Discovery and validation of plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance and diabetes progression or regression among Puerto Rican adults.

AIMS/HYPOTHESIS: Many studies have examined the relationship between plasma metabolites and type 2 diabetes progression, but few have explored saliva and multi-fluid metabolites. METHODS: We used LC/MS to measure plasma (n=1051) and saliva (n=635) metabolites among Puerto Rican adults from the San Juan Overweight Adults Longitudinal Study. We used elastic net regression to identify plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting baseline HOMA-IR in a training set (n=509) and validated these scores in a testing set (n=340). We used multivariable Cox proportional hazards models to estimate HRs for the association of baseline metabolomic scores predicting insulin resistance with incident type 2 diabetes (n=54) and prediabetes (characterised by impaired glucose tolerance, impaired fasting glucose and/or high HbA1c) (n=130) at 3 years, along with regression from prediabetes to normoglycaemia (n=122), adjusting for traditional diabetes-related risk factors. RESULTS: Plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance included highly weighted metabolites from fructose, tyrosine, lipid and amino acid metabolism. Each SD increase in the plasma (HR 1.99 [95% CI 1.18, 3.38]; p=0.01) and multi-fluid (1.80 [1.06, 3.07]; p=0.03) metabolomic scores was associated with higher risk of type 2 diabetes. The saliva metabolomic score was associated with incident prediabetes (1.48 [1.17, 1.86]; p=0.001). All three metabolomic scores were significantly associated with lower likelihood of regressing from prediabetes to normoglycaemia in models adjusting for adiposity (HRs 0.72 for plasma, 0.78 for saliva and 0.72 for multi-fluid), but associations were attenuated when adjusting for lipid and glycaemic measures. CONCLUSIONS/INTERPRETATION: The plasma metabolomic score predicting insulin resistance was more strongly associated with incident type 2 diabetes than the saliva metabolomic score. Only the saliva metabolomic score was associated with incident prediabetes.

Methicillin-Resistant Staphylococcus aureus-Associated Diarrhea in a Critically Ill Burn Patient.

Described in surgical patients after antibiotic use in the 1950s and 1960s, Staphylococcus aureus (S. aureus) enterocolitis is a rare form of nosocomial diarrhea. However, S. aureus is not routinely tested like Clostridium difficile (C. difficile). We report a case of methicillin-resistant S. aureus (MRSA) enterocolitis found on stool culture in a 22-week pregnant female with a previously negative nasal MRSA culture, and a total burn surface area greater than 60%. She also developed necrotizing MRSA pneumonia and bacteremia. After starting broad-spectrum antibiotic for the necrotizing pneumonia with subsequent acute respiratory distress syndrome, the patient exhibited large voluminous diarrhea that tested positive for MRSA and negative for C. difficile in the stool culture. Similar to other reports of high-volume diarrhea, the diarrhea resolved quickly with enteral vancomycin. S. aureus should be considered along with C. difficile during the workup of nosocomial diarrhea, especially with exposure to broad-spectrum antibiotics in the critically ill patient.

Lessons Learned From Two Survivors of Greater Than 90% TBSA Full-Thickness Burn Injuries Using NovoSorb Biodegradable Temporizing Matrix™ and Autologous Skin Cell Suspension, RECELL™: A Case Series.

Since autologous split-thickness skin grafts are scarce and lab skin growth requires a significant amount of time, there are limited available treatment approaches for patients with full-thickness burns greater than 90% TBSA. Additionally, to achieve the primary goal of skin coverage and resuscitation, there must exist a balance between fluid loss and metabolic derangement. Allografts and xenografts have traditionally been used early in the process to achieve these goals. Currently, novel approaches to treatment consider the additional use of synthetic dermal substitutes and autologous skin cell suspension to improve outcomes. This case series describes the treatment course of patients with greater than 90% TBSA full-thickness burn injuries using a staged, multifaceted approach of using NovoSorb Biodegradable Temporizing Matrix™ as the primary dermal substitute in conjunction with a RECELL™ Autologous Cell Suspensions Device applied with autograft and allograft to achieve improved resuscitation, limiting fluid loss, and finally skin coverage. Allograft and NovoSorb Biodegradable Temporizing Matrix™ were used early to cover excised burns, resulting in improved metabolic control by limiting the systemic inflammatory response syndrome and fluid loss. Both patients survived using this approach.

Alcohol, tobacco and coffee consumption and liver disease severity among individuals with Chronic Hepatitis B infection in North America.

INTRODUCTION AND OBJECTIVES: The prevalence of alcohol, tobacco, and coffee use and association with liver health among North Americans with Chronic Hepatitis B (CHB) infection has not been well described. MATERIALS AND METHODS: The Hepatitis B Research Network includes an observational study of untreated CHB adults enrolled at 21 sites in the United States and Canada. Alcohol use was categorized as none, moderate, and at-risk based on the definition from the National Institute on Alcohol Abuse and Alcoholism; tobacco use as never, current and former; coffee use as none, 1-2 cups/day, and ≥3 cups/day. Linear regression and linear mixed models were used to associate lifestyle behaviors with ALT and FIB-4 values. RESULTS: 1330 participants met eligibility: 53% males, 71% Asian and the median age was 42 years (IQR: 34-52). Median ALT was 33U/L (IQR: 22-50), 37% had HBV DNA <103IU/mL, 71% were HBeAg negative, and 65% had a FIB-4 <1.45. At baseline, 8% of participants were at-risk alcohol drinkers, 11% were current smokers and 92% drank <3 cups of coffee/day. Current tobacco and 'at-risk' alcohol use, were significantly associated with elevated ALT levels in univariable analyses, however, these associations were not statistically significant when controlling for sociodemographic and HBV characteristics. CONCLUSIONS: In this large diverse cohort of untreated CHB participants, at-risk alcohol use, current tobacco use and limited coffee consumption did not have an association with high ALT and FIB-4 values. In contrast, significant associations were found between the frequency of these lifestyle behaviors and sociodemographic factors.

Wait Time for Curative Intent Radio Frequency Ablation is Associated with Increased Mortality in Patients with Early Stage Hepatocellular Carcinoma.

INTRODUCTION: Radiofrequency ablation (RFA) is a recommended curative intent treatment option for patients with early stage hepatocellular carcinoma (HCC). We investigated if wait times for RFA were associated with residual tumor, tumor recurrence, need for liver transplantation, or death. MATERIAL AND METHODS: We conducted a retrospective study of patients diagnosed with HCC between January 2010 and December 2013 presenting to University Health Network (UHN) in Toronto, Canada. All patients receiving curative intent RFA for HCC were included. Multivariable Cox regression was used to determine if wait times were associated with clinical outcomes. RESULTS: 219 patients were included in the study. 72.6% were male and the median age was 62.7 years (IQR 55.6-71). Median tumor size at diagnosis was 21.5 mm (IQR 17-26); median MELD was 8.7 (IQR 7.2-11.4) and 57.1% were Barcelona stage 0. The cause of liver disease was viral hepatitis in 73.5% (Hepatitis B and C). The median time from HCC diagnosis to RFA treatment was 96 days (IQR 75-139). In multivariate analysis, wait time was not associated with requiring liver transplant or tumor recurrence, however, each incremental 30-day wait time was associated with an increased risk of residual tumor (HR = 1.09; 95% CI 1.01-1.19; p = 0.033) as well as death (HR = 1.23; 95% CI 1.11-1.36; p ≤ 0.001). CONCLUSION: Incremental 30-day wait times are associated with a 9% increased risk of residual tumor and a 23% increased risk of death. We have identified system gaps where quality improvement measures can be implemented to reduce wait times and allocate resources for future RFA treatment, which may improve both quality and efficiency of HCC care.

Knowledge and use of prevention measures for chikungunya virus among visitors - Virgin Islands National Park, 2015.

BACKGROUND: In June 2014, the mosquito-borne chikungunya virus (CHIKV) emerged in the U.S. Virgin Islands (USVI), a location where tourists comprise the majority of the population during peak season (January-April). Limited information is available concerning visitors' CHIKV awareness and prevention measures. METHODS: We surveyed a convenience sample of Virgin Islands National Park visitors aged ≥18 years. Respondents completed a questionnaire assessing CHIKV knowledge, attitudes, and practices; health information-seeking practices; and demographics. RESULTS: Of 783 persons contacted, 443 (57%) completed the survey. Fewer than half (208/441 [47%]) were aware of CHIKV. During trip preparation, 28% of respondents (126/443) investigated USVI-specific health concerns. Compared with persons unaware of CHIKV, CHIKV-aware persons were more likely to apply insect repellent (134/207 [65%] versus 111/231 [48%]; p < 0.001), wear long-sleeves and long pants (84/203 [41%] versus 57/227 [25%]; p < 0.001), and wear insect repellent-treated clothing (36/204 [18%] versus 22/227 [10%]; p = 0.02). CONCLUSIONS: The majority of visitors surveyed did not research destination-related health concerns and were unaware of CHIKV. However, CHIKV awareness was associated with using multiple prevention measures to reduce disease risk. These findings underscore the importance of providing tourists with disease education upon destination arrival.

Faldaprevir, pegylated interferon, and ribavirin for treatment-naïve HCV genotype-1: pooled analysis of two phase 3 trials.

INTRODUCTION & AIM: Faldaprevir is a potent once-daily (q.d.) hepatitis C virus (HCV) NS3/4A protease inhibitor. The STARTVerso1 and STARTVerso2 phase 3 studies evaluated faldaprevir plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in treatment-naïve patients with chronic HCV genotype-1 infection. MATERIAL AND METHODS: Patients were randomized 1:2:2 to receive placebo, faldaprevir 120 mg q.d. (12 or 24 weeks) or faldaprevir 240 mg q.d. (12 weeks) all with PegIFN/RBV (24-48 weeks). Faldaprevir 120 mg for 12 weeks only (STARTVerso1 only) required early treatment success (ETS, HCV RNA < 25 IU/mL at week 4 and undetected at week 8). All faldaprevir-treated patients with ETS stopped PegIFN/RBV at week 24. Primary endpoint: sustained virologic response 12 weeks post-treatment (SVR12). RESULTS: SVR12 rates were significantly higher for patients treated with faldaprevir 120 or 240 mg (72% and 73%, respectively) compared with placebo (50%); estimated differences (adjusted for trial, race, and genotype-1 subtype) faldaprevir 120 mg 24% (95% CI: 17-31%, P < 0.0001), faldaprevir 240 mg 23% (95% CI: 16-30%, P < 0.0001). Subgroup analyses consistently showed higher SVR12 rates for patients receiving faldaprevir compared with placebo. The incidence of adverse events (AEs) was similar in faldaprevir 120-mg and placebo groups and slightly higher in the faldaprevir 240-mg group. Serious Aes were reported in 6%, 7%, and 8% of patients in placebo, faldaprevir 120-mg, and faldaprevir 240-mg groups, respectively. CONCLUSION: Addition of faldaprevir to PegIFN/RBV increased SVR12 in patients with HCV genotype-1, and was well tolerated. Faldaprevir 120 mg is effective in the treatment of HCV genotype-1. ClinicalTrials.gov: NCT01343888 and NCT01297270.

Salivary Biomarkers for Detection of Oral Squamous Cell Carcinoma in a Taiwanese Population.

PURPOSE: This study evaluated the discriminatory power of salivary transcriptomic and proteomic biomarkers in distinguishing oral squamous cell carcinoma cases from controls and potentially malignant oral disorders (PMOD). EXPERIMENTAL DESIGN: A total of 180 samples (60 OSCC patients, 60 controls, and 60 PMOD patients) were used in the study. Seven transcriptomic markers (IL8, IL1ß, SAT1, OAZ1, DUSP1, S100P, and H3F3A) were measured using qPCR, and two proteomic markers (IL8 and IL1ß) were evaluated by ELISA. RESULTS: Among 7 transcriptomic markers, transcript level of DUSP1 was significantly lower in OSCC patients than in controls and PMOD patients. Between the proteomic markers, the protein concentration of IL8 and IL1ß was significantly higher in OSCC patients than controls and dysplasia patients. Univariate fractional polynomial (FP) models revealed that salivary IL8 protein (IL8p) has the highest AUC value between OSCC patients and controls (0.74) and between OSCC and PMOD patients (0.72). Applying a 2-marker FP model, salivary IL8p combined with IL1ß gave the best AUC value for discrimination between OSCC patients and controls, as well as the IL8p combined with H3F3A mRNA, which gave the best AUC value for discrimination between OSCC and PMOD patients. Multivariate models analysis combining salivary analytes and risk factor exposure related to oral carcinogenesis formed the best combinatory variables for differentiation between OSCC versus PMOL (AUC = 0.80), OSCC versus controls (AUC = 0.87), and PMOD versus controls (AUC = 0.78). CONCLUSIONS: The combination of transcriptomic and proteomic salivary markers is of great value for oral cancer detection and differentiation from PMOD patients and controls. Clin Cancer Res; 22(13); 3340-7. ©2016 AACR.

Efficacy and safety of the coadministration of tadalafil once daily with finasteride for 6 months in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia.

PURPOSE: Medical treatment for men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia is 5α-reductase inhibitor monotherapy or coadministration with an α-blocker. We assessed the effects of tadalafil 5 mg coadministered with finasteride 5 mg during 26 weeks on lower urinary tract symptoms and sexual symptoms. MATERIALS AND METHODS: In an international, randomized, double-blind, parallel study of men 45 years old or older who were 5α-reductase inhibitor naïve and had an I-PSS (International Prostate Symptom Score) of 13 or greater and prostate volume 30 ml or greater, 350 were treated with placebo/finasteride and 345 received tadalafil/finasteride for 26 weeks. Changes in lower urinary tract symptoms secondary to benign prostatic hyperplasia were assessed with the I-PSS, erectile dysfunction improvements were assessed with the IIEF-EF (International Index of Erectile Function-Erectile Function) in sexually active men and safety was assessed by evaluating adverse events. RESULTS: Least squares mean changes from baseline in I-PSS after 4, 12 and 26 weeks of tadalafil/finasteride coadministration were -4.0, -5.2 and -5.5, respectively. Corresponding values for placebo/finasteride coadministration were -2.3, -3.8 and -4.5 (p ≤ 0.022 at all visits favoring tadalafil/finasteride coadministration). I-PSS subscores (storage and voiding) and quality of life index were also numerically improved with tadalafil/finasteride coadministration. Least squares mean changes from baseline in IIEF-EF with tadalafil/finasteride coadministration were 3.7 after 4 weeks, and 4.7 after 12 and 26 weeks. Corresponding values for placebo/finasteride coadministration were -1.1, 0.6 and -0.0 (p <0.001 at all visits favoring tadalafil/finasteride coadministration). Tadalafil/finasteride coadministration was well tolerated and most adverse events were mild/moderate. CONCLUSIONS: The coadministration of tadalafil/finasteride provides early improvement in lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement. Tadalafil/finasteride coadministration also improves erectile function in men who have comorbid erectile dysfunction.

Coyote (Canis latrans) and domestic dog (Canis familiaris) mortality and morbidity due to a Karenia brevis red tide in the Gulf of Mexico.

In October 2009, during a Karenia brevis red tide along the Texas coast, millions of dead fish washed ashore along the 113-km length of Padre Island National Seashore (PAIS). Between November 2009 and January 2010, at least 12 coyotes (Canis latrans) and three domestic dogs (Canis familiaris) died or were euthanized at PAIS or local veterinary clinics because of illness suspected to be related to the red tide. Another red tide event occurred during autumn 2011 and, although fewer dead fish were observed relative to the 2009 event, coyotes again were affected. Staff at PAIS submitted carcasses of four coyotes and one domestic dog from November 2009 to February 2010 and six coyotes from October to November 2011 for necropsy and ancillary testing. High levels of brevetoxins (PbTxs) were measured by enzyme-linked immunosorbent assay in seven of the coyotes and the dog, with concentrations up to 634 ng PbTx-3 eq/g in stomach contents, 545 ng PbTx-3 eq/g in liver, 195 ng PbTx-3 eq/g in kidney, and 106 ng PbTx-3 eq/mL in urine samples. Based on red tide presence, clinical signs, and postmortem findings, brevetoxicosis caused by presumptive ingestion of toxic dead fish was the likely cause of canid deaths at PAIS. These findings represent the first confirmed report of terrestrial mammalian wildlife mortalities related to a K. brevis bloom. The implications for red tide impacts on terrestrial wildlife populations are a potentially significant but relatively undocumented phenomenon.

Impact on erectile function and sexual quality of life of couples: a double-blind, randomized, placebo-controlled trial of tadalafil taken once daily.

INTRODUCTION: Clinical research on erectile dysfunction (ED) has focused primarily on the male and the impact of treatment on their erectile function (EF) and sexual quality of life. However, ED affects the quality of life of both the male and the female partner. The literature examining the impact on the female partner resulting from treating the male's ED is somewhat limited. AIMS: To determine the efficacy of tadalafil 5 mg taken once daily compared with placebo on men's EF and sexual quality of life, and to determine the impact of this treatment on the female partner's sexual quality of life. MAIN OUTCOME MEASURES: The co-primary outcome measures for this study were changes from baseline to end point in the EF domain of the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) question 2 (SEP-2) and question 3 (SEP-3), and the Sexual Quality of Life (SQoL) domain of the Sexual Life Quality Questionnaire (SLQQ) (subject and partner). Methods. Following a 4-week treatment-free run-in phase, 342 subjects and their partners were randomly assigned to either placebo (N = 78) or tadalafil 5 mg (N = 264) for 12 weeks. The subjects' and partners' responses to study measures were collected throughout the study. RESULTS: Compared with placebo, tadalafil-treated subjects showed a significant improvement on efficacy measures (P < 0.001) including changes in the IIEF-EF, SEP-2 and SEP-3. In addition, the sexual quality of life of men and their female partners, as measured by the SQoL domain, was significantly improved with tadalafil 5 mg taken once daily (P < 0.001) compared with placebo. CONCLUSIONS: Tadalafil 5 mg once daily significantly improved EF and sexual quality of life for men with ED. In addition, the sexual quality of life of the female partners of the men treated with tadalafil was significantly improved.