Mapping of Some Further Alkylation-Initiated Pathways to Polyheterocyclic Compounds from Indigo and Indirubin.

The reaction of indigo with two equivalents of the electrophile ethyl bromoacetate with caesium carbonate as a base result in the formation of structurally complex polyheterocyclics, including a fused spiroimidazole and a spiro[1,3]oxazino derivative, together with a biindigoid-type derivative, through a convenient one-pot reaction. Further assessment of the reaction using five equivalents of the electrophile gave rise to other molecules incorporating the 2-(7,13,14-trioxo-6,7,13,14-tetrahydropyrazino[1,2-a:4,3-a']diindol-6-yl) scaffold. The reaction of ethyl bromoacetate with the less reactive indirubin resulted in the synthesis of three derivatives of a new class of polyheterocyclic system via a cascade process, although yields were low. These compounds were derived from the parent indolo[1,2-b]pyrrolo[4,3,2-de]isoquinoline skeleton. Despite the modest yields of the reactions, they represent quick cascade routes to a variety of heterocycles from cheap starting materials, with these structures otherwise being difficult to synthesise in a traditional stepwise manner. These outcomes also contribute significantly to the detailed understanding of the indigo/indirubin cascade reaction pathways initiated by base-catalysed N-alkylation.

Reactive Extrusion Printing of Zeolitic Imidazolate Framework Films.

An outstanding challenge for the field of metal-organic frameworks (MOFs) is structuring to form forms with greater useability. Reactive extrusion printing (REP) is a technique for the direct formation of films from their molecular components on-demand and on-location. Here we apply REP for the first time to zeolitic imidazolate frameworks (ZIFs) and study the interplay of solvent and molarity ratio on the phase distribution between ZIF-8 and ZIF-L in reactive printed films. Our results show that REP controllably directs phase formation between ZIF-L and ZIF-8 and that REP also gives control over crystal size and that high-quality ZIF-8 films, in particular, are produced in low-dispersity interconnected nanoparticulate form. Importantly, we show that REP is responsive to established surface-functionalization techniques to control important printing parameters of line width and thickness. This work expands the repertoire of REP to the important class of ZIFs.

Identifying Care Gaps and Referral Patterns in Acute Dermatology at Urgent Care Centers.

Limited urgent access to board-certified dermatologists drives patients to seek dermatologic care at urgent care centers (UCC). UCC are staffed by clinicians with comparatively limited dermatology training, often resulting in lower quality care for acute dermatology conditions. This study investigates health care referral outcomes of patients seeking dermatologic care at UCC, examine the appropriateness of UCC dermatologic care, and assess the feasibility of referral management by eConsult. We utilize a retrospective cohort of 807 patients and a provider survey to examine referral outcomes of patients referred to University of Rochester Dermatology (UR-Derm), a tertiary care university-based teaching hospital, from UR UCC between January 1, 2021, and August 31, 2022. Outcomes for healthcare referrals included patient demographics, referral completion rates, UR-Derm appointment wait times, and diagnostic concordance rates between UCC and UR-Derm. Outcomes from the provider survey included appropriateness of UCC treatment plans, appropriateness of UCC referral to UR-Derm, and feasibility of referral management by eConsult. Patients who utilized UCC were predominately white (77.0%) females (53.9%) with a mean age of 37.9 years. Most patients referred by UCC did not complete an in-person UR-Derm evaluation (58.6%). Of those who did complete a UR-Derm visit, the average wait time was 38.3 days. Only 56% of UCC and UR-Derm diagnoses were concordant. Our surveyed dermatologists deemed 30% of the UCC treatment plans appropriate. The majority of referrals (83.5%) were viewed as manageable with an eConsult with only 10% of referrals requiring in-person visit. Several practice gaps exist in specialty care delivery in UCC and additional inefficiencies exist in the urgent referral process. These gaps could be addressed by targeted educational interventions and availability of dermatology consultation to support urgent care.

Palladium-Catalyzed (3+2) and (4+2) Cycloaddition Reactions of Sulfamidate Imine-Derived Azadienes: Synthesis of Spirocyclic Pyrrolidines and Tetrahydroquinolines.

Diastereoselective Pd-catalyzed (3+2) and (4+2) cycloaddition reactions of sulfamidate imine-derived 1-azadienes with zwitterionic N-dipoles derived from 1-tosyl-2-vinylaziridine and 4-vinylbenzoxazinone have been developed. These reactions provide highly functionalized azaspirocycles featuring three contiguous stereocenters. The sulfonyl imine moiety of the cycloadducts can be fully reduced to access valuable ß-amino alcohols.

Effect of substituents on the ability of nickel Schiff base complexes with four pendant groups to bind to G-quadruplexes.

The synthesis of eleven new nickel Schiff base complexes each bearing four pendant groups is reported. The structures of the complexes differ in the identity of the pendant groups and/or diamine moiety. All complexes were characterised by microanalysis, Nuclear Magnetic Resonance (NMR) spectroscopy and Electrospray Ionisation Mass Spectrometry (ESI-MS), while the solid-state structures of two of the molecules were also determined using X-ray crystallographic methods. The DNA binding properties of the nickel complexes with double stranded DNA and a range of G-quadruplex DNA structures was explored using different spectroscopic methods as well as computational techniques. Results from ESI-MS experiments and Fluorescent Indicator Displacement (FID) assays were consistent with each other and indicated that varying the diamine moiety had less influence on DNA affinity than changing the pendant groups. These conclusions were also generally supported by results obtained from UV melting experiments and Fluorescence Resonance Energy Transfer (FRET) assays. The cytotoxicity of selected examples of the new complexes, and close analogues reported recently, towards V79 Chinese hamster lung cancer cells and THP-1 human leukemia cells was measured. All were found to display modest cytotoxicity, with flow cytometry experiments suggesting an apoptotic pathway was the most likely mechanism of cell death.

Tunable quantum emitters on large-scale foundry silicon photonics.

Controlling large-scale many-body quantum systems at the level of single photons and single atomic systems is a central goal in quantum information science and technology. Intensive research and development has propelled foundry-based silicon-on-insulator photonic integrated circuits to a leading platform for large-scale optical control with individual mode programmability. However, integrating atomic quantum systems with single-emitter tunability remains an open challenge. Here, we overcome this barrier through the hybrid integration of multiple InAs/InP microchiplets containing high-brightness infrared semiconductor quantum dot single photon emitters into advanced silicon-on-insulator photonic integrated circuits fabricated in a 300 mm foundry process. With this platform, we achieve single-photon emission via resonance fluorescence and scalable emission wavelength tunability. The combined control of photonic and quantum systems opens the door to programmable quantum information processors manufactured in leading semiconductor foundries.

Evaluating the Impact of Eat, Sleep, Console in Neonatal Abstinence Syndrome Treatment for Infants Exposed to Substance Use In Utero.

OBJECTIVE: An increase in maternal use of licit or illicit substances, alcohol, and tobacco has resulted in an increased incidence of neonatal abstinence syndrome (NAS). In recent years, NAS management has shifted to initiating an Eat, Sleep, Console (ESC) approach prior to pharmacologic treatment. The objective of this study was to evaluate the impact of ESC in combination with pharmacologic treatment in the management of NAS for infants exposed to substance use in utero. METHODS: This single system, multisite, retrospective cohort study evaluated infants with known exposure to substance or polysubstance use in utero or those who had signs and symptoms of withdrawal with a positive toxicology screen. The primary outcome of rate of pharmacologic therapy initiated was evaluated pre and post implementation of ESC. Secondary outcomes included hospital length of stay, day of life that pharmacologic therapy was initiated, and an evaluation of the ESC guideline. A subgroup analysis with similar outcomes was also performed for patients with maternal polysubstance use. RESULTS: A total of 2843 patients were screened, and 50 patients were randomly selected for -inclusion in both pre- and post-groups. The rate of pharmacologic therapy initiated post implementation of ESC decreased from 58% to 30% (p < 0.01). In the post-group, there was a decrease in the number of -patients requiring scheduled morphine (33%, p < 0.01) and duration of pharmacologic therapy (14.6 days vs 6.47 days, p < 0.01). CONCLUSIONS: Implementing an ESC guideline decreased the length of stay and rate of pharmacologic intervention needed for infants with NAS at our institution.

A self-referenced interferometer for in situ cryogenic wafer curvature measurements.

A self-referenced interferometer to measure time-varying curvature in mechanically unstable environments is needed in many applications. One application that demands this measurement technique with fast data acquisition, 2D sensitivity, and insensitivity to vibration is the measurement of thermal strain in thin films in operational environments. The diverging beam interferometer described here demonstrates an angular sensitivity to the local curvature using interferograms captured by a CMOS camera. Two-dimensional Fourier analysis is used to extract curvature changes. The interferometer demonstrates an experimental sensitivity to curvature changes on the order of 10-4 m-1 and is used to measure thermal stresses in a cryogenic environment of a polycrystalline titanium nitride thin film on a silicon wafer that exhibits anisotropic curvature.

Polymicrobial Purulent Pericarditis From a Pancreatico-Pericardial Fistula.

A 54-year-old male with chronic pancreatitis presented with dyspnea. Computed tomography scans demonstrated a subdiaphragmatic fluid collection with pericardial fistulization. Pericardial fluid cultures were polymicrobial in nature. Purulent pericarditis is rare but carries a high mortality rate. We present the first documented case of pancreatico-pericardial fistulization causing purulent pericarditis.

Emergency department evaluation and management of constipation.

Each year, over 1.3 million patients visit the emergency department for constipation. Most cases are benign, but serious complications, such as fecal impaction and stercoral colitis, must be ruled out. Evidence to guide the evaluation and treatment of constipation in the emergency department is limited, and many of the decades-old treatments have not been studied in modern, rigorous, controlled trials. In the emergency department, constipation is a clinical diagnosis, and ideal management includes excluding dangerous mimics or complications and, for most patients, discharging the patient with a bowel regimen tailored to the likely cause of their constipation, with appropriate referral to primary or specialty care. This review evaluates consensus guidelines on management of constipation as well as the early data on the newer prescription medications for chronic and opioid-induced constipation.

Divergent Reactivity of 1,2,3-Benzotriazin-4(3H)-ones: Photocatalytic Synthesis of 3-Substituted Isoindolinones Achieved through a Nitrogen-Mediated Hydrogen Atom Shift.

A regioselective visible-light-mediated denitrogenative alkene insertion of 1,2,3-benzotriazin-4(3H)-ones was developed to access 3-substituted isoindolinones, an important structural motif present in many biologically active molecules and natural products. Notably, divergent reactivity was achieved by switching from reported nickel catalysis (where C3-substituted 3,4-dihydroisoquinolin-1(2H)-ones form) to photocatalysis, where photocatalytic denitrogenation and a subsequent nitrogen-mediated hydrogen atom shift lead to exclusive 3-substituted isoindolinone formation. The developed photocatalytic reaction is compatible with activated terminal alkenes and cyclic α,ß-unsaturated esters and ketones, with wide functional group tolerance for N-substitution of the 1,2,3-benzotriazin-4(3H)-ones. The utility of this procedure is highlighted by a gram-scale synthesis and postsynthetic amidation. To understand the origin of this unique product selectivity, experimental and computational mechanistic studies were performed.

Scaling the EQUIPPED medication safety program: Traditional and hub-and-spoke implementation models.

BACKGROUND: The EQUIPPED (Enhancing Quality of Prescribing Practices for Older Adults Discharged from the Emergency Department) medication safety program is an evidence-informed quality improvement initiative to reduce potentially inappropriate medications (PIMs) prescribed by Emergency Department (ED) providers to adults aged 65 and older at discharge. We aimed to scale-up this successful program using (1) a traditional implementation model at an ED with a novel electronic medical record and (2) a new hub-and-spoke implementation model at three new EDs within a health system that had previously implemented EQUIPPED (hub). We hypothesized that implementation speed would increase under the hub-and-spoke model without cost to PIM reduction or site engagement. METHODS: We evaluated the effect of the EQUIPPED program on PIMs for each ED, comparing their 12-month baseline to 12-month post-implementation period prescribing data, number of months to implement EQUIPPED, and facilitators and barriers to implementation. RESULTS: The proportion of PIMs at all four sites declined significantly from pre- to post-EQUIPPED: at traditional site 1 from 8.9% (8.1-9.6) to 3.6% (3.6-9.6) (p < 0.001); at spread site 1 from 12.2% (11.2-13.2) to 7.1% (6.1-8.1) (p < 0.001); at spread site 2 from 11.3% (10.1-12.6) to 7.9% (6.4-8.8) (p = 0.045); and at spread site 3 from 16.2% (14.9-17.4) to 11.7% (10.3-13.0) (p < 0.001). Time to implement was equivalent at all sites across both models. Interview data, reflecting a wide scope of responsibilities for the champion at the traditional site and a narrow scope at the spoke sites, indicated disproportionate barriers to engagement at the spoke sites. CONCLUSIONS: EQUIPPED was successfully implemented under both implementation models at four new sites during the COVID-19 pandemic, indicating the feasibility of adapting EQUIPPED to complex, real-world conditions. The hub-and-spoke model offers an effective way to scale-up EQUIPPED though a speed or quality advantage could not be shown.

Inhibition potential of natural flavonoids against selected omicron (B.1.19) mutations in the spike receptor binding domain of SARS-CoV-2: a molecular modeling approach.

The omicron (B.1.19) variant of contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is considered a variant of concern (VOC) due to its increased transmissibility and highly infectious nature. The spike receptor-binding domain (RBD) is a hotspot of mutations and is regarded as a prominent target for screening drug candidates owing to its crucial role in viral entry and immune evasion. To date, no effective therapy or antivirals have been reported; therefore, there is an urgent need for rapid screening of antivirals. An extensive molecular modelling study has been performed with the primary goal to assess the inhibition potential of natural flavonoids as inhibitors against RBD from a manually curated library. Out of 40 natural flavonoids, five natural flavonoids, namely tomentin A (-8.7 kcal/mol), tomentin C (-8.6 kcal/mol), hyperoside (-8.4 kcal/mol), catechin gallate (-8.3 kcal/mol), and corylifol A (-8.2 kcal/mol), have been considered as the top-ranked compounds based on their binding affinity and molecular interaction profiling. The state-of-the-art molecular dynamics (MD) simulations of these top-ranked compounds in complex with RBD exhibited stable dynamics and structural compactness patterns on 200 nanoseconds. Additionally, complexes of these molecules demonstrated favorable free binding energies and affirmed the docking and simulation results. Moreover, the post-simulation validation of these interacted flavonoids using principal component analysis (PCA) revealed stable interaction patterns with RBD. The integrated results suggest that tomentin A, tomentin C, hyperoside, catechin gallate, and corylifol A might be effective against the emerging variants of SARS-CoV-2 and should be further evaluated using in-vitro and in-vivo experiments.Communicated by Ramaswamy H. Sarma.

Canine acquired pneumonia caused by Bordetella bronchiseptica.

Here, we present the case of a 55-year-old male with HIV and persistent lymphopenia who developed a paroxysmal severe cough for over three weeks. Microbiology studies were positive for abundant colonies of Bordetella bronchiseptica. He reports that his dog was also ill with a severe cough, suggesting a possible canine-to-human transmission. This zoonosis has been increasingly recognized and possesses significant morbidity and mortality, especially in immunocompromised hosts.

Diastereoselective Pd-catalyzed Decarboxylative (4+2) Cycloaddition Reactions of 4-Vinylbenzoxazinanones and 2-Nitro-1,3-enynes.

A formal palladium-catalyzed decarboxylative (4+2) cycloaddition reaction between 4-vinylbenzoxazinanones and 2-nitro-1,3-enynes has been developed to produce highly valuable, densely functionalized tetrahydroquinolines in moderate to excellent yields with high diastereoselectivity under mild reaction conditions. The optimised protocol tolerates a range of substituted 2-nitro-1,3-enynes, which represent an under-utilized class of dipolarophile for transition-metal catalyzed cycloadditions. The employed reaction methodology facilitates efficient cycloaddition with both N-H- and N-Ts-4-vinylbenzoxazinanone dipole precursors. The stereochemistry of the major and minor diastereomeric (4+2) cycloadducts was determined by single crystal X-ray analyses. A mechanistic rationale for the high intrinsic diastereoselectivity and preliminary enantioselective experiments are also presented. The tetrahydroquinoline cycloadduct products feature numerous pendant functionalities, including a vinyl handle, an internal alkyne motif and a nitro functionality (which functions as a latent C-3 nitrogen substituent) for further synthetic manipulations.

G-quadruplex DNA binding properties of novel nickel Schiff base complexes with four pendant groups.

Three new nickel Schiff base complexes were prepared using a two-step procedure that involves initial selective dialkylation of 2,4,6-trihydroxybenzaldehyde, followed by reaction with 1,2-phenylenediamine and nickel(II) acetate. Each of the complexes possessed the same Schiff base core but differed in the identity of the four pendant groups. All complexes were characterised by microanalysis, NMR spectroscopy and ESI mass spectrometry. In addition, two of the complexes were also characterised in the solid state using X-ray crystallography, which confirmed the presence of a square planar geometry around the metal ion. The DNA binding properties of the three nickel complexes with double stranded DNA and a range of G-quadruplex DNA structures were explored using ESI mass spectrometry, CD spectroscopy, UV melting curves, Fluorescence Resonance Energy Transfer (FRET) assays, Fluorescent Indicator Displacement (FID) assays and molecular docking studies. These techniques confirmed the ability of the three nickel complexes to bind to most of the DNA molecules examined, as well as stabilise the latter in several instances. In addition, the results of these investigations provided evidence that pendant groups with morpholine rings generally reduced DNA binding behaviour, whilst pendants featuring piperidine ring systems attached to the Schiff base core by three and not two methylene linkers often showed the greatest extent of binding or DNA stabilisation.