A robust heterogeneous chiral phosphoric acid enables multi decagram scale production of optically active N,S-ketals.

Asymmetric organocatalysis has been recognized as one of the "top 10 emerging technologies" in chemistry by IUPAC in 2019. Its potential to make chemical processes more sustainable is promising, but there are still challenges that need to be addressed. Developing new and reliable enantioselective processes for reproducing batch reactions on a large scale requires a combination of chemical and technical solutions. In this manuscript, we combine a robust immobilized chiral phosphoric acid with a new packed-bed reactor design. This combination allows scaling up of the enantioselective addition of thiols to imines from a few milligrams to a multi-decagram scale in a continuous flow process without physical or chemical degradation of the catalyst.

Knowledge and management of traumatic dental injuries among schoolteachers in Hungary: a cross-sectional study with educational intervention.

PURPOSE: This study aimed to evaluate the knowledge of Hungarian schoolteachers in the management of dental trauma injuries (TDI) of children between the ages of 3 and 18 and to illustrate a brief educational intervention on TDI management. METHODS: A 15-item questionnaire on dental injuries was distributed in our observational cross-sectional study to 2720 Hungarian educational institutions to explore and evaluate teachers' knowledge in January 2019. Two years later, targeted information material was made accessible regarding TDI management. In the second post-intervention phase of the study, educator knowledge was re-evaluated using the same questionnaire. Statistical analysis (Mann-Whitney and Chi-square tests) was performed using IBM SPSS Statistics 28. RESULTS: A total of 1426 answers were collected in the initial survey. Although more than half (51.9%) of the respondents previously witnessed TDIs, 86.5% still did not perceive themselves as adequately informed regarding TDI management. Most teachers submitted appropriate responses to the indicator questions relating to the urgency of referral to dental professionals (71.8%), immediate contact with parents (79.0%) or dentists (13.0%), and the solution for avulsed teeth (81.3%). However, only every second (56.2%) educator responded correctly regarding the proper cleaning method. Following accessibility to our educational material, 622 respondents completed the post-intervention questionnaire in the second phase of the study. The percentage of appropriate responses to the five indicator questions significantly increased by 5-20.6%. CONCLUSION: Teachers' knowledge of TDI was inadequate yet can improve with online education. Efforts among dental professionals, the media, and targeted interventions will ensure adequate knowledge while also improving children's dental health.

Application of an Oscillatory Plug Flow Reactor to Enable Scalable and Fast Reactions in Water Using a Biomass-Based Polymeric Additive.

The utilization of water as a sustainable reaction medium has important advantages over traditional organic solvents. Hydroxypropyl methylcellulose has emerged as a biomass-based polymeric additive that enables organic reactions in water through hydrophobic effects. However, such conditions imply slurries as reaction mixtures, where the efficacy of mass transfer and mixing decreases with increasing vessel size. In order to circumvent this limitation and establish an effectively scalable platform for performing hydroxypropyl methylcellulose-mediated aqueous transformations, we utilized oscillatory plug flow reactors that feature a smart dimensioning design principle across different scales. Using nucleophilic aromatic substitutions as valuable model reactions, rapid parameter optimization was performed first in a small-scale instrument having an internal channel volume of 5 mL. The optimal conditions were then directly transferred to a 15 mL reactor, achieving a three-fold scale-up without re-optimizing any reaction parameters. By precisely fine-tuning the oscillation parameters, the system achieved optimal homogeneous suspension of solids, preventing settling of particles and clogging of process channels. Ultimately, this resulted in a robust and scalable platform for performing multiphasic reactions under aqueous conditions.

Non-pain-related complaints of paediatric patients after dental treatment under general anaesthesia.

AIM: To investigate the prevalence, duration, and severity of non-pain-related complaints after dental treatment under general anaesthesia (DTGA) and to identify correlating factors from patient's characteristics and treatment. METHODS: Parents/caregivers of children treated under general anaesthesia were asked to fill in a dichotomous questionnaire during hospitalisation and the postoperative week. Several complaints were evaluated in relation to factors associated with dental treatment and general anaesthesia. CONCLUSION: Postoperative morbidity after DTGA is common. Patients and their parents should be informed about the possibility of experiencing mild to moderate complaints, and adverse events that may last up to 7 days.

A Telescoped Continuous Flow Enantioselective Process for Accessing Intermediates of 1-Aryl-1,3-diols as Chiral Building Blocks.

A telescoped continuous flow process is reported for the enantioselective synthesis of chiral precursors of 1-aryl-1,3-diols, intermediates in the synthesis of ezetimibe, dapoxetine, duloxetine, and atomoxetine. The two-step sequence consists of an asymmetric allylboration of readily available aldehydes using a polymer-supported chiral phosphoric acid catalyst to introduce asymmetry, followed by selective epoxidation of the resulting alkene. The process is highly stable for at least 7 h and represents a transition-metal free enantioselective approach to valuable 1-aryl-1,3-diols.

Pain-related complaints of paediatric patients after dental treatment under general anaesthesia.

AIM: To identify factors related to postoperative pain and to recognise strategies to reduce this pain after dental treatment under general anaesthesia. METHODS: Cross-sectional observational study. Children treated under general ansesthesia reported pain daily using the Wong Baker FACES® Pain Rating Scale. Their parents/caregivers filled in a related Yes/No questionnaire during hospitalisation and the first postoperative week. The duration and severity of pain were evaluated in relation to various factors. CONCLUSION: A well-established protocol is indicated to reduce operation time. Patients and their parents should be informed about the possibility of constantly subsiding postoperative pain that may last for a week. As additional local anaesthesia during general anaesthesia (GA) does not provide postoperative pain reduction in deciduous tooth extraction cases, its administration could be omitted.

Harnessing a Continuous-Flow Persulfuric Acid Generator for Direct Oxidative Aldehyde Esterifications.

Persulfuric acid is a well-known oxidant in various industrial-scale purification procedures. However, due to its tendency toward explosive decomposition, its usefulness in organic synthesis remained largely underexplored. Herein, a continuous in situ persulfuric acid generator was developed and applied for oxidative esterification of aldehydes under flow conditions. Sulfuric acid served as a readily available and benign precursor to form persulfuric acid in situ. By taking advantage of the continuous-flow generator concept, safety hazards were significantly reduced, whilst a robust and effective approach was ensured for direct transformations of aldehydes to valuable esters. The process proved useful for the transformation of diverse aliphatic as well as aromatic aldehydes, while its preparative capability was verified by the multigram-scale synthesis of a pharmaceutically relevant key intermediate. The present flow protocol demonstrates the safe, sustainable, and scalable application of persulfuric acid in a manner that would not be amenable to conventional batch processing.

Merger of Visible Light-Driven Chiral Organocatalysis and Continuous Flow Chemistry: An Accelerated and Scalable Access into Enantioselective α-Alkylation of Aldehydes.

The electron donor-acceptor complex-enabled asymmetric photochemical alkylation strategy holds potential to attain elusive chiral α-alkylated aldehydes without an external photoredox catalyst. The photosensitizer-free conditions are beneficial concerning process costs and sustainability. However, lengthy organocatalyst preparation steps as well as limited productivity and difficult scalability render the current approaches unsuitable for synthesis on enlarged scales. Inspired by these limitations, a protocol was developed for the enantioselective α-alkylation of aldehydes based on the synergistic combination of visible light-driven asymmetric organocatalysis and a controlled continuous flow reaction environment. With the aim to reduce process costs, a commercially available chiral catalyst has been exploited to achieve photosensitizer-free enantioselective α-alkylations using phenacyl bromide derivates as alkylating agents. As a result of elaborate optimization and process development, the present flow strategy furnishes an accelerated and inherently scalable entry into enantioenriched α-alkylated aldehydes including a chiral key intermediate of the antirheumatic esonarimod.

Enantioselective Flow Synthesis of Rolipram Enabled by a Telescoped Asymmetric Conjugate Addition-Oxidative Aldehyde Esterification Sequence Using in Situ-Generated Persulfuric Acid as Oxidant.

A novel approach is reported for the enantioselective flow synthesis of rolipram comprising a telescoped asymmetric conjugate addition-oxidative aldehyde esterification sequence followed by trichlorosilane-mediated nitro group reduction and concomitant lactamization. The telescoped process takes advantage of a polystyrene-supported chiral organocatalyst along with in situ-generated persulfuric acid as a robust and scalable oxidant for direct aldehyde esterification. This approach demonstrates significantly improved productivity compared with earlier methodologies while ensuring environmentally benign metal-free conditions.

Continuous flow asymmetric synthesis of chiral active pharmaceutical ingredients and their advanced intermediates.

Catalytic enantioselective transformations provide well-established and direct access to stereogenic synthons that are broadly distributed among active pharmaceutical ingredients (APIs). These reactions have been demonstrated to benefit considerably from the merits of continuous processing and microreactor technology. Over the past few years, continuous flow enantioselective catalysis has grown into a mature field and has found diverse applications in asymmetric synthesis of pharmaceutically active substances. The present review therefore surveys flow chemistry-based approaches for the synthesis of chiral APIs and their advanced stereogenic intermediates, covering the utilization of biocatalysis, organometallic catalysis and metal-free organocatalysis to introduce asymmetry in continuously operated systems. Single-step processes, interrupted multistep flow syntheses, combined batch/flow processes and uninterrupted one-flow syntheses are discussed herein.

Copper-Loaded Layered Bismuth Subcarbonate-Efficient Multifunctional Heterogeneous Catalyst for Concerted C-S/C-N Heterocyclization.

An efficient self-supported Cu(II)Bi(III) bimetallic catalyst with a layered structure was designed and developed. By careful characterization of the as-prepared material, the host structure was identified to exhibit a Sillen-type bismutite framework, with copper(II) ions being loaded as guests. The heterogeneous catalyst enabled C-N and C-S arylations under mild reaction conditions and with high chemoselectivities, thus furnishing valuable phenothiazines via heterocyclization with wide substrate tolerance. As corroborated by detailed catalytic studies, the cooperative, bifunctional catalyst, bearing Lewis acid sites along with copper(II) catalytic sites, facilitated an intriguing concerted C-N/C-S heterocyclization mechanism. The heterogeneous nature of the catalytic reactions was verified experimentally. Importantly, the catalyst was successfully recycled and reused multiple times, persevering its original structural order as well as its initial activity.

Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites-A Medicinal Chemistry Approach.

Curcuminoids are the main bioactive components of the well-known Asian spice and traditional medicine turmeric. Curcuminoids have poor chemical stability and bioavailability; in vivo they are rapidly metabolized to a set of bioreduced derivatives and/or glucuronide and sulfate conjugates. The reduced curcuminoid metabolites were also reported to exert various bioactivities in vitro and in vivo. In this work, we aimed to perform a comparative evaluation of curcuminoids and their hydrogenated metabolites from a medicinal chemistry point of view, by determining a set of key pharmacokinetic parameters and evaluating antioxidant potential in relation to such properties.Reduced metabolites were prepared from curcumin and demethoxycurcumin through continuous-flow hydrogenation. As selected pharmacokinetic parameters, kinetic solubility, chemical stability, metabolic stability in human liver microsomes, and parallel artificial membrane permeability assay (PAMPA)-based gastrointestinal and blood-brain barrier permeability were determined. Experimentally determined logP for hydrocurcumins in octanol-water and toluene-water systems provided valuable data on the tendency for intramolecular hydrogen bonding by these compounds. Drug likeness of the compounds were further evaluated by a in silico calculations. Antioxidant properties in diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and oxygen radical absorbance capacity (ORAC) assays were comparatively evaluated through the determination of ligand lipophilic efficiency (LLE). Our results showed dramatically increased water solubility and chemical stability for the reduced metabolites as compared to their corresponding parent compound. Hexahydrocurcumin was found the best candidate for drug development based on a complex pharmacokinetical comparison and high LLE values for its antioxidant properties. Development of tetrahydrocurcumin and tetrahydro-demethoxycurcumin would be limited by their very poor metabolic stability, therefore such an effort would rely on formulations bypassing first-pass metabolism.

Bismuth Subnitrate-Catalyzed Markovnikov-Type Alkyne Hydrations under Batch and Continuous Flow Conditions.

Bismuth subnitrate is reported herein as a simple and efficient catalyst for the atom-economical synthesis of methyl ketones via Markovnikov-type alkyne hydration. Besides an effective batch process under reasonably mild conditions, a chemically intensified continuous flow protocol was also developed in a packed-bed system. The applicability of the methodologies was demonstrated through hydration of a diverse set of terminal acetylenes. By simply switching the reaction medium from methanol to methanol-d4, valuable trideuteromethyl ketones were also prepared. Due to the ready availability and nontoxicity of the heterogeneous catalyst, which eliminated the need for any special additives and/or harmful reagents, the presented processes display significant advances in terms of practicality and sustainability.

Health literacy and health-promoting behaviors among adults at risk for diabetes in a remote Filipino community.

Background: Diabetes risk assessment is an essential preboarding tool before implementing health literacy programs to change an adult's health behavior positively. Research has shown an association between health literacy and health behaviors, but there is a dearth of literature that delineates the difference between the health literacy and health behaviors of adults according to their diabetes risks; high risk vs. low risk. Objective: This study aimed to determine the difference between the health literacy and health behaviors of adults and establish the relationship between the two variables when classified according to their diabetes risks. Methods: This study utilized a descriptive cross-sectional design with 400 adults in a remote Filipino community in November 2019. Data were gathered using the Health Promoting Lifestyle Profile II (HPLP II) and Health Literacy Survey-Short Form 12 (HLS-SF12) questionnaires. Descriptive statistics, independent t-test, and Pearson's r were used to analyze the data. Results: There is a significant difference between the health literacy index scores (p < .05); but no significant difference between the health behavior mean scores (p > .05) of adults when grouped according to their diabetes risks. Health literacy is significantly (p < .05) correlated with health behaviors of adults, with a moderate positive correlation in the high-risk group (r = .43), and both weak positive correlation in the low-risk group (r = .13) and entire group (r = .17). Conclusion: All adult inclusion efforts in promoting health literacy, with emphasis on the high-risk group, are needed to improve awareness of the degree of diabetes risks. Nurses should take an active role in the assessment of diabetes risks, evaluation of results, and implementation of interventions that could increase health literacy to facilitate the development of healthy behaviors. Stakeholders are urged to advance the availability of evidence-based lifestyle interventions to reduce the growth in new cases of diabetes.

Telescoped Continuous Flow Synthesis of Optically Active γ-Nitrobutyric Acids as Key Intermediates of Baclofen, Phenibut, and Fluorophenibut.

The two-step flow asymmetric synthesis of chiral γ-nitrobutyric acids as key intermediates of the GABA analogues baclofen, phenibut, and fluorophenibut is reported on a multigram scale. The telescoped process comprises an enantioselective Michael-type addition facilitated by a polystyrene-supported heterogeneous organocatalyst under neat conditions followed by in situ-generated performic acid-mediated aldehyde oxidation. Simple access to valuable optically active substances is provided with key advances in terms of productivity and sustainability compared to those of previous batch approaches.

Continuous-Flow Amide and Ester Reductions Using Neat Borane Dimethylsulfide Complex.

Reductions of amides and esters are of critical importance in synthetic chemistry, and there are numerous protocols for executing these transformations employing traditional batch conditions. Notably, strategies based on flow chemistry, especially for amide reductions, are much less explored. Herein, a simple process was developed in which neat borane dimethylsulfide complex (BH3 ⋅DMS) was used to reduce various esters and amides under continuous-flow conditions. Taking advantage of the solvent-free nature of the commercially available borane reagent, high substrate concentrations were realized, allowing outstanding productivity and a significant reduction in E-factors. In addition, with carefully optimized short residence times, the corresponding alcohols and amines were obtained in high selectivity and high yields. The synthetic utility of the inexpensive and easily implemented flow protocol was further corroborated by multigram-scale syntheses of pharmaceutically relevant products. Owing to its beneficial features, including low solvent and reducing agent consumption, high selectivity, simplicity, and inherent scalability, the present process demonstrates fewer environmental concerns than most typical batch reductions using metal hydrides as reducing agents.

A High-Yielding Synthesis of EIDD-2801 from Uridine.

A simple reordering of the reaction sequence allowed the improved synthesis of EIDD-2801, an antiviral drug with promising activity against the SARS-CoV-2 virus, starting from uridine. Compared to the original route, the yield was enhanced from 17 % to 61 %, and fewer isolation/purification steps were needed. In addition, a continuous flow procedure for the final acetonide deprotection was developed, which proved to be favorable toward selectivity and reproducibility.

Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1'-O-isopropyl ether Shows Improved Selectivity Against the Epstein-Barr Virus Lytic Cycle.

Protoflavones, a rare group of natural flavonoids with a non-aromatic B-ring, are best known for their antitumor properties. The protoflavone B-ring is a versatile moiety that might be explored for various pharmacological purposes, but the common cytotoxicity of these compounds is a limitation to such efforts. Protoapigenone was previously found to be active against the lytic cycle of Epstein-Barr virus (EBV). Further, the 5-hydroxyflavone moiety is a known pharmacophore against HIV-integrase. The aim of this work was to prepare a series of less cytotoxic protoflavone analogs and study their antiviral activity against HIV and EBV. Twenty-seven compounds, including 18 new derivatives, were prepared from apigenin through oxidative de-aromatization and subsequent continuous-flow hydrogenation, deuteration, and/or 4'-oxime formation. One compound was active against HIV at the micromolar range, and three compounds showed significant activity against the EBV lytic cycle at the medium-low nanomolar range. Among these derivatives, protoapigenone 1'-O-isopropyl ether (6) was identified as a promising lead that had a 73-times selectivity of antiviral over cytotoxic activity, which exceeds the selectivity of protoapigenone by 2.4-times. Our results open new opportunities for designing novel potent and safe anti-EBV agents that are based on the natural protoflavone moiety.

Long-Term Outcomes of Refractive Surgery Performed During the Military.

INTRODUCTION: To evaluate the long-term refractive results of laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) performed by the military in a veteran population. MATERIALS AND METHODS: Three Department of Veterans Affairs (VA) hospital sites (Puget Sound, Buffalo, and Washington D.C.) obtained IRB approval for this multi-center study. Comprehensive ophthalmologic assessment including refraction and keratometry were obtained at the time of the long-term VA examination and compared to the patients' postoperative military records. RESULTS: Eighty patients (160 eyes) enrolled in this study. At the time of treatment, patients were 21-52 years of age. Long-term post-operative data was available from 4 to 17 years post-operatively. Fifteen percent of the treatment types were LASIK and 85% PRK. At the time of their military post-operative exam (range 3-14 months, mean 4 months), 82% of patients had uncorrected visual acuity (UCVA) of 20/20 or better, and their average manifest refraction was -0.08 D (SD ± 0.48 D). At the time of the long-term ophthalmological exam at the VA medical centers (range 4-11 years, mean of 8.2 years), 49% of patients had an UCVA of 20/20 or better and an average manifest refraction was -0.64 D (SD ± 0.69 D). CONCLUSION: This is the first long-term study evaluating refractive surgery outcomes up to 17 years in a military population. Our study demonstrates safety after refractive surgery in the military with less than 0.1D increase in myopia per year and strong keratometric stability. Other changes in the eye may be the likely cause for this observed mild refractive shift.

Altered Notch Signaling in Developing Molar Teeth of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)-Deficient Mice.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with neuroprotective and neurotrophic effects. This suggests its influence on the development of teeth, which are, similarly to the nervous system, ectoderm and neural crest derivatives. Our earlier studies have shown morphological differences between wild-type (WT) and PACAP-deficient mice, with upregulated sonic hedgehog (SHH) signaling in the lack of PACAP. Notch signaling is a key element of proper tooth development by regulating apoptosis and cell proliferation. In this study, our main goal was to evaluate the possible effects of PACAP on Notch signaling pathway. Immunohistochemical staining was performed of Notch receptors (Notch1, 2, 3, 4), their ligands [delta-like protein (DLL)1, 3, 4, Jagged1, 2], and intracellular target molecules [CSL (CBF1 humans/Su (H) Drosophila/LAG1 Caenorhabditis elegans transcription factor); TACE (TNF-α converting enzyme), NUMB] in molar teeth of 5-day-old WT, and homozygous and heterozygous PACAP-deficient mice. We measured immunopositivity in the enamel-producing ameloblasts and dentin-producing odontoblasts. Notch2 receptor and DLL1 expression were elevated in ameloblasts of PACAP-deficient mice compared to those in WT ones. The expression of CSL showed similar results both in the ameloblasts and odontoblasts. Jagged1 ligand expression was elevated in the odontoblasts of homozygous PACAP-deficient mice compared to WT mice. Other Notch pathway elements did not show significant differences between the genotype groups. The lack of PACAP leads to upregulation of Notch pathway elements in the odontoblast and ameloblast cells. The underlying molecular mechanisms are yet to be elucidated; however, we propose SHH-dependent and independent processes. We hypothesize that this compensatory upregulation of Notch signaling by the lack of PACAP could represent a salvage pathway in PACAP-deficient animals.