The Assessment and Management of Biliary Atresia in Hawai'i, 2009-2023.

Although biliary atresia (BA) is a rare neonatal disorder, it remains the leading cause of pediatric end-stage liver disease. Early diagnosis of BA and treatment with the Kasai procedure can significantly reduce the need for pediatric liver transplant. Current data suggests that performing the Kasai procedure at 30-45 days of life is associated with longer native liver survival rates and reduction of the need for liver transplant.

c-KIT inhibitors reduce pathology and improve behavior in the Tg(SwDI) model of Alzheimer's disease.

Treatments for Alzheimer's disease have primarily focused on removing brain amyloid plaques to improve cognitive outcomes in patients. We developed small compounds, known as BK40143 and BK40197, and we hypothesize that these drugs alleviate microglial-mediated neuroinflammation and induce autophagic clearance of neurotoxic proteins to improve behavior in models of neurodegeneration. Specificity binding assays of BK40143 and BK40197 showed primary binding to c-KIT/Platelet Derived Growth Factor Receptors (PDGFR)α/β, whereas BK40197 also differentially binds to FYVE finger-containing phosphoinositide kinase (PIKFYVE).

Second twin outcome at birth: retrospective analysis in a single tertiary centre in Malaysia.

Objectives: To investigate factors associated with outcome of second twin during labour.

Methods: The study was a retrospective cohort study in a single tertiary centre in Malaysia from 2014 until 2018 involving all twin pregnancies delivered at or more than 24 weeks of gestation.

Results: Total of 409 twin pregnancies were included.

General alkyl fluoride functionalization via short-lived carbocation-organozincate ion pairs.

Fluorinated organic compounds are frequently used across the chemical and life sciences. Although a large, structurally diverse pool of alkyl fluorides is nowadays available, synthetic applications trail behind the widely accepted utility of other halides. We envisioned that C(sp)-C(sp) cross-coupling reactions of alkyl fluorides with fluorophilic organozinc compounds should be possible through a heterolytic mechanism that involves short-lived ion pairs and uses the stability of the Zn-F bond as the thermodynamic driving force.

Design, synthesis and biological evaluation of Nucleosidic CD99 inhibitors that selectively reduce Ewing sarcoma viability.

Ewing Sarcoma (ES) is a cancer of bone and soft tissues affecting mostly children and young adults. Aggressive progression and poor prognosis of this malignancy call for novel and targeted treatments. CD99 is a transmembrane protein that is abundantly expressed on ES cells and is a diagnostic marker for the disease.

Safety and Feasibility of Very Early Bronchoscopy-assisted Percutaneous Dilatational Tracheostomy in Anterior Cervical Spine Fixation Patients.

Background: Anterior cervical spine fixation (ACSF) is a common mode of stabilization of cervical spine injuries. These patients usually need a prolonged mechanical ventilation, so an early tracheostomy is beneficial for them. However, it is often delayed due to the close proximity to the surgical site, due to the concerns of infection, and increased bleeding.

Organocuprate Cross-Coupling Reactions with Alkyl Fluorides.

Cross-coupling of alkyl fluorides and organocuprates is accomplished via aluminum halide mediated C-F bond activation and subsequent C-C and C-C bond formation. Relatively mild conditions allow for smooth activation of notoriously challenging primary and secondary alkyl fluorides while competing alkyl chain rearrangement, HF elimination, and homocoupling reactions are effectively controlled. The utility and functional group tolerance are demonstrated with 23 examples and a variety of coupling products obtained in up to 88% yield.

Selective Csp-F Bond Functionalization with Lithium Iodide.

A highly efficient method for C-F bond functionalization of a broad variety of activated and unactivated aliphatic substrates with inexpensive lithium iodide is presented. Primary, secondary, tertiary, benzylic, propargylic and α-functionalized alkyl fluorides react in chlorinated or aromatic solvents at room temperature or upon heating to the corresponding iodides which are isolated in 91-99% yield. The reaction is selective for aliphatic monofluorides and can be coupled with nucleophilic iodide replacements to install carbon-carbon, carbon-nitrogen and carbon-sulfur bonds with high yields.

Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice.

Ubiquitin-Specific Protease-13 (USP13) promotes protein de-ubiquitination. USP13 levels are upregulated in post-mortem Parkinson's disease, whereas USP13 knockdown via shRNA reduces alpha-synuclein levels in animal models. We studied the role of USP13 in knockout mice expressing lentiviral human alpha-synuclein and investigated the impact of a small molecule inhibitor of USP13, BK50118-C, on alpha-synuclein pathology and animal behavior.

Chemodivergent Csp─F bond functionalization and cross-electrophile alkyl-alkyl coupling with alkyl fluorides.

The widespread use of fluorinated organic compounds in the health, agrochemical, and materials sciences is sustained by a steadily growing pool of commercially available fine chemicals. The synthetic utility of the increasingly ubiquitous Csp─F bond, however, remains to be fully exploited, which is often a difficult task because of its paramount stability and chemical inertness. Here, we demonstrate chemodivergent activation of monofluoroalkyl compounds toward either nucleophilic or electrophilic intermediates.

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates.

There is a need for new, cost-effective drugs to treat leishmaniasis. A strategy based on traditional medicine practiced in Bolivia led to the discovery of the 2-substituted quinoline series as a source of molecules with antileishmanial activity and low toxicity. This review documents the development of the series from the first isolated natural compounds through several hundred synthetized molecules to an optimized compound exhibiting an in vitro IC value of 0.

Palladium and Nickel Catalyzed Suzuki Cross-Coupling with Alkyl Fluorides.

Suzuki cross-coupling of benzylic and unactivated aliphatic fluorides with aryl- and alkenylboronic acids has been achieved via mechanistically distinct Pd and Ni catalyzed pathways that outperform competing protodeboronation, β-hydride elimination, and homocoupling processes. The utility is demonstrated with more than 20 examples including heterocyclic structures, 1,1-disubstituted and -1,2-disubstituted alkenes, and by the incorporation of acetonitrile into functionalized (hetero)arenes.

Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology.

Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer's disease (AD) and Parkinson's disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel analogues of spautin-1 which is a non-specific USP13 inhibitor but unable to penetrate the brain.

Management of White-Eyed Blowout Fracture in the Pediatric Population.

Aims And Objectives: Diplopia in children is uncommon. However a small group of patients present with diplopia and severe restriction of upward globe movement which requires early diagnosis and prompt intervention. This study aims to evaluate the timing of intervention and functional outcome in the management of white-eyed blowout fractures.

Discoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases.

The role of Discoidin Domain Receptors (DDRs) is poorly understood in neurodegeneration. DDRs are upregulated in Alzheimer's and Parkinson's disease (PD), and DDRs knockdown reduces neurotoxic protein levels. Here we show that potent and preferential DDR1 inhibitors reduce neurotoxic protein levels in vitro and in vivo.

Quantitative Chirality and Concentration Sensing of Alcohols, Diols, Hydroxy Acids, Amines and Amino Alcohols using Chlorophosphite Sensors in a Relay Assay.

Analytical methods that allow simultaneous determination of the concentration and enantiomeric composition of small sample amounts and are also compatible with high-throughput multi-well plate technology have received increasing attention in recent years. We now introduce a new class of broadly useful small-molecule probes and a relay sensing strategy that together accomplish these tasks with five classes of compounds including the challenging group of mono-alcohols-a scope that stands out among previously reported UV, fluorescence, and CD assays. Several chlorophosphite probes and aniline indicators have been evaluated and used for on-the-fly CD/UV sensing following a continuous workflow.

Catalytic Asymmetric Allylic Amination with Isatins, Sulfonamides, Imides, Amines, and -Heterocycles.

A generally useful palladium-catalyzed method for the asymmetric allylic amination with a large variety of isatins, sulfonamides, imides, amines, and -heterocycles is introduced. A single protocol with a readily available catalyst accomplishes this reaction at room temperature with high yields and enantioselectivities often exceeding 90%, which is demonstrated with 31 examples.

Organocatalytic Decarboxylative Cyanomethylation of Difluoromethyl and Trifluoromethyl Ketones.

An efficient organocatalytic method for the synthesis of difluoromethyl and trifluoromethyl substituted β-hydroxynitriles is introduced. The decarboxylative cyanomethylation of fluorinated ketones with readily available cyanoacetic acid gives a variety of tertiary alcohols in high yields and without concomitant water elimination. The reaction occurs in the presence of catalytic amounts of triethylamine, can be upscaled and applied to chlorofluoromethyl ketones and difluoromethyl ketimines.

Streamlined Asymmetric Reaction Development: A Case Study with Isatins.

Asymmetric reaction development within a day or two has been a dream of synthetic chemists for several decades. We now show that such a task is feasible with a highly efficient streamlined screening strategy using the asymmetric allylation of isatins with a chiral boron complex as a case study. Our high-throughput screening (HTS) method is based on fast optical UV/CD analysis of minute amounts of crude reaction mixtures (≈3 mg scale) and it obviates product isolation and the general need for reference compounds which greatly reduces preliminary work and analysis time.

Click chemistry enables quantitative chiroptical sensing of chiral compounds in protic media and complex mixtures.

Click reactions have become powerful synthetic tools with unique applications in the health and materials sciences. Despite the progress with optical sensors that exploit the principles of dynamic covalent chemistry, metal coordination or supramolecular assemblies, quantitative analysis of complex mixtures remains challenging. Herein, we report the use of a readily available coumarin conjugate acceptor for chiroptical click chirality sensing of the absolute configuration, concentration and enantiomeric excess of several compound classes.

In-vitro and in-vivo antileishmanial activity of inexpensive Amphotericin B formulations: Heated Amphotericin B and Amphotericin B-loaded microemulsion.

Amphotericin B (AmB) is effective against visceral leishmaniasis (VL), but the renal toxicity of the conventional form, mixed micelles with deoxycholate (M-AmB), is often dose-limiting, while the less toxic lipid-based formulations such as AmBisome are very expensive. Two different strategies to improve the therapeutic index of AmB with inexpensive ingredients were evaluated on this work: (i) the heat treatment of the commercial formulation (H-AmB) and (ii) the preparation of an AmB-loaded microemulsion (ME-AmB). M-AmB was heated to 70 °C for 20 min.

Stereoselective Synthesis of 3,3'-Bisindolines by Organocatalytic Michael Additions of Fluorooxindole Enolates to Isatylidene Malononitriles in Aqueous Solution.

A highly diastereoselective organocatalytic reaction for the synthesis of fluorinated 3,3'-bisindolines exhibiting adjacent tetrasubstituted carbon stereocenters is described. A broad variety of heterochiral bisindolines was prepared in 91-99% yield using 3-fluorooxindoles and isatylidene malononitriles in the presence of catalytic amounts of triethylamine in water or aqueous solution. The reaction can be upscaled without compromising yield and diastereoselectivity and the general usefulness of this method was demonstrated with various Michael acceptors and extended to aldol and Mannich reactions.

Organocatalytic Stereoselective Synthesis of Fluorinated 3,3'-Linked Bisoxindoles.

A highly diastereoselective organocatalytic method that produces 3-fluoro-3'-hydroxy-3,3'-bisoxindoles and the corresponding 3-fluoro-3'-amino derivatives having two adjacent chirality centers from fluorooxindoles and isatins in high yields is described. The reaction occurs in protic solvents at room temperature, it can be upscaled without compromising yield and stereoselectivity, and chromatographic product purification is not required.