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Adolescent girls, independent of their migration background, and adolescent boys, specifically with a migration background, experience more depressive symptoms than boys without a migration background. Adolescent girls also benefit more from depression prevention programs than boys. However, no studies have examined the role of migration background on depression prevention. This cluster-randomized trial included 439 eighth-grade students (43.5% girls, 42.4% with a migration background) in Germany. Adolescents were randomized into either a 10-week universal prevention program or school-as-usual. Following our secondary analyses and as predicted, depressive symptoms decreased in girls in the prevention but not in the control group. Consistent with our hypotheses, boys did not benefit from the prevention program, nor was there a significant interaction between gender and migration background. Independent of condition, depressive symptoms increased in adolescents with a migration background. More research is needed to improve depression prevention for adolescent boys and in adolescents with a migration background.

Purpose/objective(s) To determine, for intact melanoma brain metastases (MBM) treated with single-fraction stereotactic radiosurgery (SRS), whether planning parameter peripheral dose per lesion diameter (PDLDm, Gy/mm) and lesion control (LC) differs with versus without immunotherapy (IO). Materials/methods We performed a retrospective analysis of patients with intact MBM treated with SRS from 2008 to 2019. Cox-frailty models were constructed to include confounders selected by penalized Cox regression models with a LASSO selector. Interaction effect testing was used to determine whether a significant effect between IO and PDLDm could be demonstrated with respect to LC. Results The study cohort comprised 67 patients with 244 MBMs treated with SRS (30 patients with 122 lesions treated with both SRS and IO) were included. The logarithm of PDLDm was selected as a predictor of LC (HR 0.307, 95% CI 0.098-0.441), adjusting for IO receipt (HR 0.363, 95% CI 0.108-1.224). Interaction effect testing demonstrated a differential effect of PDLDm by IO receipt, with respect to LC (p = 0.048). Twelve-month LC rates for a 7.5 mm lesion receiving SRS (18 Gy) with IO versus without IO were 87.8% (95% CI 69.0-98.3%) versus 79.8% (95% CI 55.1-93.8%) respectively. Conclusion PDLDm predicted LC in patients with small MBMs treated with single-fraction SRS. We found a differential effect of dose per lesion size and LC by immunotherapy receipt. Future studies are needed to determine whether lower doses of single-fraction SRS afford similarly effective LC for patients with small MBMs receiving immunotherapy.

Introduction There are insufficient data on surface mold brachytherapy (SMB) in treating oral cancers. We reviewed our institutional experience to investigate the efficacy and toxicity of this treatment modality. Material and methods We retrospectively reviewed all the patients treated between 1989 and 2018 with high-dose-rate iridium-192 SMB for oral and oropharyngeal squamous cell carcinomas at our institution. Surface mold brachytherapy was delivered via an acrylic surface mold with 1–5 inserted catheters spaced 1 cm apart fabricated by our dental oncologist. The Kaplan-Meier product estimator was used to assess local control (LC), locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS). Cox proportional hazards regression analysis was used to assess the relationship of various variables and patient outcomes. Results Eighteen patients met the inclusion criteria and were evaluated. Indications for treatment were primary tumor (n = 13), local recurrence (2), locoregional recurrence (1), and oligometastatic disease (1). Ten patients received SMB alone and 8 received external beam radiotherapy with an SMB boost. The acute toxicity outcomes were as follows: no toxicity (n = 1), grade 1 (7), grade 2 (9), and grade 3 (1). Late effects were rare, only occurring in 3 patients. The one- and two-year LC were 81% and 68%, LRC 77% and 64%, DMFS 81% and 81%, and OS 77% and 46%. Conclusions Surface mold brachytherapy is a viable modality as either primary or boost treatment for superficial oral cancers. In our patients, this treatment method has a low toxicity profile and resulted in reasonable LC.

We propose a Bayesian hurdle mixed-effects model to analyze longitudinal ordinal data under a complex multilevel structure. This research was motivated by the dataset gathered from the Iowa Fluoride Study (IFS) in order to establish the relationships between fluorosis status and potential risk/protective factors. Dental fluorosis is characterized by spots on tooth enamel and is due to ingestion of excessive fluoride intake during enamel formation. Observations are collected from multiple surface zones on each tooth and on all available teeth of children from the studied cohort, which are longitudinally observed at ages 9, 13, and 17. The data not only exhibit a complex hierarchical structure, but also have a large proportion of zero values that are likely to follow different statistical patterns from non-zero categories. Therefore, we develop a hurdle model to consider the zero category separately, while a proportional odds model is used for the positive categories. The estimated parameters are obtained from a Gibbs sampler implemented by the OpenBUGS software. Our model is compared with two popular methods for ordinal data: the proportional odds model and the partial proportional odds model. We perform a comprehensive analysis of the IFS data and evaluate the accuracy and effectiveness of our methodology through simulation studies. Our discoveries provide novel insights to statisticians and dental practitioners about the associations between patient and clinical characteristics and dental fluorosis.

To assess, for intact melanoma brain metastases (MBM), whether single-fraction stereotactic radiosurgery (SRS) versus fractionated stereotactic radiotherapy (fSRT) is associated with a differential risk of post-treatment lesion hemorrhage (HA) development.A single institution retrospective database review identified consecutive patients with previously unresected MBM treated with robotic SRS/fSRT between 2013 and 2021. The presence of lesion HA was determined by multi-disciplinary imaging review. Dosimetric variables were reported as biologically effective doses using an α/β ratio of 2.5 (BEDThe cohort included 48 patients with 226 intact MBM treated with SRS/fSRT. Of lesions without prior HA, 63 of 133 lesions (47.4%) receiving SRS demonstrated evidence of post-treatment HA versus 2 of 24 lesions (8.3%) treated with fSRT (p = 0.01). A larger maximum BEDWe found an increased incidence of post-treatment HA for intact MBM receiving a larger maximum BED

Merkel Cell Carcinoma (MCC) is a rare cancer most commonly affecting White patients; less is known for Black patients. We aim to report presentation, treatment, and quality of registry data by race with a secondary endpoint of overall survival. We conducted a retrospective cohort analysis between 2006–2017 via the National Cancer Database of Black and White MCC patients with and without known staging information. Multivariable logistic, proportional odds logistic, and baseline category logistic regression models were used for our primary endpoint. Multivariable Cox regression was used to interrogate overall survival. Multiple imputation was used to mitigate missing data bias. 34,503 patients with MCC were included (2566 Black patients). Black patients were younger (median age 52 vs. 72, p < 0.0001), had higher rates of immunosuppression (28% vs. 14%, p = 0.0062), and were more likely to be diagnosed at a higher stage (proportional OR = 1.41, 95% CI 1.25–1.59). No differences were noted by race across receipt of definitive resection (DR), though Black patients did have longer time from diagnosis to DR. Black patients were less likely to receive adjuvant radiation. Black patients were more likely to have missing cancer stage (OR = 1.69, CI 1.52–1.88). Black patients had decreased adjusted risk of mortality (HR 0.73, 0.65–0.81). Given the importance of registry analyses for rare cancers, efforts are needed to ensure complete data coding. Paramount to ensuring equitable access to optimal care for all is the recognition that MCC can occur in Black patients.

e21509 Background: Immunosuppression (IS) is not currently considered in staging for Merkel cell carcinoma (MCC). We performed an analysis of the National Cancer Database (NCDB) to investigate immune status as an independent predictor of overall survival (OS) for patients with MCC and describe the relationship between immune status and other prognostic factors. Methods: The NCDB was queried for patients diagnosed with MCC from 2010 to 2016 with known immune status. Multivariable Cox proportional hazards models were used to define factors associated with OS. Adjuvant radiation and chemotherapy were treated as time-dependent predictors to limit immortal time bias. Secondary models were constructed to assess the association between IS etiology and OS. Multivariable logistic regression models were used to characterize relationships between immune status and other factors. Multiple imputation was used to minimize missing data bias. Results: The overall cohort included 3,882 patients (3,470 patients with known immunocompetence and 412 patients with known immunosuppression). Etiologies for profound IS included chronic lymphocytic leukemia (CLL, n = 118), Other including HIV/AIDS (n = 116), solid-organ transplant (n = 106), and Non-Hodgkin Lymphoma (NHL, n = 72). 2,864 patients (73.8%) underwent surgical nodal examination. The median follow-up time was 33 months (Interquartile Range: 18 to 55 months). The 3-year OS was lower for patients with IS (44.6%, CI 39.8-49.9%) compared to immunocompetent (IC) patients (68.7%, CI 67.1-70.4%, p < .0001). IS was associated with increased adjusted mortality hazard (HR 2.36, 95% CI 2.03-2.75). Etiology of IS was associated with OS ( p = .0015) with lowest 3-year OS (32.7%, CI 24.6%-43.5%) for patients with solid-organ transplantation. IS was associated with increased odds of greater nodal burden (OR 1.70, CI 1.37-2.11) and lymphovascular invasion (OR 1.58, CI 1.23-2.03). Conclusions: Immune status was independently prognostic for OS for patients with localized MCC. Etiology of IS may be associated with differential survival outcomes. Multiple adverse prognostic factors were associated with increased likelihood of IS. Immune status and potentially etiology of IS may be useful prognostic factors to consider for future MCC staging systems.

Objective To evaluate the utility of adding triamcinolone acetonide to a standard bladder instillation solution for treatment of interstitial cystitis-bladder pain syndrome. Methods This was a single-center, randomized, double-blind trial that compared symptom response in women with interstitial cystitis-bladder pain syndrome who underwent six bladder instillations with triamcinolone acetonide or six instillations without. All instillation solutions contained heparin, viscous lidocaine, sodium bicarbonate, and bupivacaine. The primary outcome was the change in interstitial cystitis-bladder pain syndrome symptoms from the first to sixth bladder instillation between groups based on the total OLS (O'Leary-Sant Questionnaire) score. Assuming a 4.03-point or larger difference in the mean total OLS score from the first to sixth bladder instillation as compared between the groups, 64 participants were needed to show a significant difference with 80% power at the 0.05 significance level. Results From January 2019 to October 2020, 90 women were enrolled-45 per group; 71 (79%) completed all six bladder instillations. Randomization resulted in groups with similar characteristics. There was no difference between groups in the primary outcome (bladder instillation with triamcinolone acetonide: mean OLS change -6.7 points, 95% CI 4.6-8.8 and bladder instillation without triamcinolone acetonide: mean OLS change -5.8 points, 95% CI 3.4-8.1; P=.31). Women in both groups had improvement in their interstitial cystitis-bladder pain syndrome symptoms as indicated by a decrease in the total OLS score from the first to sixth bladder instillation. Conclusion The addition of triamcinolone acetonide to a standard bladder instillation solution does not improve symptoms associated with interstitial cystitis-bladder pain syndrome. Clinical trial registration ClinicalTrials.gov, NCT03463915.

BackgroundThe optimal treatment of patients with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma remains unknown.ObjectiveTo compare overall survival following treatment with a hysterectomy and adjuvant radiotherapy with or without chemotherapy in this group of patients.MethodsPatients diagnosed between January 2004 and January 2016 with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma treated with hysterectomy and postoperative radiotherapy with or without adjuvant concurrent chemotherapy were identified in the National Cancer Database. Overall survival was assessed with Kaplan-Meier curves. A Cox model was constructed to evaluate survival after controlling for confounding variables. A logistic regression model was used to reveal predictors of chemotherapy use.ResultsA total of 2173 patients were included. The receipt of chemotherapy was associated with an increased 5-year overall survival from 67.6% to 75.6% (p=0.0313). This association trended toward statistical significance on multivariate analysis (adjusted HR (aHR) 0.80; 95% CI 0.63 to 1.01; p=0.0653). Other factors associated with improved survival were undergoing a lymphadenectomy, absence of lymphovascular space invasion, younger age, smaller tumor size, non-black race, and absence of comorbidities. Patients who underwent brachytherapy, had lymphovascular space invasion, were younger, were diagnosed in the more recent years, and were treated in higher volume centers were more likely to receive adjuvant chemotherapy.ConclusionAdjuvant chemotherapy and radiation therapy were associated with an increase in survival in patients with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma compared with those treated with adjuvant radiotherapy alone.

Dental caries (i.e., cavities) is one of the most common chronic childhood diseases and may continue to progress throughout a person's lifetime. The Iowa Fluoride Study (IFS) was designed to investigate the effects of various fluoride, dietary and nondietary factors on the progression of dental caries among a cohort of Iowa school children. We develop a mixed effects model to perform a comprehensive analysis of the longitudinal clustered data of IFS at ages 5, 9, 13, and 17. We combine a Bayesian hurdle framework with the Conway-Maxwell-Poisson regression model, which can account for both excessive zeros and various levels of dispersion. A hierarchical shrinkage prior distribution is used to share the temporal information for predictors in the fixed-effects model. The dependence among teeth of each individual child is modeled through a sparse covariance structure of the random effects across time. Moreover, we obtain the parameter estimates and credible intervals from a Gibbs sampler. Simulation studies are conducted to assess the accuracy and effectiveness of our statistical methodology. The results of this article provide novel tools to statistical practitioners and offer fresh insights to dental researchers on effects of various risk and protective factors on caries progression.

Objectives To evaluate whether percutaneous nerve evaluation (PNE) without fluoroscopy is inferior to fluoroscopy use in women undergoing trials of sacral neuromodulation (SNM) for pelvic floor disorders (PFDs). Materials and methods In an unblinded noninferiority trial, women undergoing PNE were randomized to fluoroscopy or no fluoroscopy. The primary outcome was "success" and defined as implantation of the permanent SNM device within three months of PNE. At an expected 40% success and a 30% noninferiority threshold, 33 participants in each group were needed for 80% power (α = 0.05). Univariate analyses and a logistic regression model adjusting for univariate variables associated with the primary outcome were performed. Results From April 2016 to December 2018, 74 participants underwent PNE of which 36 underwent PNE with fluoroscopy and 38 without. The fluoroscopy group had less baseline mean daily voids compared to the no fluoroscopy group (10.79 ± 6.48 vs. 16.21 ± 10.05, p = 0.01). PNE performed without fluoroscopy had similar success (18/38, 47.4%) compared to fluoroscopy (21/36, 58.3%), meeting our noninferiority definition (difference 10.9%, 90% CI -8% to 30%, p = 0.049). In a logistic regression model adjusting for age, Charlson comorbidity index, stage of prolapse, and number of baseline voids per day, trial success was still similar between the two groups (adjOR 1.82, 95% CI 0.52 to 6.94, p = 0.36). Conclusions PNE performed without fluoroscopy is noninferior to PNE with fluoroscopy use for the outcome of SNM device implantation within three months among women undergoing therapy for PFDs.

Objective We sought to investigate factors associated with improved feedback quality during third-year obstetrics and gynecology (OBGYN) clerkships. Design This prospective cohort study assessed relationships of student and clerkship characteristics to the quantity and quality of feedback during OBGYN clerkships according to the clerkship director and third-year medical students. Setting This study took place in a university-based hospital setting in which medical students rotate for 6 weeks on core clerkships during the third year of medical school. Participants Third year medical students participating in core OBGYN clerkships during the 2018 to 2019 academic year. Results One hundred and ten students participated. Students with better clerkship scores reported higher quality of feedback, effectiveness of teaching, and quality of the clerkship overall, but did not receive a higher quantity or quality of feedback per the clerkship director. In multivariate modeling, the only factor affecting the clerkship director's rating of feedback adequacy was the number of preceptors who had given feedback. Factors associated with better student-reported feedback quality included midclerkship feedback adequacy and attendings and residents teaching procedures. Conclusions Improved feedback for medical students on core OBGYN clerkships is associated with more preceptors offering feedback, midclerkship feedback adequacy, and preceptors teaching procedures.

Summary Count data are common in many fields such as public health. Hurdle models have been developed to model count data when the zero count could be either inflated or deflated. However, when data are repeatedly collected over time and spatially correlated, it is very challenging to model the data appropriately. For example, to study health professional shortage areas, the number of primary care physicians along with other demographic characteristics are collected at the county level in the USA and over different years. Since the data are repeatedly collected over time, counties are nested within the state, and adjacent counties are geographically correlated, the dependence structure of the data is very complex. We develop a Bayesian hurdle model with multilayered random effects to incorporate this complex structure. We use a time-varying random effect for each state to capture the time effect at the state level, and a temporal thin plate spline to capture the spatiotemporal correlation across different counties. We use STAN to obtain samples for inference from the posterior distribution. By using the model proposed, we can identify the important factors which impact health professional shortage areas. Simulation studies also confirm the effectiveness of the model.

The goal of this study was to assess how the incidence and mortality of cervical cancer in Kentucky has changed from 1995 through 2017. Additionally, trends in incidence and mortality across different geographic areas and between different races were evaluated.Age-adjusted annual incidence and mortality rates for cervical cancer were collected from the Kentucky Cancer Registry (KCR). A quadratic fit model was used to evaluate changes in the incidence and mortality over time and to compare differences in cervical cancer incidence and mortality by: 1) rural versus urban counties, 2) Appalachian versus non-Appalachian counties, and 3) black versus white women.Overall, the incidence of cervical cancer has significantly decreased throughout Kentucky since 1995. When comparing different geographic regions, the incidence was 14% and 23% higher in rural and Appalachian counties, respectively, compared to urban and non-Appalachian counties (p 0.0001) throughout the study period. The incidence of cervical cancer was significantly higher in black women compared to white women from 1995 through 2007, but since 2008 there has been no significant difference in cervical cancer incidence based on race. Similar to incidence rates, mortality from cervical cancer was 29% higher in Appalachia (p = 0.0004) throughout the studied time period. Black women had higher age-adjusted mortality than white women until 2012, but since that time there has not been a significant difference in cervical cancer mortality based on race.Women residing in rural and Appalachian Kentucky have higher cervical cancer incidence and mortality rates.

Background Gene co-expression networks (GCNs) are powerful tools that enable biologists to examine associations between genes during different biological processes. With the advancement of new technologies, such as single-cell RNA sequencing (scRNA-seq), there is a need for developing novel network methods appropriate for new types of data. Results We present a novel sparse Bayesian factor model to explore the network structure associated with genes in scRNA-seq data. Latent factors impact the gene expression values for each cell and provide flexibility to account for common features of scRNA-seq: high proportions of zero values, increased cell-to-cell variability, and overdispersion due to abnormally large expression counts. From our model, we construct a GCN by analyzing the positive and negative associations of the factors that are shared between each pair of genes. Conclusions Simulation studies demonstrate that our methodology has high power in identifying gene-gene associations while maintaining a nominal false discovery rate. In real data analyses, our model identifies more known and predicted protein-protein interactions than other competing network models.

Neoadjuvant chemotherapy (NAC) is a standard of care for locally advanced breast cancers. Adjuvant radiotherapy (RT) after NAC is an area of active research. We hypothesize overall survival (OS) is not altered by omitting RT in women with a pathologic complete response (pCR) to NAC after breast conserving survery (BCS).Patients from the National Cancer Database who underwent NAC, BCS, and had a pCR were included. Inflammatory disease,6 months follow up, and unknown variables were excluded. Descriptive statistics characterized the retained cohort. Logistic regression analyzed the influence of variables on the rate of RT omission. Cox proportional hazard modeling analyzed the influence of prognostic variables on OS.Of 5383 women included, 364 (7%) omitted RT. 5-year OS was 94.1% with RT, 93% without. RT omission was most likely in women70yo (adjusted OR2.4, 95%CI 1.58-3.65,Women ≥70, of Hispanic origin, living ≥20 miles from treatment facility, and grade 1 disease were more likely to omit RT. HER2+ patients had favorable OS, while older age and N3 disease were negative prognostic factors. Omitting RT after a pCR to NAC and BCS was not found to affect OS.

Surrogate markers of the host immune response are not currently included in AJCC staging for Merkel cell carcinoma (MCC), and have not been consistently associated with clinical outcomes. We performed an analysis of a large national database to investigate tumor infiltrating lymphocyte (TIL) grade as an independent predictor of overall survival (OS) for patients with MCC and to characterize the relationship between TIL grade and other clinical prognostic factors.The NCDB was queried for patients with resected, non-metastatic MCC with known TIL grade (absent, non-brisk and brisk). Multivariable Cox regression modeling was performed to define TIL grade as a predictor of OS adjusting for other relevant clinical factors. Multinomial, multivariable logistic regression was performed to characterize the relationship between TIL grade and other clinical prognostic factors. Multiple imputation was performed to account for missing data bias.Both brisk (HR 0.55, CI 0.36-0.83) and non-brisk (HR 0.77, CI 0.60-0.98) were associated with decreased adjusted hazard of death relative to absent TIL grade. Adverse clinical factors such as 1-3 positive lymph nodes, lymphovascular invasion (LVI) and immunosuppression were associated with increased likelihood of non-brisk TIL relative to absent TIL grade (Histopathologic TIL grade was independently predictive for OS in this large national cohort. Significant differences in the likelihood of non-brisk or brisk TIL relative to absent grade were present with regards to LVI, ECS and immune status. TIL grade may be a useful prognostic factor to consider in addition to more granular characterization of TIL morphology and immunophenotype.

Objective To evaluate differences in physical function at 6 weeks after vaginal surgery among women positioned in candy cane and boot stirrups. Methods We conducted a single-masked, randomized controlled trial of women undergoing vaginal surgery with either candy cane or boot stirrup use. The primary outcome was a change in the PROMIS (Patient-Reported Outcomes Measurement Information System) physical function short form-20a from baseline to 6 weeks after surgery. To achieve 80% power to detect a moderate Cohen effect (d=0.5), we required 64 participants in each group. Results From March 2018 to October 2019, 141 women were randomized, and 138 women (72 in the candy cane group and 66 in the boot stirrup group) were included in the final analysis. There were no baseline differences in participant characteristics including age, body mass index, comorbidities, or preoperative history of joint replacements. There were no between-group differences in surgery type, duration of surgery, estimated blood loss, or adverse events at 6 weeks postoperation. Participants in the candy cane group demonstrated worse physical function at 6 weeks compares with the improvement seen in those in the boot stirrup group; this was significantly different between groups (-1.9±7.9 candy cane vs 1.9±7.0 boot, P Conclusion Women undergoing vaginal surgery positioned in boot stirrups have significantly better physical function at 6 weeks after surgery when compared with women positioned in candy cane stirrups. Clinical trial registration ClinicalTrials.gov, NCT03446950.

Variable selection over a potentially large set of covariates in a linear model is quite popular. In the Bayesian context, common prior choices can lead to a posterior expectation of the regression coefficients that is a sparse (or nearly sparse) vector with a few nonzero components, those covariates that are most important. This article extends the “global‐local” shrinkage idea to a scenario where one wishes to model multiple response variables simultaneously. Here, we have developed a variable selection method for a K‐outcome model (multivariate regression) that identifies the most important covariates across all outcomes. The prior for all regression coefficients is a mean zero normal with coefficient‐specific variance term that consists of a predictor‐specific factor (shared local shrinkage parameter) and a model‐specific factor (global shrinkage term) that differs in each model. The performance of our modeling approach is evaluated through simulation studies and a data example.

Immunosuppressed (IS) patients are at increased risk for developing Merkel cell carcinoma (MCC) with worsened outcomes compared to immunocompetent (IC) patients. We sought to determine the effects of immune status on the efficacy of adjuvant RT regarding OS for patients with stage I, II or III (localized) MCC of the head and neck. The National Cancer Database was queried for patients with resected, localized MCC of the head and neck with known immune status. Kaplan–Meier methods were used to describe OS. Log-rank tests, multivariable Cox regression models and interaction effect testing were used to compare OS by subgroup categorized by patient and treatment factors including immune status and adjuvant RT receipt. A total of 892 (89.6%) IC and 104 (10.4%) IS patients with MCC of the head and neck were included. Adjuvant RT was associated with improved 3-year OS rate for both IS patients (49.4% vs. 35.5%, p = 0.0467) and stage I/II IC patients (72.4% vs. 62.9%, p = 0.0092). Adjuvant RT was associated with decreased hazard of death (HR 0.77, 95% CI 0.62–0.95). Interaction effect testing did not demonstrate a difference in the efficacy of adjuvant RT on OS between IC and IS status (p = 0.157). In this NCDB analysis, adjuvant RT was associated with decreased hazard of death for patients with localized MCC of the head and neck regardless of immune status and should be considered for both IS and IC patients.

In this work, we develop new data augmentation algorithms for Bayesian analysis of directional data using the von Mises-Fisher distribution in arbitrary dimensions. The approach leads to a new class of distributions, called the Modified Pólya-Gamma distribution, which we construct in detail. The proposed data augmentation strategies circumvent the need for analytic approximations to integration, numerical integration, or Metropolis-Hastings for the corresponding posterior inference. Simulations and real data examples are presented to demonstrate the applicability and to apprise the performance of the proposed procedures.

Differential network analysis plays an important role in learning how gene interactions change under different biological conditions, and the high resolution of single-cell RNA (scRNA-seq) sequencing provides new opportunities to explore these changing gene-gene interactions. Here, we present a sparse hierarchical Bayesian factor model to identify differences across network structures from different biological conditions in scRNA-seq data. Our methodology utilizes latent factors to impact gene expression values for each cell to help account for zero-inflation, increased cell-to-cell variability, and overdispersion that are unique characteristics of scRNA-seq data. Condition-dependent parameters determine which latent factors are activated in a gene, which allows for not only the calculation of gene-gene co-expression within each group but also the calculation of the co-expression differences between groups. We highlight our methodology’s performance in detecting differential gene-gene associations across groups by analyzing simulated datasets and a SARS-CoV-2 case study dataset.

Hydrocodone is the most prescribed opioid in the US. The objective was to evaluate associations between genetic, intrinsic, and extrinsic patient factors, plasma hydrocodone and metabolites, common side effects, and pain scores in a cohort of orthopedic surgery patients.Data for each patient was collected by review of the electronic hospital record (EHR), and patient interview. Patients were recruited from those with trauma or undergoing scheduled elective surgery for total knee replacement or total hip at the University of Louisville Hospital, Baptist East Hospital, and Jewish Hospital, Louisville, KY. Plasma opiate concentrations and a targeted genotyping panel was performed.There were statistically significant correlations with daily (p 0.001) and total dose (p = 0.002) of hydrocodone in hospital and duration of opioid therapy. The length of opioid administration was significantly shorter in CYP2D6 EM/UM versus CYP2D6 PM/IM patients (p = 0.018). Subjects with the OPRM1 c.118G variant were also on opioids longer (p = 0.022). The effect of co-administration of a CYP2D6 inhibitor had a significant effect on the length of opioid therapy (P 0.001). And not surprisingly the effect of the inhibitor adjusted CYP2D6 phenotype was greater in both the hospital stay period and days of opioid use post hospital discharge (p 0.001).Based on this study, patients should be evaluated for the use of inhibitors of CYP2D6, during hydrocodone therapy can alter the phenotype of the patient (phenocopy) and increase the probability that the patient will be on opioids for longer periods of time.

The optimal timing of adjuvant chemoradiation after surgical resection of glioblastoma remains unknown. The National Cancer Database was queried for all patients diagnosed with glioblastoma from 2004 to 2012 who underwent surgical resection followed by adjuvant chemoradiation. Cox proportional hazards modeling was used to determine factors influencing survival. Optimal thresholds for time to initiation (TTI) of adjuvant therapy were determined using recursive partitioning analysis (RPA). A total of 16,335 patients were included. The RPA model identified an optimal threshold of 61 days to initiation of adjuvant therapy which was confirmed with randomly selected training and validation sets using conditional inference trees repeated 1000 times for robustness. Compared to patients who initiated adjuvant therapy within 61 days (median overall survival: 14.1 months, 95% CI 13.8-14.3 months), patients who initiated adjuvant therapy after day 61 (MOS: 12.0, CI: 10.7-12.9) had higher risk of death (p 0.0001). For patients with glioblastoma, large increases in time to the initiation of adjuvant therapy leads to inferior survival with a threshold of 61 days or less following surgical resection.

Background Genetic polymorphisms of cytochrome P450 are contributors to variability in individual response to drugs. Within the P450 family, CYP2D6 is responsible for metabolizing hydrocodone, a widely prescribed opioid for pain management. Alternatively, CYP3A4 and CYP3A5 can form norhydrocodone and dihydrocodeine. We have previously found that in a postcesarean section cohort, the rate of hydromorphone formation was dependent on the genotype of CYP2D6 and that plasma hydromorphone, not hydrocodone, was predictive of pain relief. Method Blood was obtained from a postcesarean cohort that were surveyed for pain response and common side effects. Plasma samples were genotyped for CYP3A4/5, and their hydrocodone concentrations were measured by LC-MS. R statistical software was used to check for differences in the outcomes due to CYP3A4/5 and CYP2D6, and a multivariate regression model was fit to determine factors associated with pain score. Results Two-way ANOVA between CYP3A4/A5 and CYP2D6 phenotypes revealed that the former variants did not have a statistical significance on the outcomes, and only CYP2D6 phenotypes had a significant effect on total dosage (P = 0.041). Furthermore, a 3-way ANOVA analysis showed that CYP2D6 (P = 0.036) had a predictive effect on plasma hydromorphone concentrations, and CYP3A4/A5 did not have any effect on the measured outcomes. Conclusions With respect to total dosages in a cesarean section population, these results confirm that CYP2D6 phenotypes are predictors for plasma hydromorphone concentration and pain relief, but CYP3A4/A5 phenotypes have no influence on pain relief or on side effects.

Objectives The purpose of this study was to evaluate the accuracy of portable bladder scanner postvoid residual (PVR) volume measurements in patients with pelvic organ prolapse. A secondary goal was to determine whether covariates such as bladder volume and stage of prolapse affect bladder scanner accuracy. Study design Complex urodynamic studies were performed on 70 patients with stage II or greater prolapse. Complex urodynamic studies included measurement of maximum bladder capacity (MBC) as well as measurement of PVR by urethral catheterization before, and following, complex filling cystometry. For each catheterized PVR, a corresponding bladder scanner measurement was obtained; the primary outcome was the difference between these measurements. In addition, bladder scanner measurements of MBC were compared with MBC by urodynamic pump. Measurements were compared by paired t test. Linear regression was used to assess association between covariates and bladder scanner error. Results There was no significant difference between catheter and bladder scanner PVR at the initial (mean difference, 5.94 mL; 95% confidence interval [CI], -3.8 to 15.7) or final (mean difference, 1.37 mL; 95% CI, -10.9 to 13.6) measurements. Maximum bladder capacity measurements by bladder scanner were significantly smaller than catheterized measurements (mean difference, -21.3 mL; 95% CI, -40.3 to -2.3). Stage III/IV prolapse was associated with increased bladder scanner error (P = 0.03). Conclusions The portable bladder scanner accurately measures PVR in patients with pelvic organ prolapse and could be considered as an alternative to catheterized assessment. However, stage III/IV prolapse is associated with increased bladder scanner error, which should be considered when determining appropriate candidates for bladder scanner PVR assessment.

Objective The optimal treatment for medically inoperable endometrioid endometrial adenocarcinoma is unknown. The goal of this study was to evaluate the patterns of care and efficacy of radiotherapy (RT) or hormone therapy (HT) in the treatment of these patients. Methods We performed a query of the National Cancer Database (NCDB) of patients with medically inoperable endometrioid adenocarcinoma of the endometrium diagnosed between 2004 and 2016 and treated with either RT or HT. A multivariate Cox regression model and propensity weighted analyses were used to evaluate overall survival after controlling for confounding variables. A multinomial logistic regression model was used to assess predictors of RT or HT use. Results A total of 1036 patients were included in this cohort, and 73% (n = 759) were treated with RT alone. Patients who received definitive HT compared to RT were more likely to be older, diagnosed in the earlier years of this analysis, treated at lower-case volume centers, diagnosed with high-grade disease, or located outside of metropolitan areas. On multivariate analysis, treatment with HT alone versus RT alone was associated with significantly worse overall survival in the multivariate Cox model but not on propensity score weighted analysis. Interaction effect testing revealed that older patients and those treated at lower-volume centers had improved survival with RT compared to HT. Conclusions We identified factors associated with the receipt of RT or HT in medically inoperable endometrial cancer patients. Treatment with RT correlated with improved survival compared to HT in older patients and those treated at lower-volume centers.

BACKGROUND: Stereotactic body radiation therapy (SBRT) as a form of noninvasive treatment that is becoming increasingly used to manage cancers with adrenal gland metastases. There is a paucity of data on safety and efficacy of this modality. The aim of the study was to evaluate the safety and efficacy of adrenal gland SBRT in oligometastatic and oligoprogressive disease. MATERIALS AND METHODS: In this retrospective study, we performed a single-institution analysis of 26 adrenal lesions from 23 patients with oligometastatic or oligoprogressive disease treated from 2013 to 2019 with the goal of achieving durable local control. Palliative cases were excluded. Radiation dosimetry data was collected. Kaplan Meier product estimator and Cox proportional hazards regression analysis were used for statistical analysis. RESULTS: The median dose was 36 Gy in 3 fractions (range: 24–50 Gy and 3–6 fractions) with a median biologically effective dose (BED10) of 72 (range: 40–100). 1-year local control rate was 80% and median local control was not achieved due to a low number of failures. 1- and 2-year overall survival rates were 66% and 32%. Toxicity was mild with only one case of grade 2 nausea and no grade 3–5 toxicity. Higher neutrophil to lymphocyte ratio was associated with worse overall survival and a trend toward worse progression-free survival. In addition, worse performance status and lower BED10 were associated with worse survival. No such association could be shown for primary tumor location, histology, size or stage. CONCLUSION: Adrenal SBRT for oligometastatic or oligoprogressive disease is a safe and effective form of treatment.

OBJECTIVES This study aimed to determine if there are differences in (1) surgical procedures performed for pelvic organ prolapse (POP) and (2) rates of adverse events between racial groups. METHODS We conducted a retrospective cohort study of women 18 years and older who underwent POP surgery using the 2005-2015 American College of Surgeons National Surgical Quality Improvement Program database. Race was categorized as Black, White, Hispanic, and other minority. Pelvic organ prolapse procedures were organized into 4 groups: (1) hysterectomy without concurrent POP procedures, (2) vaginal wall repair(s) only without apical suspension, (3) apical suspension with or without vaginal wall repair(s), and (4) obliterative procedures. Patient characteristics and rates of adverse events were noted. A multivariable logistic regression model was used to assess the association between patient race and surgical procedures performed for POP. RESULTS We identified 48,005 women who met the inclusion criteria. Most women who underwent POP surgery were White (79.6% [n = 38,191]). Although only contributing to 4.7% (2,299) of the cohort, Black women experienced higher complication rates compared with White women (10.7% [246] for Black vs 8.9% [3,417] for White women, P < 0.01). Hispanic and other minority women were less likely to undergo an apical suspension than White women (adjusted odds ratios [aORs], 0.79 [0.75-0.84] for Hispanic women and 0.78 [0.71-0.86] for other minority women; P < 0.001 for both). Obliterative procedures were more likely to be performed in Black, in Hispanic, and especially in other minority women (aORs, 1.53 [1.20-1.92] for Black, 1.33 [1.12-1.58] for Hispanic, and 3.67 [3.04-4.42] for other minority women; P < 0.001 for all). CONCLUSIONS Racial differences exist among women who undergo POP surgery.

Objectives: The optimal treatment of FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma remains unknown. It is unclear if adjuvant chemotherapy (CHT) in addition to adjuvant radiotherapy enhances survival in this subgroup of endometrial cancer patients. The goals of the present study were to perform a National Cancer Database (NCDB) analysis in this cohort of patients to 1) compare overall survival following treatment with a hysterectomy and adjuvant radiotherapy with or without CHT, 2) evaluate CHT utilization in the United States, and 3) investigate which factors are associated with survival in stage IB grade 3 endometrioid adenocarcinoma patients. Methods: Patients diagnosed between 2004 and 2015 with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma treated with hysterectomy and postoperative radiotherapy with or without adjuvant systemic CHT were identified in the NCDB. Overall survival (OS) was assessed with Kaplan-Meier curves, and differences between groups were compared with the log-rank test. A Cox model was constructed to evaluate survival after controlling for confounders, and logistic regression was used to reveal predictors of CHT use. Results: While the receipt of CHT was associated with a trend toward increased 5-year OS from 68.1% to 74.7% (p=0.059), this association did not reach statistical significance on propensity score weighted (p=0.073) and multivariate analyses (adjusted HR (aHR) 0.86; CI: 0.70-1.06; p=0.15) as shown in the figure. Moreover, there was some evidence of a differential CHT effect in patients who did not undergo a lymphadenectomy (LND; p=0.056); CHT was associated with a trend toward reduced hazard of death in patients with LND (aHR=0.82, CI: 0.66-1.01, p=0.0634) but not in patients who did not undergo LND (aHR=1.70, CI: 0.86-3.35, p=0.1255). Patients who underwent brachytherapy as opposed to external beam radiotherapy, had lymphovascular space invasion (LVSI), were 59 years or younger, were diagnosed in the more recent years of the study and treated in higher facility case volume centers were more likely to: receive adjuvant chemotherapy. No LND (HR 1.51; CI: 1.13-2.03; p=0.0057), positive LVSI (HR 1.71; CI: 1.36-2.16; p 70 (HR 2.61; CI: 2.03-3.36; p Download : Download high-res image (275KB) Download : Download full-size image Conclusions: Adjuvant CHT plus radiotherapy was associated with a non-statistically significant increase in OS in FIGO stage IB grade 3 endometrioid adenocarcinoma patients compared to those treated with adjuvant radiotherapy alone. This potential effect is most apparent in patients who underwent LND.

Purpose Vaginal cancer is a rare tumor that is optimally treated with a combination of chemotherapy (CHT) and radiation therapy. Because of the rarity of this cancer, the benefit of a brachytherapy boost (BT) and the relevance of radiotherapy time to treatment completion (TTC) are unclear. Methods Patients diagnosed between 2004 and 2015 with non-metastatic vaginal cancer treated with definitive CHT and external beam radiotherapy with or without BT but with no surgery were identified in the National Cancer Database. Overall survival (OS) was assessed with Kaplan-Meier curves, and differences between groups were compared with the log-rank test. A Cox model was constructed to evaluate survival after controlling for confounders. A Cox model using a penalized spline function was constructed to evaluate how the length of radiation therapy correlated with OS among patients receiving BT. Results A total of 1094 patients who met the inclusion criteria were identified. The utilization of BT was associated with improved 5-year OS (62.9% vs. 49.3%, p = 0.0126) on propensity score-weighted analyses. TTC of 63 days or less was associated with improved 5-year OS (67.8% vs. 54.5%, p = 0.0031) in patients who underwent BT. Other factors associated with improved OS in patients who received CHT, external beam radiotherapy, and BT were younger age, absent comorbidity score, and negative lymph nodes. Conclusions A brachytherapy boost and shorter TTC were associated with a survival benefit in a cohort of patients with non-metastatic vaginal cancer treated with definitive chemoradiotherapy.

Summary Across several medical fields, developing an approach for disease classification is an important challenge. The usual procedure is to fit a model for the longitudinal response in the healthy population, a different model for the longitudinal response in the diseased population, and then apply Bayes’ theorem to obtain disease probabilities given the responses. Unfortunately, when substantial heterogeneity exists within each population, this type of Bayes classification may perform poorly. In this article, we develop a new approach by fitting a Bayesian nonparametric model for the joint outcome of disease status and longitudinal response, and then we perform classification through the clustering induced by the Dirichlet process. This approach is highly flexible and allows for multiple subpopulations of healthy, diseased, and possibly mixed membership. In addition, we introduce an Markov chain Monte Carlo sampling scheme that facilitates the assessment of the inference and prediction capabilities of our model. Finally, we demonstrate the method by predicting pregnancy outcomes using longitudinal profiles on the human chorionic gonadotropin beta subunit hormone levels in a sample of Chilean women being treated with assisted reproductive therapy.

Small cell lung cancer (SCLC) is an aggressive disease treated as soon as possible given its rapid doubling time. Evidence for the appropriate time to chemotherapy initiation (TCI) for SCLC is lacking. This study evaluated TCI in SCLC on a national level.The National Cancer Database identified 64,491 SCLC patients treated with chemotherapy from 2010 to 2014. Factors associated with TCI were identified with multiple linear regression analyses. TCI was categorized into 4 groups using cutoff points of 7, 14, and 28 days. Using these categories, median overall survival and log-rank test was used for univariate analysis of the survival outcome and the Cox model was used for multivariate analysis.Median TCI was 18 days with 21% treated ≤7 days, 21% in 8 to 14 days, 30% 15 to 28 days, and 28%28 days from diagnosis. Younger age, white race, no insurance, more comorbidities, and higher stage were associated with shorter TCI. Median overall survival for TCI within 7 days was 8.2 months, 8 to 14 days was 9.2 months, 15 to 28 days was 10.3 months, and28 days was 10.8 months (P0.001). In the multivariate analysis, increased TCI was associated with improved survival across all stages. Among stage IV patients, compared with TCI≤7 days, the hazard ratio (HR) is 0.92 (P0.001) for 8 to 14 days, HR 0.82 (P0.001) for 15 to 28 days, and HR 0.77 (P0.001) for28 days of TCI. Results were similar for stage III and for stages I+II.Our results show worse survival with shorter TCI. This provides evidence to inform a discussion regarding appropriate treatment timing and individualizing treatment.

To evaluate patient-reported outcomes (PROs) and cosmesis from a phase 2 trial of once-weekly hypofractionated breast irradiation (WH-WBI) after breast-conserving surgery (BCS).Patients had stage 0-II breast cancer treated with BCS and negative margins. WH-WBI was 28.5 to 30 Gy in 5 weekly fractions of 5.7 to 6 Gy delivered with or without a boost. PROs were collected for 3 years after treatment using the Breast Cancer Treatment Outcome Scale (BCTOS) and European Organization for Research and Treatment of Cancer Breast Cancer-Specific Quality of Life Questionnaire (QLQ-BR23). Physicians rated cosmetic outcome with the Global Cosmesis Score. Longitudinal growth models were used to assess changes in BCTOS across time, and baseline values and changes between time points were correlated with patient and treatment factors.From 2011 to 2015, 158 women received WH-WBI, and 148 were eligible for analysis after a median follow-up of 39.3 months. Adverse changes (P.001) in global BCTOS score and breast pain and arm function subscores were observed 6 months after radiation therapy, followed by improvement to near-baseline values at years 1 and 3. Adverse changes in BCTOS cosmetic subscore were also detected at 6 months (P.001), with no significant improvement at 1 (P = .385) and 3 (P = .644) years. No effect was detected for longitudinal changes in BCTOS scoring for age, body mass index, diabetes, smoking, breast volume, tumor size, seroma volume, dosimetric factors, dose, boost, or systemic therapy. Physician-rated cosmesis at 3 years was excellent/good in 89% and fair/poor in 11%.WH-WBI was associated with transient worsening in arm function and breast pain but persistent adverse changes in cosmetic PROs that were typically mild or moderate in severity. Physician-rated cosmetic outcomes were acceptable.

PURPOSE: DNA repair genes Minichromosome maintenance complex component (MCM) 8 and 9 have been linked with gonadal development, primary ovarian insufficiency (POI), and age at menopause. Our objective was to characterize MCM 8 and 9 gene expression in the menstrual cycle, and to compare MCM 8/9 expression in POI vs normo-ovulatory women. METHODS: Normo-ovulatory controls (n = 11) and unexplained POI subjects (n = 6) were recruited. Controls provided three blood samples within one menstrual cycle: (1) early follicular phase, (2) ovulation, and (3) mid-luteal phase. Six of 11 controls only provided a follicular phase sample. Amenorrheic POI subjects provided a single, random blood sample. MCM8/9 expression in peripheral blood was assessed with qRTPCR. Analyses were performed using delta-Ct measurements; group differences were transformed to a fold change (FC) and confidence interval (CI). Differences across menstrual cycle phases were compared using random effects ANOVA. Two-sample t tests were used to compare two groups. RESULTS: MCM8 expression was significantly lower at ovulation and during the luteal phase, when compared to the follicular phase [FC = 0.69 in the luteal vs follicular phase (p = 0.012, CI = 0.53, 0.90); and 0.65 in the ovulatory vs follicular phase (p = 0.0057, CI = 0.50, 0.85)]. No change in MCM9 expression was noted throughout the menstrual cycle. No significant difference was seen in MCM8/9 expression when comparing POI to control subjects. CONCLUSIONS: Our study showed greater MCM8 expression in the follicular phase of the menstrual cycle, compared to the ovulatory and luteal phases. No cyclic changes were seen with MCM9. Significant differences in MCM8/9 expression were not detected between POI and controls; however, we recommend further investigation with a larger sample population.