Treatment of Crohn's Disease and Concomitant Alopecia Areata With Tofacitinib.

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.

Nutrition Considerations in Inflammatory Bowel Disease.

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.

Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

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.

Baseline cocaine demand predicts contingency management treatment outcomes for cocaine-use disorder.

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).

Comparison of Outcomes in Medical Therapy vs Surgical Intervention of Esophageal Foreign Bodies.

Objectives (1) Compare efficacy of primary medical therapy vs primary surgical intervention in patients with esophageal foreign bodies (EFBs). (2) Investigate variables that may predict successful outcomes in patients treated for EFBs. Study Design Case series with chart review. Setting Single-institution academic tertiary care medical center. Subjects and Methods Adult patients (older than 18 years) seen at the University of Michigan Emergency Department (ED) over an 8-year period with the diagnosis of EFBs (January 1, 2003, to December 31, 2011; N = 250). Decision was made by ED physicians whether to treat patients with first-line medical therapy vs surgical intervention. Pertinent clinical and demographic data were extracted from medical records and summarized by descriptive statistics. Results First-line treatment with surgical intervention (flexible or rigid esophagoscopy with foreign body removal) was much more likely to lead to resolution of symptoms than medical therapy (glucagon alone or in combination with other medical therapy) (98% vs 28%, P < .0001). When delivered within 12 hours of symptom onset, medical therapy was more likely to be successful (34% resolution vs 12% resolution, P < .01). There was no difference in complication rates for primary medical therapy vs surgical intervention (8% vs 8%). Conclusions Patients with EFBs are a commonly encountered consultation for both otolaryngologists and gastroenterologists. In these patients, first-line surgical intervention is superior to medical therapy and should not be avoided for a trial of medical therapy or concern for higher morbidity. Implementation of these findings has the ability to positively affect treatment patterns, outcomes, and patient quality of life.

Systematic Review of Combined Pharmacotherapy for the Treatment of Alcohol Use Disorder in Patients Without Comorbid Conditions.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: We conducted searches using PubMed, EMBASE® through Ovid® (1974 to present), MEDLINE® through Ovid® (1946 to present), and Psychinfo® through Ovid® (1806 to present). Our primary search included the terms "alcoholism" and "drug therapy, combination". Search results were restricted to human subjects and English language. Search criteria were not restricted based on study design or patient age. Studies were evaluated for randomization, blinding, group similarity, power determination, outcome reporting, and number of patients analyzed. RESULTS: Nine 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. CONCLUSIONS: 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.

Hearing Loss and Otopathology Following Systemic and Intracerebroventricular Delivery of 2-Hydroxypropyl-Beta-Cyclodextrin.

Cyclodextrins are simple yet powerful molecules widely used in medicinal formulations and industry for their ability to stabilize and solubilize guest compounds. However, recent evidence shows that 2-hydroxypropyl-ß-cyclodextrin (HPßCD) causes severe hearing loss in mice, selectively killing outer hair cells (OHC) within 1 week of subcutaneous drug treatment. In the current study, the impact of HPßCD on auditory physiology and pathology was explored further as a function of time and route of administration. When administered subcutaneously or directly into cerebrospinal fluid, single injections of HPßCD caused up to 60 dB threshold shifts and widespread OHC loss in a dose-dependent manner. Combined dosing caused no greater deficit, suggesting a common mode of action. After drug treatment, OHC loss progressed over time, beginning in the base and extending toward the apex, creating a sharp transition between normal and damaged regions of the cochlea. Administration into cerebrospinal fluid caused rapid ototoxicity when compared to subcutaneous delivery. Despite the devastating effect on the cochlea, HPßCD was relatively safe to other peripheral and central organ systems; specifically, it had no notable nephrotoxicity in contrast to other ototoxic compounds like aminoglycosides and platinum-based drugs. As cyclodextrins find expanding medicinal applications, caution should be exercised as these drugs possess a unique, poorly understood, ototoxic mechanism.

Multifunctional bioscaffolds for 3D culture of melanoma cells reveal increased MMP activity and migration with BRAF kinase inhibition.

Matrix metalloproteinases (MMPs) are important for many different types of cancer-related processes, including metastasis. Understanding the functional impact of changes in MMP activity during cancer treatment is an important facet not typically evaluated as part of preclinical research. With MMP activity being a critical component of the metastatic cascade, we designed a 3D hydrogel system to probe whether pharmacological inhibition affected human melanoma cell proteolytic activity; metastatic melanoma is a highly aggressive and drug-resistant form of skin cancer. The relationship between MMP activity and drug treatment is unknown, and therefore we used an in situ fluorogenic MMP sensor peptide to determine how drug treatment affects melanoma cell MMP activity in three dimensions. We encapsulated melanoma cells from varying stages of progression within PEG-based hydrogels to examine the relationship between drug treatment and MMP activity. From these results, a metastatic melanoma cell line (A375) and two inhibitors that inhibit RAF (PLX4032 and sorafenib) were studied further to determine whether changes in MMP activity led to a functional change in cell behavior. A375 cells exhibited increased MMP activity despite an overall decrease in metabolic activity with PLX4032 treatment. The changes in proteolytic activity correlated with increased cell elongation and increased single-cell migration. In contrast, sorafenib did not alter MMP activity or cell motility, showing that the changes induced by PLX4032 were not a universal response to small-molecule inhibition. Therefore, we argue the importance of studying MMP activity with drug treatment and its possible implications for unwanted side effects.

Alcohol Withdrawal Treatment in the Medically Hospitalized Patient: A Pilot Study Assessing Predictors for Medical or Psychiatric Complications.

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.

Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts.

To 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.