ABSTRACT The summary paper reports on and highlights the scientific discussions and development process for new expert‐recommended physical fitness guidelines for individuals with Down syndrome that occurred at the inaugural International Summit on Health Benefits of Physical Fitness for People with Down Syndrome (ISFDS). The Summit was a two‐day event held in May 2025 at the Massachusetts General Hospital in Boston that brought together leading international scientists, clinicians, self‐advocates, community services and industries, and local and national advocacy organizations to discuss the latest research, therapies, and collaborative opportunities in physical fitness for individuals with Down syndrome. Day 1 focused on the current state of the science and the identification of research gaps; Day 2 featured working groups dedicated to developing collaborations, planning future research, and creating expert clinical guidelines on physical fitness in children and adults with Down syndrome using a Delphi approach.
ABSTRACT Sex chromosome aneuploidies (SCAs), including Klinefelter syndrome (47,XXY), Turner syndrome (45,X), XYY syndrome, trisomy X (47,XXX), and rarer tetrasomies and pentasomies, affect approximately 1 in 400 births and are associated with a wide range of developmental, cognitive, and physical health outcomes. While clinical research on SCAs has expanded over the past two decades, it is unclear whether the populations included in these studies reflect the demographic diversity of those affected. Assessing representation is critical to ensuring research findings are generalizable and applicable to diverse patient populations. We conducted a systematic review of global clinical research on SCAs published in English between January 2004 and May 2024. Searches were performed in Ovid MEDLINE ALL, Embase, and Web of Science. Studies were included if they enrolled ≥ 10 participants and excluded if they were case reports, reviews, or meta‐analyses. We extracted data from 1474 studies on geographic location, participant karyotypes, and demographic metrics, including race, ethnicity, and socioeconomic status (SES) reported. Trends in demographic reporting were examined over time and by geographic region. For US‐based studies reporting race/ethnicity, we compared pooled participant demographics to national census data. SCA research is concentrated within a small number of geographic areas, primarily in Europe (51.4%) and the United States (23.6%). Reporting rates of race or ethnicity for US papers increased over the 20‐year observation period, with an average increase of 1.5% ± 0.4% per year ( p = 0.003), peaking in 2024 with 61.4% of US‐based papers presenting demographics. When reported, studies consistently overrepresented White non‐Hispanic ( p < 0.001) and college‐educated ( p < 0.001) participants relative to US census benchmarks. This systematic review reveals persistent gaps in the demographic reporting and representation of participants in SCA research. Even in the United States, where population diversity is high, published studies do not reflect the expected racial, ethnic, and socioeconomic makeup of affected individuals. To ensure that research findings are equitable and clinically relevant, future studies should adopt standardized demographic reporting and prioritize inclusive enrollment strategies to reflect the full spectrum of individuals with SCAs.
ABSTRACT Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder–Robinson syndrome results from hemizygous loss‐of‐function variants in the spermine synthase ( SMS ) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann–Bupp syndrome results from heterozygous gain‐of‐function variants in the ornithine decarboxylase 1 ( ODC1 ) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes–Banka syndrome results from heterozygous loss‐of‐function variants in the eukaryotic translation initiation factor 5A ( EIF5A ) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi‐allelic hypomorphic variants in the deoxyhypusine synthase ( DHPS ) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi‐allelic loss‐of‐function variants in the deoxyhypusine hydroxylase ( DOHH ) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder–Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.
ABSTRACT Isoquinolin‐1(2 H )‐ones represent an important class of nitrogen‐containing heterocycles widely found in natural products and pharmacologically active compounds. Recent developments in their functionalization have enabled the construction of structurally diverse and bioactive derivatives through selective halogenation and C–X (X = S, N) bond formation. This review summarizes key methodologies, including transition‐metal‐catalyzed processes and metal‐free radical‐based approaches. Adopting sustainable techniques such as visible‐light photocatalysis, electrochemical methods, and solvent‐free protocols has significantly improved the environmental profile of these transformations. These advances offer versatile and efficient tools for synthesizing functionally rich isoquinolone derivatives with broad relevance in medicinal chemistry and materials science.
ABSTRACT A selectfluor‐mediated metal‐free approach has been developed for the synthesis of methylene‐bound benzotriazolation, triazolation, and pyrazolation of 3‐acetylindoles at 90°C. The reaction is kinetically controlled and uses DMSO as one carbon source. Further, α ‐methylenation of 3‐acetylindoles was observed when benzotriazole, triazole, and pyrazole were absent in the reaction at a higher temperature (120°C). The reaction uses DMSO as one‐carbon synthon and is thermodynamically controlled. The base is needed for α ‐methylenation of 3‐acetylindoles. The current method expands the scope of metal‐free organic reactions and offers new opportunities for developing a library of bioactive indoles for pharmaceutical science.
ABSTRACT Pyrimidines are aromatic nitrogen‐containing heterocycles with significant applications in medicinal chemistry and materials science. Conventional two‐step strategies for synthesizing 2,5‐disubstituted pyrimidines from 2,5‐dihalopyrimidines often require toxic reagents, transition metal (TM) catalysts, harsh conditions, specialized substrates, or non‐commercially available reagents. Therefore, this study aims to develop a TM‐free synthetic route for producing 2,5‐disubstituted pyrimidines via heterocyclic skeletal editing. This one‐pot tandem reaction sequence integrates nucleophilic aromatic C─O, C─N, and C─S substitutions with an amidine‐based inverse‐electron demand Diels–Alder reaction, providing efficient synthesis of pyrimidine derivatives in moderate to excellent yields. The modular skeletal editing strategy employs 5‐bromo‐1,2,3‐triazine 1 as a molecular platform, facilitating orthogonal coupling with various phenols, thiophenols, and sodium azide, followed by amidines to achieve skeletal editing under mild conditions using only Cs 2 CO 3 . This method offers several advantages, including ready substrate availability, operational simplicity, and high atom economy. To further demonstrate the functional utility of the pyrimidine derivatives, pyrimidine‐based Ru(II) complexes were synthesized for fluorescence imaging in live cells. An alkynylated Ru(II) complex 13 served as a key precursor for the modular incorporation of organelle‐targeting moieties via copper‐catalyzed azide–alkyne cycloaddition. These functionalized metal complexes facilitate selective labeling of the nucleus and mitochondria in live cells.
ABSTRACT Trifluoromethylated internal alkynes are presented as a class of versatile building blocks for efficient assembly of various trifluoromethyl group‐containing useful organic molecules through either direct nucleophilic addition or cyclization. Therefore, it has attracted significant attention from organic synthetic chemists and tremendous efforts have been devoted to the development of its rapid preparation. In this review, we aim to provide a comprehensive summary of the latest advances in the straightforward preparation of trifluoromethylated internal alkynes. We would also like to spur the recent discoveries and developments of innovative reaction paradigms in this field. Additionally, crucial challenges and future perspectives on this hot topic are also discussed, with the wish to provide a profound insight for not only future organofluorine chemistry but also fluorine‐containing pharmaceutical science. This manuscript mainly focuses on the direct synthetic methodology to construct various unsymmetrical trifluoromethylated internal alkynes, and it is categorized according to various synthetic methods as well as different types of trifluoromethyl source.
ABSTRACT N‐Aryl phenothiazines are privileged scaffolds in materials science and medicinal chemistry, yet their synthesis often relies on transition metals or stoichiometric oxidants. Herein, we report a sustainable, metal‐free electrochemical (EC) method for the C–H amination of phenols and anilines with phenothiazines. This protocol employs stable platinum electrodes under mild, oxidant‐free conditions, enabling the late‐stage functionalization of pharmaceuticals and natural products with high efficiency (up to 97% yield) and excellent regioselectivity. Furthermore, we introduce a complementary photoelectrochemical (PEC) strategy that, for a subset of substrates, provides superior yields, including several near‐quantitative transformations. Mechanistic studies via cyclic voltammetry and EPR spectroscopy confirm the generation of a persistent phenothiazine radical cation (PTZ• + ) as the key electrophilic intermediate. The efficiency of both EC and PEC pathways is rationalized by the stability of these radical cations, which is tunable by substituent effects.
ABSTRACT Fluoroalkyl amides have attracted significant attention in drug discovery and materials science. However, conventional synthetic methods often involve toxic reagents and multi‐step procedures, limiting their practicality, safety, and sustainability. In this study, we report a visible‐light‐driven synthesis of perfluoroalkyl amides from amines and perfluoroalkyl iodides employing an organic photocatalyst under ambient air. This reaction proceeds under mild, metal‐free conditions and demonstrates broad compatibility with various fluorinated substrates, including amines and perfluoroalkyl iodides. Moreover, when using diiodoperfluoroalkanes, compounds linking amides and other functional groups via fluoroalkylene are readily synthesized.