A pragmatic patient-reported outcome strategy for rare disease clinical trials: application of the EORTC item library to myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia.

BackgroundNovel, pragmatic, patient-centered strategies are needed to ensure fit-for-purpose patient-reported outcomes (PRO) instruments in clinical trial research for rare diseases such as myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). The objective of the current study was to select supplemental items to add to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30) to ensure content coverage of all important clinical concepts in patients with higher-risk (HR) MDS, low-blast count (LB) AML, and CMML, thus, improving the instrument's ability to detect clinically meaningful treatment benefit for this context of use.MethodsOur mixed methods approach comprised literature review, clinician consultation (n = 3), and qualitative and quantitative analysis of two stages of patient interview data (n = 14, n = 18) to select library bank items to supplement a generic cancer PRO, the EORTC QLQ-C30.ResultsUnique symptom (n = 54) and impact (n = 72) concepts were organized into conceptual frameworks of treatment benefit, compared with EORTC QLQ-C30 items and conceptual gaps identified. Supplemental items (n = 13) addressing those gaps were selected from the EORTC Item Library and tested with patients. Supplemental item endorsement frequencies met World Health Organization Quality of Life criteria, suggesting good targeting and relevance for this sample. However, three supplemental items were confirmed as problematic based upon cognitive debriefing results, and expert clinical consultations. Ultimately, 10 supplemental items (n = 7 symptom; n = 3 impact) were selected for the MDS/AML/CMML context.ConclusionSupplemental items were selected to enhance the conceptual coverage of the EORTC QLQ-C30 in the areas of fatigue, shortness of breath, and functioning

Phenotypes of Non-Attached Pseudomonas aeruginosa Aggregates Resemble Surface Attached Biofilm

For a chronic infection to be established, bacteria must be able to cope with hostile conditions such as low iron levels, oxidative stress, and clearance by the host defense, as well as antibiotic treatment. It is generally accepted that biofilm formation facilitates tolerance to these adverse conditions. However, microscopic investigations of samples isolated from sites of chronic infections seem to suggest that some bacteria do not need to be attached to surfaces in order to establish chronic infections. In this study we employed scanning electron microscopy, confocal laser scanning microscopy, RT-PCR as well as traditional culturing techniques to study the properties of Pseudomonas aeruginosa aggregates. We found that non-attached aggregates from stationary-phase cultures have comparable growth rates to surface attached biofilms. The growth rate estimations indicated that, independently of age, both aggregates and flow-cell biofilm had the same slow growth rate as a stationary phase shaking cultures. Internal structures of the aggregates matrix components and their capacity to survive otherwise lethal treatments with antibiotics (referred to as tolerance) and resistance to phagocytes were also found to be strikingly similar to flow-cell biofilms. Our data indicate that the tolerance of both biofilms and non-attached aggregates towards antibiotics is reversible by physical disruption. We provide evidence that the antibiotic tolerance is likely to be dependent on both the physiological states of the aggregates and particular matrix components. Bacterial surface-attachment and subsequent biofilm formation are considered hallmarks of the capacity of microbes to cause persistent infections. We have observed non-attached aggregates in the lungs of cystic fibrosis patients; otitis media; soft tissue fillers and non-healing wounds, and we propose that aggregated cells exhibit enhanced survival in the hostile host environment, compared with non-aggregated bacterial populations

Extracellular DNA Chelates Cations and Induces Antibiotic Resistance in Pseudomonas aeruginosa Biofilms

Biofilms are surface-adhered bacterial communities encased in an extracellular matrix composed of DNA, bacterial polysaccharides and proteins, which are up to 1000-fold more antibiotic resistant than planktonic cultures. To date, extracellular DNA has been shown to function as a structural support to maintain Pseudomonas aeruginosa biofilm architecture. Here we show that DNA is a multifaceted component of P. aeruginosa biofilms. At physiologically relevant concentrations, extracellular DNA has antimicrobial activity, causing cell lysis by chelating cations that stabilize lipopolysaccharide (LPS) and the outer membrane (OM). DNA-mediated killing occurred within minutes, as a result of perturbation of both the outer and inner membrane (IM) and the release of cytoplasmic contents, including genomic DNA. Sub-inhibitory concentrations of DNA created a cation-limited environment that resulted in induction of the PhoPQ- and PmrAB-regulated cationic antimicrobial peptide resistance operon PA3552–PA3559 in P. aeruginosa. Furthermore, DNA-induced expression of this operon resulted in up to 2560-fold increased resistance to cationic antimicrobial peptides and 640-fold increased resistance to aminoglycosides, but had no effect on β-lactam and fluoroquinolone resistance. Thus, the presence of extracellular DNA in the biofilm matrix contributes to cation gradients, genomic DNA release and inducible antibiotic resistance. DNA-rich environments, including biofilms and other infection sites like the CF lung, are likely the in vivo environments where extracellular pathogens such as P. aeruginosa encounter cation limitation

Systemic Biomarkers of Neutrophilic Inflammation, Tissue Injury and Repair in COPD Patients with Differing Levels of Disease Severity

The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV1, FEV1/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV1 related parameters. Associations of Fibrinogen with DLCO and MPO with FEV1/FVC were stronger in patients without metabolic syndrome (r  =  −0.52, p  = 0.005 and r  =  −0.61, p  = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r  =  −0.25, p  = 0.47 and r  =  −0.15, p  = 0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV1, FEV1/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Role of Deformation in the Oxidation Behavior of Binary Nickel-Chromium Alloys

Nickel-based alloys are well suited for high temperature applications due to their retention of mechanical performance at elevated temperatures; however, these high temperatures are also conducive to accelerated oxidation in these alloys. Oxidation of these alloys can be mitigated by the addition of chromium to the alloy composition and the use of deformation that provides short-circuit diffusion pathways to the surface allowing the rapid formation of protective oxide scales. The beneficial effects of deformation on oxide scale protection have been widely observed in nickel alloy systems, but the fundamental mechanisms on the microscale and nanoscale remain poorly understood. We characterized alloy and scale microstructures developing in model Ni alloys with varying levels of deformation during oxidation at intermediate and high temperatures to establish a mechanistic understanding and advance the current framework for oxidation resistant alloy design.http://deepblue.lib.umich.edu/bitstream/2027.42/176951/1/NiCrPaper-cookeam_-_Aaron_Cooke.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/176951/2/NiCrPosterforDesignExpo-cookeam.pptx_-_Aaron_Cooke.pd

BCI-Triggered functional electrical stimulation therapy for upper limb

We present here the integration of brain-computer interfacing (BCI) technology with functional electrical stimulation therapy to restore voluntary function. The system was tested with a single man with chronic (6 years) severe left hemiplegia resulting from a stroke. The BCI, implemented as a simple “brain-switch” activated by power decreases in the 18 Hz – 28 Hz frequency range of the participant’s electroencephalograpic signals, triggered a neuroprosthesis designed to facilitate forward reaching, reaching to the mouth, and lateral reaching movements. After 40 90-minute sessions in which the participant attempted the reaching tasks repeatedly, with the movements assisted by the BCI-triggered neuroprosthesis, the participant’s arm function showed a clinically significant six point increase in the Fugl-Meyer Asessment Upper Extermity Sub-Score. These initial results suggest that the combined use of BCI and functional electrical stimulation therapy may restore voluntary reaching function in individuals with chronic severe hemiplegia for whom the rehabilitation alternatives are very limited

EEG-Triggered Functional Electrical Stimulation Therapy for Restoring Upper Limb Function in Chronic Stroke with Severe Hemiplegia

We report the therapeutic effects of integrating brain-computer interfacing technology and functional electrical stimulation therapy to restore upper limb reaching movements in a 64-year-old man with severe left hemiplegia following a hemorrhagic stroke he sustained six years prior to this study. He completed 40 90-minute sessions of functional electrical stimulation therapy using a custom-made neuroprosthesis that facilitated 5 different reaching movements. During each session, the participant attempted to reach with his paralyzed arm repeatedly. Stimulation for each of the movement phases (e.g., extending and retrieving the arm) was triggered when the power in the 18 Hz–28 Hz range (beta frequency range) of the participant’s EEG activity, recorded with a single electrode, decreased below a predefined threshold. The function of the participant’s arm showed a clinically significant improvement in the Fugl-Meyer Assessment Upper Extremity (FMA-UE) subscore (6 points) as well as moderate improvement in Functional Independence Measure Self-Care subscore (7 points). The changes in arm’s function suggest that the combination of BCI technology and functional electrical stimulation therapy may restore voluntary motor function in individuals with chronic hemiplegia which results in severe upper limb deficit (FMA-UE ≤ 15), a population that does not benefit from current best-practice rehabilitation interventions

EEG-Triggered Functional Electrical Stimulation Therapy for Restoring Upper Limb Function in Chronic Stroke with Severe Hemiplegia

We report the therapeutic effects of integrating brain-computer interfacing technology and functional electrical stimulation therapy to restore upper limb reaching movements in a 64-year-old man with severe left hemiplegia following a hemorrhagic stroke he sustained six years prior to this study. He completed 40 90-minute sessions of functional electrical stimulation therapy using a custom-made neuroprosthesis that facilitated 5 different reaching movements. During each session, the participant attempted to reach with his paralyzed arm repeatedly. Stimulation for each of the movement phases (e.g., extending and retrieving the arm) was triggered when the power in the 18 Hz–28 Hz range (beta frequency range) of the participant’s EEG activity, recorded with a single electrode, decreased below a predefined threshold. The function of the participant’s arm showed a clinically significant improvement in the Fugl-Meyer Assessment Upper Extremity (FMA-UE) subscore (6 points) as well as moderate improvement in Functional Independence Measure Self-Care subscore (7 points). The changes in arm’s function suggest that the combination of BCI technology and functional electrical stimulation therapy may restore voluntary motor function in individuals with chronic hemiplegia which results in severe upper limb deficit (FMA-UE ≤ 15), a population that does not benefit from current best-practice rehabilitation interventions.Peer Reviewe

Infant and young child feeding practices are associated with childhood anaemia and stunting in sub-Saharan Africa

Abstract Background The co-occurrence of anaemia and stunting (CAS) presents acute development and morbidity challenges to children particularly in sub-Saharan Africa (SSA). Evidence on the effect of child feeding recommendations on CAS is scarce. Methods We used data from 22 recent Demographic and Health Surveys in SSA countries to examine the association between caregivers’ implementation of recommendations on infant and young child feeding and the CAS in their 6- to 23-mo-old children. Results Overall, in multiple logistic regression models, child feed index score, high wealth of household, increasing household size, household head with at least secondary school education, improved sanitation of household, an increase in caregiver’s age and caregiver’s with at least secondary education were associated with lower odds of CAS (i.e., AOR: 0.86; 95% CI; 0.84 – 0.88: 0.75; 0.69 – 0.82: 0.98, 0.98 – 0.99: 0.76, 0.70 – 0.83: 0.81, 0.74 – 0.87: 0.87, 0.81 – 0.94: 0.69, 0.62 – 0.77 respectively). Having a diarrhoea in the past 2 weeks and having fever in the past month were associated with higher odds of CAS (AOR:1.1, 95% CI; 1.0 – 1.2: 1.1, 1.0 – 1.2, respectively). Results from the decision tree analysis showed that the educational level of women was the most important predictor of CAS, followed by child feeding score, the level of education of the family head and state of drinking water. Conclusion The results buttress the importance of interventions aimed at improving feeding practices and parental educational as a vehicle to improve children’s nutritional status