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This article presents data that examine the patient's perception of health care delivery for mitochondrial disease in the US. It also presents the opinions of mitochondrial disease expert physicians about creating a specialised network of clinics to oversee the care of patients with this disease within the US. Two separate electronic surveys were developed; one for mitochondrial disease patients and their families ascertaining their satisfaction with their current health care and the challenges they face. The other for the physicians group assessing the usefulness, feasibility and readiness to develop specialized care clinics for mitochondrial disease in the US. Survey responses and descriptive analysis are presented here. The data in this article is supplemental, and supports the information presented in the research article “Harmonizing care for rare diseases: How we developed the mitochondrial care network in the United States.” Karaa et al., 2019 Keywords: Mitochondrial disease, Health care delivery, Patients' perception of care, Physicians' opinion on care delivery

The mitochondrial medicine society (MMS) has previously highlighted the clinical landscape and physician practice patterns of mitochondrial medicine in the US and attempted to develop consensus criteria for diagnosis and management to improve patient coordinated care. Most recently, and in collaboration with US-based patient advocacy groups, we developed a clinical care network to formally unify US-based clinicians who provide medical care to individuals with mitochondrial disease; to define, design and implement best practices in mitochondrial medicine building on the current consensus guidelines and to improve patients' clinical outcomes. Here we review the steps taken in collaboration with several stakeholders to develop goals and expectations for a mitochondrial care network (MCN), criteria for MCN site selection and formal launch of the network.

In December 2014, a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD.

Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondria] Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondria! disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource (GEM.app) that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases. (C) 2014 Elsevier Inc. All rights reserved.

The inherent high reactivity and color instability of primary amines has limited their applicability in polyisocyanate-based coatings. However, recent developments in the use of modified amine functional coreactants in such formulations shows significant progress towards having two-component systems with excellent application and durability properties. The systems reviewed here use amine functional groups which are either blocked by addition of carbonyl compounds, or are of reduced reactivity through steric hindrance and intramolecular hydrogen bonding. The relative benefits and drawbacks of the various systems are detailed along with their applicability to high solids coatings.

The cycloaddition reactions of several phenylsulfonyl-substituted allenes with diazomethane have been investigated. The major products formed were identified as 3-(phenylsulfonyl)-4-methylene-2-pyrazolines. These pyrazolines engage in a variety of mechanistically interesting transformations, ranging from base-catalyzed rearrangements to addition of Grignard regents. The dipolar cycloadduct derived from the reaction of diazomethane with 3-(phenylsulfonyl)-1,2-butadiene undergoes a 1,3-phenylsulfonyl shift upon irradiation to give 3-methyl-4-[(phenylsulfonyl)methyl] pyrazole. The cycloadduct derived from the reaction of 2,3-bis(phenylsulfonyl)-1-propene with diazomethane readily loses nitrogen upon photolysis to give 1-[(phenylsulfonyl)methyl]-1-(phenylsulfonyl)cyclopropane

Recent progress in the development of new strategies and tactics for natural products synthesis is described. An emphasis is placed on the development of new sequences of radical reactions. A new approach to the crinipellin family of tetraquinanes and a recently completed formal total synthesis of camptothecin are highlighted. We recently compiled a review to bring together recent advances in "Radical Reactions in Natural Products Synthesis."' This paper will summarize some of our recent progress in developing new strategies for the use of radical reactions in the synthess of natural products. Often, the implementation of these new strategies will require the development of new reactions. Most synthetic applications of radical methods conduct only one key reaction in between generation of a radical and its removal.2 Starting from our earliest work in this field, one of our major themes has been the sequencing of radical reactions.3 Radical reactions are naturally suited to sequencing because the product of every radical reaction is a radical. We defiie a tandem radical reaction as a sequence of radical reactions which has inore than one step between radical generation and radical removal. Chemoselectivity is a big issue in tandem sequences, and a variety of powerful strategies have emerged to solve selectivity problems.*a,4 One of the simplest, yet most powerful, strategies is to plan only rapid intramolecular radical reactions between radical generation and removal. In this way, it is often as easy to form two or three bonds as it is to form one. This tandem cyclization strategy has been an early and continuing theme in our work.3 Figure 1 uses a new radical notation4 to summarize tandem radical strategies to two large, important classes of triquinane sesquiterpenes: linear and angular.5 Though the two ring systems are quite different, the strategies are closely related. Each case calls for a central cyclopentene ring bearing two side chains: one with a radical donor and one with a radical acceptor. The tandem cyclization then occurs through the middle of the cyclopentene ring. The only difference between the two strategies is where the two side chains are located on the central ring.

Le traitement du 2,3-dibromo-1-benzenesulfonyl-1-propene avec des composes β-dicarbonyles en presence de methoxyde de sodium conduit avec un haut rendement au furane bicyclique 2,4-disubstitue et au furane bicyclique 2,3-fusionne. La formation du cycle furane implique une sequence d'addition-elimination, une deacetylation et des reactions de deplacement de type SN2

2,3-Dihalo-1-(phenylsulfonyl)-1-propenes, obtained by the addition of bromine or iodine onto (phenylsulfonyl)propadiene, were found to exhibit interesting reactivity as both mono- and dielectrophiles, with the mode of reactivity depending upon the nature of the nucleophile as well as the reaction conditions. Thus, amines or thiophenols smoothly effected substitution at the allylic site, while sodium methoxide reacted at the vinylic position through an addition-elimination process

Recent progress in the development of new strategies and tactics for natural products synthesis is described. An emphasis is placed on the development of new sequences of radical reactions. A new approach to the crinipellin family of tetraquinanes and a recently completed formal total synthesis of camptothecin are highlighted. We recently compiled a review to bring together recent advances in "Radical Reactions in Natural Products Synthesis."' This paper will summarize some of our recent progress in developing new strategies for the use of radical reactions in the synthess of natural products. Often, the implementation of these new strategies will require the development of new reactions. Most synthetic applications of radical methods conduct only one key reaction in between generation of a radical and its removal.2 Starting from our earliest work in this field, one of our major themes has been the sequencing of radical reactions.3 Radical reactions are naturally suited to sequencing because the product of every radical reaction is a radical. We defiie a tandem radical reaction as a sequence of radical reactions which has inore than one step between radical generation and radical removal. Chemoselectivity is a big issue in tandem sequences, and a variety of powerful strategies have emerged to solve selectivity problems.*a,4 One of the simplest, yet most powerful, strategies is to plan only rapid intramolecular radical reactions between radical generation and removal. In this way, it is often as easy to form two or three bonds as it is to form one. This tandem cyclization strategy has been an early and continuing theme in our work.3 Figure 1 uses a new radical notation4 to summarize tandem radical strategies to two large, important classes of triquinane sesquiterpenes: linear and angular.5 Though the two ring systems are quite different, the strategies are closely related. Each case calls for a central cyclopentene ring bearing two side chains: one with a radical donor and one with a radical acceptor. The tandem cyclization then occurs through the middle of the cyclopentene ring. The only difference between the two strategies is where the two side chains are located on the central ring.

2,3-Dihalo-1-(phenylsulfonyl)-1-propenes, obtained by the addition of bromine or iodine onto (phenylsulfonyl)propadiene, were found to exhibit interesting reactivity as both mono- and dielectrophiles, with the mode of reactivity depending upon the nature of the nucleophile as well as the reaction conditions. Thus, amines or thiophenols smoothly effected substitution at the allylic site, while sodium methoxide reacted at the vinylic position through an addition-elimination process

Radical attack on the double bond of 2,3-bis(phenylsulfonyl)-1-propene leads to an intermediate sulfonyl stabilized radical. This species readily fragments to produce a new vinyl sulfone which can undergo further radical cyclization to give a six ring sulfone.

Le traitement du 2,3-dibromo-1-benzenesulfonyl-1-propene avec des composes β-dicarbonyles en presence de methoxyde de sodium conduit avec un haut rendement au furane bicyclique 2,4-disubstitue et au furane bicyclique 2,3-fusionne. La formation du cycle furane implique une sequence d'addition-elimination, une deacetylation et des reactions de deplacement de type SN2

Les cycloadditions dipolaires 1,3 de l'[arylidene hydroxytrimethylsilyl] ammonium (A) sont etudiees. Selon la nature du dipolarophile, (A) se comporte soit comme une nitrone soit comme un ylure d'ammoniomethanure