Rh-Catalyzed α-Arylation of Cyclic 1,3-Dicarbonyls with Benzocyclobutenols Enabled by a Cyclic Iodonium Ylide Strategy.

To date, the general and catalytic α-arylation of cyclic 1,3-dicarbonyls remains elusive. We now report the first Rh-catalyzed α-arylation of cyclic 1,3-dicarbonyls with benzocyclobutenols through a cyclic iodonium ylide strategy. Our strategy represents a good solution for the previously challenging α-arylation of cyclic 1,3-dicarbonyls with sterically demanding aryl partners, which is especially appropriate for structurally unique heteroaromatic 1,3-dicarbonyls. Our approach features mild conditions, readily available starting materials, high yields, excellent functional group-tolerance, and simple operation, providing expedient access toward medically important 2-aryl (hetero)cyclic 1,3-dicarbonyls. The practicality of this approach is demonstrated by the gram-scale synthesis, one-pot synthesis, and numerous downstream transformations.

Impact of removing ESBL status labelling from culture reports on the use of carbapenems for non-bacteraemic patients diagnosed with ESBL-positive urinary tract infections.

OBJECTIVES: To evaluate carbapenem prescribing rates for initial definitive treatment of urinary tract infections and clinical outcomes before and after removing ESBL status labels on antibiotic susceptibility reports. METHODS: This was a retrospective cohort study of adult patients treated for at least 48 h for an ESBL-producing/ceftriaxone-resistant Enterobacterales urinary tract infection. ESBL status reporting ceased in September 2022 for a network of seven community hospitals within the USA. The primary endpoint was the rate of carbapenem prescribing for initial definitive treatment of urinary tract infections. Secondary endpoints included total days of therapy for initial definitive treatment with carbapenems, clinical cure rates, time to transition to oral antibiotic therapy for initial definitive treatment, rate of guideline-compliant therapy, rate of relapsed infection within 30 days, 30 day readmission rate, and 30 day all-cause in-hospital mortality. RESULTS: Of 3055 patients screened, 199 were included in the pre group and 153 were included in the post group. The rate of carbapenem prescribing for initial definitive treatment was 156 patients (78%) in the pre group, compared with 93 patients (61%) in the post group (P = <0.01). Days of therapy for initial definitive therapy with carbapenem was 620 in the pre group compared with 372 in the post group (P < 0.01). There was no difference between other secondary outcomes. CONCLUSIONS: Removing ESBL status labels from laboratory reports reduced carbapenem use for initial definitive treatment of urinary tract infections from 78% to 61% (P < 0.01) without impacting clinical outcomes.

Ru(II)-Catalyzed Carboamination of Olefins with α-Carbonyl Sulfoxonium Ylides.

The first ruthenium-catalyzed carboamination of olefins with α-carbonyl sulfoxonium ylides is reported. The utilization of an inexpensive ruthenium catalyst enables the concise synthesis of pharmaceutically important isoindolin-1-ones, which possess both a stereogenic center and ß-carbonyl side chain. This method is mild, efficient, and scalable and allows for the coupling of a wide range of aryl-, heteroaryl-, alkenyl-, and alkyl-substituted sulfoxonium ylides. Moreover, the carbonyl side chain in the resulting product provides a good handle for downstream transformations. For mechanistic studies, a ruthacyle complex is obtained and proven to be the key intermediate in both catalytic and stoichiometric reactions.

Preparation of RDX/F2311/Fe2O3/Al Composite Hollow Microspheres by Electrospray and Synergistic Energy Release during Combustion between Components.

Nanothermites and high-energy explosives have significantly improved the performance of high-energy composites and have broad application prospects. Therefore, in this study, RDX/F2311/Fe2O3/Al composite hollow microspheres were successfully prepared utilizing the electrospray method using F2311 as a binder between components. The results show that the combustion time of the composite hollow microspheres is shortened from 2400 ms to 950 ms, the combustion process is more stable, and the energy release is more concentrated. The H50 of the composite hollow microspheres increased from 14.49 cm to 24.57 cm, the explosion percentage decreased from 84% to 72%, and the sensitivity of the composite samples decreased significantly. This is mainly the result of the combination of homogeneous composition and synergistic reactions. The combustion results show that F2311 as a binder affects the tightness of the contact between the components. By adjusting its content, the combustion time and the intensity of the combustion of the composite microspheres can be adjusted, which provides a feasible direction for its practical application.

The spectrum of pre-mRNA splicing in autism.

Disruptions in spatiotemporal gene expression can result in atypical brain function. Specifically, autism spectrum disorder (ASD) is characterized by abnormalities in pre-mRNA splicing. Abnormal splicing patterns have been identified in the brains of individuals with ASD, and mutations in splicing factors have been found to contribute to neurodevelopmental delays associated with ASD. Here we review studies that shed light on the importance of splicing observed in ASD and that explored the intricate relationship between splicing factors and ASD, revealing how disruptions in pre-mRNA splicing may underlie ASD pathogenesis. We provide an overview of the research regarding all splicing factors associated with ASD and place a special emphasis on five specific splicing factors-HNRNPH2, NOVA2, WBP4, SRRM2, and RBFOX1-known to impact the splicing of ASD-related genes. In the discussion of the molecular mechanisms influenced by these splicing factors, we lay the groundwork for a deeper understanding of ASD's complex etiology. Finally, we discuss the potential benefit of unraveling the connection between splicing and ASD for the development of more precise diagnostic tools and targeted therapeutic interventions. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution RNA Evolution and Genomics > Computational Analyses of RNA RNA-Based Catalysis > RNA Catalysis in Splicing and Translation.

2-Pyran-4-Ylidene Malononitrile Based Conjugated Microporous Polymers as Metal-Free Heterogeneous Photocatalysts for Organic Synthesis.

Photoactive conjugated microporous polymers (CMPs) as heterogeneous photocatalysts provide a sustainable alternative to classical metal-based semiconductor photosensitizers. However, previously reported CMPs are typically synthesized through metal catalyzed coupling reactions, which bears product separation, but also increases the price of materials. Herein, a new type of sp2 carbon linked DCM-CMPs are successfully designed and synthesized by organic base catalyzed Knoevenagel reaction using 2,6-Dimethyl-4H-pyran-4-ylidene-malononitrile and aromatic polyaldehydes as monomers. The new polymers feature inherent porosity, excellent stability, and fully π-conjugated skeleton with broad visible-light absorption. They effectively induce the synthesis of benzimidazole compounds under light irradiation, and exhibit wide substrate adaptability with outstanding recyclability.

Rhodium-Catalyzed Difunctionalization of Alkenes Using Cyclic 1,3-Dicarbonyl-Derived Iodonium Ylides.

Herein, we introduce an iodonium ylide strategy to achieve novel α-alkylation of cyclic 1,3-dicarbonyls through harnessing C(sp3)-Rh species generated from 5-exo-trig cyclization to provide rapid access to molecular hybridization of medically important isoindolin-1-ones and cyclic 1,3-dicarbonyls from readily available substrates. This approach features mild conditions, good yield, excellent functional group tolerance, and the simultaneous formation of two new chemical bonds and one stereogenic center. Moreover, the hydroxyl group of resulting product provides a good handle for downstream transformations. Importantly, we also demonstrate this strategy can be achieved in a one-pot manner. A C(sp3)-Rh complex was prepared and proved to be the key intermediate.

Evaluating the Impact of Source-specific Order Sets for Sepsis on Empiric Antibiotic Selection in the Emergency Department.

This retrospective cohort study found that implementing source-specific antibiotic order sets for sepsis in the emergency department increased appropriate empiric antibiotic selection from 51% to 74% (P = .01).

Cryo-EM analyses of dimerized spliceosomes provide new insights into the functions of B complex proteins.

The B complex is a key intermediate stage of spliceosome assembly. To improve the structural resolution of monomeric, human spliceosomal B (hB) complexes and thereby generate a more comprehensive hB molecular model, we determined the cryo-EM structure of B complex dimers formed in the presence of ATP γ S. The enhanced resolution of these complexes allows a finer molecular dissection of how the 5' splice site (5'ss) is recognized in hB, and new insights into molecular interactions of FBP21, SNU23 and PRP38 with the U6/5'ss helix and with each other. It also reveals that SMU1 and RED are present as a heterotetrameric complex and are located at the interface of the B dimer protomers. We further show that MFAP1 and UBL5 form a 5' exon binding channel in hB, and elucidate the molecular contacts stabilizing the 5' exon at this stage. Our studies thus yield more accurate models of protein and RNA components of hB complexes. They further allow the localization of additional proteins and protein domains (such as SF3B6, BUD31 and TCERG1) whose position was not previously known, thereby uncovering new functions for B-specific and other hB proteins during pre-mRNA splicing.

Gender Differences in Hospital Outcomes among COVID-19 Hospitalizations.

OBJECTIVES: Many epidemiological studies have shown that coronavirus disease 2019 (COVID-19) disproportionately affects males, compared with females, although other studies show that there were no such differences. The aim of the present study was to assess differences in the prevalence of hospitalizations and in-hospital outcomes between the sexes, using a larger administrative database. METHODS: We used the 2020 California State Inpatient Database for this retrospective analysis. International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis code U07.1 was used to identify COVID-19 hospitalizations. These hospitalizations were subsequently stratified by male and female sex. Diagnosis and procedures were identified using the International Classification of Diseases, Tenth Revision, Clinical Modification codes. The primary outcome of the study was hospitalization rate, and secondary outcomes were in-hospital mortality, prolonged length of stay, vasopressor use, mechanical ventilation, and intensive care unit (ICU) admission. RESULTS: There were 95,180 COVID-19 hospitalizations among patients 18 years and older, 52,465 (55.1%) of which were among men and 42,715 (44.9%) were among women. In-hospital mortality (12.4% vs 10.1%), prolonged length of hospital stays (30.6% vs 25.8%), vasopressor use (2.6% vs 1.6%), mechanical ventilation (11.8% vs 8.0%), and ICU admission rates (11.4% versus 7.8%) were significantly higher among male compared with female hospitalizations. Conditional logistic regression analysis showed that the odds of mortality (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.38-1.44), hospital lengths of stay (OR 1.35, 95% CI 1.31-1.39), vasopressor use (OR 1.59, 95% CI 1.51-1.66), mechanical ventilation (OR 1.62, 95% CI 1.47-1.78), and ICU admission rates (OR 1.58, 95% CI 1.51-1.66) were significantly higher among male hospitalizations. CONCLUSION: Our findings show that male sex is an independent and strong risk factor associated with COVID-19 severity.

DBU-catalyzed diastereoselective 1,3-dipolar [3+2] cycloaddition of trifluoroethyl amine-derived isatin ketimines with chalcones: synthesis of 5'-CF3-substituted 3,2'-pyrrolidinyl spirooxindoles.

A diastereoselective 1,3-dipolar cycloaddition reaction between trifluoroethyl amine-derived isatin ketimines and chalcones was successfully achieved in the presence of DBU. A series of 5'-CF3-substituted 3,2'-pyrrolidinyl spirooxindoles were efficiently synthesized with high yields and excellent diastereoselectivities (up to 89% yield, and >99 : 1 dr). The in vitro anticancer activities of these highly functionalized spiro[pyrrolidin-3,2'-oxindole] derivatives were evaluated.

Engineering Nanosensitizer to Remodel the TME for Hypoimmunogenic "Cold"-"Hot" Tumor Transformations.

α-PD-L1 therapy has shown encouraging results at harnessing the immune system to combat cancer. However, the treatment effect is relatively low due to the dense extracellular matrix (ECM) and tumor immunosuppressive microenvironment (TIME). Therefore, an ultrasound (US)-responsive nanosensitizer (URNS) is engineered to deliver losartan (LST) and polyethylenimine (PEI) to remolde the TME, driving "cold"-"hot" tumor transformation and enhancing the sensitivity of α-PD-L1 therapy. In the tumor site, noninvasive US can make MTNP generate ROS, which cleave ROS-sensitive bonds to dissociate MTNPtK@LST-PEI, shedding PEI and releasing LST from mesoporous spheres. The results demonstrated that URNS combined with α-PD-L1 therapy effectively inhibited tumor growth with an inhibition rate as high as 90%, which was 1.7-fold higher than that of the α-PD-L1 treatment in vivo. In summary, the URNS improves the sensitivity of α-PD-L1 therapy by remodeling the TME, which provides promising insights for optimizing cancer immunotherapy.

Direct in situ photolithography of ultra-stable CsPbBr3 quantum dot arrays based on crosslinking polymerization.

CsPbX3 (X = Br, Cl, I) perovskite quantum dots (PQDs) are the rising star for various display applications owing to their excellent opto-electrical properties, such as an adjustable spectrum, narrow emission linewidth and high quantum yield. However, these PQDs are well known to suffer from intrinsic instability under atmospheric conditions. In this work, a novel photosensitive ligand, phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide (XBPO), was employed as a dual-functional reagent for PQD surface engineering. The XBPO ligand could cleave to produce phenylphosphinyl radicals and trimethylbenzoyl radicals under UV light irradiation. The phenylphosphinyl radicals with PO bonds could effectively passivate the PQD surface defects, leading to quantum yield improvement. The CsPbBr3 and CsPbI3 PQDs with XBPO modification could achieve a photoluminescence quantum yield (PLQY) of near unity and 92%, respectively. Additionally, the in situ encapsulation of the PQDs was achieved by the subsequent crosslinking polymerization, which significantly improved the stability of the PQDs against solvents and the environment. By combining a standard photolithography procedure, we demonstrated a micro-pattern of CsPbBr3 PQDs. These results establish a universal route for PQD patterning, compatible with the existing photolithography processes, which could facilitate the application of PQDs in next-generation display technology.

Stereotactic body radiotherapy for primary renal cell carcinoma: a systematic review and practice guideline from the International Society of Stereotactic Radiosurgery (ISRS).

Surgery is the standard of care for patients with primary renal cell carcinoma. Stereotactic body radiotherapy (SBRT) is a novel alternative for patients who are medically inoperable, technically high risk, or who decline surgery. Evidence for using SBRT in the primary renal cell carcinoma setting is growing, including several rigorously conducted prospective clinical trials. This systematic review was performed to assess the safety and efficacy of SBRT for primary renal cell carcinoma. Review results then formed the basis for the practice guidelines described, on behalf of the International Stereotactic Radiosurgery Society. 3972 publications were screened and 36 studies (822 patients) were included in the analysis. Median local control rate was 94·1% (range 70·0-100), 5-year progression-free survival was 80·5% (95% CI 72-92), and 5-year overall survival was 77·2% (95% CI 65-89). These practice guidelines addressed four key clinical questions. First, the optimal dose fractionation was 25-26 Gy in one fraction, or 42-48 Gy in three fractions for larger tumours. Second, routine post-treatment biopsy is not recommended as it is not predictive of patient outcome. Third, SBRT for primary renal cell carcinoma in a solitary kidney is safe and effective. Finally, guidelines for post-treatment follow-up are described, which include cross-axial imaging of the abdomen including both kidneys, adrenals, and surveillance of the chest initially every 6 months. This systematic review and practice guideline support the practice of SBRT for primary renal cell carcinoma as a safe and effective standard treatment option. Randomised trials with surgery and invasive ablative therapies are needed to further define best practice.

Numerical simulation validating of a duck-mouth type marine debris collection device's collection mechanism.

Marine debris (MD) poses a significant threat to global coastal ecosystems around the world, necessitating effective strategies for its collection and removal. As a new type of fixed collection device, the duck-mouth type marine debris collection device (MDCD) consists primarily of two components: a central collection system and floating fences which are positioned at a certain angle and open towards the outer bay located on both sides of it. This paper aims to establish a coupling drift model based on hydrodynamic model to study the performance of duck-mouth type MDCD, verify its effectiveness. Before simulation, the model was fully validated. The results demonstrate that wind has the greatest influence on MD movement, as the direction of the wind directly determines the movement direction of the debris. It was observed that only under onshore wind conditions did the MD move towards the bay when the duck-mouth type MDCD can effectively collect MD, which moves along the barrier net towards the central trash bin and eventually be fully collected.

The Potential of Berberine to Target Telocytes in Rabbit Heart.

A brand-new class of interstitial cells, called telocytes, has been detected in the heart. Telocytes can connect and transmit signals to almost all cardiomyocytes; this is highly interrelated with the occurrence and development of heart diseases. Modern studies have shown that berberine has a therapeutic effect on cardiovascular health. However, berberine's mechanism of action on the cardiovascular system through cardiac telocytes is unclear. Interestingly, 5 µm of berberine remarkably decreased the concentration of intracellular calcium and membrane depolarization in cultured telocytes, upregulated the expression of CX43 and ß-catenin, and downregulated the expressions of TRPV4 and TRPV1. Here, telocytes were identified in the vascular adventitia and intima, endocardium, myocardium, adventitia, and heart valves. Moreover, telocytes were broadly dispersed around cardiac vessels and interacted directly through gap junctions and indirectly through extracellular vesicles. Together, cardiac telocytes interact with berberine and then deliver drug information to the heart. Telocytes may be an essential cellular target for drug therapy of the cardiovascular system.

Prevalence and effects of acute myocardial infarction on hospital outcomes among COVID-19 patients.

BACKGROUND: Acute myocardial infarction (AMI) is one of the most lethal complications of COVID-19 hospitalization. In this study, we looked for the occurrence of AMI and its effects on hospital outcomes among COVID-19 patients. METHODS: Data from the 2020 California State Inpatient Database was used retrospectively. All COVID-19 hospitalizations with age ≥ 18 years were included in the analyses. Adverse hospital outcomes included in-hospital mortality, prolonged length of stay (LOS), vasopressor use, mechanical ventilation, and ICU admission. Prolonged LOS was defined as any hospital LOS ≥ 75th percentile. Multivariate logistic regression analyses were used to understand the strength of associations after adjusting for cofactors. RESULTS: Our analysis had 94 114 COVID-19 hospitalizations, and 1548 (1.6%) had AMI. Mortality (43.2% vs. 10.8%, P  < 0.001), prolonged LOS (39.9% vs. 28.2%, P  < 0.001), vasopressor use (7.8% vs. 2.1%, P  < 0.001), mechanical ventilation (35.0% vs. 9.7%, P  < 0.001), and ICU admission (33.0% vs. 9.4%, P  < 0.001) were significantly higher among COVID-19 hospitalizations with AMI. The odds of adverse outcomes such as mortality (aOR 3.90, 95% CI: 3.48-4.36), prolonged LOS (aOR 1.23, 95% CI: 1.10-1.37), vasopressor use (aOR 3.71, 95% CI: 3.30-4.17), mechanical ventilation (aOR 2.71, 95% CI: 2.21-3.32), and ICU admission (aOR 3.51, 95% CI: 3.12-3.96) were significantly more among COVID-19 hospitalizations with AMI. CONCLUSION: Despite the very low prevalence of AMI among COVID-19 hospitalizations, the study showed a substantially greater risk of adverse hospital outcomes and mortality. COVID-19 patients with AMI should be aggressively treated to improve hospital outcomes.

Management of sporadic intracanalicular vestibular schwannomas: A critical review and International Stereotactic Radiosurgery Society (ISRS) practice guidelines.

BACKGROUND: The choice of an appropriate strategy for intracanalicular vestibular schwannoma (ICVS) is still debated. We conducted a systematic review and meta-analysis with the aim to compare treatment outcomes amongst management strategies (conservative surveillance (CS), microsurgical resection (MR), or stereotactic radiosurgery (SRS)) aiming to inform guideline recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS: Using PRISMA guidelines, we reviewed manuscripts published between January 1990 and October 2021 referenced in PubMed or Embase. Inclusion criteria were peer-reviewed clinical studies or case series reporting a cohort of ICVS managed with CS, MR, or SRS. Primary outcome measures included tumor control, the need for additional treatment, hearing outcomes, and posttreatment neurological deficits. These were pooled using meta-analytical techniques and compared using meta-regression with random effect. RESULTS: Forty studies were included (2371 patients). The weighted pooled estimates for tumor control were 96% and 65% in SRS and CS series, respectively (P < .001). Need for further treatment was reported in 1%, 2%, and 25% for SRS, MR, and CS, respectively (P = .001). Hearing preservation was reported in 67%, 68%, and 55% for SRS, MR, and CS, respectively (P = .21). Persistent facial nerve deficit was reported in 0.1% and 10% for SRS and MR series, respectively (P = .01). CONCLUSIONS: SRS is a noninvasive treatment with at least equivalent rates of tumor control and hearing preservation as compared to MR, with the caveat of better facial nerve preservation. As compared to CS, upfront SRS is an effective treatment in achieving tumor control with similar rates of hearing preservation.

Racial difference in mortality among COVID-19 hospitalizations in California.

In the US, racial disparities in hospital outcomes are well documented. We explored whether race was associated with all-cause in-hospital mortality and intensive care unit (ICU) admission among COVID-19 patients in California. This was a retrospective analysis of California State Inpatient Database during 2020. Hospitalizations ≥ 18 years of age for COVID-19 were included. Cox proportional hazards with mixed effects were used for associations between race and in-hospital mortality. Logistic regression was used for the association between race and ICU admission. Among 87,934 COVID-19 hospitalizations, majority were Hispanics (56.5%), followed by White (27.3%), Asian, Pacific Islander, Native American (9.9%), and Black (6.3%). Cox regression showed higher mortality risk among Hispanics, compared to Whites (hazard ratio, 0.91; 95% CI 0.87-0.96), Blacks (hazard ratio, 0.87; 95% CI 0.79-0.94), and Asian, Pacific Islander, Native American (hazard ratio, 0.89; 95% CI 0.83-0.95). Logistic regression showed that the odds of ICU admission were significantly higher among Hispanics, compared to Whites (OR, 1.70; 95% CI 1.67-1.74), Blacks (OR, 1.70; 95% CI 1.64-1.78), and Asian, Pacific Islander, Native American (OR, 1.82; 95% CI 1.76-1.89). We found significant disparities in mortality among COVID-19 hospitalizations in California. Hispanics were the worst affected with the highest mortality and ICU admission rates.

Yeast polysaccharide supplementation: impact on lactation, growth, immunity, and gut microbiota in Dezhou donkeys.

Introduction: The Dezhou donkey, a prominent Chinese breed, is known for its remarkable size, rapid growth, and resilience to tough feeding conditions, and disease resistance. These traits are crucial in meeting the growing demand for Ejiao and donkey meat. Yeast polysaccharide (YPS), a functional polysaccharide complex known for its immune-enhancing and growth-promoting properties in livestock and poultry, remains relatively understudied in donkeys. Objectives: This study aimed to investigate the impact of YPS supplementation on lactating and growing Dezhou donkey jennies and foals. Materials and methods: Twelve 45-day-old Dezhou donkey foals and their jennies, matched for body weight and age, were randomly allocated to two dietary groups: a control group receiving a basal diet and an experimental group receiving the basal diet supplemented with 10 g/pen of YPS. The experiment was conducted over a 23-day period, during which donkey foals and lactating jennies were co-housed. Results and discussion: The findings revealed that YPS supplementation had no adverse effects on milk production or composition in Dezhou donkey jennies but significantly increased feed intake. Additionally, YPS was associated with increased plasma glucose and creatinine concentrations in foals, while tending to decrease alkaline phosphatase, white blood cell count, red blood cell count, and hemoglobin levels (p < 0.10). Immune indices demonstrated that YPS supplementation elevated the levels of immunoglobulin A (IgA) and immunoglobulin G (IgG) in jennies (p < 0.05) and increased complement component C4 concentrations in foals (p < 0.05). Moreover, YPS positively influenced the fecal microbiome, promoting the abundance of beneficial microorganisms such as Lactobacillus and Prevotella in donkey foals and Terriporobacter and Cellulosilyticum in jennies, all of which contribute to enhanced feed digestion. Additionally, YPS induced alterations in the plasma metabolome for both jennies and foals, with a predominant presence of lipids and lipid-like molecules. Notably, YPS increased the concentrations of specific lipid metabolites, including 13,14-Dihydro PGF2a, 2-Isopropylmalic acid, 2,3-Dinor-TXB2, Triterpenoids, Taurocholic acid, and 3b-Allotetrahydrocortisol, all of which are associated with improved animal growth. Conclusion: In conclusion, this study suggests that dietary supplementation of YPS enhances feed intake, boosts immunity by increasing immunoglobulin levels, stimulates the growth-promoting gut microbiota (Lactobacillus and Prevotella), and exerts no adverse effects on the metabolism of both Dezhou donkey jennies and foals.