In Patients With Inflammatory Bowel Disease, Racial Disparities Exist in Burden of Vaccine-preventable Disease Hospitalizations and Outcomes.

OBJECTIVE: Patients with inflammatory bowel disease (IBD) are at increased risk of vaccine-preventable diseases (VPDs). Despite the increasing prevalence of IBD in non-white populations, little is known regarding racial disparities in VPD burden. METHODS: Retrospectively analyzing the 2016 to 2020 National Inpatient Sample, we identified adults with IBD hospitalized for a principal diagnosis of VPD. The primary outcome investigated was hospitalization for VPD stratified by patient-reported race. Secondary outcomes were in-hospital morbidity, mortality, length of stay, and health care utilization. Multivariable regression analysis was performed to adjust for patient and hospital characteristics. RESULTS: The search identified 554,114 hospitalizations for VPD, including 4170 hospitalizations in patients with IBD. Patients with IBD had significantly greater odds of hospitalization from herpes zoster virus (adjusted odds ratio [aOR]: 1.73) and varicella zoster virus (aOR: 2.31). Comparing white and non-white patients with IBD, significant racial disparities were noted. Non-white patients were at greater odds of hospitalization from influenza (aOR: 1.74), herpes zoster virus (aOR: 1.77), and varicella zoster virus (aOR: 1.62). In-hospital morbidity was greater in non-white patients, including greater odds of requiring intensive care unit stay (aOR: 1.18). Morbidity was elevated in African Americans, with greater odds of acute kidney injury (aOR: 1.25), venous thromboembolism (aOR: 1.17), respiratory failure (aOR: 1.16), and intensive care unit stay (aOR: 1.18). No differences were found in mortality, length of stay, and health care utilization. CONCLUSIONS: Significant racial disparities in VPD hospitalization and in-hospital morbidity were found among adults with IBD in the United States. With the increasing prevalence of IBD in non-white populations, targeted efforts are needed to improve health equity.

Predictive Model for Positive Video Capsule Endoscopy in Iron Deficiency Anemia.

BACKGROUND AND AIMS: Bleeding from the gastrointestinal tract can contribute to the development of iron deficiency anemia (IDA) among individuals without another obvious source of bleeding. In order to identify patients most likely to benefit from examination of the small bowel, our aim was to create a risk score for positive video capsule endoscopy (VCE) in IDA utilizing a multicenter collection of studies. METHODS: We performed a retrospective multicenter study utilizing VCE studies performed for an indication of IDA between 1/1/2005 and 7/31/2018. VCE findings were graded based on the P0-P2 grading system. The primary outcome of interest was a positive (P2) VCE. Data were analyzed with Student's t test for continuous variables and the Fisher's exact test for categorical variables. Logistic regression was used to identify independent associations with positive VCE. RESULTS: In total, 765 VCE procedures were included with 355 (46.5%) male subjects and a median age of 63.2 (SD 15.3) years. One hundred ninety studies (24.8%) were positive (P2) for small bowel bleeding. Four variables associated with positive VCE which were incorporated into a point scoring system: (+) 1 for age ≥ 66 years, active smoking and cardiac arrythmia and (-) 1 for preceding hemoglobin level ≥ 8.5. The risk probabilities for positive VCE-assigned scores - 1, 0, 1, and 2 + were 12.3% (95% CI 7.3-17.3%), 20% (14.9-25.1%), 34.8% (28.6-41%), and 39% (30-47.8%). CONCLUSION: In order to improve the diagnostic yield of capsule examinations, risk factors should be applied to clinical decision-making. We created a risk score for positive VCE in IDA, including the risk factors of age, smoking, history of cardiac arrythmia, and preceding hemoglobin level.

Modeling lay people's ethical views on abortion: A Q-methodology study.

BACKGROUND: It isn't clear how lay people balance the various ethical interests when addressing medical issues. We explored lay people's ethical resolution models in relation to abortion. METHODS: In a tertiary healthcare setting, 196 respondents rank-ordered 42 opinion-statements on abortion following a 9-category symmetrical distribution. Statements' scores were analyzed by averaging-analysis and Q-methodology. RESULTS: Respondents' mean (SD) age was 34.5(10.5) years, 53% were women, 68% Muslims (31% Christians), 28% Saudis (26% Filipinos), and 38% healthcare-related. The most-agreeable statements were "Acceptable if health-benefit to woman large," "Acceptable if congenital disease risk large," and "Woman's right if fetus has congenital disease." The most-disagreeable statements were "State's right even if woman disagrees," "Acceptable even with no congenital disease risk," and "Father's right even if woman disagrees." Q-methodology identified several resolution models that were multi-principled, consequentialism-dominated, and associated with respondents' demographics. The majority of Christian women and men identified with and supported a relatively "fetus rights plus State authority-oriented" model. The majority of Muslim women and men identified with and supported a "conception-oriented" model and "consequentialism plus virtue-oriented" model, respectively. One or more of three motives-related statements received extreme ranks on averaging-analysis and in 33% of the models. CONCLUSIONS: 1) On average, consequentialism, focusing on a woman's health-benefit and congenital disease risk, was the predominant approach. This was followed by the rights approach, favoring a woman's interest but taking context into account. 2) Q-methodology identified various ethical resolution models that were multi-principled and partially associated with respondents' demographics. 3) Motives were important to some respondents, providing empirical evidence against adequacy of principlism.

Misleading localization by 18F-fluorocholine PET/CT in familial hypocalciuric hypercalcemia type-3: a case report.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is a heterogeneous autosomal-dominant disorder of calcium hemostasis that may be difficult to distinguish clinically from mild primary hyperparathyroidism. Loss-of-function mutations mainly involving Arg15 residue of the adaptor-related protein complex 2, sigma subunit 1 (AP2S1) cause a rarer, more recently recognized form of FHH, FFH type-3. Recently, 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) showed superior sensitivity to conventional imaging in localizing parathyroid adenomas. We report a new FFH type-3 patient who underwent unnecessary parathyroidectomy in association with misleading FCH-PET/CT imaging. CASE PRESENTATION: A 29-year old woman was initially evaluated for parathyroid hormone (PTH)-dependent hypercalcemia in 2013. Medical history was positive only for chronic constipation and malaise with no personal or family history of hypercalcemia, kidney stones, or neck surgery. Over seven years, serum calcium level was 2.51-2.89 mmol/L with concomitant PTH level of 58.7-94.8 mmol/L. Serum phosphate levels were in the low/low normal range. Serum creatinine and magnesium levels were normal. 25-hydroxy vitamin D level was 13 nmol/L. 24-hour urine calcium level was 1.92 mmol/day but increased to 6.99 mmol/day after treatment with cholecalciferol 1000 IU daily. Bone mineral density and renal ultrasound were normal. Parathyroid ultrasound showed two hypoechoic nodules inferior to the left and right thyroid lobes; however, 99mtechnitium-sestamibi scans (2013, 2016, 2018) were negative. FCH-PET/CT (2019) showed focal uptake co-localizing with the nodule inferior to the left thyroid lobe. The patient underwent left inferior parathyroidectomy and pathology was consistent with parathyroid hyperplasia. However, postoperatively, serum calcium and PTH levels remained elevated and FCH-PET/CT and ultrasound showed persistence of the uptake/nodule. Whole exome sequencing showed Arg15Cys mutation in the AP2S1 gene characteristic of FHH type-3. CONCLUSIONS: In this new case of FHH type-3, FCH-PET/CT failed to localize to the hyperplastic parathyroid glands and localized instead to apparently a lymph node. This, together with increased urinary calcium after vitamin D supplementation, led to unnecessary parathyroidectomy. Given the increasingly lower cost of genetic testing and the cost of follow up and unnecessary surgery, it may prudent to include genetic testing for FHH early on in patients with mild PTH-dependent hypercalcemia.

Clinical course of COVID-19 in a liver transplant recipient on hemodialysis and response to tocilizumab therapy: A case report.

The novel coronavirus disease 2019 (COVID-19) is a highly infectious and rapidly spreading disease. There are limited published data on the epidemiology and outcomes of COVID-19 infection among organ transplant recipients. After initial flulike symptoms, progression to an inflammatory phase may occur, characterized by cytokine release rapidly leading to respiratory and multiorgan failure. We report the clinical course and management of a liver transplant recipient on hemodialysis, who presented with COVID-19 pneumonia, and despite completing a 5-day course of hydroxychloroquine, later developed marked inflammatory manifestations with rapid improvement after administration of off-label, single-dose tocilizumab. We also highlight the role of lung ultrasonography in early diagnosis of the inflammatory phase of COVID-19. Future investigation of the effects of immunomodulators among transplant recipients with COVID-19 infection will be important.

Dietary Guidance From the International Organization for the Study of Inflammatory Bowel Diseases.

Recent evidence points to a plausible role of diet and the microbiome in the pathogenesis of both Crohn's disease (CD) and Ulcerative Colitis (UC). Dietary therapies based on exclusion of table foods and replacement with nutritional formulas and/or a combination of nutritional formulas and specific table foods may induce remission in CD. In UC, specific dietary components have also been associated with flare of disease. While evidence of varying quality has identified potential harmful or beneficial dietary components, physicians and patients at the present time do not have guidance as to which foods are safe, may be protective or deleterious for these diseases. The current document has been compiled by the nutrition cluster of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) based on the best current evidence to provide expert opinion regarding specific dietary components, food groups and food additives that may be prudent to increase or decrease in the diet of patients with inflammatory bowel diseases to control and prevent relapse of inflammatory bowel diseases.

Men With Inflammatory Bowel Disease: Sexual Function, Fertility, Medication Safety, and Prostate Cancer.

Half of patients with inflammatory bowel disease (IBD) are men, yet less attention has been focused on their sexual issues despite higher rates of sexual dysfunction and infertility than the general population. Depression and IBD disease activity are the most consistently reported risk factor for sexual dysfunction among men with IBD. Methotrexate and sulfasalazine have been rarely associated with impotence. Sulfasalazine reversibly reduces male fertility. No other medications used in IBD significantly affect fertility in humans. There is no increase in adverse fetal outcomes among offspring of fathers with IBD. Patients with IBD seem to be at a higher risk for prostate cancer; therefore, screening as recommended for high-risk patients should be considered.

Factors underlying surrogate medical decision-making in middle eastern and east Asian women: a Q-methodology study.

BACKGROUND: It is not clear how lay people prioritize the various, sometimes conflicting, interests when they make surrogate medical decisions, especially in non-Western cultures. The extent such decisions are perspective-related is also not well documented. METHODS: We explored the relative importance of 28 surrogate decision-making factors to 120 Middle-Eastern (ME) and 120 East-Asian (EA) women from three perspectives, norm-perception (N), preference as patient (P), and preference as surrogate decision-maker (S). Each respondent force-ranked (one to nine) 28 opinion-items according to each perspective. Items' ranks were analyzed by averaging-analysis and Q-methodology. RESULTS: Respondents' mean (SD) age was 33.2 (7.9) years; all ME were Muslims, 83% of EA were Christians. "Trying everything possible to save patient," "Improving patient health," "Patient pain and suffering," and/or "What is in the best interests of patient" were the three most-important items, whereas "Effect of caring for patient on all patients in society," "Effect of caring for patient on patients with same disease," and/or "Cost to society from caring for patient" were among the three least-important items, in each ME and EA perspectives. P-perspective assigned higher mean ranks to family and surrogate's needs and burdens-related items, and lower mean rank to "Fear of loss" than S-perspective (p<0.001). ME assigned higher mean ranks to "Medical facts" and "Surrogate own wishes for patient" and lower mean rank to "Family needs" in all perspectives (p<0.001). Q-methodology identified models that were relatively patient's preference-, patient's religious/spiritual beliefs-, or emotion-dependent (all perspectives); medical facts-dependent (N- and S-perspectives), financial needs-dependent (P- and S-perspectives), and family needs-dependent (P-perspective). CONCLUSIONS: 1) Patient's health was more important than patient's preference to ME and EA women; society interest was least important. 2) Family and surrogate's needs/ burdens were more important, whereas fear of loss was less important to respondents as patients than as surrogate decision-makers. 3) Family needs were more important to EA than ME respondents, the opposite was true for medical facts and surrogate's wishes for patient. 4) Q-methodology models that relatively emphasized various surrogate decision-making factors overlapped the ME and EA women' three perspectives.

Circumferential Negative Intermittent Pressure to the Midarm Does Not Impair Digital O2 Saturation: A Randomized Controlled Study.

BACKGROUND: Circumferential negative pressure wound therapy is commonly used to manage wounds and enhance the healing process. A theoretical concern was recently raised that circumferential negative pressure wound therapy may have a negative effect on perfusion distally. METHODS: In a randomized study, we applied circumferential negative pressure (125 mm Hg) to the midarm of 13 healthy volunteers through InfoV.A.C. Therapy Unit device. The pressure was applied intermittently (5 minutes on and 2 minutes off) for 9 hours. The same device without negative pressure was applied to the contralateral midarm as control. Bilateral index finger O2 saturation (SpO2) was measured every 30 minutes using digital pulse oximetry. RESULTS: Mean (SD) age of the volunteers was 32.2 (9.5) years, and 61.5% were male. Mean (SD) area under the curve from time 0 to 9 hours of SpO2 was 890.56 (6.69) and 889.71 (6.23) %xh in the intervention and control arms, respectively (P = 0.35). O2 saturation was ≥94% at all observation times in both arms, and no adverse events were identified. CONCLUSIONS: Circumferential negative intermittent pressure of 125 mm Hg applied to the midarm of healthy volunteers for 9 hours does not adversely affect digital SpO2.

Vitamin-D2 treatment-associated decrease in 25(OH)D3 level is a reciprocal phenomenon: a randomized controlled trial.

BACKGROUND: Vitamin-D2 (D2) treatment has been associated with a decrease in 25-hydroxy (25(OH)) vitamin-D3 (D3) level, suggesting that D3 treatment would be preferred to raise total 25(OH) vitamin-D (D) level. We postulated that D2 treatment-associated decrease in 25(OH)D3 level is related to the increase in 25(OH)D level rather than being D2-specific, and thus there would be a similar D3 treatment-associated decrease in 25(OH)D2 level. METHODS: Fifty volunteers were block-randomized to 50,000 IU D2 or placebo orally once (study-1) and fifty volunteers received 50,000 IU D2 orally once and 4 days later block-randomized to 50,000 IU D3 or placebo orally once (study-2). Interventions were concealed from volunteers and research coordinators and blindly-administered. Serum 25(OH)D2 and 25(OH)D3 levels were blindly-determined at baseline and days 14, 28, 42, and 56, post-randomization by high performance liquid chromatography assay. Results of 97 participants were analyzed. Primary outcome measure was day-28 D2-associated change in 25(OH)D3 level in study-1 and D3-associated change in 25(OH)D2 level in study-2, adjusted for baseline levels. RESULTS: Mean (95% confidence interval) difference between the active and placebo arms in the decrease in day-28 25(OH)D3 (study-1) and 25(OH)D2 (study-2) levels was 13.2 (9.7 to 16.6) and 9.8 (5.2 to 14.4) nmol/L, respectively. Corresponding differences at day-56 were 10.8 (6.8 to 14.8) and 1.7 (- 7.6 to 11.1) nmol/L, respectively. The difference between the placebo and active arms in area-under-the-curve at day-28 (AUC28) and day-56 (AUC56) were 262.3 (197.8 to 326.7) and 605.1 (446.3 to 784.0) for 25(OH)D3 (study-1) and 282.2 (111.2 to 453.3) and 431.2 (179.3 to 683.2) nmol.d/L for 25(OH)D2 (study-2), respectively. There were significant correlations between day-28 changes in 25(OH)D2 and 25(OH)D3 levels in study-1 (rho = - 0.79, p < 0.001) and study-2 (rho = - 0.36, p = 0.01), and between day-28 changes in 25(OH)D2 level and baseline 25(OH)D level in study-2 (rho = - 0.42, p = 0.003). CONCLUSIONS: Compared to placebo, D3 treatment is associated with a decrease in 25(OH)D2 level similar in magnitude to D2-treatment associated decrease in 25(OH)D3 level; however, the D3-placebo difference in 25(OH)D2 level is shorter-lasting. Changes in 25(OH)D2 and 25(OH)D3 levels are correlated with each other and with baseline 25 (OH) D levels, suggesting a common regulatory mechanism. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT03035084 (registered January 27, 2017).

Prediction of life-story narrative for end-of-life surrogate's decision-making is inadequate: a Q-methodology study.

BACKGROUND: Substituted judgment assumes adequate knowledge of patient's mind-set. However, surrogates' prediction of individual healthcare decisions is often inadequate and may be based on shared background rather than patient-specific knowledge. It is not known whether surrogate's prediction of patient's integrative life-story narrative is better. METHODS: Respondents in 90 family pairs (30 husband-wife, 30 parent-child, 30 sibling-sibling) rank-ordered 47 end-of-life statements as life-story narrative measure (Q-sort) and completed instruments on decision-control preference and healthcare-outcomes acceptability as control measures, from respondent's view (respondent-personal) and predicted pair's view (respondent-surrogate). They also scored their confidence in surrogate's decision-making (0 to 4 = maximum) and familiarity with pair's healthcare-preferences (1 to 4 = maximum). Life-story narratives' prediction was examined by calculating correlation of statements' ranking scores between respondent-personal and respondent-surrogate Q-sorts (projection) and between respondent-surrogate and pair-personal Q-sorts before (simulation) and after controlling for correlation with respondent-personal scores (adjusted-simulation), and by comparing percentages of respondent-surrogate Q-sorts co-loading with pair-personal vs. respondent-personal Q-sorts. Accuracy in predicting decision-control preference and healthcare-outcomes acceptability was determined by percent concordance. Results were compared among subgroups defined by intra-pair relationship, surrogate's decision-making confidence, and healthcare-preferences familiarity. RESULTS: Mean (SD) age was 35.4 (10.3) years, 69% were females, and 73 and 80% reported ≥ very good health and life-quality, respectively. Mean surrogate's decision-making confidence score was 3.35 (0.58) and 75% were ≥ familiar with pair's healthcare-preferences. Mean (95% confidence interval) projection, simulation, and adjusted-simulation correlations were 0.68 (0.67-0.69), 0.42 (0.40-0.44), and 0.26 (0.24-0.28), respectively. Out of 180 respondent-surrogate Q-sorts, 24, 9, and 32% co-loaded with respondent-personal, pair-personal, or both Q-sorts, respectively. Accuracy in predicting decision-control preference and healthcare-outcomes acceptability was 47 and 52%, respectively. Surrogate's decision-making confidence score correlated with adjusted-simulation's correlation score (rho = 0.18, p = 0.01). There were significant differences among the husband-wife, parent-child, and sibling-sibling subgroups in percentage of respondent-surrogate Q-sorts co-loading with pair-personal Q-sorts (38, 32, 55%, respectively, p = 0.03) and percent agreement on healthcare-outcomes acceptability (55, 35, and 67%, respectively, p = 0.002). CONCLUSIONS: Despite high self-reported surrogate's decision-making confidence and healthcare-preferences familiarity, family surrogates are variably inadequate in simulating life-story narratives. Simulation accuracy may not follow the next-of-kin concept and is 38% based on shared background.

Evaluation of Omeprazole Limited Sampling Strategies to Estimate Constitutive Cytochrome P450 2C19 Activity in Healthy Adults.

BACKGROUND: Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity. METHODS: Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile. RESULTS: Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r, range: 0.14-0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r (range: 0.02-0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers. CONCLUSIONS: Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.

Differential effects of vitamin D2 and D3 supplements on 25-hydroxyvitamin D level are dose, sex, and time dependent: a randomized controlled trial.

BACKGROUND: Vitamin D (D) supplements are indispensable for its world-wide deficiency. Controversy continues on ergocalciferol (D2) and cholecalciferol (D3) relative potency as well as on dosing-schedule and sex role in raising 25-hydroxy D (25(OH)D) level, the best indicator of D status. METHODS: We randomized 279 adults to daily D2, D3, D2/D3, or placebo; 2-weekly D2 or D3; or 4-weekly D2 or D3 (250,000 IU over/140 days). Randomization sequence, stratified by body-mass-index (BMI) and sex, was concealed from study coordinators and participants who were then blinded to capsules' content. D2, D3, 25(OH)D2, and 25(OH)D3 Serum levels were determined blindly on days 0,1,2,3,4,7,14, and 2-weekly thereafter by high performance liquid chromatography assay. The results of 269 participants were available for analysis. Primary endpoint was area-under-the-curve (AUC) of 25(OH)D (25(OH)D2 + 25(OH)D3) adjusted for sex, BMI, and baseline 25(OH)D level. RESULTS: Mean(SD) age was 33.0(8.5) year, 41% were males, and 85% completed follow-up. Baseline 25(OH)D level was 39.8(11.9) and increased by 3.3(11.6) and 28.6(16.3) nmol/L, in the placebo and active-treatment groups, respectively. AUC from day 0 to 140 (AUC140) of 25(OH)D was 40% (D3 daily) to 55% (D3 2-weekly) higher with active-treatment than placebo (p < 0.001). 25(OH)D2 AUC140 was higher in daily than 2-weekly (17%, p = 0.006) and 4-weekly (20%, p = 0.001) D2-treated groups. 25(OH)D3 AUC140 was lower in daily than 2-weekly (11%, p = 0.002) and 4-weekly D3-treated groups (10%, p = 0.008). In D2-treated groups, there was 16.4 nmol/L decrease in 25(OH)D3 level that correlated (p < 0.001) with 25(OH)D2 level increase (r = 0.48) and baseline 25(OH)D level (r = 0.58), in one participant with measurable baseline 25(OH)D2 level, D3 caused a similar decrease in 25(OH)D2 level, while in the D2/D3-treated group, 25(OH)D3 level didn't increase. Incremental AUC from day 0 to 7 (AUC7) of D3 and 25(OH)D3 in D3-treated groups were 118-243% higher and 31-39% lower, respectively, than incremental AUC7 of D2 and 25(OH)D2 in D2-treated groups. Incremental AUC7 of D3 and 25(OH)D3 in D3-treated groups and D2 and 25(OH)D2 in D2-treated groups were higher in females than males (55, 13, 64, and 28%, respectively). Baseline 25(OH)D level predicted response to D2 and D3 (p < 0.001), whereas, BMI was significant predictor only for early response to D2. CONCLUSIONS: Effects of D2 and D3 supplements on 25 (OH)D level may be dosing-schedule and sex-dependent. D2-associated reduction in 25(OH)D3 level may be related to total 25(OH)D level rather than being D2-specific. D2 may be 25-hydroxylated faster than D3. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT01170494 (registered July 25, 2010).

Does the placebo effect modulate drug bioavailability? Randomized cross-over studies of three drugs.

BACKGROUND: Medication effect is the sum of its drug, placebo, and drug*placebo interaction effects. It is conceivable that the interaction effect involves modulating drug bioavailability; it was previously observed that being aware of caffeine ingestion may prolong caffeine plasma half-life. This study was set to evaluate such concept using different drugs. METHODS: Balanced single-dose, two-period, two-group, cross-over design was used to compare the pharmacokinetics of oral cephalexin, ibuprofen, and paracetamol, each described by its name (overt) or as placebo (covert). Volunteers and study coordinators were deceived as to study aim. Drug concentrations were determined blindly by in-house, high performance liquid chromatography assays. Terminal-elimination half-life (t½) (primary outcome), maximum concentration (Cmax), Cmax first time (Tmax), terminal-elimination-rate constant (λ), area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or to Tmax of overt drug (AUCOverttmax), and Cmax/AUCI were calculated blindly using standard non-compartmental method. Covert-vs-overt effect on drug pharmacokinetics was evaluated by analysis-of-variance (ANOVA, primary analysis), 90% confidence interval (CI) using the 80.00-125.00% bioequivalence range, and percentage of individual pharmacokinetic covert/overt ratios that are outside the +25% range. RESULTS: Fifty, 30, and 50 healthy volunteers (18%, 10%, and 6% females, mean (SD) age 30.8 (6.2), 31.4 (6.6), and 31.2 (5.4) years) participated in 3 studies on cephalexin, ibuprofen, and paracetamol, respectively. Withdrawal rate was 4%, 0%, and 4%, respectively. Eighteen blood samples were obtained over 6, 10, and 14 h in each study period of the three drugs, respectively. ANOVA showed no significant difference in any pharmacokinetic parameter for any of the drugs. The 90% CIs for AUCT, AUCI, Cmax, AUCOverttmax, and Cmax/AUCI were within the bioequivalence range, except for ibuprofen Cmax (76.66-98.99), ibuprofen Cmax/AUCI (77.19-98.39), and ibuprofen (45.32-91.62) and paracetamol (51.45-98.96) AUCOverttmax. Out of the 126 individual covert/overt ratios, 2.0-16.7% were outside the +25% range for AUCT, 2.0-4.2% for AUCI, 25.0-44.9% for Cmax, 67.3-76.7% for AUCOverttmax, and 45.8-71.4% for Tmax. CONCLUSIONS: This study couldn't confirm that awareness of drug ingestion modulates its bioavailability. However, it demonstrates the trivial effect of blinding in bioequivalence studies and the extent of bio-variability that would be expected when comparing a drug product to itself. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01501747 (registered Dec 26, 2011).

Eluxadoline-Associated Pancreatitis in a Post-Cholecystectomy Patient: A Case Report.

Eluxadoline has emerged as an effective treatment option for patients with diarrhea- predominant irritable bowel syndrome (IBS-D). It was approved by the Food and Drug Administration (FDA) in May 2015 for treatment of IBS-D. It is a p-opioid receptor agonist and 6-receptor antagonist that acts locally in the gastrointestinal (GI) tract. In recently published phase IlIl IBS-3001 and IBS- 3002 trials, eight patients experienced abdominal pain due to sphincter of Oddi dysfunction (SOD), and one patient had acute pancreatitis, thought to be related to eluxadoline. Here, we describe a patient with eluxadoline- induced pancreatitis, the first case we know of to be reported outside of phase Ill clinical trials. Interestingly, only patients with prior cholecystectomy developed SOD and acute pancreatitis in the IBS 3001/3002 trials which also stands true with our patient. The enthusiasm with the efficacy of this drug should not have clinicians disregard the potential adverse effects, particularly serious ones, such as acute pancreatitis. We expect more cases of eluxadoline-induced pancreatitis and SOD to be reported, and future studies should focus on better understanding this association so as to guide treatment recommendations.