Critically Ill Older Adults' Representation in Intervention Trials: A Systematic Review.

Objectives: Older adults may be under-represented in critical care research, and results may not apply to this specific population. Our primary objective was to evaluate the prevalence of inclusion of older adults across critical care trials focused on common ICU conditions or interventions. Our secondary objective was to evaluate whether older age was used as a stratification variable for randomization or outcome analysis.

Navigating the multifaceted intricacies of the Na-Cl cotransporter, a highly regulated key effector in the control of hydromineral homeostasis.

The Na-Cl cotransporter (NCC; SLC12A3) is a highly regulated integral membrane protein that is known to exist as three splice variants in primates. Its primary role in the kidney is to mediate the cosymport of Na and Cl across the apical membrane of the distal convoluted tubule. Through this role and the involvement of other ion transport systems, NCC allows the systemic circulation to reclaim a fraction of the ultrafiltered Na, K, Cl, and Mg loads in exchange for Ca and [Formula: see text].

N-Heterocyclic Carbene Organocatalyzed Redox-Active/Ring Expansion Reactions: Mechanistic Insights Unveiling Base Cooperativity.

N-Heterocyclic carbene (NHC) organocatalyzed transformations of redox-active chemical manifolds is a powerful strategy for interconverting and expanding the chemical space. This approach in the context of ring expansion holds promise for preparing lactones from plentiful redox active aldehydes, despite a lack of rigorous mechanistic insights into the underlying elements governing this reactivity and with-it relevance to other NHC organocatalyzed transformations. Herein, in investigating this reactivity under the lens of modern day quantum mechanical calculations, we explore the mechanism of redox-active/ring expansion reactions of aldehydes furnishing lactone products by means of NHC organocatalysis.

An Alternative Method for the Synthesis of -Pentafluorophenyl Triazolium Salts.

A route for the synthesis of 1,2,4-triazolium salts via oxidation of a thione precursor is demonstrated. -Pentafluorophenyl-substituted salts are produced in 20-63% overall yields. Isolation and purification of the azolium salts are simplified compared to the traditional synthetic route.

Inclusion of autistic students: promising modalities for supporting a school team.

Purpose: School staff who work with autistic students are at a high risk of exhaustion. More training and guidance are needed to enable them to respond to these students' needs. The purpose of this study was to design and evaluate a professional development program offered by an occupational therapist to help a team of school staff facilitate the participation of autistic students and their peers.

"We are still doing some magic": Exploring the effectiveness of online therapeutic clowning.

Background: Therapeutic clowns use embodied practices to engage with clients, their families and healthcare staff to empower patients and create therapeutic relationships. This study explored the effectiveness of a virtual therapeutic clown initiative.

Methods: Thirteen therapeutic clowns participated in a semi-structured interview to discuss their experiences with online clowning; additionally, four dyads consisting of a clown duo and a client explored multiple perspectives of a shared online clowning experience.

Total Synthesis of (+)-Hyacinthacine A Using a Chemoselective Cross-Benzoin Reaction and a Furan Photooxygenation-Amine Cyclization Strategy.

We report the shortest synthesis of glycosidase inhibitor (+)-hyacinthacine A using a highly chemoselective N-heterocyclic carbene-catalyzed cross-benzoin reaction as well as a furan photooxygenation-amine cyclization strategy. This is the first such cyclization on a furylic alcohol, an unprecedented reaction due to the notorious instability of the formed intermediates. The photooxygenation strategy was eventually incorporated into a three-step one-pot process that formed the requisite pyrrolizidine framework of (+)-hyacinthacine A.

Enantioselective Stetter Reactions Catalyzed by Bis(amino)cyclopropenylidenes: Important Role for Water as an Additive.

The first highly enantioselective intermolecular Stetter reaction using simple enones is reported. A series of novel chiral BAC structures were designed and prepared. They were tested in the Stetter reaction with simple aldehydes and enones.

Differential role of planar cell polarity gene Vangl2 in embryonic and adult mammalian kidneys.

Planar cell polarity (PCP) pathway is crucial for tissue morphogenesis. Mutations in PCP genes cause multi-organ anomalies including dysplastic kidneys. Defective PCP signaling was postulated to contribute to cystogenesis in polycystic kidney disease.

Theoretical Study of Diastereoselective NHC-Catalyzed Cross-Benzoin Reactions between Furfural and -Boc-Protected α-Amino Aldehydes.

The mechanism and origins of and selectivity of cross-benzoin reactions between furfural and α-amino aldehydes, catalyzed by a triazolium-based NHC, were investigated using density functional theory calculations. -Boc-α-amino aldehydes were found to react with selectivity, while -Bn--Boc-α-amino aldehydes react with selectivity. We find that the product is more thermodynamically favored than the product for reactions with -Boc-α-amino aldehydes, and that the formation of the product for reactions involving -Bn--Boc-α-amino aldehydes is kinetically favored.

TREX-1-Related Disease Associated with the Presence of Cryofibrinogenemia.

Purpose: Cryofibrinogenemia is a rare cryopathy presenting as acrocyanosis following exposure to cold. Familial presentation has been described but the underlying molecular cause remained undetermined.

Methods: Forty (40) members from a large family with an initial diagnosis of familial cryofibrinogenemia were interviewed and examined to determine affected status and collect DNA.

Oxazolium Salts as Organocatalysts for the Umpolung of Aldehydes.

Oxazolium salts were successfully employed for the first time as organocatalysts for benzoin, Stetter, and redox esterification reactions. An N-mesityl oxazolium salt catalyzed homobenzoin reaction of aromatic, heteroaromatic, and aliphatic aldehydes delivered α-hydroxy ketones in high yields. This new type of catalyst proved remarkably effective for the Stetter reaction of challenging substrates such as β-alkyl-α,β-unsaturated ketones and electron-rich aromatic aldehydes in comparison to common thiazolium and triazolium salts.

Rare coding variants in genes encoding GABA receptors in genetic generalised epilepsies: an exome-based case-control study.

Background: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.

DZ-2384 has a superior preclinical profile to taxanes for the treatment of triple-negative breast cancer and is synergistic with anti-CTLA-4 immunotherapy.

Triple-negative breast cancer (TNBC) is typically aggressive, difficult to treat, and commonly metastasizes to the visceral organs and soft tissues, including the lungs and the brain. Taxanes represent the most effective and widely used therapeutic class in metastatic TNBC but possess limiting adverse effects that often result in a delay, reduction, or cessation of their use. DZ-2384 is a candidate microtubule-targeting agent with a distinct mechanism of action and strong activity in several preclinical cancer models, with reduced toxicities.

Global characterization of copy number variants in epilepsy patients from whole genome sequencing.

Epilepsy will affect nearly 3% of people at some point during their lifetime. Previous copy number variants (CNVs) studies of epilepsy have used array-based technology and were restricted to the detection of large or exonic events. In contrast, whole-genome sequencing (WGS) has the potential to more comprehensively profile CNVs but existing analytic methods suffer from limited accuracy.

Assembly of Complex Macrocycles by Incrementally Amalgamating Unprotected Peptides with a Designed Four-Armed Insert.

We describe the asymmetric synthesis of a highly substituted ω-octynoic acid derivative and demonstrate its utility for generating complex macrocycles from unprotected peptides. The molecule harbors an isolated quaternary center that displays four uniquely functionalized arms, each of which can be reacted orthogonally in sequence as the molecule is integrated into peptide structure. These processing sequences entail (1) scaffold ligation, (2) macrocyclization via internal aromatic alkylations or catalyzed etherifications, (3) acyliminium ion mediated embedding of condensed heterocycles, and (4) terminal alkyne derivatization or dimerization reactions.

Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy.

Tumor cells are particularly dependent on NAD due to higher rates of metabolism, DNA synthesis and repair. Nicotinamide phosphoribosyltransferase inhibitors (NAMPTis) inhibit NAD biosynthesis and represent promising new anti-cancer agents. However, clinical efficacy has been limited by toxicities demonstrating the need for drug combinations to broaden the therapeutic index.

Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo.

TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) has long been considered a tantalizing target for cancer therapy because it mediates activation of the extrinsic apoptosis pathway in a tumor-specific manner by binding to and trimerizing its functional receptors DR4 or DR5. Despite initial promise, both recombinant human TRAIL (native TRAIL) and dimeric DR4/DR5 agonist monoclonal antibodies (mAbs) failed in multiple human clinical trials. Here we show that in-frame fusion of human C-propeptide of α1(I) collagen (Trimer-Tag) to the C-terminus of mature human TRAIL leads to a disulfide bond-linked homotrimer which can be expressed at high levels as a secreted protein from CHO cells.

Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-Benzoin Reactions Using N-Boc-N-Bn-Protected α-Amino Aldehydes.

The effectiveness of utilizing N-Bn-N-Boc-α-amino aldehydes in cross-benzoin reactions with heteroaromatic aldehydes is demonstrated. The reaction is both chemoselective and syn-selective, making it complementary to the anti-selective cross-benzoin reaction of NHBoc-α-amino aldehydes. Good diastereoselectivity is obtained for a variety of amino aldehydes, including nonhindered ones.

Studies Directed toward the Synthesis of Aspidophytine: Construction of Its Perhydroquinoline Core.

We have developed an efficient route for the synthesis of the perhydroquinoline core of the indole alkaloid aspidophytine (2), starting from commercially available and inexpensive 3-acetylpyridine. This densely functionalized perhydroquinoline core displays four contiguous stereocenters including an all-carbon quaternary center. The synthetic sequence features a highly effective Diels-Alder reaction using a carbamate-substituted siloxy diene accompanied by a spontaneous intramolecular substitution of the newly formed 3°-alkyl bromide with a carbamate group.

Chemo- and Diastereoselective N-Heterocyclic Carbene-Catalyzed Cross-Benzoin Reactions Using N-Boc-α-amino Aldehydes.

N-Boc-α-amino aldehydes are shown to be excellent partners in cross-benzoin reactions with aliphatic or heteroaromatic aldehydes. The chemoselectivity of the reaction and the facial selectivity on the amino aldehyde allow cross-benzoin products to be obtained in good yields and good diastereomeric ratios. The developed method is utilized as the key step in a concise total synthesis of d-arabino-phytosphingosine.

IL-10 Controls Early Microglial Phenotypes and Disease Onset in ALS Caused by Misfolded Superoxide Dismutase 1.

While reactive microgliosis is a hallmark of advanced stages of amyotrophic lateral sclerosis (ALS), the role of microglial cells in events initiating and/or precipitating disease onset is largely unknown. Here we provide novel in vivo evidence of a distinct adaptive shift in functional microglial phenotypes in preclinical stages of superoxide dismutase 1 (SOD1)-mutant-mediated disease. Using a mouse model for live imaging of microglial activation crossed with SOD1(G93A) and SOD1(G37R) mouse models, we discovered that the preonset phase of SOD1-mediated disease is characterized by development of distinct anti-inflammatory profile and attenuated innate immune/TLR2 responses to lipopolysaccharide (LPS) challenge.

X-linked focal epilepsy with reflex bathing seizures: Characterization of a distinct epileptic syndrome.

Objective: We recently reported a Q555X mutation of synapsin 1 (SYN1) on chromosome Xp11-q21 in a family segregating partial epilepsy and autistic spectrum disorder. Herein, we provide a detailed description of the epileptic syndrome in the original family.

Methods: A total of 34 members from a large French-Canadian family were evaluated.