Faculty Bibliography

The rapid increase of carbapenem resistance in Gram-negative bacteria has resurrected the importance of the polymyxin antibiotics. The recent discovery of plasmid-mediated polymyxin resistance (mcr-1) in carbapenem-resistant Enterobacteriaceae serves as an important indicator that the golden era of antibiotics is under serious threat. We assessed the bacterial killing of 15 different FDA-approved antibiotics alone and in combination with polymyxin B in time-killing experiments against Escherichia coli MCR1_NJ, the first reported isolate in the United States to coharbor mcr-1 and a New Delhi metallo-β-lactamase gene (bla_NDM-5). The most promising regimens were advanced to the hollow-fiber infection model (HFIM), where human pharmacokinetics for polymyxin B, aztreonam, and amikacin were simulated over 240 h. Exposure to polymyxin B monotherapy was accompanied by MCR1_NJ regrowth but not resistance amplification (polymyxin B MIC from 0 to 240 h [MIC_0h to MIC_240h] of 4 mg/liter), whereas amikacin monotherapy caused regrowth and simultaneous resistance amplification (amikacin MIC_0h of 4 mg/liter versus MIC_240h of >64 mg/liter). No MCR1_NJ colonies were observed for any of the aztreonam-containing regimens after 72 h. However, HFIM cartridges for both aztreonam monotherapy and the polymyxin B-plus-aztreonam regimen were remarkably turbid, and the presence of long, filamentous MCR1_NJ cells was evident in scanning electron microscopy, suggestive of a nonreplicating persister (NRP) phenotype. In contrast, the 3-drug combination of polymyxin B, aztreonam, and amikacin provided complete eradication (>8-log₁₀ CFU/ml reduction) with suppression of resistance and prevention of NRP formation. This is the first comprehensive pharmacokinetic/pharmacodynamic study to evaluate triple-drug combinations for polymyxin- and carbapenem-resistant E. coli coproducing MCR-1 and NDM-5 and will aid in the preparation for a so-called "postantibiotic" era.IMPORTANCE A global health crisis may be on the horizon, as the golden era of antibiotics is under serious threat. We recently reported the first case in the United States of a highly resistant, Escherichia coli so-called "superbug" (MCR1_NJ), coharboring two of the most worrying antibiotic resistance genes, encoding mobile colistin resistance (mcr-1) and a New Delhi metallo-β-lactamase (bla_NDM-5). Worryingly, the medical community is vulnerable to this emerging bacterial threat because optimal treatment strategies are undefined. Here, we report the activity of an optimized combination using simulated human doses of commercially available antibiotics against MCR1_NJ. A unique triple combination involving a cocktail of polymyxin B, aztreonam, and amikacin eradicated the MCR-1- and NDM-5-producing E. coli Each antimicrobial agent administered as monotherapy or in double combinations failed to eradicate MCR1_NJ at a high inoculum. To our knowledge, this is the first study to propose 3-drug therapeutic solutions against superbugs coharboring mcr-1 and bla_NDM, seeking to prepare clinicians for future occurrences of these pathogens.

BACKGROUND:The etiology of pre-eclampsia (PE) is not yet fully understood, though current literature indicates an upregulation of inflammatory mediators produced by the placenta as a potential causal mechanism. Vitamin D is known to have anti-inflammatory properties and there is evidence of an inverse relationship between dietary calcium intake and the incidence of PE. Evidence of the role of vitamin D status and supplementation in the etiology and prevention of PE is reviewed in this article along with identification of research gaps to inform future studies. METHODS:We conducted a structured literature search using MEDLINE electronic databases to identify published studies until February 2015. These sources were retrieved, collected, indexed, and assessed for availability of pregnancy-related data on PE and vitamin D. RESULTS:Several case-control studies and cross-sectional studies have shown an association between vitamin D status and PE, although evidence has been inconsistent. Clinical trials to date have been unable to show an independent effect of vitamin D supplementation in preventing PE. CONCLUSIONS:The included clinical trials do not show an independent effect of vitamin D supplementation in preventing PE; however, issues with dose, timing, and duration of supplementation have not been completely addressed.

We describe a case of a 36-year-old man with a history of chronic hepatitis C who presented with abdominal pain 3 days after undergoing a percutaneous ultrasound-guided liver biopsy. Initial investigations revealed a venobiliary fistula with haemobilia and obstructive jaundice with direct bilirubin peaking at 9.2 mg/dL. He underwent an endoscopic retrograde cholangiopancreatography with sphincterotomy and stent placement, bilirubin decreased to 3.7 mg/dL, and the patient was discharged. The patient returned with recurrent abdominal pain and upper gastrointestinal bleeding with haemoglobin of 8.6 g/dL, requiring multiple transfusions. He underwent transcatheter arterial embolisation but continued bleeding. Radiofrequency ablation was pursued and was able to achieve haemostasis. The patient was discharged. The patient returned again with a fever of 39.2 degrees C and was found to have a large right hepatic lobe abscess. The patient underwent abscess drainage with drain placement and was treated with antibiotics for 6 weeks. He followed up in the clinic with resolution of symptoms and infection.

Objectives:KPC-producing Klebsiella pneumoniae are an emerging public health problem around the globe. We defined the combinatorial pharmacodynamics and ability to suppress resistance of two 'old' antibiotics, fosfomycin and colistin, in time-kill experiments and hollow-fibre infection models (HFIM). Methods:Two KPC-2-producing K. pneumoniae isolates were used: one susceptible to both colistin and fosfomycin (KPC 9A: MIC colistin 0.25 mg/L and MIC fosfomycin ≤8 mg/L) and the other resistant to colistin and susceptible to fosfomycin (KPC 5A: MIC colistin 64 mg/L and MIC fosfomycin 32 mg/L). Time-kill experiments assessed an array of colistin and fosfomycin concentrations against both isolates. Colistin and fosfomycin pharmacokinetics from critically ill patients were simulated in the HFIM to define the pharmacodynamic activity of humanized regimens over 5 days against KPC 9A. Results:In time-kill experiments, synergy was demonstrated for all colistin/fosfomycin combinations containing >8 mg/L fosfomycin against the double-susceptible KPC strain, 9A. Synergy versus KPC strain 5A was only achieved at the highest concentrations of colistin (4 mg/L) and fosfomycin (512 mg/L) at 48 h. In the HFIM, colistin or fosfomycin monotherapies resulted in rapid proliferation of resistant subpopulations; KPC 9A regrew by 24 h. In contrast to the monotherapies, the colistin/fosfomycin combination resulted in a rapid 6.15 log 10  cfu/mL reduction of KPC 9A by 6 h and complete suppression of resistant subpopulations until 120 h. Conclusions:Colistin and fosfomycin may represent an important treatment option for KPC-producing K. pneumoniae otherwise resistant to traditional antibiotics.

OBJECTIVE: This study compared health care access, utilization, and functional indicators among adults with and without serious psychological distress (SPD) in the years surrounding implementation of the Patient Portable and Affordable Care Act (ACA). METHODS: Adults ages 18 to 64 from the 2006-2014 National Health Interview Survey (N=207, 853) were examined on 11 access, utilization, and functional indicators: health insurance coverage (health coverage), insufficient money for medications, delay in health care (delay in care), insufficient money for health care, visiting a doctor ten or more times in the past 12 months, change in place of health care, change in place of health care due to insurance, limitations in ability to work, limitations in activities of daily living (ADLs), insufficient money for mental health care, and having seen a mental health care provider. RESULTS: Multivariate models that were adjusted for health coverage and sociodemographic characteristics indicated that compared with adults without SPD, adults with SPD had greater odds of lacking money for medications (AOR=10.0) and health care (AOR=3.1), experiencing delays in care (AOR=2.7), visiting a doctor ten or more times in the past 12 months (AOR=3.2), changing usual place of health care (AOR=1.5), changing usual place of health care because of insurance (AOR=1.5), and experiencing limitations in ADLs (AOR=3.6) and ability to work (AOR=1.8). The proportions of adults with SPD who lacked health coverage and money to buy prescriptions increased during the study period. Although this trend reversed in 2014, the proportion with SPD experiencing barriers remained above 2006 levels. CONCLUSIONS: Health care patterns among adults with SPD require greater attention.

OBJECTIVES:Classify and describe the policy approaches used by countries to regulate e-cigarettes. METHODS:National policies regulating e-cigarettes were identified by (1) conducting web searches on Ministry of Health websites, and (2) broad web searches. The mechanisms used to regulate e-cigarettes were classified as new/amended laws, or existing laws. The policy domains identified include restrictions or prohibitions on product: sale, manufacturing, importation, distribution, use, product design including e-liquid ingredients, advertising/promotion/sponsorship, trademarks, and regulation requiring: taxation, health warning labels and child-safety standards. The classification of the policy was reviewed by a country expert. RESULTS:The search identified 68 countries that regulate e-cigarettes: 22 countries regulate e-cigarettes using existing regulations; 25 countries enacted new policies to regulate e-cigarettes; 7 countries made amendments to existing legislation; 14 countries use a combination of new/amended and existing regulation. Common policies include a minimum-age-of-purchase, indoor-use (vape-free public places) bans and marketing restrictions. Few countries are applying a tax to e-cigarettes. CONCLUSIONS:A range of regulatory approaches are being applied to e-cigarettes globally; many countries regulate e-cigarettes using legislation not written for e-cigarettes.

The treatment of hormone hypersecretory syndromes caused by neuroendocrine tumors (NETs) can be a major challenge. NETs originating from the small intestine often secrete serotonin causing flushing, diarrhea and valve fibrosis, leading to dehydration or heart failure in severe cases. NETs from the pancreas can secrete a wider variety of hormones, like insulin, glucagon and gastrin leading to distinct clinical syndromes. Historically mortality in patients with functioning NETs was high due to the complications caused by the hypersecretion of hormones. This has been reduced with several drugs: proton-pump inhibitors decrease acid secretion caused by gastrinomas. Somatostatin analogs can inhibit the secretion of multiple hormones and these are now the cornerstone for treating patients with a gastroenteropancreatic NET. However, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs and everolimus can also decrease symptoms of hypersecretion and increase progression-free survival. Several factors affect the survival in patients with a functioning NET. Complications of hypersecretion negatively impact survival; however, secretion of hormones is also often a sign of a well-differentiated NET and due to the symptoms, functioning NETs can be detected in an earlier stage suggesting a positive effect on prognosis. The effect on survival is also dependent on the type of hormone being secreted. This review aims to study the effect of hormone secretion on the prognosis of NETs with the contemporary treatments options available today.

Background: Although liver cancer has the second-highest mortality rate among cancers internationally, accurate and scalable assays for the early detection and longitudinal monitoring of hepatocellular carcinoma are lacking. Circulating tumor cells are released from invasive cancers into the blood stream, but the difficulty inherent in isolating, identifying, and characterizing these ultra-rare cells has precluded their widespread implementation as a biomarker. By combining a high-throughput microfluidic negative depletion CTC isolation strategy with the absolute quantification of lineage-specific RNAs, we report the highly specific detection of hepatocellular carcinoma CTCs from patient blood draws. Methods: Blood draws from 48 hepatocellular carcinoma patients, 31 chronic liver disease patients, 25 healthy donors, and 44 patients with primary cancers other than hepatocellular carcinoma were processed through the microfluidic device (CTC-iChip). RNA was extracted, whole-transcriptome amplified, and quantified using droplet digital PCR. Transcript counts were used to fit a logistic regression model to integrate distinct transcript levels into a single CTC-score. The technical feasibility of utilizing RNA sequencing for identification of novel CTC transcripts of interest was also demonstrated with a liver cancer cell line spike-in study. Results: 9 of the 16 untreated HCC patients were successfully detected, while only 1/31 chronic liver disease patients were incorrectly classified. HCC patients undergoing treatment showed a significant decrease in their CTC-score; only 9/32 patients actively receiving treatment were positive. The CTC-score was not correlated with the HCC serum biomarker alpha-fetoprotein, and combining these two orthogonal measures led to estimated positive and negative predictive values of 80% and 86%, respectively, in a high-risk cohort. RNAseq analysis of cell line spike-in data revealed the potential of RNA sequencing for uncovering novel transcripts of interest. Conclusion: Coupling microfluidic depletion with droplet digital PCR allows for the highly specific detection of hepatocellular carcinoma. The CTC-score generated from these data tracks with clinical intervention and is orthogonal to the existing biomarker AFP; combining these two assays has the potential to provide superior detection compared to either individual approach

PURPOSE: Patient education is critical in ensuring patient compliance and good health outcomes. Fellows must be able to effectively communicate with their patients, delivering enough information for the patient to understand their medical problem and maximize patient compliance. We created an objective structured clinical examination (OSCE) with four liver disease cases to assess fellows' knowledge and ability to inform standardized patients about their clinical condition. METHODS: We developed four cases highlighting different aspects of liver disease and created a four station OSCE: hepatitis B, acute hepatitis C, new diagnosis of cirrhosis, and an end-stage cirrhotic non transplant candidate. The standardized patient (SP) with hepatitis B was minimizing the fact that she could not read English. The acute hepatitis C SP was a nursing student who is afraid that having hepatitis C might jeopardize her career. The SP with the new diagnosis of alcoholic cirrhosis needed to stop drinking, and the end-stage liver disease patient had to grapple with his advanced directives. Twelve fellows from four GI training programs participated. Our focus was to assess the fellows' knowledge about liver diseases and the ACGME competencies of health literacy, shared decision making, advanced directives and goals of care. The goal for the fellows was to communicate effectively with the SPs, and acknowledge that each patient had an emotionally charged issue to overcome. The SPs used a checklist to rate fellow's performance. Faculty and the SPs observed the cases and provided feedback. The fellows were surveyed on their performance regarding the case. RESULTS: The majority of fellows were able to successfully summarize findings and discuss a plan with the patient in the new diagnosis of cirrhosis (76.92%) and hepatitis C case (100%), but were less successful in the hepatitis B (30.77%) and end-of-life case (41.67%). Overall, a small percentage of fellows reflected that they did a good job (22-33%), except at the end-of-life case (67%). The fellows' greatest challenge was trying to cover a lot of information in a single outpatient visit. CONCLUSION: Caring for patients with liver diseases can be complex and time consuming. The patients and fellows' observations were discordant in several areas: for example. the fellows believed they excelled in the end-of-life case, but the SP thought only a small percentage of fellows were able to successfully summarize and discuss the plan. This discrepancy and others highlight important areas of focus in training programs. OSCEs are important to help the fellows facilitate striking the right balance of information delivery and empathy, and this will lead to better patient education, compliance, rapport, and satisfaction.

The combination of carfilzomib, lenalidomide, and dexamethasone (CRd) has induced deep responses in patients with newly diagnosed multiple myeloma. While vascular endothelial growth factor (VEGF) pathway polymorphisms have been associated with clinical outcomes for antiangiogenesis agents, we explored associations between such polymorphisms and CRd clinical response. The VEGF-1498C>T (rs833061) and VEGFR2 V297I (rs2305948) were associated with CRd response (OR ≤ 0.10, P ≤ 0.009), whereas VEGF-1498C>T and VEGFR2 Q472H (rs1870377) were associated with minimum residual disease negativity (P ≤ 0.023). As these SNPs were not associated with disease parameters (e.g., plasma VEGF, albumin, or beta-2-microglobin concentration), data suggest these SNPs may be markers of CRd response.