Multimorbidity and Evidence Generation

Most people with a chronic disease actually have more than one, a condition known as multimorbidity. Despite this, the evidence base to prevent adverse disease outcomes has taken a disease-specific approach. Drawing on a conference, Improving Guidelines for Multimorbid Patients, the goal of this paper is to identify challenges to the generation of evidence to support the care of people with multimorbidity and to make recommendations for improvement. We identified three broad categories of challenges: 1) challenges to defining and measuring multimorbidity; 2) challenges related to the effects of multimorbidity on study design, implementation and analysis; and 3) challenges inherent in studying heterogeneity of treatment effects in patients with differing comorbid conditions. We propose a set of recommendations for consideration by investigators and others (reviewers, editors, funding agencies, policymaking organizations) involved in the creation of evidence for this common type of person that address each of these challenges. The recommendations reflect a general approach that emphasizes broader inclusion (recruitment and retention) of patients with multimorbidity, coupled with more rigorous efforts to measure comorbidity and comorbidity burden and the influence of multimorbidity on outcomes and the effects of therapy. More rigorous examination of heterogeneity of treatment effects requires careful attention to prioritizing the most important comorbid-related questions, and also requires studies that provide greater statistical power than conventional trials have provided. Relatively modest changes in the orientation of current research along these lines can be helpful in pointing to and partially addressing selected knowledge gaps. However, producing a robust evidence base to support patient-centered decision making in complex individuals with multimorbidity, exposed to many different combinations of potentially interacting factors that can modify the risks and benefits of therapies, is likely to require a clinical research enterprise fundamentally restructured to be more fully integrated with routine clinical practice.     

Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease

BACKGROUND: Systemic sclerosis (SSc, scleroderma) in either its diffuse or limited skin forms has a high mortality when vital organs are affected. No treatment has been shown to influence the outcome or significantly affect the skin score, though many forms of immunosuppression have been tried. Recent developments in haemopoietic stem cell transplantation (HSCT) have allowed the application of profound immunosuppression followed by HSCT, or rescue, to autoimmune diseases such as SSc. METHODS: Results for 41 patients included in continuing multicentre open phase I/II studies using HSCT in the treatment of poor prognosis SSc are reported. Thirty seven patients had a predominantly diffuse skin form of the disease and four the limited form, with some clinical overlap. Median age was 41 years with a 5:1 female to male ratio. The skin score was >50% of maximum in 20/33 (61%) patients, with some lung disease attributable to SSc in 28/37 (76%), the forced vital capacity being <70% of the predicted value in 18/36 (50%). Pulmonary hypertension was described in 7/37 (19%) patients and renal disease in 5/37 (14%). The Scl-70 antibody was positive in 18/32 (56%) and the anticentromere antibody in 10% of evaluable patients. Peripheral blood stem cell mobilisation was performed with cyclophosphamide or granulocyte colony stimulating factor, alone or in combination. Thirty eight patients had ex vivo CD34 stem cell selection, with additional T cell depletion in seven. Seven conditioning regimens were used, but six of these used haemoimmunoablative doses of cyclophosphamide +/- anti-thymocyte globulin +/- total body irradiation. The median duration of follow up was 12 months (3-55). RESULTS: An improvement in skin score of >25% after transplantation occurred in 20/29 (69%) evaluable patients, and deterioration in 2/29 (7%). Lung function did not change significantly after transplantation. One of five renal cases deteriorated but with no new occurrences of renal disease after HSCT, and the pulmonary hypertension did not progress in the evaluable cases. Disease progression was seen in 7/37 (19%) patients after HSCT with a median period of 67 (range 49-255) days. Eleven (27%) patients had died at census and seven (17%) deaths were considered to be related to the procedure (direct organ toxicity in four, haemorrhage in two, and infection/neutropenic fever in one). The cumulative probability of survival at one year was 73% (95% CI 58 to 88) by Kaplan-Meier analysis. CONCLUSION: Despite a higher procedure related mortality rate from HSCT in SSc compared with patients with breast cancer and non-Hodgkin's lymphoma, the marked impact on skin score, a surrogate marker of mortality, the trend towards stabilisation of lung involvement, and lack of other treatment alternatives justify further carefully designed studies. If future trials incorporate inclusion and exclusion criteria based on this preliminary experience, the predicted procedure related mortality should be around 10%.     

Conventional and Reciprocal Approaches to the Inverse Dipole Localization Problem for N20–P20 Somatosensory Evoked Potentials

The non-invasive localization of the primary sensory hand area can be achieved by solving the inverse problem of electroencephalography (EEG) for N₂₀–P₂₀ somatosensory evoked potentials (SEPs). This study compares two different mathematical approaches for the computation of transfer matrices used to solve the EEG inverse problem. Forward transfer matrices relating dipole sources to scalp potentials are determined via conventional and reciprocal approaches using individual, realistically shaped head models. The reciprocal approach entails calculating the electric field at the dipole position when scalp electrodes are reciprocally energized with unit current—scalp potentials are obtained from the scalar product of this electric field and the dipole moment. Median nerve stimulation is performed on three healthy subjects and single-dipole inverse solutions for the N₂₀–P₂₀ SEPs are then obtained by simplex minimization and validated against the primary sensory hand area identified on magnetic resonance images. Solutions are presented for different time points, filtering strategies, boundary-element method discretizations, and skull conductivity values. Both approaches produce similarly small position errors for the N₂₀–P₂₀ SEP. Position error for single-dipole inverse solutions is inherently robust to inaccuracies in forward transfer matrices but dependent on the overlapping activity of other neural sources. Significantly smaller time and storage requirements are the principal advantages of the reciprocal approach. Reduced computational requirements and similar dipole position accuracy support the use of reciprocal approaches over conventional approaches for N₂₀–P₂₀ SEP source localization.     

Development of an immunofiltration-based antigen-detection assay for rapid diagnosis of Ebola virus infection

Ebola virus (EBOV) has caused outbreaks of severe viral hemorrhagic fever in regions of Central Africa where medical facilities are ill equipped and diagnostic capabilities are limited. To obtain a reliable test that can be implemented easily under these conditions, monoclonal antibodies to the EBOV matrix protein (VP40), which previously had been found to work in a conventional enzyme-linked immunosorbent assay, were used to develop an immunofiltration assay for the detection of EBOV antigen in chemically inactivated clinical specimens. The assay was evaluated by use of defined virus stocks and specimens from experimentally infected animals. Its field application was tested during an outbreak of Ebola hemorrhagic fever in 2003. Although the original goal was to develop an assay that would detect all EBOV species, only the Zaire and Sudan species were detected in practice. The assay represents a first-generation rapid field test for the detection of EBOV antigen that can be performed in 30 min without electrical power or expensive or sensitive equipment.     

In vivo investigation of the inflammatory response against allylamine plasma polymer coated titanium implants in a rat model

Titanium (Ti) is an established biomaterial for bone replacement. However, facilitation of osteoblast attachment by surface modification with chemical groups could improve the implant performance. Therefore, this study aimed to evaluate the effect of a plasma polymerized allylamine (PPAAm) layer on the local inflammation in a rat model. Three series (RM76AB, RM78AB, RM77AB) of PPAAm-treated Ti plates were prepared using different plasma conditions. Twelve male LEW.1A rats received one plate of each series and one uncoated control plate implanted into the back musculature. After 7, 14 and 56 days, four rats were euthanized to remove the implants with surrounding tissue. Total monocytes/macrophages, tissue macrophages, T-cells and MHC-class-II-positive cells were morphometrically counted. On day 14, the macrophage/monocyte number was significantly higher for the controls than for the PPAAm samples. On day 56, the RM76AB and RM78AB samples had significantly lower numbers than RM77AB and the controls. The same was found for the tissue macrophages. No change over time and no differences between the implants were found for the T-cells. For the number of MHC-class-II-positive cells, a significant decrease was found only for the RM78AB implants between day 14 and day 56. Physico-chemical analysis of the PPAAm implants revealed that the RM77AB implants had the lowest water absorption, the highest nitrogen loss and the lowest oxygen uptake after sonication. These results demonstrate that the PPAAm samples and the controls were comparable regarding local inflammation, and that different plasma conditions lead to variations in the material properties which influence the tissue reaction.