Publications

BACKGROUND

The widespread use of artesunate-amodiaquine (ASAQ) for treating uncomplicated malaria makes it important to gather and analyse information on its tolerability.

METHODS

An individual-patient tolerability analysis was conducted using data from eight randomized controlled clinical trials conducted at 17 sites in nine sub-Saharan countries comparing ASAQ to other anti-malarial treatments. All patients who received at least one dose of the study drug were included in the analysis. Differences in adverse event (AE) and treatment emergent adverse event (TEAE) were analysed by Day 28.

RESULTS

Of the 6,179 patients enrolled (74% <5 years of age), 50% (n = 3,113) received ASAQ, 20% (n = 1,217) another ACT, and 30% (n = 1,849) a non-ACT (combination or single-agent) treatment. Overall, 8,542 AEs were recorded. The proportion of patients experiencing at least one gastro-intestinal AE on ASAQ was 43% (and higher than that with artemether-lumefantrine and dihydroartemisinin-piperaquine at two sites), and was 23% for any other AEs (not different from other treatments). Specifically, the risk of diarrhoea, vomiting, cough and weakness was lower with artemether-lumefantrine; artemether-lumefantrine and dihydroartemisinin-piperaquine carried a higher risk of pruritus, chloroquine-SP had a higher risk of nausea. Parasitological recurrence increased the risk of occurrence of any AE. No other difference was detected. Comparing AE to TEAE in patients who had pre-treatment occurrence and grades of intensity recorded, AEs were significantly more related to the pre-treatment prevalence of the symptom (p = 0.001, Fisher test); AEs overestimated TEAEs by a factor ranging from none to five-fold. The overall incidence of serious AEs (SAEs) with ASAQ was nine per 1,000 (29/3,113) and mortality was one per 1,000 (three deaths, none drug-related); both were similar to other treatments.

CONCLUSION

ASAQ was comparatively well-tolerated. Safety information is important, and must be collected and analysed in a standardized way. TEAEs are a more objective measure of treatment-induced toxicity.

The identification of homologies, whether morphological, molecular, or genetic, is fundamental to our understanding of common biological principles. Homologies bridging the great divide between deuterostomes and protostomes have served as the basis for current models of animal evolution and development. It is now appreciated that these two clades share a common developmental toolkit consisting of conserved transcription factors and signaling pathways. These patterning genes sometimes show common expression patterns and genetic interactions, suggesting the existence of similar or even conserved regulatory apparatus. However, previous studies have found no regulatory sequence conserved between deuterostomes and protostomes. Here we describe the first such enhancers, which we call bilaterian conserved regulatory elements (Bicores). Bicores show conservation of sequence and gene synteny. Sequence conservation of Bicores reflects conserved patterns of transcription factor binding sites. We predict that Bicores act as response elements to signaling pathways, and we show that Bicores are developmental enhancers that drive expression of transcriptional repressors in the vertebrate central nervous system. Although the small number of identified Bicores suggests extensive rewiring of cis-regulation between the protostome and deuterostome clades, additional Bicores may be revealed as our understanding of cis-regulatory logic and sample of bilaterian genomes continue to grow.

BACKGROUND

Reducing symptom burden is paramount at the end-of-life, but typically considered secondary to risk factor control in chronic disease, such as diabetes. Little is known about the symptom burden experienced by adults with type 2 diabetes and the need for symptom palliation.

OBJECTIVE

To examine pain and non-pain symptoms of adults with type 2 diabetes over the disease course - at varying time points before death and by age.

DESIGN

Survey follow-up study.

PARTICIPANTS

13,171 adults with type 2 diabetes, aged 30-75 years, from Kaiser Permanente, Northern California, who answered a baseline symptom survey in 2005-2006.

MAIN MEASURES

Pain and non-pain symptoms were identified by self-report and medical record data. Survival status from baseline was categorized into ≤ 6, >6-24, or alive >24 months.

KEY RESULTS

Mean age was 60 years; 48 % were women, and 43 % were non-white. Acute pain was prevalent (41.8 %) and 39.7 % reported chronic pain, 24.6 % fatigue, 23.7 % neuropathy, 23.5 % depression, 24.2 % insomnia, and 15.6 % physical/emotional disability. Symptom burden was prevalent in all survival status categories, but was more prevalent among those with shorter survival, p< .001. Adults ≥ 60 years who were alive >24 months reported more physical symptoms such as acute pain and dyspnea, whereas participants <60 years reported more psychosocial symptoms, such as depressed mood and insomnia. Adjustment for duration of diabetes and comorbidity reduced the association between age and pain, but did not otherwise change our results.

CONCLUSIONS

In a diverse cohort of adults with type 2 diabetes, pain and non-pain symptoms were common among all patients, not only among those near the end of life. However, symptoms were more prevalent among patients with shorter survival. Older adults reported more physical symptoms, whereas younger adults reported more psychosocial symptoms. Diabetes care management should include not only good cardiometabolic control, but also symptom palliation across the disease course.

OBJECTIVES

We sought to assess the effectiveness of automated mechanical dyssynchrony (MD) parameters based on regional heterogeneity of strain (circumferential [CURE], longitudinal [LURE], and radial uniformity ratio estimates) relative to parameters based on regional time to peak contraction with cardiac magnetic resonance (CMR) cine DENSE (Displacement Encoding with Stimulated Echoes) validated with myocardial tissue tagging (MTT) strain data.

BACKGROUND

Dyssynchrony measures based on the Fourier transformation (FT) of regional strain, such as CURE (previously evaluated in cardiac resynchronization therapy candidates), directly assess MD and yield straightforward global dyssynchrony indexes; however, performance relative to the 12-segment standard deviation of time to peak strain (SD12) or maximal regional delay in time to peak strain is unknown.

METHODS

Cine DENSE and MTT were obtained with CMR (1.5-T Siemens Avanto, Siemens, Erlangen, Germany) in 13 canines: 3 normal control subjects, 5 with tachycardia pacing-induced heart failure (HF) and left bundle branch ablation (LBBB-HF), and 5 with HF and narrow QRS (NQRS-HF). Strain and dyssynchrony parameters were determined with both CMR methods.

RESULTS

Both HF groups had reduced peak strains and left ventricular ejection fraction compared with normal cases. There was strong agreement between cine DENSE and MTT on the basis of intraclass correlation coefficients (CURE: 0.99, 95% CI: 0.96 to 1.00; LURE: 0.92, 95% CI: 0.77 to 0.98; circumferential strain [E(CC)]: 0.95, 95% CI: 0.72 to 0.99; longitudinal strain [E(LL)]: 0.82, 95% CI: 0.42 to 0.97). The FT-based metrics (scale 0 to 1), in particular CURE, discriminated highly between LBBB-HF and NQRS-HF groups (median difference): CURE: 0.60, 95% CI: 0.43 to 0.76; LURE: 0.39, 95% CI: 0.19 to 0.58; radial uniformity ratio estimate: 0.22, 95% CI: 0.04 to 0.40). In contrast, relative confidence intervals for group differences in time-to-peak parameters were wide, indicating less consistent discrimination (median difference): SD12-E(CC): 52.5, 95% CI: -4.0 to 109.2; SD12-E(LL): 40.9, 95% CI: -5.3 to 87.1; SD12-radial strain: 42.0, 95% CI: 0.4 to 83.6). Correlations between FT-based and time-to-peak parameters were significant (CURE/SD12-E(CC): r = -0.62, p = 0.03; LURE/SD12-E(LL): r = -0.76, p = 0.005) but not as tight as correlations between time-to-peak parameters.

CONCLUSIONS

Automated FT-based circumferential, radial, and longitudinal dyssynchrony measures compare favorably with time-to-peak parameters. Cine DENSE was effective for this application and validated with MTT. Further clinical evaluation in cardiac resynchronization therapy candidates with CMR or other imaging modalities is warranted.