Measuring patient-centred long-term outcome following a bloodstream infection: a pilot study.

OBJECTIVES: To evaluate the sequential organ failure assessment (SOFA) and modified SOFA (mSOFA) scoring and a novel performance score based on the Karnofsky score for measuring outcome following a bloodstream infection (BSI). METHOD: This prospective observational cohort study assessed patients with BSI for mortality and functional outcomes with a novel performance score: the functional bloodstream infection score (FBIS). We also tested the SOFA and, given the difficulties with measuring SOFA on ward-based patients, the mSOFA over the first 7 days following a BSI for their association with outcomes. RESULTS: One hundred participants were prospectively recruited. Mortality at 52 weeks following BSI was 21% (21/100). Only 57% of survivors (39/69) were at their baseline functional status at 52 weeks. Stable or improved SOFA/mSOFA over the first 7 days was associated with survival and return to premorbid performance score (risk ratio 3.2, 95%CI 1.3-9.4, p < 0.01). CONCLUSIONS: The acute change in SOFA/mSOFA was associated with 52-week survival and return to premorbid functional performance. The FBIS measurement represents a simple and easy-to-apply measure of functional performance for patients with BSI and was associated with a high response rate (89%) from participants.

Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition.

OBJECTIVES: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). METHODS: Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. RESULTS: Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. CONCLUSIONS: These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.

Expression and function of the ghrelin axis, including a novel preproghrelin isoform, in human breast cancer tissues and cell lines.

While oestrogen, progesterone and growth factors, including growth hormone (GH), are clearly implicated in the pathogenesis of breast cancer, there is now evidence that the newly described ghrelin axis is also involved. The aims of this study were to investigate the expression of the ghrelin axis in breast cancer tissues and cell lines and to examine the effect of ghrelin on breast cancer cell proliferation in vitro. Ghrelin and its functional receptor, the growth hormone secretagogue receptor (GHSR) type 1a, were expressed in normal breast tissue and breast cancer specimens and cell lines. In contrast, the truncated GHSR type 1b isoform was exclusively expressed in breast carcinoma, suggesting that it has potential as a diagnostic marker. Ghrelin treatment significantly increases the proliferation of the MDA-MB-435 and MDA-MB-231 breast cancer cell lines in vitro. In addition, we have described the expression of a human preproghrelin isoform, exon 3-deleted preproghrelin, which encodes mature ghrelin plus a novel C-terminal peptide. Quantitative RT-PCR was used to demonstrate that this mRNA isoform is highly expressed in the MDA-MB-435 metastatic breast cancer cell line relative to the benign MCF-10A breast epithelial cell line. The unique C-terminal peptide of exon 3-deleted preproghrelin is expressed in the glandular epithelium of breast cancer tissues, with high-grade carcinoma exhibiting the strongest immunoreactivity. The data presented here suggest that components of the ghrelin axis may represent novel markers for breast cancer and potential therapeutic targets.

An efficient solid-phase strategy for the construction of chemokines.

Synthesis of chemokines via stepwise SPPS approaches has been shown to be a challenge. Herein, a complete study of different coupling methods, solvents and temperature combined with a continuous-flow synthesizer equipped with feedback monitoring was carried out. The results from this study indicate that this family of molecules can be prepared using an Fmoc/Bu(t) chemical approach and provide a general method to apply for the elongation of other difficult sequences.