Frequency of Poison Center Exposures for Pediatric Accidental Unsupervised Ingestions of Acetaminophen after the Introduction of Flow Restrictors.

OBJECTIVE: To assess the temporal association of flow restrictor introduction and the rate of accidental unsupervised ingestions (AUIs) of liquid acetaminophen products. STUDY DESIGN: The National Poison Data System was used to identify AUIs of single ingredient acetaminophen in patients aged <12 years reported between 2007 and 2015. Six regional poison centers obtained additional information using a structured telephone survey. RESULTS: Pediatric AUIs involving acetaminophen averaged 30 000 exposures per year between 2007 and 2012. From 2012 to 2015, after flow restrictor introduction, exposures steadily decreased at a rate of 2400 fewer exposures annually, reaching 21 877 exposures in 2015. Normalized to sales volume, exposures involving liquid acetaminophen products decreased by 40% from 2010 to 2015. Exposures involving products with flow restrictors tended to have a lower estimated ingestion per exposure, fewer exposures exceeding a 150 mg/kg acetaminophen threshold, and were associated with lower rates of hospital admissions when compared with products without restrictors. Caregivers reported improper storage and child confusion of the medicine with treats as common contributing factors to exposures. CONCLUSIONS: The introduction of flow restrictors was associated with a decrease in pediatric AUIs of liquid acetaminophen products. Decreases in the dose ingested and risk of hospital admission per exposure may also have resulted. Efforts to optimize flow restrictors and increase their use with medicines associated with high pediatric overdose risk should be encouraged.

Pathogenesis of the limb manifestations and exercise limitations in peripheral artery disease.

Patients with peripheral artery disease have a marked reduction in exercise performance and daily ambulatory activity irrespective of their limb symptoms of classic or atypical claudication. This review will evaluate the multiple pathophysiologic mechanisms underlying the exercise impairment in peripheral artery disease based on an evaluation of the current literature and research performed by the authors. Peripheral artery disease results in atherosclerotic obstructions in the major conduit arteries supplying the lower extremities. This arterial disease process impairs the supply of oxygen and metabolic substrates needed to match the metabolic demand generated by active skeletal muscle during walking exercise. However, the hemodynamic impairment associated with the occlusive disease process does not fully account for the reduced exercise impairment, indicating that additional pathophysiologic mechanisms contribute to the limb manifestations. These mechanisms include a cascade of pathophysiological responses during exercise-induced ischemia and reperfusion at rest that are associated with endothelial dysfunction, oxidant stress, inflammation, and muscle metabolic abnormalities that provide opportunities for targeted therapeutic interventions to address the complex pathophysiology of the exercise impairment in peripheral artery disease.

Patient and hospital-level characteristics associated with the use of do-not-resuscitate orders in patients hospitalized for sepsis.

BACKGROUND: Identifying factors associated with do-not-resuscitate (DNR) orders is an informative step in developing strategies to improve their use. As such, a descriptive analysis of the factors associated with the use of DNR orders in the early and late phases of hospitalizations for sepsis was performed. METHODS: A retrospective cohort of adult patients hospitalized for sepsis was identified using a statewide administrative database. DNR orders placed within 24 h of hospitalization (early DNR) and after 24 h of hospitalization (late DNR) were the primary outcome variables. Multivariable logistic regression analysis was used to identify patient, hospital, and healthcare system-related factors associated with the use of early and late DNR orders. RESULTS: Among 77,329 patients hospitalized for sepsis, 27.5 % had a DNR order during their hospitalization. Among the cases with a DNR order, 75.5 % had the order within 24 h of hospitalization. Smaller hospital size and the absence of a teaching program increased the likelihood of an early DNR order being written. Additionally, greater patient age, female gender, White race, more medical comorbidities, Medicare payer status and admission from a skilled nursing facility were all significantly associated with the likelihood of having an early DNR. The strength of association between these factors and the use of late DNR orders was weaker. In contrast, the greater the burden of medical comorbidities, the more likely a patient was to receive a late DNR order. CONCLUSION: Multiple patient, hospital, and healthcare system-related factors are associated with the use of DNR orders in sepsis, many of which appear to be independent of a patient's clinical status. Over the course of the hospitalization, the burden of medical illness shows a stronger association relative to other variables. The influence of these multi-level factors needs to be recognized in strategies to improve the use of DNR orders. .

Association of clinical attributes and treadmill walking performance in patients with claudication due to peripheral artery disease.

BACKGROUND: Patients with claudication secondary to peripheral artery disease have a substantial impairment in walking capacity. This study evaluated factors suspected to be correlated with treadmill walking performance in an effort to gain insights into the pathophysiology of the impairment. METHODS: A multivariate model was developed to define the associations between clinical and laboratory biomarkers with treadmill peak walking time (PWT) in patients enrolled in three clinical trials. The model was initially developed in a cohort of 385 patients from one trial using 23 candidate-independent variables and then tested in the combined data from the other two trials (351 patients). RESULTS: The final model was built from 14 variables that met the predefined univariate criteria of P < .15. Main effects remaining in the model were age, resting ankle-brachial index, smoking status, hypertension, statin use, country (United States vs non-United States countries), and high-sensitivity C-reactive protein. The model was highly statistically significant (P < .0001) but explained only a limited portion of the population heterogeneity (r(2) = 0.173). The main effects plus interaction terms had an r(2) = 0.2178. The main effects model was tested in an independent cohort of 351 patients from two other clinical trials in peripheral arterial disease that did not include high-sensitivity C-reactive protein. The model successfully fit the data set, based on prospectively defined root mean squared error and was statistically significant (P = .0005) but had lower overall explanatory power than in the index cohort (r(2) = 0.0687). CONCLUSIONS: As expected, age and ankle-brachial index contributed to exercise limitation among patients with PAD. The association of C-reactive protein, hypertension, and smoking with PWT is consistent with a role for inflammation or oxidative stress in determining treadmill walking performance. In contrast to previous reports from smaller and more homogenous populations, clinical attributes and biomarkers explain only a small portion of PWT heterogeneity.

A systematic review and meta-analysis of propionyl-L-carnitine effects on exercise performance in patients with claudication.

Propionyl-L-carnitine (PLC) may improve exercise performance in patients with peripheral artery disease, but results from clinical trials have been inconsistent. The safety and efficacy of PLC for treatment of claudication was evaluated by a systematic review and meta-analysis of clinical trials for which data were available through September 2010. Eighty-five studies were identified, of which 13 were randomized controlled trials. Owing to database availability for the six phase III studies carried out with PLC (1 g orally, twice daily), a patient-level meta-analysis was conducted as the primary analysis. Treadmill performance data from these six studies were harmonized to peak walking distance (PWD) on a 7% grade at a speed of 3 km/hour. PLC (n = 440) was associated with a net 16 meter improvement (95% CI, 8-20 meters) in PWD as compared with placebo (n = 427) in the primary analysis (p = 0.002). The effect of PLC was similar in subpopulations defined using clinical and demographic variables, with possible enhanced benefit in patients engaged in an exercise program or enrolled at study sites in Russia. The systematic review of the effect of PLCs on claudication identified seven additional randomized controlled trials for a total of 13 trials, which included 681 patients on placebo and 672 on PLC. This meta-analysis confirmed a 45 meter net improvement on PLC using a random-effects model. In conclusion, oral PLC is associated with a statistically significant increase in PWD in patients with claudication, which may be clinically relevant.

Modeling the potential benefit of an over-the-counter progestin-only pill in preventing unintended pregnancies in the U.S.

OBJECTIVES: To develop a model to estimate the possible impact of use of an over-the-counter (OTC) progestin-only pill (POP) on the number of unintended pregnancies in the United States. STUDY DESIGN: Using typical use failure rates (7% for POPs), we compared the expected number of unintended pregnancies for two theoretical cohorts of 100,000 women: one which purchased and used an OTC POP exclusively for contraception, the other using contraceptive methods at proportions obtained from an actual-use clinical trial simulating OTC use of norgestrel 0.075 mg (including 35% using no method and only 19% using hormonal contraception or long-acting contraceptives). Sensitivity analyses were conducted using alternative model inputs such as different failure rates for OTC POPs and varied alternative contraceptive method mix. RESULTS: An estimated 37,624 unintended pregnancies would occur annually if 100,000 women continued their usual contraceptive method as used at baseline in the actual use trial. This would be reduced by 81% to 7,000 pregnancies with the exclusive use of an OTC POP - a net reduction of 30,624 unintended pregnancies annually. While the number of unintended pregnancies prevented varied as the model parameters were modified (ranging from 1,461 to 34,124), a net benefit of OTC POP use was observed over a wide range of input values. CONCLUSIONS: Using data from a real-world contraception user profile, our model suggests that use of an OTC POP could reduce the overall number of unintended pregnancies in the United States. This conclusion remains true across a wide range of modeled scenarios. IMPLICATIONS: The estimates suggested by this model are supportive of an OTC switch for a POP.

The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial.

OBJECTIVES: Host iron availability is fundamental to mucormycosis pathogenesis. The combination of liposomal amphotericin B (LAmB) and deferasirox iron chelation therapy synergistically improved survival in diabetic mice with mucormycosis. To determine the safety of combination deferasirox plus LAmB therapy for mucormycosis, a multicentred, placebo-controlled, double-blinded clinical trial was conducted. METHODS: Twenty patients with proven or probable mucormycosis were randomized to receive treatment with LAmB plus deferasirox (20 mg/kg/day for 14 days) or LAmB plus placebo (NCT00419770, clinicaltrials.gov). The primary analyses were for safety and exploratory efficacy. RESULTS: Patients in the deferasirox arm (n=11) were more likely than those in the placebo arm (n=9) to have active malignancy, neutropenia and corticosteroid therapy, and were less likely to receive concurrent non-study antifungal therapy. Reported adverse events and serious adverse events were similar between the groups. However, death was more frequent in the deferasirox than in the placebo arm at 30 days (45% versus 11%, P=0.1) and 90 days (82% versus 22%, P=0.01). Global success (alive, clinically stable, radiographically improved) for the deferasirox arm versus the placebo arm at 30 and 90 days, respectively, was 18% (2/11) versus 67% (6/9) (P=0.06) and 18% (2/11) versus 56% (5/9) (P=0.2). CONCLUSIONS: Patients with mucormycosis treated with deferasirox had a higher mortality rate at 90 days. Population imbalances in this small Phase II study make generalizable conclusions difficult. Nevertheless, these data do not support a role for initial, adjunctive deferasirox therapy for mucormycosis.

A phase II dose-ranging study of the phosphodiesterase inhibitor K-134 in patients with peripheral artery disease and claudication.

BACKGROUND: Phosphodiesterase inhibitors have been shown to improve claudication-limited exercise performance in patients with peripheral artery disease. K-134, a novel phosphodiesterase inhibitor, was evaluated in a phase II trial incorporating an adaptive design to assess its safety, tolerability, and effect on treadmill walking time. DESIGN: Patients with peripheral artery disease were randomized to receive placebo (n = 87), K-134 at a dose of 25 mg (n = 42), 50 mg (n = 85), or 100 mg (n = 84), or cilostazol at a dose of 100 mg (n = 89), each twice daily for 26 weeks. Peak walking time (PWT) was assessed using a graded treadmill protocol at baseline and after 14 and 26 weeks of treatment. A Data and Safety Monitoring Board-implemented adaptive design was used that allowed early discontinuation of unsafe or minimally informative K-134 arms. RESULTS: As determined by the prospectively defined adaptive criteria, the 25-mg K-134 arm was discontinued after 42 individuals had been randomized to the arm. During the 26-week treatment period, PWT increased by 23%, 33%, 37%, and 46% in the placebo, 50-mg K-134, 100-mg K-134, and cilostazol arms, respectively (primary analysis placebo vs 100-mg K-134 arm not statistically significant, P = .089). Secondary analyses showed that cilostazol significantly increased PWT after 14 weeks of treatment and that the 100-mg K-134 dose and cilostazol both increased PWT vs placebo after 14 and 26 weeks in those individuals who completed the 26-week trial and were compliant with the study drug, or when the data were analyzed using a mixed-effects model incorporating all time points. K-134 had tolerability and adverse effect profiles similar to that of cilostazol. Both drugs were associated with an increase in withdrawals before study completion due to adverse events compared with placebo. CONCLUSIONS: K-134 was generally well tolerated. K-134 at a dose of 100 mg twice daily did not affect PWT according to the primary analysis, but K-134 and cilostazol both increased PWT when analyzed using a mixed-effects model and in the per-protocol population.

Risk factors for mortality in patients with mucormycosis.

Optimal clinical care and clinical investigation of patients with mucormycosis are limited by absence of controlled trials, and absence of well-defined predictors of mortality or clinical response. The Deferasirox-AmBisome Therapy for mucormycosis (DEFEAT Mucor) study was the first randomized clinical trial conducted on patients with mucormycosis, and demonstrated that adjunctive deferasirox therapy did not improve outcomes of the disease. The current study describes clinical factors from the 20 patients enrolled to identify those associated with 90-day mortality of the 11 (55%) patients who died by day 90. Age, diabetes mellitus, transplant status, or antifungal therapy were not associated with mortality. However, active malignancy or neutropenia at enrollment were associated with increased mortality. Pulmonary infection was linked with lower Kaplan-Meier survival compared to non-pulmonary infection. Higher baseline serum concentrations of iron and ferritin were also associated with mortality. No patient who progressed clinically during the first 14 days of study therapy survived; however, many patients who clinically improved during that time did not survive to 90 days. In contrast, day 30 clinical response was predictive of 90-day survival. These factors may be useful in defining enrollment randomization stratification critieria for future clinical trials, and in supporting clinical care of patients with mucormycosis.

The influence of need for cognition and principal display panel factors on over-the-counter drug facts label comprehension.

Nearly all work aimed at optimizing the ability of labeling to communicate over-the-counter (OTC) drug information has focused on back-of-the-package characteristics, such as the Drug Facts label. The effects of front of the package, or principal display panel (PDP) factors, have largely been neglected by researchers. Similarly, heterogeneity in consumers' approach to new information has received scant attention in the context of OTC drugs. This preliminary study tested the hypothesis that display of a drug's brand name on the PDP and individuals' need for cognition influence comprehension of Drug Facts label information. University students (n = 212) that had experienced heartburn but not used the drug class being studied constituted the primary analysis cohort. Students were randomly assigned to review one of two PDPs (brand name or generic), followed by a Drug Facts label and a series of questions related to selection and usage of the drug. Participants with low need for cognition were influenced by the brand name PDP, as those exposed to a PDP featuring a brand (vs. generic) spent less time reading the Drug Facts label and demonstrated lower comprehension of the label information on proper drug selection. These findings suggest that further research is needed to understand the impact of PDP contents and cognitive characteristics of consumers on the communication of OTC drug information. Health care providers should consider communication strategies that account for the challenges patients face in using OTC drugs properly.

Potential biomarkers of muscle injury after eccentric exercise.

Proteomics was utilized to identify novel potential plasma biomarkers of exercise-induced muscle injury. Muscle injury was induced in nine human volunteers by eccentric upper extremity exercise. Liquid chromatography-mass spectrometry identified 30 peptides derived from nine proteins which showed significant change in abundance post-exercise. Four of these proteins, haemoglobin alpha chain, haemoglobin beta chain, alpha1-antichymotrypsin (ACT) and plasma C-1 protease inhibitor (C1 Inh), met the criterion for inclusion based on changes in at least two distinct peptides. ACT and C1 Inh peptides peaked earlier post-exercise than creatine kinase, and thus appear to provide new information on muscle response to injury.

Cerebrotendinous xanthomatosis-associated diarrhea and response to chenodeoxycholic acid treatment.

BACKGROUND: In patients with cerebrotendinous xanthomatosis (CTX), chronic diarrhea is one of the earliest and main symptoms of the disease. In the current study, we evaluated the characteristics of the diarrhea and its response to chenodeoxycholic acid (CDCA) therapy in a cohort of Dutch CTX patients. METHODS: We performed a retrospective review of medical records for 33 genetically confirmed CTX patients, and abstracted the characteristics of the diarrhea and the response to CDCA therapy (15 mg/kg/day up to 750 mg/day). The Bristol Stool Scale (BSS) was used for qualitative characterization of the stool. RESULTS: Twenty-five patients had diarrhea documented at baseline (76%). Of these patients, 10 had diarrhea rated as 6 (fluffy pieces with ragged edges, a mushy stool), and 6 had diarrhea rated as 7 (watery, no solid pieces, entirely liquid) using the BSS. In 10 patients for whom data were recorded, the median stool frequency at baseline was 3 per day (range 2-6 per day). The response rate with CDCA for diarrhea resolution was 100% based on at least one post-baseline visit without diarrhea and 95% as assessed at the first post-baseline visit. In 68% of cases resolution was complete and sustained as no episodes of diarrhea were documented for follow-up periods as long as 25 years. CONCLUSIONS: Chronic diarrhea persisting for years without spontaneous remission is a common feature of CTX at diagnosis. Chenodeoxycholic acid is an effective treatment for symptomatic relief of diarrhea in patients with CTX.