

Citation Format: Gary Siuzdak. XCMS cloud-based metabolomics: A platform for the cancer biologist. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr ED04-02.
Abstract ED05-01: Targeting nuclear hormone receptors for breast cancer prevention
Authors: Mazumdar Abhijit , Uray Ivan , Litzenburger Beate , Zhang Yun , Hill Jamal , Suh Nanjoo , Brown Powel
Published: May 2019

Nuclear receptors are key proteins that regulate cell proliferation, death, and differentiation. In breast cells, estrogen receptors (ERs) are critical for mammary gland development, differentiation, and tumorigenesis, and selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene, and aromatase inhibitors can prevent the development of ER-positive breast cancer. Other nuclear transcription factors are critical regulators of proliferation and differentiation including retinoic acid receptors (RARs), vitamin D receptors (VDR), and peroxisome proliferator-activator receptors (PPARs). Each of these ligand activated nuclear hormone receptors bind the retinoid X receptors (RXRs) to regulate gene expression. Ligands of these nuclear hormone receptors have been shown to prevent many different types of cancer, including breast cancer. I will present results in preclinical and early clinical studies testing retinoids, rexinoids, Vitamin D analogs, and PPAR ligands for the prevention of breast cancer. Our results and the results of others have shown that ligands that bind and activate the rexinoid receptor are highly effective in preventing breast cancer in animals, particularly ER-negative breast cancer. These preclinical results supported the testing of the RXR ligand bexarotene in women at high risk of breast cancer. This early study demonstrated a biological effect of bexarotene on breast tissue in women. We and other have conducted preclinical studies testing combinations of nuclear hormone receptor ligands (RXR ligand + anti-estrogen SERMS)(RXR ligand + Vitamin D analog) and (RXR ligand + PPAR agonist). These results demonstrate that nuclear hormone receptor ligands can be used to prevent breast cancer and that rexinoids and other ligands provide an opportunity to prevent all forms of breast cancer.

Supported by RO1CA078480-11

Citation Format: Abhijit Mazumdar, Ivan Uray, Beate Litzenburger, Yun Zhang, Jamal Hill, Nanjoo Suh, Powel Brown. Targeting nuclear hormone receptors for breast cancer prevention. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr ED05-01.
Abstract ED06-01: Detection and characterization of viable circulating tumor cells
Authors: Alix-Panabières Catherine
Published: May 2019

The enumeration and characterization of circulating tumor cells (CTCs) in the peripheral blood and disseminated tumor cells (DTCs) in bone marrow may provide important prognostic information and might help to monitor efficacy of therapy.

Since current assays cannot distinguish between apoptotic and viable DTCs/CTCs, it is now possible to apply a novel ELISPOT assay (designated ‘EPISPOT’) that detects proteins secreted/released/shed from single epithelial cancer cells. Cells are cultured for a short time on a membrane coated with antibodies that capture the secreted/released/shed proteins that are subsequently detected by secondary antibodies labeled with fluorochromes.

In breast cancer, we measured the release of cytokeratin-19 (CK19) and mucin-1 (MUC1) and demonstrated that many cancer patients harbored viable DTCs in their bone marrow, even in patients with apparently localized tumors (stage M0 : 54%). Preliminary clinical data (n=57) showed that patients with DTC-releasing CK19 have an unfavorable outcome. We also studied CTCs or CK19-releasing cells (CK19-RC) in the peripheral blood of 194 M1 breast cancer patients and showed that patients with CK19-RC had a worse clinical outcome.

In prostate cancer patients (n=48), we used prostate-specific antigen (PSA) secretion as marker to detect PSA-secreting cells and observed that 83% and 42% of M1 & M0 cancer patients, respectively, had CTCs with a difference in the CTC median (29 for M1 & 9 for M0) and found that a significant fraction of CTCs also secreted fibroblast growth factor-2 (FGF-2), a known stem cell growth factor.

More recently, in colon cancer, a considerable portion of viable CTCs detectable by the Epispot assay is trapped in the liver as the first filter organ in colon cancer patients. The enumeration of CK19-RC by the CK19-Epispot assay in 75 colorectal cancer patients revealed viable CTCs in 65.9% and 55.4% (p=0.04) patients in mesenteric and peripheral blood, respectively, whereas CellSearch detected CTCs in 55.9% and 29.0% (p=0.0046) patients. In mesenteric blood, the number of CTC was significantly higher than in the peripheral blood. Our clinical data showed that localized colon cancer patients with a high level of CTCs have an unfavorable outcome (n=60).

In conclusion, the EPISPOT assay offers a new opportunity to detect and characterize viable DTCs/CTCs in cancer patients and it can be extended to a multi-parameter analysis revealing a CTC/DTC protein fingerprint.

Citation Format: Catherine Alix-Panabières. Detection and characterization of viable circulating tumor cells. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr ED06-01.
Abstract ED06-03: Circulating tumor cells versus circulating tumor cell products
Authors: Pantel Klaus
Published: May 2019

Metastasis is the main cause of cancer-related death and prevention of metastatic relapse is, therefore, the most important goal of cancer therapy. Distant metastases harbour unique genomic characteristics not detectable in the corresponding primary tumor of the same patient and metastases located at different sites show a considerable intra-patient heterogeneity. Thus, the mere analysis of the resected primary tumor alone (current standard practise in oncology) or, if possible, even re-evaluation of tumor characteristics based on the biopsy of the most accessible metastasis may not reveal sufficient information for treatment decisions. This dilemma can be solved by a new diagnostic concept: Liquid biopsy, i.e., analysis of therapeutic targets and drug resistance-conferring gene mutations on circulating tumor cells (CTCs) and cell-free circulating tumor DNA (ctDNA) released into the peripheral blood from metastatic deposits. In addition, cell-free microRNAs in the peripheral blood of cancer patients may provide real-time insights into the biology of cancer, including the effects of therapeutic interventions. MicroRNA levels in plasma, serum, urine and other body fluids have been used to detect cancer, predict the prognosis and response to therapy. Here the current challenges and future perspectives of CTCs and circulating nucleic acids as biomarkers in clinical oncology will be discussed. Both CTCs and circulating nucleic acids are interesting complementary technologies that can be used in parallel in future trials assessing new drugs or drug combinations. We postulate that the liquid biopsy concept will contribute to a better understanding and prevention of metastatic relapse and progression in cancer patients.

Citation Format: Klaus Pantel. Circulating tumor cells versus circulating tumor cell products. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr ED06-03.
Abstract FO01-01: Global impact of HPV vaccination
Authors: Giuliano Anna R.
Published: May 2019

HPV causes multiple cancers in men and women, accounting for ~5% of all cancers worldwide. In 2006 a 4-valent HPV vaccine was licensed for use for cervical cancer prevention in the US and other countries. After completion of a male HPV vaccine efficacy trial, the 4-valent HPV vaccine was also licensed for the prevention of genital warts in 2009 and anal cancer in 2010. Since licensure, several countries have developed policies promoting national dissemination of the vaccine. Australia has led the way with a robust public health program that rapidly reached ~80% of the age eligible female population. With up to six full years of vaccine dissemination to adolescent females countries are now able to report population effectiveness, or the impact of the vaccine to prevent HPV-related diseases. There are three main outcome variables of interest: short-term (HPV infection and genital wart rates), intermediate-term (reduction in incident cervical lesions), and long-term (incidence and mortality from HPV-related cancers). Effectiveness data for short-term outcomes have recently been reported for Australia, New Zealand, Denmark, Sweden, Germany, Belgium, Canada, and the US. Significant declines in genital wart incidence in females have been reported from all countries to date that have evaluated effectiveness. In Australia, where there was early vaccine adoption nationally and high vaccine penetrance, concomitant declines in genital warts among unvaccinated males have also been documented. Intermediate-term endpoints, such as cervical pre-cancerous lesions have also significantly declined in Australia, Denmark, and the US. These results provide early evidence that routine vaccination significantly reduces HPV infection and early disease endpoints attributed to the 4 major disease causing types of HPV among young adult females at the population level. However, to achieve the full promise of eliminating HPV vaccine type-related disease, broad dissemination of the vaccine is required. Several strategies are under consideration to improve population coverage, including dissemination of vaccine to low resource countries through the GAVI program, alternative dose schedules, and two vs. three dose schedules. Ultimately, strong public health and physician recommendations, as well as population acceptability, are needed to eliminate HPV-related disease through a vaccine approach.

Citation Format: Anna R. Giuliano. Global impact of HPV vaccination. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr FO01-01.
Abstract PL04-01: The epidemiology of sitting time and cancer
Authors: Patel Alpa V.
Published: May 2019

With technological advancements, the amount of time individuals spend sitting has increased significantly over the past few decades. Emerging evidence supports that sitting time is distinctly different from physical inactivity and may have independent deleterious health effects. Sitting time, independent of physical activity, has been associated with total mortality, cardiovascular disease, type II diabetes, and obesity. It has also been associated with intermediate markers of disease risk such as abdominal weight gain, high cholesterol, insulin levels, high blood pressure, and other biomarkers in healthy adults. A recent report concluded that the average life expectancy in the USA would be increased by 2.00 years if sitting time were reduced to <3 hours per day.

More than 60 years of research supports the role of physical activity in prevention of various cancers including colorectal, postmenopausal breast, and endometrial cancers. More recently, many epidemiologic studies have examined the role of sitting time in relation to cancer risk, independent of or in combination with physical activity. This presentation will review the epidemiologic literature on the role of sitting time in relation to cancer risk.

Citation Format: Alpa V. Patel. The epidemiology of sitting time and cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr PL04-01.
Abstract PL05-03: Progress towards routine use of aspirin by people at increased risk of cancer
Authors: Burn John
Published: May 2019

A consistent result of cohort, case control, post-trial follow up and randomized controlled trials into the antineoplastic effects of aspirin is that this agent has a major protective effect. It is ubiquitous and cheap and has the longest safety record of any drug in widespread use. Despite this, proposals for widespread use meet resistance which could be seen as disproportionate. Historic over use leading to a global awareness of adverse events, academic clinical biases, commercial competition and a contempt for the familiar may all be invoked; “I went to see a specialist and all he said was take an aspirin!”

The lesson from the anti-smoking lobby is to just keep pressing. Our CAPP2 study revealed an impressive effect of aspirin even in hereditary cancer (Burn et al 2011) and subsequent data reinforce this. The 600mg dose used was in the sub-analgesic range and there were minimal adverse events but the perception of “great risk” justifies CaPP3 which will be a 7 year long dose non-inferiority study comparing 600mg, 300mg or 100mg doses daily as a blinded intervention in at least 3000 proven carriers of a mismatch repair gene defect. Public and professional education should continue in parallel to emphasize the benefits of H pylori eradication, acid suppressants and anti-hypertensives in minimizing adverse events which may, even without such measures, be considered tolerable in the context, at least, of those at increased statistical risk due to a positive family history of solid tumors.

Citation Format: John Burn. Progress towards routine use of aspirin by people at increased risk of cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr PL05-03.
Abstract PR01: HPV genotype distribution and cervical intraepithelial neoplasia in African American and white women living in the Southeastern United States
Authors: Vidal Adriana C , Smith Jennifer S , Iversen Edwin , Valea Fidel , Bentley Rex , Gradison Margaret , Yarnall Kimberly , Ford Anne , Overcash Francine , Grant Katherine , Murphy Susan , Hoyo Cathrine
Published: May 2019

Background: Differential distributions of oncogenic HPV genotypes among racial/ethnic groups may explain observed disparities in ICC incidence and mortality rates. We describe HPV genotypes associated with CIN1-3 in a multiethnic cohort of women visiting colposcopy clinic following a cervical abnormality.

Methods: We enrolled 516 women attending colposcopic evaluation following an abnormal liquid-based cytology screen. HPV infection was measured using HPV linear array that measures 37 HPV types, and chi-squared tests were used to compare HPV genotypes in African American and Whites overall, and by CIN stage.

Results: Of 516 participants, 373 (72%) were HPV-positive; 137 (37%) had no CIN lesion, 174 (47%) had CIN1, 38 (10%) had CIN2, and 24 (6%) had CIN-3. Twenty-seven percent of women were infected with one HPV genotype, and 73% were infected with multiple HPV genotypes. In women with CIN1, 75% of HPV single infections were of high risk (HR) genotypes, and 70% of women had multiple HR-HPV genotype infections. The most frequent HR-HPV genotypes detected among CIN1 cases were 16, 18, 31, 45, 52, 56, 59 and 66 in White women, while HPV subtypes 33, 35, 58 and 68 were the most common in African American women. Restricting analyses to women with CIN2-3 revealed a change in HR-HPV genotype distribution; HR-HPV 16, 18, 33, 35, 39, and 59 were most common in White women with CIN2-3, whereas HR-HPV 31, 45, 51 and 66 were the most prevalent in African American women.

Conclusion: Our data suggest that while HPV 16 and 18 are the most common genotypes among women with CIN in Whites; African Americans may harbor different genotypes. The preponderance of non-16/18 HR-HPV genotypes in African Americans with increasing CIN grade has implications for both reflex testing following cytological abnormalities and vaccine development.

This abstract is also presented as Poster B11.

Citation Format: Adriana C Vidal, Jennifer S Smith, Edwin Iversen, Fidel Valea, Rex Bentley, Margaret Gradison, Kimberly Yarnall, Anne Ford, Francine Overcash, Katherine Grant, Susan Murphy, Cathrine Hoyo. HPV genotype distribution and cervical intraepithelial neoplasia in African American and white women living in the Southeastern United States. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr PR01.
Abstract SS03-01: Cut melanoma deaths in half with screening? Current status
Authors: Weinstock Martin A.
Published: May 2019

Melanoma kills almost 10,000 Americans each year, and early detection has the potential to cut that number in half within a decade. However, our ability to do so will depend on the evidence that screening for melanoma saves lives and that the benefits outweigh the harms. The past 5 years have seen a profound change in the published findings on this issue. Both short, free, online videos regarding skin self-examination http://www.cancer.org/Healthy/ToolsandCalculators/Videos/keep-my-skin-healthy-video and the INFORMED program for clinician skin examination http://www.skinsight.com/info/for_professionals/skin-cancer-detection-informed/skin-cancer-education , have been used to produce key evidence that will help us move forward to substantially reduce the burden of this disease.

Citation Format: Martin A. Weinstock. Cut melanoma deaths in half with screening? Current status. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr SS03-01.
5-Hydroxyhexanoic Acid Predicts Early Renal Functional Decline in Type 2 Diabetes Patients with Microalbuminuria
Authors: Tang Xiaofang , You Jing , Liu Di , Xia Ming  , He Liyu , Liu Hong
Published: May 2019

Background/Aims: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. Microalbuminuria (MA) is widely used to predict early progressive renal function decline (ERFD) of DN in type 2 diabetes mellitus (T2D) patients, but the sensitivity and specificity of MA have been questioned. Here, we determined the urine metabolites differences between T2D patients with MA who maintained stable renal function and those who progressed to ERFD in order to identify specific biomarkers of the progression of renal dysfunction. Methods: A total of 102 T2D patients with MA and normal renal function at baseline were followed up for 5–6 years. Of these, 52 patients were selected and classified into two groups according to the later renal function; 25 patients who experienced ERFD were regarded as the progressive group, while 27 patients who maintained stable renal function were considered as the stable group. In the pilot study, untargeted, broad-spectrum urine metabolomics was performed on the urine of 12 subjects from the progressive group (5 patients as “progressors”) and stable group (7 patients as “non-progressors”) to discover candidate markers. We then used a targeted metabolomics analysis to identify the selected markers in the urine of an additional 40 patients (20 from the progressive group as cases, and 20 from the stable group as controls) in the validation study. Results: A total of 318 known metabolites were detected in the pilot study and 6 metabolites with significant difference between progressors and non-progressors were identified. The levels of 4 metabolites, including azelaic acid, adipic acid, 5-hydroxyhexanoic acid, and L-tryptophan decreased significantly, while levels of L-pyroglutamic acid and D-norvaline increased observably in the progressors compared with non-progressors. Furthermore, in the validation study, 6 metabolites were confirmed by quantitative measurements and their concentrations were consistent with the changes in the pilot study. Concentrations of L-pyroglutamic acid and D-norvaline still increased in the cases, but were not statistically significant. Of the 4 metabolites with decreased concentrations among the cases, only 5-hydroxyhexanoic acid remained statistically significant while the other 3 metabolites did not differ between cases and controls. Conclusion: We have identified urine metabolites and shown that 5-hydroxyhexanoic acid can be used as a predictor of progression of ERFD in T2D patients with MA. This finding provides the new perspective that 5-hydroxyhexanoic acid may be useful to identify T2D patients with MA who are at risk of ERFD.
Examining Relationships between Multiple Self-Reported Sleep Measures and Gait Domains in Cognitively Healthy Older Adults
Authors: Bernstein John P.K. , De Vito Alyssa , Weitzner Daniel S. , MacAulay Rebecca , Calamia Matthew , Brouillette Robert , Foil Heather , Carmichael Owen T. , Keller Jeffrey N.
Published: May 2019

Background: Gait-related changes in older adulthood may be related to changes in cognition (e.g., executive functioning), and recent work suggests that different self-reported measures of sleep may be tied to contrasting aspects of executive functioning. However, the relationship between these self-reported sleep measures and gait domains has not been explored. Such an investigation would be useful in helping to determine which older adults might exhibit changes in gait as well as experience other gait-associated changes (e.g., increased fall risk). Objective: To examine associations between different aspects of self-reported sleep and gait domains in a sample of cognitively healthy older adults. Method: A total of 423 older adults (mean age 69.9 years, range 50–92) completed self-report measures of sleep quality, daytime sleepiness, and sleep-related distress. The participants also completed an objective, electronic measure of both single-task and dual-task gait (i.e., GAITRite). Principal component analyses were used to elucidate the solution for each gait condition, and multiple linear regression was used to examine the contributions of sleep measures to variability in gait performance. Results: A 5-component solution of the single-task condition and a 4-component solution of the dual-task condition were identified. Multiple linear regressions revealed that a poorer sleep quality was associated with greater single-task and dual-task asymmetry. Greater daytime sleepiness was associated with increased dual-task gait variability and postural control. After controlling for the effects of other facets of sleep, sleep-related distress was not associated with any gait domain. Conclusions: Among cognitively healthy older adults,sleep quality and daytime sleepiness, but not sleep-related distress, are associated with aspects of gait. Patients who report these symptoms should be assessed and monitored for possible changes in gait.
Digital Medicine: A Primer on Measurement
Authors: Coravos Andrea , Goldsack Jennifer C. , Karlin Daniel R. , Nebeker Camille , Perakslis Eric , Zimmerman Noah , Erb M. Kelley
Published: May 2019

Technology is changing how we practice medicine. Sensors and wearables are getting smaller and cheaper, and algorithms are becoming powerful enough to predict medical outcomes. Yet despite rapid advances, healthcare lags behind other industries in truly putting these technologies to use. A major barrier to entry is the cross-disciplinary approach required to create such tools, requiring knowledge from many people across many fields. We aim to drive the field forward by unpacking that barrier, providing a brief introduction to core concepts and terms that define digital medicine. Specifically, we contrast “clinical research” versus routine “clinical care,” outlining the security, ethical, regulatory, and legal issues developers must consider as digital medicine products go to market. We classify types of digital measurements and how to use and validate these measures in different settings. To make this resource engaging and accessible, we have included illustrations and figures throughout that we hope readers will borrow from liberally. This primer is the first in a series that will accelerate the safe and effective advancement of the field of digital medicine.
Myocardial Involvement in Patients With Histologically Diagnosed Cardiac Sarcoidosis: A Systematic Review and Meta‐Analysis of Gross Pathological Images From Autopsy or Cardiac Transplantation Cases
Authors: Okasha Osama , Kazmirczak Felipe , Chen Ko‐Hsuan Amy , Farzaneh‐Far Afshin , Shenoy Chetan
Published: May 2019

Background

In patients with suspected cardiac sarcoidosis, late gadolinium enhancement on cardiovascular magnetic resonance imaging and/or
18
F‐fluorodeoxyglucose uptake on positron emission tomography are often used to reach a clinical diagnosis of cardiac sarcoidosis. On the basis of data from the imaging literature of clinical cardiac sarcoidosis, no specific features of myocardial involvement are regarded as pathognomonic for cardiac sarcoidosis. Thus, a diagnosis of cardiac sarcoidosis is challenging to make. There has been no systematic analysis of histologically diagnosed cardiac sarcoidosis for patterns of myocardial involvement. We hypothesized that certain patterns of myocardial involvement are more frequent in histologically diagnosed cardiac sarcoidosis.

Methods and Results

We performed a systematic review and meta‐analysis of gross pathological images from the published literature of patients with histologically diagnosed cardiac sarcoidosis who underwent autopsy or cardiac transplantation. Thirty‐three eligible articles provided images of 49 unique hearts. Analysis of these hearts revealed certain features of myocardial involvement in >90% of cases: left ventricular (LV) subepicardial, LV multifocal, septal, and right ventricular free wall involvement. In contrast, other patterns were seen in 0% to 6% of cases: absence of gross LV myocardial involvement, isolated LV midmyocardial involvement, isolated LV subendocardial involvement, isolated LV transmural involvement, absence of septal involvement, or isolated involvement of only one LV level.

Conclusions

In this systematic review and meta‐analysis of histologically diagnosed cardiac sarcoidosis, we identified certain features of myocardial involvement that occurred frequently and others that occurred rarely or never. These patterns could aid the interpretation of cardiovascular magnetic resonance imaging and positron emission tomography imaging and improve the diagnosis and the prognostication of patients with suspected cardiac sarcoidosis.
Effect of Lidocaine Injection of Ganglionated Plexi in a Canine Model and Patients With Persistent and Long‐Standing Persistent Atrial Fibrillation
Authors: Lee Seungyup , Khrestian Alexander , Waldo Albert L. , Khrestian Celeen M. , Markowitz Alan , Sahadevan Jayakumar
Published: May 2019

Background

This study assessed the effect of blockading neural transmission in the ganglionated plexi by injecting lidocaine into fat pads in the vagal nerve stimulation canine model and patients with persistent atrial fibrillation (
AF
).

Methods and Results

An efficacy test of lidocaine injection was performed in 7 canines. During vagal nerve stimulation,
AF
was sustained for >5 minutes. The lidocaine was injected into ganglionated plexi during sinus rhythm and reinduction of
AF
was attempted. Six patients with persistent
AF
were studied at open heart surgery. Lidocaine was injected into ganglionated plexi. Atrial electrograms were recorded from 96 epicardial electrodes covering Bachmann's bundle and atrial appendages. In the canine vagal nerve stimulation
AF
model,
AF
was not inducible in 4 of 7 after lidocaine injection. In patients with persistent
AF
, during baseline
AF
, there was a left atrium (
LA
)‐to‐right atrium (
RA
) frequency gradient (
LA
, mean cycle length [
CL
] 175±17 ms;
RA
, mean
CL
192±17 ms;
P
<0.01). After lidocaine injection,
AF
persisted in all patients, and the
LA
‐to‐
RA
frequency gradient disappeared (
LA
, mean
CL
186±13 ms;
RA
, mean
CL
199±23 ms;
P
=0.08). Comparison of mean
CL
s before and after lidocaine demonstrated prolongation of
LA CL
s (
P
<0.05) with no effect on
RA CL
s.

Conclusions

In the canine vagal nerve stimulation
AF
model, lidocaine injection decreased inducibility of
AF
. In patients with persistent
AF
, atrial electrograms from the
LA
had shorter
CL
s than
RA
, indicating an
LA
‐to‐
RA
frequency gradient. Lidocaine injection significantly prolonged only
LA CL
s, explaining disappearance of the
LA
‐to‐
RA
frequency gradient. The mechanism of localized atrial electrogram
CL
prolongation in patients with persistent
AF
is uncertain.
Early Clinical Outcomes of Surgical Myocardial Revascularization for Acute Coronary Syndromes Complicated by Cardiogenic Shock: A Report From the North‐Rhine‐Westphalia Surgical Myocardial Infarction Registry
Authors: Liakopoulos Oliver J. , Schlachtenberger G. , Wendt Daniel , Choi Yeong‐Hoon , Slottosch Ingo , Welp Henryk , Schiller Wolfgang , Martens Sven , Welz Armin , Neuhäuser Markus , Jakob Heinz , Wahlers Thorsten , Thielmann Matthias
Published: May 2019

Background

Coronary artery bypass grafting for acute coronary syndrome complicated by cardiogenic shock (
CS
) is associated with a high mortality. This registry study aimed to distinguish between early surgical outcomes of
CS
patients with non–
ST
‐segment–elevation myocardial infarction (
NSTEMI
) and
ST
‐segment–elevation myocardial infarction (
STEMI
).

Methods and Results

Patients with
NSTEMI
(n=1218) or
STEMI
(n=618) referred for coronary artery bypass grafting were enrolled in a prospective multicenter registry between 2010 and 2017. CS was present in 227
NSTEMI
(18.6%) and 243
STEMI
patients (39.3%). Key clinical end points were in‐hospital mortality (
IHM
) and major adverse cardiocerebral events (
MACCEs
). Predictors for
IHM
and
MACCEs
were identified using multivariable logistic regression analysis.
STEMI
patients with
CS
were younger, had a lower prevalence of diabetes mellitus and multivessel disease, and exhibited higher myocardial injury (troponin 9±17 versus 3±6 ng/mL) before surgery compared with patients with
NSTEMI
(
P
<0.05). Emergency coronary artery bypass grafting was performed more often in
STEMI
(58%) versus NSTEMI (40%;
P
=0.002). On‐pump surgery with cardioplegia was the preferred surgical technique in
CS
. IHM and
MACCE
rates were 24% and 49% in
STEMI
patients with
CS
and were higher compared with
NSTEMI
(
IHM
15% versus
MACCE
34%;
P
<0.001). Predictors for
IHM
and
MACCE
in
CS
were a reduced ejection fraction and a higher European System for Cardiac Operative Risk Evaluation score.

Conclusions

Surgical revascularization in
NSTEMI
and
STEMI
patients with
CS
is associated with a substantial but not prohibitive
IHM
and
MACCE
rate. Worse early outcomes were found for patients with
STEMI
complicated by
CS
compared with
NSTEMI
patients.
Six new species of Stenometopiini (Hemiptera: Cicadellidae: Deltocephalinae) with redescription of additional species and new distributional records
Authors: DUAN YANI , ZHANG YATING , DIETRICH CHRISTOPHER H.
Published: May 2019

Six new species of Stenometopiini are described: Stirellus paracatalinus sp. nov. from Mexico, Stirellus lesioensis sp. nov. from Republic of Congo, Stirellus paralesioensis sp. nov. from South Africa, Stirellus kitwensis sp. nov. from Zambia, Stirellus madagascarensis sp. nov. from Madagascar, and Stirellus petfordensis sp. nov. from Australia. Ten species are redescribed: Kinonia elongata Ball, Stirellus catalinus (Beamer & Tuthill), Stirellus labiatus (Gillette), Stirellus mexicanus (Osborn & Ball), Stirellus picinus (Berg), Stirellus laetus (Melichar), Stirellus multipunctatus Duan, Webb & Zhang, Stirellus neospeciosus Duan, Webb & Zhang, Stirellus rubrolineatus (Distant), and Stirellus sagittarius (Naudé). Kinonia elongata Ball, S. catalinus (Beamer & Tuthill) and S. labiatus (Gillette), all described from the Southwestern USA, are recorded from Mexico for the first time. Stirellus picinus (Berg) is recorded from the Virgin Islands (Guana Island) for the first time. Stirellus laetus (Melichar), S. multipunctatus Duan, Webb & Zhang, S. neospeciosus Duan, Webb & Zhang, and S. rubrolineatus (Distant) are recorded from Thailand for the first time.
Evaluation of Six Atmospheric Reanalyses over Arctic Sea Ice from Winter to Early Summer
Authors: Graham Robert M. , Cohen Lana , Ritzhaupt Nicole , Segger Benjamin , Graversen Rune G. , Rinke Annette , Walden Von P. , Granskog Mats A. , Hudson Stephen R.
Published: May 2019

This study evaluates the performance of six atmospheric reanalyses (ERA-Interim, ERA5, JRA-55, CFSv2, MERRA-2, and ASRv2) over Arctic sea ice from winter to early summer. The reanalyses are evaluated using observations from the Norwegian Young Sea Ice campaign (N-ICE2015), a 5-month ice drift in pack ice north of Svalbard. N-ICE2015 observations include surface meteorology, vertical profiles from radiosondes, as well as radiative and turbulent heat fluxes. The reanalyses simulate surface analysis variables well throughout the campaign, but have difficulties with most forecast variables. Wintertime (January–March) correlation coefficients between the reanalyses and observations are above 0.90 for the surface pressure, 2-m temperature, total column water vapor, and downward longwave flux. However, all reanalyses have a positive wintertime 2-m temperature bias, ranging from 1° to 4°C, and negative (i.e., upward) net longwave bias of 3–19 W m−2. These biases are associated with poorly represented surface inversions and are largest during cold-stable periods. Notably, the recent ERA5 and ASRv2 datasets have some of the largest temperature and net longwave biases, respectively. During spring (April–May), reanalyses fail to simulate observed persistent cloud layers. Therefore they overestimate the net shortwave flux (5–79 W m−2) and underestimate the net longwave flux (8–38 W m−2). Promisingly, ERA5 provides the best estimates of downward radiative fluxes in spring and summer, suggesting improved forecasting of Arctic cloud cover. All reanalyses exhibit large negative (upward) residual heat flux biases during winter, and positive (downward) biases during summer. Turbulent heat fluxes over sea ice are simulated poorly in all seasons.
Comparing Adaptive Prior and Posterior Inflation for Ensemble Filters Using an Atmospheric General Circulation Model
Authors: El Gharamti Mohamad , Raeder Kevin , Anderson Jeffrey , Wang Xuguang
Published: May 2019

Sampling errors and model errors are major drawbacks from which ensemble Kalman filters suffer. Sampling errors arise because of the use of a limited ensemble size, while model errors are deficiencies in the dynamics and underlying parameterizations that may yield biases in the model’s prediction. In this study, we propose a new time-adaptive posterior inflation algorithm in which the analyzed ensemble anomalies are locally inflated. The proposed inflation strategy is computationally efficient and is aimed at restoring enough spread in the analysis ensemble after assimilating the observations. The performance of this scheme is tested against the relaxation to prior spread (RTPS) and adaptive prior inflation. For this purpose, two model are used: the three-variable Lorenz 63 system and the Community Atmosphere Model (CAM). In CAM, global refractivity, temperature, and wind observations from several sources are incorporated to perform a set of assimilation experiments using the Data Assimilation Research Testbed (DART). The proposed scheme is shown to yield better quality forecasts than the RTPS. Assimilation results further suggest that when model errors are small, both prior and posterior inflation are able to mitigate sampling errors with a slight advantage to posterior inflation. When large model errors, such as wind and temperature biases, are present, prior inflation is shown to be more accurate than posterior inflation. Densely observed regions as in the Northern Hemisphere present numerous challenges to the posterior inflation algorithm. A compelling enhancement to the performance of the filter is achieved by combining both adaptive inflation schemes.
Acceptance of Behavior Guidance Techniques Used in Pediatric Dentistry by Parents From Diverse Backgrounds
Authors: Martinez Mier E. Angeles , Walsh Christopher R. , Farah Christopher C. , Vinson LaQuia A. , Soto-Rojas Armando E. , Jones James E.
Published: May 2019

Objective. To investigate if parental background affects acceptance of behavior guidance techniques. Background. Behavior guidance techniques are used for the safe and effective treatment of pediatric patients. Acceptance of these techniques may vary by racial and ethnic background. Methods. A total of 142 parents were recruited and asked to rate videos showing: active restraint/protective stabilization (AR), general anesthesia (GA), nitrous oxide sedation (N2O), oral premedication/sedation (OP), passive restraint/protective stabilization (PR), tell-show-do (TSD), and voice control (VC) techniques. Results. Hispanic parents rated VC most acceptable, followed by TSD, PR, and pharmacologic techniques. Black and white parents rated TSD, followed by N2O, as most acceptable, and AR and PR as least favorable. Hispanics found GA significantly less acceptable than whites or blacks. Hispanics were less accepting of AR than blacks; but more accepting of PR than whites. TSD was highly rated among all 3 cohorts. Parental background affected acceptance of the techniques in this study.
Caries Progression Rates Revisited: A Systematic Review
Authors: Hummel R. , Akveld N.A.E. , Bruers J.J.M. , van der Sanden W.J.M. , Su N. , van der Heijden G.J.M.G.
Published: May 2019

Caries progression seems to follow universal, predictable rates, depending largely on the caries severity in populations: the higher the caries severity, the higher the progression rates. Quantification of these rates would allow prediction of future caries increments. Our aim was to describe caries progression rates in the primary and permanent dentition in Western populations (not in lesions) of children and adolescents. Therefore, we systematically searched MEDLINE-PubMed, Embase, CINAHL, and the Cochrane library for studies reporting caries progression data. Eligibility criteria were reporting empirical data from at least 2 full-mouth dental caries examinations in a closed cohort during a follow-up of at least 3 y, a first examination after 1974, a second examination before the age of 22 y, caries assessed as dentine caries (d3/D3), and caries reported in dmfs/DMFS (decayed, missing, and filled surfaces), dmft/DMFT (decayed, missing, and filled teeth), or caries-free participants. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, we described the results for the primary and permanent dentition in a systematic review, performed a meta-analysis for the caries incidence rate in the permanent dentition, and conducted multivariate, hierarchical meta-regression analyses for the caries incidence rate and the increments in DMFS and DMFT. Of the 6,343 unique studies retrieved, 43 studies (56,376 participants) were included for systematic review and 32 for meta-analyses (39,429 participants). The annual decline in caries-free children in the permanent dentition ranged from 0.8% to 10.2%. The annual increment ranged from 0.07 to 1.77 in DMFS and from 0.06 to 0.73 in DMFT. The pooled caries incidence rate was 0.11 (0.09–0.13) per person-year at risk. Meta-regression analyses showed that the methods of individual studies influenced pooled caries incidence rates and increments in DMFS and DMFT. This should be taken into account in planning and evaluation of oral health care services. However, the caries incidence rate is promising for prediction of future caries increments in populations.
Natural Christianity
Authors: Pratt Richard
Published: May 2019

Why and how Christianity could talk about God without using the category of the supernatural. The article looks at the conceptual background of Jesus' day, the need to abandon the supernatural, some previous attempts to do this, the issues raised and how we could deal with them.
Difficult texts: 1 Timothy 2.11–15
Authors: Erickson Amy J.
Published: May 2019

1 Timothy 2.11–15 is prevalently misread to sanction blanket dismissal of female teachers and preachers in the Church. This article reconsiders these verses in light of Paul’s expressed aims in writing to suggest a reading that takes its Ephesian address fully into account. In so doing, it offers the most theologically responsible interpretation of verse 15, one of the most troubling and perplexing verses in the biblical canon.
Segregated Worlds? The Level of Overlap Between Dutch Offenders’ Criminal and Core Discussion Networks
Authors: Mollenhorst Gerald , De Cuyper Ruben , Volker Beate , Dirkzwager Anja , Nieuwbeerta Paul
Published: May 2019

We examine the level of overlap between offenders’ criminal networks (i.e., those with whom they discuss criminal activities and exchange criminal knowledge and skills) and offenders’ core discussion networks (i.e., those with whom they discuss important personal matters). We formulate four hypotheses based on social capital and focus theory. Empirical data from 1,904 Dutch pretrial detainees reveal that one third of the criminal network members also function as core discussion partners and that half of the criminal network members know at least one core discussion partner. This implies that offenders do not completely separate their criminal network from their core discussion network. Multilevel analyses show that this network overlap is larger if criminal network members live close to the offender and/or if they share multiple social settings. Our findings have implications for policies regarding the prevention of recidivism and the reintegration of offenders into society.