Recommendations for observational studies of comorbidity in multiple sclerosis

Objective: To reach consensus about the most relevant comorbidities to study in multiple sclerosis (MS) with respect to incidence, prevalence, and effect on outcomes; review datasets that may support studies of comorbidity in MS; and identify MS outcomes that should be prioritized in such studies. Methods: We held an international workshop to meet these objectives, informed by a systematic review of the incidence and prevalence of comorbidity in MS, and an international survey regarding research priorities for comorbidity. Results: We recommend establishing age- and sex-specific incidence and prevalence estimates for 5 comorbidities (depression, anxiety, hypertension, hyperlipidemia, and diabetes); evaluating the effect of 7 comorbidities (depression, anxiety, hypertension, diabetes, hyperlipidemia, chronic lung disease, and autoimmune diseases) on disability, quality of life, brain atrophy and other imaging parameters, health care utilization, employment, and mortality, including age, sex, race/ethnicity, socioeconomic status, and disease duration as potential confounders; harmonizing study designs across jurisdictions; and conducting such studies worldwide. Ultimately, clinical trials of treating comorbidity in MS are needed. Conclusion: Our recommendations will help address knowledge gaps regarding the incidence, prevalence, and effect of comorbidity on outcomes in MS

Cell-based therapeutic strategies for multiple sclerosis.

The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials

Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 201

Evaluation Research and Institutional Pressures: Challenges in Public-Nonprofit Contracting

This article examines the connection between program evaluation research and decision-making by public managers. Drawing on neo-institutional theory, a framework is presented for diagnosing the pressures and conditions that lead alternatively toward or away the rational use of evaluation research. Three cases of public-nonprofit contracting for the delivery of major programs are presented to clarify the way coercive, mimetic, and normative pressures interfere with a sound connection being made between research and implementation. The article concludes by considering how public managers can respond to the isomorphic pressures in their environment that make it hard to act on data relating to program performance.This publication is Hauser Center Working Paper No. 23. The Hauser Center Working Paper Series was launched during the summer of 2000. The Series enables the Hauser Center to share with a broad audience important works-in-progress written by Hauser Center scholars and researchers

Chemical and Electrochemical Reduction of Polyarene Manganese Tricarbonyl Cations: Hapticity Changes and Generation of Syn- and Anti-Facial Bimetallic η4,η6-Naphthalene Complexes

(η6-Naphthalene)Mn(CO)3+ is reduced reversibly by two electrons in CH2Cl2 to afford (η4-naphthalene)Mn(CO)3-. The chemical and electrochemical reductions of this and analogous complexes containing polycyclic aromatic hydrocarbons (PAH) coordinated to Mn(CO)3+ indicate that the second electron addition is thermodynamically easier but kinetically slower than the first addition. Density functional theory calculations suggest that most of the bending or folding of the naphthalene ring that accompanies the η6 → η4 hapticity change occurs when the second electron is added. As an alternative to further reduction, the 19-electron radicals (η6-PAH)Mn(CO)3 can undergo catalytic CO substitution when phosphite nucleophiles are present. Chemical reduction of (η6-naphthalene)Mn(CO)3+ and analogues with one equivalent of cobaltocene affords a syn-facial bimetallic complex (η4,η6-naphthalene)Mn2(CO)5, which contains a Mn−Mn bond. Catalytic oxidative activation under CO reversibly converts this complex to the zwitterionic syn-facial bimetallic (η4,η6-naphthalene)Mn2(CO)6, in which the Mn−Mn bond is cleaved and the naphthalene ring is bent by 45°. Controlled reduction experiments at variable temperatures indicate that the bimetallic (η4,η6-naphthalene)Mn2(CO)5 originates from the reaction of (η4-naphthalene)Mn(CO)3- acting as a nucleophile to displace the arene from (η6-naphthalene)Mn(CO)3+. Heteronuclear syn-facial and anti-facial bimetallics are formed by the reduction of mixtures of (η6-naphthalene)Mn(CO)3+ and other complexes containing a fused polycyclic ring, e.g., (η5-indenyl)Fe(CO)3+ and (η6-naphthalene)FeCp+. The great ease with which naphthalene-type manganese tricarbonyl complexes undergo an η6 → η4 hapticity change is the basis for the formation of both the homo- and heteronuclear bimetallics, for the observed two-electron reduction, and for the far greater reactivity of (η6-PAH)Mn(CO)3+ complexes in comparison to monocyclic arene analogues

The challenge of comorbidity in clinical trials for multiple sclerosis

Objective: We aimed to provide recommendations for addressing comorbidity in clinical trial design and conduct in multiple sclerosis (MS). Methods: We held an international workshop, informed by a systematic review of the incidence and prevalence of comorbidity in MS and an international survey about research priorities for studying comorbidity including their relation to clinical trials in MS. Results: We recommend establishing age- and sex-specific incidence estimates for comorbidities in the MS population, including those that commonly raise concern in clinical trials of immunomodulatory agents; shifting phase III clinical trials of new therapies from explanatory to more pragmatic trials; describing comorbidity status of the enrolled population in publications reporting clinical trials; evaluating treatment response, tolerability, and safety in clinical trials according to comorbidity status; and considering comorbidity status in the design of pharmacovigilance strategies. Conclusion: Our recommendations will help address knowledge gaps regarding comorbidity that interfere with the ability to interpret safety in monitored trials and will enhance the generalizability of findings from clinical trials to "real world" settings where the MS population commonly has comorbid conditions