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Cocaine use disorder (CUD) is a significant public health issue. Behavioral interventions such as contingency management (CM) have been demonstrated to be highly effective in promoting cocaine abstinence. However, identifying individual characteristics associated with cocaine relapse may help improve treatment outcomes. Cocaine demand is a behavioral economic measure that shares a scientific foundation with CM. In the current study, we assessed baseline cocaine demand using a hypothetical cocaine purchasing task. Participants (N = 58) consisted of treatment-seeking individuals with CUD. All participants received 1 month of CM treatment for cocaine abstinence, and treatment responders were defined as presenting 6 consecutive cocaine negative urine samples from thrice weekly clinic visits. Demand data were well described by the exponentiated demand model. Indices of demand (intensity of demand [Q₀], elasticity [α]) were significantly associated with recent (last 30 days) cocaine use. Importantly, linear regression revealed that CM treatment nonresponders presented significantly higher Q₀ (p = .025). Subsequent quantile regression analyses examining the relationship between CM treatment response and Q₀ revealed statistically reliable effects of being a nonresponder across 3 of the lower percentiles (i.e., 15, 25, and 30). Overall, these findings provide further support for the utility of exponentiated demand model. To our knowledge, this is the first study to demonstrate an association between baseline demand and contingency management response and systematically extend the findings of prior demand research to a novel drug class, cocaine. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

The purpose of this article is to provide an updated review of the definition, prevalence, causes, and clinical management of malnutrition in inflammatory bowel disease (IBD). Prevalence of malnutrition in IBD is estimated to be between 6.1% and 69.7% depending on the definition used, the type of IBD, the clinical setting, and whether the IBD is active or in remission. Whereas older definitions of malnutrition have been found to be correlated with mortality and length of hospital stay, the more recent European Society for Clinical Nutrition and Metabolism (ESPEN) 2015 and the Global Leadership Initiative on Malnutrition (GLIM) definitions provide significantly different prevalence estimates of malnutrition when applied to the same patient population, and further work is needed to validate these two definitions against clinical outcomes. In patients with IBD with identified malnutrition, oral nutrition supplementation, enteral nutrition, or parenteral nutrition should be started. In malnourished patients with Crohn's disease undergoing surgery, preoperative enteral nutrition has been demonstrated to reduce the rate of postoperative complications. Overall, patients with IBD are at significant risk for malnutrition and should be screened for malnutrition by using a validated screening tool. The management of malnutrition in IBD is complex, and studies are often limited in their size or their ability to demonstrate an improvement in clinical outcomes based on specific nutrition-related interventions. Future studies particularly regarding the validation of new screening tools and perioperative management of malnutrition may provide insight into the standardization of diagnosis and management of malnutrition in IBD.

Background Nonalcoholic fatty liver disease (NAFLD) is a significant public health burden, with up to 30% of the US population affected. The prevalence of NAFLD among inflammatory bowel disease (IBD) patients is unknown. Understanding risk factors for NAFLD in IBD patients has implications in the treatment of these patients. The purpose of this study was to determine the prevalence of NAFLD among IBD patients and to identify risk factors associated with NAFLD development. Methods Embase and MEDLINE databases were searched using Medical Subject Headlines to find studies that assessed the prevalence of NAFLD among IBD patients. Twenty-seven English-language research abstracts/articles were identified between January 2005 and April 2018. Meta-analyses were performed using random-effects models. Prevalence of NAFLD among IBD patients was compared with prevalence of NAFLD in the general population. Results Based on data pooled from all 27 studies, the prevalence of NAFLD among IBD patients was 32% (95% CI, 24%–40%) with substantial heterogeneity (I2 = 98%). The prevalence of NAFLD among IBD patients (32%) is statistically significantly higher than the prevalence of NAFLD in the general population (25.2%; P < 0.001). Factors associated with the development of NAFLD among IBD patients included age, BMI, diabetes, IBD duration, and prior history of bowel resection. Conclusions There is a higher prevalence of NAFLD among IBD patients compared with the general population. Previous treatment regimens may be a risk factor for the development of NAFLD. Future studies are needed to further clarify these risk factors and determine screening recommendations.

Alopecia areata (AA) is a type of immune-mediated hair loss and is reported in patients with inflammatory bowel disease. This suggests that there might be a shared molecular pathway in the pathogenesis of AA and inflammatory bowel disease. In addition, tumor necrosis factor-alpha antagonists are also rarely associated with new-onset AA. We present a patient with Crohn's disease treated with adalimumab who developed AA that rapidly progressed to alopecia totalis and universalis. We describe the use of tofacitinib, a Janus kinase 1/3 inhibitor, to not only successfully treat the AA but also maintain her Crohn's disease.

Previous reviews have examined the use of theoretically supported combinations of drugs for the treatment of alcohol use disorder. This review seeks to examine the strengths and limitations of current clinical evidence for the use of combined pharmacological interventions intended to treat alcohol use disorder.The objective of this review was to identify combinations of pharmacological treatments for alcohol use disorder, and assess the strength of clinical evidence for these treatments.We conducted searches using PubMed, EMBASENine hundred and eighty-four publications were initially screened for inclusion after duplicates were removed. The search identified 16 publications evaluating drug combinations for the treatment of alcohol use disorder. The majority of published trials included naltrexone combined with one of the following: gabapentin, ondansetron, acamprosate, gamma-hydroxybutyrate, sertraline, quetiapine, or escitalopram plus gamma-hydroxybutyrate. Other combinations included 5-hydroxytryptophan with carbidopa/levodopa, gamma-hydroxybutyrate with disulfiram, acamprosate with disulfiram, and mirtazapine with quetiapine. Interpretation of results across studies was limited by low statistical power, and heterogeneity of drug combinations and outcome measures. Drug combination effect sizes were comparable to those observed in single-agent trials.No significant benefit for the use of combinations over single agents was observed. However, benefit may be observed when combined pharmacological interventions address specific symptoms of alcohol use disorder known to be influenced by combination components, or when combinations are used in specific subpopulations in which combination components demonstrate benefit.

Background Optimizing alcohol withdrawal treatment is a clinical priority, yet it is difficult to predict on presentation which patients would require benzodiazepines or in which patients withdrawal would be complicated. Detoxification studies typically exclude patients with medical comorbidities, psychiatric comorbidities, or multiple substance use disorders; therefore, it is difficult to generalize their conclusions to all types of patients. Objective This retrospective study with no exclusion criteria identifies the risk factors for complicated withdrawal. Methods A retrospective medical record review of 47 veterans admitted to a tertiary veteran's medical hospital for alcohol detoxification. Demographics, blood alcohol level, Charlson Comorbidity Index, drinks per drinking day, pre–psychiatry consult benzodiazepine administration, and length of stay were compared for veterans with complications vs those without. Results Overall, 21% patients experienced significant complications during their medically-managed detoxification, including behavioral disruptions and delirium tremens. Of the patients, 79% were initially assessed using the Clinical Institute Withdrawal Assessment for Alcohol-Revised scale, and 34% continued to be monitored with the Clinical Institute Withdrawal Assessment for Alcohol-Revised scale during their hospital stay. A Clinical Institute Withdrawal Assessment for Alcohol-Revised scale score ≥15 at presentation was significantly associated with increased odds of complications ( p = 0.005). There was a trend toward significance of association of complications with tachycardia, history of delirium tremens, and benzodiazepines being administered before psychiatric consultation. The groups did not significantly differ with respect to age, admission blood alcohol level, Charlson Comorbidity Index, comorbid recent substance abuse, or length of stay. Conclusion Clinical Institute Withdrawal Assessment for Alcohol-Revised scale scores ≥15 at presentation was significantly associated with increased odds of complicated alcohol withdrawal (odds ratio=28, 95% CI: 2.5–317.6, p = 0.005), which supports findings from previous studies.

Objectives. To examine the effect of simulated birth injury in an animal model as part of a study on the pathogenesis of stress urinary incontinence (SUI) and the urinary continence mechanism. Methods. A balloon was inflated in the vaginas of rats for 4 hours to simulate prolonged labor. The effect on the continence mechanism was assessed by functional, anatomic, biochemical, and histologic examinations. The functional test consisted of placing chili powder or a clipped whisker into the rat’s nostrils to induce sneezing. Anatomic measurement of the genital hiatus was performed with a caliper. Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) were measured to examine the value of muscle injury in predicting incontinence. c-Fos immunostaining in the spinal cord was used as a marker of nerve injury. These data were then correlated with histopathologic examination of the urethra and pelvic floor tissues. Results. Four weeks after simulated birth injury, SUI was noted in 19 of 48 experimental rats. The genital hiatus was significantly wider in incontinent rats. The serum CPK and LDH levels were markedly elevated, but no difference was noted between the continent and incontinent rats. All experimental rats showed many c-Fos immunostaining neurons in the L6 to S1 spinal cord segments, but none was seen in control rats. Histologic study revealed a marked decrease of ganglion cells in the neural plexuses posterolateral to the vagina in experimental rats. After 4 weeks, muscle necrosis and degeneration, irregular shape and size of muscle fibers, and a change in the type I/II ratio were prominent features in the levator ani. In the urethra, we noted a significant decline in urethral wall musculature (both smooth and striated) in incontinent rats. Conclusions. In this novel rat model, simulated birth injury resulted in SUI in a portion of the animals. Pathologic changes in the urethra, pelvic ganglia, and levator muscles seem to be the contributing factors to SUI.

Deeper understanding the mechanisms by which luminal-type breast cancer develops resistance to endocrine therapy and development of novel strategies to treat these patients requires model systems recapitulate human breast cancer as accurately as possible. An increasing body of work suggests patient derived xenografts (PDX) may represent an informative model for development of novel therapeutics. We therefore established seven xenograft tumor lines from late-stage breast cancer patients with estrogen positive (ER+) disease. To date five ER+ PDX lines have been tested for responses to estradiol treatment in overiectomized NOD/SCID mice. Three showed estradiol independent-growth, one estrogen-stimulated growth and in one estradiol-induced a regression. These patterns mimicked the clinical phenotypes of each patient, tracking survival and responses to serial endocrine treatments. To define new mechanisms for resistance, whole genome DNA sequencing, RNA sequencing and Reverse Phase Protein Assay analysis was conducted. These studies identified an ESR1/YAP1 balanced translocation in a PDX model and tumor of origin showing low levels of ER, paradoxical high level expression form luminal genes and extreme ET resistance. The ESR1 YAP1 fusion maintained the N terminal DNA binding motif of ESR1, but the hormone binding and AF2 motifs were replaced with the C terminal transactivation domain of YAP1. Expression ESR1 YAP1 in ER+ breast cancer models down-regulated ER and induced estrogen independent growth. PDX endocrine phenotypes parallel tumor of origin responses to endocrine therapy and revel novel mechanism for endocrine therapy resistance. Citation Format: Matthew J. Ellis, Shunqiang Li, Dong Shen, Li Ding, Robert Crowder, Jeiya Shao, Rodrigo Goncalves, Yu Tao, Jingqin Luo, Aleix Prat, Wenbin Liu, Ana Maria Gonzalez-Angulo, Shuying Liu, Joshua F. McMichael, Chris Miller, Dave Larson, Robert S. Fulton, Tom Mooney, Jeremy Hoog, Li Lin, Therese Giuntoli, Caroline Bumb, Crystal Cooper, Rebecca Aft, Robert T. Kitchens, Stephen N. Johnson, Chanpheng Phommaly, Megha Shiyam Kavuri, Katherine DeSchryver, Austin Lin, YiYu Dong, Cynthia X. Ma, Timothy Pluard, Michael Naughton, Ron Bose, Rama Suresh, Reida G. McDowell, Loren Michel, Richard Wilson, Shaomeng Wang, Christopher Maher, Gordon B. Mills, Charles Perou, Elaine R. Mardis. Patient-derived xenografts from advanced luminal-type breast cancer: insights into endocrine therapy resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-265. doi:10.1158/1538-7445.AM2013-LB-265

Excluding skin cancers, about 1.5 million new cases of cancer and about 450,000 cancer related deaths occur each year in the United States. The validation and molecular profiling of tumor markers are contributing to new paradigms in cancer research. In this presentation, we will discuss the information that can be obtained by using an Intelligent Single-Cell Optical Profiling Engine (I-SCOPE), consisting of hyperspectral imaging, multiplexed biomarker kits, and bioinformatics tools, to markedly expand the molecular profiling of tumor markers on individual carcinoma cells.Using biomarker antibodies conjugated to particular fluorochromes, we developed a multiplex of 10 different fluorochrome conjugates, one for each different tumor marker plus a nuclear dye. Staining and scanning using the I-SCOPE system showed that it can presently distinguish 10 different fluorochromes in a single pass, resulting in the identification of spatial location and relative intensity of each biomarker being interrogated. By using this system, we analyzed thousands of tumor cells from touch preparations of tumor tissue, circulating tumor cells (CTCs) in pleural fluid and blood, and disseminated tumor cells (DTCs) from bone marrow with 2 multiplex kits for a total of 17 different tumor markers. We have utilized clinically-accepted markers such as estrogen receptor (ER), progesterone receptor (PR), and HER2 in addition to biomarkers undergoing investigation such as B-cell lymphoma 2 (Bcl-2) and urokinase-type plasminogen receptor (uPAR). Furthermore, with the ability to simultaneously image 10 markers, each panel can also contain desired positive and negative controls such as CD45 (positive for white blood cells, negative for CTCs) and cytokeratin (positive for epithelial cells).The results of immunophenotyping of individual tumor cells with 17 different tumor markers indicated that the average expression of each tumor marker in 25 tumor cells was a reproducible representation of the tumor. However, comparison of individual CTCs' expression levels revealed remarkable heterogeneity in primary breast cancer cases.We conclude that hyperspectral microscope imaging together with individual tumor cell analysis represents a major step forward in developing a far more detailed and precise molecular signature of a patient's cancer. Further studies might demonstrate how it can facilitate treatment tailored to the individual patient's tumor, an important objective as new oncology drugs with specific molecular targets become more prevalent. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6002.

SummaryTo characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.