Clinical outcomes in borderline and locally advanced pancreatic cancer with the addition of low-dose-rate brachytherapy to standard of care therapy.

PURPOSE: Surgical resection remains the only curative therapy for pancreatic cancer. Unfortunately, many patients have borderline or unresectable disease at diagnosis due to proximity of major abdominal vessels. Neoadjuvant chemotherapy and radiation are used to down-stage, however, there is a risk that there will be a positive/close surgical margin. The CivaSheet is a low-dose-rate (LDR) brachytherapy device placed at the time of surgery to target the area of highest risk of margin positivity. The purpose of this study is to assess the clinical value of brachytherapy in addition to standard-of-care therapy in pancreatic therapy. METHODS AND MATERIALS: Between 2017 and 2022 patients with borderline and locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and radiation followed by surgical resection were included. There were 2 cohorts of patients: (1) Those who had the LDR brachytherapy device placed at the time of surgery and (2) those who did not. Sixteen of 19 (84%) patients who had brachytherapy were enrolled in a prospective clinical trial (NCT02843945). Patients were matched for comorbidities, cancer staging, and treatment details. The primary outcome was progression-free survival (PFS). RESULTS: Thirty-five patients were included in this analysis, 19 in the LDR brachytherapy group and 16 in the comparison cohort. The 2-year PFS was 21% vs. 0% (p = 0.11), 2-year OS was 26% vs. 13% (p = 0.43), and the pancreatic cancer cause-specific survival was 84% vs. 56% (p = 0.13) in favor of the brachytherapy patients. CONCLUSIONS: Use of LDR brachytherapy at the time of resection shows a trend towards improved progression free and overall survival for patients with borderline or locally advanced pancreatic cancer treated with neoadjuvant chemoradiation.

Reference database of teeth images from the Family Bovidae.

Researchers typically rely on fossils from the Family Bovidae to generate African paleoenvironmental reconstructions due to their strict ecological tendencies. Bovids have dominated the southern African fauna for the past four million years and, therefore, dominate the fossil faunal assemblages, especially isolated teeth. Traditionally, researchers reference modern and fossil comparative collections to identify teeth. However, researchers are limited by the specific type and number of bovids at each institution. B.O.V.I.D. (Bovidae Occlusal Visual IDentification) is a repository of images of the occlusal surface of bovid teeth. The dataset currently includes extant bovids from 7 tribes and 20 species (~3900). B.O.V.I.D. contains two scaled images per specimen: a color and a black and white (binarized) image. The database is a useful reference for identifying bovid teeth. The large sample size also allows one to observe the natural variation that exists in each taxa. The binarized images can be used in statistical shape analyses, such as taxonomic classification. B.O.V.I.D. is a valuable supplement to other methods for taxonomically identifying bovid teeth.

Comparative morphometric analyses of the deciduous molars of Homo naledi from the Dinaledi Chamber, South Africa.

OBJECTIVES: The purpose of this study is to help elucidate the taxonomic relationship between Homo naledi and other hominins. MATERIALS AND METHODS: Homo naledi deciduous maxillary and mandibular molars from the Dinaledi Chamber, South Africa were compared to those of Australopithecus africanus, Australopithecus afarensis, Paranthropus robustus, Paranthropus boisei, early Homo sp., Homo erectus, early Homo sapiens, Upper Paleolithic H. sapiens, recent southern African H. sapiens, and Neanderthals by means of morphometric analyses of crown outlines and relative cusp areas. The crown shapes were analyzed using elliptical Fourier analyses followed by principal component analyses (PCA). The absolute and relative cusp areas were obtained in ImageJ and compared using PCA and cluster analyses. RESULTS: PCA suggests that the crown shapes and relative cusp areas of mandibular molars are more diagnostic than the maxillary molars. The H. naledi deciduous mandibular first and second molar (dm1 and dm2 ) do not have a strong affinity to any taxon in the comparative sample in all analyses. While the H. naledi dm2 plots as an outlier in the relative cusp analysis, the H. naledi specimen fall closest to Australopithecus due to their relatively large metaconid, a primitive trait for the genus Homo. Although useful for differentiating Neanderthals from recent southern African H. sapiens and UP H. sapiens, the PCA of the relative cusp areas suggests that the deciduous maxillary second molars (dm2 ) do not differentiate other groups. The three H. naledi dm2 cuspal areas are variable and fall within the ranges of other Homo, as well as Australopithecus, and Paranthropus suggesting weak diagnostic utility. DISCUSSION: This research provides another perspective on the morphology of, and variation within, H. naledi. The H. naledi deciduous molars do not consistently align with any genus or species in the comparative sample in either the crown shape or relative cusp analyses. This line of inquiry is consistent with other cranial and postcranial studies suggesting that H. naledi is unique.

Anteroposterior skeletofacial classification and its relationship to maxillary second molar buccopalatal angulation.

OBJECTIVE: To compare second molar angulation to the occlusal plane with cephalometric measurements corresponding to AP skeletal discrepancy. MATERIALS AND METHODS: 72 patients' pre-orthodontic records were analyzed. A plane was constructed along the cusps of the upper second molar and measured to a proxy for the occlusal plane. The angle between the planes was measured. ANB, Wits appraisal, U1-SN, IMPA, A-B perpendicular to Frankfort, and overjet were measured on the patients' cephalograms. Generalized additive mixed model analysis was performed to analyze the relationship between the second molar angulation and the cephalometric measurements. RESULTS: All six cephalometric measurements showed a significant relationship with the second molar angulation, with Class III patients having a larger angle than Class II and I patients. CONCLUSIONS: Class III patients have upper second molars that are significantly tipped from the occlusal plane. The second molars require special attention for correction prior to orthognathic surgery for Class III patients in order to avoid deleterious effects from the malpositioned teeth.

Anterior tooth-use behaviors among early modern humans and Neandertals.

Early modern humans (EMH) are often touted as behaviorally advanced to Neandertals, with more sophisticated technologies, expanded resource exploitation, and more complex clothing production. However, recent analyses have indicated that Neandertals were more nuanced in their behavioral adaptations, with the production of the Châtelperronian technocomplex, the processing and cooking of plant foods, and differences in behavioral adaptations according to habitat. This study adds to this debate by addressing the behavioral strategies of EMH (n = 30) within the context of non-dietary anterior tooth-use behaviors to glean possible differences between them and their Neandertal (n = 45) counterparts. High-resolution casts of permanent anterior teeth were used to collect microwear textures of fossil and comparative bioarchaeological samples using a Sensofar white-light confocal profiler with a 100x objective lens. Labial surfaces were scanned, totaling a work envelope of 204 x 276 µm for each individual. The microwear textures were examined for post-mortem damage and uploaded to SSFA software packages for surface characterization. Statistical analyses were performed to examine differences in central tendencies and distributions of anisotropy and textural fill volume variables among the EMH sample itself by habitat, location, and time interval, and between the EMH and Neandertal samples by habitat and location. Descriptive statistics for the EMH sample were compared to seven bioarchaeological samples (n = 156) that utilized different tooth-use behaviors to better elucidate specific activities that may have been performed by EMH. Results show no significant differences between the means within the EMH sample by habitat, location, or time interval. Furthermore, there are no significant differences found here between EMH and Neandertals. Comparisons to the bioarchaeological samples suggest both fossil groups participated in clamping and grasping activities. These results indicate that EMH and Neandertals were similar in their non-dietary anterior tooth-use behaviors and provide additional evidence for overlapping behavioral strategies employed by these two hominins.

Confidence Intervals for the Area Under the Receiver Operating Characteristic Curve in the Presence of Ignorable Missing Data.

Receiver operating characteristic curves are widely used as a measure of accuracy of diagnostic tests and can be summarised using the area under the receiver operating characteristic curve (AUC). Often, it is useful to construct a confidence interval for the AUC; however, because there are a number of different proposed methods to measure variance of the AUC, there are thus many different resulting methods for constructing these intervals. In this article, we compare different methods of constructing Wald-type confidence interval in the presence of missing data where the missingness mechanism is ignorable. We find that constructing confidence intervals using multiple imputation based on logistic regression gives the most robust coverage probability and the choice of confidence interval method is less important. However, when missingness rate is less severe (e.g. less than 70%), we recommend using Newcombe's Wald method for constructing confidence intervals along with multiple imputation using predictive mean matching.

Children's orthodontic utilization in the United States: Socioeconomic and surveillance considerations.

INTRODUCTION: There has been no epidemiologic study of malocclusion prevalence and treatment need in the United States since the Third National Health and Nutrition Examination Survey, conducted from 1988 to 1991. In this descriptive study, the authors sought to estimate orthodontic treatment prevalence by examining a nationally representative survey to assess current pediatric dental and orthodontic utilization. METHODS: The 2009 and 2013 Medical Expenditure Panel Surveys were used to categorize and compare all types of pediatric dental and orthodontic procedures in children and adolescents up to 20 years old. Descriptive variables included dental insurance, poverty level, and racial/ethnic background. RESULTS: Visits for orthodontic procedures constituted the third largest treatment category (14.5%) and were greatest among the uninsured and higher income populations. Children with public insurance had the fewest orthodontic visits (9.4%). Racial/ethnic disparities were most pronounced among orthodontic visits, with black and Hispanic children receiving the fewest orthodontic procedures (8.89% and 10.56%, respectively). CONCLUSIONS: Orthodontic treatment prevalence data suggest that significant disparities exist in orthodontic utilization based on race/ethnicity, poverty level, and insurance status. To establish the burden of malocclusion, describe populations in greatest need of interventions, and craft appropriate programs and policies, an active orthodontic surveillance system is essential.

Examining the use of Amazon's Mechanical Turk for edge extraction of the occlusal surface of fossilized bovid teeth.

In order to reconstruct environments associated with Plio-Pleistocene hominins in southern Africa, researchers frequently rely upon the animals associated with the hominins, in particular, animals in the Family Bovidae. Bovids in southern Africa are typically identified by their teeth. However, identifying the taxon of a bovid tooth is challenging due to various biasing factors. Furthermore, inaccurate identification of fossil bovids can have significant consequences on the reconstructed paleoenvironment. Recent research on the classification of bovid fossil teeth has relied on using elliptical Fourier analysis to summarize the shape of the outline of the occlusal surface of the tooth and the resulting harmonic amplitudes. Currently, an expert in the field must manually place landmarks around the edges of each tooth which is slow and time consuming. This study tests whether it is possible to crowdsource this task, while maintaining the necessary level of quality needed to perform a statistical analysis on each tooth. Amazon Mechanical Turk workers place landmarks on the edge of the tooth which is compared to the performance of an expert in the field. The results suggest that crowdsourcing the digitization process is reliable and replicable. With the technical aspects of digitization managed, researchers can concentrate on analyzing and interpreting the data.

A Review of Statistical Disclosure Control Techniques Employed by Web-Based Data Query Systems.

We systematically reviewed the statistical disclosure control techniques employed for releasing aggregate data in Web-based data query systems listed in the National Association for Public Health Statistics and Information Systems (NAPHSIS). Each Web-based data query system was examined to see whether (1) it employed any type of cell suppression, (2) it used secondary cell suppression, and (3) suppressed cell counts could be calculated. No more than 30 minutes was spent on each system. Of the 35 systems reviewed, no suppression was observed in more than half (n = 18); observed counts below the threshold were observed in 2 sites; and suppressed values were recoverable in 9 sites. Six sites effectively suppressed small counts. This inquiry has revealed substantial weaknesses in the protective measures used in data query systems containing sensitive public health data. Many systems utilized no disclosure control whatsoever, and the vast majority of those that did deployed it inconsistently or inadequately.

Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD. STUDY DESIGN: Cross-sectional and longitudinal observational analysis. SETTING & PARTICIPANTS: Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. PREDICTOR: Quartiles of plasma CX3CL1 levels at baseline. OUTCOMES: Baseline estimated glomerular filtration rate from a creatinine and cystatin C-based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality. RESULTS: Among 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P=0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P<0.001) in adjusted models. During a mean follow-up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 composite outcomes. In fully adjusted models, 1-SD higher CX3CL1 level increased the hazard for all-cause mortality (1.11; 95% CI, 1.00-1.22; P=0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P=0.04). LIMITATIONS: Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect. CONCLUSIONS: Circulating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of atherosclerosis and diabetes.

Higher plasma CXCL12 levels predict incident myocardial infarction and death in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort study.

AIMS: Genome-wide association studies revealed an association between a locus at 10q11, downstream from CXCL12, and myocardial infarction (MI). However, the relationship among plasma CXCL12, cardiovascular disease (CVD) risk factors, incident MI, and death is unknown. METHODS AND RESULTS: We analysed study-entry plasma CXCL12 levels in 3687 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a prospective study of cardiovascular and kidney outcomes in chronic kidney disease (CKD) patients. Mean follow-up was 6 years for incident MI or death. Plasma CXCL12 levels were positively associated with several cardiovascular risk factors (age, hypertension, diabetes, hypercholesterolaemia), lower estimated glomerular filtration rate (eGFR), and higher inflammatory cytokine levels (P < 0.05). In fully adjusted models, higher study-entry CXCL12 was associated with increased odds of prevalent CVD (OR 1.23; 95% confidence interval 1.14, 1.33, P < 0.001) for one standard deviation (SD) increase in CXCL12. Similarly, one SD higher CXCL12 increased the hazard of incident MI (1.26; 1.09,1.45, P < 0.001), death (1.20; 1.09,1.33, P < 0.001), and combined MI/death (1.23; 1.13-1.34, P < 0.001) adjusting for demographic factors, known CVD risk factors, and inflammatory markers and remained significant for MI (1.19; 1.03,1.39, P = 0.01) and the combined MI/death (1.13; 1.03,1.24, P = 0.01) after further controlling for eGFR and urinary albumin:creatinine ratio. CONCLUSIONS: In CKD, higher plasma CXCL12 was associated with CVD risk factors and prevalent CVD as well as the hazard of incident MI and death. Further studies are required to establish if plasma CXCL12 reflect causal actions at the vessel wall and is a tool for genomic and therapeutic trials.

An examination of data confidentiality and disclosure issues related to publication of empirical ROC curves.

RATIONALE AND OBJECTIVES: Grant funding institutions often require organizations to share their collected data as widely as possible while safeguarding the privacy of individuals. Summaries based on these data are often released. Here, the receiver operating characteristic (ROC) curve is explored for potential statistical disclosures in the presence of auxiliary data. MATERIALS AND METHODS: Formulas are introduced for calculating the missing data points from the full data set, given that a user has an empirical ROC curve and a subset of the data used to generate such a curve. Further, a discussion of the plausibility of this scenario is presented. RESULTS: Diagnostic test data were simulated and an ROC curve was produced. Using a subset of the true data and the points on the empirical ROC curve, an attempt was made to reproduce the missing parts of the data. Disease statuses were able to be determined exactly, whereas test scores were solved for up to their rank. CONCLUSIONS: If an individual or organization possessed the points of an empirical ROC curve and a subset of the true data, the true data underlying the ROC curve can be reproduced relatively accurately. As a result, the release of summaries of data, including the ROC curve, must be given careful thought before their release from a statistical disclosure perspective.

Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort).

OBJECTIVES: This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD). BACKGROUND: CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD. METHODS: We performed a candidate gene study (∼2,100 genes; ∼50,000 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) study (N = 1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885). RESULTS: Of 268 SNPs reaching p < 5 × 10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (p < 0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e.g., ATP2B1). In PROMIS, 4 of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1, and ABCA4) had significant associations with MI, consistent with their direction of effect on CAC. CONCLUSIONS: We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.

Mixed modeling of meta-analysis P-values (MixMAP) suggests multiple novel gene loci for low density lipoprotein cholesterol.

Informing missing heritability for complex disease will likely require leveraging information across multiple SNPs within a gene region simultaneously to characterize gene and locus-level contributions to disease phenotypes. To this aim, we introduce a novel strategy, termed Mixed modeling of Meta-Analysis P-values (MixMAP), that draws on a principled statistical modeling framework and the vast array of summary data now available from genetic association studies, to test formally for locus level association. The primary inputs to this approach are: (a) single SNP level p-values for tests of association; and (b) the mapping of SNPs to genomic regions. The output of MixMAP is comprised of locus level estimates and tests of association. In application of MixMAP to summary data from the Global Lipids Gene Consortium, we suggest twelve new loci (PKN, FN1, UGT1A1, PPARG, DMDGH, PPARD, CDK6, VPS13B, GAD2, GAB2, APOH and NPC1) for low-density lipoprotein cholesterol (LDL-C), a causal risk factor for cardiovascular disease and we also demonstrate the potential utility of MixMAP in small data settings. Overall, MixMAP offers novel and complementary information as compared to SNP-based analysis approaches and is straightforward to implement with existing open-source statistical software tools.