Background: Renal replacement therapy (RRT) has not always been shown to benefit end-stage renal failure patients who are elderly or have multiple comorbidities in terms of survival or symptom control. Conservative management may be a viable alternative offering comparable health-related quality of life. Methods: This is a prospective observational study of 101 patients who reached an estimated glomerular filtration rate of 8-12 ml/min and were either ≥75 years old or had an age-adjusted Charlson Comorbidity Index ≥8. Patients were all initially on conservative management; 38 later commenced renal replacement therapy while the rest remained conservatively managed. The Kidney Disease Quality of Life-Short Form was assessed at baseline and various scheduled time points over 24 months. The mixed model methodology was used to estimate the quality of life patterns and adjust for covariates. Results: In the conservative management group, the Physical Component Summary and Mental Component Summary scores were stable and showed no significantly different trajectories from the RRT group (both p > 0.05). Though RRT was associated with an improvement in the Cognitive Function Scale score, it was also associated with worse scores on the Effect of Kidney Disease and Burden of Kidney Disease Scale scores. Conclusions: RRT does not improve health-related quality of life of end-stage kidney failure patients who are elderly or have a high comorbidity burden.

A Plasmodium falciparum chimeric protein 2.9 (PfCP-2.9) was constructed consisting of the C-terminal regions of two leading malaria vaccine candidates, domain III of apical membrane ag-1 (AMA-1) and 19-kDa C-terminal fragment of the merozoite surface protein 1 (MSP1). The PfCP-2.9 was produced by Pichia pastoris in secreted form with a yield of 2600 mg/L and ∼1 g/L of final product was obtained from a three-step purification process. Analysis of conformational properties of the chimeric protein showed that all six conformational mAbs interacted with the recombinant protein were reduction-sensitive, indicating that fusion of the two cysteine-rich proteins retains critical conformational epitopes. PfCP-2.9 was found to be highly immunogenic in rabbits as well as in rhesus monkeys (Macaca mulatta). The chimeric protein induced both anti-MSP1–19 and anti-AMA-1(III) Abs at levels 11- and 18-fold higher, respectively, than individual components did. Anti-PfCP-2.9 sera from both rabbits and rhesus monkeys almost completely inhibited in vitro growth of the P. falciparum FCC1/HN and 3D7 lines when tested at a 6.7-fold dilution. It was shown that the inhibition is dependent on the presence of Abs to the chimeric protein and their disulfide bond-dependent conformations. Moreover, the activity was mediated by a combination of growth-inhibitory Abs generated by the individual MSP1–19 and AMA-1(III) of PfCP-2.9. The combination of the extremely high yield of the protein and enhancement of its immune response provides a basis to develop an effective and affordable malaria vaccine.

BackgroundThe P. falciparum chimeric protein 2.9 (PfCP-2.9) consisting of the sequences of MSP1-19 and AMA-1 (III) is a malaria vaccine candidate that was found to induce inhibitory antibodies in rabbits and monkeys. This was a phase I randomized, single-blind, placebo-controlled, dose-escalation study to evaluate the safety and immunogenicity of the PfCP-2.9 formulated with a novel adjuvant Montanide ISA720. Fifty-two subjects were randomly assigned to 4 dose groups of 10 participants, each receiving the test vaccine of 20, 50, 100, or 200 µg respectively, and 1 placebo group of 12 participants receiving the adjuvant only.Methods and FindingsThe vaccine formulation was shown to be safe and well-tolerated, and none of the participants withdrew. The total incidence of local adverse events (AEs) was 75%, distributed among 58% of the placebo group and 80% of those vaccinated. Among the vaccinated, 65% had events that were mild and 15% experienced moderate AEs. Almost all systemic adverse reactions observed in this study were graded as mild and required no therapy. The participants receiving the test vaccine developed detectable antibody responses which were boosted by the repeated vaccinations. Sixty percent of the vaccinated participants had high ELISA titers (>1∶10,000) of antigen-specific antibodies which could also recognize native parasite proteins in an immunofluorescence assay (IFA).ConclusionThis study is the first clinical trial for this candidate and builds on previous investigations supporting PfCP-2.9/ISA720 as a promising blood-stage malaria vaccine. Results demonstrate safety, tolerability (particularly at the lower doses tested) and immunogenicity of the formulation. Further clinical development is ongoing to explore optimizing the dose and schedule of the formulation to decrease reactogenicity without compromising immunogenicity.Trial RegistrationChinese State Food and Drug Administration (SFDA) 2002SL0046; Controlled-Trials.com ISRCTN66850051 [66850051]

Most of the scales in the Chinese version of the KDQOL-SF were valid and achieved internal consistency reliability, except for the Work Status scale. Also, the internal consistency reliability of two disease-targeted scales was too high, suggesting room for reduction of some items to reduce burden on respondents.

This exploratory study shows that IV Fentanyl can alleviate dyspnea in some patients but is an example of the difficulties conducting dyspnea research. Future studies would benefit from novel developments in the areas of measuring dyspnea in dying patients and statistical analysis of small sample sizes.