Atypical hemolytic uremic syndrome: a syndrome in need of clarity.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) originally understood to be limited to renal and hematopoietic involvement. Whereas aberrations in complement regulatory proteins (CRPs), C3 or complement factor B (CFB) are detected in ∼60% of patients, a complement-derived pathogenesis that reflects dysregulation of the alternative pathway (AP) of complement activation is present in ∼90% of patients. aHUS remains a diagnosis of exclusion. The discovery of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) and its utility in the diagnosis of thrombotic thrombocytopenic purpura (TTP) has resulted in the appreciation that cases of aHUS have been inappropriately diagnosed as TTP. Thus there has been an evolving appreciation of clinical manifestations of aHUS that renders the appellation aHUS misleading. This article will review the pathogenesis and the evolving clinical presentations of aHUS, present a hypothesis that there can be a phenotypic expression of aHUS due to a complement storm in a disorder where direct endothelial damage occurs and discuss future areas of research to more clearly define the clinical spectrum and management of aHUS.

An Open-Label, Randomized Bioavailability Study of Alternative Methods of Oral Administration of Naloxegol in Healthy Subjects.

Naloxegol is a peripherally acting µ-opioid receptor antagonist approved as an orally administered tablet for the treatment of opioid-induced constipation. Patients with swallowing difficulties may benefit from alternative approaches to the oral administration of the whole-tablet formulation of naloxegol. This open-label, randomized, 4-period, 4-treatment, crossover, single-dose study (NCT02446171) evaluated the pharmacokinetic (PK) characteristics of crushed naloxegol 25-mg tablets (suspended in water) administered orally or by nasogastric tube and a naloxegol solution compared with the commercially available 25-mg tablet formulation in healthy volunteers. The PK profiles for the crushed tablet, whether administered orally or by nasogastric tube, and the 25-mg oral solution were similar to that of the 25-mg tablet administered orally. Compared with naloxegol commercial tablets, the relative bioavailability of naloxegol using 3 alternative methods of administration was approximately 100%. For each pairwise treatment comparison of the 3 alternative methods with the approved whole tablet, the geometric least-squares mean ratio ranges were 94.37%-100.04%, 94.83%-100.44%, and 97.05%-102.05% for area under the curve (AUC), AUC0-t , and maximum plasma concentration, respectively, and their 90% confidence intervals were entirely within the predefined 80% to 125% bioequivalence limits. Naloxegol was well tolerated when administered in both liquid and solid form.

The Alternative Pathway of Complement and the Evolving Clinical-Pathophysiological Spectrum of Atypical Hemolytic Uremic Syndrome.

Complement-mediated atypical hemolytic uremic syndrome (aHUS) comprises approximately 90% of cases of aHUS, and results from dysregulation of endothelial-anchored complement activation with resultant endothelial damage. The discovery of biomarker ADAMTS13 has enabled a more accurate diagnosis of thrombotic thrombocytopenic purpura (TTP) and an appreciation of overlapping clinical features of TTP and aHUS. Given our present understanding of the pathogenic pathways involved in aHUS, it is unlikely that a specific test will be developed. Rather the use of biomarker data, complement functional analyses, genomic analyses and clinical presentation will be required to diagnose aHUS. This approach would serve to clarify whether a thrombotic microangiopathy present in a complement-amplifying condition arises from the unmasking of a genetically driven aHUS versus a time-limited complement storm-mediated aHUS due to direct endothelial damage in which no genetic predisposition is present. Although both scenarios result in the phenotypic expression of aHUS and involve the alternate pathway of complement activation, long-term management would differ.

Relationship of urinary endothelin-1 with estimated glomerular filtration rate in autosomal dominant polycystic kidney disease: a pilot cross-sectional analysis.

BACKGROUND: The pathogenesis of progressive renal insufficiency in autosomal dominant polycystic kidney disease (ADPKD) is unclear. Evidence from experimental models of ADPKD suggests that elevated endothelin-1 (ET-1) drives cyst growth, renal fibrosis and loss of renal function, but whether ET-1 is elevated in humans with ADPKD is uncertain. METHODS: In a cross-sectional study of ADPKD we measured urinary ET-1, a surrogate for ET-1 in kidney cortex, in spot collections corrected for creatinine. The volume of each kidney was measured using MRI-based stereology. The relationship of urine ET-1 with MDRD eGFR and kidney volume was modeled by multiple linear regression with adjustment for clinical covariates. RESULTS: Patients with ADPKD were ages 18 to 53 with eGFRs (median, interquartile range) of 63.2 (43.5-80.2) ml/min/1.73 m(2) and albumin/creatinine ratios (ACR) of 115.0 (7.5-58.5) µg/mg. Urine ET-1 was inversely associated with eGFR (r = -0.480, P < 0.05) and positively (r = 0.407, P = 0.066) with ACR independent of age and female sex (P < 0.01). ET-1 appeared to be positively associated with total kidney volume (r = 0.426, P = 0.100), with a test for trend across urine ET-1 quartiles yielding z = 1.83, P = 0.068. ET-1 strongly correlated with NAGase (r = 0. 687, P = 0.001), a marker of tubular damage and a surrogate marker of renal disease progression in ADPKD. Of note, ET-1 levels in urine were not correlated with hypertension. CONCLUSIONS: In a translational study of patients with ADPKD, urinary ET-1 was inversely associated with eGFR and positively correlated with total kidney volume. Taken together with results from experimental models, these findings suggest that the role of ET-1 in ADPKD warrants further investigation.

Motivational interviewing and specialty pharmacy.

It is well documented in substance abuse and health care literature that motivational interviewing is an evidenced-based and effective intervention for influencing patient behaviors and associated positive health outcomes. The introduction of motivational interviewing training in specialty pharmacy has great potential to increase patient and pharmacist satisfaction, maximize adherence rates, and improve health outcomes. This commentary examines the need for effective approaches for improving patient adherence and outcomes and briefly describes the history and efficacy of motivational interviewing. Case studies using traditional approaches to patient care and motivational interviewing are analysed, and real-world experience using motivational interviewing is presented in the form of a specialty pharmacy case study.

Pharmacist self-reported antidepressant medication counseling.

OBJECTIVES: To identify the extent of pharmacists' self-reported antidepressant counseling (SRAC) and to identify factors that may affect pharmacists' decisions to provide antidepressant counseling. DESIGN: Cross-sectional study. SETTING: Alabama community pharmacies in 2011. PARTICIPANTS: Full-time pharmacists from 600 community pharmacies. INTERVENTION: Self-administered survey; three mail contacts with alternate electronic surveys were used. MAIN OUTCOME MEASURES: Pharmacists' SRAC behavior and its relationship with pharmacists' illness perceptions of depression, self-efficacy, and organizational and environmental influences. RESULTS: 600 surveys were sent; 22 were undeliverable, 1 was partially completed (<80% questions answered), and 118 were completed (20.6% overall response rate). Pharmacists reported low rates of involvement in antidepressant counseling; 61% reported assessing patient knowledge and understanding of depression, and 36% discussed options for managing adverse effects with no more than a few patients. More than one-quarter (28.6%) never asked patients whether they had barriers to taking antidepressants. Pharmacists' perceptions regarding consequences, control/cure, and the episodic nature of depression, as well as their self-efficacy, had significant relationships ( P < 0.05) with pharmacists' involvement in antidepressant counseling. CONCLUSION: Low rates of pharmacists' involvement in antidepressant counseling were reported. Pharmacists must become more involved in counseling patients about their antidepressant medications and overcoming barriers preventing greater involvement.

The renal transcriptome of db/db mice identifies putative urinary biomarker proteins in patients with type 2 diabetes: a pilot study.

We sought to identify novel urinary biomarkers of kidney function in type 2 diabetes. We screened the renal transcriptome of db/db and db/m mice for differentially expressed mRNA transcripts that encode secreted proteins with human orthologs. Whether elevated urine levels of the orthologous proteins correlated with diminished glomerular filtration rate was tested in a cross-sectional study of n = 56 patients with type 2 diabetes. We identified 36 putative biomarker genes in db/db kidneys: 31 upregulated and 5 downregulated. Urinary protein levels of six selected candidates (endothelin-1, lipocalin-2, transforming growth factor-ß, growth and differentiation factor-15, interleukin-6, and macrophage chemoattractant protein-1) were elevated in type 2 diabetic patients with subnormal glomerular filtration rate (i.e., <90 ml·min(-1)·1.73 m(-2)), independent of microalbuminuria, age, sex, race, and use of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. In contrast, urinary levels of fibroblast growth factor were not increased. A composite variable of urine albumin and any of the six candidate markers was associated with subnormal estimated glomerular filtration rate more closely than albumin alone. In addition, urinary endothelin-1, growth and differentiation factor-15, and interleukin-6 were associated with a marker of proximal tubule damage, N-acetyl-ß-d-glucosaminidase activity. These results suggest that gene expression profiling in diabetic mouse kidney can complement existing proteomic-based approaches for renal biomarker discovery in humans.

Dispensing errors and counseling quality in 100 pharmacies.

OBJECTIVE: To evaluate the dispensing accuracy and counseling provided in community chain pharmacies. DESIGN: Cross-sectional study. SETTING: Community chain pharmacies in large metropolitan areas of Florida, Georgia, New Jersey, and New York. PARTICIPANTS: Community chain pharmacies and trained shoppers. INTERVENTIONS: Trained shoppers presented a new prescription order for one of five study drugs to each randomly selected pharmacy, and all encounters with pharmacy staff were recorded on video by ABC News 20/20 staff using hidden cameras. MAIN OUTCOME MEASURES: Dispensing errors on prescriptions for selected medications were the indicator of prescription dispensing accuracy. Frequency of verbal counseling and information categories discussed or included in written information were used to assess the quality of counseling. RESULTS: Of 100 prescriptions dispensed, 22 had one or more deviation from the physician's written order, for a 22% dispensing error rate. Three of the errors were judged to be potentially harmful when dispensed to a typical patient requiring these therapies. A total of 43 shoppers (43%) received verbal counseling, including 16 cases in which the shopper prompted counseling. All shoppers received written information with their prescription, covering an average of 90% of the required topics. Some 68% of the warfarin shoppers purchased aspirin without the pharmacist verbally warning about taking the drugs simultaneously. CONCLUSION: The dispensing error rate of more than one in five prescriptions is similar to the rate found in a similar study conducted 14 years ago, but counseling frequency has decreased significantly during the period.

Use of personal digital assistants for documentation of pharmacists' interventions: a literature review.

PURPOSE: The literature describing pharmacists' use of personal digital assistants (PDAs) as intervention documentation tools in health systems is reviewed. METHODS: A literature search was conducted using MEDLINE and International Pharmaceutical Abstracts to find articles whose title and abstract indicated that the articles' content addressed pharmacists' use of PDAs as intervention documentation tools. Qualitative analyses were conducted to characterize the existing literature on pharmacists' use of PDAs to document interventions in health systems. The articles were categorized using eight characteristics: study type, objective, setting, participants, PDA platform, documentation software, results, and conclusions. RESULTS: A total of 12 articles were included in this review. All articles were classified as descriptive. Two studies lacked objectives, while 10 contained explicitly stated objectives or objectives that could be inferred from article content. The majority of implementation processes occurred in acute care teaching facilities. All study participants were pharmacists. The majority of articles described PDA-based documentation by more than one pharmacist. Results from the articles can be divided into four categories: no measurable comparison performed, anecdotal comparison performed, survey data reported, and measurable comparison performed. Three articles specifically presented information regarding security and confidentiality of patient information. Each article described the use of password protection for the PDAs. CONCLUSION: The use of PDAs may increase the frequency and number of interventions documented by pharmacists; however, there is a lack of well-designed studies reporting the overall outcomes of using PDAs for intervention documentation by pharmacists.

Learning motivational interviewing: scripting a virtual patient.

OBJECTIVES: This article describes a written assignment for a first-year professional communication course to facilitate the understanding and mastery of motivational interviewing in dealing with patient ambivalence and resistance. The goal was to immerse students in how motivational interviewing differs from traditional biomedical counseling with regard to phrasing individual responses to the patient and managing the flow of interaction. METHODS: Students were required to write a script for a working prototype of the Auburn University Virtual Patient. The script had to specify the text for the virtual patient's comments, 2-5 possible responses for the student pharmacist to choose from, and multiple interactional paths representing motivational interviewing, biomedical counseling, and a mix of the 2. RESULTS: Student feedback and test results are reported. Qualitative analysis of written student feedback indicated that (1) the project took too much time because of the complexities of the computer procedures resulting from the Virtual Patient being a prototype, and (2) the computer procedures deflected attention from the critical thinking involved in writing the script. Quantitative item analysis of final examination results indicated that students scored an average one full-letter grade better on the questions about motivational interviewing than on the questions covering other topics. CONCLUSION: The scriptwriting assignment is a challenging exercise in assimilating the verbal skills necessary for using motivational interviewing in patient counseling. Many students exhibited greater interest in motivational interviewing, greater knowledge of why motivational interviewing is successful, greater facility with wording responses, and greater confidence in their ability to use motivational interviewing in the future. Because almost all students had negative reactions to the difficulty and time involved in making their scripts actually work with the virtual patient prototype, future assignments should delete this requirement.

HspE7 treatment of pediatric recurrent respiratory papillomatosis: final results of an open-label trial.

OBJECTIVES: We sought to evaluate the effectiveness of HspE7, a recombinant fusion protein of Hsp65 from Mycobacterium bovis BCG and E7 protein from human papillomavirus 16, to improve the clinical course of pediatric patients with recurrent respiratory papillomatosis. METHODS: An open-label, single-arm intervention study was conducted in 8 university-affiliated medical centers. Twenty-seven male and female patients with recurrent respiratory papillomatosis, ages 2 to 18 years, were enrolled and followed up to 60 weeks. Before enrollment, these patients required surgery on average every 55 days. After a baseline debulking surgery, the patients received HspE7 500 microg subcutaneously monthly, for 3 doses over 60 days. The primary end point was the length of the interval from the last surgery during the treatment period until the first debulking surgery in the posttreatment period, compared with the median intersurgical interval (ISI) of the 4 surgeries before the treatment. RESULTS: The mean of the first posttreatment ISI increased 93% (from 55 days to 106 days; p < .02). The median ISI for all surgeries after treatment was similarly prolonged (mean, 107 days; p < .02), indicating a sustained treatment effect, and was associated with a significant decrease in the number of required surgeries (p < .003). Unexpectedly, the treatment effect was most striking in the 13 female patients, who had statistically significant increases in both the first posttreatment ISI (142%; p < .03) and the median ISI (147%; p < .03). The most common adverse events were mild-to-moderate injection site reactions. CONCLUSIONS: Treatment with HspE7 appears to significantly improve the clinical course in pediatric patients with RRP insofar as it reduces the frequency of required surgeries. These results warrant a confirmatory phase III trial.

Evaluation of software-based telephone counseling to enhance medication persistency among patients with multiple sclerosis.

OBJECTIVE: To evaluate the effect of a software-supported intervention based on the Transtheoretical Model of Change and motivational interviewing on decreasing discontinuation (or increasing persistency) of Avonex (interferon beta-1a--Biogen), a medication for treatment of multiple sclerosis (MS). DESIGN: Randomized controlled experimental design comparison of software-based telephone counseling (intervention group) and standard care (control group). SETTING: United States. PARTICIPANTS: 366 patients with MS. INTERVENTION: Software-based telephone counseling. MAIN OUTCOME MEASURE: Discontinuation of Avonex treatment and movement among stages of the Transtheoretical Model of Change. RESULTS: Patients in the software intervention group demonstrated a statistically significantly lower proportion of Avonex treatment (1.2%) discontinuation than the standard care group (8.7%). In addition, stage movement away from discontinuation of Avonex (i.e., toward continuation of therapy) was significantly higher in the treatment group. CONCLUSION: The Transtheoretical Model of Change constructs and motivational interviewing processes were effectively incorporated into a software-based intervention program, and this significantly decreased the proportion of patients who discontinued treatment of MS with Avonex. The integration of behavioral theory with information systems offers a promising approach for pharmacists and other providers to promote medication persistency.

Patient decision making: strategies for diabetes diet adherence intervention.

BACKGROUND: Patient self-care is critical in controlling diabetes and its complications. Lack of diet adherence is a particular challenge to effective diabetes intervention. The Transtheoretical Model (TTM) of Change, decision-making theory, and self-efficacy have contributed to successful tailoring of interventions in many target behaviors. OBJECTIVE: The purpose of this study was to develop a diagnostic tool, including TTM measures for the stages of change, decisional balance, and self-efficacy, that pharmacists involved in diabetes intervention can use for patients resistant to a diet regimen. METHODS: A questionnaire was developed through a literature review, interviews with diabetic patients, an expert panel input, and pretesting. Cross-sectional implementation of the questionnaire among a convenience sample of 193 type 1 and type 2 diabetic patients took place at 4 patient care sites throughout the southeastern United States. Validated measures were used to collect respondent self-report for the TTM variables and for demographic and diabetes history variables. Social desirability was also assessed. RESULTS: Relationships among TTM measures for diet adherence generally replicated those established for other target behaviors. Salient items were identified as potential facilitators (decisional balance pros) or barriers (decisional balance cons and self-efficacy tempting situations) to change. Social desirability exhibited a statistically significant relationship with patient report of diet adherence, with statistically significant differences in mean social desirability across race categories. CONCLUSIONS: The TTM measures for the stages of change, decisional balance, and self-efficacy are useful for making decisions on individually tailored interventions for diet adherence, with caution asserted about the potential of diabetes patients to self-report the target behavior in a socially desirable manner. Future research directions, implications, and limitations of the findings are also presented.

Medication adherence and persistence: a comprehensive review.

Estimates of adherence to long-term medication regimens range from 17% to 80%, and nonadherence (or nonpersistence) can lead to increased morbidity, mortality, and healthcare costs. Multifaceted interventions that target specific barriers to adherence are most effective, because they address the problems and reinforce positive behaviors. Providers must assess their patients' understanding of the illness and its treatment, communicate the benefits of the treatment, assess their patients' readiness to carry out the treatment plan, and discuss any barriers or obstacles to adherence that patients may have. A positive, supporting, and trusting relationship between patient and provider improves adherence. Individual patient factors also affect adherence. For example, conditions that impair cognition have a negative impact on adherence. Other factors--such as the lack of a support network, limited English proficiency, inability to obtain and pay for medications, or severe adverse effects or the fear of such effects--are all barriers to adherence. There are multiple reasons for nonadherence or nonpersistence; the solution needs to be tailored to the individual patient's needs. To have an impact on adherence, healthcare providers must understand the barriers to adherence and the methods or tools needed to overcome them. This report describes the barriers to medication adherence and persistence and interventions that have been used to address them; it also identifies interventions and compliance aids that practitioners and organizations can implement.

Predicting treatment discontinuation among patients with multiple sclerosis: application of the transtheoretical model of change.

OBJECTIVE: To delineate factors associated with discontinued use of the multiple sclerosis (MS) medication Avonex (interferon beta-1a--Biogen) as part of an effort to develop an intervention to promote treatment persistency. DESIGN: In-depth telephone interviews followed by a 12-page written questionnaire delivered by mail. SETTING: United States. PARTICIPANTS: Of 946 patients with MS who were contacted, 531 (56%) completed questionnaires; 79% of respondents were currently using Avonex for treatment of MS. MAIN OUTCOME MEASURE: Discontinuation of Avonex treatment, with analysis based on the theoretical framework of the Transtheoretical Model of Change. RESULTS: Four key variables (pros of Avonex use, cons of Avonex use, highest level of education completed, and level of disability) accurately identified 82% of patients who discontinued Avonex use, while also correctly identifying 81% of patients who stayed on the drug. CONCLUSION: Constructs from the Transtheoretical Model of Change were effective in differentiating patients who had discontinued their Avonex treatment versus patients who continued treatment. This behavioral model likely would be an effective framework for a medication persistency intervention.