An indirect treatment comparison of the efficacy of patisiran and tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy

Background: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a progressive, life-threatening disease. Until recently, tafamidis was the only approved pharmacotherapy. Patisiran significantly improved polyneuropathy and quality of life (QoL) in the phase III APOLLO trial. In the absence of direct comparisons, this analysis aimed to evaluate the comparative efficacy of tafamidis and patisiran in hATTR amyloidosis with polyneuropathy.

Research design and methods: Randomized controlled trial evidence for tafamidis was identified by systematic literature review. Indirect treatment comparisons were performed using the standard pairwise Bucher method for endpoints used in both APOLLO and the tafamidis Fx-005 trial: change from baseline in Neuropathy Impairment Score-lower limbs (NIS-LL), Norfolk QoL-Diabetic Neuropathy questionnaire (QoL-DN), NIS-LL response, and mBMI vs. placebo. Inter-trial population differences were assessed by sensitivity analysis.

Results: The base-case analysis (FAP Stage 1 APOLLO patients vs. intent-to-treat Fx-005 population) suggested patisiran had a greater treatment effect vs. tafamidis for all endpoints, with significant improvements in mean change in NIS-LL (–5.49) and QoL-DN (–13.10) from baseline to Month 18. Similar trends were observed in all sensitivity analyses.

Conclusions: In the absence of direct comparisons, this analysis suggests patisiran has a greater treatment effect than tafamidis in patients with hATTR amyloidosis with polyneuropathy.     

Using educational games to promote the seeking of a pharmacist and to teach key medication use messages: Results from an inner city health party

BackgroundLow health literacy affects 80–90 million Americans with low-income, minority populations being more vulnerable to this condition. One method of addressing limited literacy that may be particularly well accepted within vulnerable populations is the use of educational board games in order to emphasize seeking health information from reliable sources such as pharmacists.ObjectiveThe research objective was to determine if the use of educational board games could impact community pharmacy patron intentions to seek pharmacist advice in an urban, minority, economically-disadvantaged population.MethodsFour medication-related educational games were played at an urban community pharmacy under the leadership of pharmacy students in the setting of a health party. Game messages, design, and evaluation processes were uniquely guided by community members' input. A verbally administered questionnaire measured game impact via knowledge and perception questions with responses compared between a non-randomly allocated intervention group and a control group.ResultsNinety-nine adults were included in the intervention (or game) group and 94 adults were in the control group. Game participants were significantly more likely than the control group to indicate they would seek pharmacist medication advice in the future.ConclusionEducational board games played in the setting of a health party can be a fun and effective way to convey selected health messages within an urban, minority, economically disadvantaged population. Community input into game development and layering multiple strategies for overcoming health literacy barriers were essential components of this initiative.     

Focus group interviews: how aromatherapists feel about changing their practice through undertaking a randomised controlled trial?

In 2003/2007 a randomised controlled trial (RCT) was undertaken into the efficacy of aromatherapy in reducing levels of anxiety amongst palliative care patients. In the study patients were randomised into one of three treatment groups. The participating aromatherapists treated patients according to a strict research protocol. As the trial commenced, the therapists indicated a concern about a potential loss of their holistic principles while undertaking the trial. These genuine concerns formed the impetus to undertake a qualitative study to illuminate the aromatherapists' experience of changing their practice. Findings and discussions are through the themes that emerged. It appears that participating in a RCT does impact on aromatherapists' holistic practice but equally important is their commitment to undertake the research.     

Elevated L-lactate Promotes Major Cellular Pathologies Associated with Neurodegenerative Diseases

Dear Editor,Small,short-chain fatty acids(SCFAs)(acetic acid,propionic acid,and butyric acid:conjugate bases,acetate,propionate,and butyrate)as well as the alpha-hydroxy acid,L-lactic acid(conjugate base,L-lactate)are important energy substrates and signaling molecules in the central nervous system(CNS)[1,2].L-lactic acid is produced by glycolysis[3]and gut microbes[4]and is released in large quantities during exercise[5].     

Biocompatible fluorocarbon liquid underlays for in situ extraction of isoprenoids from microbial cultures

Microbial production of heterologous metabolites is now a mature technology in many host organisms, opening new avenues for green production processes of specialty chemicals. At lab scale, petroleum-based hydrophobic bio-compatible solvents like dodecane can be used as a second phase on top of microbial cultures to act as a physical sink for heterologous hydrocarbon products like isoprenoids. However, this approach has significant drawbacks at scale due to the difficulty of handling solvents and their potential contamination with unwanted byproducts of their manufacture. We discovered that synthetic perfluorocarbon liquids (FCs), commonly used for heat transfer, can also act as physical sinks for microbially produced isoprenoid compounds. FCs are stable, inert, and are amenable to direct liquid–liquid extraction with alcohols for rapid product isolation. These liquids are more dense than water and form a lower phase to microbial cultures rather than an upper phase as with other solvents. Their ability to form an under-layer or ‘underlay’ also enables the cultivation of microbes directly at the FC–culture medium interface via gravity settling, which could open their application for filamentous or mat-forming organisms. We present comparisons of the isoprenoid extraction potential of three commercial FCs: FC-3283, FC-40, and FC-770 with engineered green microalga cultures producing patchoulol, taxadiene, casbene, or 13R(+) manoyl oxide. We demonstrate that FCs are promising alternatives to traditional solvents and open new avenues in bio-process design for microbial heterologous metabolite milking.

A novel bioprocess to capture and purify terpenoids produced by engineered microbes using 2-phase cultivation of the algae with liquid perfluorocarbons followed by liquid–liquid extraction of the terpenoids with ethanol.     

Current national practice patterns for inpatient management of ventral abdominal wall hernia in the United States

Background

The health-care burden related to ventral hernia management is substantial, with more than 3 billion dollars in expenditures annually in the US. Previous studies have suggested that the utilization of laparoscopic repair remains relatively low although national volume estimates have not been reported. We sought to estimate the inpatient national volume of elective ventral hernia surgery and characterize the proportion of laparoscopic versus open operations.

Methods

We analyzed data from the Nationwide Inpatient Sample to identify adults with a diagnosis of an umbilical, incisional, or ventral hernia who underwent an elective inpatient repair between 2009 and 2010. Cases that involved other major abdominal or pelvic operations were excluded. Covariates included patient demographics, surgical approach, and use of mesh. National surgical volume estimates were generated and length of stay and total hospital charges were compared for laparoscopic versus open repairs.

Results

A total of 112,070 ventral hernia repairs were included in the analysis: 72.1 % (n = 80,793) were incisional hernia repairs, while umbilical hernia repairs comprised only 6.9 % (n = 7,788). Laparoscopy was utilized in 26.6 % (n = 29,870) of cases. Mesh was placed in 85.8 % (n = 96,265) of cases, including 49.3 % (n = 3,841) of umbilical hernia repairs and 90.1 % (n = 72,973) of incisional hernia repairs. Length of stay and total hospital charges were significantly lower for laparoscopic umbilical, incisional, and “other” ventral hernia repairs (p values all <0.001). Total hospital charges during this 2-year period approached 4 billion dollars ($746 million for laparoscopic repair; $3 billion for open repair).

Conclusions

Utilization of laparoscopy for elective abdominal wall hernia repair remains relatively low in the US despite its excellent outcomes. Given the substantial financial burden associated with these hernias, future research focused on preventing the development and optimizing the surgical treatment of ventral abdominal wall hernias is warranted.     

A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin

The oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and up-regulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.     

The Availability and Use of Out-of-Hospital Physiologic Information to Identify High-Risk Injured Children in a Multisite,Population-Based Cohort

Objective. The validity of using adult physiologic criteria to triage injured children in the out-of-hospital setting remains unproven. Among children meeting adult field physiologic criteria, we assessed the availability of physiologic information, the incidence of death or prolonged hospitalization, and whether age-specific criteria would improve the specificity of the physiologic triage step. Methods. We analyzed a prospective, out-of-hospital cohort of injured children aged ≤14 years collected from December 2005 through February 2007 by 237 emergency medical services (EMS) agencies transporting to 207 acute care hospitals (trauma and nontrauma centers) in 11 sites across the United States and Canada. Inclusion criteria were standard adult physiologic values: systolic blood pressure (SBP) ≤90 mmHg, respiratory rate < 10 or > 29 breaths/min, Glasgow Coma Scale (GCS) score ≤12, and field intubation attempt. Seven physiologic variables (including age-specific values) and three demographic and mechanism variables were included in the analysis. “High-risk” children included those who died (field or in-hospital) or were hospitalized > 2 days. The decision tree was derived and validated using binary recursive partitioning. Results. Nine hundred fifty-five children were included in the analysis, of whom 62 (6.5%) died and 117 (12.3%) were hospitalized > 2 days. Missing values were common, ranging from 6% (respiratory rate) to 53% (pulse oximetry), and were associated with younger age and high-risk outcome. The final decision rule included four variables (assisted ventilation, GCS score < 11, pulse oximetry < 95%, and SBP > 96 mmHg), which demonstrated improved specificity (71.7% [95% confidence interval (CI) 66.7–76.6%]) at the expense of missing high-risk children (sensitivity 76.5% [95% CI 66.4–86.6%]). Conclusions. The incidence of high-risk injured children meeting adult physiologic criteria is relatively low and the findings from this sample do not support using age-specific values to better identify such children. However, the amount and pattern of missing data may compromise the value and practical use of field physiologic information in pediatric triage.