The severity of intrahepatic cholestasis of pregnancy and its association with pregnancy complications and neonatal asphyxia: A single-center case analysis and systematic review.

Intrahepatic cholestasis of pregnancy (ICP) poses significant risks to maternal and neonatal health. Our study at Jiangxi Provincial Maternal and Child Health Hospital analyzed clinical and biochemical markers in singleton pregnancies diagnosed with ICP from October 2016 to December 2022. This research, supported by a systematic review and meta-analysis of existing studies, highlights the increasing incidence of ICP and its association with elevated levels of total bile acids, transaminases, and bilirubin. Our findings indicate a marked increase in the risk of preterm birth, cesarean delivery, and neonatal asphyxia as the severity of ICP escalates. This underscores the need for vigilant monitoring and management of affected pregnancies. By confirming the relationship between biochemical marker abnormalities and adverse pregnancy outcomes, our study advocates for enhanced clinical strategies and paves the way for future research aimed at improving prevention, diagnosis, and treatment methods for ICP.

Mild ketyl radical generation and coupling with alkynes enabled by Cr catalysis: stereoselective access to E-exocyclic allyl alcohols.

The mild catalytic generation of ketyl radicals for organic transformations remains an unsolved issue, although it facilitates the discovery of metal-catalyzed reactions with the features of high functional group tolerance. Here, we report the generation of the ketyl radicals and coupling with alkynes that was enabled by cost-effective chromium catalysis, allowing for the formation of valuable E-exocyclic allyl alcohols with high stereo- and chemoselectivity. A broad range of synthetically useful functional groups that are sensitive to strong reductants are compatible with the catalytic system, providing access to diverse substituted E-exocyclic allyl alcohols under mild conditions. Appended hydroxyl groups in products are facilely late-stage functionalized in accessing numerous derivatives, as well as the enantio-enrichment of exocyclic allyl alcohol using chiral ligands. Mechanistic studies suggest that bipyridine-ligated Cr(ii) complex serves as a reactive catalyst enabling the generation of the ketyl radical for coupling, giving vinyl radical, followed by the combination of Cr and transmetalation with Cp2ZrCl moiety in affording oxazirconiumacycle. This reaction provides a new opportunity for the mild formation of transient ketyl radicals from widely accessible aliphatic aldehydes for coupling with Earth-abundant metal catalysis.

Metal-carbene-guided twofold cross-coupling of ethers with chromium catalysis.

Coupling by metal-carbene transfer enables the formation of several different bonds at the carbenoid site, enabling prochiral Csp3 centers that are fundamental three-dimensional substructures for medicines to be forged with increased efficiency. However, strategies using bulk chemicals are rare because of the challenge of breaking two unactivated geminal bonds. Herein, we report the reactivity of ethers to form metal-carbene intermediate by cleavage of α-Csp3-H/Csp3-O bonds, which achieve selective coupling with arylmagnesium bromides and chlorosilanes. These couplings are catalysed by cyclic (alkyl)(amino)carbene-chromium complex and enable the one-step formation of 1,n-arylsilyl alcohols and α-arylated silanes. Mechanistic studies indicate that the in-situ formed low-valent Cr might react with iodobenzene to form phenyl radical species, which abstracts the α-H atom of ether in giving α-oxy radical. The latter combines with Cr by breaking α-Csp3-O bond to afford metal-carbene intermediate, which couples with aryl Grignard and chlorosilane to form two σ-bonds.

Single-cell RNA sequencing reveals heterogeneity and differential expression of the maternal-fetal interface during ICP and normal pregnancy.

OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) can cause adverse perinatal outcomes. Previous studies have demonstrated that the placenta of an ICP pregnancy differs in morphology and gene expression from the placenta of a normal pregnancy. To date, however, the genetic mechanism by which ICP affects the placenta is poorly understood. Therefore, the aim of this study was to investigate the differences in main cell types, gene signatures, cell ratio, and functional changes in the placenta between ICP and normal pregnancy. METHODS: Single-cell RNA sequencing (scRNA-seq) technology was used to detect the gene expression of all cells at the placental maternal-fetal interface. Two individuals were analyzed - one with ICP and one without ICP. The classification of cell types was determined by a graph-based clustering algorithm. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the R software phyper () function and DAVID website. The differentially expressed genes (DEGs) encoding transcription factors (TFs) were identified using getorf and DIAMOND software. RESULTS: We identified 14 cell types and 22 distinct cell subtypes that showed unique functional properties. Additionally, we found differences in the proportions of fibroblasts 1, helper T (Th) cells, extravillous trophoblasts, and villous cytotrophoblasts, and we observed heterogeneity of gene expression between ICP and control placentas. Furthermore, we identified 263 DEGs that belonged to TF families, including zf-C2H2, HMGI/HMGY, and Homeobox. In addition, 28 imprinted genes were preferentially expressed in specific cell types, such as PEG3 and PEG10 in trophoblasts as well as DLK1 and DIO3 in fibroblasts. CONCLUSIONS: Our results revealed the differences in cell-type ratios, gene expression, and functional changes between ICP and normal placentas, and heterogeneity was found among cell subgroups. Hence, the imbalance of various cell types affects placental activity to varying degrees, indicating the complexity of the cell networks that form the placental tissue system, and this alteration of placental function is associated with adverse events in the perinatal period.

Cr-Catalyzed Intramolecular Arylative Cross-Coupling of Unactivated C-H Bonds with C-Halide Bonds.

We report here a chromium-catalyzed intramolecular arylation of unactivated C-H bonds with C-halide bonds under mild conditions. This reaction was enabled by using a low-cost CrCl2 salt as the precatalyst in combination with allylmagnesium bromide and E/Z-mixed 1-halo-2-styrylarenes as substates, providing a strategy for the construction of functionalized phenanthrene compounds without using external ligands.

Ring Contraction by Rearrangement of Sterically Congested Cyclic (Amino)(aryl)carbenes.

The rearrangement of sterically congested cyclic (amino)(aryl)carbenes (CAArCs) by the reaction of related iminium salts with potassium bis(trimethylsilyl)amide is reported, allowing for forming benzocyclobutanimines via a ring contraction process. Mechanistic studies by theoretical calculations indicate that the formation of conjugated ketenimines as intermediates could be considered, in which steric hindrance caused by N-alkyl motifs of CAArCs plays an important role in promoting the ring-opening by the cleavage of C-N bond.

Cr-catalyzed borylation of C(aryl)-F bonds using a terpyridine ligand.

The defluoroborylation of fluoroarenes by chromium-catalyzed cleavage of unactivated C-F bonds is described. The reaction uses HBpin as the boron source, low-cost and commercially available chromium salt as the precatalyst, and terpyridine as a crucial ligand, providing a protocol with atom-efficient benefits and a wide range of applicable substrates for the functionalization of aryl C-F bonds. Preliminary mechanistic studies indicate that an unprecedented Cr-catalyzed magnesiation of the unactivated C-F bond occurred. The generated arylmagnesium intermediates then participated in the subsequent borylation reaction. The application of the strategy in the preparation of valuable derivatives is demonstrated by the late-stage functionalization of boronate ester groups.

Chromium-Catalyzed Alkene Isomerization with Switchable Selectivity.

We report a single additive-responsive chromium-catalyzed system for selectively producing either of two different internal alkene isomers. The chromium catalyst, in the presence of HBpin/LiOtBu, enables the isomerization of alkenes over multiple carbon atoms to give the most thermodynamically stable isomers. The same catalyst allows for the selective isomerization of terminal alkenes over one carbon atom without an additive, exhibiting efficient and controllable alkene transposition selectivity.

Landscapes of gut bacterial and fecal metabolic signatures and their relationship in severe preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific disease leading to maternal and perinatal morbidity. Hypertension and inflammation are the main characteristics of preeclampsia. Many factors can lead to hypertension and inflammation, including gut microbiota which plays an important role in hypertension and inflammation in humans. However, alterations to the gut microbiome and fecal metabolome, and their relationships in severe preeclampsia are not well known. This study aims to identify biomarkers significantly associated with severe preeclampsia and provide a knowledge base for treatments regulating the gut microbiome. METHODS: In this study, fecal samples were collected from individuals with severe preeclampsia and healthy controls for shotgun metagenomic sequencing to evaluate changes in gut microbiota composition. Quantitative polymerase chain reaction analysis was used to validate the reliability of our shotgun metagenomic sequencing results. Additionally, untargeted metabolomics analysis was performed to measure fecal metabolome concentrations. RESULTS: We identified several Lactobacillaceae that were significantly enriched in the gut of healthy controls, including Limosilactobacillus fermentum, the key biomarker distinguishing severe preeclampsia from healthy controls. Limosilactobacillus fermentum was significantly associated with shifts in KEGG Orthology (KO) genes and KEGG pathways of the gut microbiome in severe preeclampsia, such as flagellar assembly. Untargeted fecal metabolome analysis found that severe preeclampsia had higher concentrations of Phenylpropanoate and Agmatine. Increased concentrations of Phenylpropanoate and Agmatine were associated with the abundance of Limosilactobacillus fermentum. Furthermore, all metabolites with higher abundances in healthy controls were enriched in the arginine and proline metabolism pathway. CONCLUSION: Our research indicates that changes in metabolites, possibly due to the gut microbe Limosilactobacillus fermentum, can contribute to the development of severe preeclampsia. This study provides insights into the interaction between gut microbiome and fecal metabolites and offers a basis for improving severe preeclampsia by modulating the gut microbiome.

Racial Disparities in Clozapine Prescription Patterns Among Patients With Schizophrenia.

OBJECTIVE: Previous research has suggested that demographic factors affect the likelihood of a patient with schizophrenia receiving a clozapine prescription. The authors aimed to determine the impact of race, social determinants of health, gender, rurality, and care patterns on clozapine prescription rates. METHODS: This cross-sectional observational study used structured electronic health records data from 3,160 adult patients diagnosed as having schizophrenia between October 1, 2015, and November 30, 2021, in a multifacility health system. The social vulnerability index (SVI) was used to quantify social determinants of health. Descriptive data analysis, logistic regression, and sensitivity analysis were conducted to identify differences between patients with schizophrenia who received a clozapine prescription and those who received antipsychotic medications other than clozapine. RESULTS: Overall, 401 patients with schizophrenia were given a clozapine prescription during the study period, and 2,456 received antipsychotics other than clozapine. Results of the logistic regression indicated that White race (OR=1.71, compared with Black race), community minority status and language SVI score (OR=2.97), and increased treatment duration (OR=1.36) were significantly associated with a higher likelihood of clozapine prescription; gender, rurality, age at first diagnosis, and ethnicity did not influence the likelihood of receiving clozapine. CONCLUSIONS: Black patients with schizophrenia had a lower likelihood of receiving a clozapine prescription compared with White patients, even after analyses accounted for demographic variables, social determinants of health, and care access patterns. Given the effectiveness of clozapine in managing treatment-resistant schizophrenia, it is crucial for future research to better understand the factors contributing to this treatment disparity.

Enhanced nonlinear effects in femtosecond laser-inscribed depressed cladding waveguides in sapphire crystals.

High-performance depressed cladding waveguides can be fabricated in crystals using ultrafast laser inscription. The investigation of nonlinear phenomena, which manifest during the transmission of high peak power femtosecond pulses within waveguides, holds significant importance for their practical integration into waveguide lasers and waveguide-based components, among other pioneering applications. In this study, the depressed cladding waveguides were successfully prepared in sapphire crystal by a femtosecond laser. The nonlinear phenomena occurring in this waveguide were investigated. The experimental results show that the nonlinearity in the depressed cladding waveguides is significantly enhanced compared with that of the bulk. This enhancement notably manifests through augmented nonlinear losses (NLs) and the third harmonic (TH) blueshift increase. Meanwhile, we theoretically investigate the influence of nonlinear effects on the TH, such as self-phase modulation (SPM), cross-phase modulation (XPM), and group delay. Our results reveal that the phase mismatch between the TH and the pump pulses is the main reason for the asymmetric broadening and blueshift of the TH spectrum. Our study reveals the unique nonlinear properties of the waveguides and lays the foundation for further relevant studies and applications of such waveguides.

Associations between ALDOB polymorphisms and intrahepatic cholestasis of pregnancy susceptibility in the Chinese Han population.

OBJECTIVES: To research the associations between fructose-bisphosphate aldolase B (ALDOB) gene polymorphisms and intrahepatic cholestasis of pregnancy (ICP) risk. MATERIAL AND METHODS: Whole-genome sequencing (WGS) was performed to detect ALDOB polymorphisms. Five web-available tools were employed to predict the effect of the site variant on the protein. Protein structure comparisons between the reference and ALDOB-modified samples were performed by SWISS-MODEL and Chimera 1.14rc, respectively. RESULTS: We identified 28 genetic variants in the ALDOB gene. When the cut-off value of minor allele frequency (MAF) of loci was 0.001 in four databases, five missense variants, including rs747604233, rs759204107, rs758242037, rs371526091 and rs77718928, were reserved for subsequent analysis. These variants were absent from the 1029 control individuals. The influence of all five variants on protein function was predicted to be damaging by the abovementioned five prediction software programs. Bioinformatics analysis demonstrated that these five missense variants were highly conserved among vertebrates. Compared to the wild-type protein structure, all five mutated protein structures showed a slight change in the chemical bond lengths of the enzyme activity domains. The combined clinical data indicate that the variant group had a significantly older age (p = 0.038), a higher level of indirect bilirubin (IDBIL, p = 0.033), and lower counts of white blood cells (WBCs, p = 7.38E-05) and platelets (PLTs, p = 0.018) than the wild-type group. CONCLUSIONS: This is the first study to examine the associations between ALDOB polymorphisms and ICP disease in 249 Chinese patients with ICP. Our present study expands the understanding of the pathogenesis of ICP.

Factors Associated with Reliance on Audio-Only Technology (Telephone) for Completion of Telepsychiatry Visits.

Introduction: The ability to access telepsychiatry through audio-video technology versus audio-only (telephone) technology potentially leads to inequitable outcomes. This study examines the characteristics of patients who relied on the telephone to complete outpatient telepsychiatry visits in a large health system. Methods: This is a retrospective analysis of all telepsychiatry outpatient visits conducted from May 1, 2020, to December 31, 2021. Demographic, clinical, and socioeconomic factors were extracted from the electronic health record. Two-sample t tests were used for continuous variables and χ2 tests for categorical variables for bivariate analyses. Multiple logistic regression was used to examine the association between only telephone visits and all input variables. Results: Eight hundred ninety-four (8.9%) patients completed all visits only by telephone during the study period. In bivariate analyses, factors associated with telephone-only visits included male sex, non-English primary language, Black race, unmarried status, non-Hispanic ethnicity, older age, Medicare enrollment, uninsured status, and higher social vulnerability index (SVI). Psychiatric diagnoses associated with only telephone visits included substance use disorders and psychotic disorders. In multivariate analyses, factors associated with higher odds of only telephone visits included older age, inactive patient portal, comorbid diabetes, higher SVI, and higher broadband adoption. Psychiatric diagnoses associated with higher odds of completing only telephone visits included psychotic disorders, substance use disorders, or intellectual/developmental disabilities. Conclusions: Several patient-level factors are associated with a reliance on the telephone to complete telepsychiatry appointments.

Torreya grandis oil attenuates cognitive impairment in scopolamine-induced mice.

The oil of Torreya grandis (TGO), a common nut in China, is considered to be a bioactive edible oil and has a great value in functional food development. In this study, the neuroprotective effects of TGO were investigated on a scopolamine (SCOP)-induced C57BL/6J mouse model. The mice were pretreated with TGO for 30 days (1000 mg per kg per day and 3000 mg per kg per day, i.g.). Behavioral tests showed that the supplementation of TGO could prevent the cognitive deficits induced by SCOP. TGO rebalanced the disorder of the cholinergic system by upgrading the level of acetylcholine. TGO also alleviated the over-activation of microglia and inhibited neuroinflammation and oxidative stress. Additionally, TGO could regulate the composition of gut microbiota, increase the production of short-chain fatty acids, and decrease the content of lipopolysaccharides in the serum. In conclusion, TGO has the potential to prevent loss of memory and impairment of cognition, which may be related to its regulation of the gut microbiota-metabolite-brain axis.

Reductive transamidation of tertiary amides with nitroarenes enabled by magnesium and chlorosilane.

Reported here is the reductive transamidation of tertiary amides with nitroarenes promoted by main group metal magnesium and chlorosilane. The reaction uses commercially available and air-stable nitroarenes as nitrogen sources, so it can occur under transition-metal- and ligand-free conditions, thus providing a step-economic and cost-effective strategy for forming centrally important secondary amides. Several biologically interesting amide motifs are readily accessible by the Mg-promoted reductive transamidation.

Influence of optical surface distortion in a cylindrical Offner stretcher on the far-field signal-to-noise ratio.

In a stretcher, the surface distortion of the optical elements can introduce spectral phase modulations into the laser, which can affect the laser's signal-to-noise ratio. In this paper, by combining ray tracing methods and angular spectrum diffraction methods, the impact of the mid-frequency surface distortion of the optical elements in an cylindrical Offner stretcher on the far-field signal-to-noise ratio of the laser is simulated. The results show that reducing the spatial chirp on the convex cylindrical mirror can effectively improve the far-field signal-to-noise ratio of the laser, and two methods to improve the far-field signal-to-noise ratio are presented.

Chemoselective Three-Component Geminal Cross Couplings of Dihaloalkanes with Cr Catalysis: Rapid Access to Tertiary and Quaternary Alkanes via a Metal-Carbene Intermediate.

Geminal cross couplings using multiple components enable the formation of several different bonds at one site in the building of tertiary and quaternary alkanes. Nevertheless, there are remaining issues of concern-cleavage of two geminal bonds and control of selectivity present challenges. We report here the geminal cross couplings of three components by reactions of dihaloalkanes with organomagnesium and chlorosilanes or alkyl tosylates by Cr catalysis, affording the formation of geminal C-C/C-Si or C-C/C-C bonds in the creation of tertiary and quaternary alkanes. The geminal couplings are catalyzed by low-cost CrCl2 , enabling the sluggishness of competitive Kumada-type side couplings and homocouplings of Grignard reagents, in achieving high chemoselectivity. Experimental and theoretical studies indicate that two geminal C-halide bonds are continuously cleaved by Cr to afford a metal carbene intermediate, which couples with a Grignard reagent, followed by silylation, in the formation of geminal C-C and C-Si bonds via a novel inner-sphere radical coupling mechanism. These three-component geminal cross couplings are value-addition to the synthesis of commercial drugs and bioactive molecules in medicinal chemistry.

Chromium-Catalyzed Diastereoselective Synthesis of Conformationally Constrained Spirotetrahydroquinolines.

We report the diastereoselective cyclization of anilines with cyclobutanones and congeners by chromium catalysis. This reaction can link two strained four-membered rings with tetrahydroquinolines by forming four bonds in a diastereocontrolled manner, forming medicinally interesting cyclobutane-fused and constrained spirotetrahydroquinolines (STHQs) and complex multiple spiro carbon-containing polyazacycles. The constrained STHQs have been used as versatile feedstocks to derive a range of oxygen-, nitrogen-, and thio-substituted spiro analogues, and dioxygen-incorporated spiroazacycles.

A Comprehensive Examination of Pediatric Behavioral Health Service Demand and Utilization in a Large, Academic Health System from 2019 to 2021.

Studies of the effects of COVID-19 on youth suggest a worsening in mental health globally. We performed a retrospective analysis of data from January 2019-November 2021 for all outpatient referrals, as well as outpatient, inpatient, and emergency department (ED) encounters for behavioral health (BH) reasons in children aged < 18 in a large academic health system in the United States. Mean weekly rates of outpatient psychiatry referrals, outpatient psychiatry visits, ED visits, and inpatient admissions for BH reasons were compared between pre-pandemic and pandemic periods. The average weekly rate of ambulatory referrals (8.0 ± 0.33 to 9.4 ± 0.31) and completed appointments (194.2 ± 0.72 to 213.1 ± 0.71) significantly increased during the pandemic, driven largely by teenagers. The weekly average of ED pediatric encounters for BH did not increase during the pandemic, although the percentage of all pediatric ED encounters that were for BH did increase from 2.6 to 4.1% (p < 0.001). Length of stay for pediatric BH ED patients increased from 1.59 ± 0.09 days pre-pandemic to 1.91 ± 0.11 days post-pandemic (p < 0.0001). Inpatient admissions for BH reasons overall decreased during the pandemic, due to a decrease in inpatient psychiatric bed capacity. However, the weekly percentage of inpatient hospitalizations for BH reasons that occurred on medical units increased during the pandemic (15.2% ± 2.8-24.6% ± 4.1% (p = 0.0006)). Taken together, our data suggest the COVID-19 pandemic had varying degrees of impact, depending on the setting of care.

Chromium-Catalyzed Three-Component Synthesis of Monofluoroalkenes from gem-Difluoroalkenes via C-O/C-H and C-F Bond Activation.

We report here the chromium-catalyzed three-component defluorinative cross-couplings of gem-difluoroalkenes with benzyl 2-pyridinyl ethers and aryl Grignard reagents under mild conditions, enabling the convenient synthesis of diarylmethylated monofluoroalkenes in good chemo- and stereoselectivity.