The object of this article was to systematically review available methods to measure comorbidity and to assess their validity and reliability. A search was made in Medline and Embase, with the keywords comorbidity and multi-morbidity, to identify articles in which a method to measure comorbidity was described. The references of these articles were also checked, and using a standardized checklist the relevant data were extracted from these articles. An assessment was made of the content, concurrent, predictive and construct validity, and the reliability. Thirteen different methods to measure comorbidity were identified: one disease count and 12 indexes. Data on content and predictive validity were available for all measures, while data on construct validity were available for nine methods, data on concurrent validity, and interrater reliability for eight methods, and data on intrarater reliability for three methods. The Charlson Index is the most extensively studied comorbidity index for predicting mortality. The Cumulative Illness Rating Scale (CIRS) addresses all relevant body systems without using specific diagnoses. The Index of Coexisting Disease (ICED) has a two-dimensional structure, measuring disease severity and disability, which can be useful when mortality and disability are the outcomes of interest. The Kaplan Index was specifically developed for use in diabetes research. The Charlson Index, the CIRS, the ICED and the Kaplan Index are valid and reliable methods to measure comorbidity that can be used in clinical research. For the other indexes, insufficient data on the clinimetric properties are available.

The object of this article was to systematically review available methods to measure comorbidity and to assess their validity and reliability. A search was made in Medline and Embase, with the keywords comorbidity and multi-morbidity, to identify articles in which a method to measure comorbidity was described. The references of these articles were also checked, and using a standardized checklist the relevant data were extracted from these articles. An assessment was made of the content, concurrent, predictive and construct validity, and the reliability. Thirteen different methods to measure comorbidity were identified: one disease count and 12 indexes. Data on content and predictive validity were available for all measures, while data on construct validity were available for nine methods, data on concurrent validity, and interrater reliability for eight methods, and data on intrarater reliability for three methods. The Charlson Index is the most extensively studied comorbidity index for predicting mortality. The Cumulative Illness Rating Scale (CIRS) addresses all relevant body systems without using specific diagnoses. The Index of Coexisting Disease (ICED) has a two-dimensional structure, measuring disease severity and disability, which can be useful when mortality and disability are the outcomes of interest. The Kaplan Index was specifically developed for use in diabetes research. The Charlson Index, the CIRS, the ICED and the Kaplan Index are valid and reliable methods to measure comorbidity that can be used in clinical research. For the other indexes, insufficient data on the clinimetric properties are available.

ABSTRACT. van der Lee JH, de Groot V, Beckerman H, Wagenaar RC, Lankhorst GJ, Bouter LM. The intra-and interrater reliability of the Action Research Arm test: a practical test of upper extremity function in patients with stroke. Arch Phys Med Rehabil 2001;82:14-9.Objectives: To determine the intra-and interrater reliability of the Action Research Arm (ARA) test, to assess its ability to detect a minimal clinically important difference (MCID) of 5.7 points, and to identify less reliable test items.Design: Intrarater reliability of the sum scores and of individual items was assessed by comparing (1) the ratings of the laboratory measurements of 20 patients with the ratings of the same measurements recorded on videotape by the original rater, and (2) the repeated ratings of videotaped measurements by the same rater. Interrater reliability was assessed by comparing the ratings of the videotaped measurements of 2 raters. The resulting limits of agreement were compared with the MCID.Patients: Stratified sample, based on the intake ARA score, of 20 chronic stroke patients (median age, 62yr; median time since stroke onset, 3.6yr; mean intake ARA score, 29.2).Main Outcome Measures: Spearman's rank-order correlation coefficient (Spearman's rho); intraclass correlation coefficient (ICC); mean difference and limits of agreement, based on ARA sum scores; and weighted kappa, based on individual items.Results: All intra-and interrater Spearman's rho and ICC values were higher than .98. The mean difference between ratings was highest for the interrater pair (.75; 95% confidence interval, .02-1.48), suggesting a small systematic difference between raters. Intrarater limits of agreement were Ϫ1.66 to 2.26; interrater limits of agreement were Ϫ2.35 to 3.85. Median weighted kappas exceeded .92. Conclusion:The high intra-and interrater reliability of the ARA test was confirmed, as was its ability to detect a clinically relevant difference of 5.7 points.

Spinal cord abnormalities are prevalent in patients with early-stage MS, have distinct morphologic characteristics, and help to determine dissemination in space at time of diagnosis.

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A linker-drug platform was built on the basis of a cleavable linker-duocarmycin payload for the development of new-generation antibody-drug conjugates (ADC). A leading ADC originating from that platform is SYD983, a HER2-targeting ADC based on trastuzumab. HER2-binding, antibody-dependent cell-mediated cytotoxicity and HER2-mediated internalization are similar for SYD983 as compared with trastuzumab. HER2-expressing cells in vitro are very potently killed by SYD983, but SYD983 is inactive in cells that do not express HER2. SYD983 dose dependently reduces tumor growth in a BT-474 mouse xenograft in vivo. The ADC is stable in human and cynomolgus monkey plasma in vitro but shows relatively poor stability in mouse plasma due to mouse-specific carboxylesterase. SYD983 could be dosed up to 30 mg/kg in cynomolgus monkeys with high exposure, excellent stability in blood, and without severe toxic effects. The monkey safety study showed no SYD983-induced thrombocytopenia and no induction of peripheral sensory neuropathy, both commonly observed in trials and studies with ADCs based on tubulin inhibitors. Finally, to improve homogeneity, SYD983 was further purified by hydrophobic interaction chromatography resulting in an ADC (designated SYD985) predominantly containing DAR2 and DAR4 species. SYD985 showed high antitumor activity in two patient-derived xenograft models of HER2-positive metastatic breast cancers. In conclusion, the data obtained indicate great potential for this new HER2-targeting ADC to become an effective drug for patients with HER2-positive cancers with a favorable safety profile. More generally, this new-generation duocarmycin-based linker-drug technology could be used with other mAbs to serve more indications in oncology. Mol Cancer Ther; 13(11); 2618-29. Ó2014 AACR.

In patients with central neurological disorders, gait is often limited by a reduced ability to push off with the ankle. To overcome this reduced ankle push-off, energy-storing, spring-like carbon-composite Ankle Foot Orthoses (AFO) can be prescribed. It is expected that the energy returned by the AFO in late stance will support ankle push-off, and reduce the energy cost of walking. In 10 patients with multiple sclerosis and stroke the energy cost of walking, 3D kinematics, joint power, and joint work were measured during gait, with and without the AFO. The mechanical characteristics of the AFO were measured separately, and used to calculate the contribution of the AFO to the ankle kinetics. We found a significant decrease of 9.8% in energy cost of walking when walking with the AFO. With the AFO, the range of motion of the ankle was reduced by 12.3°, and the net work around the ankle was reduced by 29%. The total net work in the affected leg remained unchanged. The AFO accounted for 60% of the positive ankle work, which reduced the total amount of work performed by the leg by 11.1% when walking with the AFO. The decrease in energy cost when walking with a spring-like energy-storing AFO in central neurological patients is not induced by an augmented net ankle push-off, but by the AFO partially taking over ankle work.