Interval estimation of relative risks for combined unilateral and bilateral correlated data.

Measurements are generally collected as unilateral or bilateral data in clinical trials, epidemiology, or observational studies. For example, in ophthalmology studies, the primary outcome is often obtained from one eye or both eyes of an individual. In medical studies, the relative risk is usually the parameter of interest and is commonly used. In this article, we develop three confidence intervals for the relative risk for combined unilateral and bilateral correlated data under the equal dependence assumption. The proposed confidence intervals are based on maximum likelihood estimates of parameters derived using the Fisher scoring method. Simulation studies are conducted to evaluate the performance of proposed confidence intervals with respect to the empirical coverage probability, the mean interval width, and the ratio of mesial non-coverage probability to the distal non-coverage probability. We also compare the proposed methods with the confidence interval based on the method of variance estimates recovery and the confidence interval obtained from the modified Poisson regression model with correlated binary data. We recommend the score confidence interval for general applications because it best controls converge probabilities at the 95% level with reasonable mean interval width. We illustrate the methods with a real-world example.

Fixed dose ketamine for prehospital management of hyperactive delirium with severe agitation.

INTRODUCTION: Patients exhibiting signs of hyperactive delirium with severe agitation (HDSA) may require sedating medications for stabilization and safe transport to the hospital. Determining the patient's weight and calculating the correct weight-based dose may be challenging in an emergency. A fixed dose ketamine protocol is an alternative to the traditional weight-based administration, which may also reduce dosing errors. The objective of this study was to evaluate the frequency and characteristics of adverse events following pre-hospital ketamine administration for HDSA. METHODS: Emergency Medical Services (EMS) records from four agencies were searched for prehospital ketamine administration. Cases were included if a 250 mg dose of ketamine was administered on standing order to an adult patient for clinical signs consistent with HDSA. Protocols allowed for a second 250 mg dose of ketamine if the first dose was not effective. Both the 250 mg initial dose and the total prehospital dose were analyzed for weight based dosing and adverse events. RESULTS: Review of 132 cases revealed 60 cases that met inclusion criteria. Patients' median weight was 80 kg (range: 50-176 kg). No patients were intubated by EMS, one only requiring suction, three required respiratory support via bag valve mask (BVM). Six (10%) patients were intubated in the emergency department (ED) including the three (5%) supported by EMS via BVM, three (5%) others who were sedated further in the ED prior to requiring intubation. All six patients who were intubated were discharged from the hospital with a Cerebral Performance Category (CPC) 1 score. The weight-based dosing equivalent for the 250 mg initial dose (OR: 2.62, CI: 0.67-10.22) and the total prehospital dose, inclusive of the 12 patients that were administered a second dose, (OR: 0.74, CI: 0.27, 2.03), were not associated with the need for intubation. CONCLUSION: The 250 mg fixed dose of ketamine was not >5 mg/kg weight-based dose equivalent for all patients in this study. Although a second 250 mg dose of ketamine was permitted under standing orders, only 12 (20%) of the patients were administered a second dose, none experienced an adverse event. This indicates that the 250 mg initial dose was effective for 80% of the patients. Four patients with prehospital adverse events likely related to the administration of ketamine were found. One required suction, three (5%) requiring BVM respiratory support by EMS were subsequently intubated upon arrival in the ED. All 60 patients were discharged from the hospital alive. Further research is needed to determine an optimal single administration dose for ketamine in patients exhibiting signs of HDSA, if employing a standardized fixed dose medication protocol streamlines administration, and if the fixed dose medication reduces the occurrence of dosage errors.

Association of ambient fine particulate matter exposure with gestational diabetes mellitus and blood glucose levels during pregnancy.

BACKGROUND: Previous studies have examined the associations between ambient fine particulate matter (PM2.5) exposure and gestational diabetes mellitus (GDM). However, limited studies explored the relationships between PM2.5 exposure and blood glucose levels during pregnancy, especially in highly polluted areas. OBJECTIVES: To examine the associations of prenatal ambient PM2.5 exposure with GDM and blood glucose levels, and to identify the sensitive exposure windows in a highly air-polluted area. METHODS: From July 2016 to October 2017, a birth cohort study was conducted in Beijing, China. Participants were interviewed in each trimester regarding demographics, lifestyle, living and working environment, and medical conditions. Participant's daily ambient PM2.5 levels from 3 m before last menstrual period (LMP) to the third trimester was estimated by a hybrid spatiotemporal model. Indoor air quality index was calculated based on environmental tobacco smoke, ventilation, cooking, painting, pesticide, and herbicide use. Distributed lag non-linear model was applied to explore the sensitive weeks of PM2.5 exposure. RESULTS: Of 165 pregnant women, 23 (13.94%) developed GDM. After adjusting for potential confounders, PM2.5 exposure during the 1st trimester was associated with higher odds of GDM (10 µg/m3 increase: OR = 1.89, 95% CI: 1.04-3.49). Each 10 µg/m3 increase in PM2.5 during the 2nd trimester was associated with 17.70% (2.21-33.20), 15.99% (2.96-29.01), 18.82% (4.11-33.52), and 17.10% (3.28-30.92) increase in 1-h, 2-h, Δ1h-fasting (1-h minus fasting), and Δ2h-fasting (2-h minus fasting) blood glucose levels, respectively. PM2.5 exposure at 24th-27th weeks after LMP was associated with increased GDM risk. We identified sensitive exposure windows of 21st-24th weeks for higher 1-h and 2-h blood glucose levels and of 20th-22nd weeks for increased Δ1h-fasting and Δ2h-fasting. CONCLUSIONS: Ambient PM2.5 exposure during the second trimester was associated with higher odds of GDM and higher blood glucose levels. Avoiding exposure to high air pollution levels during the sensitive windows might prevent women from developing GDM.

Testing the homogeneity of proportions for combined unilateral and bilateral data.

Measurements are generally collected as unilateral or bilateral data in clinical trials or observational studies. For example, in ophthalmologic studies, statistical tests are often based on one or two eyes of an individual. For the bilateral data, recent literatures have shown some test procedures that take into account the intraclass correlation between paired organs of the same person. Ma et al. investigated three test procedures under Rosner's model. In this paper, we extend Ma's work for bilateral data to combined bilateral and unilateral data. The proposed procedures are based on the likelihood estimate algorithm derived from the root of 4th order polynomial equations and the Fisher scoring iterations. Simulation studies are performed to compare the testing procedures under different parameter configurations. The result shows that score test has satisfactory type I error rates and powers. Therefore, we recommend score test for testing the homogeneity of proportions. We illustrate the application of the proposed methods with two real world examples.

Fast QLB algorithm and hypothesis tests in logistic model for ophthalmologic bilateral correlated data.

In ophthalmologic or otolaryngologic studies, bilateral correlated data often arise when observations involving paired organs (e.g., eyes, ears) are measured from each subject. Based on Donner's model , in this paper, we focus on investigating the relationship between the disease probability and covariates (such as ages, weights, gender, and so on) via the logistic regression for the analysis of bilateral correlated data. We first propose a new minorization-maximization (MM) algorithm and a fast quadratic lower bound (QLB) algorithm to calculate the maximum likelihood estimates of the vector of regression coefficients, and then develop three large-sample tests (i.e., the likelihood ratio test, Wald test, and score test) to test if covariates have a significant impact on the disease probability. Simulation studies are conducted to evaluate the performance of the proposed fast QLB algorithm and three testing methods. A real ophthalmologic data set in Iran is used to illustrate the proposed methods.

Association of SLCO1B1 c.521T>C (rs4149056) with discontinuation of atorvastatin due to statin-associated muscle symptoms.

The most common adverse drug reaction from statins are statin-associated muscle symptoms (SAMS), characterized by myopathy (weakness), myalgia (muscle pain), and commonly elevation in serum creatine kinase. All statins are substrates of the organic anion transporter 1B1 (OATP1B1; gene: SLCO1B1), albeit to different degrees. A genetic polymorphism in SLCO1B1, c.521T>C (rs4149056), markedly decreases OATP1B1 function. The literature is currently unclear as to whether SLCO1B1 c.521T>C is significantly associated with discontinuation of atorvastatin specifically due to SAMS. Our hypothesis was that individuals carrying the SLCO1B1 decreased function 521C allele are more likely to discontinue atorvastatin due to SAMS. This was a retrospective analysis of survey data from 379 Caucasians genotyped for rs4149056 and treated with atorvastatin for at least 12 months. Crude and multivariable logistic regression, adjusted for established risk factors for SAMS, determined the association of SLCO1B1 c.521T>C with discontinuation of atorvastatin due to SAMS (SLCO1B1 521T-homozygotes vs. 521C-carriers). The sample was 51% male, with a mean age of 57 years (SD = 11). Sixty-one percent of participants reported discontinuing atorvastatin due to SAMS, and 32% overall carried the 521C allele. SLCO1B1 521C-carrier status was not a significant predictor of atorvastatin discontinuation in any model: crude OR = 1.07; 95% CI, 0.68-1.66; P = 0.78 and adjusted OR = 1.07; 95% CI, 0.68-1.69; P = 0.76. The results were similar in a sub-group of participants treated with higher doses of atorvastatin (>20 mg). In summary, SLCO1B1 c.521T>C was not significantly associated with discontinuation of atorvastatin therapy due to SAMS.

Retrospective Analysis of Short-Term Respiratory Outcomes of Three Different Steroids Used in Clinical Practice in Intubated Preterm Infants.

OBJECTIVE: This study aimed to compare short-term respiratory outcomes of three steroids (dexamethasone, hydrocortisone, and methylprednisolone) to facilitate extubation by improving respiratory status in preterm infants. STUDY DESIGN: This is a retrospective, single-center, cohort study of 98 intubated preterm infants ≤346/7 weeks' gestation, admitted to a 64-bed, level III neonatal intensive care unit at the Women & Children's Hospital of Buffalo, Buffalo, NY, between 2006 and 2012, who received a short course of low-dose steroids for lung disease after first week of life. RESULTS: Study infants received dexamethasone (34%), hydrocortisone (44%), or methylprednisolone (22%) based on clinical team preference. By day 7 after initiation of steroids, extubation occurred in 59, 44, and 41%, respectively, in infants on dexamethasone, hydrocortisone, and methylprednisolone (p = 0.3). The mean respiratory severity score (RSS = fraction of inspired oxygen × mean airway pressure), a quantitative measure of respiratory status, decreased by 44% for all infants and by 59% in the dexamethasone group by day 7. CONCLUSION: Steroids improved short-term respiratory outcomes in all infants (RSS and extubation); by day 7, dexamethasone treatment was associated with the greatest decrease in RSS. Additional prospective, randomized trials of short-course low-dose steroids are warranted to substantiate these findings to guide clinical decision making and in evaluating differential steroid effects on long-term neurodevelopmental outcomes.

Improvement in Gastrointestinal Symptoms After Cognitive Behavior Therapy for Refractory Irritable Bowel Syndrome.

BACKGROUND & AIMS: There is an urgent need for safe treatments for irritable bowel syndrome (IBS) that relieve treatment-refractory symptoms and their societal and economic burden. Cognitive behavior therapy (CBT) is an effective treatment that has not been broadly adopted into routine clinical practice. We performed a randomized controlled trial to assess clinical responses to home-based CBT compared with clinic-based CBT and patient education. METHODS: We performed a prospective study of 436 patients with IBS, based on Rome III criteria, at 2 tertiary centers from August 23, 2010, through October 21, 2016. Subjects (41.4 ± 14.8 years old; 80% women) were randomly assigned to groups that received the following: standard-CBT (S-CBT, n = 146, comprising 10 weekly, 60-minute sessions that emphasized the provision of information about brain-gut interactions; self-monitoring of symptoms, their triggers, and consequences; muscle relaxation; worry control; flexible problem solving; and relapse prevention training), or 4 sessions of primarily home-based CBT requiring minimal therapist contact (MC-CBT, n = 145), in which patients received home-study materials covering the same procedures as S-CBT), or 4 sessions of IBS education (EDU, n = 145) that provided support and information about IBS and the role of lifestyle factors such as stress, diet, and exercise. The primary outcome was global improvement of IBS symptoms, based on the IBS-version of the Clinical Global Impressions-Improvement Scale. Ratings were performed by patients and board-certified gastroenterologists blinded to treatment allocation. Efficacy data were collected 2 weeks, 3 months, and 6 months after treatment completion. RESULTS: A higher proportion of patients receiving MC-CBT reported moderate to substantial improvement in gastrointestinal symptoms 2 weeks after treatment (61.0% based on ratings by patients and 55.7% based on ratings by gastroenterologists) than those receiving EDU (43.5% based on ratings patients and 40.4% based on ratings by gastroenterologists) (P < .05). Gastrointestinal symptom improvement, rated by gastroenterologists, 6 months after the end of treatment also differed significantly between the MC-CBT (58.4%) and EDU groups (44.8%) (P = .05). Formal equivalence testing applied across multiple contrasts indicated that MC-CBT is at least as effective as S-CBT in improving IBS symptoms. Patients tended to be more satisfied with CBT vs EDU (P < .05) based on immediate posttreatment responses to the Client Satisfaction Questionnaire. Symptom improvement was not significantly related to concomitant use of medications. CONCLUSIONS: In a randomized controlled trial, we found that a primarily home-based version of CBT produced significant and sustained gastrointestinal symptom improvement for patients with IBS compared with education. Clinicaltrials.gov no.: NCT00738920.

Durability and Decay of Treatment Benefit of Cognitive Behavioral Therapy for Irritable Bowel Syndrome: 12-Month Follow-Up.

BACKGROUND: There is a need for safe and effective IBS treatments that provide immediate and sustained improvement of IBS symptoms, particularly among more severe patients. The aim was to assess long-term clinical response of cognitive behavioral therapy (CBT) with reference to IBS education. METHODS: A total of 436 Rome III-diagnosed IBS patients (80% F, M age = 41 years) were randomized to: 4 session home-based CBT (minimal contact (MC-CBT)), 10 session clinic-based CBT (standard (S-CBT)), or 4 session IBS education (EDU). Follow-up occurred at 2 weeks and 3, 6, 9, and 12 months following treatment completion. Treatment response was based a priori on the Clinical Global Improvement Scale (global IBS symptom improvement) and IBS Symptom Severity Scale (IBS-SSS). RESULTS: Post-treatment CGI gains were generally maintained by MC-CBT patients at quarterly intervals through 12-month follow-up with negligible decay. For MC-CBT and S-CBT, 39 and 33% of respondents maintained treatment response at every follow-up assessment. The corresponding percent for EDU was 19%, which was significantly lower (p < 0.05) than for the CBT groups. On the IBS-SSS, therapeutic gains also showed a pattern of maintenance with trends towards increased efficacy over time in all conditions, with the mean unit reductions between baseline and follows-up being approximately -76 at immediate and approximately -94 at 12 months (-50 = clinically significant). CONCLUSIONS: For treatment-refractory IBS patients, home- and clinic-based CBT resulted in substantial and enduring relief of multiple IBS symptoms that generally extended to 12-month post treatment.

Clinical features related to statin-associated muscle symptoms.

INTRODUCTION: Statins reduce cardiovascular disease risk and are generally well tolerated, yet up to 0.5% of statin-treated patients develop incapacitating muscle symptoms including rhabdomyolysis. Our objective was to identify clinical factors related to statin-associated muscle symptoms (SAMS). METHODS: Clinical and laboratory characteristics were evaluated in 748 statin-treated Caucasians (634 with SAMS and 114 statin-tolerant controls). Information was collected on statin type, concomitant drug therapies, muscle symptom history, comorbidities, and family history. Logistic regression was used to identify associations. RESULTS: Individuals with SAMS were 3.6 times (odds ratio [OR] 3.60, 95% confidence interval [CI] 2.08-6.22) more likely than statin-tolerant controls to have a family history of heart disease. Additional associations included obesity (OR 3.08, 95% CI 1.18, 8.05), hypertension (OR 2.24, 95% CI 1.33, 3.77), smoking (OR 2.08, 95% CI 1.16, 3.74), and statin type. DISCUSSION: Careful medical monitoring of statin-treated patients with the associated coexisting conditions may ultimately reduce muscle symptoms and lead to improved compliance. Muscle Nerve 59:537-537, 2019.

Confidence intervals for proportion ratios of stratified correlated bilateral data.

In stratified bilateral studies, responses from two paired body parts are correlated. Confidence intervals (CIs), which reveal various features of the data, should take the correlations into account. In this article, five CI methods (sample-size weighted naïve Maximum likelihood estimation (MLE)-based Wald-type CI, complete MLE-based Wald-type CI, profile likelihood CI, MLE-based score CI and pooled MLE-based Wald-type CI) are derived for proportion ratios under the assumption of equal correlation coefficient within each stratum. Monte Carlo simulation shows that the complete MLE-based Wald-type CI approach generally produces the shortest mean interval width and satisfactory empirical coverage probability with close form solution; while the profile likelihood CI and the MLE-based score CI provide preferred ratio of non coverage probability and are more symmetric. Two real examples are used to demonstrate the performance of the proposed methods.

Asymptotic confidence interval construction for proportion ratio based on correlated paired data.

In ophthalmological and otolaryngology studies, measurements obtained from both organs (e.g., eyes or ears) of an individual are often highly correlated. Ignoring the intraclass correlation between paired measurements may yield biased inferences. In this article, four different confidence interval (CI) construction methods (maximum likelihood estimates based Wald-type CI, profile likelihood CI, asymptotic score CI and an existing method adjusted for correlated bilateral data) are applied to this type of correlated bilateral data to construct CI for proportion ratio, taking the intraclass correlation into consideration. The coverage probabilities and widths of the resulting CIs are compared with each other in a Monte Carlo simulation study to evaluate their performances. A real dataset from an ophthalmologic study is used to illustrate our methodology.

Efficient statistical inference for a parallel study with missing data by using an exact method.

In a parallel group study comparing a new treatment with a standard of care, missing data often occur for various reasons. When the outcome is binary, the data from such studies can be summarized into a 2 × 3 contingency table, with the missing observations in the last column. When the missingness is neither related to the outcome of interest nor related to other outcomes from the study but it is covariate dependent with the sole covariate being treatment, this type of missing data mechanism is considered as missing at random. In 2016, Tian et al.  proposed three statistics to test the hypothesis that the response rate is equivalent for a parallel group study with missing data. The asymptotic limiting distributions of these test statistics were used for statistical inference. However, asymptotic approaches for testing proportions generally do not have satisfactory performance with regard to type I error rate control for a clinical trial with the sample size from small to medium. For this reason, we consider an exact approach based on maximization to provide valid and efficient statistical inference for a parallel group study with missing data. Exact approaches can guarantee the type I error rate and they are computationally feasible in this setting. We conduct extensive numerical studies to compare the performance of the exact approach based on the three statistics for a one-sided hypothesis testing problem. We conclude that the exact approach based on the likelihood ratio statistic is more powerful than the exact approach based on the other two statistics. Two real clinical trial data sets are used to illustrate the application of the proposed exact approach.

Boundary problem in Simon's two-stage clinical trial designs.

The activity of a new treatment in clinical trials with binary endpoints can be assessed by comparing the observed response rate to the target response rate. Traditionally, a one-sided hypothesis is used to make statistical inference, and the actual Type I error rate has to be computed over the parameter space of the null hypothesis. The monotonicity property is a fundamental property that guarantees the actual Type I error rate occurring at the boundary. One-arm two-stage designs are considered in this article. We theoretically proved this important property when the final threshold value of a design is less than the first-stage sample size together with another weak condition being satisfied. The method used in this article may finally lead to the final complete proof of this property in the future. We also numerically proved that the monotonicity property is satisfied for designs with the first-stage and the second-stage sample sizes from 10 to 100.

Testing equality of proportions for correlated binary data in ophthalmologic studies.

In ophthalmologic studies, bilateral correlated data often arise when information involving paired organs (e.g., eyes) are measured from each subject. Adjusted chi-square approach for testing the equality of proportions has been proposed in the literature. In this article, we investigate and derive three alter- native testing procedures for the problem. Our simulation results show the score testing procedure usually produces satisfactory type I error control with higher power, and therefore is recommended. Examples from ophthalmologic studies are used to illustrate our proposed methods.

Impact of bradycardia or asystole on neonatal cardiopulmonary resuscitation at birth.

BACKGROUND: Fetal hypoxia from intrapartum events can lead to absent heart rate (HR) or bradycardia at birth requiring aggressive neonatal resuscitation. Neonatal resuscitation guidelines do not differentiate bradycardia (HR <100 beats/min) from absent HR at birth. Given that HR is the primary determinant of resuscitation, we hypothesize that infants with no HR at 1 min would require more extensive resuscitation with worse clinical outcome than infants with bradycardia at 1 min. METHODS: A retrospective analysis was performed in infants born between 1 January 2000 and 31 December 2015 with no HR at 1 min (defined as Apgar score [AS] = 0 at 1 min; absent HR [AHR] group) or bradycardia at 1 min (AS = 1 at 1 min). Patient demographics, resuscitation characteristics and clinical outcomes were analyzed in both the groups. RESULTS: Apgar score was significantly lower in the AHR group over time. The AHR group had significantly higher rates of intubation, chest compression (CC) and i.v. epinephrine (i.v. epi); resulting in longer duration of CC, time to HR > 100 beats/min and duration of resuscitation. Systematic hypotension and death were higher in the AHR group. On logistic regression, CC and cord pH were significantly correlated with AS = 0 at 1 min. Gestational age, birthweight, AS at 5 min, cord pH and first blood gas pH after resuscitation were related to overall mortality. CONCLUSIONS: Infants with AHR at 1 min did worse than infants with bradycardia. Education focused on effective positive pressure ventilation and early use of i.v. epinephrine is essential for successful resuscitation of the depressed newborn.

Early Use of Inhaled Nitric Oxide in Preterm Infants: Is there a Rationale for Selective Approach?

Background Inhaled nitric oxide (iNO) is being increasingly used in preterm infants < 34 weeks with hypoxemic respiratory failure (HRF) and/or pulmonary hypertension (PH). Objective To evaluate the risk factors, survival characteristics, and lung histopathology in preterm infants with PH/HRF. Methods Retrospective chart review was conducted to determine characteristics of 93 preterm infants treated with iNO in the first 28 days and compared with 930 matched controls. Factors associated with survival with preterm HRF and smooth muscle actin from nine autopsies were evaluated. Results Preterm neonates treated with iNO had a higher incidence of preterm prolonged rupture of membrane (pPROM ≥ 18 hours), oligohydramnios and delivered by C-section. In infants treated with iNO, antenatal steroids (odds ratio [OR],3.7; confidence interval [CI], 1.2-11.3; p = 0.02), pPROM (OR, 1.001; CI, 1.0-1.004; p = 0.3), and oxygenation response to iNO (OR, 3.7; CI, 1.08-13.1; p = 0.037) were associated with survival. Thirteen infants with all three characteristics had 100% (13/13) survival without severe intraventricular hemorrhage (IVH)/periventricular leukomalacia (PVL) compared with 48% survival (12/25, p = 0.004) and 16% severe IVH/PVL without any of these factors. Severity of HRF correlated with increased smooth muscle in pulmonary vasculature. Conclusion Preterm infants with HRF exposed to antenatal steroids and pPROM had improved oxygenation with iNO and survival without severe IVH/PVL. Precisely targeting this subset may be beneficial in future trials of iNO.

Trimethoprim-Sulfamethoxazole Therapy Reduces Failure and Recurrence in Methicillin-Resistant Staphylococcus aureus Skin Abscesses after Surgical Drainage.

OBJECTIVE: To determine whether a 3-day vs 10-day course of antibiotics after surgical drainage of skin abscesses is associated with different failure and recurrence rates. STUDY DESIGN: Patients age 3 months to 17 years seeking care at a pediatric emergency department with an uncomplicated skin abscess that required surgical drainage were randomized to receive 3 or 10 days of oral trimethoprim-sulfamethoxazole therapy. Patients were evaluated 10-14 days later to assess clinical outcome. Patients were followed for 6 months to determine the cumulative rate of recurrent skin infections. RESULTS: Among the 249 patients who were enrolled, 87% of wound cultures grew Staphylococcus aureus (S aureus) (55% methicillin-resistant S aureus [MRSA], 32% methicillin-sensitive S aureus), 11% other organisms, and 2% no growth. Thirteen patients experienced treatment failure. Among all patients, no significant difference in failure rates between the 3- and 10-day treatment groups was found. After we stratified patients by the infecting organism, only patients with MRSA infection were more likely to experience treatment failure in the 3-day group than the 10-day group (P = .03, rate difference 10.1%, 95% CI 2.1%-18.2%) Recurrent infection within 1 month of surgical drainage was more likely in patients infected with MRSA who received 3 days of antibiotics. (P = .046, rate difference 10.3%, 95% CI 0.8%-19.9%). CONCLUSION: Patients with MRSA skin abscesses are more likely to experience treatment failure and recurrent skin infection if given 3 rather than 10 days of trimethoprim-sulfamethoxazole after surgical drainage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02024867.

Limiting cardiac ischemic injury by pharmacological augmentation of macrophage migration inhibitory factor-AMP-activated protein kinase signal transduction.

BACKGROUND: Macrophage migration inhibitory factor (MIF) exerts a protective effect on ischemic myocardium by activating AMP-activated protein kinase (AMPK). Small molecules that increase the affinity of MIF for its receptor have been recently designed, and we hypothesized that such agonists may enhance AMPK activation and limit ischemic tissue injury. METHODS AND RESULTS: Treatment of cardiomyocytes with the candidate MIF agonist, MIF20, augmented AMPK phosphorylation, increased by 50% the surface localization of glucose transporter, and enhanced by 25% cellular glucose uptake in comparison with MIF alone. In mouse hearts perfused with MIF20 before no-flow ischemia and reperfusion, postischemic left ventricular function improved commensurately with an increase in cardiac MIF-AMPK activation and an augmentation in myocardial glucose uptake. By contrast, small-molecule MIF agonism was not effective in cells or tissues genetically deficient in MIF or the MIF receptor, verifying the specificity of MIF20 for MIF-dependent AMPK signaling. The protective effect of MIF20 also was evident in an in vivo regional ischemia model. Mice treated with MIF20 followed by left coronary artery occlusion and reperfusion showed a significant reduction in infarcted myocardium. CONCLUSIONS: These data support the pharmacological utility of small-molecule MIF agonists in enhancing AMPK activation and reducing cardiac ischemic injury.

Fear of GI symptoms has an important impact on quality of life in patients with moderate-to-severe IBS.

OBJECTIVES: Because irritable bowel syndrome (IBS) is a functional medical condition for which there is no curative therapy, treatment goals emphasize relieving gastrointestinal (GI) symptoms and optimizing the quality of life (QOL). This study sought to characterize the magnitude of the associations between QOL impairment, fear of IBS symptoms, and confounding variables. METHODS: Subjects included 234 Rome III-diagnosed IBS patients (mean age, 41 years, 79%, female) without comorbid organic GI disease who were referred to two specialty care clinics of an National Institutes of Health trial for IBS. Subjects completed a testing battery that included the IBS-specific QOL (IBS-QOL), SF-12 (generic QOL), the UCLA GI Symptom Severity Scale, the Visceral Sensitivity Index, Trait Anxiety Inventory, and Brief Symptom Inventory. RESULTS: Multiple linear regression was used to develop a model for predicting QOL. Data supported an overall model that included sociodemographic, clinical (e.g., current severity of GI symptoms), and psychosocial (e.g., fear of GI symptoms, distress, neuroticism) variables, accounting for 48.7% of the variance in IBS-QOL (F=15.1, P <0.01). GI symptom fear was the most robust predictor of IBS-QOL (ß=-0.45 P <0.01), accounting for 14.4% of the total variance. CONCLUSIONS: Patients' fear that GI symptoms have aversive consequences, is a predictor of QOL impairment that cannot be fully explained by the severity of their GI symptoms, overall emotional well-being, neurotic personality style, or other clinical features of IBS. An understanding of the unique impact that GI symptom fears have on QOL can inform treatment planning and help gastroenterologists to better manage more severe IBS patients seen in tertiary care clinics.