Direct Formation of Amide-Linked C-Glycosyl Amino Acids and Peptides via Photoredox/Nickel Dual Catalysis.

Glycoproteins account for numerous biological processes including those associated with diseases and infections. The advancement of glycopeptides has emerged as a promising strategy for unraveling biological pathways and discovering novel medicines. In this arena, a key challenge arises from the absence of efficient synthetic strategies to access glycopeptides and glycoproteins. Here, we present a highly concise approach to bridging saccharides with amino acids and peptides through an amide linkage. Our amide-linked C-glycosyl amino acids and peptides are synthesized through cooperative Ni-catalyzed and photoredox processes. The catalytic process generates a glycosyl radical and an amide carbonyl radical, which subsequently combine to yield the C-glycosyl products. The saccharide reaction partners encompass mono-, di-, and trisaccharides. All 20 natural amino acids, peptides, and their derivatives can efficiently undergo glycosylations with yields ranging from acceptable to high, demonstrating excellent stereoselectivities. As a substantial expansion of applications, we have shown that simple C-glycosyl amino acids can function as versatile building units for constructing C-glycopeptides with intricate spatial complexities.

Site-Selective C-O Bond Editing of Unprotected Saccharides.

Glucose and its polyhydroxy saccharide analogs are complex molecules that serve as essential structural components in biomacromolecules, natural products, medicines, and agrochemicals. Within the expansive realm of saccharides, a significant area of research revolves around chemically transforming naturally abundant saccharide units to intricate or uncommon molecules such as oligosaccharides or rare sugars. However, partly due to the presence of multiple hydroxyl groups with similar reactivities and the structural complexities arising from stereochemistry, the transformation of unprotected sugars to the desired target molecules remains challenging. One such formidable challenge lies in the efficient and selective activation and modification of the C-O bonds in saccharides. In this study, we disclose a modular 2-fold "tagging-editing" strategy that allows for direct and selective editing of C-O bonds of saccharides, enabling rapid preparation of valuable molecules such as rare sugars and drug derivatives. The first step, referred to as "tagging", involves catalytic site-selective installation of a photoredox active carboxylic ester group to a specific hydroxyl unit of an unprotected sugar. The second step, namely, "editing", features a C-O bond cleavage to form a carbon radical intermediate that undergoes further transformations such as C-H and C-C bond formations. Our strategy constitutes the most effective and shortest route in direct transformation and modification of medicines and other molecules bearing unprotected sugars.

Effect of continuous hypertonic saline infusion on clinical outcomes in patients with traumatic brain injury.

Osmotic therapy has been recognized as an important treatment option for patients with traumatic brain injury (TBI). Nevertheless, the effect of hypertonic saline (HTS) remains unknown, as findings are primarily based on a large database. This study aimed to elucidate the effect of HTS on the clinical outcomes of patients with TBI admitted to the intensive care unit (ICU). We retrospectively identified patients with moderate-to-severe TBI from two public databases: Medical Information Mart for Intensive Care (MIMIC)-IV and eICU Collaborative Research Database (eICU-CRD). A marginal structural Cox model (MSCM) was used, with time-dependent variates designed to reflect exposure over time during ICU stay. Trajectory modeling based on the intracranial pressure evolution pattern allowed for the identification of subgroups. Overall, 130 (6.65%) of 1955 eligible patients underwent HTS. MSCM indicated that the HTS significantly associated with higher infection complications (e.g., urinary tract infection (HR 1.88, 95% CI 1.26-2.81, p = 0.002)) and increased ICU LOS (HR 2.02, 95% CI 1.71-2.40, p < 0.001). A protective effect of HTS on GCS was found in subgroups with medium and low intracranial pressure. Our study revealed no significant difference in mortality between patients who underwent HTS and those who did not. Increased occurrence rates of infection and electrolyte imbalance are inevitable outcomes of continuous HTS infusion. Although the study suggests slight beneficial effects, including better neurological outcomes, these results warrant further validation.

Temporal trends and outcomes in acute ischaemic stroke patients with a current or historical diagnosis of cancer.

BACKGROUND AND PURPOSE: The aim was to evaluate the temporal trends, characteristics and in-hospital outcomes of patients hospitalized with acute ischaemic stroke (AIS) between those with and without current or historical malignancies. METHODS: Adult hospitalizations with a primary diagnosis of AIS were identified from the National Inpatient Sample database 2007-2017. Logistic regression was used to compare the differences in the utilization of AIS interventions and in-hospital outcomes. For further analysis, subgroup analyses were performed stratified by cancer subtypes. RESULTS: There were 892,862 hospitalizations due to AIS, of which 108,357 (12.14%) had a concurrent diagnosis of current cancer (3.41%) or historical cancer (8.72%). After adjustment for confounders, patients with current malignancy were more likely to have worse clinical outcomes. The presence of historical cancers was not associated with an increase in poor clinical outcomes. Additionally, AIS patients with current malignancy were less likely to receive intravenous thrombolysis (adjusted odds ratio 0.66, 95% confidence interval 0.63-0.71). Amongst the subgroups of AIS patients treated with intravenous thrombolysis or mechanical thrombectomy, outcomes varied by cancer types. Notably, despite these acute stroke interventions, outcome remains poor in AIS patients with lung cancer. CONCLUSIONS: Although AIS patients with malignancy generally have worse in-hospital outcomes versus those without, there were considerable variations in these outcomes according to different cancer types and the use of AIS interventions. Finally, treatment of these AIS patients with a current or historical cancer diagnosis should be individualized.

Impact of Early Tracheostomy on Clinical Outcomes in Trauma Patients Admitted to the Intensive Care Unit: A Retrospective Causal Analysis.

OBJECTIVES: To assess the indications, timing, and clinical outcomes that result from the early tracheostomy (ET) administration, by causal inference models. DESIGN: A retrospective observational study. SETTING: Multiinstitutional intensive care unit in the United States PARTICIPANTS: The study comprised 626 trauma patients. INTERVENTIONS: An ET versus late tracheostomy (LT). MEASUREMENTS AND MAIN RESULTS: Trauma patients with tracheostomy were identified from 2 public databases named Medical Information Mart for the Intensive Care-IV and eICU Collaborative Research Database. Tracheostomy was defined as early (≤7 days) or late (>7 days) from intensive care unit admission. A marginal structural Cox model (MSCM) with inverse probability weighting was employed. For comparison, the authors also used time-dependent propensity-score matching (PSM) to account for differences in the probability of receiving an ET or LT. A total of 626 eligible patients were enrolled in the study, of whom 321 (51%) received a ET. The MSCM and time-dependent PSM indicated that the ET group was associated with reduced ventilation-associated pneumonia (VAP) and a shorter mechanical ventilation (MV) duration than the LT group. Yet, mortality did not show any difference between the two groups. CONCLUSIONS: The authors' study observed that ET was not associated with reduced mortality in trauma patients, but it was associated with reduced VAP risk and MV duration. The results warrant further validation in randomized controlled trials.

A Machine Learning Approach for the Prediction of Severe Acute Kidney Injury Following Traumatic Brain Injury.

BACKGROUND: Acute kidney injury (AKI), a prevalent non-neurological complication following traumatic brain injury (TBI), is a major clinical issue with an unfavorable prognosis. This study aimed to develop and validate machine learning models to predict severe AKI (stage 3 or greater) incidence in patients with TBI. METHODS: A retrospective cohort study was conducted by using two public databases: the Medical Information Mart for Intensive Care IV (MIMIC)-IV and the eICU Collaborative Research Database (eICU-CRD). Recursive feature elimination was used to select candidate predictors obtained within 24 h of intensive care unit admission. The area under the curve and decision curve analysis curves were used to determine the discriminatory ability. On the other hand, the calibration curve was employed to evaluate the calibrated performance of the newly developed machine learning models. RESULTS: In the MIMIC-IV database, there were 808 patients diagnosed with moderate and severe TBI (msTBI) (msTBI is defined as Glasgow Coma Score < 12). Of these, 60 (7.43%) patients experienced severe AKI. External validation in the eICU-CRD indicated that the random forest (RF) model had the highest area under the curve of 0.819 (95% confidence interval 0.783-0.851). Furthermore, in the calibration curve, the RF model was well calibrated (P = 0.795). CONCLUSIONS: In this study, the RF model demonstrated better discrimination in predicting severe AKI than other models. An online calculator could facilitate its application, potentially improving the early detection of severe AKI and subsequently improving the clinical outcomes among patients with msTBI.

Research Advances on the Bioactivity of 1,2,3-Triazolium Salts.

1,2,3-Triazolium salts have demonstrated significant potential in the fields of medicine and agriculture, exhibiting exceptional antibacterial, antifungal, anticancer, and antileishmanial properties. Moreover, these salts can be utilized as additives or components to produce nano- and fiber-based materials with antibacterial properties. In this review, we summarize several synthetic strategies to obtain 1,2,3-triazolium salts and the structures of 1,2,3-triazolium derivatives with biological activities in the domains of pharmaceuticals, pesticides, and functional materials. Additionally, the structure-activity relationship (SAR) of 1,2,3-triazolium salts with different biological activities has been analyzed. Finally, this review presents the potential applications and prospects of 1,2,3-triazolium salts in the fields of agriculture, medicine, and industrial synthesis.

Carbene-Catalyzed Atroposelective Annulation for Quick Access to Axially Chiral Thiazine Derivatives.

An N-heterocyclic carbene (NHC)-catalyzed atroposelective annulation reaction is disclosed for quick and efficient access to thiazine derivatives. A series of axially chiral thiazine derivatives bearing various substituents and substitution patterns were produced in moderate to high yields with moderate to excellent optical purities. Preliminary studies revealed that some of our products exhibit promising antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) that causes rice bacterial blight.

Temporal trends, predictors of blood transfusion and in-hospital outcomes among patients with severe burn injury in the United States-A national database-based analysis.

BACKGROUND: Severe burn can be accompanied by life-threatening bleeding on some occasions, thus, blood transfusion is often required in these patients during their hospitalization. Therefore, we aimed to examine temporal trends, predictors, and in-hospital outcomes of blood transfusion in these patients in the United States. METHODS: The National Inpatient Sample was used to identify severe burn patients between January 2010 and September 2017 in the United States. Trends in the utilization of blood transfusion were analyzed using the Cochran-Armitage trend test. Moreover, propensity score matching (PSM) was employed, and then in-hospital outcomes were compared between these two groups in the matched cohort. Multivariable logistic regressions were further used to validate the results of PSM. RESULTS: Among 27,260 severe burn patients identified during the study period, 2120 patients (7.18%) received blood transfusion. Blood transfusion rates decreased significantly from 9.52% in 2010 to 5.02% in 2017 (p for trend <.001). In the propensity-matched cohort (2120 pairs with and without transfusion), patients transfused were at increased risk of in-hospital mortality (13.3% vs 8.77%, p < .001), overall postoperative complications (88.3% vs 72.59%, p < .001), longer hospital stays (defined as > median hospital stays = 5 d) (73.8% vs 50.6%, p < .001) and increased overall cost (defined as > median overall costs = 30,746) (81.6% vs 57.3%, p < .001). This was also the case for the multivariable analysis. CONCLUSIONS: Blood transfusion following severe burn injury may be associated with worse clinical outcomes. The utility for blood transfusion in burn patients warrants further prospective exploration.

Machine learning approach for the prediction of 30-day mortality in patients with sepsis-associated encephalopathy.

OBJECTIVE: Our study aimed to identify predictors as well as develop machine learning (ML) models to predict the risk of 30-day mortality in patients with sepsis-associated encephalopathy (SAE). MATERIALS AND METHODS: ML models were developed and validated based on a public database named Medical Information Mart for Intensive Care (MIMIC)-IV. Models were compared by the area under the curve (AUC), accuracy, sensitivity, specificity, positive and negative predictive values, and Hosmer-Lemeshow good of fit test. RESULTS: Of 6994 patients in MIMIC-IV included in the final cohort, a total of 1232 (17.62%) patients died following SAE. Recursive feature elimination (RFE) selected 15 variables, including acute physiology score III (APSIII), Glasgow coma score (GCS), sepsis related organ failure assessment (SOFA), Charlson comorbidity index (CCI), red blood cell volume distribution width (RDW), blood urea nitrogen (BUN), age, respiratory rate, PaO2, temperature, lactate, creatinine (CRE), malignant cancer, metastatic solid tumor, and platelet (PLT). The validation cohort demonstrated all ML approaches had higher discriminative ability compared with the bagged trees (BT) model, although the difference was not statistically significant. Furthermore, in terms of the calibration performance, the artificial neural network (NNET), logistic regression (LR), and adapting boosting (Ada) models had a good calibration-namely, a high accuracy of prediction, with P-values of 0.831, 0.119, and 0.129, respectively. CONCLUSIONS: The ML models, as demonstrated by our study, can be used to evaluate the prognosis of SAE patients in the intensive care unit (ICU). Online calculator could facilitate the sharing of predictive models.

Carbene-Catalyzed Activation of C-Si Bonds for Chemo- and Enantioselective Cross Brook-Benzoin Reaction.

The first carbene-catalyzed asymmetric chemoselective cross silyl benzoin (Brook-Benzoin) reaction has been developed. Key steps of this reaction involve activation of the carbon-silicon bond of an acylsilane by a chiral N-heterocyclic carbene (NHC) catalyst to form a silyl acyl anion intermediate. These acyl anions then undergo an addition reaction with indole aldehydes in a highly chemo- and enantioselective manner to afford α-silyloxy ketones with excellent optical purities. The reaction mechanism of this cross Brook-Benzoin reaction was investigated through both experimental and computational methods. The chiral α-hydroxy ketone derivatives obtained by this approach show promising, agrochemically interesting activity against harmful plant bacteria.

Carbene-Catalyzed Asymmetric Construction of Atropisomers.

Atropisomeric molecules have found proven applications and have shown promising potential in chemistry and medicine. The design of N-heterocyclic carbene (NHC) catalyzed reactions to construct atropisomerically enriched molecules has emerged as an important research topic in recent years. These reactions include kinetic resolutions, asymmetric desymmetrizations, central-to-axial chirality conversions, and cycloadditions. This Minireview evaluates and summarizes the progress in NHC-based organic catalysis for access to atropisomers, and briefly states our personal perspectives on the future advancement of this topic. NHC catalysis has provided rich and unique reaction modes that have led to success in the asymmetric synthesis of central-chiral molecules. It is expected that similar success could also be achieved in developing NHC catalysis to prepare atropisomeric molecules, including those not easily accessible by other methods.

Carbene-Catalyzed Enantioselective Hydrophosphination of α-Bromoenals to Prepare Phosphine-Containing Chiral Molecules.

Disclosed herein is the first carbene-organocatalyzed asymmetric addition of phosphine nucleophiles to the in situ generated α,ß-unsaturated acyl azolium intermediates. Our reaction enantioselectively constructs carbon-phosphine bonds and prepares chiral phosphines with high optical purities. The phosphine products are suitable for transforming to chiral ligands or catalysts with applications in asymmetric catalysis. The diarylalkyl or trialkyl phosphine products from our catalytic reactions, air-sensitive and reactive in nature, can be trapped (and stored) in their sulfur-oxidized form for operational simplicities.

Access to Allene-Containing Molecules via Enantioselective Reactions of Azolium Cumulenolate Intermediates.

Azolium cumulenolates are a special type of intermediates in N-heterocyclic carbene catalysis. They contain elongated linear structures with three contiguous C=C bonds and sterically unhindered α-carbon atoms. These structural features make it difficult to develop enantioselective reactions for these intermediates. Here we disclose the first carbene-catalyzed highly enantioselective addition reactions of azolium cumulenolates. The reaction starts with alkynals as the precursors for azolium cumulenolate intermediates that undergo enantioselective addition to activated ketones. From the same set of substrates, both allene and spirooxindole products can be obtained with high yields and excellent enantioselectivities. The allene moieties in our optically enriched products carry rich reactivities and can be transformed to diverse molecules. The spirooxindole scaffolds in our products are important structural motifs in natural products and medicines.

Carbene-Catalyzed Activation of Remote Nitrogen Atoms of (Benz)imidazole-Derived Aldimines for Enantioselective Synthesis of Heterocycles.

A new mode of carbene-catalyzed heteroatom activation and asymmetric reactions is disclosed. The reaction starts with addition of a carbene catalyst to a (benz)imidazole-derived aldimine substrate. Subsequent oxidation and proton transfer lead to the formation of a catalyst-bound triaza-diene as the key intermediate, in which the nitrogen atom at a site remote to the catalyst-substrate bond is activated. This unusual triaza-diene intermediate then undergoes highly enantioselective reactions with activated ketones through a concerted asynchronous pathway, as supported by mechanistic studies and preliminary density function theory calculation.

N-Heterocyclic Carbene-Catalyzed Atroposelective Annulation for Access to Thiazine Derivatives with C-N Axial Chirality.

A catalytic atroposelective cycloaddition reaction between thioureas and ynals is developed. This reaction features the first NHC-catalyzed addition of thioureas to acetylenic acylazolium intermediates to eventually set up C-N axial chirality with excellent optical purities. The obtained axially chiral thiazine derivative products bear multiple functional groups and are feasible for further transformations.

Carbene-Catalyzed Enantioselective Aldol Reaction: Post-Aldol Stereochemistry Control and Formation of Quaternary Stereogenic Centers.

The dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon-carbon bond-forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post-aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non-enantioselective manner. This reversible aldol event is subsequently followed by an enantioselective acylative kinetic resolution that is mediated by the same (chiral) NHC catalyst without introducing any additional substance. This post-aldol process takes care of the enantioselectivity issues and drives the otherwise reversible aldol reaction toward a complete conversion. The acylated aldol products bearing quaternary/tetrasubstituted carbon stereogenic centers are formed in good yields and high optical purities.

Dynamic statistical model for predicting the risk of death among older Chinese people, using longitudinal repeated measures of the frailty index: a prospective cohort study.

BACKGROUND: Frailty is a common characteristic of older people with the ageing process. We aimed to develop and validate a dynamic statistical prediction model to calculate the risk of death in people aged ≥65 years, using a longitudinal frailty index (FI). METHODS: One training dataset and three validation datasets from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) were used in our study. The training dataset and validation datasets 1 to 3 included data from 9,748, 7,459, 9,093 and 6,368 individuals, respectively. We used 35 health deficits to construct the FI and a longitudinal FI based on repeated measurement of FI at every wave of the CLHLS. A joint model was used to build a dynamic prediction model considering both baseline covariates and the longitudinal FI. Areas under time-dependent receiver operating characteristic curves (AUCs) and calibration curves were employed to assess the predictive performance of the model. RESULTS: A linear mixed-effects model used time, sex, residence (city, town, or rural), living alone, smoking and alcohol consumption to calculate a subject-specific longitudinal FI. The dynamic prediction model was built using the longitudinal FI, age, residence, sex and an FI-age interaction term. The AUCs ranged from 0.64 to 0.84, and both the AUCs and the calibration curves showed good predictive ability. CONCLUSIONS: We developed a dynamic prediction model that was able to update predictions of the risk of death as updated measurements of FI became available. This model could be used to estimate the risk of death in individuals aged >65 years.

Carbene-Catalyzed Enantioselective Aromatic N-Nucleophilic Addition of Heteroarenes to Ketones.

The aromatic nitrogen atoms of heteroarylaldehydes are activated by carbene catalysts to react with ketone electrophiles. Multi-functionalized cyclic N,O-acetal products are afforded in good to excellent yields and optical purities. Our reaction involves the formation of an unprecedented aza-fulvene-type acylazolium intermediate. A broad range of N-heteroaromatic aldehydes and electron-deficient ketone substrates works effectively in this transformation. Several of the chiral N,O-acetal products afforded through this protocol exhibit excellent antibacterial activities against Ralstonia solanacearum (Rs) and are valuable in the development of novel agrichemicals for plant protection.

Carbene-Catalyzed Dynamic Kinetic Resolution and Asymmetric Acylation of Hydroxyphthalides and Related Natural Products.

A catalytic dynamic kinetic resolution and asymmetric acylation reaction of hydroxyphthalides is developed. The reaction involves formation of a carbene catalyst derived chiral acyl azolium intermediate that effectively differentiates the two enantiomers of racemic hydroxyphthalides. The method allows quick access to enantiomerically enriched phthalidyl esters with proven applications in medicine. It also enables asymmetric modification of natural products and other functional molecules that contain acetal/ketal groups, such as corollosporine and fimbricalyxlactone C.