Development of international consensus recommendations using a modified Delphi approach

Funding Information: This work was supported by BioMarin Pharmaceutical Inc . Funding Information: The content of this manuscript was based on preparatory pre-meeting activities and presentations and discussions during two advisory board meetings that were coordinated and funded by BioMarin Pharmaceutical Inc. All authors or their institutions received funding from BioMarin to attend at least one or both meetings. Additional disclosures: BKB received consulting payments from BioMarin, Shire, Genzyme, Alexion, Horizon Therapeutics, Denali Therapeutics, JCR Pharma, Moderna, Aeglea BioTherapeutics, SIO Gene Therapies, Taysha Gene Therapy, Ultragenyx, and Inventiva Pharma, participated as clinical trial investigator for BioMarin, Shire, Denali Therapeutics, Homology Medicines, Ultragenyx, and Moderna as well as received speaker fees from BioMarin, Shire, Genzyme, and Horizon Therapeutics. AH received consulting payments from BioMarin, Chiesi, Shire, Genzyme, Amicus, and Ultragenyx, participated as clinical trial investigator for Ultragenyx as well as received speaker fees from Alexion, Amicus, BioMarin, Genzyme, Nutricia, Sobi, and Takeda. ABQ received consulting payments from BioMarin, speaker fees from BioMarin, Nutricia, Vitaflo, Sanofi, Takeda, Recordati, and travel support from Vitaflo . SEC received consulting payments and speaker fees from BioMarin as well as consulting payments from Synlogic Therapeutics. COH was clinical trial investigator for BioMarin and received consulting and speaker payments from BioMarin. SCJH received consulting payments and travel support from BioMarin and Homology Medicines. NL received consulting payments from Alnylam, Amicus, Astellas, BioMarin, BridgeBio, Chiesi, Genzyme/Sanofi, HemoShear, Horizon Therapeutics, Jaguar, Moderna, Nestle, PTC Therapeutics, Reneo, Shire, Synlogic, and Ultragenyx, participated as clinical trial investigator for Aeglea, Amicus, Astellas, BioMarin, Genzyme/Sanofi, Homology, Horizon, Moderna, Pfizer, Protalix, PTC Therapeutics, Reneo, Retrophin/Travere therapeutics, Shire, and Ultragenyx, as well as received speaker fees from Cycle Pharmaceuticals, Leadiant and Recordati. MCM II received consulting payments from BioMarin, Horizon Therapeutics, Rhythm Pharmaceuticals, Applied Therapeutics, Cycle Therapeutics, and Ultragenyx. ALSP received speaker fees from BioMarin. JCR received consulting payments from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, and Nutricia, speaker fees from Applied Pharma Research, Merck Serono, BioMarin Pharmaceutical, Vitaflo, Cambrooke, PIAM, LifeDiet, and Nutricia, as well as travel support from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, Cambrooke, PIAM, and Nutricia. SS received consulting payments, research grants, speaker fees, and travel support from BioMarin and participated as clinical trials investigator for BioMarin. ASV received consulting payments from BioMarin, Horizon Therapeutics, and Ultragenyx and participated as clinical trial investigator for Acadia, Alexion, BioMarin, Genzyme, Homology Medicines, Kaleido, Mallinckrodt, and Ultragenyx. JV received consulting payments from BioMarin, LogicBio Pharmaceuticals, Sangamo Therapeutics, Orphan Labs, Synlogic Therapeutics, Sanofi, Axcella Health, Agios Pharmaceuticals, and Applied Therapeutics as well as travel grants from BioMarin and LogicBio Pharmaceuticals. MW received consulting payments, speaker fees, and travel support from BioMarin, and participated as clinical trial investigator for Mallinckrodt, Roche, Wave, Cycle Therapeutics, and Intrabio. ACM participated in strategic advisory boards and received honoraria as a consultant and as a speaker for Merck Serono, BioMarin, Nestlé Health Science (SHS), Applied Pharma Research, Actelion, Retrophin, Censa, PTC Therapeutics, and Arla Food. Funding Information: Ideally, access to (neuro)psychological/psychiatric support should assist adolescents with identifying, understanding, and reporting of PKU-specific challenges (Table 3), offering individualized recommendations on managing these challenges. Although there is no replacement for mental health services for patients with identified needs, psychosocial support from PKU peers, e.g., through PKU camps, virtual social events, etc., can at least in the short-term help to improve metabolic control by providing individuals an opportunity to participate in supportive PKU-related educational activities potentially reducing perceived social isolation [91]. In addition to PKU camps, which may be very specific to certain regions or countries, HCPs should consider encouraging involvement in local, regional, national and international PKU patient/family advocacy and social support organizations, introducing adolescents and young adults to national/international patient registries [92,93]. Besides support from PKU peers, patients can benefit from non-PKU peer support, although some adolescents and young adults with PKU may not disclose to others and may avoid eating in with others or eating in public due to potential feelings of anxiety or feelings of being ashamed of their disease. In addition, patients with PKU of all ages, but particularly vulnerable adolescents and young adults, can benefit from having the opportunity to learn about and practice strategies that help promote feelings of empowerment and self-efficacy that can be used in both familiar and unfamiliar environments where they may experience peer pressure and feel the need to ‘fit in’. For example, a role-play approach involving behavioral rehearsal, self-monitoring, goal setting, and training in problem-solving skills with emphasis on initiation and inhibition (i.e., how to say no) could be provided by parents, PKU peers, or even members of the PKU team. These types of activities can be used to teach adolescents with PKU how to react in social situations, such as dining out, helping to avoid indulging and increased risk-taking behavior, a hallmark of the adolescent period [94].This work was supported by BioMarin Pharmaceutical Inc.The content of this manuscript was based on preparatory pre-meeting activities and presentations and discussions during two advisory board meetings that were coordinated and funded by BioMarin Pharmaceutical Inc. All authors or their institutions received funding from BioMarin to attend at least one or both meetings. Additional disclosures: BKB received consulting payments from BioMarin, Shire, Genzyme, Alexion, Horizon Therapeutics, Denali Therapeutics, JCR Pharma, Moderna, Aeglea BioTherapeutics, SIO Gene Therapies, Taysha Gene Therapy, Ultragenyx, and Inventiva Pharma, participated as clinical trial investigator for BioMarin, Shire, Denali Therapeutics, Homology Medicines, Ultragenyx, and Moderna as well as received speaker fees from BioMarin, Shire, Genzyme, and Horizon Therapeutics. AH received consulting payments from BioMarin, Chiesi, Shire, Genzyme, Amicus, and Ultragenyx, participated as clinical trial investigator for Ultragenyx as well as received speaker fees from Alexion, Amicus, BioMarin, Genzyme, Nutricia, Sobi, and Takeda. ABQ received consulting payments from BioMarin, speaker fees from BioMarin, Nutricia, Vitaflo, Sanofi, Takeda, Recordati, and travel support from Vitaflo. SEC received consulting payments and speaker fees from BioMarin as well as consulting payments from Synlogic Therapeutics. COH was clinical trial investigator for BioMarin and received consulting and speaker payments from BioMarin. SCJH received consulting payments and travel support from BioMarin and Homology Medicines. NL received consulting payments from Alnylam, Amicus, Astellas, BioMarin, BridgeBio, Chiesi, Genzyme/Sanofi, HemoShear, Horizon Therapeutics, Jaguar, Moderna, Nestle, PTC Therapeutics, Reneo, Shire, Synlogic, and Ultragenyx, participated as clinical trial investigator for Aeglea, Amicus, Astellas, BioMarin, Genzyme/Sanofi, Homology, Horizon, Moderna, Pfizer, Protalix, PTC Therapeutics, Reneo, Retrophin/Travere therapeutics, Shire, and Ultragenyx, as well as received speaker fees from Cycle Pharmaceuticals, Leadiant and Recordati. MCM II received consulting payments from BioMarin, Horizon Therapeutics, Rhythm Pharmaceuticals, Applied Therapeutics, Cycle Therapeutics, and Ultragenyx. ALSP received speaker fees from BioMarin. JCR received consulting payments from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, and Nutricia, speaker fees from Applied Pharma Research, Merck Serono, BioMarin Pharmaceutical, Vitaflo, Cambrooke, PIAM, LifeDiet, and Nutricia, as well as travel support from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, Cambrooke, PIAM, and Nutricia. SS received consulting payments, research grants, speaker fees, and travel support from BioMarin and participated as clinical trials investigator for BioMarin. ASV received consulting payments from BioMarin, Horizon Therapeutics, and Ultragenyx and participated as clinical trial investigator for Acadia, Alexion, BioMarin, Genzyme, Homology Medicines, Kaleido, Mallinckrodt, and Ultragenyx. JV received consulting payments from BioMarin, LogicBio Pharmaceuticals, Sangamo Therapeutics, Orphan Labs, Synlogic Therapeutics, Sanofi, Axcella Health, Agios Pharmaceuticals, and Applied Therapeutics as well as travel grants from BioMarin and LogicBio Pharmaceuticals. MW received consulting payments, speaker fees, and travel support from BioMarin, and participated as clinical trial investigator for Mallinckrodt, Roche, Wave, Cycle Therapeutics, and Intrabio. ACM participated in strategic advisory boards and received honoraria as a consultant and as a speaker for Merck Serono, BioMarin, Nestlé Health Science (SHS), Applied Pharma Research, Actelion, Retrophin, Censa, PTC Therapeutics, and Arla Food. Publisher Copyright: © 2022 The AuthorsBackground: Early treated patients with phenylketonuria (PKU) often become lost to follow-up from adolescence onwards due to the historical focus of PKU care on the pediatric population and lack of programs facilitating the transition to adulthood. As a result, evidence on the management of adolescents and young adults with PKU is limited. Methods: Two meetings were held with a multidisciplinary international panel of 25 experts in PKU and comorbidities frequently experienced by patients with PKU. Based on the outcomes of the first meeting, a set of statements were developed. During the second meeting, these statements were voted on for consensus generation (≥70% agreement), using a modified Delphi approach. Results: A total of 37 consensus recommendations were developed across five areas that were deemed important in the management of adolescents and young adults with PKU: (1) general physical health, (2) mental health and neurocognitive functioning, (3) blood Phe target range, (4) PKU-specific challenges, and (5) transition to adult care. The consensus recommendations reflect the personal opinions and experiences from the participating experts supported with evidence when available. Overall, clinicians managing adolescents and young adults with PKU should be aware of the wide variety of PKU-associated comorbidities, initiating screening at an early age. In addition, management of adolescents/young adults should be a joint effort between the patient, clinical center, and parents/caregivers supporting adolescents with gradually gaining independent control of their disease during the transition to adulthood. Conclusions: A multidisciplinary international group of experts used a modified Delphi approach to develop a set of consensus recommendations with the aim of providing guidance and offering tools to clinics to aid with supporting adolescents and young adults with PKU.publishersversionpublishe

Expert Consensus on the Long-Term Effectiveness of Medical Nutrition Therapy and Its Impact on the Outcomes of Adults with Phenylketonuria

Many adults with phenylketonuria (PKU) rely on medical nutrition therapy (MNT; low phenylalanine (Phe) diet with protein substitutes/medical foods) to maintain blood Phe concentrations within recommended ranges and prevent PKU-associated comorbidities. Despite disease detection through newborn screening and introduction of MNT as early as birth, adherence to MNT often deteriorates from childhood onwards, complicating the assessment of its effectiveness in the long term. Via a modified Delphi process, consensus (≥70% agreement) was sought on 19 statements among an international, multidisciplinary 13-member expert panel. After three iterative voting rounds, the panel achieved consensus on 17 statements related to the limitations of the long-term effectiveness of MNT (7), the burden of long-term reliance on MNT (4), and its potential long-term detrimental health effects (6). According to the expert panel, the effectiveness of MNT is limited in the long term, is associated with a high treatment burden, and demonstrates that adults with PKU are often unable to achieve metabolic control through dietary management alone, creating an unmet need in the adult PKU population

Biomoléculas extraídas por SBAs: ejemplos prácticos

The actual biotechnology industry demands fast and economic upstream and downstream processes to purify biomolecules. In this context, different purification techniques, that offer both high recovery and purity to the final product, have been assayed by different research groups. Liquid-liquid extraction with aqueous two-phase systems is one of the most studied methodologies for bio-separation. This technique presents several advantages such as mild conditions of working, cost-effectiveness, short-time consumption and high recovery percentage of the final product. With the aim to present a comparison of liquid-liquid extractions with other techniques, several aqueous two-phase extraction processes of biomolecules are presented in this review. We presented the advantages and disadvantages of them as of the compared systems. In general, the highest final product purities are achieved when different methodologies are combine, being the chromatographic ones the most applied in the last stages for the high purification factor obtained after them. Alternative methodologies, such as aqueous two-phase systems (ATPS), i.e., PEG/salts or ionic liquids; aqueous two-phase micellar systems, using solvents and surfactants; and extractive fermentation with ATPS, are relevant for both cost-effectiveness and time-saving of the purification process.La industria biotecnologica actual exige procesos rápidos y económicos para la producción y la purificación de biomoléculas. En este contexto, diferentes técnicas separativas que ofrezcan un alto rendimiento y una alta pureza del producto final han sido evaluadas por diferentes grupos de investigación. La extracción líquido-líquido con sistemas bifasicos acuosos (SBAs) es una de las metodologías más estudiadas para bio-separación. Esta técnica presenta varias ventajas, tales como condiciones suaves de trabajo, alta relación costo-beneficio, cortos tiempos de consumo y alto porcentaje de recuperación del producto final. Con el objetivo de comparar extracciones líquido-líquido con otras técnicas de separación, diferentes procesos de extracción de biomoléculas seran presentados en este trabajo de revisión. Adicionalmente, se presentaran las ventajas y desventajas de cada uno de ellos. En general, los más altos grados de pureza del producto final fueron obtenidos al combinar diferentes metodologías, siendo las cromatográficas las más aplicados en las últimas etapas debido a los elevados factores de purificación obtenidos después de ellas. Metodologías alternativas como por ejemplo, SBAs basados en mezclas de PEG/sal o liquídos iónicos/sal, sistemas micelares de dos fases acuosas (SMDFAs) formados por solventes o surfactantes; fermentación extractiva utilizando SBA, también resultan ser relevantes debido a sus bajos costos y cortos tiempo en sus procesos de purificación

Biomolecules extracted by ATPs: practical examples

The actual biotechnology industry demands fast and economic upstream and downstream processes to purify biomolecules. In this context, different purification techniques, that offer both high recovery and purity to the final product, have been assayed by different research groups. Liquid-liquid extraction with aqueous two-phase systems is one of the most studied methodologies for bio-separation. This technique presents several advantages such as mild conditions of working, cost-effectiveness, short-time consumption and high recovery percentage of the final product. With the aim to present a comparison of liquid-liquid extractions with other techniques, several aqueous two-phase extraction processes of biomolecules are presented in this review. We presented the advantages and disadvantages of them as of the compared systems. In general, the highest final product purities are achieved when different methodologies are combine, being the chromatographic ones the most applied in the last stages for the high purification factor obtained after them. Alternative methodologies, such as aqueous two-phase systems (ATPS), i.e., PEG/salts or ionic liquids; aqueous two-phase micellar systems, using solvents and surfactants; and extractive fermentation with ATPS, are relevant for both cost-effectiveness and time-saving of the purification process.La industria biotecnologica actual exige procesos rápidos y económicos para la producción y la purificación de biomoléculas. En este contexto, diferentes técnicas separativas que ofrezcan un alto rendimiento y una alta pureza del producto final han sido evaluadas por diferentes grupos de investigación. La extracción líquido-líquido con sistemas bifasicos acuosos (SBAs) es una de las metodologías más estudiadas para bio-separación. Esta técnica presenta varias ventajas, tales como condiciones suaves de trabajo, alta relación costo-beneficio, cortos tiempos de consumo y alto porcentaje de recuperación del producto final. Con el objetivo de comparar extracciones líquido-líquido con otras técnicas de separación, diferentes procesos de extracción de biomoléculas seran presentados en este trabajo de revisión. Adicionalmente, se presentaran las ventajas y desventajas de cada uno de ellos. En general, los más altos grados de pureza del producto final fueron obtenidos al combinar diferentes metodologías, siendo las cromatográficas las más aplicados en las últimas etapas debido a los elevados factores de purificación obtenidos después de ellas. Metodologías alternativas como por ejemplo, SBAs basados en mezclas de PEG/sal o liquídos iónicos/sal, sistemas micelares de dos fases acuosas (SMDFAs) formados por solventes o surfactantes; fermentación extractiva utilizando SBA, también resultan ser relevantes debido a sus bajos costos y cortos tiempo en sus procesos de purificación.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Synthesis and Evaluation of Cytotoxic Effects of Amino-ester Derivatives of Natural α,β-Amyrin Mixture

<div><p>Natural α,β-amyrins were isolated from endemic Brazilian Esenbeckia grandiflora Mart., and eight synthetic derivatives were obtained by esterification reactions with bromo acetate, followed by amine treatment. The structures of the all compounds were confirmed by 1H and 13C nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR) and high-resolution mass spectrometry (HRMS) data analysis. The derivatives were screened for cytotoxic activity against human tumor cell-lines PC3 (prostate carcinoma), HCT-116 (colon carcinoma) and HL60 (leukemia). HCT-116 and PC3 cell-lines showed weak tumor growth inhibition (range of 13.9-25.4 and 10.3-28.8%, respectively), but the derivatives presented moderate activity against HL60 (range of 13.6-59.0%). Diethyl, aniline, morpholine and imidazole moieties presented higher activities (range of 45.9-59.0%).</p></div

Brazilian Flora 2020: Leveraging the power of a collaborative scientific network

International audienceThe shortage of reliable primary taxonomic data limits the description of biological taxa and the understanding of biodiversity patterns and processes, complicating biogeographical, ecological, and evolutionary studies. This deficit creates a significant taxonomic impediment to biodiversity research and conservation planning. The taxonomic impediment and the biodiversity crisis are widely recognized, highlighting the urgent need for reliable taxonomic data. Over the past decade, numerous countries worldwide have devoted considerable effort to Target 1 of the Global Strategy for Plant Conservation (GSPC), which called for the preparation of a working list of all known plant species by 2010 and an online world Flora by 2020. Brazil is a megadiverse country, home to more of the world's known plant species than any other country. Despite that, Flora Brasiliensis, concluded in 1906, was the last comprehensive treatment of the Brazilian flora. The lack of accurate estimates of the number of species of algae, fungi, and plants occurring in Brazil contributes to the prevailing taxonomic impediment and delays progress towards the GSPC targets. Over the past 12 years, a legion of taxonomists motivated to meet Target 1 of the GSPC, worked together to gather and integrate knowledge on the algal, plant, and fungal diversity of Brazil. Overall, a team of about 980 taxonomists joined efforts in a highly collaborative project that used cybertaxonomy to prepare an updated Flora of Brazil, showing the power of scientific collaboration to reach ambitious goals. This paper presents an overview of the Brazilian Flora 2020 and provides taxonomic and spatial updates on the algae, fungi, and plants found in one of the world's most biodiverse countries. We further identify collection gaps and summarize future goals that extend beyond 2020. Our results show that Brazil is home to 46,975 native species of algae, fungi, and plants, of which 19,669 are endemic to the country. The data compiled to date suggests that the Atlantic Rainforest might be the most diverse Brazilian domain for all plant groups except gymnosperms, which are most diverse in the Amazon. However, scientific knowledge of Brazilian diversity is still unequally distributed, with the Atlantic Rainforest and the Cerrado being the most intensively sampled and studied biomes in the country. In times of “scientific reductionism”, with botanical and mycological sciences suffering pervasive depreciation in recent decades, the first online Flora of Brazil 2020 significantly enhanced the quality and quantity of taxonomic data available for algae, fungi, and plants from Brazil. This project also made all the information freely available online, providing a firm foundation for future research and for the management, conservation, and sustainable use of the Brazilian funga and flora