Development of an imidazole-based N,N-bidentate ligand for the manganese catalyzed direct coupling of nitriles with alcohols.

3d-Metal catalyzed borrowing hydrogen (BH) reactions represent powerful and environmentally friendly approaches for the direct coupling of alcohols with nitriles to assemble various important branched nitriles. The development of simple and efficient ligands is a crucial issue in this field. In this study, we designed a series of readily available N,N-bidentate ligands that demonstrated good efficiency in the Mn-catalyzed BH reaction of alcohols and nitrile derivatives, yielding the targeted nitriles in moderate to good yields. Remarkably, the mildness and practicality of this protocol were further demonstrated by the successful synthesis of anipamil via a two-cascade borrowing hydrogen procedure.

NHC-catalyzed radical acylation of cycloalkyl silyl peroxides to access 1,6-,1,7-, and 1,8-diketones.

An unprecedented N-heterocyclic carbene (NHC)-catalyzed radical acylation of cycloalkyl silyl peroxides was developed using readily available aldehydes as the acylating agents. This protocol provides an exceptionally useful method for the efficient and rapid synthesis of long-chain 1,6-/1,7-/1,8-diketones, especially unsymmetrical ones. This strategy also has the advantages of mild conditions, good functional group compatibility, and potential applications in the late-stage functionalization of aldehydes with bioactive fragments and in the construction of long-chain complex bioactive molecules.

Association between serum-free thyroxine level and all-cause mortality in critically ill patients: a retrospective study from MIMIC-IV.

Background: Low thyroxine (T4) levels have been observed in critically ill patients; however, controversial results regarding T4 supplemental therapy are reported. The association between serum free T4 (FT4) levels and mortality in critically ill patients has not been fully established and needs to be clarified. Methods: Data from the Medical Information Mart for Intensive Care (MIMIC)-IV were collected and analyzed. The association between FT4 level and 30-day mortality after ICU admission was analyzed using Kaplan-Meier curves, spline smoothing fitting, martingale residuals of the null Cox model, and restricted cubic spline (RCS). Logistic regression, Cox regression, and receiver operating characteristic curve (ROC) were used to uncover the relationship and predictive value of serum FT4 and 30-day mortality in critically ill patients. Results: In the final analysis, 888 patients were enrolled, and the serum FT4 levels were divided into four groups. A significant difference in 30-day mortality was observed between the four groups. Kaplan-Meier curves also presented significantly higher 30-day mortality in groups 1 and 2 (p < 0.0001). Further multivariance logistic regression showed that group 1 with FT4 levels lower than 0.7 µg/dl can predict 30-day mortality (odds ratio (OR) = 3.30, 95% confidence interval (CI) = 1.04-11.31). Spline smoothing fitting analysis showed a "V"-shaped line between 30-day mortality and FT4 level within 0-3 µg/dl. Further RCS analysis showed that the risk of death decreased rapidly as FT4 levels increased when serum FT4 levels were lower than 1.2 µg/dl and started to become flat afterward. The area under the ROC of the lower FT4 level to predict 30-day mortality was 0.833 (95% CI = 0.788-0.878). Both multivariant Cox regression and logistic regression showed that FT4 levels lower than 1.2 µg/dl can independently predict 30-day mortality when adjusted for other potential confounders (HR = 0.34, 95% CI = 0.14-0.82; OR = 0.21, 95% CI = 0.06-0.79, respectively), but its predictive power disappeared when adjusted for T3 or total T4. Conclusion: Serum FT4 levels were significantly negatively associated with 30-day mortality when they were lower than 1.2 µg/dl and could predict the risk of 30-day mortality. A higher FT4 level is potentially related to increased 30-day mortality.

NHC-Catalyzed Synthesis of α-Sulfonyl Ketones via Radical-Mediated Sulfonyl Methylation of Aldehydes.

An N-heterocyclic carbene (NHC)-catalyzed facile assembly of α-sulfonyl ketones has been successfully developed through a radical-mediated sulfonyl methylation of readily available aldehydes. This protocol involves the effective single-electron transfer reduction of α-iodosulfones by NHC-bound Breslow intermediates, thus allowing a subsequent radical-radical coupling to afford the target compounds. Moreover, the catalytic system was found to be equally effective for difunctionalization of styrenes and 1,3-enynes via a three-component radical relay process.

Organocatalytic radical relay trifunctionalization of unactivated alkenes by a combination of cyano migration and alkylacylation.

The first N-heterocyclic carbene organocatalytic three-component radical relay trifunctionalization of unactivated alkenes through the combination of remote 1,4-cyano migration and alkylacylation was reported. This protocol features mild reaction conditions, readily available materials, excellent regioselectivity, and capability of late-stage functionalization.

Alkynyl Acylazolium: A Versatile 1,3-Bielectrophilic 3C-Synthon in NHC-Organocatalysis.

N-Heterocyclic carbene (NHC) organocatalysis has emerged as a powerful tool in the field of modern organic synthesis especially in the asymmetric construction of various cyclic skeletons. As an emerging NHC-bound 1,3-bielectrophilic intermediate, alkynyl acylazolium has drawn substantial attention in recent years, and has been used as a versatile 3C-synthon in synthesizing valuable organic molecules since its discovery. In this review, focused on the different pathways for the formation of alkynyl acylazoliums from different precursors like alkynoic esters, alkynoic acids and ynals, the recent advances in the transformations and applications of alkynyl acylazoliums pioneered or developed over the last decade under NHC-catalysis were summarized comprehensively. At the same time, the outlook for further investigation and exploration of novel reaction modes for alkynyl acylazoliums in the future was also discussed.

Construction of Functionalized 2H-Pyran-2-ones via N-Heterocyclic Carbene-Catalyzed [3 + 3] Annulation of Alkynyl Esters with Enolizable Ketones.

A new synthesis of functionalized 2H-pyran-2-ones has been developed through N-heterocyclic carbene-catalyzed formal [3 + 3] annulation of alkynyl esters with enolizable ketones. The key to the success of this protocol relies on the use of an NHC instead of a tertiary amine as the catalyst. This protocol also features a broad substrate scope and mild metal-free conditions, offering simple and rapid access to the target molecules in a highly regioselective manner.

Time to Local Recurrence as a Predictor of Survival in Adult Head and Neck Soft Tissue Sarcoma.

OBJECTIVES: We sought to evaluate the impact of the time interval from surgical resection to local recurrence (TTLR) on clinical outcomes in head and neck soft tissue sarcoma (HNSTS). METHODS: A total of 401 patients who underwent R0 resection for primary HNSTS were included in this study. Patients with local recurrence as the first event after their initial resection were divided into early local recurrence (ELR) or late local recurrence (LLR) groups according to TTLR. Multiple survival analyses were performed to identify the independent prognostic predictors of overall survival (OS) and survival after local recurrence (SAR). RESULTS: Two hundred and nine of the 401 patients (52.1%) developed local recurrence during a median follow-up period of 134.6 months. Patients in the ELR group had a shorter median OS time (35.0 vs. 120.6, p < 0.001) and lower 5-year OS rate (47.7% vs. 80.9%, p < 0.001) than those in the LLR group. Moreover, the ELR group exhibited worse SAR (p = 0.001) than the LLR group, and multivariate analyses demonstrated TTLR as an independent prognostic factor for SAR (p = 0.048) and OS (p = 0.004). Additionally, re-resection significantly prolonged SAR than other salvage interventions or no treatment (p < 0.001). CONCLUSION: In patients with HNSTS, ELR after R0 resection presents adverse effects on OS and SAR than those with LLR, and TTLR could serve as a promising predictor for survival. Salvage therapies, especially the re-resection could improve SAR and should be recommended when there are surgical indications after recurrence. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2174-2182, 2023.

Atroposelective Synthesis of Triaryl α-Pyranones with 1,2-Diaxes by N-Heterocyclic Carbene Organocatalysis.

Atropisomers bearing multiple stereogenic axes are of increasing importance to the field of material science, pharmaceuticals, and catalysis. However, the atroposelective construction of multi-axis atropisomers remains rare and challenging, due to the intrinsical difficulties in the stereo-control of the multiple stereogenic axes. Herein, we demonstrate a single-step construction of a new class of 1,2-diaxially chiral triaryl α-pyranones by an N-heterocyclic carbene organocatalytic asymmetric [3+3] annulation of well-designed alkynyl acylazolium precursors and enolizable sterically hindered 2-aryl ketones. The protocol features broad substrate scope (>50 examples), excellent stereo-control (most cases >20 : 1 dr, up to 99.5 : 0.5 er), and potentially useful synthetic applications. The success of this reaction relies on the rational design of structurally matched reaction partners and the careful selection of the asymmetric catalytic system. DFT calculations have also been performed to discover and rationalize the origin of the high stereoselectivity of this reaction.

CF2Br2 as a Source for Difluoroolefination of 1,3-Enynes via N-Heterocyclic Carbene Catalysis.

Commercially available CF2Br2 has been used as a convenient source for the rapid and reliable incorporation of the gem-difluorovinyl motif into an allene framework via an N-heterocyclic carbene catalyzed difluoroolefination of 1,3-enynes. The reaction proceeds through a cascade three-component radical relay/elimination process. This protocol is distinguished by its mild conditions, readily accessible starting materials, wide substrate scope, and ease of late-stage functionalization, thus unlocking an untraditional strategy to construct a new class of functionalized gem-difluorovinyl allenes.

Management and outcome of bronchial trauma due to blunt versus penetrating injuries.

BACKGROUND: The number of patients with bronchial trauma (BT) who survived to hospital admission has increased with the improvement of prehospital care; early diagnosis and treatment should be considered, especially among blunt trauma patients, whose diagnosis is frequently delayed. AIM: To describe the early recognition and surgical management considerations of blunt and penetrating BTs, and to elaborate the differences between them. METHODS: All patients with BTs during the past 15 years were reviewed, and data were retrospectively analyzed regarding the mechanism of injury, diagnostic and therapeutic procedures, and outcomes. According to the injury mechanisms, the patients were divided into two groups: Blunt BT (BBT) group and penetrating BT (PBT) group. The injury severity, treatment procedures, and prognoses of the two groups were compared. RESULTS: A total of 73 patients with BT were admitted during the study period. The proportion of BTs among the entire cohort with chest trauma was 2.4% (73/3018), and all 73 underwent thoracotomy. Polytrauma patients accounted for 81.6% in the BBT group and 22.9% in the PBT group, and the mean Injury Severity Score was 38.22 ± 8.13 and 21.33 ± 6.12, respectively. Preoperative three-dimensional spiral computed tomography (CT) and/or fiberoptic bronchoscopy (FB) were performed in 92.1% of cases in the BBT group (n = 38) and 34.3% in the PBT group (n = 35). In the BBT group, a delay in diagnosis for over 48 h occurred in 55.3% of patients. In the PBT group, 31 patients underwent emergency thoracotomy due to massive hemothorax, and BT was confirmed during the operation. Among them, 22 underwent pulmo-tractotomy for hemostasis, avoiding partial pneumonectomy. In this series, the overall mortality rate was 6.9% (5/73), and it was 7.9% (3/38) and 5.7% (2/35) in the BBT group and PBT group, respectively (P > 0.05). All 68 survivors were followed for 6 to 42 (23 ± 6.4) mo, and CT, FB, and pulmonary function examinations were performed as planned. All patients exhibited normal lung function and healthy conditions except three who required reoperations. CONCLUSION: The difference between blunt and penetrating BTs is obvious. In BBT, patients generally have no vessel injury, and the diagnosis is easily missed, leading to delayed treatment. The main cause of death is ventilation disturbance due to tension pneumothorax early and refractory atelectasis with pneumonia late. However, in PBT, most patients require emergency thoracotomy because of simultaneous vessel trauma and massive hemothorax, and delays in diagnosis are infrequent. The leading cause of death is hemorrhagic shock.

Enantioselective Synthesis of δ-Carbolinones via N-Heterocyclic Carbene Catalysis.

An enantioselective synthesis of δ-carbolinones was accomplished through N-heterocyclic carbene-catalyzed formal [3+3] annulation of 3-aminoindoles with 2-bromoenals. This protocol offers a rapid and efficient synthetic approach for accessing a wide range of enantioenriched structurally interesting δ-carbolinones under mild reaction conditions.

N-Heterocyclic Carbene-Catalyzed Enantioselective Synthesis of Carbocycle-Fused Uracils via Formal [4 + 2] Annulation/Lactone Formation/Decarboxylation Cascade.

An unprecedented organocatalytic asymmetric construction of novel six-membered carbocycle fused uracils has been demonstrated by the reaction of the remotely enolizable 6-methyluracil-5-carbaldehydes with 2-bromoenals. The reaction involves an N-heterocyclic carbene-catalyzed formal [4 + 2] annulation of o-quinodimethane (oQDM) dienolates with α,ß-unsaturated acylazoliums, followed by a cascade lactone formation/decarboxylation process. This protocol unlocks a new platform to access enantioenriched carbocycle-fused uracils.

Geomorphic processes of a dammed palaeo-lake in the middle Yarlung Tsangpo River, Tibet.

The failure of a natural dam is an extreme geological event. Palaeo-lake sediments were discovered in the broad Xigazê valley and Dazhuka-Yueju gorge in the middle reach of the Yarlung Tsangpo River in Tibet. However, the sedimentary processes, dam failure, and peak flood of the Xigazê dammed palaeo-lake are poorly understood. Hence, we conducted a field survey of eight lacustrine sedimentary terraces in the area. We divided the sedimentary processes of the palaeo-lake into five stages and deposit types: pre-palaeo-lake sediments (fluvial or aeolian deposits); early stage sediments of the palaeo-lake (coarse sand); main stage palaeo-lake sediments (clayey silt and sand), sediments following the discharge of the palaeo-lake (sand and gravel-cobbles); and cover deposits (aeolian sediments and colluvium). Additionally, the water level along the palaeo-lake was almost constant (3811 m a.s.l.). The dam was likely located at the eastern end of the Dazhuka-Yueju gorge. Based on the water level, dam location and 30-m ASTER GDEM2 data, the capacity of the palaeo-lake was estimated as 22.55 km3. To separate the water volume and sediment volume, the sediment surface elevation along the palaeo-lake was simulated based on the elevations of the six lacustrine sedimentary terraces. The volume of the sediment was ~11.56 km3, which was calculated from the dam location, sediment surface elevation, and the ASTER GDEM2 data. Finally, subtraction of the sediment volume from the capacity of the palaeo-lake gave a backwater volume of 10.99 km3. The peak flood possibly exceeded 3.4 × 105 m3/s as a moraine dam joined the discharge during the dam failure. However, the dammed event probably had a limited effect on the landforms at downstream because of the presence of another dammed palaeo-lake in the broad Zetang valley; moreover, the bedrock upstream of the dam was protected from erosion.

The Chinese consensus for surgical treatment of traumatic rib fractures 2021 (C-STTRF 2021).

Rib fracture is the most common injury in chest trauma. Most of patients with rib fractures were treated conservatively, but up to 50% of patients, especially those with combined injury such as flail chest, presented chronic pain or chest wall deformities, and more than 30% had long-term disabilities, unable to retain a full-time job. In the past two decades, surgery for rib fractures has achieving good outcomes. However, in clinic, there are still some problems including inconsistency in surgical indications and quality control in medical services. Before the year of 2018, there were 3 guidelines on the management of regional traumatic rib fractures were published at home and abroad, focusing on the guidance of the overall treatment decisions and plans; another clinical guideline about the surgical treatment of rib fractures lacks recent related progress in surgical treatment of rib fractures. The Chinese Society of Traumatology, Chinese Medical Association, and the Chinese College of Trauma Surgeons, Chinese Medical Doctor Association organized experts from cardiothoracic surgery, trauma surgery, acute care surgery, orthopedics and other disciplines to participate together, following the principle of evidence-based medicine and in line with the scientific nature and practicality, formulated the Chinese consensus for surgical treatment of traumatic rib fractures (STTRF 2021). This expert consensus put forward some clear, applicable, and graded recommendations from seven aspects: preoperative imaging evaluation, surgical indications, timing of surgery, surgical methods, rib fracture sites for surgical fixation, internal fixation method and material selection, treatment of combined injuries in rib fractures, in order to provide guidance and reference for surgical treatment of traumatic rib fractures.

N-Heterocyclic Carbene-Catalyzed Formal [3+3] Annulation of Alkynyl Acylazoliums for the Synthesis of Benzofuro[3,2-b]pyridin-2-ones.

Through ß-activation of alkynoic acid esters with N-heterocyclic carbene catalysis, a formal [3+3] annulation of alkynyl acylazoliums with indolin-3-ones has been developed for the rapid construction of structurally interesting benzofuro[3,2-b]pyridin-2-ones with potential bioactivities. This protocol provides a highly efficient and simple method for the synthesis of the target molecules under mild reaction conditions with a wide substrate scope and excellent chemoselectivity. The synthetic utility of this protocol was also demonstrated by the versatile late-stage modifications.

Atroposelective Synthesis of Axially Chiral 4-Aryl α-Carbolines via N-Heterocyclic Carbene Catalysis.

The first catalytic asymmetric construction of axially chiral 4-aryl α-carboline skeletons has been accomplished through an N-heterocyclic carbene (NHC)-catalyzed atroposelective formal [3 + 3] annulation of 4-nitrophenyl 3-arylpropiolates with 2-sulfonamidoindolines. The synthetic utility of the title compounds has been demonstrated by the diverse late-stage structural modifications. Density functional theory calculations were also conducted to illuminate the key factors for controlling the origin of the enantioselectivity. This strategy not only provides an efficient pathway to access axially chiral α-carboline atropisomers but also offers a novel catalytic enantioselective mode for the construction of axially chiral heterobiaryls by using NHC-bound alkynyl acylazoliums.

N-Heterocyclic Carbene/Magnesium Cocatalyzed Radical Relay Assembly of Aliphatic Keto Nitriles.

An unprecedented N-heterocyclic carbene and magnesium cocatalyzed three-component acylcyanoalkylation of alkenes with cycloketone oxime esters and aldehydes is presented. This method displayed good scope generality, providing a transition-metal- and photoredox-free pathway to access various multifunctionalized aliphatic keto nitrile structures under mild reaction conditions. Moreover, this strategy is supposed to follow a radical relay mechanism via a single electron transfer event of a Mg/matched Breslow intermediate/oxime ester electron-donating acceptor (EDA) complex.

Structure-based discovery of 1H-indole-2-carboxamide derivatives as potent ASK1 inhibitors for potential treatment of ulcerative colitis.

Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase (MAPK) family, is implicated in many human diseases. Here, we describe the structural optimization of hit compound 7 and conduct further structure-activity relationship (SAR) studies that result in the development of compound 19 with a novel indole-2-carboxamide hinge scaffold. Compound 19 displays potent anti-ASK1 kinase activity and stronger inhibitory effect on ASK1 in AP1-HEK293 cells than previously described ASK1 inhibitor GS-4997. Besides improved in vitro activity, compound 19 also exhibits an appropriate in vivo PK profile. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 19 shows significant anti-UC efficacy and markedly attenuates DSS-induced body weight loss, colonic shortening, elevation in disease activity index (DAI) and inflammatory cell infiltration in colon tissues. Mechanistically, compound 19 represses the phosphorylation of ASK1-p38/JNK signaling pathways and suppresses the overexpression of inflammatory cytokines. Together, these findings suggest that ASK1 inhibitors can potentially be used as a therapeutic strategy for UC.

Entropy-Based Measures of Hypnopompic Heart Rate Variability Contribute to the Automatic Prediction of Cardiovascular Events.

Surges in sympathetic activity should be a major contributor to the frequent occurrence of cardiovascular events towards the end of nocturnal sleep. We aimed to investigate whether the analysis of hypnopompic heart rate variability (HRV) could assist in the prediction of cardiovascular disease (CVD). 2217 baseline CVD-free subjects were identified and divided into CVD group and non-CVD group, according to the presence of CVD during a follow-up visit. HRV measures derived from time domain analysis, frequency domain analysis and nonlinear analysis were employed to characterize cardiac functioning. Machine learning models for both long-term and short-term CVD prediction were then constructed, based on hypnopompic HRV metrics and other typical CVD risk factors. CVD was associated with significant alterations in hypnopompic HRV. An accuracy of 81.4% was achieved in short-term prediction of CVD, demonstrating a 10.7% increase compared with long-term prediction. There was a decline of more than 6% in the predictive performance of short-term CVD outcomes without HRV metrics. The complexity of hypnopompic HRV, measured by entropy-based indices, contributed considerably to the prediction and achieved greater importance in the proposed models than conventional HRV measures. Our findings suggest that Hypnopompic HRV assists the prediction of CVD outcomes, especially the occurrence of CVD event within two years.