Enduring Effects of Paternal Deprivation in California Mice (Peromyscus californicus): Behavioral Dysfunction and Sex-Dependent Alterations in Hippocampal New Cell Survival

Partial funding for Open Access provided by the UMD Libraries' Open Access Publishing Fund.Early-life experiences with caregivers can significantly affect offspring development in human and non-human animals. While much of our knowledge of parent-offspring relationships stem from mother-offspring interactions, increasing evidence suggests interactions with the father are equally as important and can prevent social, behavioral, and neurological impairments that may appear early in life and have enduring consequences in adulthood. In the present study, we utilized the monogamous and biparental California mouse (Peromyscus californicus). California mouse fathers provide extensive offspring care and are essential for offspring survival. Non-sibling virgin male and female mice were randomly assigned to one of two experimental groups following the birth of their first litter: (1) biparental care: mate pairs remained with their offspring until weaning; or (2) paternal deprivation (PD): paternal males were permanently removed from their home cage on postnatal day (PND) 1. We assessed neonatal mortality rates, body weight, survival of adult born cells in the dentate gyrus of the hippocampus, and anxiety-like and passive stress-coping behaviors in male and female young adult offspring. While all biparentally-reared mice survived to weaning, PD resulted in a ~35% reduction in survival of offspring. Despite this reduction in survival to weaning, biparentally-reared and PD mice did not differ in body weight at weaning or into young adulthood. A sex-dependent effect of PD was observed on new cell survival in the dentate gyrus of the hippocampus, such that PD reduced cell survival in female, but not male, mice. While PD did not alter classic measures of anxiety-like behavior during the elevated plus maze task, exploratory behavior was reduced in PD mice. This observation was irrespective of sex. Additionally, PD increased some passive stresscoping behaviors (i.e., percent time spent immobile) during the forced swim task—an effect that was also not sex-dependent. Together, these findings demonstrate that, in a species where paternal care is not only important for offspring survival, PD can also contribute to altered structural and functional neuroplasticity of the hippocampus. The mechanisms contributing to the observed sex-dependent alterations in new cell survival in the dentate gyrus should be further investigated

An analytic approach using candidate gene selection and logic forest to identify gene by environment interactions (G×E) for systemic lupus erythematosus in African Americans

Development and progression of many human diseases, such as systemic lupus erythematosus (SLE), are hypothesized to result from interactions between genetic and environmental factors. Current approaches to identify and evaluate interactions are limited, most often focusing on main effects and two-way interactions. While higher order interactions associated with disease are documented, they are difficult to detect since expanding the search space to all possible interactions of p predictors means evaluating 2p − 1 terms. For example, data with 150 candidate predictors requires considering over 1045 main effects and interactions. In this study, we present an analytical approach involving selection of candidate single nucleotide polymorphisms (SNPs) and environmental and/or clinical factors and use of Logic Forest to identify predictors of disease, including higher order interactions, followed by confirmation of the association between those predictors and interactions identified with disease outcome using logistic regression. We applied this approach to a study investigating whether smoking and/or secondhand smoke exposure interacts with candidate SNPs resulting in elevated risk of SLE. The approach identified both genetic and environmental risk factors, with evidence suggesting potential interactions between exposure to secondhand smoke as a child and genetic variation in the ITGAM gene associated with increased risk of SLE

Trends in Textbook Outcomes over Time: Are Optimal Outcomes Following Complex Gastrointestinal Surgery for Cancer Increasing?

Background: The use of composite measures like "textbook outcome" (TO) may provide a more accurate measure of surgical quality. We sought to determine if TO has improved over time and to characterize the association of achieving a TO with trends in survival among patients undergoing complex gastrointestinal surgery for cancer. Methods: Medicare beneficiaries who underwent pancreas, liver, or colon resection for a cancer diagnosis between 2004 and 2016 were identified using the SEER-Medicare database. Rates of TO (no complication, extended length of stay, 90-day readmission, or 90-day mortality) were assessed over time. Results: Among 94,329 patients, 6765 (7.2%), 1985 (2.1%), and 85,579 (90.7%) patients underwent resection for primary pancreatic, hepatic, or colon cancer, respectively. In total, 53,464 (56.7%) patients achieved a TO; achievement of TO varied by procedure (pancreatectomy: 48.1% vs. hepatectomy: 55.2% vs. colectomy: 57.4%, p < 0.001). The proportion of patients achieving a textbook outcome increased over time for all patients (2004-2007, 53.3% vs. 2008-2011, 56.5% vs. 2012-2016, 60.1%) (5-year increase: OR 1.16 95%CI 1.13-1.18) (p < 0.001). Survival at 1-year following pancreatic, liver, or colon resection for cancer had improved over time among both patients who did and did not achieve a postoperative TO. TO was independently associated with a marked reduction in hazard of death (HR 0.44, 95%CI 0.43-0.45). The association of TO and survival was consistent among patients stratified by procedure. Conclusion: Less than two-thirds of patients undergoing complex gastrointestinal surgery for a malignant indication achieved a TO. The likelihood of achieving a TO increased over time and was associated with improved survival

Impact of skilled nursing facility quality on postoperative outcomes after pancreatic surgery

Background: Data on skilled nursing facility utilization among patients undergoing pancreatic surgery remain scarce. We sought to define the incidence of utilization of skilled nursing facilities and determine the impact of skilled nursing facility quality markers on postoperative outcomes among patients who underwent pancreatic surgery. Methods: Medicare Standard Analytic Files were used to identify patients who underwent pancreatic resection during 2013\u20132015. Nursing Home Compare datasets were used to examine the influence of skilled nursing facility quality as estimated by quality markers (Medicare star ratings) on postoperative outcomes. Results: Among 13,018 patients who underwent pancreatectomy, 2,247 (17.3%) were discharged to a skilled nursing facility. Compared with patients discharged home, patients discharged to a skilled nursing facility were older (median age: 72 [interquartile range 68\u201376] vs 76 [interquartile range 71\u201380]), more likely female (44.4% vs 56.8%), and had greater Charlson comorbidity index scores (median score: 3 [interquartile range 2\u20138] vs 4 [interquartile range 2\u20138]) (all P &lt; .001). Most patients were discharged to an above-average skilled nursing facility (N = 1,463, 65.1%), and a lesser subset was discharged to a skilled nursing facility with a below-average (N = 490, 21.8%) or average (N = 294, 13.1%) star rating. The 30-day hospital readmission was greatest among patients discharged to a below-average skilled nursing facility (below average N = 217, 44.3%; average N = 110, 37.4%; above average N = 517, 35.3%; P = .002). On multivariate analysis, patients discharged to below-average skilled nursing facilities remained 64% more likely to be readmitted within 30 days (OR 1.64, 1.29\u20132.02, P &lt; .001). In contrast, 30-day mortality was comparable across the skilled nursing facility star rating categories (P = .08). Conclusion: Roughly 1 in 6 patients undergoing pancreatic surgery were discharged to a skilled nursing facility. Patients discharged to a below-average skilled nursing facility were more likely to be readmitted compared with patients discharged to an above-average skilled nursing facility

Predictors and outcomes of nonroutine discharge after hepatopancreatic surgery

Background: Data on predictors of nonroutine discharge among patients undergoing hepatopancreatic surgery remain poorly defined. We sought to define factors associated with nonroutine discharge to home with home health care or to a skilled nursing facility or intermediate care facility and determine the impact of discharge destination on outcomes after hepatopancreatic surgery. Methods: The Nationwide Readmissions Database was queried for individuals who underwent hepatopancreatic surgeries 2010\u20132014 and were discharged home with home health care or to a skilled nursing facility/intermediate care facility. Results: A total of 42,189 patients underwent hepatopancreatic surgery. Of those, 2,825 (6.70%) were discharged to a skilled nursing facility or intermediate care facility, whereas 10,925 (25.9%) were discharged with home health care. A majority of patients underwent major hepatectomy (N = 14,516, 34.4%) or minor pancreatectomy (N = 13,824, 32.8%). Compared with patients discharged home, patients discharged to a skilled nursing facility or intermediate care facility were older (median age: 60 years, interquartile range: 50\u201368 vs 73, 67\u201379) and had more comorbidities (median score: 3, interquartile range: 1\u20138 vs 4, interquartile range: 2\u20138; P &lt; .001). Type of operative procedure was not associated with discharge to a skilled nursing facility versus with home health care. Rather, patients with extreme loss of function, based on preoperative assessment, had 2.76 times higher odds of discharge to a skilled nursing facility or intermediate care facility versus with home health care (odds ratio 2.76, 95% confidence interval 1.98\u20133.85). Similarly, older (odds ratio 1.06, 95% confidence interval 1.06\u20131.07) and female patients (odds ratio 1.37, 95% confidence interval 1.25\u20131.51) were more likely to be discharged to a skilled nursing facility or intermediate care facility versus with home health care. Conclusion: One in four patients undergoing hepatopancreatic surgery were readmitted within 90 days of surgery. Age, severity of comorbidities, and perioperative course, including incidence of complications, were associated with nonroutine discharge

Machine Learning Approach to Stratifying Prognosis Relative to Tumor Burden after Resection of Colorectal Liver Metastases: An International Cohort Analysis

BACKGROUND: Assessing overall tumor burden on the basis of tumor number and size may assist in prognostic stratification of patients after resection of colorectal liver metastases (CRLM). We sought to define the prognostic accuracy of tumor burden by using machine learning (ML) algorithms compared with other commonly used prognostic scoring systems.STUDY DESIGN: Patients who underwent hepatectomy for CRLM between 2001 and 2018 were identified from a multi-institutional database and split into training and validation cohorts. ML was used to define tumor burden (ML-TB) based on CRLM tumor number and size thresholds associated with 5-year overall survival. Prognostic ability of ML-TB was compared with the Fong and Genetic and Morphological Evaluation scores using Cohen's d.RESULTS: Among 1,344 patients who underwent resection of CRLM, median tumor number (2, interquartile range 1 to 3) and size (3 cm, interquartile range 2.0 to 5.0) were comparable in the training (n = 672) vs validation (n = 672) cohorts; patient age (training 60.8 vs validation 61.0) and preoperative CEA (training 10.2 ng/mL vs validation 8.3 ng/mL) was also similar (p &gt; 0.05). ML empirically derived optimal cutoff thresholds for number of lesions (3) and size of the largest lesion (1.3 cm) in the training cohort, which were then used to categorize patients in the validation cohort into 3 prognostic groups. Patients with low, average, or high ML-TB had markedly different 5-year overall survival (51.6%, 40.9%, and 23.1%, respectively; p &lt; 0.001). ML-TB was more effective at stratifying patients relative to 5-year overall survival (low vs high ML-TB, d = 2.73) vs the Fong clinical (d = 1.61) or Genetic and Morphological Evaluation (d = 0.84) scores.CONCLUSIONS: Using a large international cohort, ML was able to stratify patients into 3 distinct prognostic categories based on overall tumor burden. ML-TB was noted to be superior to other CRLM prognostic scoring systems. (c) 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved

Resection of Colorectal Liver Metastasis: Prognostic Impact of Tumor Burden vs KRAS Mutational Status

BACKGROUND: The prognostic impact of colorectal liver metastasis (CRLM) morphologic characteristics relative to KRAS mutational status after hepatic resection remains ill defined.STUDY DESIGN: Patients undergoing hepatectomy for CRLM between 2001 and 2018 were identified using an international multi-institutional database. Tumor burden score (TBS) was defined as distance from origin on a Cartesian plane that incorporated maximum tumor size (x-axis) and number of lesions (y-axis). Impact of TBS on overall survival (OS) relative to KRAS status (wild type [wtKRAS] vs mutated [mutKRAS]) was assessed.RESULTS: Among 1,361 patients, the median number of metastatic lesions was 2 (interquartile range [IQR] 1-3), and median size of the largest metastatic lesion was 3.0 cm (IQR 2.0-5.0 cm), resulting in a median TBS of 4.1 (IQR 2.8-6.1); KRAS status was wtKRAS (n = 420, 30.9%), mutKRAS (n = 251, 18.4%), and unknown (n = 690, 50.7%). Overall median and 5-year OS were 49.5 months (95% CI 45.2e53.8) and 43.2%, respectively. In examining the entire cohort, TBS was associated with long-term prognosis (5-year OS, low TBS: 49.4% vs high TBS: 36.7%), as was KRAS mutational status (5-year OS, wtKRAS: 48.2% vs mutKRAS: 31.1%; unknown KRAS: 44.0%)(both p &lt; 0.01). Among patients with wtKRAS tumors, TBS was strongly associated with improved OS (5-year OS, low TBS: 59.1% vs high TBS: 38.4%, p = 0.002); however, TBS failed to discriminate long-term prognosis among patients with mutKRAS tumors (5-year OS, low TBS: 37.4% vs high TBS: 26.7%, p = 0.19). In fact, patients with high TBS/wtKRAS CRLM had comparable outcomes to patients with low TBS/mut KRAS tumors (5-year OS, 38.4% vs 37.4%, respectively; p = 0.59). On multivariable analysis, while TBS was associated with OS among patients with wtKRAS CRLM (hazard ratio 1.43, 95%CI 1.02-2.00; p = 0.03), TBS was not an independent predictor of survival among patients with mutKRAS CRLM (HR 1.36, 95%CI 0.92-1.99; p = 0.12).CONCLUSIONS: While TBS was associated with survival among patients with wtKRAS tumors, CRLM morphology was not predictive of long-term outcomes among patients with mutKRAS CRLM. (C) 2020 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved